Patterson’s Allergic Diseases
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Acquisitions Editor: Kate Heaney Development Editor: Sean McGuire Production Project Manager: Linda Van Pelt Senior Manufacturing Manager: Beth Welsh Marketing Manager: Rachel Mante-Leung Design Coordinator: Joan Wendt Prepress Vendor: S4Carlisle Publishing Services Eighth Edition 2018 Copyright © 2018 by Wolters Kluwer. © 2009, 2002, 1997 by Lippincott Williams & Wilkins, 1993, 1985, 1980 by JB Lippincott Company All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the abovementioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at
[email protected], or via our website at lww.com (products and services). 987654321 Printed in China Library of Congress Cataloging-in-Publication Data Names: Grammer, Leslie Carroll, editor. Title: Patterson’s allergic diseases / [edited by] Leslie C. Grammer, MD, Director, Ernest S. Bazley, Asthma and Allergic Diseases Center, Professor, Feinberg School of Medicine, Clinic Practice Director, Division of Allergy-Immunology, Northwestern University, Chicago, Illinois, Paul A. Greenberger, MD, Professor, Feinberg School of Medicine, Associate Chief, Education and Clinical Affairs, Division of Allergy-Immunology, 3
Northwestern University Medical School, Attending Physician, Northwestern Memorial Hospital, Chicago, Illinois. Other titles: Allergic diseases Description: Eighth edition. | Philadelphia : Wolters Kluwer Health, 2018. | Revised edition of: Patterson’s allergic diseases / editors, Leslie C. Grammer, Paul A. Greenberger. 7th ed. 2009. | Includes bibliographical references. Identifiers: LCCN 2017035250 | eISBN 9781496360304 Subjects: LCSH: Allergy. Classification: LCC RC584 .A34 2018 | DDC 616.97/3—dc23 LC record available at https://lccn.loc.gov/2017035250 This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data and other factors unique to the patient. The publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. 4
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Preface Our goal is for the 8th edition of Patterson’s Allergic Diseases to be an excellent source of current practical information just as the first edition was when it was published in 1972 with Dr Roy Patterson as the sole editor. He was an extremely gifted clinical allergist-immunologist, investigator, and educator, a true “triple threat.” We are committed to extending Roy’s tradition of allergyimmunology excellence with this newest edition, which we believe is replete with knowledge that continues to exponentially expand in our fascinating field. We have es-pecially tried to include references to the most recent evidencebased guidelines including the Practice Parameters from The Joint Task Force (JTF) on Practice Parameters, which was formed in 1989, and comprises members from the American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma, and Immunology. Like every edition before it, this book is written principally as a guide for physicians and other health care providers. Although it is intended to be oriented toward patient evaluation and management, there are also discussions of underlying immunologic mechanisms, pathophysiology, pharmacology, and diagnostic techniques. Because atopic diseases are common and becoming increasingly prevalent, we hope that a variety of health care providers will find this edition useful as they care for patients with allergic and other immunologic diseases. We have added two new chapters dealing with laboratory tests in allergy-immunology and personalized medicine in the discipline of allergyimmunology. We believe that caring for patients with atopic diseases sometimes is best accomplished in collaboration with physicians from other specialties. Therefore, about one quarter of the chapters are written by other specialists with whom the allergist-immunologist is likely to collaborate. Those specialties include dermatology, gastroenterology, otolaryngology, psychiatry, pulmonology, and radiology. We are indebted to each of the contributing authors and hereby express our heartfelt gratitude for their participation in this 8th edition of 6
Patterson’s Allergic Diseases. Leslie C. Grammer, MD Paul A. Greenberger, MD
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Contributing Authors Sultan Alandijani, MD Instructor Department of Internal Medicine Division of Allergy and Immunology University of South Florida Tampa, Florida Andrea J. Apter, MD, MA, MSc Professor Department of Medicine Section of Allergy & Immunology Division of Pulmonary, Allergy, & Critical Care University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Pedro C. Avila, MD Allergist-Immunologist Allergy and ENT Associates Woodlands, Texas Melvin Berger, MD, PhD Adjunct Professor Pediatrics and Pathology Case Western Reserve University Cleveland, Ohio
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Senior Director Medical Research and Education Global Medical Affairs CSL Behring, LLC King of Prussia, Pennsylvania David I. Bernstein, MD Professor of Clinical Medicine & Environmental Health Department of Internal Medicine Division of Immunology University of Cincinnati Medical Center Cincinnati, Ohio Jonathan A. Bernstein, MD Professor Department of Internal Medicine Division of Immunology/Allergy University of Cincinnati College of Medicine Cincinnati, Ohio Gregory D. Brooks, MD Associate Professor Department of Medicine Section of Allergy, Pulmonary and Critical Care University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Wesley Burks, MD Professor University of North Carolina at Chapel Hill Chapel Hill, North Carolina Robert K. Bush, MD 9
Professor Department of Medicine Section of Allergy, Pulmonary and Critical Care University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Tara F. Carr, MD, FAAAAI Assistant Professor Division of Pulmonary, Allergy, Critical Care and Sleep Medicine University of Arizona Tucson, Arizona Rakesh Chandra, MD Associate Professor Vanderbilt University Nashville, Tennessee Seong H. Cho, MD Associate Professor Department of Internal Medicine Division of Allergy and Immunology University of South Florida Tampa, Florida David B. Conley, MD Professor Northwestern University Feinberg School of Medicine Chicago, Illinois Susan J. Corbridge, PhD, APN, ACND Clinical Associate Professor College of Nursing and Department of Medicine Director of Graduate Clinical Studies 10
College of Nursing University of Illinois at Chicago Chicago, Illinois Thomas Corbridge, MD, FCCP Professor Northwestern University Feinberg School of Medicine Chicago, Illinois Jane E. Demattee, MD Professor of Medicine Division of Pulmonary and Critical Care Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois Anne M. Ditto, MD Associate Professor Northwestern University Feinberg School of Medicine Chicago, Illinois Tolly G. Epstein, MD Assistant Professor University of Cincinnati Medical Center Cincinnati, Ohio Olajumoke O. Fadugba, MD Assistant Professor Division of Pulmonary, Allergy, & Critical Care Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Theodore M. Freeman, MD, FACP, FAAAAI, FACAAI Allergist-Immunologist San Antonio Asthma and Allergy Clinic 11
San Antonio, Texas Jackie K. Gollan, PhD Associate Professor Northwestern University Feinberg School of Medicine Chicago, Illinois Nirmala Gonsalves, MD Associate Professor of Medicine Division of Gastroenterology & Hepatology Northwestern University Feinberg School of Medicine Chicago, Illinois Leslie C. Grammer, MD Director Ernest S. Bazley Asthma and Allergic Diseases Center Professor Northwestern University Feinberg School of Medicine Clinic Practice Director Division of Allergy-Immunology Northwestern University Chicago, Illinois Thomas Grant, DO, FACR Professor of Radiology Northwestern University Feinberg School of Medicine Chicago, Illinois Paul A. Greenberger, MD Professor Feinberg School of Medicine Associate Chief Education and Clinical Affairs 12
Division of Allergy-Immunology Northwestern University Feinberg School of Medicine Attending Physician Northwestern Memorial Hospital Chicago, Illinois Kathleen E. Harris, BS Research Lab Manager Northwestern University Feinberg School of Medicine Chicago, Illinois Ikuo Hirano, MD Professor Northwestern University Feinberg School of Medicine Chicago, Illinois Mary B. Hogan, MD Professor University of Nevada Las Vegas, Nevada Karen S. Hsu Blatman, MD Instructor Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Kathryn E. Hulse, PhD Research Assistant Professor Division of Allergy-Immunology Northwestern University Feinberg School of Medicine Chicago, Illinois Ravi Kalhan, MD, MS 13
Associate Professor of Medicine and Preventive Medicine Division of Pulmonary and Critical Care Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois Achilles G. Karagianis, DO Assistant Professor of Neuroradiology Northwestern University Feinberg School of Medicine Chief Head and Neck Radiology Northwestern Memorial Hospital Chicago, Illinois Robert C. Kern, MD Professor and Chairman Department of Otolaryngology Northwestern University Feinberg School of Medicine Chicago, Illinois Alexander S. Kim, MD Assistant Professor Department of Medicine University of California San Diego La Jolla, California Edwin Kim, MD, MS Assistant Professor University of North Carolina at Chapel Hill Chapel Hill, North Carolina Jennifer S. Kim, MD Clinician Educator Allergy & Immunology 14
NorthShore University HealthSystem Senior Clinician Educator Pritzker School of Medicine University of Chicago Chicago, Illinois Barry Ladizinski, MD Instructor Division of Dermatology John H. Stroger, Jr. Hospital of Cook County Chicago, Illinois Theodore M. Lee, MD Clinical Faculty Department of Medicine Division of Pulmonary, Allergy & Critical Care Emory University School of Medicine Peachtree Allergy and Asthma Clinic, PC Atlanta, Georgia Tabi Leslie, MD Consultant Dermatologist Department of Dermatology Royal Free Hospital London, United Kingdom Donald Y. M. Leung, MD, PhD Professor Head, Division of Pediatric Allergy & Immunology Department of Pediatrics National Jewish Health University of Colorado–Denver 15
Denver, Colorado Estelle Levetin, PhD Professor Faculty of Biological Science University of Tulsa Tulsa, Oklahoma Phil Lieberman, MD Clinical Professor Departments of Medicine and Pediatrics Division of Allergy and Immunology University of Tennessee Memphis, Tennessee Umbreen S. Lodi, MD Assistant Professor Department of Medicine Division of Pulmonology, Allergy & Critical Care Emory University School of Medicine Department of Allergy/Immunology Emory University/Grady Hospital Atlanta, Georgia Mahboobeh Mahdavinia, MD, PhD Assistant Professor Department of Internal Medicine Division of Allergy and Immunology Rush University Medical Center Chicago, Illinois Melanie M. Makhija, MD Assistant Professor 16
Northwestern University Feinberg School of Medicine Ann and Robert H. Lurie Children’s Hospital of Chicago Chicago, Illinois Erin N. McComb, MD Assistant Professor Department of Radiology Northwestern Memorial Healthcare Chicago, Illinois Kris G. McGrath, MD Professor of Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois Sheniz Moonie, MD Associate Professor School of Community Health Sciences Epidemiology and Biostatistics Program University of Nevada, Las Vegas Las Vegas, Nevada Michelle J. Naidich, MD Assistant Professor Department of Radiology Northwestern Memorial Healthcare Chicago, Illinois Peck Y. Ong, MD Associate Professor of Clinical Pediatrics Department of Pediatrics Division of Clinical Immunology and Allergy University of Southern California Keck School of Medicine 17
Children’s Hospital Los Angeles Los Angeles, California Snehal Patel, DO Fellow Division of Pulmonary, Allergy, Critical Care and Sleep Medicine University of Arizona Tucson, Arizona Anju T. Peters, MD Professor Department of Medicine Division of Allergy-Immunology Northwestern University Feinberg School of Medicine Chicago, Illinois Neill T. Peters, MD Clinical Instructor Northwestern University Feinberg School of Medicine Chicago, Illinois Jacqueline A. Pongracic, MD Professor Departments of Pediatrics and Medicine Division of Allergy-Immunology Northwestern University Feinberg School of Medicine Ann and Robert H. Lurie Children’s Hospital of Chicago Northwestern Memorial Hospital Chicago, Illinois David C. Reid, MD Dermatologist Division of Dermatology 18
John H. Stroger, Jr. Hospital of Cook County Chicago, Illinois Anthony J. Ricketti, MD Clinical Assistant Professor Department of Medicine Rowan University School of Osteopathic Medicine Stratford Mercer Allergy and Pulmonary Associates, LLC Trenton, New Jersey Peter A. Ricketti, MD Fellow Department of Internal Medicine Division of Allergy and Immunology Morsani College of Medicine University of South Florida Tampa, Florida Rachel G. Robison, MD Assistant Professor of Pediatrics Department of Pediatrics Division of Allergy-Immunology Northwestern University Feinberg School of Medicine Attending Physician Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, Illinois Karolina Roszko, MD Dermatologist University of Illinois at Urbana-Champaign Champaign, Illinois 19
Eric J. Russell, MD, FARC Chairman Department of Radiology Northwestern University Feinberg School of Medicine Attending Physician Department of Radiology Northwestern Memorial Healthcare Chicago, Illinois Carol A. Saltoun, MD Assistant Professor Northwestern University Feinberg School of Medicine Chicago, Illinois Hatice Savas, MD Assistant Professor Department of Radiology Division of Thoracic Imaging Northwestern University Feinberg School of Medicine Chicago, Illinois Andrew J. Scheman, MD Associate Professor of Clinical Dermatology Department of Dermatology Northwestern University Feinberg School of Medicine Chicago, Illinois Rahul Sharma, MD Fellow Department of Medicine Division of Pulmonary and Critical Care Medicine Northwestern University Feinberg School of Medicine 20
Chicago, Illinois Whitney W. Stevens, MD, PhD Assistant Professor Northwestern University Feinberg School of Medicine Chicago, Illinois Rachel E. Story, MD Clinician Educator Pritzker School of Medicine University of Chicago Attending Physician NorthShore University HealthSystems Glenview, Illinois Sherlyana Surja, MD Instructor Department of Internal Medicine Section of Allergy & Immunology Division of Allergy and Immunology Rush University Medical Center Chicago, Illinois Abba I. Terr, MD Professor Emeritus Department of Medicine University of California San Francisco School of Medicine San Francisco, California Ravi K. Viswanathan, MD Assistant Professor (CHS) Department of Medicine Section of Allergy, Pulmonary and Critical Care 21
University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Stephen I. Wasserman, MD Professor of Medicine School of Medicine University of California San Diego La Jolla, California Carol A. Wiggins, MD Clinical Assistant Professor Department of Medicine Emory University School of Medicine Piedmont Hospital Atlanta, Georgia Nevin W. Wilson, MD Professor and Chair of Pediatrics Department of Pediatrics University of Nevada Las Vegas School of Medicine Las Vegas, Nevada Lisa Wolfe, MD Associate Professor Department of Medicine Division of Pulmonary and Critical Care Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois Chester R. Zeiss, MD Professor Emeritus Northwestern University Feinberg School of Medicine Jesse Brown VA Medical Center 22
Chicago, Illinois Michael S. Ziffra, MD Assistant Professor Department of Psychiatry and Behavioral Sciences Northwestern University Feinberg School of Medicine Chicago, Illinois
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Acknowledgments This book is the result of contributions of many individuals that allow us to edit this text, which we hope will help physicians and other health care providers deliver the best possible care to their patients who suffer from allergic, immunologic, and related diseases. In particular, we owe a debt of gratitude to all of the following for their support in producing this book: The Ernest S. Bazley Charitable Fund to Northwestern Memorial Hospital and Northwestern University, which has provided continuing research support that has been invaluable to the Allergy-Immunology Division of Northwestern University Our patients, from whom we learn every day Our trainees, including allergy-immunology fellows, residents, and medical students whose curiosity inspires us Graduates of the Northwestern Allergy-Immunology fellowship training program Our clinical colleagues, many of whom contributed chapters to this book Our families, who’ve allowed us to work on this book which is a “labor of love” To Matthew, Jennifer & Kevin –Leslie C. Grammer To Rosalie –Paul A. Greenberger
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Contents SECTION I
The Immune System: Biologic and Clinical Aspects 1 Review of Immunology 2 Immunology of IgE-Mediated and Other Hypersensitivity Responses 3 Biochemical Mediators of Allergic Reactions 4 Evaluation and Management of Immune Deficiency in Allergy Practice 5 Evaluation of Eosinophilia SECTION II
Pathogenic and Environmental Aspects in Allergy and Asthma 6 Allergens and Other Factors Important in Atopic Disease 7 Airborne Pollen Prevalence in the United States SECTION III
Principles of Evaluation and Treatment 8 Diagnosis of Immediate Hypersensitivity 9 Physiologic and Biologic Evaluation of Allergic Lung Diseases 10 Radiologic Evaluation of Allergic and Related Diseases of the Upper Airway 11 Radiologic Evaluation of Allergic and Related Diseases of the Lower Airway 12 Chronic Rhinosinusitis: Role of Rhinoscopy and Surgery
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Principles of Immunologic Management of Allergic Diseases Due to 13 Extrinsic Antigens SECTION IV
Anaphylaxis and Other Generalized Hypersensitivity 14 Anaphylaxis 15 Allergy to Stinging Insects 16 Erythema Multiforme, Stevens–Johnson Syndrome, and Toxic Epidermal Necrolysis 17 Drug Allergy Part A Introduction, Epidemiology, Classification of Adverse Reactions, Immunochemical Basis, Risk Factors, Evaluation of Suspected Drug Allergy, and Patient Management Considerations Part B
Allergic Reactions to Individual Drugs: Low-Molecular-Weight
Part C
Immunologic Reactions to High-Molecular-Weight Therapeutic Agents
18 Food Allergies SECTION V
Asthma 19 Asthma 20 The Infant and Toddler with Asthma 21 Acute Severe Asthma 22 Asthma Clinical Trials SECTION VI
Other Immunologic Pulmonary Diseases 23 Hypersensitivity Pneumonitis 24 Allergic Bronchopulmonary Aspergillosis 25 Occupational Immunologic Lung Disease and Occupational Rhinitis SECTION VII 26
Upper Respiratory Tract Diseases 26 Allergic Rhinitis 27 Nasal Polyposis, Rhinosinusitis, and Nonallergic Rhinitis 28 Allergic Diseases of the Eye and Ear SECTION VIII
Cutaneous Allergic Diseases 29 Atopic Dermatitis 30 Contact Dermatitis 31 Urticaria, Angioedema, and Hereditary Angioedema 32 Approach to the Patient with Pruritus SECTION IX
Pharmacology 33 Antihistamines 34 β Agonists 35 Corticosteroids in Treatment of Allergic Diseases 36 Other Antiallergic Drugs: Cromolyn, Nedocromil, Antileukotrienes, Anticholinergics, and Theophylline 37 Delivery Devices for Inhaled Medications 38 Novel Immunologic Therapies, Including Biologics SECTION X
Special Situations 39 Allergic Disorders in Pregnancy 40 Eosinophilic Esophagitis 41 Chronic Cough 42 Sleep Disorders in the Allergic Patient 43 Management of the Psychologically Complicated Patient
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44 In Vivo and In Vitro Testing in Allergy and Immunology 45 Controversial and Unproved Methods in Allergy Diagnosis and Treatment 46 Personalized Medicine in Allergy-Immunology Index
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INTRODUCTION Although immunology is a relative newcomer among the sciences, its phenomena have long been recognized and manipulated. Ancient peoples understood that survivors of particular diseases were protected from those diseases for the remainder of their lives, and the ancient Chinese and Egyptians even practiced forms of immunization. Surgeons have also long understood that tissues and organs would not survive when exchanged between different individuals (e.g., from cadaver donors) but could succeed when transplanted from one site to another within the same individual. However, only during the past century have the mechanisms of the immune system been illuminated, at least in part. Our immune system is divided into a fast-acting innate immune response and a slower-responding acquired, or adaptive, immune system, which is present only in vertebrates. The critical cells and effectors of our immune response develop principally in the bone marrow and thymus, although during fetal development, the liver is also an important site of immune cell development. The immune system is honed to respond to and clear an astonishing number of different potentially pathogenic organisms, but it can also be the source of disease when it is not regulated properly. This chapter provides 29
a basic overview of the major components of the innate and adaptive immune responses in humans, which will be important for understanding many of the concepts presented throughout the remainder of this textbook.
INNATE IMMUNITY The innate immune system is our first line of defense against potentially pathogenic organisms (1,2). The cells of the innate immune system recognize pathogens through the expression of receptors that are “hard-wired” into our genomes as a result of evolution and selection over the long period of divergence between the microbial world and our own. As a result, the innate immune system is poised to rapidly respond to pathogens and initiate the adaptive immune responses that are generally necessary to fully eliminate pathogens. The innate immune system comprises a wide variety of cells and mediators, which have a multitude of functions, including inhibition of pathogen replication, phagocytosis of infected cells and pathogens, and activation of the adaptive immune response.
Cytokines and Chemokines Cytokines and chemokines are critical meditators produced by both innate and adaptive immune cells. The term cytokine refers to a large number of different mediators that play a role in immune responses. Cytokines are also often referred to as interleukins (ILs), and they can act in an autocrine (on the same cell that released the cytokine) or paracrine (on a different cell) manner (1,2). Cytokines, and their receptors, are grouped into families based on structural similarities. The four families are the IL-1 family, the hematopoietic family, the interferons, and the tumor necrosis factor (TNF) family (3–5). Cytokines are secreted by cells of the immune system and bind to receptors on other immune cells, or even structural cells, to mediate their effects. Chemokines are another group of small molecules that play a critical role in immunity. Chemokines have conserved cysteine motifs that are critical to their structure, and they are divided into different families based on the specific location of these conserved cysteine motifs (6). All chemokines bind to seven transmembrane G-protein-coupled receptors to mediate their effects. Unlike cytokines, which generally cause activation of their target cells, chemokines induce target cells to migrate in the direction of the chemokine gradient. This effect is critical for the correct movement and positioning of cells at all phases of immune responses.
Pattern Recognition Receptors The hard-wired receptors of the innate immune system are called pattern 30
recognition receptors (PRRs) because they recognize evolutionarily conserved microbial patterns (i.e., viral RNA, bacterial lipopolysaccharide [LPS], or flagellin), or they recognize stress signals from infected and/or damaged cells. The microbial patterns recognized by PRRs are also called pathogen-associated molecular patterns (PAMPs), whereas the stress signals are referred to as dangerassociated molecular patterns (DAMPs). Cells of the adaptive immune system also express PRRs and can respond to PAMPs, but the innate immune system relies exclusively on PRRs for pathogen recognition. There are four main categories of PRRs in humans. The toll-like receptors (TLRs) are an evolutionarily conserved family of PRRs that are the mammalian homologue to the Toll protein in Drosophila (7). Ten TLRs have been identified in humans, TLR1–10 (Table 1.1), whereas mice lack TLR10 but express three additional TLRs: TLR11–13 (1). TLRs are expressed as membrane-bound or intracellular receptors, and they can respond to both microbial PAMPs and host cell stress signals. The membrane-bound TLRs recognize PAMPs in the extracellular environment, such as LPS, whereas the intracellular TLRs detect a wide variety of nucleic acids associated with pathogens, such as double-stranded viral RNA. Activation of TLRs leads to the expression of various proinflammatory and antiviral proteins that help to orchestrate the appropriate downstream immune responses necessary to clear the pathogen. TABLE 1.1 HUMAN TOLL-LIKE RECEPTORS TLR
CELLULAR LOCATION
LIGAND(S)
TLR1:TLR2 heterodimer
Cell surface
Lipomannans (mycobacteria)
TLR2:TLR6 heterodimer
Lipoproteins (bacteria) Lipoteichoic acids (bacteria) β-Glucans (bacteria and fungi) Zymosan (fungi) TLR3
Intracellular
dsRNA (viruses)
TLR4
Cell surface
LPS (bacteria) Lipoteichoic acids (bacteria)
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TLR5
Cell surface
Flagellin (bacteria)
TLR7
Intracellular
ssRNA (viruses)
TLR8
Intracellular
ssRNA (viruses)
TLR9
Intracellular
CpG DNA (bacteria)
TLR10
Cell surface
Unknown
dsRNA, double-stranded RNA; LPS, lipopolysaccharide; ssRNA, single-stranded RNA; TLR, Toll-like receptor.
The NOD-like receptors (NLRs) are a conserved family of PRRs with more than 20 different members (8). The NLRs are exclusively expressed in the cytosol, where they recognize a variety of PAMPs and DAMPs, similar to the intracellular TLRs. A key feature of the NLRs is their ability to bind to one another and form oligomers. These NLR oligomers can also recruit additional, unrelated proteins to form signaling complexes. The NLRs can also cooperate with TLRs to induce an inflammatory response. One key response that is mediated by NLRs is the formation of the inflammasome, which plays a critical role in the production of activated IL-1β and IL-18, which are important for the induction of inflammation. The RIG-I–like receptors (RLRs) are a family of intracellular PRRs that specialize in the recognition of viral RNA (9). There are three members in the RLR family: RIG-I, MDA5, and LGP2. These receptors bind to both singlestranded and double-stranded viral RNA products, which are produced during viral infections. Upon their activation, the RLRs can then trigger expression of important antiviral genes leading to the production of type I interferons. Similar to the NLRs, RIG-I and MDA5 can recruit other signaling molecules to induce an inflammatory response. However, LGP2 cannot itself initiate an inflammatory response, but it does seem to be necessary for the other two RLR members to function effectively (10). The C-type lectin receptors (CLRs) are a conserved family of PRRs that recognize carbohydrates on the surface of microbes (11). These receptors can be 32
membrane bound or soluble proteins found in blood and other fluids. Recognition of microbial carbohydrates by CLRs results in the induction of phagocytosis of the microbe and inflammatory responses that activate an adaptive immune response. The CLRs are able to recognize a wide variety of microbial-associated carbohydrates, including mannose, glucose, Nacetylglucosamine, and b-glucans. This allows the CLRs to respond to a wide variety of potential pathogens, including bacteria, fungi, viruses, and helminths.
Epithelial Cells as Innate Immune Cells Epithelial cells are not traditionally thought of as immune cells, but they provide our first lines of defense against pathogens through multiple mechanisms (12). First, because epithelial cells form tight junctions between adjacent cells, they are able to form a physical barrier that prevents the entry of foreign microbes and antigens into our tissues. In addition to the formation of tight junctions, many epithelial cells, such as those in the airways and intestines, have cilia and produce mucus. The mucus layer covering many epithelial barriers helps to trap potential pathogens before they can reach the epithelial cells themselves, and the cilia function to sweep cells and debris out of our bodies. These structural defenses play a critical role in preventing exposure to many potential pathogens. Epithelial cells also have the ability to function as innate immune cells that can trigger a variety of immune responses. They express TLRs, which allows them to respond directly to invading microbes and alert the immune system, and they can express powerful antimicrobial molecules that can directly kill or weaken microbes. Upon recognition of a potential pathogen, epithelial cells are also able to produce proinflammatory chemokines and cytokines. These molecules then function to recruit and activate effector cells of both the innate and adaptive immune systems, including dendritic cells (DCs), innate lymphoid cells (ILCs), granulocytes, and lymphocytes. As such, epithelial cells often play a critical role in orchestrating the induction of immune responses and are a vital part of our innate immune defenses.
Innate Lymphoid Cells ILCs are a newly defined group of cells that play an important role in innate immunity (13). ILCs develop in the bone marrow from a common lymphoid progenitor (CLP) cell, which also gives rise to T and B lymphocytes (see later) (1). ILCs and T cells share many common functions, but ILCs do not express the T cell receptor (TCR) and thus do not respond to microbes in the same way as T cells. ILCs are important for early recognition of pathogens and cellular damage, 33
often receiving activating signals from the epithelium, and they function to influence the ensuing adaptive immune response. ILCs can be divided into three main groups based on their function, similar to CD4+ T-helper (Th) cell subsets (see later). The most well-studied ILCs are natural killer (NK) cells, which are part of the ILC1 family. ILC1s depend on the transcription factor T-bet for their development, are activated by IL-12 and IL-18, secrete IFN-γ, and play an important role in defense against viral infections. ILC2s are dependent on the transcription factor GATA-3, are activated by IL-25, IL-33, and TSLP, secrete IL-5 and IL-13, and play an important role in defense against helminthic infections. ILC3s are dependent on the transcription factor RORγt for their development, are activated by IL-1 and IL-23, secrete IL-17 and IL-22, and play an important role in intestinal barrier function and the generation of lymphoid organs.
Myeloid Cells Myeloid cells are a large family of innate immune effector cells that develop in the bone marrow from the common myeloid progenitor (CMP) cell (1). In addition to expressing a variety of PRRs, many myeloid cells also express Fc receptors. These receptors recognize the Fc portion of antibody molecules, and they play an important role in the activation of myeloid cells during immune responses. Monocytes are found in the circulation and are capable of phagocytizing microbes and presenting antigens to T cells, but they are not efficient at either of these functions. However, when monocytes enter the tissue in response to an infection, they can rapidly differentiate into macrophages. Macrophages are highly efficient phagocytes that help to destroy invading microbes and present antigens to and activate effector memory T cells. Although macrophages are capable of activating memory T cells, which have a lower threshold of activation, they are not effective activators of naïve T cells. Monocytes can also differentiate into inflammatory DCs in the tissue. In addition, DCs can be derived directly from the CMP in the bone marrow and migrate into tissues themselves. DCs can develop into either conventional DCs, which play a role in a wide variety of immune responses, or plasmacytoid DCs (pDCs), which are critical for induction of immune responses against viruses (1). Conventional DCs serve as immune sentinels in the tissue. Upon microbial infection, they capture antigens via phagocytosis, which activates the DC and triggers its migration to the draining lymph node. Within the lymph node, activated DCs are excellent antigen presenting cells (APCs) and express all the necessary costimulatory 34
molecules and cytokines needed to efficiently activate naïve T cells. Granulocytes are another group of myeloid cells that contain different preformed granules in their cytoplasm. These preformed granules contain a variety of molecules that can be rapidly released upon cellular activation, and they function to neutralize pathogens and recruit other immune cells to the site of infection. Neutrophils are the most abundant type of granulocyte in the peripheral blood. During infections, particularly bacterial infections, neutrophils are one of the first innate immune cells to traffic into the infected tissue. Once in the tissue, neutrophils can release their granules through a process called degranulation. These granules contain enzymes (i.e., myeloperoxidase and elastase), and antimicrobial peptides (i.e., defensins) that can kill invading organisms in the tissue. In addition, neutrophils can phagocytose pathogens, which leads to intracellular killing of the microbe. Finally, neutrophils can form a structure called a neutrophil extracellular trap, which is composed of DNAs, enzymes, and antimicrobial peptides that can trap and kill microbes (14). Eosinophils are another type of granulocyte that compose about 1% to 6% of cells in the peripheral blood. Like neutrophils, eosinophils are also induced to traffic into infected tissues, but eosinophils are more associated with infections by parasites and helminths, as opposed to bacteria. Eosinophils also undergo degranulation in response to infections. Eosinophil granules are composed of toxic molecules that function to kill invading microbes, and they include eosinophil cationic protein and major basic protein. These mediators can form pores in target cell membranes, cause toxic oxidative stress in target cells, activate other immune cells, and increase mucus production. Basophils are the least common granulocyte in the peripheral blood. Once in the tissue, basophils can degranulate and release a variety of inflammatory mediators that function to kill pathogens. These mediators include histamine and proteoglycans. After their initial activation and degranulation, usually in response to IgE (see later), basophils can also release cytokines, such as IL-4, and proteolytic enzymes, including elastase. These molecules function to activate other immune cells, particularly T cells, and help in the destruction of the pathogen. Mast cells are granulocytes that are similar to basophils. However, unlike the other granulocytes, mast cells do not fully mature until they reach the tissues and thus are not found in the circulation. Mast cells are also activated by IgE to undergo degranulation. Mast cell granules contain, among other mediators, histamine and b-hexsoaminidase, and they can also produce prostaglandins, IL-4, and TNF after activation. Along with eosinophils and 35
basophils, mast cells play a critical role in the response to parasite infections, but they are also associated with allergic disease and anaphylaxis.
ADAPTIVE IMMUNITY The adaptive immune response is often our last line of immune defense. Unlike the innate immune response, the effector cells of the adaptive response are able to recognize a multitude of highly specific antigenic structures, and they provide long-lasting protection against encountered antigens through the formation of a memory response (1,2). The adaptive response also takes more time to develop than the innate response. The main effector cells of the adaptive immune system are the T and B lymphocytes.
Antigens Antigens are any substance that can bind to the specific lymphocyte receptors, that is, the TCR and the B cell receptor (BCR). Antigens can be derived from foreign substances, such as an invading virus or bacteria, or from our own cells, and they may or may not induce an immune response. Antigens that specifically trigger an adaptive immune response are called immunogens, and the terms antigen and immunogen are often used interchangeably. In contrast, a tolerogen is a substance that after an initial exposure to the immune system inhibits future responses against itself. Because of the genetic diversity among individuals, a substance that is an immunogen for one person may be a tolerogen for another and may go unrecognized by the immune system of yet another. Also, a substance that acts as an immunogen when administered by one route (e.g., intramuscularly) may act as a tolerogen when applied by a different route (e.g., orally), in a different form (e.g., denatured), or following treatment of the individual with therapeutic agents. In addition to antigens, there are other molecules that contribute to activation of adaptive immune responses through the TCR and/or BCR. A hapten is a small molecule that cannot stimulate an immune response on its own. However, if a hapten is attached to a larger immunogenic molecule (a “carrier”), immune responses can be stimulated against both the carrier and the hapten, and the hapten itself can subsequently serve as the target of a response. Similarly, adjuvants are substances that enhance the immune response to an immunogen. Unlike a hapten, adjuvants are not directly linked to the immunogen but are delivered at the same time. Adjuvants are often used in vaccines to ensure that a robust adaptive immune response is generated.
36
T Cell Antigen Recognition T lymphocytes, or T cells, initially develop from the CLP in the bone marrow but then travel to the thymus for the majority of their differentiation (1). Within the specialized microenvironment of the thymus, developing T cells transition through a series of distinct developmental stages that lead to the generation of mature naïve T cells. A key step in this process is the expression of a unique antigen recognition receptor, the TCR, on each T cell clone. The TCR recognizes antigens, mainly peptides, that are presented in the context of major histocompatibility complex (MHC) molecules expressed on other cells. The TCR is a heterodimer composed of either an α and β or a γ and δ chain, and it forms a complex with CD3, which is expressed on, and unique to, all T cells. In addition, the TCR usually pairs with a co-receptor, either CD4 or CD8, which is expressed on specific subsets of T cells. During development in the thymus, all T cells undergo a brief stage where they express both CD4 and CD8, but in the periphery, αβ T cells express only one of these two receptors, whereas γδ T cells often do not express either. TCRs are generated via a unique process that has the capacity to generate up to 1018 different receptors with unique specificities. Each individual T cell expresses only one unique TCR, and the ability to generate such a wide variety of unique TCRs is critical for the immune system’s ability to recognize and respond to antigens from a wide variety of pathogens and confer protection. Each of the two chains of the TCR is composed of a variable and constant region (Fig. 1.1). The variable region determines which peptide/MHC complex the TCR will bind to, and thus it confers antigen specificity. Unlike most other proteins, the chains of the TCR are not encoded by a single gene. Instead, they are encoded by a series of genes that occur in clusters, which are randomly recombined during thymic T cell development through a process termed V(D)J recombination (Fig. 1.1). During this process, random V, D (in the case of the β and δ chains), and J gene segments are selected and recombined to form a unique variable region. The α chain is composed of one V gene segment and one J gene segment, whereas the β chain is composed of one V gene segment, one D gene segment, and one J gene segment. Additional variability is introduced by the imprecise cutting and annealing of each gene segment and the random addition of nucleotides to fill in these gaps, which is termed junctional diversity. All the intervening genomic DNA between the selected gene segments is removed during this process. Once a T cell has successfully undergone V(D)J recombination, all its progeny will express the same TCR clone and have the 37
same antigen specificity.
FIGURE 1.1 Generation of the T cell receptor (TCR). In general, TCRs recognize only antigenic peptides presented by MHC molecules (Fig. 1.2). In humans, the MHC molecules are encoded by the genes of the human leukocyte antigen (HLA) region. The MHC locus contains more than 200 MHC class I and class II genes, and it is highly polymorphic. As such, each person will generally express at least three different MHC class I molecules and three or four different MHC class II molecules. This diversity of MHC molecules ensures that a wide variety of antigenic peptides will be able to be presented to T cells. The class I MHC molecules are encoded by the HLA-A, -B, and -C loci, whereas the class II MHC molecules are encoded by the HLA-DP, DQ, and -DR loci (Fig. 1.2). MHC class I molecules are heterodimers composed of a membrane-bound α chain associated with a smaller molecule, called β2microglobulin. MHC class I molecules are expressed on all nucleated cells and generally present peptides derived from intracellular proteins. Under steady-state conditions, MHC class I molecules present self-peptides, which do not trigger an adaptive response and are critical for the inhibition of NK-cell responses. However, upon intracellular infection, MHC class I molecules can present 38
peptides derived from the infectious organism, which will trigger a T cell response. MHC class II molecules are also heterodimers composed of two membrane-bound chains, the α and β chain. Expression of MHC class II molecules is restricted to APCs, including DCs, monocytes, macrophages, and B cells. MHC class II molecules present peptides from antigens produced in endocytic compartments within APCs. T cells that express the CD8 co-receptor recognize antigen presented by class I MHC, and T cells that express the CD4 co-receptor recognize antigen presented by class II MHC. Finally, there is another set of MHC genes that are similar to the MHC class I, referred to as nonclassic MHC class I molecules. These genes are encoded by the HLA-E, -F, G, and -H genes, and they generally present nonprotein antigens to a limited subset of T cells.
FIGURE 1.2 T cell receptor antigen recognition. (A) Presentation of peptide antigen by MHC II to the TCR. (B) The MHC locus. APC, antigen presenting cell; HLA, human leukocyte antigen; MHC, major histocompatibility complex; TCR, T cell receptor. As discussed earlier, the majority of antigens recognized by the T cells are processed into peptides, which are loaded onto MHC molecules and presented to the TCR. However, superantigens are a unique class of proteins that are not processed and presented in the context of MHC molecules, but they are still recognized by T cells. Superantigens are able to bind to MHC class II molecules outside the peptide-binding region and to the variable region of the TCR β chain. Because this binding is less specific than the classic peptide–MHC–TCR interaction, superantigens are able to activate a much larger number of T cells. Many superantigens are derived from pathogenic bacteria, such as 39
Staphylococcus aureus.
T Cell Subsets There are several distinct subsets of T cells, and they are generally defined by the expression of specific molecules on their surface. CD4 and CD8 T cells are the most abundant T cell subsets, the majority of which express αβ TCRs, and the commitment of a T cell to one of these two subtypes occurs during development in the thymus. Other important T cell subsets include γδ T cells and NKT cells, both of which tend to recognize and respond to nonprotein antigens. CD4 T cells are also called helper T (Th) cells, because they perform a variety of functions that stimulate other immune cells, including CD8 T cells, B cells, and macrophages. CD4 T cells produce a variety of cytokines, and they express many surface molecules that are important for their interaction with, and activation of, other immune cells. The outcome of these cellular interactions is largely dependent on the specific cytokines expressed by CD4 T cells, and CD4 T cells are often classified based on their cytokine signatures and the transcription factors they express (Table 1.2) (15). Th1 and Th2 cells were so named because they were the first two subsets to be identified and described. The other subsets were identified later, and the majority of these were named based on the primary cytokine they produced, with the exception of T follicular helper (Tfh) and regulatory T (Treg) cells, which were named based on their function. CD8 T cells are also called cytotoxic (Tc) cells, because they express molecules such as granzyme and perforin that can directly kill target cells. Classically, CD8 T cells are associated with antiviral responses after their activation by Th1 cells, and they also play a role in the killing of cancer cells. However, it is important to note that Tc-cell subsets that express cytokine patterns similar to all the Th-cell subsets mentioned earlier have been described in the literature and likely play a role in a variety of immune responses (16). TABLE 1.2 CHARACTERISTICS OF CD4+ T CELL SUBSETS CD4+ CELL
Th1
T INDUCING CYTOKINE(s)
IL-12, IFNγ
TRANSCRIPTIONCYTOKINES FACTOR(s) PRODUCED
T-bet, STAT1, STAT4
40
IFNγ
FUNCTION(s)
Immunity to intracellular pathogens; autoimmunity
Th2
IL-4
GATA3, STAT6 IL-4, IL-5, IL-13 Immunity to helminths and parasites; allergy
Th9
IL-4, TGFβ
PU.1
IL-9
Th17
IL-6, IL-23, TGFβ
RORγt, STAT3
IL-17, IL-22, IL- Immunity to 26 extracellular pathogens; autoimmunity
Th22
IL-6, TNF
AHR
IL-22
Immunity to pathogens, wound repair
Tfh
IL-6, IL-21
Bcl6
IL-4, IL-21
B cell help during antibody production
Treg
IL-10, TGFβ
Foxp3
TGFβ
Tolerance; immunosuppression
Autoimmunity; allergy
IFN, interferon; IL, interleukin; Tfh, T follicular helper cell; TGF, transforming growth factor; Th, helper T cells; TNF, tumor necrosis factor; Treg, regulatory T cell.
One key aspect of the adaptive immune response is its ability to form a longlasting memory response, meaning that the specific immune response to an antigen that has been previously encountered occurs much more rapidly than the response generated during the first exposure (1). This rapid response is due to the formation of memory cells that are poised to rapidly respond to their cognate antigen, and it is the underlying mechanism for the success of vaccines. For T cells, there are two main types of memory cells, effector memory (Tem) and central memory (Tcm), that form after a naïve T cell comes into contact with the cognate antigen recognized by its TCR. Tcm cells recirculate through secondary lymphoid organs until they encounter their cognate antigen and rapidly proliferate to produce new effector T cells that can home in on sites of infection. Tem cells generally stay within the tissue and are poised to rapidly respond to pathogens at the original site of infection. 41
B Cell Antigen Recognition B lymphocytes, or B cells, also develop from the CLP, but, unlike T cells, B cell development occurs exclusively in the bone marrow. Similar to T cells, however, B cell development into mature naïve B cells is dependent on the expression of a unique antigen recognition receptor, the BCR, on each B cell clone. The BCR is composed of two chains, the heavy and light chains, and two of these heterodimers are linked by disulfide bonds to form a functional BCR (Fig. 1.3). The BCR can be expressed as a surface-bound molecule or as a secreted molecule. The membrane-bound form of the BCR forms a signaling complex with CD19, which is exclusively expressed by B cells, and CD21 and CD81. The secreted form of the BCR is called an immunoglobulin, or antibody, and it plays many key roles in the control of pathogens. Each B cell expresses only one unique BCR, and all its daughter cells will also express the same BCR and have the same antigen specificity. The heavy chain is composed of a variable region and at least two constant regions, whereas the light chain is composed of one variable region and one constant region (Fig. 1.3). The variable region of the paired heavy and light chains, also called the Fab, determines the antigen specificity of the BCR, whereas the constant region of the heavy chain, also called the Fc, determines the downstream interactions that may occur between the secreted antibody and other components of the immune system. There are five main heavy chain constant regions, or isotypes: Cδ, Cμ, Cγ, Cα, and Cε, and two light chain constant regions: Cκ and Cλ. Each BCR will use only one of the two light chains, with the κ chain generally being favored over the λ chain. The variable regions of the heavy and light chains are also generated via V(D)J recombination and junctional diversity which together have the capacity to generate at least 1011 unique BCRs. During development in the bone marrow, the recombined heavy chain variable region is joined only to the Cδ or Cμ regions, leading to the expression of immunoglobulin (Ig) D and IgM on the surface of the developing B cells.
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FIGURE 1.3 The B cell receptor. In addition to antigen-binding specificity, variability among immunoglobulin molecules derives from three further sources: allotypes, isotypes, and idiotypes. Allotypes are determined by minor amino acid sequence differences in the constant regions of heavy or light chains, which result from slight polymorphisms in the genes encoding these molecules. Allotypic differences typically do not affect the function of the molecule and segregate within families like typical Mendelian traits. Isotypes, as already discussed, are determined by more substantial differences in the heavy chain constant regions affecting the functional properties of the immunoglobulins (Table 1.3). Finally, many antigenic determinants may be bound in more than one way, and thus there may be multiple, structurally distinct, immunoglobulins with the same antigenic specificity. These differences within the antigen-binding domains of immunoglobulins that bind the same antigenic determinants are termed idiotypes. TABLE 1.3 HUMAN IMMUNOGLOBULIN ISOTYPES HALF-
43
ISOTYPE
MOLECULARADDITIONAL % OF SERUMLIFE FUNCTIONS WEIGHT (Da) COMPONENTSIMMUNOGLOBULIN(d)
IgA Monomera,b 160,000 Dimerb
385,000
—
13–19
6
Found in bodily secretions, including mucus, saliva, and tears. Prevents microbes from interacting with epithelial surfaces. In humans, subclasses are IgA1 and IgA2.
J chain
0.3
1,500/μL on at least two occasions separated by a month, in order to reduce the progression risk of waiting the 6-month diagnostic period previously required by Chusid’s criteria. In addition, the requirement for end-organ damage was removed because some patients do not develop end-organ dysfunction, and the molecular pathology underlying some forms of HES that have since been discovered, were included (53). HES can be classified into the following variants (Fig. 5.2): myeloproliferative HES (M-HES), lymphocytic HES (L-HES) (each of these account for 10% to 20% of HES cases), familial HES, organ-restricted (or overlap) HES, specific syndromes associated with hypereosinophilia, and idiopathic HES (54). These variants, organ manifestations, and treatments are discussed later.
Myeloproliferative Hypereosinophilic Syndrome Before M-HES was specifically defined, there were descriptions of a subset of patients who were often young males with myeloproliferative features, such as hepatomegaly, splenomegaly, anemia, thrombocytopenia, elevated serum B12, and tryptase; these patients were more often refractory to glucocorticoid therapy and had overall poor prognosis (50,54). This group of patients are categorized as having M-HES. After a subset of these patients were noted to have dramatic response to treatment with imatinib, a tyrosine kinase inhibitor, it was discovered that the majority of responsive patients have a gene fusion of Fip1-like 1 (FIP1L1) and platelet-derived growth factor receptor alpha (PDGFRA), or FIP1L1-PDGFRA (F/P) on chromosome 4q12. The F/P fusion, which can be detected by fluorescence in situ hybridization or reverse transcription polymerase chain reaction of the bone marrow or peripheral blood, leads to a constitutively active tyrosine kinase, the target of imatinib. This fusion product in one series was found in 11% of HES patients, all of whom were male (55). There are patients lacking the F/P mutation who are also responsive to imatinib; some of them have other rare abnormalities, including KIF5B-PDGFRA and ETV6-PDGFRB fusions and PDGFRA point mutations (54). Clonal eosinophilia has been reported in patients with Janus kinase 2 (JAK2) gene abnormalities and D816V KIT mutation seen in systemic mastocytosis (56). Finally, there are reports of patients termed chronic eosinophilic leukemia-not otherwise specified who have increased bone marrow blasts with clonal eosinophils not meeting criteria for other known lymphoid or myeloid neoplasm (54). In M-HES, 175
examination of the bone marrow reveals increased numbers of eosinophils, often 30% to 60% of marrow cells. When blast forms are present in the blood or make up more than 5% to 10% of the eosinophils in the marrow, the diagnosis is eosinophilic leukemia (50,54).
FIGURE 5.2 Classification of hypereosinophilic syndromes (HESs). CEL, chronic eosinophilic leukemia; EGID, eosinophilic gastrointestinal disorders; EGPA, eosinophilic granulomatous polyangiitis; F/P, FIP1L1/PDGFRA; FISH, fluorescence in situ hybridization; HEus, HES of undetermined significance; HIV, human immunodeficiency virus; M-HES, myeloproliferative hypereosinophilic syndrome; RT-PCR, reverse transcription polymerase chain reaction. (Adapted from Simon HU, Rothenberg ME, Bochner BS, et al. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol. 2010;126[1]:45–49.)
Lymphocytic Hypereosinophilic Syndrome In lymphocytic or T-lymphocytic HES, eosinophilia is driven by IL-5 produced by abnormal population of T-cell subsets, mostly CD3−CD4+ (less commonly CD3+CD4−CD8− or CD3+CD4+CD7−). These can be identified in peripheral blood by flow cytometry or T-cell receptor rearrangement studies (57). Distinguishing features of L-HES include high prevalence (up to 94%) of skin and soft tissue involvement, and elevated levels of serum IgE and thymus and activation-regulated chemokine (TARC) (57,58). L-HES affects males and females equally, usually follows an indolent course, but may progress to lymphoma and requires monitoring (54). Episodic angioedema and eosinophilia (also called Gleich syndrome) represents a very rare subset of L-HES characterized by cyclic (every 28 to 32 days) episodes of urticaria and 176
angioedema with associated transient elevation in serum IL-5 and severe eosinophilia, which all self-resolve between episodes. These patients have clonal CD3−CD4+ population and often have elevated serum IgM (59,60).
Other Forms of Hypereosinophilic Syndrome Patients with overlap HES have single organ involvement with peripheral eosinophilia. These include eosinophilic GI disorders, eosinophilic dermatitis (Well syndrome), and eosinophilic pneumonia. Distinguishing these diseases from HES is important because therapy for these disorders may not be helpful for managing multisystem HES (54). Patients with associated HES have a distinct condition, with associated eosinophilia. Examples include inflammatory bowel disease, sarcoidosis (61), IgG4RD (62), and HIV; treatment targets the underlying disorder. The familial form of HES is usually lifelong and asymptomatic, although there is a report of two members of an affected family developing fatal endomyocardial fibrosis (63). After comprehensive evaluation, greater than 50% of patients do not fall into a defined category, and are considered to have idiopathic HES. Finally, a group of patients who do not develop end-organ manifestations are described as having hypereosinophilia of undetermined significance.
End-Organ Complications of Hypereosinophilic Syndrome The most common organ systems involved in HES include cardiovascular, cutaneous, hematologic, pulmonary, and neurologic. Cardiac manifestations are seen in up to 60% of HES cases, and can contribute significantly to morbidity and mortality (50,64). Cardiac damage is thought to progress through three stages: acute necrosis, thrombosis, and late endocardial fibrosis (65,66). The acute necrotic stage is often clinically silent, although on histology may reveal damage to the endocardium with necrosis and eosinophilic infiltration of myocardium with eosinophil degranulation products and microabscesses. Treatment in the first stage with corticosteroids may prevent progression to the other irreversible stages (66). Within approximately 1 year of the necrotic stage, the second stage is characterized by thrombi in the ventricle and, occasionally, in the atrium, likely due to hypercoagulability and endothelial disruption. In the third stage, an average of 2 years after eosinophilia onset, cardiac fibrosis may lead to entrapment of the chordae tendineae and resultant mitral, tricuspid valve insufficiency, or a restrictive or dilated cardiomyopathy. Patients may present with dyspnea, chest pain, or congestive heart failure (CHF). Because the heart is the most common site of organ involvement and because the first stage may be 177
clinically silent, an initial and/or a serial electrocardiogram and echocardiogram must be obtained if HES is suspected. Cardiac magnetic resonance imaging may be a more reliable test for noninvasive diagnosis of myocardial complications of HES (67). The most common cutaneous findings, particularly with L-HES but also MHES, are erythroderma, urticarial plaques, angioedema, pruritic papules, and nodules (66,68). Painful mucosal ulceration, which may be confused with Behcet disease, is rare, difficult to treat, and is mainly seen in M-HES (65). Patients who have urticaria or angioedema as skin manifestations tend to have a better prognosis because they are less likely to have cardiac or neurologic manifestations (65,66). Biopsy specimens of the papular and nodular lesions reveal perivascular infiltrates of eosinophils, neutrophils, and mononuclear cells without evidence of vasculitis (66). Neurologic involvement occurs in about half of cases and has three forms: thromboembolic disease from the heart, primary central nervous system dysfunction, and peripheral neuropathy (50,69). Clinically, patients with thromboembolic events present with strokes, transient ischemic attacks, or visual symptoms. Central nervous system dysfunction can manifest as gait disturbance, behavioral changes, memory loss, or upper motor neuron signs, such as increased muscle tone. Peripheral neuropathy may be expressed as mononeuritis multiplex with symmetric or asymmetric sensory deficits, painful paresthesias, or as motor neuropathies. About half of HES patients have respiratory findings, including cough, dyspnea, and abnormal lung imaging findings (66). Pulmonary involvement is believed to result from infiltration of lung tissue by eosinophils, less commonly fibrotic lung disease, or may originate from primary cardiac events, such as CHF or emboli from right ventricular thrombi (66,70). Hematologic abnormalities in HES include anemia seen in up to 75% of patients in one of the National Institutes of Health series, thrombocytopenia, and hepatosplenomegaly (50). The eosinophils may have normal morphology or atypical features, including larger cells, cytoplasmic vacuoles, and both hyposegmented and hypersegmented nuclei (71). Diarrhea is the most frequent sign of GI tract involvement. Eosinophilic gastritis, enterocolitis, colitis, pancreatitis, hepatitis, and the Budd–Chiari syndrome all have been described in HES (66). Rheumatologic manifestations include eosinophilic vasculitis, arthralgias, joint effusions, arthritis, Raynaud phenomenon, and digital necrosis.
178
Treatment of Hypereosinophilic Syndrome Treatment of HES requires the clinician to assess the degree of eosinophilia, urgency needed to reduce eosinophilia, end-organ damage, underlying pathophysiology, and potential treatment toxicity (50). An algorithm for the treatment of HESs (Fig. 5.3) was proposed by Klion. Urgent therapy is indicated in the case of extremely elevated eosinophil levels, signs and symptoms of leukostasis, and evidence of potentially fatal complications, including thromboembolic events or heart failure. For urgent treatment of eosinophilia, high-dose glucocorticoid at 1 mg/kg prednisone or 1 g methylprednisolone is administered, while patients with possible Strongyloides infection should receive empiric ivermectin. Eosinophilia typically responds rapidly within 24 to 48 hours. In the case of steroid-unresponsiveness and suspected myeloproliferative HES, empiric imatinib 400 mg daily can be administered. Steroid-refractory patients are more likely to have F/P, and response to imatinib is expected within 1 to 2 weeks. F/P-negative HES patients may require a higher dose up to 800 mg, can take up to 4 weeks or longer, or may not respond at all—particularly if they have lymphocyte-variant HES (50,54).
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FIGURE 5.3 Management algorithm for hypereosinophilic syndrome. F/P, FIP1L1/PDGFRA; HCT, hematopoietic cell transplantation; M-HES, myeloproliferative hypereosinophilic syndrome; TKI, tyrosine kinase inhibitors. First-line therapy for F/P M-HES (as well as PDGFRB rearrangements), whether urgent or stable, is imatinib—with steroids if there is cardiac involvement (72). With F/P, virtually all patients achieve complete remission. Typically, after the initial 400 mg dosage, patients require maintenance dosing at 100 mg daily indefinitely after remission, but there are reported cases of prolonged remission after stopping (73). In the rare cases of imatinib resistance, associated with T6741 mutation, other tyrosine kinase inhibitors, including sorafenib, nilotinib, and dasatinib, have been used in case reports (54). Other forms of HES are treated with first-line corticosteroids. If eosinophilia is unresponsive to corticosteroids and/or imatinib therapy, second-line, steroid180
adjunctive agents should be considered. Hydroxyurea, which is easily accessible and inexpensive, is administered orally at 500 to 2,000 mg/day. It acts by impairing eosinophil development, hence can take up to 2 weeks to be effective. Vincristine 1 to 2 mg/m2 intravenously weekly to monthly, can lower extremely high eosinophil counts. Interferon-α, which has effects on eosinophils and T cells, can be used as adjunctive therapy (with corticosteroids) in various forms of HES, including L-HES and idiopathic HES, but is limited by its significant sideeffect profile (74). Alemtuzumab, an anti-CD52 antibody, is effective in some cases of HES, but is not curative and can cause severe cytopenias and immunosuppression, and is now withdrawn from the US market with limited access (75). Other cytotoxic therapies, including cyclophosphamide, methotrexate, cyclosporine, azathioprine, cladribine, and chlorambucil, have been used in case reports (50,74). Novel therapies for HES not responsive to the first- and second-line therapies include mepolizumab, which is a humanized monoclonal antibody against IL-5. It has been used in other eosinophilic conditions, including asthma, eosinophilic esophagitis, and EGPA. The effectiveness and safety of mepolizumab in F/Pnegative HES patients has been demonstrated in clinical trials, but it is not currently Food and Drug Administration approved (76,77). Benralizumab, an anti-IL5 receptor monoclonal antibody and neutralizing antibodies to CCR3 and CCL11 (CCR3 ligand), are also under investigation in clinical trials (50). Allogeneic nonmyeloablative hematopoietic cell transplantation (HCT) can be curative in those with refractory disease, particularly imatinib-resistant PDGFRA-associated HES, or L-HES with associated T-cell lymphoma. This is not a routine option owing to the potential morbidity and mortality of HCT (74).
Eosinophilic Granulomatosis with Polyangiitis EGPA, formally called Churg–Strauss syndrome and allergic angiitis and granulomatosis, is a small and medium vessel vasculitis characterized by eosinophilia, asthma, and other organ manifestations. The estimated incidence of EGPA is about 0.11 to 2.66 cases per 1 million people per year, with an overall prevalence of 10.7 to 14 cases per 1 million adults (78–82). However, the true incidence of EGPA is likely unknown because of diagnostic uncertainties, and it is not always readily recognized. The mean age at diagnosis is 40 to 50 years. It affects men and women equally (83). EGPA is uncommon in children and people older than 65 years of age. When it does occur in children, the course tends to be more aggressive (84).
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The precise pathogenesis of EGPA is unknown, but it likely derives from an autoimmune mechanism involving endothelial cells and leukocytes (85). Although antineutrophil cytoplasmic antibodies (ANCA) have been detected in approximately half of EGPA patients, its role in the pathogenesis of the disease is not established (86). Immune system factors which may play a role in the pathogenesis of EGPA include Th2 presence (87), Th1 involvement particularly with granuloma formation (88), eosinophil dysregulation (increased recruitment and decreased apoptosis) (89), and a possible role of reduced IL-10 producing Tregulatory cells (90). EGPA has been associated with various asthma medications, including leukotriene antagonists, inhaled glucocorticoids, and omalizumab (91–93). However, it is more likely that the addition of these asthma therapies in the setting of evolving EGPA allowed systemic corticosteroids to be tapered, unmasking EGPA symptoms. Despite this, a causal link cannot be ruled out. One of the most commonly used diagnostic criteria for EGPA was formulated by the American College of Rheumatology. It yields a sensitivity of 85% and a specificity of 99.7%, if four of the following six criteria are satisfied (94): asthma, peripheral eosinophilia (>10%), mononeuropathy or polyneuropathy, nonfixed pulmonary infiltrates, paranasal sinus abnormality, and biopsy containing a blood vessel with extravascular eosinophils. The Lanham criteria require all the following three criteria: asthma, eosinophil count greater than 1,500/μL, and vasculitis involving at least two extrapulmonary organs (95). There are three clinical phases in EGPA patients, which may not be easily distinguished practically (95). In the prodromal phase, patients have asthma and other atopic disease such as allergic rhinitis; these precede the development of the other manifestations by a mean of 8.9 ± 10.9 years (96). In the eosinophilic phase, patients have peripheral eosinophilia and eosinophilic infiltrates in various organs. The vasculitic phase is often accompanied by constitutional symptoms, such as fever, malaise, and weight loss, and can involve potentially fatal systemic vasculitis of small and medium vessels. This phase typically begins years after asthma is diagnosed but sometimes occurs within months of the diagnosis of asthma. While EGPA can affect almost any organ, the lung, peripheral nervous system, and skin are the most commonly involved (97). Virtually all patients have pulmonary involvement, with over 90% having the cardinal feature of asthma, which may become increasingly refractory to treatment. Other lung manifestations include fleeting pulmonary infiltrates and other nonspecific 182
abnormalities (96). Allergic rhinitis occurs in about 75% of patients and is frequently an early symptom. Recurrent sinusitis, nasal polyps, nasal obstruction, and serous otitis media may also be seen (98). Peripheral nervous system involvement is seen in up to 80% of patients, and mononeuritis multiplex is the most common form of neurologic involvement (96,99). Skin manifestations are commonly seen in the vasculitic phase, and include palpable purpura, nodules, pustules, urticaria, and livedo (96). Skin biopsy shows leukocytoclastic vasculitis, and nodules are seen as granulomas. Cardiac manifestations, which accounts for half of deaths from EGPA, include CHF, eosinophilic endomyocarditis, coronary vasculitis, valvular heart disease, pericarditis, pericardial effusions, and dysrhythmias (97,99). In one review, almost two-thirds of patients were found to have findings at autopsy, including fibrosis, myocarditis, pericarditis, and eosinophilic granulomas in the pericardium (99). In one series, patients with cardiac involvement were more likely to have higher peripheral eosinophil count and more likely to be ANCA negative (100). The most common GI symptoms are abdominal pain, nausea, vomiting, diarrhea, and hematochezia. Ulcers and bowel perforation are rare (101,102). Renal disease, seen in 22% in the largest series of EGPA (97), is most commonly manifested as proteinuria. The degree of renal insufficiency is typically not severe (96). Patients with glomerulonephritis are more likely to be ANCA positive. Renal biopsy has shown pauci-immune focal segmental glomerulonephritis with necrosis or crescent formation (98). Myalgias and arthralgias are the most common musculoskeletal symptoms; however, true arthritis is rare (99). Laboratory studies reveal fluctuating peripheral blood eosinophilia >1,500/ μL, with peaks between 20% and 90% of the WBC. Perinuclear ANCA (pANCA) directed against myeloperoxidase occur in 40% to 60% of patients. The erythrocyte sedimentation rate and C-reactive protein are frequently elevated, but are not specific for EGPA. Anemia and elevated total IgE are often present (98). Chest X-ray findings include bilateral transient patchy consolidations in a nonsegmental distribution, hilar infiltrates, diffuse interstitial opacities, and noncavitating nodular opacities (103). High-resolution computed tomography (HRCT) abnormalities include bilateral ground-glass opacities, peripheral airspace consolidation, and peribronchial and septal thickening (86,103). Bronchioalveolar lavage (BAL) in a patient with interstitial infiltrates may reveal high percentage of eosinophils. It is more practical to biopsy a noninvasive site such as skin or nerve, but if lung tissue is required, a surgical lung biopsy, the gold standard for EGPA, is more useful than a transbronchial biopsy. Biopsy of involved tissues is characterized by eosinophil infiltration, necrotizing vasculitis 183
of the small arteries and veins, eosinophils, and extravascular granulomas (104). The histopathologic findings can vary depending on the disease phase. An electrocardiogram and echocardiogram should be performed on all patients with EGPA to assess for cardiac involvement. Without treatment, the prognosis is poor with 50% dying within 3 months of the onset of vasculitis (105). With modern treatment options, survival rate has improved to 70% to 90% at 5 years and up to 90% initial remission rate with relapse between 41% and 81% off immunosuppressive therapy (106–108). The patients at risk for a poor outcome are those with myocardial involvement, severe GI symptoms (intestinal bleeding, perforation, pancreatitis, or requiring laparotomy), renal insufficiency, or a short duration of asthma before the presentation of the vasculitic phase (96,98). A revised five-factors score system also includes age over 65 and absence of ear/nose/throat manifestations as poor prognostic indicators (109). In patients without systemic involvement or indicators of poor prognosis, therapy consists of corticosteroids alone with prednisone 1 mg/kg for 2 to 4 weeks, then gradual taper to the minimal effective dose over the course of a year if no disease activity recurs (110). If there is systemic involvement or indicators of poor prognosis, cyclophosphamide is given either orally (2 mg/kg/day) or via intravenous pulses (0.6 mg/m2 every 2 to 3 weeks) concurrently with steroids (110). Other potential treatment regimens for steroid-sparing maintenance or milder disease have included intravenous immunoglobulin, cyclosporine, interferon-α, mycophenolate mofetil, methotrexate, and azathioprine (52). Biologic therapies, including rituximab (anti-CD20) (111,112), omalizumab (anti-IgE) (113), and mepolizumab (anti-IL5) (114,115), have been used successfully in EGPA.
Eosinophilic Pneumonias The eosinophilic pneumonias are a group of pulmonary diseases characterized by pulmonary eosinophilic infiltrates with or without peripheral blood eosinophilia (116). Eosinophilic lung disorders can be classified as acute (less than 1 month), chronic (greater than 1 month), or transient (Löffler syndrome). It can be secondary to a known specific cause such as drug reaction, infection, malignancy, or other pulmonary conditions such as asthma, or can be idiopathic. It can be isolated to the lung or occur as part of a systemic disease. Drug-induced pulmonary eosinophilia (48,117), EGPA, and HES with pulmonary eosinophilia have been discussed in this chapter. Allergic bronchopulmonary aspergillosis is
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discussed in Chapter 10. Four eosinophilic pneumonias have not been previously discussed: tropical pulmonary eosinophilia, Löffler syndrome, CEP, and acute eosinophilic pneumonia (AEP). Tropical pulmonary eosinophilia is thought to be a hypersensitivity response to filarial parasites, W. bancrofti and Brugia malayi (116). It is characterized by paroxysmal cough, dyspnea, and wheezing predominantly at night, with marked peripheral eosinophilia and diffuse reticulonodular infiltrates on chest radiographs (118). Diagnostic criteria include appropriate exposure history such as a mosquito bite after travel to an endemic area of filariasis, a history of paroxysmal nocturnal cough and dyspnea, pulmonary infiltrates, leukocytosis with eosinophilia >3,000/μL, increased serum IgE, serum antifilarial antibodies (IgE and/or IgG), and a clinical response to diethylcarbamazine citrate (116,118). Löffler syndrome, or simple pulmonary eosinophilia, is characterized by fleeting migratory infiltrates, peripheral blood eosinophilia, low-grade fever, dry cough, wheezing, and dyspnea (116). Three helminth larvae have transpulmonary passage before reaching the GI tract: Ascaris lumbricoides (most common), hookworms, and Strongyloides stercoralis (119). Other parasite infections can be accompanied by pulmonary eosinophilia via mechanisms distinct from that described above, including Paragonimus, Trichinella, and Schistosoma (120). Most patients with Löffler syndrome have either a parasitic infection or drug reaction, although no cause can be found in about one-third of cases (121). The condition typically self-resolves spontaneously within 4 weeks. Idiopathic CEP has an insidious onset of symptoms, including cough, dyspnea, malaise, fever, and weight loss (117). The cough, which affects up to 90% of patients, is initially nonproductive, but may become productive. Wheezing occurs in half the cases with respiratory failure being extremely rare (122). Women are affected twice as often as men (116). Although CEP may affect every age group, patients are generally at least 30 years old (122). Many have a history of atopy, and up to two-thirds have a history of asthma (122). There has been an association in some patients with prior radiation for breast cancer (123). The course is chronic, with symptoms usually present for weeks to months before diagnosis (116,117). Blood eosinophilia is present in 66% to 95% of patients, but its absence does not exclude the diagnosis of CEP (116). BAL cell count consists of more than 25% eosinophils (often greater than 40%), a key diagnostic criteria of CEP (117). The classic chest radiograph reveals progressive peripheral dense alveolar 185
infiltrates, which resemble a “photographic negative” of pulmonary edema (124). However, this finding occurs in less than half of patients. Other less common radiographic findings may include nodular infiltrates, atelectasis, unilateral or bilateral involvement, pleural effusion, and rarely cavitation (117). HRCT of the chest may identify peripheral infiltrates, bilateral confluent consolidations, and ground-glass opacities in the upper lobes and subpleural regions (122,125). Pulmonary function tests may reveal a restrictive, normal, or obstructive pattern (122). The diffusion capacity of the lungs for carbon monoxide is frequently reduced. Lung biopsy is not necessary for diagnosis of CEP, but histopathologic examination reveals a predominantly eosinophilic infiltrate involving the alveoli and interstitium. Interstitial fibrosis, bronchiolitis, and bronchiolitis obliterans can be present, and, occasionally, eosinophilic microabscesses and noncaseating granulomas are observed. Necrosis is rare. Symptoms and pulmonary infiltrates resolve rapidly with initiation of corticosteroids, usually 0.5 to 1 mg/kg of prednisone for 4 to 6 weeks followed by a taper. The duration of treatment should be 6 to 9 months but, in some cases, may require up to 3 years (116). Relapses are very responsive to reinstitution of steroids (116,122). Although the prognosis is excellent, up to 50% of patients experience a relapse (122,124,126). Idiopathic AEP has a rapid onset, and is characterized by hypoxemia and respiratory failure with profound eosinophilia on bronchoalveolar lavage fluid. Patients commonly present with fever, cough, tachypnea, dyspnea, chest pain and myalgia of less than 7 days duration, mimicking acute respiratory distress syndrome, or infectious pneumonia (117). However, the largest published case series reported patients with a duration of symptoms of up to a month before presentation (127). AEP typically occurs in previously healthy patients, and up to 70% of affected patients are smokers (128). There is equal to slight male predominance in contrast to the female predominance of CEP. AEP is a diagnosis of exclusion; hypersensitivity reactions, reactions to medications and toxins, and infectious etiologies must be ruled out. Various inhalational exposures have been associated with AEP, including World Trade Center dust, indoor renovation work, gasoline tank cleaning, tear gas, firework smoke, cave exploration, woodpile moving, plant repotting, crystal methamphetamine smoking, cocaine and heroin inhalation, and, most frequently, new-onset tobacco smoking (127–133). Early radiographic findings of AEP show reticular or ground-glass infiltrates with Kerley B-lines and small pleural effusions. Subsequent findings include mixed reticular and alveolar infiltrates with progression to dense alveolar 186
infiltrates (128). HRCT of the chest demonstrates any combination of the following: diffuse interstitial infiltrates, patchy alveolar infiltrates, diffuse ground-glass infiltrates, interlobular septal thickening, bilateral pleural effusion, or alveolar consolidation (128,134). Patients with AEP generally lack peripheral blood eosinophilia at presentation, but most develop this later in the disease course (127,128). BAL eosinophilia greater than 25% is a key feature of AEP (117). TARC/CCL17 has been suggested as a possible peripheral blood marker to help differentiate AEP from other acute lung injuries because its level is elevated in the acute phase before peripheral eosinophilia is present (135). In addition, a lower level of KL6, a marker of alveolar cell damage, and elevated fraction of exhaled nitric oxide may also help to distinguish AEP from other acute lung injuries (135,136). Lung biopsy in not necessary for diagnosis, but histopathology is characterized by marked infiltration of eosinophils in the interstitium and alveolar spaces with common findings, including diffuse alveolar damage with hyaline membranes, fibroblast proliferation, interstitial edema, and basal lamina damage (128,137). Pulmonary function testing may reveal a restrictive defect with reduced diffusion capacity (117). The treatment for AEP is respiratory support and high-dose corticosteroids. Recommended regimens have consisted of methylprednisolone 60 to 125 mg every 6 hours until respiratory failure resolves and then a total oral corticosteroid course of 2 to 12 weeks duration (116,128). There have been reports of some patients recovering without corticosteroids (127,138), but they are generally recommended for all patients. Most patients recover without long-term complications, and relapse is extremely rare.
Eosinophilic Cystitis Eosinophilic cystitis is a rare disease characterized by urinary frequency, hematuria, suprapubic pain, and urinary retention (139,140). It is distributed equally between males and females, but in childhood, males are more commonly affected. Peripheral eosinophilia was present in 43% of patients in one series (140). Cystoscopy reveals hyperemic mucosa with areas of elevation and nodularity. Biopsy is characterized by eosinophilic infiltrate, mucosal edema, and muscle necrosis. This inflammatory pattern may progress to chronic inflammation and fibrosis of the bladder mucosa and muscularis. Cases have been associated with transitional cell carcinoma of the bladder, intravesical chemotherapy, various medications, allergic respiratory disease, bladder outlet
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obstruction, autoimmune disorders, nonurological parasitic disorders, and eosinophilic enteritis (141). No underlying etiology was noted in 29% of patients in one series (141). Recommended treatment includes observation of mild cases, oral antihistamine, nonsteroidal anti-inflammatory agents, and systemic corticsoteroids. In cases that are refractory, severe, or with mass effect, surgical intervention such as tumor resection or cystectomy may be undertaken. (139,140).
IgG4-Related Disease IgG4RD is one of several connective tissue disorders which may present with eosinophilia. IgG4RD is an increasingly recognized group of inflammatory disorders which can involve many different organs. These include autoimmune pancreatitis, retroperitoneal fibrosis, IgG4-related sclerosing cholangitis, IgG4related dacryoadenitis and sialadenitis, and Riedel thyroiditis (83). These diseases share features such as tumor-like appearance in the affected organ, lymphoplasmacytic infiltrate with high number of IgG4-positive plasma cells, fibrosis with a storiform pattern, tissue with mild-to-moderate eosinophilia, and elevated tissue IgG4. Elevated serum IgG4 is seen in 60% to 70% of patients (142,143). Th2 responses are predominant, and a high proportion of patients have a history of allergic rhinitis, asthma, peripheral blood eosinophilia, and serum IgE elevation (62). The true epidemiology is not yet known, but, in a Japanese series, prevalence was 2.2 per 100,000 persons, with a male to female ratio of 3.7:1 and mean age of 63 years (144). First-line treatment consists systemic corticosteroids. In some cases, nonsteroid immunosuppressive agents and rituximab have been used with limited experience (83,145).
EVALUATION EOSINOPHILIA
OF
THE
PATIENT
WITH
The most important factor in the evaluation of a patient with eosinophilia (Fig. 5.4) is a thorough history with careful attention to medical, travel, dietary, occupational, and medication history. A history consistent with atopy and possible family history of diseases associated with eosinophilia should be elicited. If parasitic disease is a consideration, multiple examinations of the stool and appropriate serologic tests based on travel history should be ordered. Review of systems identifying organ involvement should be obtained. Physical examination with particular attention to skin, lymphadenopathy, hepatosplenomegaly, and possible masses should be performed (146). Laboratory tests and diagnostic studies to assess for hematologic and organ 188
involvement should be performed. The labs and diagnostic tests depend on the suspected disease and potential organ involved. An echocardiogram and chest radiograph or CT may be indicated. If the etiology remains unclear and/or the degree of eosinophilia is substantial, further examination for lymphoproliferative disease and HES should be pursued. Patients with persistent eosinophilia without a clear etiology should be monitored for evidence of end-organ damage (147).
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FIGURE 5.4 Algorithm for evaluation of eosinophilia. aStudies that may be affected by concurrent steroid use. bOther studies for end-organ involvement 190
may be warranted based on clinical presentation. AEC, absolute eosinophil count; ANA, antinuclear antibody; CBC, complete blood count; CRP, C-reactive protein; CT, computed tomography; ECG, electrocardiogram; ESR, erythrocyte sedimentation rate; FISH, fluorescent in situ hybridization; MRI, magnetic resonance imaging; RT-PCR, reverse transcription polymerase chain reaction. (Reprinted from Curtis C, Ogbogu P. Evaluation and differential diagnosis of persistent marked eosinophilia. Immunol Allergy Clin North Am. 2015;35:387– 402.)
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An allergen is an antigen that evokes a clinical allergic reaction. In atopic diseases, allergens are antigens that elicit an immunoglobulin E (IgE) antibody response. Sensitivity to an allergen can be demonstrated by a wheal-and-flare reaction to that antigen in a skin test, or by in vitro immunoassays such as the radioallergosorbent test (RAST), or enzyme-linked immunosorbent assay (ELISA), which measures antigen-specific IgE in serum. RAST testing has fallen out of favor in the past decade and has been replaced by more sensitive fluorescence-enzyme-labeled assays. When assessing the contribution of a particular antigen to an observed symptom, the nature of the immune response must be clarified. The clinician must differentiate the allergic (or atopic) response from the irritant response. The immediate type I IgE-mediated allergic response is distinctly different from the type IVa pathophysiologic mechanism mediating the delayed hypersensitivity reactions, which result from contact antigens, such as poison ivy or nickel. Allergens most commonly associated with atopic disorders are inhalants or 206
foods, reflecting the most common entry sites into the body through the respiratory or gastrointestinal tract. Drugs, biologic products, insect venoms, and certain chemicals also may induce an immediate-type hypersensitivity reaction. In practice, however, most atopic reactions involve pollens, fungal spores, house dust mites, animal epithelial materials, and other substances that impinge directly on the respiratory mucosa. They cross-link IgE antibodies attached to mast cells or basophils, initiating an inflammatory milieu that results in mediator release and allergic symptoms. This chapter is confined to the exploration of these naturally occurring inhalant substances; other kinds of allergens are discussed elsewhere in this text. Aeroallergens are airborne proteins that can cause respiratory, cutaneous, or conjunctival allergic symptoms. It is common for a single airborne particle, such as a mold spore or a pollen grain, to contain multiple allergens.
AEROALLERGENS Certain aeroallergens, such as animal danders, house dust mites, and fungi, may be localized to individual homes. Others may be associated with occupational exposures, as is the case with bakers who inhale flour. Some sources of airborne allergens are narrowly confined geographically, such as the mayfly and the caddis fly, whose scales and body parts are a cause of respiratory allergy in the eastern Great Lakes area in the late summer. Several methods can be used to determine whether a protein is an allergen. The most clinically relevant method is an allergen challenge. In a conjunctival or nasal challenge, the extract is introduced directly to the affected mucosa to look for typical allergy symptoms. In a bronchoprovocation challenge, the allergen is inhaled and pulmonary function is performed to determine when and if the FEV1 declines by more than 20%. These methods are generally too impractical to perform in an office setting. Most often, a skin test (percutaneous or intradermal) is performed to determine whether an extract can elicit the typical wheal-andflare response. Finally, tests to estimate allergen-specific IgE can be performed with patient sera. Although most tests are performed with crude extracts, specific IgE tests can be performed on serum to examine individual allergenic proteins within an extract. From a practical standpoint, it is the presence of specific IgE to a protein in the sera of clinically allergic patients that defines it as an allergen. The chemical nature of certain allergens has been studied intensively, although the precise composition of many other allergens remains undefined. For an increasing number of allergens, the complementary DNA (cDNA) sequence 207
has been derived. For others, the physiochemical characteristics or the aminoacid sequence is known. Still other allergens are known only as complex mixtures of proteins and polypeptides with varying amounts of carbohydrate. Details of the chemistry of known allergens are described under their appropriate headings. The methods of purifying and characterizing allergens include biochemical, immunologic, and biologic techniques. The methods of purification involve techniques such as chromatography, immunoprecipitation, and molecular biology. All of these purification techniques rely on sensitive and specific assay techniques for the allergen as reviewed here.
Allergen Nomenclature To be recognized as an allergen by the International Union of Immunological Societies (IUIS), a protein must have evidence of allergenicity in at least five individuals or 5% of the population studied with ideally at least 50 patient sera being screened (1). Allergens to a specific source such as ragweed pollen or cat dander can be classified as either major or minor allergens. Major allergens are those that elicit specific IgE in greater than 50% of the population sensitized to the source. Minor allergens are those that result in specific IgE in less than 50% of those individuals sensitized to the specific source. Sometimes authors refer to allergens that result in specific IgE in about 50% of the sensitized population as intermediate allergens. The nomenclature for individual allergen proteins may have been originally conceived by a meeting of the minds on a boat ride on Lake Boedensee (Germany) by Dr. David Marsh, Dr. Henning Lowenstein, and Dr. Thomas Platts-Mills in 1980. A formal naming system has since been established and maintained by the IUIS: the first three letters of the genus, followed by the first letter of the species, and an Arabic numeral (2). For example, the primary allergen in cat (Felis domesticus) is Fel d 1. Prior to the adoption of this nomenclature system, grass allergens, ragweed allergens, cockroach allergens, and dust mite allergens all had separate naming systems, that are now only of historical interest. The numbering given to the allergen is often adjusted to account for proteins in separate species that are either cross-reactive or structurally similar. The nomenclature of the German cockroach (Blattella germanica) and the American cockroach (Periplaneta americana) allergens illustrates this principle well (see Table 6.6). Notice that Bla g 6 and Per a 6 are both members of the Troponin C family of molecules. Bla g 1 and Per a 1 have
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similar attributes as well. As allergenic proteins are matched by number, they often must be assigned new names, which can lead to confusion when reading even relatively recent journal articles. An updated list of all established allergens with reference to obsolete names is maintained by the IUIS (1). Isoallergens are proteins within a species that have similar immunologic properties and/or molecular structures, but differ in some way such as isoelectric point, carbohydrate content, or amino-acid composition. For example, the ragweed allergen Amb a 1 has four isoallergenic variants based on biochemical studies and cDNA analyses (1). The Amb a 1 isoallergen sequences all have the same first 25 proteins, but vary in the rest of their structure.
Sampling Methods for Airborne Allergens Patients commonly seek out daily reports of pollen or mold spore levels from the newspaper, radio, television, Internet, or via apps on the smartphone (3,4). They often use these levels to correlate and predict their allergy symptoms. It is important to understand that all of the current methods for reporting these levels involve averaging pollen levels from the day before. Thus the levels may be helpful in correlating previous symptoms but are of limited use in correlating current symptoms or predicting future symptoms. There are commercial companies that claim to have computer models that predict pollen counts. However, there are no publications that have prospectively determined the value of computer models in predicting pollen counts (5,6). Aerobiological sampling attempts to identify and quantify the allergenic particles in the ambient atmosphere, both outdoors and indoors. Commonly, an adhesive substance is applied to a microscope slide or other transparent surface, and the pollens and spores that stick to the surface are microscopically enumerated. Devices of varying complexity have been used to reduce the most common sampling errors relating to particle size, wind velocity, and rain. Fungi also may be sampled by culture techniques. Although many laboratories use various immunoassays to identify and quantify airborne allergens, the microscopic examination of captured particles remains the method of choice. Two types of sampling devices are most commonly used: impaction and suction. Gravitational samplers were used historically, but are rarely used today because they provide qualitative data not quantitative. Several factors are important to consider with regard to placement of an outdoor sampler: local architectural obstruction, airflow patterns and prevailing wind directions, and agrarian activities. The location of samplers is important. Ground level is usually
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unsatisfactory because of liability, tampering, and similar considerations. Rooftops are used most frequently. The apparatus should be placed at least 6 m (20 ft) away from obstructions and 90 cm (3 ft) higher than the parapet on the roof. For indoor sampling, an understanding of the interior architecture and heating, ventilation, and air conditioning that is in place is necessary. The property of the allergen or particle being counted and reservoir need to be understood in choosing the appropriate sampler. Impaction Samplers Impaction samplers are the most common outdoor allergen samplers. Rotating arm impaction samplers have two vertical, adhesive-coated collecting arms mounted on a crossbar, which is rotated by a vertical motor shaft. Small particles, particularly pollen grains, are prone to blowing in the wind in a way that interferes with gravitational settling. They become more likely to impact on an adhesive surface. The sampler rotates up to several thousand revolutions per minute to overcome the effects of wind. However, at this speed turbulence may “push” the pollen away and decrease sampling. For this reason, the sampling surface is small (1 to a few millimeters) to get the highest rate of impaction. Small surface areas, however, are rapidly overloaded, causing a decrease in the efficiency of capture. These samplers usually are run intermittently (20 to 60 seconds every 10 minutes) to reduce overloading. In some models, the impacting arms are retracted or otherwise protected while not in use. The Rotorod sampler (Fig. 6.1) is a popular commercially available impaction sampler and has been shown to be over 90% efficient at capturing pollen particles of approximately 20 μm diameter. It is much less efficient at capturing smaller particles, especially those 8 to 10 mm) indicate an even greater likelihood of clinical reactivity with ingestion (62). Intradermal testing is contraindicated for food allergens because of its high false-positive rate and risk of systemic reactions (anaphylaxis). Occasionally, patients with a history highly suggestive for food allergy may have negative skin test results for the suspected antigens. In these cases, the H&P should be revisited, and the possibility of false-negative skin test results must be excluded. Specific IgE to foods may be checked in the serum to confirm lack of food allergy, and if present then the presence of food allergy in the setting of a clinically relevant history. Oral food challenges are still the method of choice to confirm food allergies. Studies have determined specific values for certain foods that obviate the need to confirm clinical sensitivity by challenge test (64). TABLE 8.3 INTERPRETATION OF SKIN TESTS IF
AND
THEN
History suggests sensitivity,
skin tests are positive,
strong possibility that antigen is responsible
364
History does not suggest skin test results are sensitivity, positive,
may want to observe patient during time of high natural exposure
History suggests sensitivity,
1. Review medications the patient has taken: antihistamines and antidepressants
skin tests are negative,
2. Review other reasons for falsenegative tests such as poor quality of testing materials or poor technique or assess for other conditions that cause similar symptoms 3. Observe patient during a period of high natural exposure 4. Perform provocative challenge (rarely)
Skin testing for Hymenoptera venoms, latex hypersensitivity is discussed in Chapters 12 and 17.
allergy,
and
drug
Extracts for Skin Tests Skin testing should be performed with clinically relevant, potent, and stable allergens. Currently, a number of standardized allergenic extracts are available and should be used when possible. Standardized extracts increase skin test reproducibility, decrease false positives, and facilitate cross-comparisons among extracts from different physicians (65). Factors that decrease stability of extracts include extended periods of storage, temperatures above 40°F or below 33°F, and the presence of proteases. Refrigeration of extracts and addition of glycerin diminishes loss of potency (66). Food extracts often lose potency over time and may be less stable, and therefore a skin test with freshly made extract is preferable. Prick testing with fresh plant food may be advisable if a food extract skin test is negative and there is suspicion for food allergy. Currently, many recombinant allergen extracts are being investigated for skin testing (67,68). Even though, the use of these recombinant allergens may be useful to improve 365
allergy diagnosis and allergy treatment by means of immunotherapy, these tools are still not available for routine clinical applications (69,70). Late Phase Response Occasionally delayed reactions characterized by erythema and induration will occur at the site of skin tests. They become apparent 1 to 2 hours after application, peak at 6 to 12 hours, and usually disappear after 24 to 48 hours (71). In contrast to the immediate reactions, they are inhibited by conventional doses of corticosteroids but not by antihistamines (72–74). It is uncertain if the presence of a cutaneous late phase response (LPR) to an antigen will predict occurrence of LPR in the nose or lung of the same patient. Some investigators believe there is a correlation and others do not (75–80). Adverse Reactions from Skin Testing Large local reactions at the site of testing are the most common adverse reactions from skin testing. These usually resolve with cold compresses and antihistamines. Systemic reactions are rare but have been reported, particularly with intradermal testing. They usually occur within 30 minutes of testing (81–83). In a recent survey of American College of Allergy, Asthma, and Immunology and American Academy of Allergy, Asthma, and Immunology members, 74 out of 269 practices reported at least one systemic reaction to skin testing between 2008 and 2012, an average of one mild to moderate systemic reaction per each center in a 4-year period. Most of the reported reactions (54%) were with intradermal skin testing (49). The rate of systemic reactions after skin test was reported by another recent study to be 0.077%. Systemic reactions were associated with a history of severe reactions to the culprit allergen (84). Patients with unstable asthma are at a greater risk of an adverse reaction from skin testing and should not be tested until their asthma is stabilized. Other risk factors for systemic reactions include intradermal testing (as opposed to skin prick test) and atopic dermatitis (85,86). Emergency treatment should be available during testing, and patients should be kept under observation for at least 30 minutes after testing. Variables Affecting Skin Testing Skin prick and intradermal tests could be affected by (1) the site of testing, (2) age, (3) BMI, (4) medications, (5) allergen immunotherapy, (6) circadian and seasonal variations, (7) menstrual cycles, and (8) stress and anxiety. 1. Site of Testing: The skin tests may be performed on the back or on the volar 366
surface of the forearm. Specific locations on the back and forearms vary in reactive intensity. The upper back is more reactive than the forearm (57,87), but the clinical significance of the greater reactivity of the back is considered to be minimal. Furthermore, once performed on the arm, the patient can witness the positive skin test, which may assist in patient education. Tests should be performed 5 cm from the wrist and/or 3 cm from the antecubital fossae (48). 2. Age: Although people of all ages can be skin tested, skin reactivity has been demonstrated to be reduced in infants (20% after the highest dose of methacholine (16 mg/mL) is delivered (21). The ATS suggests the following interpretation of MCT (21): • PC20 > 16 mg/mL—normal bronchial responsiveness • PC20 4 to 16 mg/mL—borderline BHR • PC20 1 to 4 mg/mL—mild BHR (positive test) • PC20 < 1.0 mg/mL—moderate to severe BHR Because BHR is not specific to asthma, bronchoprovocation testing may have more utility in excluding asthma than in actually confirming a diagnosis (3). There are some implicit challenges associated with the use of PC20 as the defining feature of BHR that have become relevant as the English-Wright nebulizer, used to develop the validated delivery protocol, is no longer available. Many newer nebulizers are breath-actuated and deliver aerosols more efficiently (22). Data suggest that the provocative dose 20% (PD20) results in better agreement when MCT are performed using nonvalidated nebulizers because differences in nebulizer output can be accounted for by calculating delivered dose. Use of PC20 in the setting of more efficient nebulizers will result in a higher false positive rate (23). Furthermore, the concept of cumulative dose when determining PD20 allows for a shorter dose delivery time of methacholine with more efficient nebulizers, wherein the inhalation inducing BHR may be influenced by the effects of prior inhalations. The delivered dose of methacholine at a given concentration requires knowledge of rate of output for a given nebulizer, the inhalation time, and the concentration being used. In a study comparing the obsolete English-Wright nebulizer with 2-minute inhalation to a modern breath-actuated nebulizer requiring only 30 seconds of inhalation, the PD20 was directly comparable, whereas the PC20 was not (23). Protocols for 395
MCT using a newer nebulizer have been studied in both children and adults (22,23). Whether guidelines are adapted to recommend the use of either PC20 or cumulative PD20 when defining BHR remains to be seen at the time of this writing.
FRACTION OF EXHALED NITRIC OXIDE Nitric oxide (FENO) is a noninvasive marker of eosinophilic airway inflammation (24–26) with potential utility in monitoring asthma (3). FENO is elevated in asthma patients never treated with steroids (27,28), and decreases following treatment with inhaled steroids (25). The magnitude of FENO may be a useful predictor of steroid responsiveness (29). A commercially available system that provides instantaneous FENO measurement has been approved by the U.S. Food and Drug Administration for monitoring asthma (30). Because of the correlation of FENO with eosinophilic airways inflammation and its potential predictive power in determining steroid responsiveness, recent studies have attempted to use FENO to guide therapy with inhaled corticosteroids and determine asthma control. The results of studies using FENO to guide therapy have been inconsistent (31,32). Two studies have indicated that FENO may be helpful as a marker of asthma control (33,34) with the test having particular utility in patients treated with low doses of inhaled corticosteroids (34). Several issues remain before FENO becomes routine clinical practice including a better understanding of normal and abnormal cut-point values and a determination of the minimally important clinical difference for a FENO reduction.
Components of Lung Volume Testing Full pulmonary function tests (PFTs) comprise measurement of absolute lung volumes and diffusing capacity in addition to forced spirometry. Absolute lung volumes include: residual volume (RV), the volume of gas that remains in the lung after a complete expiration; functional residual capacity (FRC), the volume of gas remaining in the lung after exhaling a normal tidal breath; and TLC, the maximal amount of gas in the lung after maximal inspiration (Fig. 9.3). Lung volumes are typically measured by plethysmographic, helium gas dilution or nitrogen washout methods. Body plethysmography is considered the optimal method because both ventilated and nonventilated lung volumes are measured. A discussion of the methodology used to measure lung volumes is beyond the 396
scope of this chapter but was published by the ATS/ERS task force (35). Measurement of lung volumes is required for the definitive diagnosis of a restrictive ventilatory impairment, defined as a reduction of the TLC below the fifth percentile of the predicted value (2). A restrictive pattern on PFTs suggests the presence of parenchymal lung disease wherein there is concentric reduction in all volumes, the TLC, FRC, RV, and VC. Severity of the restrictive impairment is based on the degree of reduction in the TLC as set forth by the ATS in 1991 (36). • Mild restriction—TLC > 70% predicted 60% predicted 85%) FEV1/FVC ratio and a diminished FVC (2). In the setting of restrictive lung disease, the flow-volume loop is often narrowed and the expiratory limb has a convex upward shape (2). This spirometric pattern lacks specificity for restrictive lung disease and can be associated with poor patient effort on the forced spirometry. A low FVC, therefore, cannot be deemed diagnostic of a restrictive ventilatory defect and measurement of lung volumes and diffusing capacity is required. A diminished FVC carries a positive predictive value for an actual restrictive ventilatory defect of only 41% (44,45). The negative predictive value for an FVC in excluding a restrictive defect, however, is 97.5% (44). Therefore, forced spirometry may serve as a useful screening tool to exclude restrictive lung diseases. Once a restrictive impairment has been established by lung volume measurements, spirometric measure of FVC can be used to monitor progression of disease and response to treatment (46). Measurement of lung volumes is also required to establish a mixed obstructive and restrictive impairment.
Pulmonary Function Tests in Allergic Lung Disease Hypersensitivity Pneumonitis PFTs alone are rarely helpful in establishing a diagnosis of, or in classifying, HP; however, they are useful in quantifying the extent of disease and monitoring response to exposure avoidance and/or treatment. In its stereotypical acute form, HP demonstrates a prevailing pattern of a restrictive ventilatory defect on pulmonary function testing, whereas in subacute or chronic HP, obstructive and mixed patterns are common (47–50). A restrictive pattern correlates with ground-glass infiltrates and reticulation on chest computed tomography (CT). Obstructive patterns, which include decreased FEV1, decreased MMEF, and air trapping, correlate with areas of decreased attenuation and bronchiolitis on chest CT (50,51). In chronic HP, emphysematous changes are also seen on chest CT scans and correspond with obstructive patterns on PFTs (48). Patients with HP related to farmer’s lung demonstrate airflow obstruction and gas trapping after 399
acute exposure to antigen and airway hyperreactivity to methacholine (52). Regardless of the pattern of impairment, the DLCO is often reduced (47,48) in HP. In early, acute forms of the disease, an isolated reduction in DLCO may be the only abnormality detected (48). PFTs may be normal in early, mild disease (53). In patients with acute or subacute HP, the PFT abnormalities are reversible with removal from exposure and/or treatment. In subacute disease, abnormalities may be intermittent corresponding to exposure, but may become chronically progressive. In chronic HP, the impairment in pulmonary function is irreversible (48,50,54,55). Idiopathic Eosinophilic Pneumonia PFT data in EP are limited but most studies describe abnormalities in the majority of patients. The pattern of impairment on presentation may be either obstructive or restrictive; mixed patterns are rarely seen (56–59). Idiopathic chronic EP (ICEP) is often associated with underlying asthma and although obstruction is more common in those with a history of asthma, it was also seen in those without this preexisting diagnosis. The presence of obstructive impairment is consistent with extension of eosinophilic inflammation to the distal airways (57). Abnormalities in DLCO are also found in the majority of patients (57,60). In ICEP, pulmonary function tests normalized rapidly with treatment; however, long-term follow-up demonstrated an obstructive impairment in a high percentage of patients, some of whom had fixed disease (56,57). Those with underlying asthma often experienced worsening of symptoms (61). Idiopathic acute EP (IAEP) is also associated with abnormal PFTs, most often with small airway disease, as evidenced by reduced mid- and low lung volume flows, but mild restrictive impairment is also reported. DLCO is reduced in nearly all patients and hypoxemia is common at presentation (62,63). PFTs return to normal with treatment in most patients (62–64); however, residual restriction has been reported (63).
BRONCHOALVEOLAR LAVAGE FLUID CELLS IN ALLERGIC LUNG DISEASE Analysis of bronchoalveolar lavage fluid (BALF) provides important, and often diagnostic, information in allergic lung diseases. In health, macrophages predominate in BALF constituting 89% of cells in nonsmokers. Lymphocytes account for 9%; most are T-cells with a CD4:CD8 ratio averaging 1.9 (±1). 400
Neutrophils make up 1% of BALF cells (65,66).
BALF in Hypersensitivity Pneumonitis In contrast to healthy subjects, BALF in patients with HP demonstrates a lymphocytic alveolitis (67). The percentage of lymphocytes is higher in subacute disease as compared with chronic disease (in one study, 53% versus 38% respectively). Furthermore, lymphocytes are more abundant in patients without radiographic evidence of fibrosis, 59% compared with 20% in those with fibrosis (68). Neutrophils are also present in a higher percentage (48,49) and may be the predominant cell in early acute HP (69). BALF lymphocytosis is more sensitive for the diagnosis of early and/or mild HP wherein both high-resolution chest CT and PFTs may be normal (53). A lymphocyte percentage of 40% in ICEP (57,61,63). In patients with IAEP, the eosinophils are atypical with few granules and greater than two nuclear lobes. Eosinophils decrease to 27 mg/dL Serum bicarbonate < 20 mEq/L Serum glucose > 252 mg/dL Epidermal detachment > 10% of body surface area at day 1
Mortality can be predicted by the total score: 0–1 points = 3.2%; 2 points = 12.1%; 3 points = 35.3%; 4 points = 58.3%; >5 points = 90% mortality. Adapted from Bastuji-Garin S, Rouchard N, Bertocchi M, et al. SCORTEN: a severity of illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;114:149–153.
In general, systemic corticosteroid therapy has been avoided in TEN and has not been proved to be beneficial in the treatment of patients (53). An uncontrolled series of patients with SJS, SJS/TEN overlap, and TEN suggests reduced mortality with dexamethasone pulse therapy; however, this was based on a small study of 12 patients (51). Therapy for TEN is supportive. Patients with TEN need aggressive fluid and electrolyte correction, local skin care, and fastidious infection precautions. This is best achieved in a burn unit (53,54). Intravenous immunoglobulin (IVIG) has been used in treatment of SJS and TEN with variable success. Some groups have shown reduction in healing time as well as improved survival (55–57). Others, however, have suggested no benefit with IVIG and, possibly, increased mortality (58–60). More recently, cyclosporine has been reported to improve outcomes in SJS/TEN in terms of reduction in predicted mortality and enhanced skin epithelialization (61–63). In small retrospective series, cyclosporine was superior to systemic corticosteroids and intravenous IgG replacement (62,63). These results are based on small series of patients, and at the present time, the use of cyclosporine is not universally accepted for the treatment of SJS/TEN. Long-term sequelae from SJS and TEN can lead to significant morbidity. Chronic ocular disease is one of the most common long-term complications related to SJS and TEN, and patients need to be monitored for ocular complications. These can range from dryness, chronic and/or recurrent trichiasis, 651
corneal epithelial defects, corneal scarring and ulceration, and even blindness (64). Long-term complications can also involve other organ systems including cutaneous, pulmonary, and genitourinary organs (65–67). It is thus important to note that patients with SJS and TEN may require multidisciplinary care acutely for long term.
Pathogenesis The exact immunologic basis for SJS and TEN is unknown. SJS/TEN is thought to occur through cell-mediated responses. CD8+ T cells, the predominant cells found in the epidermis in bullous exanthems, SJS, and TEN, are thought to mediate keratinocyte destruction (68–71). Perforin, a cytoplasmic peptide found in cytotoxic T cells, has been detected in the dermis of SJS patients (72). Perforin can damage target cell membranes and therefore facilitate the entry of other granules such as granzymes into the target cell. These granules are known to trigger a series of reactions culminating in apoptosis (73). Histopathologic specimens from patients with SJS and TEN exhibit apoptosis (72,74). Another mechanism involved in keratinocyte apoptosis in SJS and TEN involves the Fas–Fas ligand interactions. Studies have identified high concentrations of soluble Fas ligand in the sera of SJS/TEN patients (55,56,75). In addition to T cells, NK cells, dendritic cells, and macrophages have been implicated in the keratinocyte destruction characteristic of SJS/TEN (71,76,77). The mononuclear cells activate the T cells and also mediate keratinocyte destruction through the release of cytokines such as tumor necrosis factor α (78). Genetic links have been described for severe drug reactions with strong associations between human leukocyte antigen (HLA) alleles and susceptibility to SJS/TEN. Initial studies identified an association with HLA-B*15:02 and carbamazepine-induced SJS/TEN in Asian populations (79). The study demonstrated that HLA-B*15:02 is specific for carbamazepine-induced activation of cytotoxic T cells implicated in the pathogenesis of SJS/TEN. Since then, HLA-B*15:02 and other HLA associations have been reported for drugs including allopurinol, lamotrigine, oxcarbazepine, and phenytoin (80–82).
CONCLUSION SJS and TEN are severe cutaneous reactions most commonly caused by medications. Early recognition and withdrawal of the causative drug decreases the risk of death. Patients should be labeled allergic to the potential causative agent and counseled on strictly avoiding that drug in the future. Multidisciplinary 652
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Cartotto R, Mayich M, Nickerson D, et al. SCORTEN accurately predicts 45. mortality among toxic epidermal necrolysis patients treated in a burn center. J Burn Care Res. 2008;29(1):141–146. 46. Araki Y, Sotozono C, Inatomi T, et al. Successful treatment of StevensJohnson syndrome with steroid pulse therapy at disease onset. Am J Ophthalmol. 2009;147(6):1004–1011, 1011 e1. 47. Rasmussen JE. Erythema multiforme in children. Response to treatment with systemic corticosteroids. Br J Dermatol. 1976;95(2):181–186. 48. Nethercott JR, Choi BC. Erythema multiforme (Stevens-Johnson syndrome)—chart review of 123 hospitalized patients. Dermatologica. 1985;171(6):383–396. 49. Kakourou T, Klontza D, Soteropoulou F, et al. Corticosteroid treatment of erythema multiforme major (Stevens-Johnson syndrome) in children. Eur J Pediatr. 1997;156(2):90–93. 50. Schneck J, Fagot JP, Sekula P, et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol. 2008;58(1):33–40. 51. Kardaun SH, Jonkman MF. Dexamethasone pulse therapy for StevensJohnson syndrome/toxic epidermal necrolysis. Acta Derm Venereol. 2007;87(2):144–148. 52. Cheriyan S, Rosa RM, Patterson R. Stevens-Johnson syndrome presenting as intravenous line sepsis. Allergy Proc. 1995;16(2):85–87. 53. Palmieri TL, Greenhalgh DG, Saffle JR, et al. A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century. J Burn Care Rehabil. 2002;23(2):87–96. 54. Mahar PD, Wasiak J, Hii B, et al. A systematic review of the management and outcome of toxic epidermal necrolysis treated in burns centres. Burns. 2014;40(7):1245–1254. 55. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282(5388):490–493. 56. Prins C, Kerdel FA, Padilla RS, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter 657
retrospective analysis of 48 consecutive cases. Arch Dermatol. 2003;139(1):26–32. 57. Trent JT, Kirsner RS, Romanelli P, et al. Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: the University of Miami Experience. Arch Dermatol. 2003;139(1):39–43. 58. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol. 2003;139(1):33–36. 59. Huang YC, Li YC, Chen TJ. The efficacy of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. Br J Dermatol. 2012;167(2):424–432. 60. Firoz BF, Henning JS, Zarzabal LA, et al. Toxic epidermal necrolysis: five years of treatment experience from a burn unit. J Am Acad Dermatol. 2012;67(4):630–635. 61. Valeyrie-Allanore L, Wolkenstein P, Brochard L, et al. Open trial of ciclosporin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2010;163(4):847–853. 62. Singh GK, Chatterjee M, Verma R. Cyclosporine in Stevens Johnson syndrome and toxic epidermal necrolysis and retrospective comparison with systemic corticosteroid. Indian J Dermatol Venereol Leprol. 2013;79(5):686–692. 63. Kirchhof MG, Miliszewski MA, Sikora S, et al. Retrospective review of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporine. J Am Acad Dermatol. 2014;71(5):941–947. 64. Saeed HN, Chodosh J. Ocular manifestations of Stevens-Johnson syndrome and their management. Curr Opin Ophthalmol. 2016;27(6):522– 529. 65. Virant FS, Redding GJ, Novack AH. Multiple pulmonary complications in a patient with Stevens-Johnson syndrome. Clin Pediatr (Phila). 1984;23(7):412–414. 66. Kamada N, Kinoshita K, Togawa Y, et al. Chronic pulmonary complications associated with toxic epidermal necrolysis: report of a 658
severe case with anti-Ro/SS-A and a review of the published work. J Dermatol. 2006;33(9):616–622. 67. Meneux E, Paniel BJ, Pouget F, et al. Vulvovaginal sequelae in toxic epidermal necrolysis. J Reprod Med. 1997;42(3):153–156. 68. Hertl M, Bohlen H, Jugert F, et al. Predominance of epidermal CD8+ T lymphocytes in bullous cutaneous reactions caused by beta-lactam antibiotics. J Invest Dermatol. 1993;101(6):794–799. 69. Nassif A, Bensussan A, Dorothée G, et al. Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. J Invest Dermatol. 2002;118(4):728–733. 70. Nassif A, Bensussan A, Boumsell L, et al. Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J Allergy Clin Immunol. 2004;114(5):1209–1215. 71. Caproni M, Torchia D, Schincaglia E, et al. The CD40/CD40 ligand system is expressed in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum. Br J Dermatol. 2006;154(2):319–324. 72. Inachi S, Mizutani H, Shimizu M. Epidermal apoptotic cell death in erythema multiforme and Stevens-Johnson syndrome. Contribution of perforin-positive cell infiltration. Arch Dermatol. 1997;133(7):845–849. 73. Cohen JJ, Duke RC, Fadok VA, et al. Apoptosis and programmed cell death in immunity. Annu Rev Immunol. 1992;10:267–293. 74. Paul C, Wolkenstein P, Adle H, et al. Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol. 1996;134(4):710–714. 75. Tohyama M, Shirakata Y, Sayama K, et al. A marked increase in serum soluble Fas ligand in drug-induced hypersensitivity syndrome. Br J Dermatol. 2008;159(4):981–984. 76. Schlapbach C, Zawodniak A, Irla N, et al. NKp46+ cells express granulysin in multiple cutaneous adverse drug reactions. Allergy. 2011;66(11):1469–1476. 77. Tohyama M, Watanabe H, Murakami S, et al. Possible involvement of CD14+ CD16+ monocyte lineage cells in the epidermal damage of Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 659
2012;166(2):322–330. 78. Paquet P, Nikkels A, Arrese JE, et al. Macrophages and tumor necrosis factor alpha in toxic epidermal necrolysis. Arch Dermatol. 1994;130(5):605–608. 79. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486. 80. Somkrua R, Eickman EE, Saokaew S, et al. Association of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. BMC Med Genet. 2011;12:118. 81. Cheung YK, Cheng SH, Chan EJ, et al. HLA-B alleles associated with severe cutaneous reactions to antiepileptic drugs in Han Chinese. Epilepsia. 2013;54(7):1307–1314. 82. Hung SI, Chung WH, Liu ZS, et al. Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. Pharmacogenomics. 2010;11(3):349–356.
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In the fifth edition of this book, the subject of drug allergy was extensively reviewed (1). Although a reasonably comprehensive overview of this important topic is addressed in the sixth and seventh editions (2) and in the current edition, an effort has been made to focus more sharply on clinically applicable information. An even more concise, practical review is published elsewhere (3). Other reviews of drug allergy are also recommended (4). Further, although specific recommendations are suggested regarding drug challenges and desensitization protocols, it is advisable, if possible, for those inexperienced in such matters to consult with physicians who regularly evaluate and manage hypersensitivity phenomena.
EPIDEMIOLOGY A consequence of the rapid development of new drugs to diagnose and treat human illness has been the increased incidence of adverse reactions to these agents, which may produce additional morbidity and, on occasion, mortality. Their occurrence violates a basic principle of medical practice, primum non nocere (above all, do no harm). It is a sobering fact that adverse drug reactions are responsible for most iatrogenic illnesses. This should serve to remind physicians not to select potent and often unnecessary drugs to treat
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inconsequential illnesses. Many patients have come to expect drug treatments for the most trivial of symptoms. On the other hand, a physician should not deprive a patient of necessary medication for fear of a reaction. Fortunately, most adverse reactions are not severe, but the predictability of seriousness is usually not possible in the individual case or with the individual drug. An adverse drug reaction (ADR) may be defined as any undesired and unintended response that occurs at doses of an appropriate drug given for the therapeutic, diagnostic, or prophylactic benefit of the patient. The reaction should appear within a reasonable time after administration of the drug. This definition excludes therapeutic failure, which the patient may perceive as an ADR. A drug may be defined as any substance used in diagnosis, therapy, and prophylaxis of disease. Although the exact incidence of ADRs is unknown, some estimates of their magnitude are available. Reported estimates of the incidence of ADRs leading to hospitalization vary, and this is complicated by inconsistency with definitions used, with methods used to collect and analyze data, and with some studies measuring prevalence while others measure incidence. A recent study based on an extensive literature search determined what proportion of hospital admissions was a result of ADRs (5). They reported that in developed countries, 6.3% of hospital admissions were due to ADRs, whereas in developing countries, 5.5% of admissions were for ADRs (5). A meta-analysis of 33 prospective studies from 1966 to 1996 in the United States showed that an incidence of 3.1% to 6.2% of hospital admissions was due to ADRs (6). Other studies from various countries, including Switzerland, Australia, and Germany, showed that ADRs were the reason for 2% to 6.1% of hospital admissions (7–11). As many as 15% to 30% of medical inpatients experience an ADR (12). Severe cutaneous adverse drug reactions (SCARs), which include Stevens– Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS), occurs in approximately 2% of hospitalized patients (13). The incidence of SJS/TEN ranges from 2 to 7 cases/million/year (14), and the risk of death ranges from 5% to 10% in SJS to 50% in TEN (15). Drug-attributed deaths occur in 0.01% of surgical inpatients and in 0.14% to 0.17% of medical inpatients (7,10). Most of these fatalities occurred among patients who were terminally ill (16); in a study of ADR and hospital admissions in Australia, admissions for ADRs increased with patient age (10). Most deaths were caused by a small number of drugs that, by their nature, are known to be quite toxic: 662
anticoagulants, opioids, and immunosuppressants (13). Information about outpatient ADRs is scant by comparison because most are not reported to pharmaceutic companies and appropriate national registries. Such surveys are complicated by the problem of differentiating between signs and symptoms attributable to the natural disease and those related to its treatment. ADRs may mimic virtually every disease, including the disease being treated. The challenge of monitoring ADRs is further complicated by multiple drug prescribing and the frequent use of nonprescription medications. Despite these limitations, such monitoring did identify the drug-induced skin rash that often follows ampicillin therapy. Although most drug safety information is obtained from clinical trials before drug approval, premarketing studies are narrow in scope and thus cannot uncover ADRs in all patient populations. Adverse effects that occur over time or that are less frequent than 1 in 1,000, such as drug hypersensitivity, will not be detected until used by large numbers of patients after drug approval (17). Thus, postmarketing surveillance is essential to the discovery of unexpected adverse drug effects. However, one estimate is that only 1% of ADRs are voluntarily reported to pharmaceutic companies and the US Food and Drug Administration (FDA) (18). In an attempt to ensure the timely collection of ADRs, the FDA introduced a simplified medical products reporting program in 1993, MedWatch (19). Although the FDA had an ADR reporting system in place before MedWatch, it was awkward to use and understandably discouraged health professionals’ participation. Using MedWatch, the reporting individual does not have to prove absolutely an association between the drug and the adverse reaction. When reported, the information becomes part of a large database and can be investigated further. A simple, self-addressed, 1-page form is available and can be sent by mail, fax, or electronically (http://www.fda.gov/medwatch). The website also has an e-list where one can sign up to receive safety information reports directly by e-mail. Table 17A.1 summarizes how to report ADRs to MedWatch. Voluntary reporting led to the observation that ventricular arrhythmias, such as torsades de pointes, may occur when terfenadine is administered with erythromycin or ketoconazole (20). Most ADRs do not have an allergic basis. What follows is a discussion that primarily focuses on those reactions that are, or possibly could be, mediated by immunologic mechanisms. Allergic drug reactions account for 6% to 10% of all observed ADRs. It has been suggested that the risk of an allergic reaction is about 1% to 3% for most 663
drugs. It is estimated that about 5% of adults may be allergic to one or more drugs. However, as many as 15% believe themselves to be or have been incorrectly labeled as being allergic to one or more drugs and, therefore, may be denied treatment with an essential medication. At times, it may be imperative to establish the presence or absence of allergy to a drug when its use is necessary and there are no safe alternatives. Although many patients with a history of reacting to a drug could safely receive that drug again, the outcome could be serious if that patient is truly allergic. Hence, a suspicion of drug hypersensitivity must be evaluated carefully. TABLE 17A.1 MEDWATCH
REPORTING
ADVERSE
REACTIONS
TO
By Mail • Use postage-paid MedWatch form 3500 By Phone • 1-800-FDA-1088 to report by phone, to receive copies of form 3500 or a copy of FDA Desk Guide for Adverse Event and Product Problem Reporting • 1-800-FDA-0178 to FAX report • 1-800-FDA-7967 for a Vaccine Adverse Event Reporting System (VAERS) form for vaccines
By Internet • http://www.fda.gov/medwatch
FDA, Food and Drug Administration.
CLASSIFICATION REACTIONS
OF
ADVERSE
DRUG
Before proceeding with a detailed analysis of drug hypersensitivity, it is appropriate to attempt to place it in perspective with other ADRs. Physicians should carefully analyze ADRs to determine their nature because this will influence future use. For example, a drug-induced side effect may be corrected by simply reducing the dose. On the other hand, an allergic reaction to a drug may mean that drug cannot be used or may require special considerations before future administration. 664
ADRs may be divided into two major groups: (a) predictable adverse reactions, also called type A reactions, which are (i) often dose dependent, (ii) related to the known pharmacologic actions of the drug, (iii) occur in otherwise normal patients, and (iv) account for at least 80% of adverse drug effects; and (b) unpredictable adverse reactions, also called type B reactions, which are (i) usually dose independent, (ii) usually unrelated to the drug’s pharmacologic actions, and (iii) often related to the individual’s immunologic responsiveness or, on occasion, to genetic differences in susceptible patients. Not included in this classification are those reactions that are unrelated to the drug itself but are attributable to events associated with and during its administration. Such events are often mistakenly ascribed to the drug, and the patient is inappropriately denied that agent in the future. Particularly after parenteral administration of a drug, psychophysiologic reactions in the form of hysteria, hyperventilation, or vasovagal response may ensue. Some of these reactions may be manifestations of underlying psychiatric disorders (21). Even anaphylactoid symptoms have been observed in placebo-treated patients (22). Another group of signs and symptoms is considered a coincidental reaction. They are a result of the disease under treatment and may be incorrectly attributed to the drug, for example, the appearance of viral exanthems and even urticaria during the course of a treatment with an antibiotic. Although it may be difficult to characterize a particular drug reaction, a helpful classification is shown in Table 17A.2, followed by a brief description of each.
Overdosage: Toxicity The toxic effects of a drug are directly related to the systemic or local concentration of the drug in the body. Such effects are usually predictable on the basis of animal experimentation and may be expected in any patient provided a threshold level has been exceeded. Each drug tends to have its own characteristic toxic effects. Overdosage may result from an excess dose taken accidentally or deliberately. It may be due to accumulation as a result of some abnormality in the patient that interferes with normal metabolism and excretion of the drug. The toxicity of morphine is enhanced in the presence of liver disease (inability to detoxify the drug) or myxedema (depression of metabolic rate). The toxicity of chloramphenicol in infants is caused by immaturity of the glucuronide conjugating system, allowing a toxic concentration to accumulate. In the presence of renal failure, drugs such as the aminoglycosides, normally excreted by this route, may accumulate and produce toxic reactions.
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TABLE 17A.2 CLASSIFICATION OF ADVERSE DRUG REACTIONS PREDICTABLE ADVERSE REACTIONS OCCURRING IN NORMAL PATIENTS (TYPE A REACTIONS)
Overdosage: toxicity Side effects • Immediate expression • Delayed expression Secondary or indirect effects • Drug related • Disease associated Drug–drug interactions
UNPREDICTABLE ADVERSE REACTIONS PATIENTS (TYPE B REACTIONS)
OCCURRING
IN
SUSCEPTIBLE
Intolerance
Idiosyncratic reactions
Allergic (hypersensitivity) reactions
Pseudoallergic reactions
Side Effects Side effects are the most frequent ADRs. They are therapeutically undesirable, 666
but often unavoidable, pharmacologic actions occurring at usual prescribed drug dosages. A drug frequently has several pharmacologic actions, and only one of those may be the desired therapeutic effect. The others may be considered side effects. The first-generation antihistamines commonly cause adverse central nervous system effects, such as sedation. Their anticholinergic side effects include dry mouth, blurred vision, and urinary retention. Other side effects may be delayed in expression and include teratogenicity and carcinogenicity. Methotrexate, which has been used in some steroiddependent asthmatic patients, is teratogenic and should not be used during pregnancy. Immunosuppressive agents can alter host immunity and may predispose the patient to malignancy (23).
Secondary or Indirect Effects Secondary effects are indirect, but not inevitable, consequences of the drug’s primary pharmacologic action. They may be interpreted as the appearance of another naturally occurring disease rather than being associated with administration of the drug. Some appear to be due to the drug itself, creating an ecologic disturbance and permitting the overgrowth of microorganisms. In the presence of antimicrobial (notably ampicillin, clindamycin, or cephalosporins) exposure, Clostridium difficile can flourish in the gastrointestinal tract in an environment in which there is reduced bacterial competition. Toxins produced by this organism may result in the development of pseudomembranous colitis (24). Antimicrobial agents may be associated with another group of reactions that may mimic hypersensitivity, but appear to be disease associated. The Jarisch– Herxheimer phenomenon involves the development of fever, chills, headaches, skin rash, edema, lymphadenopathy, and often an exacerbation of preexisting skin lesions. The reaction is believed to result from the release of microbial antigens or endotoxins or both (25). This has usually followed penicillin treatment of syphilis and leptospirosis but has also been observed during treatment of parasitic and fungal infections. With continued treatment, the reaction subsides, thus confirming it is not an allergic response. Unfortunately, treatment is often discontinued and the drug blamed for the reaction. Another example would include the high incidence of skin rash in patients with the Epstein–Barr virus treated with ampicillin.
Drug–Drug Interactions 667
A drug–drug interaction is generally regarded as the modification of the effect of one drug by prior or concomitant administration of another. Fortunately, drug– drug interactions of major clinical consequence are relatively infrequent (26). It is also important to recall that not all drug interactions are harmful and that some may be used to clinical advantage. An increase in the number of drugs taken concurrently increases the likelihood of an adverse drug interaction. When an interaction is reported, an average of between four and eight drugs are being taken by the patient. Therefore, elderly patients constitute the largest risk group, because they often receive polypharmacy. The danger of an interaction also escalates when several physicians are treating a patient, each for a separate condition. It is the physician’s responsibility to determine what other medications the patient is taking, even nonprescription drugs. Several widely prescribed agents used to treat allergic rhinitis and asthma interacted significantly with other drugs. The second-generation antihistamines, terfenadine and astemizole, were metabolized by cytochrome P-450 mixedfunction oxidase enzymes. These antihistamines, in combination with drugs that inhibited the P-450 enzyme system, such as the imidazole antifungals ketoconazole and itraconazole or the macrolide antibiotics erythromycin and clarithromycin, resulted in increased concentrations of the antihistamines. This caused potential for prolongation of the QT interval, sometimes producing torsades de pointes or other serious cardiac arrhythmias (19). These antihistamines are no longer available in the United States. Although plasma concentrations of loratadine increased with concomitant administration of ketoconazole, this did not cause prolongation of the QT interval and the risk of torsades de pointes (27). A number of drug–drug interaction programs are available online, including those hosted by WebMD and Medscape. Their accuracy is variable; using more than one program may improve the accuracy. Many electronic medical records (EMRs) show alerts not only for allergies but also when prescribing medications with possible interactions. However, this is limited to medications being prescribed or entered in the EMR. An excellent review of other adverse drug interactions may be found in a loose-leaf publication authored by Hansten and Horn (28).
Intolerance Intolerance is a characteristic pharmacologic effect of a drug that is 668
quantitatively increased, and often is produced, by an unusually small dose of medication. Most patients develop tinnitus after large doses of salicylates and quinine, but few experience it after a single average dose or a smaller dose than usual. This untoward effect may be genetically determined and appears to be a function of the recipient, or it may occur in individuals lying at the extremes of dose–response curves for pharmacologic effects. In contrast to intolerance, which implies a quantitatively increased pharmacologic effect occurring among susceptible individuals, idiosyncratic and allergic reactions are qualitatively aberrant and inexplicable in terms of the normal pharmacology of the drug given in usual therapeutic doses.
Idiosyncratic Reactions Idiosyncrasy is a term used to describe a qualitatively abnormal, unexpected response to a drug, differing from its pharmacologic actions and thus resembling hypersensitivity. However, this reaction does not involve a proven, or even suspected, allergic mechanism. A familiar example of an idiosyncratic reaction is the hemolytic anemia occurring commonly in African and Mediterranean populations and in 10% to 13% of African American males (sex-linked) exposed to oxidant drugs or their metabolites. About 25% of African American females are carriers, and only onefifth of these have a sufficiently severe expression of the deficiency to be clinically important. A more severe form of the deficiency occurs in Caucasian Americans, primarily among people of Mediterranean origin. The erythrocytes of such individuals lack the enzyme glucose-6-phosphate dehydrogenase (G6PD) that is essential for aerobic metabolism of glucose and, consequently, cellular integrity (29). Although the original observations of this phenomenon were among susceptible individuals receiving primaquine, more than 50 drugs are known that induce hemolysis in G6PD-deficient patients. Clinically, the three classes of drugs most important in terms of their hemolytic potential are sulfonamides, nitrofurans, and water-soluble vitamin K analogues. If G6PD deficiency is suspected, simple screening tests dependent on hemoglobin oxidation, dye reduction, or fluorescence generation provide supporting evidence. The study of genetic G6PD deficiency and other genetic defects leading to ADRs has been termed pharmacogenetics (30).
Allergic Reactions Allergic drug reactions occur in only a small number of individuals, are 669
unpredictable and quantitatively abnormal, and are unrelated to the pharmacologic action of the drug. Unlike idiosyncrasy, allergic drug reactions are the result of an immune response to a drug following previous exposure to the same drug or to an immunochemically related substance that had resulted in the formation of specific antibodies or sensitized T lymphocytes or both. Ideally, the term drug allergy or hypersensitivity should be restricted to those reactions proved, or more often presumed, to be the result of an immunologic mechanism. The establishment of an allergic mechanism should be based on the demonstration of specific antibodies or sensitized lymphocytes or both. This is not often possible for many reactions ascribed to drug allergy. The diagnosis is usually based on clinical observations and, in selected instances, reexposure to the suspected agent under controlled circumstances. Even in the absence of direct immunologic evidence, an allergic drug reaction is often suspected when certain clinical and laboratory criteria are present, as suggested in Table 17A.3. Obviously, none of these are absolutely reliable (31). Immediate reactions occurring within minutes often include manifestations of anaphylaxis. Accelerated reactions taking place after 1 hour to 3 days are frequently manifested as urticaria and angioedema and occasionally as other rashes, especially exanthems with fever. Delayed or late reactions do not appear until 3 days or longer after drug therapy is initiated and commonly include a diverse group of skin rashes, drug fever, and serum sickness–like reactions and, less commonly, hematologic, pulmonary, hepatic, and renal reactions, vasculitis, and a condition resembling lupus erythematosus. Because clinical criteria are often inadequate, specific immunologic testing is desirable. Until this is accomplished, the relationship can at best be considered only presumptive. With few exceptions, safe, reliable in vivo tests and simple, rapid, predictable in vitro tests for the absolute diagnosis of drug allergy are unavailable. The most conclusive test is cautious readministration of the suspected drug, but usually the risk is not justified.
Pseudoallergic Reactions Pseudoallergy refers to an immediate generalized reaction involving mast cell mediator release by an immunoglobulin E (IgE)-independent mechanism. Although the clinical manifestations often mimic or resemble IgE-mediated events (anaphylaxis), the initiating event does not involve an interaction between the drug or drug metabolites and drug-specific IgE antibodies. A receptor responsible for many pseudoallergic reactions has recently been identified; it is 670
the MAS-related G protein–coupled receptor X2 (MRGPRX2) (32). A difference is that these reactions may occur in patients without a previous exposure to these substances. TABLE 17A.3 CLINICAL CRITERIA OF ALLERGIC DRUG REACTIONS 1. Allergic reactions occur in only a small percentage of patients receiving the drug and cannot be predicted from animal studies. 2. The observed clinical manifestations do not resemble known pharmacologic actions of the drug. 3. In the absence of prior exposure to the drug, allergic symptoms rarely appear before 1 week of continuous treatment. After sensitization, even years previously, the reaction may develop rapidly on reexposure to the drug. As a rule, drugs used with impunity for several months or longer are rarely the culprits. This temporal relationship is often the most vital information in determining which of many drugs being taken needs to be considered most seriously as the cause of a suspected drug hypersensitivity reaction. 4. The reaction may resemble other established allergic reactions, such as anaphylaxis, urticaria, asthma, and serum sickness–like reactions. However, a variety of skin rashes (particularly exanthems), fever, pulmonary infiltrates with eosinophilia, hepatitis, AIN, and lupus syndrome have been attributed to drug hypersensitivity. 5. The reaction may be reproduced by small doses of the suspected drug or other agents possessing similar or cross-reacting chemical structures. 6. Eosinophilia may be suggestive if present. 7. Rarely, drug-specific antibodies or T lymphocytes have been identified that react with the suspected drug or relevant drug metabolite. 8. As with ADRs in general, the reaction usually subsides within several days after discontinuation of the drug.
ADR, adverse drug reaction; AIN, acute interstitial nephritis.
Cationic peptides, such as ciprofloxacin, icatibant, and D-tubocurarine, bind MRGPRX2, causing release of mediators from mast cells, resulting in urticaria, angioedema, or even a clinical picture resembling anaphylaxis. Human β defensins and neuropeptides such as substance P are known to activate mast cells through MRGPRX2. In general, pseudoallergic reactions can be prevented by pretreatment with corticosteroids and antihistamines, as outlined for radiographic contrast media (RCM) (33). IgE-mediated allergic reactions, however, cannot. 671
Summary The classification of ADRs presented here must be considered tentative. At times, it may be impossible to place a particular drug reaction under one of these headings. However, the common practice of labeling any ADR as “allergic” should be discouraged.
IMMUNOCHEMICAL BASIS OF DRUG ALLERGY Drugs as Immunogens The allergenic potential of drugs depends largely on their chemical properties. Increases in molecular size and complexity are associated with an increased ability to elicit an immune response. Hence, high-molecular-weight drugs, such as heterologous antisera, and recombinant proteins (e.g., infliximab and etanercept), streptokinase, L-asparaginase, and insulin, are complete antigens that can induce immune responses and elicit hypersensitivity reactions. Immunogenicity is weak or absent when substances have a molecular weight of less than 4,000 Da (34). Most drugs are simple organic chemicals of low molecular weight, usually less than 1,000 Da. For such low-molecular-weight drugs to become immunogenic, the drug or a drug metabolite must be bound to a macromolecular carrier, often by covalent bonds, for effective antigen processing. The simple chemical (hapten), nonimmunogenic by itself, becomes immunogenic in the presence of the carrier macromolecule and now directs the specificity of the response. β-Lactam antibiotics are highly reactive with proteins and can directly haptenate carrier macromolecules. However, most drugs are not sufficiently reactive to form a stable immunogenic complex. It is likely that haptens derived from most drugs are reactive metabolites of the parent compound, which then bind to carrier macromolecules to become immunogenic. This requirement for metabolic processing may help to explain the low incidence of drug allergy, the predisposition of certain drugs to cause sensitization because they are prone to form highly reactive metabolites, and the inability of skin testing and other immunologic tests with the unaltered drug to predict or identify the reaction as being allergic in nature. Another model describing immunogenicity of low-molecular-weight compounds is the pharmacologic interactive (p-i) model in which nonreactive drugs form noncovalent bonds with major histocompatibility complex (MHC) 672
receptors and directly stimulate T cells (35,36). A third model proposed by Matzinger is the danger model, which states that an antigen presenting cell becomes activated when it receives “danger signals” from damaged or stressed cells, thus forming necessary co-stimulatory molecules and cytokines that propagate as well as determine the immunogenic response (37,38). Other proposed mechanisms include the “altered peptide repertoire,” in which the drug binds to and alters the conformation of the self-peptide repertoire, which is then presented to human leukocyte antigen (HLA) and the T-cell receptor (TCR), eliciting a drug-specific T-cell response. The “altered TCR repertoire” model is one in which the drug binds to the TCR, altering its conformation and allowing it to bind HLA–self-peptide complex and eliciting an immune response. Another mechanism proposed specifically for SJS/TEN, in which granulysin plays a significant role, is the possible role of retinoids, which are thought to be released from the liver during initial injury from the drug, resulting in a type of hypervitaminosis A with resulting cytotoxicity and granulysin damage seen in SJS/TEN. Penicillin allergy has received the most attention as a model of drug haptenization (39). Unfortunately, relevant drug haptens have not been identified for most allergic drug reactions. Studies of human IgE and IgG to sulfonamides have established the N4-sulfonamidoyl determinant to be the major sulfonamide haptenic determinant (40). It should be noted that an antigen must have multiple combining sites (multivalent) to elicit hypersensitivity reactions. This requirement permits bridging of IgE- and IgG-antibody molecules or antigen receptors on lymphocytes. Conjugation of the free drug or metabolite (hapten) with a macromolecular carrier to form a multivalent hapten-carrier conjugate is necessary to initiate an immune response and elicit a hypersensitivity reaction. The univalent ligand (free drug or metabolite), in large excess, may inhibit the response by competing with the multivalent conjugates for the same receptors. Therefore, the relative concentration of each will determine the frequency, severity, and rate of allergic drug reactions. Also, removal of haptens from carrier molecules by plasma enzymes (dehaptenation) will influence the likelihood of such reactions (41). Finally, some low-molecular-weight drugs, such as quaternary ammonium muscle relaxants and aminoglycosides, have enough distance between determinants to act as bivalent antigens without requiring conjugation to a carrier (42).
Immunologic Response to Drugs 673
Drugs often induce an immune response, but only a small number of patients actually experience clinical hypersensitivity reactions. For example, most patients exposed to penicillin and insulin develop demonstrable antibodies; however, in most instances, these do not result in allergic reactions or reduced effectiveness of the drug.
Mechanisms of Drug-induced Immunopathology An immunologic response to any antigen may be quite diverse and the attendant reactions quite complex. Drugs are no exception and have been associated with all of the immunologic reactions proposed by Coombs and Gell (43) subsequently modified by Janeway (44) and Kay (45). It is likely that more than one mechanism may contribute to a particular reaction, but often one will predominate. Table 17A.4 is an attempt to provide an overview of the immunopathology of allergic drug reactions based on the original Coombs and Gell classification. Penicillin alone has been associated with many of these reactions. Anaphylaxis and urticaria following penicillin administration are examples of type I reactions. The hemolytic anemia associated with high-dose penicillin therapy is a type II reaction. A serum sickness–like reaction, now most commonly associated with penicillin treatment, is a type III reaction. Finally, the contact dermatitis that occurred when penicillin was used topically in the past is an example of a type IV reaction.
RISK FACTORS FOR DRUG ALLERGY Several factors have been identified that may influence the induction of drugspecific immune responses and the elicitation of clinical reactions to these agents (46,47) (Table 17A.5). TABLE 17A.4 IMMUNOPATHOLOGY OF ALLERGIC REACTIONS TO DRUGS CLINICAL PRESENTATION
CLASSIFICATIONIMMUNOREACTANTS
Type I
Mast cell–mediated IGR
Anaphylaxis, urticaria, angioedema, asthma, rhinitis
• IgE dependent (anaphylactic) • IgE independent anaphylactoid)
(pseudoallergic
674
or
Type IIa
Antibody-mediated cytotoxic reactions— IgG and IgM antibodies Complement often involved
Type III
Immune complex–mediated reactions Complement involved
Type IVa1
T-lymphocyte–mediated reactions (CD4 and TH1) type 1 cytokines
Immune cytopenias Some organ inflammation Serum sickness, vasculitis
Contact dermatitis Some exanthems
(includes hapten model, p-i model, altered TCR or peptide repertoire)
IgE, immunoglobulin E; IgM, immunoglobulin M; IGR, immediate generalized reactions; p-i, pharmacologic interactive; TCR, T-cell receptor. Adapted from Kay AB. Concepts of allergy and hypersensitivity. In: Kay AB, ed. Allergy and Allergic Diseases. Oxford, UK: Blackwell Science, 1997:23.
Drug- and Treatment-Related Factors Nature of the Drug Macromolecular drugs, such as heterologous antisera and insulin, are complex antigens and have the potential to sensitize any patient. As noted earlier, most drugs have molecular weights of less than 1,000 Da and are not immunogenic by themselves. Immunogenicity is determined by the potential of the drug or, more often, a drug metabolite to form conjugates with carrier proteins. β-Lactam antibiotics, aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), and sulfonamides account for 80% of allergic or pseudoallergic reactions. Drug Exposure Cutaneous application of a drug is generally considered to be associated with the greatest risk of sensitizing patients (47). In fact, penicillin, sulfonamides, and antihistamines are no longer used topically because of this potential. The adjuvant effect of some intramuscular preparations may increase the risk of sensitization; for example, the incidence of reactions to benzathine penicillin is higher than that to other penicillin preparations. The intravenous (IV) route may be the least likely to sensitize patients. 675
Once a patient is sensitized, the difference in reaction rates between oral and parenteral drug administration is likely related to the rate of drug administration. Anaphylaxis is less common after oral administration of a drug, although severe reactions have occurred. For other allergic drug reactions, the evidence supporting oral administration is less clear. The dose and duration of treatment appear to affect the development of a drug-specific immunologic response. In drug-induced lupus erythematosus (DIL), the dose and duration of hydralazine therapy are important factors. Penicillin-induced hemolytic anemia follows high, sustained levels of drug therapy. There is currently evidence that the frequency of drug administration affects the likelihood of sensitization (48). Thus, frequent courses of treatment are more likely to elicit an allergic reaction as is interrupted therapy. The longer the intervals between therapy, the less likely there will be an allergic reaction.
Patient-Related Factors Age and Gender There is a general impression that children are less likely than adults to become sensitized to drugs. However, serious allergic drug reactions do occur in children. Some confusion may arise in that the rash associated with a viral illness in children may incorrectly be ascribed to the administration of an antibiotic as treatment. Women are reported to have a higher incidence of ADRs than men (49,50). Genetic Factors Allergic drug reactions occur in only a small percentage of individuals treated with a given drug. It is likely that many factors, both genetic and environmental, are involved in determining which individuals in a large random population will develop an allergic reaction to a given drug. TABLE 17A.5 RISK FACTORS FOR DRUG ALLERGY DRUG- AND TREATMENT-RELATED FACTORS
Nature of the drug Immunologic reactivity Nonimmunologic activity
676
Drug exposure Route of administration Dose, duration, and frequency of treatment
PATIENT-RELATED FACTORS
Age and gender Genetic factors Role of atopy Acetylator status Human leukocyte antigen type/single nucleotide polymorphisms Familial drug allergy Prior drug reactions Persistence of drug-immune response Cross-sensitization Multiple drug allergy syndrome Concurrent medical illness Asthma Cystic fibrosis Chronic kidney disease Cardiovascular disease Epstein–Barr viral infection Human immunodeficiency virus–infected patients Human herpesvirus 6 (HHV6) infection Coxsackievirus A6 infection Concurrent medical therapy β-Adrenergic receptor blocking agents
677
This is not an exhaustive list. For example, with the increasing use of biologics, ADRs are being recognized more commonly, some with specific patterns and pretreatment/treatment allowing continuation of the drug. For biologics, please refer to Section 17.C.
Patients with a history of allergic rhinitis, asthma, or atopic dermatitis (the atopic constitution) are not at increased risk for being sensitized to drugs compared with the general population (47). However, it does appear that atopic patients are more likely to develop pseudoallergic reactions, especially to RCM (51). The rate of metabolism of a drug may influence the prevalence of sensitization. Individuals who are genetically slow acetylators are more likely to develop DIL associated with the administration of hydralazine and procainamide (52,53). Adverse reactions to sulfonamides may be more severe among slow acetylators (54). Specific HLA genes have been associated with the risk of drug allergy. The susceptibility to drug-induced nephropathy in patients with rheumatoid arthritis treated with gold salts or penicillamine is associated with the HLA-DRw3 and HLA-B8 phenotypes, respectively (55). In addition, specific HLA genes have been associated with hydralazine-induced lupus erythematosus, levamisoleinduced agranulocytosis, and sulfonamide-induced TEN (56). In a Han Chinese population, studies have shown a strong association between carbamazapimeinduced SJS and HLA-B*1502 (57) as well as a strong association between HLA-B*5801 and severe cutaneous drug reactions (SJS and TEN) due to allopurinol (58). An association between HLA-B*5701 and hypersensitivity to abacavir, a potent reverse transriptase inhibitor, was shown in an HIV population in Western Australia (59). This has been confirmed in several other cohort studies (60–62); however, this association has not been found in black populations (61). Genetic risk may contribute not only to the severity of the reaction but also to the organs affected. HLA-A02:06 is associated with SJS/TEN with severe ocular complications (SOC) associated with cold medicine in Korean and Japanese populations but not Indian or Brazilian populations in whom SOC with cold medicine–induced SJS was associated with HLA-B44:03 (63,64). In addition, genome-wide association studies (GWAS) showed IKZF1 single nucleotide polypmorhphisms (SNPs) significantly associated with the disease in the Japanese, Korean, and Indian populations with a trend found in the Brazilian population (65). GWAS have also identified SNPs associated with other drugs such as phenytoin-associated SCAR. These are CYP2C variants 678
linked to drug metabolism and thought to increase toxicity by reducing clearance (66). This is certainly plausible because higher doses or alterations in clearance have been shown to increase the risk of toxicity, as is seen with lamotrigine, which lead to changes in prescribing, initiating with low dose and slowly escalating (67). In populations with a high risk of severe ADR, genetic testing has proved beneficial. Prior to being prescribed abacavir, testing for HLA-B57:01 was studied and shown to reduce the frequency of abacavir-associated hypersensitivity in Australia, the United Kingdom, and France (68,68a,68). Its cost-effectiveness was demonstrated in the United Kingdom, Spain, and other countries (69). Preventive genetic screening has also been shown to be effective in preventing SCAR associated with carbamazepine in Asians with HLA-B1502 allele (70) and, in those with HLA-B5801, allopurinol-induced SCAR. In fact, the US Department of Agriculture recommends screening for HLA-B1502 in those with Asian ancestry prior to administering carbamazepine (70), and in some hospitals, alerts are incorporated in the EMR, warning of the genetic association with hypersensitivity (71). As genetic screening costs continue to decline, and more and more genetic associations are found, this may be the most cost-effective way to identify patients at risk, reducing significant morbidity and mortality. A list of some known genetic associations can be found in Table 17A.6. The possibility of familial drug allergy has been reported (56). Among adolescents whose parents had sustained an allergic reaction to antibiotics, 25.6% experienced an allergic reaction to an antimicrobial agent, whereas only 1.7% reacted when their parents tolerated antibiotics without an allergic reaction. Prior Drug Reactions Undoubtedly, the most important risk factor is a history of a prior hypersensitivity reaction to a drug being considered for treatment or one that may be immunochemically similar. However, drug hypersensitivity may not persist indefinitely. It is well established that, after an allergic reaction to penicillin, the half-life of antipenicilloyl IgE antibodies in serum ranges from 55 days to an indeterminate, long interval in excess of 2,000 days (47). Ten years after an immediate-type reaction to penicillin, only about 20% of individuals are still skin test positive. There may be cross-sensitization between drugs. The likelihood of crossreactivity among the various sulfonamide groups (antibacterials, sulfonylureas, and diuretics) is an issue that has not been resolved. There is little supporting 679
evidence in the medical literature that cross-sensitization is a significant problem. Patients who have demonstrated drug hypersensitivity in the past appear to have an increased tendency to develop sensitivity to new drugs. Penicillin-allergic patients have about a 10-fold increased risk of an allergic reaction to non–β-lactam antimicrobial drugs. The reactions were not restricted to immediate-type hypersensitivity. Fifty-seven percent reacted to a sulfonamide. With the exception of the aminoglycosides, reaction rates were much higher than expected in all other antibiotic classes, including erythromycin. Among children with multiple antibiotic sensitivities by history, 26% had positive penicillin skin tests. These observations suggest that such patients are prone to react to haptenating drugs during an infection, possibly because of the “danger” signals induced by infection. Obviously, such patients present difficult clinical management problems. Concurrent Medical Illness Although atopy does not predispose to the development of IgE-mediated drug hypersensitivity, it appears to be a risk factor for more severe reactions once sensitivity has occurred, especially in asthmatic patients (46,47). Children with cystic fibrosis are more likely to experience allergic drug reactions, especially during drug desensitization. In particular, they have a high incidence of piperacillin hypersensitivity and have been shown to have multiple haptens on circulating albumin as well as antigen-specific T cells (72). In a populationbased study in Taiwan, chronic kidney disease (CKD) and cardiovascular disease (CVD) were associated with increased risk of hypersensitivity to allopurinol as was age > 60 with initial use, female sex, and dose > 100 mg/day (73). Mortality was also increased with CKD, CVD, and increased age. Clearance of the drug’s metabolite, oxypurinol, was shown to be decreased in patients with CKD, and this may be one mechanism by which CKD and even dose and older age may contribute to increased risk (74). Immune deficiency is associated with an increased frequency of ADRs, many of which appear to be allergic in nature. Patients who are immunosuppressed may become deficient in regulatory T lymphocytes that control IgE antibody synthesis. Infection itself is associated with increased T-cell–mediated drug hypersensitivity. Exanthematous rashes following the administration of ampicillin occur more frequently during Epstein–Barr viral infections (100% of children and 70% of adults) and among patients with lymphatic leukemia (68). Human herpesvirus 6 680
(HHV6) activation is associated with carbamazepine-induced DRESS (75), also known as drug-induced hypersensitivity syndrome (DIHS). Interestingly, idiosyncratic cutaneous disorders resembling ADRs, seen in occupational exposure to trichloroethylene were also shown to be associated with HHV6 (76). A recent study showed patients infected with a new variant of coxsackievirus A6 who presented with clinicopathologic features similar to SJS (77). ADRs, in particular hypersensitivity, occur with a much higher frequency among human immunodeficiency virus (HIV)–infected patients than among patients who are HIV seronegative. A retrospective study comparing Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome (AIDS) to a similar pneumonia in patients with other underlying immunosuppressive conditions reported adverse reactions to trimethoprim–sulfamethoxazole (TMP– SMX) in 65% of AIDS patients compared with 12% of patients with other immunosuppressive diseases, suggesting the abnormality may be due to the HIV infection. Slow acetylator phenotype is a risk factor for TMP–SMX in HIVnegative patients but not HIV-positive patients. TMP–SMX has been associated with rash, fever, and hematologic disturbances and, less frequently, with more severe reactions such as SJS, TEN, and anaphylactic reactions. Also, pentamidine, antituberculosis regimens containing isoniazid and rifampin, amoxicillin-clavulanate, and clindamycin have been associated with an increased incidence of ADRs, some of which may involve an allergic mechanism. It also appears that progression of HIV disease to a more advanced stage confers an increased risk of hypersensitivity reactions. It is thought that viruses may enhance ADRs through molecular mimicry, much like inducing autoimmune disease. Indeed, expansion of virus-specific cytotoxic T lymphocytes has been found in patients with drug hypersensitivity reactions (78). TABLE 17A.6 ETHNICITY
ASSOCIATIONS
OF
ETHNIC GROUP
DRUG
HLA
REACTION
Australian
Abacavir
B*57:01
Hypersensitivity
Nevirapine
DRB1*01:01
MPE/DIHS
Cambodian
Abacavir
B*57:01
Hypersensitivity
European
Abacavir
B*57:01
Hypersensitivity
681
ADR
WITH
HLA
AND
Allopurinol
B*58:01
SJS/TEN/DIHS
Carbamazepine
A*31:01
MPE/DIHS
Oxicam
B*73, A*2, B*12
TEN
Sulfamethoxazole
B*38
SJS/TEN
Sulfonamide
A29, B12,DR7
TEN
French
Nevirapine
DRB1*01:01
MPE/DIHS
Han Chinese
Allopurinol
B*58:01
SJS/TEN/DIHS
Carbamazepine
B*15:02
SJS/TEN
Dapsone
B*15:11
SJS/TEN
Oxcarbazepine
A*31:01
MPE/DIHS
Phenytoin
B*13:01
DIHS
B*15:02
SJS/TEN
B*15:02
SJS/TEN
Indian
Carbamazepine
B*15:02
SJS/TEN
Japanese
Allopurinol
B*58:01
SJS/TEN/DIHS
Carbamazepine
B*15:11
SJS/TEN
Methazolamide
B*59:01
SJS/TEN
A*31:01
SJS/TEN/DIHS
B*59:01
SJS/TEN
CW*01:02
SJS/TEN
Allopurinol
B*58:01
SJS/TEN/DIHS
Carbamazepine
B*15:11
SJS/TEN
Methazolamide
A*31:01
MPE/DIHS
B*59:01
SJS/TEN
CW*01:02
SJS/TEN
B*15:02
SJS/TEN
Korean
Malaysian
Carbamazepine
682
North American
Abacavir
B*57:01
Hypersensitivity
Sardinian
Nevirapine
B*14:02
Hypersensitivity
Cw*08:01 Cw*08:02 Thai
Other
Abacavir
B*57:01
Hypersensitivity
Allopurinol
B*58:01
SJS/TEN/DIHS
Carbamazepine
B*15:02
SJS/TEN
Nevirapine
B*35:05
DIHS/MPE
Phenytoin
B*15:02
SJS/TEN
Statins
DRB1*11:01
Clozapine
DQB1
Autoimmune myopathy
Flucloxacillin
B*57:01
Lumiracoxib
DRB1*15:01
Agranulocytosis Hepatotoxicity Liver injury
Co-amoxiclav
ADR, adverse drug reaction; DIHS, drug-induced hypersensitivity syndrome; HLA, human leukocyte antigen; MPE, maculopapular exanthema; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis.
Concurrent Medical Therapy Some medications may alter the risk and severity of reactions to drugs. Patients treated with β-adrenergic blocking agents, even timolol maleate ophthalmic solution, may be more susceptible to, and prove to be more refractory to, treatment of drug-induced anaphylaxis, requiring greater fluid resuscitation and, possibly, more epinephrine to overcome the β-blockade.
CLINICAL CLASSIFICATION REACTIONS TO DRUGS
OF
ALLERGIC
A useful classification is based primarily on the clinical presentation or manifestations of such reactions. The presumption of allergy is based on clinical criteria cited earlier (Table 17A.3). Table 17A.7 provides an overview of a clinical classification based on organ systems involved; namely, generalized 683
multisystem involvement and predominantly organ-specific responses. What follows is a brief discussion of each of these clinical entities, including a list of most commonly implicated drugs. Detailed lists of implicated drugs appear in periodic literature reviews (79).
Generalized or Multisystem Involvement Immediate Generalized Reactions The acute systemic reactions are among the most urgent of drug-related events. Greenberger has used the term immediate generalized reactions to underscore the fact that many are not IgE mediated. Drug-induced anaphylaxis should be reserved for a systemic reaction proved to be IgE mediated. Drug-induced anaphylactoid reactions are clinically indistinguishable from anaphylaxis but occur through IgE-independent mechanisms. Both ultimately result in the release of potent vasoactive and inflammatory mediators from mast cells and basophils. TABLE 17A.7 CLINICAL REACTIONS TO DRUGS
CLASSIFICATION
GENERALIZED OR MULTISYSTEM INVOLVEMENT
Immediate generalized reactions Anaphylaxis (IgE-mediated reactions) Anaphylactoid reactions (IgE independent) Serum sickness and serum sickness–like reactions Drug fever Drug-induced autoimmunity Reactions simulating systemic lupus erythematosus Other reactions Hypersensitivity vasculitis
REACTIONS PREDOMINANTLY ORGAN SPECIFIC
684
OF
ALLERGIC
Dermatologic manifestationsa Pulmonary manifestations Asthma Pulmonary infiltrates with eosinophilia Pneumonitis and fibrosis Noncardiogenic pulmonary edema Hematologic manifestations Eosinophilia Drug-induced immune cytopenias Thrombocytopenia Hemolytic anemia Agranulocytosis Hepatic manifestations Cholestasis Hepatocellular damage Mixed pattern Renal manifestations Glomerulonephritis Nephrotic syndrome Acute interstitial nephritis Lymphoid system manifestations Pseudolymphoma Infectious mononucleosis–like syndrome Cardiac manifestations Neurologic manifestations
685
a
A separate listing of dermatologic manifestations is included in that section (Table 17A.8). IgE, immunoglobulin E.
In a series of 32,812 continuously monitored patients, such reactions occurred in 12 patients (0.04%), and there were two deaths. Because anaphylaxis is more likely to be reported when a fatality occurs, its prevalence may be underestimated. Drug-induced anaphylaxis does not appear to confer increased risk of such generalized reactions to allergens from other sources (80). Most reactions occur within 30 minutes, and death may ensue within minutes. In a retrospective study by Pumphrey in the United Kingdom investigating fatalities associated with anaphylaxis, more than one-half of the fatal reactions were iatrogenic. The majority of these reactions were caused by IV medications and took 5 minutes or less from the time of administration to the time of arrest (81). Anaphylaxis occurs most commonly after parenteral administration, but it has also followed oral, percutaneous, and respiratory exposure. Symptoms usually subside rapidly with appropriate treatment, but may last 24 hours or longer, and recurrent symptoms may appear several hours after apparent resolution of the reaction. As a rule, the severity of the reaction decreases with increasing time between exposure to the drug and onset of symptoms. Death is usually due to cardiovascular collapse or respiratory obstruction, especially laryngeal or upper airway edema. Although most reactions do not terminate fatally, the potential for such must be borne in mind, and the attending physician must respond immediately with appropriate treatment. Table 17A.8 summarizes agents most frequently associated with immediate generalized reactions. In some situations, drugs, such as general anesthetic agents and vancomycin, which are primarily direct mast cell mediator releasers, can produce an IgE-mediated reaction (42,82). This distinction has clinical relevance in that IgE-independent reactions may be prevented or modified by pretreatment with corticosteroids and antihistamines, whereas such protection from drug-induced IgE-mediated reactions is less likely. In the latter situation, when the drug is medically necessary, desensitization is an option. The β-lactam antibiotics, notably penicillin, are by far the most common causes of drug-induced anaphylaxis. Essentially all β-lactam anaphylactic reactions are IgE mediated. Immediate generalized reactions to other antibiotics occur but are relatively uncommon. Anaphylactoid reactions have been reported after the administration of ciprofloxacin and norfloxacin (83); as described earlier, these are likely due to MRGPRX2 binding (32). 686
TABLE 17A.8 DRUGS IMPLICATED GENERALIZED REACTIONS
IN
IMMEDIATE
ANAPHYLAXIS (IgE-MEDIATED)
β-Lactam antibiotics Allergen extracts Heterologous antisera Insulin Vaccines (egg based) Streptokinase Chymopapain L-Asparaginase
Cisplatin Carboplatin Latexa
ANAPHYLACTOID (IgE-INDEPENDENT)
Radiocontrast material Aspirin Nonsteroidal anti-inflammatory drugs Dextran and iron dextran Anesthetic drugs Induction agentsb Muscle relaxantsb Protamineb Vancomycinb Ciprofloxacin Taxanes (i.e., paclitaxel) Epipodophylotoxins (i.e., etoposide, teniposide)
a
Not a drug per se, but often an important consideration in a medical setting.
687
b
Some reactions may be mediated by IgE antibodies.
IgE, immunoglobulin E.
Cancer chemotherapeutic agents have been associated with hypersensitivity reactions, most commonly type I immediate generalized reactions (84). LAsparaginase has the highest risk for such reactions. Serious anaphylactic reactions with respiratory distress and hypotension occur in about 10% of patients treated. It is likely that most of these reactions are IgE mediated. However, skin testing appears to be of no value in predicting a reaction because there are both false-positive and false-negative results. Therefore, one must be prepared to treat anaphylaxis with each dose. For those reacting to Lasparaginase derived from Escherichia coli, one derived from Erwinia chyoanthermia (a plant pathogen) or a modified asparaginase (pegaspargase) may be a clinically effective substitute. Cisplatin and carboplatin are second only to L-asparaginase in producing such reactions. Skin testing with these agents appears to have predictive value, and desensitization has been successful when these drugs are medically necessary (85). The initial use of paclitaxel and other taxanes to treat ovarian and breast cancer was associated with a 10% risk for anaphylactoid reactions. However, with premedication and lengthening of the infusion time, the risk is significantly reduced (86). All other antitumor drugs, except altretamine, the nitrosoureas, and dactinomycin, have occasionally been associated with hypersensitivity reactions (84). Some appear to be IgE mediated, but most are probably IgE independent. Anaphylactic and anaphylactoid reactions occurring during the perioperative period have received increased attention. The evaluation and detection of these reactions is complicated by the use of multiple medications and the fact that patients are often unconscious and draped, which may mask the early signs and symptoms of an immediate generalized reaction (87). During anesthesia, the only feature observed may be cardiovascular collapse (88) or airway obstruction. Cyanosis resulting from oxygen desaturation may be noted. One large multicenter study indicated that 70% of cases were caused by muscle relaxants and 12% were caused by latex (89). Other agents, such as IV induction drugs, plasma volume expanders (dextran), opioid analgesics and antibiotics, also require consideration (31). With the increased use of cardiopulmonary bypass surgery, the incidence of protamine-induced immediate life-threatening reactions has risen (90). Anaphylaxis to ethylene oxide–sterilized devices has been described; hence, such devices used during anesthesia could potentially cause anaphylaxis (91).
688
Psyllium seed is an active ingredient of several bulk laxatives, and has been responsible for asthma following inhalation and anaphylaxis after ingestion, particularly in atopic subjects (92). Anaphylactoid reactions following IV fluorescein may be modified by pretreatment with corticosteroids and antihistamines (93). Of patients reacting to iron dextran, 0.6% had a lifethreatening anaphylactoid reaction (94). Anaphylactoid reactions may also be caused by blood and blood products through the activation of complement and the production of anaphylatoxins. Adverse reactions to monoclonal antibodies include immediate generalized manifestations, but the mechanism for such remains unclear (95). Most appear not to be IgE mediated (96) and protocols including rapid desensitization have been established for managing these reactions (97,98). If one surveys the medical literature, one will find that virtually all drugs, including corticosteroids, tetracycline, cromolyn, erythromycin, and cimetidine, have been implicated in such immediate generalized reactions. However, these infrequent reports should not be a reason to withhold essential medication. Serum Sickness and Serum Sickness–Like Reactions Serum sickness results from the administration of heterologous (often equine) antisera and is the human equivalent of immune complex–mediated serum sickness observed in experimental animals (99). A serum sickness–like illness has been attributed to a number of nonprotein drugs, notably the β-lactam antibiotics. These reactions are usually self-limited and the outcome favorable, but H1 blockers and prednisone may be needed. With effective immunization procedures, antimicrobial therapy, and the availability of human antitoxins, the incidence of serum sickness has declined. Currently, heterologous antisera are still used to counteract potent toxins such as snake venoms, black widow and brown recluse spider venom, botulism, and gas gangrene toxins as well as to treat diphtheria and rabies. Equine and rabbit antisera, used as antilymphocyte or antithymocyte globulins and as monoclonal antibodies for immunomodulation and cancer treatment, may cause serum sickness (100). Serum sickness has also been reported in patients receiving streptokinase (101). β-Lactam antibiotics are considered to be the most common nonserum causes of serum sickness–like reactions (102). One literature review did not support this assertion (103). In fact, such reactions appear to be quite infrequent, with an incidence of 1.8 per 100,000 prescriptions of cefaclor and 1 per 10 million for
689
amoxicillin and cephalexin (104). Other drugs occasionally incriminated include ciprofloxacin, metronidazole, streptomycin, sulfonamides, allopurinol, carbamazepine, hydantoins, methimazole, phenylbutazone, propanolol, and thiouracil. It should be noted that the criteria for diagnosis might not be uniform for each drug. The onset of serum sickness typically begins 6 to 21 days after administration of the causative agent. The latent period reflects the time required for the production of antibodies. The onset of symptoms coincides with the development of immune complexes. Among previously immunized individuals, the reaction may begin within 2 to 4 days following administration of the inciting agent. The manifestations include fever and malaise, skin eruptions, joint symptoms, and lymphadenopathy. There is no laboratory finding specific for the diagnosis of serum sickness or serum sickness–like reactions. Laboratory abnormalities may be helpful, if present. The erythrocyte sedimentation rate may be elevated, although it has been noted to be normal or low (102). There may be a transient leukopenia or leukocytosis during the acute phase (79,105). Plasmacytosis may occasionally be present; in fact, serum sickness is one of the few illnesses in which plasma cells may be seen in the peripheral blood (106). The urinalysis may reveal slight proteinuria, hyaline casts, hemoglobinuria, and microscopic hematuria. However, nitrogen retention is rare. Transaminases and serum creatinine may be transiently elevated (100). Serum concentrations of C3, C4, and total hemolytic complement are depressed, providing some evidence that an immune complex mechanism is operative. These may rapidly return to normal. Immune complex and elevated plasma concentrations of C3a and C5a anaphylatoxins have been documented (107). The prognosis for complete recovery is excellent. The symptoms may be mild, lasting only a few days, or quite severe, persisting for several weeks or longer. Antihistamines control urticaria. If symptoms are severe, corticosteroids (e.g., prednisone, 40 mg/day for 1 week and then taper) are indicated. However, corticosteroids do not prevent serum sickness, as noted in patients receiving antithymocyte globulin (100). Skin testing with foreign antisera is routinely performed to avoid anaphylaxis with future use of foreign serum. Drug Fever 690
Fever is a well-known drug hypersensitivity reaction. An immunologic mechanism is often suspected. Fever may be the sole manifestation of drug hypersensitivity and is particularly perplexing in a clinical situation in which a patient is being treated for an infection. The height of the temperature does not distinguish drug fever, and there does not appear to be any fever pattern typical of this entity. Although a distinct disparity between the recorded febrile response and the relative well-being of the patient has been emphasized, clearly, such individuals may be quite ill with high fever and shaking chills. Drug fever may be the sole manifestation of a drug allergy but is commonly seen with other signs of drug hypersensitivity such as rash, elevated liver enzymes, and eosinophils. Laboratory studies usually reveal leukocytosis with a shift to the left, thus mimicking an infectious process. Mild eosinophilia may be present. An elevated erythrocyte sedimentation rate and abnormal liver function tests are present in most cases. The most consistent feature of drug fever is prompt defervescence, usually within 48 to 72 hours after withdrawal of the offending agent. Subsequent readministration of the drug produces fever, and occasionally chills, within a matter of hours. In general, the diagnosis of drug fever is one of exclusion after eliminating other potential causes of the febrile reaction. Prompt recognition of drug fever is essential. If not appreciated, patients may be subjected to multiple diagnostic procedures and inappropriate treatment. Of greater concern is the possibility that the reaction may become more generalized with resultant tissue damage. Autopsies on patients who died during drug fever show arteritis and focal necrosis in many organs, such as the myocardium, lung, and liver.
Drug-Induced Autoimmunity Drug-Induced Systemic Lupus Erythematosus DIL is the most familiar drug-induced autoimmune disease, in part because systemic lupus erythematosus (SLE) remains the prototype of autoimmunity. DIL is termed autoimmune because of its association with the development of antinuclear antibodies (ANAs). However, these same autoantibodies are found frequently in the absence of frank disease. An excellent review of drug-induced autoimmunity appears elsewhere (108) as well as a comprehensive review of the medications implicated (109). 691
Convincing evidence for DIL first appeared in 1953 after the introduction of hydralazine for treatment of hypertension (110) although it was first described in 1945 associated with sulfadiazine (111). Procainamide-induced lupus was first reported in 1962 and is now the most common cause of DIL in the United States (112). These drugs have also been the best studied. Other agents for which there has been definite proof of an association include isoniazid, chlorpromazine, methyldopa, quinidine, and minocycline. Another group of drugs probably associated with the syndrome includes many anticonvulsants, β-blockers, antithyroid drugs, penicillamine, sulfasalazine, and lithium. There have been case reports of DIL associated with monoclonal antibodies such as inflixamab and etanercept (113,114), and an ANA-negative, antihistone-positive DIL has been described with lisinopril (115). There are case reports linking statins such as lovastatin, fluvastatin, and atorvastatin with DIL but with varying clinical manifestations, including pneumonitis, and cutaneous manifestations (116). The incidence of DIL is not precisely known. In a recent survey of patients with lupus erythematosus seen in a private practice, 3% had DIL (117). The estimated incidence is 15,000 to 20,000 cases per year (118). In contrast to SLE, patients with DIL tend to be older, and males and females are equally affected (119). Patients with idiopathic SLE do not appear to be at increased risk from drugs implicated in DIL (120). Identified risk factors for developing DIL include HLA-DR4 (121), HLA-DR*0301 (122), slow acetlylator status (123), and complement C4 null allele (124). Fever, malaise, arthralgias, myalgias, pleurisy, and slight weight loss may appear acutely in a patient receiving an implicated drug. Pleuropericardial manifestations, such as pleurisy, pleural effusions, pulmonary infiltrates, pericarditis, and pericardial effusions, are more often seen in patients taking procainamide. Unlike idiopathic SLE, the classic butterfly malar rash, discoid lesions, oral mucosal ulcers, Raynaud phenomenon, alopecia, and renal and central nervous system disease are unusual in DIL. Glomerulonephritis has occasionally been reported in hydralazine-induced lupus. As a rule, DIL is a milder disease than idiopathic SLE. Because many clinical features are nonspecific, the presence of ANAs (homogeneous pattern) or antihistone antibodies is essential in the diagnosis of drug-induced disease. Clinical symptoms usually do not appear for many months after institution of drug treatment. Clinical features of DIL usually subside within days to weeks after the offending drug is discontinued. In an occasional patient, the symptoms may persist or recur over several months before disappearing. ANAs often 692
disappear in a few weeks to months but may persist for 1 year or longer. Mild symptoms may be managed with NSAIDs; more severe disease may require corticosteroid treatment. If no satisfactory alternative drug is available and treatment is essential, the minimum effective dose of the drug and corticosteroids may be given simultaneously with caution and careful observation. With respect to procainamide, DIL can be prevented by giving N-acetylprocainamide, the major acetylated metabolite of procainamide. In fact, remission of procainamideinduced lupus has occurred when patients were switched to Nacetylprocainamide therapy (125,126). Finally, there are no data to suggest that the presence of ANAs necessitates discontinuance of the drug in asymptomatic patients. The low probability of clinical symptoms in seroreactors and the fact that major organs are usually spared in DIL support this recommendation (127). Other Drug-Induced Autoimmune Disorders In addition to DIL, D-penicillamine has been associated with several other autoimmune syndromes, such as myasthenia gravis, polymyositis and dermatomyositis, pemphigus and pemphigoid, membranous glomerulonephritis, Goodpasture’s syndrome, and immune cytopenias (128). It has been suggested that by binding to cell membranes as a hapten, penicillamine could induce an autologous T-cell reaction, B-cell proliferation, autoantibodies, and autoimmune disorders (129). Hypersensitivity Vasculitis Vasculitis is a condition that is characterized by inflammation and necrosis of blood vessels. Organs or systems with a rich supply of blood vessels are most often involved. Thus, the skin is often involved in vasculitic syndromes. In the systemic necrotizing vasculitis group (polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis) and granulomatous vasculitides (granulomatosis with polyangiitis, lymphomatoid granulomatosis, giant cell arteritides), cutaneous involvement is not as common a presenting feature as seen in the hypersensitivity vasculitides (HSV). Also, drugs do not appear to be implicated in the systemic necrotizing and granulomatous vasculitic syndromes. Drugs appear to be responsible for or associated with a significant number of cases of HSV (130). These may occur at any age, but the average age of onset is in the fifth decade (131). The older patient is more likely to be taking medications that have been associated with this syndrome, for example, diuretics and cardiac drugs. Other frequently implicated agents include penicillin, 693
sulfonamides, thiouracils, hydantoins, iodides, and allopurinol. Allopurinol administration, particularly in association with renal compromise and concomitant thiazide therapy, has produced a vasculitic syndrome manifested by fever, malaise, rash, hepatocellular injury, renal failure, leukocytosis, and eosinophilia. The mortality rate approaches 25% (132). However, in many cases of HSV, no cause is ever identified. Fortunately, idiopathic cases tend to be selflimited. The most common clinical feature of HSV is palpable purpura, and the skin may be the only site where vasculitis is recognized. The lesions occur in recurrent crops of varying size and number and are usually distributed in a symmetric pattern on the lower extremities and sacral area. Fever, malaise, myalgia, and anorexia may accompany the appearance of skin lesions. Usually, only cutaneous involvement occurs in drug-induced HSV, but glomerulonephritis, arthralgias or arthritis, abdominal pain and gastrointestinal bleeding, pulmonary infiltrates, and peripheral neuropathy are occasionally present. The diagnosis of HSV is established by skin biopsy of a lesion demonstrating characteristic neutrophilic infiltrate of the blood vessel wall terminating in necrosis, leukocytoclasis (nuclear dust or fragmentation of nuclei), fibrinoid changes, and extravasation of erythrocytes. This inflammation involves small blood vessels, predominantly postcapillary venules. Recent studies indicate that in drug-induced vasculitis, multispecific antinuclear cytoplasmic antibody (ANCA) (ANCA positive to several neutrophil antigens) is commonly found. This is distinguished from ANCA to only one neutrophil antigen as is seen with idiopathic vasculitis and may serve to distinguish between the two (133). When a patient presents with palpable purpura and has started a drug within the previous few months, consideration should be given to stopping that agent. Generally, the prognosis for HSV is excellent, and elimination of the offending agent, if one exists, usually suffices for therapy. For a minority of patients who have persistent lesions or significant involvement of other organ systems, corticosteroids are indicated.
Predominantly Organ-Specific Reactions Dermatologic Manifestations Cutaneous eruptions are the most frequent manifestations of ADRs and occur in 2% to 3% of hospitalized inpatients (134). The offending drug could be identified in most cases, and in one study was confirmed by drug challenges in 694
62% of patients (135). Frequently implicated agents include β-lactam antibiotics (especially ampicillin and amoxicillin), sulfonamides (especially TMP–SMX), NSAIDs, anticonvulsants, and central nervous system depressants (136). Drug eruptions are most often exanthematous or morbilliform in nature. Most are of mild or moderate severity, often fade within a few days, and pose no threat to life or subsequent health. Much less common are SCARs, which include SJS, TEN, and drug-induced liver injury (DILI)/DRESS. These reactions, although rare, are responsible for significant morbidity and mortality. As noted earlier, some populations may be at higher risk for SCAR from certain medications based on HLA genotype. Typical features of a drug-induced eruption include an acute onset within 1 to 2 weeks after drug exposure (DILI/DRESS is more commonly delayed, occurring 4 to 6 weeks after initiation of the medication), symmetric distribution, predominant truncal involvement, brilliant coloration, and pruritus. Features that suggest that a reaction is serious include the presence of urticaria, blisters, mucosal involvement, facial edema, ulcerations, palpable purpura, fever, lymphadenopathy, and eosinophilia (137). The presence of these usually necessitates prompt withdrawal of the offending drug. Table 17A.9 provides a list of recognizable cutaneous eruptions frequently induced by drugs, presumably on an immunologic basis. Exanthematous or Morbilliform Eruptions Exanthematous or morbilliform eruptions are the most common drug-induced eruptions and may be difficult to distinguish from viral exanthems. The rash may be predominantly erythematous, maculopapular, or morbilliform (measles-like), and often begins on the trunk or in areas of pressure, for example, the backs of bedridden patients. Pruritus is variable or minimal. Occasionally, pruritus may be an early symptom, preceding the development of cutaneous manifestations. Gold salts and sulfonamides have been associated with pruritus as an isolated feature. This rarely progresses to overt exfoliation, although this is possible (138). Usually, this drug-induced eruption appears within a week or so after institution of treatment. Unlike the generally benign nature of this ADR, a syndrome with a similar rash and fever, often with hepatitis, arthralgias, lymphadenopathy, and eosinophilia, has been termed drug-induced hypersensitivity syndrome (DIHS) (137), now referred to as drug rash with esoinophilia and systemic symptoms (DRESS) (139). It has a relatively later onset (2 to 6 weeks after initiation of treatment), evolves slowly, and may be difficult to distinguish from drug-induced vasculitis. Anticonvulsants, sulfonamides, and allopurinol are the most frequent causes of DRESS, although 695
other drugs such as antituberculous medication have been reported (140). Recovery is usually complete, but the rash and hepatitis may persist for weeks. TABLE 17A.9 DRUG-INDUCED CUTANEOUS MANIFESTATIONS MOST FREQUENT
Exanthematous or morbilliform eruptions Urticaria and angioedema Contact dermatitisa Allergic eczematous contact dermatitis Systemic eczematous “contact-type” dermatitis
LESS FREQUENT
Fixed drug eruptions Erythema multiforme–like eruptions Stevens–Johnson syndrome (SJS) Generalized exfoliative dermatitis Photosensitivity
UNCOMMON
Purpuric eruptions SCAR—Toxic epidermal necrolysis (Lyell syndrome), SJS, and drug-induced liver injury/drug reaction with eosinophilia and systemic symptoms (DILI/DRESS) Erythema nodosum Acute generalized exanthematous pustulosis
a
Contact dermatitis is still listed among the top three, but there is evidence that this problem may be decreasing with the purposeful avoidance of topical sensitizers.
Urticaria and Angioedema Urticaria with or without angioedema is the second most frequent drug-induced eruption. It may occur alone or may be part of an immediate generalized reaction, such as anaphylaxis, or serum sickness. An allergic IgE-mediated 696
mechanism is often suspected, but it may be the result of a pseudoallergic reaction. One study reported that β-lactam antibiotics (through an allergic mechanism) accounted for one-third, and NSAIDs (through a pseudoallergic mechanism) accounted for another one-third, of drug-induced urticarial reactions (141). Often, urticaria appears shortly after drug therapy is initiated, but its appearance may be delayed for days to weeks. Usually, individual urticarial lesions do not persist much longer than 24 hours, but new lesions may continue to appear in different areas of the body for 1 to 2 weeks. If the individual lesions last longer than 24 hours, or if the rash persists for much longer than 2 weeks, the possibility of another diagnosis such as urticarial vasculitis should be considered. A drug etiology should be considered in any patient with chronic urticaria, which is defined as lasting more than 6 weeks. Angioedema is most often associated with urticaria, but it may occur alone. Angiotensin-converting enzyme (ACE) inhibitors are responsible for most cases of angioedema requiring hospitalization (142). The risk of angioedema is estimated to be between 0.1% and 0.2% in patients receiving such therapy (143). Patients with ididopathic angioedema are at increased risk of ACE inhibitor– induced angioedema, as are African Americans and women; therefore, caution should be used in treating these populations (144,145). The angioedema commonly involves the face and oropharyngeal tissues and may result in acute airway obstruction necessitating emergency intervention. Most episodes occur within the first week or so of therapy, but there are occasional reports of angioedema occurring years after initiation of treatment (146). The mechanism of angioedema is probably ACE inhibitor potentiation of bradykinin production (147), because icatibant has been reported to be a successful treatment (148). Angioedema has been reported with angiotensin II receptor blockers (ARBs) as well (149). Because treatment with epinephrine, antihistamines, and corticosteroids may be ineffective, the physician must be aware of the potential for airway compromise and the possible need for early airway intervention measures and treatment with icatibant (148). When angioedema follows the use of any one of these agents, treatment with any ACE inhibitor should be avoided. ARBs may be a good alternative. Angioedema has been reported with these, although the incidence is much lower (149). Allergic Contact Dermatitis Allergic contact dermatitis is produced by medications or by components of the drug delivery system applied topically to the skin and is an example of a type IV 697
cell-mediated immune reaction (Tables 17.4 and 17.9). Following topical sensitization, the contact dermatitis may be elicited by subsequent topical application. The appearance of the skin reaction and diagnosis by patch testing is similar to allergic contact dermatitis from other causes. The diagnosis should be suspected when the condition for which the topical preparation is being applied, such as eczema, fails to improve or worsens. Patients at increased risk of allergic contact dermatitis include those with stasis dermatitis, leg ulcers, perianal dermatitis, and hand eczema (150). Common offenders include neomycin, benzocaine, and ethylenediamine. Less common sensitizers include paraben esters, thimerosal, antihistamines, bacitracin, and, rarely, sunscreens and topical corticosteroids (151). Neomycin is the most widely used topical antibiotic and has become the most sensitizing of all antibacterial preparations. Other aminoglycosides (e.g., streptomycin, kanamycin, gentamicin, tobramycin, amikacin, and netilmicin) may cross-react with neomycin, but this is variable (152). Neomycin-allergic patients may develop a systemic “contact-type” dermatitis when exposed to some of these drugs systemically. Many neomycin-allergic patients also react to bacitracin. In addition to neomycin, other topical antibiotics that are frequent sensitizers include penicillin, sulfonamides, chloramphenicol, and hydroxyquinolones. For this reason, they are seldom prescribed in the United States. Benzocaine, a para-aminobenzoic acid (PABA) derivative, is the most common topical anesthetic associated with allergic contact dermatitis. It is found in many nonprescription preparations, such as sunburn and poison ivy remedies, topical analgesics, throat lozenges, and hemorrhoid preparations. In some benzocaine-sensitive patients, there may be cross-reactivity with other local anesthetics that are based on PABA esters, such as procaine, butacaine, and tetracaine. Suitable alternatives are the local anesthetics based on an amide structure, such as lidocaine, mepivacaine, and bupivacaine. Such individuals may also react to other para-amino compounds, such as some hair dyes (paraphenylenediamine), PABA-containing sunscreens, aniline dyes, and sulfonamides. Ethylenediamine, a stabilizer used in some antibiotics, corticosteroids, and nystatin-containing combination creams, is a common sensitizer. Once sensitized to ethylenediamine topically, a patient may experience widespread dermatitis following the systemic administration of medicaments that contain ethylenediamine, such as aminophylline, hydroxyzine, and tripelennamine (153); 698
however, this is not common. Among the less frequent topical sensitizers, paraben esters, used as preservatives in topical corticosteroid creams, were thought to be important; however, a recent study failed to support this assertion (154). Thimerosal is used topically as an antiseptic and also as a preservative. In one study, 7.5% of patients had a positive patch test with this material. Not all such patients are mercury allergic; many react to the thiosalicylic moiety. Local and even systemic reactions have been ascribed to thimerosal used as a preservative in some vaccines (155). However, if a patient’s allergic history to thimerosal is topical sensitization only, skin testing to the vaccine followed by cautious test dosing may be considered. Systemic administration of antihistamines is rarely, if ever, associated with an allergic reaction; however, topical antihistamines are potential sensitizers, and their use should be avoided. Most instances of allergic contact dermatitis attributed to topical corticosteroids are due to the vehicle, not to the steroid itself. Patch testing with the highest concentration of the steroid ointment may help identify whether the steroid itself or the vehicle constituent is responsible. Some attention has already been focused on systemic eczematous contact-type dermatitis. In summary, physicians should attempt to avoid or minimize the use of common sensitizers, such as neomycin and benzocaine, in the treatment of patients with chronic dermatoses, such as stasis dermatitis and hand eczema. A more comprehensive review of drug-induced allergic contact dermatitis is found elsewhere (156) and in Chapter 30. Fixed Drug Eruptions Fixed drug eruptions, in contrast to most other drug-induced dermatoses, are considered to be pathognomonic of drug hypersensitivity. Men are more frequently affected than women, and ages 20 to 40 are most common (157,158), but children may also be affected (159,160). The term fixed relates to the fact that these lesions tend to recur in the same sites each time the specific drug is administered. On occasion, the dermatitis may flare with antigenically related and even unrelated substances. The characteristic lesion is well delineated and round or oval; it varies in size from a few millimeters to 25 to 30 cm. Edema appears initially, followed by erythema, which then darkens to become a deeply colored, reddish purple, dense raised lesion. On occasion, the lesions may be eczematous, urticarial, vesiculobullous, hemorrhagic, or nodular. Lesions are most common on the lips and genitals but may occur anywhere on the skin or mucous membranes 699
(161,162). Usually, a solitary lesion is present, but the lesions may be more numerous, and additional ones may develop with subsequent administration of the drug. The length of time from reexposure to the drug to the onset of symptoms is 30 minutes to 8 hours (mean, 2.1 hours). The lesions usually resolve within 2 to 3 weeks after drug withdrawal, leaving transient desquamation and residual hyperpigmentation. The mechanism is unknown, but the histopathology is consistent with T-cell– mediated destruction of epidermal cells, resulting in keratinocyte damage (163). Studies point to a possible role for CD8+ T-cell infiltration mediating keratinocyte apoptosis through a Fas–Fas ligand mechanism (164). Commonly implicated drugs include phenolphthalein, barbiturates, sulfonamides, tetracycline, and NSAIDs, although many drugs have been implicated, such as antifungals, antieleptics, narcotics, and many antibiotics (165). Drugs most commonly implicated vary depending on the country, the availability of drugs, and their pattern of use (166,167). In addition, some authors believe the location of lesions may be specific to the drug (168). Treatment is usually not required after the offending drug has been withdrawn because most fixed drug eruptions are mild and not associated with significant symptoms. Corticosteroids may decrease the severity of the reaction without changing the course of the dermatitis (159). Acute Generalized Exanthematous Pustulosis Acute generalized exanthematous pustulosis (AGEP) is an acute eruption of numerous small (less than 5 mm), sterile, mostly nonfollicular pustules in conjunction with fever more than 38°C and peripheral neutrophil count greater than 7 × 103/μL. The pustules are subcorneal or intraepidermal and appear on an erythematous, edematous base, and most commonly involve the trunk, upper extremities, and main skinfolds such as the neck, axilla, and groin. Transient renal failure and hypocalcemia are not uncommon (169). AGEP can be distinguished histologically from pustular psoriasis, and focal keratinocyte necrosis, vasculitis, perivascular eosinphils, as well as dermal edema can be seen on biopsy (170,171). AGEP is rare and for years was classified as pustular psoriasis and in 1968 was first thought to be a separate entity (172) and then better characterized in 1980 (173). Unlike pustular psoriasis, AGEP is most commonly caused by drug hypersensitivity, with antibiotics, in particular aminopenicillins, and diltiazem most commonly implicated (174). It is selflimited, with skin eruptions occurring soon after the medication is first administered (less than 2 days), followed by superficial desquamation and 700
spontaneous resolution in less than 15 days (171). AGEP is a predominantly neutrophilic inflammatory process in which drug-specific T cells have been found to play a role (175,176). Erythema Multiforme–Like Eruptions A useful classification for the heterogeneous syndrome of erythema multiforme has been suggested (177). Additional details can be found in Chapter 16. It is often a benign cutaneous illness with or without minimal mucous membrane involvement and has been designated erythema multiforme minor (EM minor). A more severe cutaneous reaction with marked mucous membrane (at least two mucosal surfaces) involvement and constitutional symptoms has been termed erythema multiforme major (EM major). SJS has become synonymous with EM major. In addition, some have considered TEN to represent the most severe form of this disease process, but others believe it should be considered a separate entity. EM minor is a mild, self-limited cutaneous illness characterized by the sudden onset of symmetric erythematous eruptions on the dorsum of the hands and feet and on the extensor surfaces of the forearms and legs; palms and soles are commonly involved. Lesions rarely involve the scalp or face. Truncal involvement is usually sparse. The rash is minimally painful or pruritic. It is a relatively common condition in young adults 20 to 40 years of age and is often recurrent in nature. Mucous membrane involvement is usually limited to the oral cavity. Typically, the lesions begin as red, edematous papules that may resemble urticaria. Some lesions may develop concentric zones of color change, producing the pathognomonic “target” or “iris” lesions. The rash usually resolves in 2 to 4 weeks, leaving some residual postinflammatory hyperpigmentation but no scarring or atrophy. Constitutional symptoms are minimal or absent. The most common cause is believed to be herpes simplex infection, and oral acyclovir has been used to prevent recurrence of EM minor (178). Most instances of drug-induced erythema multiforme result in more severe manifestations, classified as EM major or SJS. This bullous-erosive form can result in skin loss of up to 10% of the total body surface area (TBSA) and is often preceded by constitutional symptoms of high fever, headache, and malaise. Involvement of mucosal surfaces is a prominent and consistent feature. The cutaneous involvement is more extensive than in EM minor, and there is often more pronounced truncal involvement. Painful oropharyngeal mucous membrane lesions may interfere with nutrition. The vermilion border of the lips becomes denuded and develops serosanguinous crusts, a typical feature of this syndrome. 701
Eighty-five percent of patients develop conjunctival lesions, ranging from hyperemia to extensive pseudomembrane formation. Serious ocular complications include the development of keratitis sicca, corneal erosions, uveitis, and even bulbar perforation. Permanent visual impairment occurs in about 10% of patients. Mucous membrane involvement of the nares, anorectal junction, vulvovaginal region, and urethral meatus is less common. The epithelium of the tracheobronchial tree and esophagus may be involved, leading to stricture formation. EM major has a more protracted course, but most cases heal within 6 weeks (177). The mortality rate approaches 10% among patients with extensive disease. Sepsis is a major cause of death. Visceral involvement may include liver, kidney, or pulmonary disease. The pathogenesis of this disorder is uncertain; however, the histopathologic features are similar to graft-versus-host disease and suggest an immune mechanism. Deposition of C3, IgM, and fibrin can be found in the upper dermal blood vessels (179). Upregulation of intercellular adhesion molecule 1, an adhesion molecule that facilitates recruitment of inflammatory cells, has been found in the epidermis of patients with erythema multiforme (180). However, unlike immune complex–mediated cutaneous vasculitis in which the cell infiltrate is mostly polymorphonuclear leukocytes, a mononuclear cell infiltrate (mostly lymphocytes) is present around the upper dermal blood vessels (181,182). Activated lymphocytes, mainly CD8+ cells, are present, and there is increasing evidence that they are responsible for keratinocyte destruction (182–185). Epidermal apoptosis has also been reported in patients with SJS and TEN (182–186), and the role of the T cell in apoptosis is well established. It is possible that a drug or drug metabolite may bind to the cell surface, after which the patient then develops lymphocyte reactivity directed against the drug–cell complex. Genetic susceptibility likely also plays a role. In a Han Chinese population, HLA-B*5801 was found to have a strong association with the development of SJS and TEN to allopurinol (58) and HLA-B*1502 with the development of SJS to carbamazapime (57). Other studies have shown a possible susceptibility to ocular involvement with HLA-Bw44 (part of HLA-B12) and HLA-oq81*0601 (187). Drugs are the most common cause of SJS, accounting for at least half of cases (137). Drugs most frequently associated with this syndrome and also TEN include sulfonamides (especially TMP–SMX), anticonvulsants (notably carbamazepine), barbiturates, phenylbutazone, piroxicam, allopurinol, and 702
aminopenicillins. Occasional reactions have followed the use of cephalosporins, fluoroquinolones, vancomycin (188), antituberculous drugs, and NSAIDs, and proton pump inhibitors (PPIs) have been reported as a cause of SJS (189,190). Typically, symptoms begin 1 to 3 weeks after initiation of therapy. Although there is some disagreement based on a series of 67 patients, early management of SJS with high-dose corticosteroids (160 to 240 mg methylprednisolone a day initially) should be implemented (191,192). Corticosteroids hastened recovery, produced no major side effects, and were associated with 100% survival and full recovery with no significant residual complications. This recommendation does not apply to the management of TEN. Drug challenges to establish whether a patient can safely tolerate a drug following a suspected reaction should not be considered with serious adverse reactions such as SJS, TEN, and exfoliative dermatitis. Generalized Exfoliative Dermatitis Exfoliative dermatitis is a serious and potentially life-threatening skin disease characterized by erythema and extensive scaling in which the superficial skin is shed over virtually the entire body. Even hair and nails are lost. Fever, chills, and malaise are often prominent, and there is a large extrarenal fluid loss. Secondary infection frequently develops, and on occasion, a glomerulonephritis has developed. Fatalities occur most often in elderly or debilitated patients. Laboratory tests and skin biopsy are helpful only to exclude other causes, such as psoriasis or cutaneous lymphoma. High-dose systemic corticosteroids and careful attention to fluid and electrolyte replacement are essential. Exfoliative dermatitis may occur as a complication of preexisting skin disorders (e.g., psoriasis, seborrheic dermatitis, atopic dermatitis, and contact dermatitis); in association with lymphomas, leukemias, and other internal malignancies; or as a reaction to drugs. At times, a predisposing cause is not evident. The drug-induced eruption may appear abruptly or may follow an apparently benign, drug-induced exanthematous eruption. The process may continue for weeks or months after withdrawal of the offending drug. Many drugs have been implicated in the development of exfoliative dermatitis, but the most frequently encountered are sulfonamides, penicillins, barbiturates, carbamazepine, phenytoin, phenylbutazone, allopurinol, and gold salts (193). No immunologic mechanism has been identified. The diagnosis is based on clinical grounds, the presence of erythema followed by scaling, and drug use compatible with this cutaneous reaction. The outcome is usually favorable if the causative agent is identified and then discontinued and 703
corticosteroids are initiated. However, an older study reported a 40% mortality rate, reminding us of the potential seriousness of this disorder (194). Photosensitivity Photosensitivity reactions are produced by the interaction of a drug present in the skin and light energy. The drug may be administered topically, orally, or parenterally. Although direct sunlight (ultraviolet spectrum 2,800 to 4,500 nm or 280 to 450 mm) is usually required, filtered or artificial light may produce reactions. African Americans have a lower incidence of drug photosensitivity, presumably because of greater melanin protection. The eruption is limited to light-exposed areas, such as the face, the V area of the neck, the forearms, and the dorsa of the hands. Often, a triangular area on the neck is spared because of shielding by the mandible. The intranasal areas and the groove of the chin are also spared. Although symmetric involvement is usual, unilateral distribution may result from activities such as keeping an arm out of the window while driving a car. Photosensitivity may occur as a phototoxic nonimmunologic phenomenon and, less frequently, as a photoallergic immunologic reaction. Differential features are shown in Table 17A.10. Phototoxic reactions are nonimmunologic, occurring in a significant number of patients on first exposure when adequate light and drug concentrations are present. The drug absorbs light, and this oxidative energy is transferred to tissues, resulting in damage. The light absorption spectrum is specific for each drug. Clinically, the reaction resembles an exaggerated sunburn developing within a few hours after exposure. On occasion, vesiculation occurs, and hyperpigmentation remains in the area. Most phototoxic reactions are prevented if the light is filtered through ordinary window glass. Tetracycline, fluoroquinolones, and amiodarone are some of the many agents implicated in phototoxic reactions (195). Photoallergic reactions, in contrast, generally start with an eczematous phase and more closely resemble contact dermatitis. Here, the radiant energy presumably alters the drug to form reactive metabolites that combine with cutaneous proteins to form a complete antigen, to which a T-cell–mediated immunologic response is directed. Such reactions occur in only a small number of patients exposed to the drug and light. The sensitization period may be days or months. The concentration of drug required to elicit the reaction can be very small, and there is cross-reactivity with immunochemically related substances. Flare-ups may occur at lightly covered or unexposed areas and at distant, previously exposed sites. The reaction may recur over a period of days or months 704
after light exposure, even without further drug administration. As a rule, longer ultraviolet light waves are involved, and window glass does not protect against a reaction. The photoallergic reaction may be detected by a positive photopatch test, which involves application of the suspected drug as an ordinary patch test for 24 hours, followed by exposure to a light source. Drugs implicated include the sulfonamides (antibacterials, hypoglycemics, and diuretics), phenothiazines, NSAIDs, and griseofulvin (196). Purpuric Eruptions Purpuric eruptions may occur as the sole expression of drug allergy, or they may be associated with other severe eruptions, notably erythema multiforme. Purpura caused by drug hypersensitivity may be due to thrombocytopenia. TABLE 17A.10 PHOTOSENSITIVITY
DIFFERENTIAL
FEATURES
OF
FEATURE
PHOTOTOXIC
PHOTOALLERGIC
Incidence
Common
Uncommon
Clinical picture
Sunburn-like
Eczematous
Reaction possible with first drug exposure
Yes
Requires sensitization period of days to months
Onset
4–8 h after exposure
12–24 h after exposure once sensitized
Chemical alteration of drug
No
Yes
Ultraviolet range
2,800–3,100 nm 3,200–4,500 nm
Drug dosages
Dose related
Dose independent once sensitized
Immunologic mechanism
None
T-cell mediated
Flares at distant previously
No
May occur
705
involved sites Recurrence from exposure to ultraviolet light alone
No
May occur in persistent eruptions
Simple, nonthrombocytopenic purpura has been described with sulfonamides, barbiturates, gold salts, carbromal, iodides, antihistamines, and meprobamate. Phenylbutazone has produced both thrombocytopenic and nonthrombocytopenic purpuras. The typical eruption is symmetric and appears around the feet and ankles or on the lower part of the legs, with subsequent spread upward. The face and neck are usually not involved. The eruption is composed of small, welldefined macules or patches of a reddish brown color. The lesions do not blanch on pressure and often are quite pruritic. With time, the dermatitis turns brown or grayish brown, and pigmentation may persist for a relatively long period. The mechanism of simple purpura is unknown. A very severe purpuric eruption, often associated with hemorrhagic infection and necrosis with large sloughs, has been associated with coumarin anticoagulants. Although originally thought to be an immune-mediated process, it is now believed to be the result of an imbalance between procoagulant and fibrinolytic factors (197,198). Toxic Epidermal Necrolysis TEN (Lyell syndrome) induced by drugs is a rare, fulminating, potentially lethal syndrome characterized by the sudden onset of widespread blistering of the skin, extensive epidermal necrosis, and exfoliation of the skin involving more than 30% of the TBSA. Overlap syndrome (199) is the term used for a 10% to 30% loss associated with severe constitutional symptoms. It has been suggested that TEN may represent the extreme manifestation of EM major, but this position has been contested by others who cite the explosive onset of widespread blistering, the absence of target lesions, the peridermal necrosis without dermal infiltrates, and the paucity of immunologic deposits in the skin in TEN (200). However, it has generally been assumed that TEN is an immunologically mediated disease because of its association with graft-versus-host disease, reports of immunoreactants in the skin, drug-dependent antiepidermal antibodies in some cases, and altered lymphocyte subsets in peripheral blood and the inflammatory infiltrate (200). An increased expression of HLA-B12 has been reported in TEN cases (56), and in a Han Chinese population, a very strong 706
association has been shown with HLA-B*5801 and SJS and TEN to allopurinol (58). High concentrations of soluble Fas ligand have been found in the sera of patients with TEN (201). Recent evidence suggests that Fas–FasL interaction on keratinocytes is responsible for apoptosis seen in TEN. Conserved levels of Fas are found on keratinocytes along with increased levels of bound FasL in lesional skin of patients with TEN. FasL on keratinocytes had been shown to be cytolytic in TEN and can be blocked with antibodies that interfere with Fas–FasL binding (201–203). TEN usually affects adults and is not to be confused with the staphylococcal scalded skin syndrome seen in children. The latter is characterized by a staphylococcal elaborated epidermolytic toxin, a cleavage plane high in the epidermis, and response to appropriate antimicrobial therapy. Features of TEN include keratinocyte necrosis and cleavage at the basal layer with loss of the entire epidermis (204). In addition, the mucosa of the respiratory and gastrointestinal tracts may be affected. These patients are seriously ill with high fever, asthenia, skin pain, and anxiety. Marked skin erythema progresses over 1 to 3 days to the formation of huge bullae, which peel off in sheets, leaving painful denuded areas. Detachment of more than 30% of the epidermis is expected, whereas detachment of less than 10% is compatible with SJS (199), and 10% to 30% is considered overlap syndrome. A positive Nikolsky sign (i.e., dislodgment of the epidermis by lateral pressure) is present on erythematous areas. Mucosal lesions, including painful erosions and crusting, may be present on any surface. The complications of TEN and extensive thermal burns are similar. Unlike SJS, high-dose corticosteroids are of no benefit (191,192). Mortality may be reduced from an overall rate of 50% to less than 30% by early transfer to a burn center (205). Intravenous immunoglobulin (IVIG) contains antibodies to Fas and is therefore able to block Fas–FasL interaction (201). To date, most case reports of using IVIG in the treatment of TEN suggest that it may be beneficial clinically (206,207), particularly when used in doses greater than 2 g/kg (208). The drugs most frequently implicated in TEN include sulfonamides (20% to 28%; especially TMP–SMX), allopurinol (6% to 20%), barbiturates (6%), carbamazepine (5%), phenytoin (18%), and NSAIDs (especially oxyphenbutazone, 18%; piroxicam, isoxicam, and phenylbutazone, 8% each) (209,210). Erythema Nodosum Erythema nodosum–like lesions are usually bilateral, symmetric, ill-defined, warm, and tender subcutaneous nodules involving the anterior aspects (shins) of the legs. The lesions are usually red or sometimes resemble a hematoma and may 707
persist for a few days to several weeks. They do not ulcerate or suppurate, and usually resemble contusions as they involute. Mild constitutional symptoms of low-grade fever, malaise, myalgia, and arthralgia may be present. The lesions occur in association with streptococcal infections, tuberculosis, leprosy, deep fungal infections, cat scratch fever, lymphogranuloma venereum, sarcoidosis, ulcerative colitis, and other illnesses. There is some disagreement as to whether drugs may cause erythema nodosum. Because the etiology of this disorder is unclear, its occurrence simultaneously with drug administration may be more coincidental than causative. Drugs most commonly implicated include sulfonamides, bromides, and oral contraceptives. Several other drugs, such as penicillin, barbiturates, and salicylates, are often suspected but seldom proved as causes of erythema nodosum. Treatment with corticosteroids is effective but is seldom necessary after withdrawal of the offending drug. Pulmonary Manifestations Bronchial Asthma Pharmacologic agents are a common cause of acute exacerbations of asthma, which, on occasion, may be severe or even fatal. Drug-induced bronchospasm most often occurs in patients with known asthma but may unmask subclinical reactive airways disease. It may occur as a result of inhalation, ingestion, or parenteral administration of a drug. Although asthma may occur in drug-induced anaphylaxis or anaphylactoid reactions, bronchospasm is usually not a prominent feature; laryngeal edema is far more common, as is shock (81). Airborne exposure to drugs during manufacture or during final preparation in the hospital or at home has resulted in asthma. Parents of children with cystic fibrosis have developed asthma following inhalation of pancreatic extract powder in the process of preparing their children’s meals (211). Occupational exposure to some of these agents has caused asthma in nurses, for example, psyllium in bulk laxatives (212), and in pharmaceutic workers following exposure to various antibiotics (213). Spiramycin used in animal feeds has resulted in asthma among farmers, pet shop owners, and laboratory animal workers who inhale dusts from these products. NSAIDs account for more than two-thirds of drug-induced asthmatic reactions, with aspirin being responsible for more than half of these (214). Both oral and ophthalmic preparations that block β-adrenergic receptors may induce bronchospasm among individuals with asthma or subclinical bronchial 708
hyperreactivity. This may occur immediately after initiation of treatment, or rarely after several months or years of therapy. Metoprolol, atenolol, and labetalol are less likely to cause bronchospasm than are propranolol, nadolol, and timolol (215). Timolol has been associated with fatal bronchospasm in patients using this ophthalmic preparation for glaucoma. Occasional subjects without asthma have developed bronchoconstriction after treatment with β-blocking drugs (216). One should also recall that β-blockers may increase the occurrence and magnitude of immediate generalized reactions to other agents (75), make resuscitation with epinephrine more difficult, and lead to larger volume loss. Cholinesterase inhibitors, such as echothiophate ophthalmic solution used to treat glaucoma, and neostigmine or pyridostigmine used for myasthenia gravis, have produced bronchospasm. For obvious reasons, methacholine is no longer used in the treatment of glaucoma. Although ACE inhibitors have been reported to cause acute bronchospasm or aggravate chronic asthma (217), a harsh, at times disabling, cough is a more likely side effect that may be confused with asthma. This occurs in 10% to 25% of patients taking these drugs, usually within the first 8 weeks of treatment, although it may develop within days or may not appear for up to 1 year (218). Switching from one agent to another is of no benefit. The cough typically resolves within 1 to 2 weeks after discontinuing the medication; persistence longer than 4 weeks should trigger a more comprehensive diagnostic evaluation. The mechanism of ACE inhibitor–induced cough is unclear. Cough may be avoided with the use of an ARB (219,220). As stated previously, ACE inhibitors may cause angioedema and may be a source of cough and dyspnea (221). Sulfites and metabisulfites can provoke bronchospasm in a subset of asthmatic patients. The incidence is probably low but may be higher among those who are steroid dependent (222). These agents are used as preservatives to reduce microbial spoilage of foods, as inhibitors of enzymatic and nonenzymatic discoloration of foods, and as antioxidants that are often found in bronchodilator solutions. The mechanism responsible for sulfite-induced asthmatic reactions may be the result of the generation of sulfur dioxide from stomach acid, which is then inhaled. However, sulfite-sensitive asthmatic patients are not more sensitive to inhaled sulfur dioxide than are other asthmatic patients (223). The diagnosis of sulfite sensitivity may be established on the basis of sulfite challenge. There is no cross-reactivity between sulfites and aspirin (224). Bronchospasm in these patients may be treated with metered-dose inhalers or nebulized bronchodilator solutions containing negligible amounts of metabisulfites. Although epinephrine 709
contains sulfites, its use in an emergency situation even among sulfite-sensitive asthmatic patients should not be discouraged (223). Pulmonary Infiltrates with Eosinophilia An immunologic mechanism is probably operative in two forms of drug-induced acute lung injury, namely, hypersensitivity pneumonitis and pulmonary infiltrates associated with peripheral eosinophilia. Peripheral eosinophilia syndrome has been associated with the use of a number of drugs, including sulfonamides, penicillin, NSAIDs, methotrexate, carbamazepine, nitrofurantoin, phenytoin, cromolyn sodium, imipramine, and L-tryptophan (163). Although a nonproductive cough is the main symptom, headache, malaise, fever, nasal symptoms, dyspnea, and chest discomfort may occur. The chest radiograph may show diffuse or migratory focal infiltrates. Peripheral blood eosinophilia is usually present. Pulmonary function testing reveals restriction with decreased carbon dioxide diffusing capacity. A lung biopsy demonstrates interstitial and alveolar inflammation consisting of eosinophils and mononuclear cells. The outcome is usually excellent, with rapid clinical improvement on drug cessation and corticosteroid therapy. Usually, the patient’s pulmonary function is restored with little residual damage. Nitrofurantoin may also induce an acute syndrome, in which peripheral eosinophilia is present in about one-third of patients. However, this reaction differs from the drug-induced pulmonary infiltrates with peripheral eosinophilia syndrome just described because tissue eosinophilia is not present, and the clinical picture frequently includes the presence of a pleural effusion (225). Adverse pulmonary reactions occur in less than 1% of those taking the drug. Typically, the onset of the acute pulmonary reaction begins a few hours to 7 to 10 days after commencement of treatment. Typical symptoms include fever, dry cough, dyspnea (occasional wheezing), and, less commonly, pleuritic chest pain. A chest radiograph may show diffuse or unilateral involvement, with an alveolar or interstitial process that tends to involve lung bases. A small pleural effusion, usually unilateral, is seen in about one-third of patients. With the exception of DIL, nitrofurantoin is one of the only drugs producing an acute drug-induced pleural effusion. Knowledge of this reaction can prevent unnecessary hospitalization for suspected pneumonia. Acute reactions have a mortality rate of less than 1%. On withdrawal of the drug, resolution of the chest radiograph findings occurs within 24 to 48 hours. Although the acute nitrofurantoin-induced pulmonary reaction is rarely fatal, a chronic reaction that is uncommon has a higher mortality rate of 8%. Cough 710
and dyspnea develop insidiously after 1 month or often longer of treatment. The chronic reaction mimics idiopathic pulmonary fibrosis clinically, radiologically, and histologically. Although somewhat controversial, if no improvement occurs after the drug has been withdrawn for 6 weeks, prednisone, 40 mg/day, should be given and continued for 3 to 6 months (225,226). Of the cytotoxic chemotherapeutic agents, methotrexate is the most common cause of a noncytotoxic pulmonary reaction in which peripheral blood, but not tissue, eosinophilia may be present (227). In recent years, this drug has also been used to treat nonmalignant conditions, such as psoriasis, rheumatoid arthritis, and asthma. Symptoms usually begin within 6 weeks after initiation of treatment. Fever, malaise, headache, and chills may overshadow the presence of a nonproductive cough and dyspnea. Eosinophilia is present in 40% of cases. The chest radiograph demonstrates a diffuse interstitial process, and 10% to 15% of patients develop hilar adenopathy or pleural effusions. Recovery is usually prompt on withdrawal of methotrexate, but fatalities can occur. The addition of corticosteroid therapy may hasten recovery time. Although an immunologic mechanism has been suggested, some patients who have recovered may be able to resume methotrexate without adverse sequelae. Bleomycin and procarbazine, chemotherapeutic agents usually associated with cytotoxic pulmonary reactions, have occasionally produced a reaction similar to that of methotrexate. Pneumonitis and Fibrosis Slowly progressive pneumonitis or fibrosis is usually associated with cytotoxic chemotherapeutic drugs, such as bleomycin. However, some drugs, such as amiodarone, may produce a clinical picture similar to hypersensitivity pneumonitis without the presence of eosinophilia. In many cases, this category of drug-induced lung disease is often dose dependent. Amiodarone, an important therapeutic agent in the treatment of many lifethreatening arrhythmias, has produced an adverse pulmonary reaction in about 6% of patients, with 5% to 10% of these reactions being fatal (228). Symptoms rarely develop in a patient receiving less than 400 mg/day for less than 2 months. The clinical presentation is usually subacute with initial symptoms of nonproductive cough, dyspnea, and occasionally low-grade fever. The chest radiograph reveals an interstitial or alveolar process. Pulmonary function studies demonstrate a restrictive pattern with a diffusion defect. The sedimentation rate is elevated, but there is no eosinophilia. Histologic findings include the intraalveolar accumulation of foamy macrophages, alveolar septal thickening, and occasional diffuse alveolar damage (229). Amiodarone has the unique ability to 711
stimulate the accumulation of phospholipids in many cells, including type II pneumocytes and alveolar macrophages. It is unclear whether these changes cause interstitial pneumonitis, because these findings are seen in most patients receiving this drug without any adverse pulmonary reactions. Although an immunologic mechanism has been suggested, the role of hypersensitivity in amiodarone-induced pneumonitis remains speculative (230). Most patients recover completely after cessation of therapy, although the addition of corticosteroids may be required. Further, when the drug is absolutely required to control a potentially fatal cardiac arrhythmia, patients may be able to continue treatment at the lowest dose possible when corticosteroids are given concomitantly (231). Gold-induced pneumonitis is subacute in onset, occurring after a mean duration of therapy of 15 weeks and a mean cumulative dose of 582 mg (232). Exertional dyspnea is the predominant symptom, although a nonproductive cough and fever may be present. Radiographic findings include interstitial or alveolar infiltrates, whereas pulmonary function testing reveals findings compatible with a restrictive lung disorder. Peripheral blood eosinophilia is rare. Intense lymphocytosis is the most common finding in bronchoalveolar lavage. The condition is usually reversible after discontinuation of the gold injections, but corticosteroids may be required to reverse the process. Although this pulmonary reaction is rare, it must not be confused with rheumatoid lung disease. Drug-induced chronic fibrotic reactions are probably nonimmunologic in nature, but their exact mechanism is unknown. Cytotoxic chemotherapeutic agents (azathioprine, bleomycin sulfate, busulfan, chlorambucil, cyclophosphamide, hydroxyurea, melphalan, mitomycin, nitrosoureas, and procarbazine hydrochloride) may induce pulmonary disease that is manifested clinically by the development of fever, nonproductive cough, and progressive dyspnea of gradual onset after treatment for 2 to 6 months or, rarely, years (233). It is essential to recognize this complication because such reactions may be fatal and could mimic other diseases, such as opportunistic infections. The chest radiograph reveals an interstitial or intra-alveolar pattern, especially at the lung bases. A decline in carbon monoxide diffusing capacity may even precede chest radiograph changes. Frequent early etiologic findings include damage to type I pneumocytes, which are the major alveolar lining cells, and atypia and proliferation of type II pneumocytes. Mononuclear cell infiltration of the interstitium may be seen early, followed by interstitial and alveolar fibrosis, which may progress to honeycombing. The prognosis is often poor, and the 712
response to corticosteroids is variable. Even those who respond to treatment may be left with clinically significant pulmonary function abnormalities. Although an immunologic mechanism has been suspected in some cases (234), it is now generally believed that these drugs induce the formation of toxic oxygen radicals that produce lung injury. Noncardiogenic Pulmonary Edema Another acute pulmonary reaction without eosinophilia is drug-induced noncardiogenic pulmonary edema. This develops very rapidly and may even begin with the first dose of the drug. The chest radiograph is similar to that caused by congestive heart failure. Hydrochlorothiazide is the only thiazide associated with this reaction (234). Most of the drugs associated with this reaction are illegal, including cocaine, heroin, and methadone (235,236). Salicylate-induced noncardiogenic pulmonary edema may occur when the blood salicylate level is over 40 mg/dL (237). In most cases, the reaction resolves rapidly after the drug is stopped. However, some cases may follow the clinical course of acute respiratory distress syndrome, notably with chemotherapeutic agents, such as mitomycin C or cytosine arabinoside (238), and rarely 2 hours after administration of RCM (239). The mechanism is unknown. Hematologic Manifestations Many instances of drug-induced thrombocytopenia and hemolytic anemia have been unequivocally shown by in vitro methods to be mediated by immunologic mechanisms. There is less certainty regarding drug-induced agranulocytosis. These reactions usually appear alone, without other organ involvement. The onset is usually abrupt, and recovery is expected within 1 to 2 weeks after drug withdrawal. Eosinophilia Eosinophilia may be present as the sole manifestation of drug hypersensitivity (240). More commonly, it is associated with other manifestations of drug allergy. Its recognition is useful because it may give early warning of hypersensitivity reactions that could produce permanent tissue damage or even death. However, most would agree that eosinophilia alone is not sufficient reason to discontinue treatment. In fact, some drugs, such as digitalis, may regularly produce eosinophilia, yet hypersensitivity reactions to this drug are rare. Drugs that may be associated with eosinophilia in the absence of clinical disease include gold salts, allopurinol, aminosalicylic acid, ampicillin, tricyclic antidepressants, capreomycin sulfate, carbamazepine, digitalis, phenytoin, 713
sulfonamides, vancomycin, and streptomycin. There does not appear to be a common chemical or pharmacologic feature of these agents to account for the development of eosinophilia. Although the incidence of eosinophilia is probably less than 0.1% for most drugs, gold salts have been associated with marked eosinophilia in up to 47% of patients with rheumatoid arthritis and may be an early sign of an adverse reaction (241). Drug-induced eosinophilia does not appear to progress to a chronic eosinophilia or hypereosinophilic syndrome. However, in the face of a rising eosinophil count, discontinuing the drug may prevent further problems. Thrombocytopenia Thrombocytopenia is a well-recognized complication of drug therapy. The usual clinical manifestations are widespread petechiae and ecchymoses and occasionally gastrointestinal bleeding, hemoptysis, hematuria, and vaginal bleeding. Fortunately, intracranial hemorrhage is rare. On occasion, there may be associated fever, chills, and arthralgia. Bone marrow examination shows normal or increased numbers of normal-appearing megakaryocytes. With the exception of gold-induced immune thrombocytopenia, which may continue for months because of the persistence of the antigen in the reticuloendothelial system, prompt recovery within 2 weeks is expected on withdrawal of the drug (242). Fatalities are relatively infrequent. Readministration of the drug, even in minute doses, may produce an abrupt recrudescence of severe thrombocytopenia, often within a few hours. Although many drugs have been reported to cause immune thrombocytopenia, the most common offenders in clinical practice today are quinidine, the sulfonamides (antibacterials, sulfonylureas, and thiazide diuretics), gold salts, and heparin. The mechanism of drug-induced immune thrombocytopenia is thought to be the “innocent bystander” type. Shulman suggested the formation of an immunogenic drug–plasma protein complex to which antibodies are formed; this antibody–drug complex then reacts with the platelet (the innocent bystander), thereby initiating complement activation with subsequent platelet destruction (243). Some studies indicate that quinidine antibodies react with a platelet membrane glycoprotein in association with the drug (244). Patients with HLADR3 appear to be at increased risk for gold-induced thrombocytopenia. Because heparin has had more widespread clinical use, the incidence of heparin-induced thrombocytopenia is about 5% (245). Some of these patients simultaneously develop acute thromboembolic complications. A heparin714
dependent IgG antibody has been demonstrated in the serum of these patients. A low-molecular-weight heparinoid can be substituted for heparin in patients who previously developed heparin-induced thrombocytopenia (246). The diagnosis is often presumptive because the platelet count usually returns to normal within 2 weeks (longer if the drug is slowly excreted) after the drug is discontinued. Many in vitro tests are available at some centers to demonstrate drug-related platelet antibodies. A test dose of the offending drug is probably the most reliable means of diagnosis, but this involves significant risk and is seldom justified. Treatment involves stopping the suspected drug and observing the patient carefully over the next few weeks. Corticosteroids do not shorten the duration of thrombocytopenia but may hasten recovery because of their capillary protective effect. Platelet transfusions should not be given because transfused platelets are destroyed rapidly and may produce additional symptoms. Hemolytic Anemia Drug-induced immune hemolytic anemia may develop through three mechanisms: (1) immune complex type, (2) hapten or drug adsorption type, and (3) autoimmune induction (108). Another mechanism involves nonimmunologic adsorption of protein to the red blood cell membrane, which results in a positive Coombs test but seldom causes a hemolytic anemia. Hemolytic anemia after drug administration accounts for about 16% to 18% of acquired hemolytic anemias. The immune complex mechanism accounts for most cases of drug-induced immune hemolysis. The antidrug antibody binds to a complex of drug and a specific blood group antigen, for example, Kidd, Kell, Rh, or Ii, on the red blood cell membrane (247). Drugs implicated include quinidine, chlorpropamide, nitrofurantoin, probenecid, rifampin, and streptomycin. Of note is that many of these drugs have also been associated with immune complex–mediated thrombocytopenia. The serum antidrug antibody is often IgM, and the direct Coombs test is usually positive. Penicillin is the prototype of a drug that induces a hemolytic anemia by the hapten or drug absorption mechanism (248). Penicillin normally binds to proteins on the red blood cell membrane, and among patients who develop antibodies to the drug hapten on the red blood cell, a hemolytic anemia may occur. In sharp contrast to immune complex–mediated hemolysis, penicillininduced hemolytic anemia occurs only with large doses of penicillin, at least 10 million units daily IV. Anemia usually develops after 1 week of therapy, more rapidly in patients with preexisting penicillin antibodies. The antidrug antibody 715
is IgG, and the red blood cells are removed by splenic sequestration independent of complement. About 3% of patients receiving high-dose penicillin therapy develop positive Coombs test results, but only some of these patients actually develop hemolytic anemia. The anemia usually abates promptly, but mild hemolysis may persist for several weeks. Other drugs occasionally associated with hemolysis by this mechanism include cisplatin and tetracycline. Methyldopa is the most common cause of an autoimmune drug-induced hemolysis. A positive Coombs test develops in 11% to 36% of patients, depending on drug dosage, after 3 to 6 months of treatment (249). However, less than 1% of patients develop hemolytic anemia. The IgG autoantibody has specificity for antigens related to the Rh complex. The mechanism of autoantibody production is not clear. Hemolysis usually subsides within 1 to 2 weeks after the drug is stopped, but the Coombs test may remain positive for up to 2 years. These drug-induced antibodies will react with normal red blood cells. Because only a small number of patients actually develop hemolysis, a positive Coombs test alone is not sufficient reason to discontinue the medication. Several other drugs have induced autoimmune hemolytic disease, including levodopa, mefenamic acid, procainamide, and tolmetin. A small number of patients treated with cephalothin develop a positive Coombs test as a result of nonspecific adsorption of plasma proteins onto red blood cell membranes. This does not result in a hemolytic anemia but may provide confusion in blood bank serology. Finally, several other drugs have been associated with hemolytic disease, but the mechanism is unclear. Such agents include chlorpromazine, erythromycin, ibuprofen, isoniazid, mesantoin, paraaminosalicylic acid, phenacetin, thiazides, and triamterene. Agranulocytosis Most instances of drug-induced neutropenia are due to bone marrow suppression, but they can also be mediated by immunologic mechanisms (250). The process usually develops 6 to 10 days after initial drug therapy; readministration of the drug after recovery may result in a hyperacute fall in granulocytes within 24 to 48 hours. Patients frequently develop high fever, chills, arthralgias, and severe prostration. The granulocytes disappear within a matter of hours, and this may persist 5 to 10 days after the offending drug is stopped. The role of drug-induced leukoagglutinins in producing the neutropenia has been questioned because such antibodies have also been found in patients who are not neutropenic. The exact immunologic mechanism by which some drugs induce neutropenia is unknown (251). Although many drugs have been 716
occasionally incriminated, sulfonamides, sulfasalazine, propylthiouracil, quinidine, procainamide, phenytoin, phenothiazines, semisynthetic penicillins, cephalosporins, and gold salts are more commonly reported offenders. After withdrawal of the offending agent, recovery is usual within 1 to 2 weeks, although it may require many weeks or months. Treatment includes the use of antibiotics and other supportive measures. The value of leukocyte transfusions is unclear. Hematopoietic growth factors appear to be of value (252). Hepatic Manifestations The liver is especially vulnerable to drug-induced injury because high concentrations of drugs are presented to it after ingestion and also because it plays a prominent role in the biotransformation of drugs to potentially toxic reactive metabolites. These reactive metabolites may induce tissue injury through inherent toxicity, or possibly on an immunologic basis (253). Druginduced hepatic injury may mimic any form of acute or chronic hepatobiliary disease; however, these hepatic reactions are more commonly associated with acute injury. Some estimates of the frequency of liver injury due to drugs are as follows (254): • >2%: Aminosalicylic acid, troleandomycin, dapsone, and chenodeoxycholate • 1% to 2%: Lovastatin, cyclosporine, and dantrolene • 1%: Isoniazid and amiodarone • 0.5% to 1%: Phenytoin, sulfonamides, and chlorpromazine • 0.1% to 0.5%: Gold salts, salicylates, methyldopa, chlorpropamide, and erythromycin estolate • 95%), if good quality food extracts are utilized (136–140). There are exceptions to this general statement: (a) the commercial extracts commonly used in testing can potentially lack the relevant allergen especially with less common allergens (141) or have the allergen but in a nonintact form owing to the lability of the responsible allergen (111); (b) children less than 2 years of age may have less skin reactivity, resulting in a negative or small wheal size despite a strong histories suggestive of IgE-mediated food allergy (142). As a positive skin test only demonstrates the presence of allergen-specific IgE but not necessarily clinical allergy, investigators have been interested in determining predictive values based on mean wheal diameter. Recent studies have reported that for the diagnosis of cow’s milk, hen’s egg, and peanut allergy, skin-prick tests inducing mean wheal diameters >8 mm correlate with a >95% positive predictive value for clinical reactivity (143–145). Intradermal skin testing is more sensitive than the skin-prick test when detecting specific IgE but is much less specific when compared to the DBPCFC (136). No patients with a positive intradermal skin test to a food and a concomitant negative skin-prick test have been shown to have a positive DBPCFC. In addition to its poor predictive value, intradermal skin testing can significantly increase the risk of inducing a systemic reaction compared to skinprick testing and, therefore, is not recommended.
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Atopy Patch Test The atopy patch test (APT) is a means of testing for delayed-type hypersensitivity reactions and has been considered for the diagnosis of non–IgEmediated food allergy (146–149). In a recent study of children with atopic dermatitis, the investigators concluded that the patch test added little diagnostic benefit compared to standard diagnostic tests (150). Several studies looking at APT for the identification of food triggers in eosinophilic esophagitis have suggested a potential role (151–153); however, further study is needed before it can be recommended for regular use.
In Vitro Allergen-Specific Immunoglobin E Tests In vitro allergen-specific IgE tests (including radioallergosorbent test [RAST]; enzyme-linked immunosorbent assay; CAP System FEIA and UniCAP [Phadia; Uppsala, Sweden]; Magic Lite; ALK-Abello, Denmark) are utilized for measuring serum for IgE-mediated food allergies. Although generally considered slightly less sensitive than skin tests, one study comparing Phadebas RAST with DBPCFCs found skin-prick tests and RASTs to have similar sensitivity and specificity to food challenge outcome when a Phadebas score of 3 or greater was considered positive (137). In the past 10 years, the use of a quantitative measurement of food-specific IgE antibodies (CAP System FEIA or UniCAP) has been shown to be predictive of symptomatic IgE-mediated food allergy (154,155) (Table 18.5). Food-specific IgE levels exceeding the diagnostic values established as cutoff points indicate that the patient is greater than 95% likely to experience an allergic reaction if he or she ingests the specific food. In addition, the IgE levels can be monitored and if they fall to less than 2 kUA/L for eggs, milk, or peanuts, the patient should be rechallenged to determine whether he or she has “outgrown” their food allergy (155–157). The ability to measure IgE specific to individual allergens within certain foods has recently become commercially available and is referred to as component-resolved diagnostics (CRD). Studies have demonstrated predictive values for CRD in the diagnosis of certain food allergies, such as peanut and hen’s egg allergy (158,159). However, CRD has not been shown to perform better than currently available food extracts to be recommended for regular use (160). TABLE 18.5 FOOD-SPECIFIC IgE ANTIBODIES: DIAGNOSTIC UTILITY TO PREDICT A POSITIVE FOOD CHALLENGE
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Cow’s Milk
IgE ≥ 15:
95% PPV
IgE ≥ 5:
95% PPV (age < 2 y)
Egg
IgE ≥ 7:
95% PPV
IgE ≥ 2:
95% PPV (age < 2 y)
Peanut
IgE ≥ 14:
95% PPV
Tree Nuts
IgE ≥ 15:
95% PPV
Fish
IgE ≥ 20:
95% PPV
IgE, immunoglobin E; PPV, positive predictive value.
Oral Food Challenge The DBPCFC has been labeled the “gold standard” for the diagnosis of food allergies; it controls for the variability of chronic disorders like urticaria and other precipitating factors such as psychogenic (161). Many investigators have utilized DBPCFCs successfully in children and adults to examine a variety of
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food-related complaints (162–165). However, the time required to perform both a suspect food and placebo challenge, difficulty in many cases of finding an appropriate placebo, and the need for a third party to maintain blinding make DBPCFCs impractical for everyday clinical use. As a result, open or occasionally single-blind food challenges are much more commonly used in clinical settings with DBPCFCs mostly reserved for research studies. The selection of foods to be tested in DBPCFCs is based on patient history and usually skin test or in vitro specific IgE results. Prior to undertaking an OFC, several factors need to be taken into consideration. Suspect foods should be eliminated for 7 to 14 days prior to challenge, longer in some non–IgE-mediated gastrointestinal disorders. Antihistamines should be discontinued long enough to establish a normal histamine skin test, typically 2 to 3 days for first-generation H1 antihistamines and 5 to 7 days for second-generation H1 antihistamines. In some asthmatic patients, short bursts of corticosteroids may be necessary to insure adequate pulmonary reserve (forced expiratory volume in 1 second [FEV1] > 70% predicted) prior to the OFC. The food challenge is administered in the fasting state, starting with a dose unlikely to provoke symptoms (166). Many different dosing schedules have been suggested in the literature, but generally speaking, doses are gradually escalated and administered about every 15 minutes over a 90-minute period. A joint expert panel in 2012 consisting of American and European academic allergy societies sought to address the variation in protocols by releasing consensus guidelines referred to as PRACTALL (167). An OFC by PRACTALL guidelines includes the following doses: 3, 10, 30, 100, 300, 1,000, and 3,000 mg of food protein. Once the patient has tolerated all of the lyophilized food, clinical reactivity is generally ruled out. If a challenge is performed using a food in a form that is not typically eaten, a negative result should be confirmed by an open feeding of the food in a typically ingested form to rule out the possibility of a false-negative result because of alteration of the food allergen. The length of observation after an OFC is typically dependent on the type of reaction suspected, for example, generally up to 2 hours for IgE-mediated reactions, up to 4 to 8 hours for milk-induced enterocolitis, and 3 to 4 days for allergic eosinophilic gastroenteritis. Results of blinded challenges for objective signs and symptoms are rarely equivocal, but can be made more objective by monitoring a variety of laboratory parameters, such as plasma histamine, pulmonary function tests, and nasal airway resistance; serum β-tryptase is rarely shown to rise following food-allergic reactions (71,168). 886
In non–IgE-mediated food allergies (e.g., dietary protein–induced enterocolitis), allergen challenges may require up to 0.15 to 0.3 g of food/kg of body weight given in one or two doses (169,170). In other non–IgE-mediated disorders (e.g., allergic eosinophilic esophagitis or gastroenteritis), the patient may require several feedings over a 1- to 3-day period to elicit symptoms. In most IgE-mediated disorders, challenges to more foods often may be conducted every 1 to 2 days, whereas with non–IgE-mediated disorders, challenges to new foods often need to be at least 3 to 5 days apart. OFCs should be conducted in a clinic or hospital setting, especially if an IgEmediated reaction or a dietary protein-induced enterocolitis is suspected, and only when trained personnel and equipment for treating systemic anaphylaxis are immediately available (162,171). Patients with histories of life-threatening anaphylaxis should be challenged only when the causative antigen cannot be conclusively determined by history and laboratory testing, or the patient is believed to have “outgrown” his or her sensitivity. The evaluation of many socalled delayed reactions (e.g., most IgE-negative gastrointestinal allergies) can be conducted safely in a physician’s office, except perhaps for FPIES where intravenous access is generally required because of the risk of hypotension.
Practical Approach to Diagnosing Food Allergy The diagnosis of food allergy remains a clinical exercise primarily dependent on a careful history. For IgE-mediated and mixed immune food allergy, selective skin tests and in vitro measurement of food-specific IgE can then be used to confirm the diagnosis by establishing the presence of food-specific IgE (156). When the history is less clear or in the case of non–IgE-mediated food allergy, a targeted exclusion diet can help to determine whether an association between the food and the patient’s symptoms exists. Unfortunately, elimination diets are unable to prove causality and thus are not commonly diagnostic. Ultimately, an OFC, with its inherent risks, may be needed to make the diagnosis. At the present time, there are no controlled trials supporting the diagnostic value for food-specific IgG or IgG4 antibody levels, food antigen–antibody complexes, evidence of lymphocyte activation (3H uptake, IL-2 production, leukocyte inhibitory factor production), or sublingual or intracutaneous provocation.
TREATMENT Once the diagnosis of food allergy is established, the only proven therapy 887
continues to be strict elimination of the offending allergen. In the case of IgEmediated food allergy, avoidance is coupled with ready access to self-injectable epinephrine for the treatment of allergic reactions. Patients and their families must be educated about how to avoid accidental ingestion of food allergens and to recognize early symptoms of an allergic reaction, in particular those that may herald the onset of an anaphylactic reaction. Patients must learn to read all food ingredient labels for the presence of specific food allergens, to become familiar with situations where cross-contamination is likely, and to avoid high-risk situations, such as buffets, ice cream parlors, and unlabeled candies and desserts (172). Numerous label reading patient resources have been created, and the Food Allergen Labeling and Consumer Protection Act passed in 2004 has helped in the identification of food allergen ingredients; however, accidental ingestions and reactions have continued to occur (173). Patients with multiple food allergies, especially children, are at risk for nutritional deficiencies resulting from their restricted diets. If feasible, it is important to utilize the services of a nutritionist for education of the patient and family. Their help in managing the patient’s diet is extremely important to ensure that there is adequate nutritional intake while on a restricted diet. An emergency treatment plan indicating symptoms that require treatment with an oral antihistamine (preferably liquid diphenhydramine or cetirizine) or self-injectable epinephrine or both should be provided to the patient. Templates of anaphylaxis emergency treatment plans are readily available at patient advocacy and academic allergy society websites. The use of the epinephrine autoinjector should be demonstrated to the patient (and caregivers) and the technique reviewed periodically. At every physician encounter, patients should be reminded about the importance of having their emergency medications with them at all times and to check the expiration dates of their autoinjectors. Patients must also be instructed to seek evaluation at an emergency department or contact emergency services following the use of epinephrine, because there is an approximate 20% risk of recurrence of allergic symptoms following initial improvement with or without treatment (the so-called biphasic anaphylaxis). Case reports on the use of immunotherapy for food allergy have sporadically been in the medical literature (174,175), but over the past 10 years, the interest in food immunotherapy has grown significantly. Traditional subcutaneous immunotherapy was attempted for peanut allergy, and despite some suggestion of clinical improvement, the significant numbers of adverse events associated with dosing has discouraged further research into this modality (176,177). 888
Attention has instead primarily focused on orally ingested food treatment termed oral immunotherapy (OIT). Several open and blinded studies in cow’s milk, hen’s egg, and peanut allergy have demonstrated the ability of OIT to induce desensitization defined as an increase in the threshold of food required to induce a clinical reaction while on active therapy (178–181). Concurrent immunologic changes in these studies have suggested a modulation of the immune response and the potential for a lasting response. To date, it has not been proven that OIT can induce true immunologic tolerance; however, the desensitization effect may last for a prolonged but finite amount of time after discontinuation of the therapy, an effect called sustained unresponsiveness (179,182). Unfortunately, these promising results have been tempered by concerns about the risks of therapy; most importantly, the potential development of eosinophilic esophagitis (183). Alternative modalities of immunotherapy have more recently been investigated, including sublingual immunotherapy and epicutaneous immunotherapy. These modalities provide an easier method of administration and potentially an improved safety profile because of the lower doses typical of these therapies. Early studies have suggested the ability to induce desensitization, but the effect may be less robust than seen with OIT (184,185). Further research is needed to understand the magnitude and duration of the desensitization effect, the potential for tolerance, and, most importantly, the risk profile before any of these treatments can be recommended for clinical practice. Another approach that has been investigated for food allergy is the use of anti-IgE antibody therapy. Studies on the use of anti-IgE therapy as monotherapy for the treatment of peanut allergy were inconclusive. However, results on the use of anti-IgE therapy in combination with OIT have suggested improved safety and short-term efficacy over OIT alone (186,187). Ultimately, the treatment for food allergy may involve combinations of available therapies potentially tailored to the individual patient.
PREVENTION The role of dietary manipulation in the prevention of atopic disease in infants of allergic parents has been debated for many years (188). Delayed introduction of highly allergenic foods was recommended until recently as the safest approach that could also potentially prevent the development of allergy (189). Further consideration of these guidelines in 2008 concluded that there was insufficient evidence to support delayed introduction and led to the removal of these
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recommendations from general pediatric feeding guidelines (188). In direct contrast to these previous guidelines, an interesting epidemiologic study suggested that early, not delayed, introduction could provide a protective effect against the development of food allergy. Jewish children living in the United Kingdom and Israel were compared for their peanut introduction behaviors and subsequent rates of peanut allergy. Significantly higher rates of peanut allergy were found in the children living in the United Kingdom. Because the cohorts had similar genetic backgrounds, the primary difference between the groups was thought to be the routine introduction of peanut in early infancy in Israel compared to the delayed introduction common in the United Kingdom (190). The Learning Early About Peanut allergy study was designed to prospectively investigate this finding and demonstrated a significantly lower rate of peanut allergy in high-risk children who introduced peanut in early infancy and maintained routine peanut dosing up to 5 years of age (191). This protective effect was shown to persist even after discontinuing peanut dosing for 1 year (192). Although the generalizability of these results has been questioned by some, these groundbreaking results leave little justification for the delayed introduction of peanut and, on the contrary, support the early introduction of peanut and potentially other highly allergenic foods.
NATURAL HISTORY The vast majority of childhood food allergies are lost over time, although certain food allergies tend to persist, such as those to peanuts, tree nuts, fish, and shellfish (82,193–198). Of note, even after the development clinical tolerance, the presence of IgE, as detected by skin test or RAST, has been found to persist in IgE-mediated food allergy (199–201). For hen’s egg allergy, the majority of cases resolve within a few years (202,203); however, patients with an eggspecific IgE level greater than 50 kU/L seem less likely to develop egg tolerance (204). Cow’s milk allergy affects 2.5% of children younger than 2 years of age (205,206). The potential for persistence of cow’s milk allergy along with cow’s milk–specific IgE levels effect on prognosis should be taken into consideration when counseling families regarding expected clinical outcomes (207). Non–IgEmediated cow’s milk allergy is typically a transient childhood condition that is almost always outgrown but must be managed carefully because challenges can be hazardous. IgE-mediated cow’s milk allergy may persist in up to 20% of 890
children. It has been thought that in children with cow’s milk or hen’s egg IgEmediated sensitivity, those who became tolerant had antibodies to conformational epitopes, whereas those with persistent hypersensitivity reacted primarily to linear epitopes (37). Peanut and tree nut allergies affect about 0.5% to 1.3% of children and may be increasing over time (48,197,208). It is likely to be a lifelong disorder for most patients, although 20% to 25% outgrow peanut (197,209–211) and up to 9% outgrow tree nut allergies (193). A peanut-specific IgE of 2 kU/L has been shown to correlate with a 50% chance of passing an OFC (156,197), and thus IgE levels 90% of peanut-allergic individuals) and Ara h 2 are linear (212,213) and may explain the persistence of peanut allergy. A food allergy rarely recurs once it has resolved; however, recurrence has been documented in unusual cases with peanut and tree nut (214).
SUMMARY Food allergy is a common medical problem seen particularly early in life. Many of the common food allergies are outgrown in the first few years of life. Ingestion of foods in an allergic individual can quickly provoke cutaneous, respiratory, and gastrointestinal symptoms, and in a subset of patients, anaphylaxis can occur. Recent research has continued to characterize the various food hypersensitivity disorders, but our understanding of the basic immunopathologic mechanisms remains incomplete. Recent research has suggested that food allergy may possibly be prevented with dietary therapy. For those who go on to develop food allergy, the future seems bright because new forms of therapy continue to be studied and approved treatments seem to be on the horizon. references 1. Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAIDsponsored expert panel. J Allergy Clin Immunol. 2010;126(6 Suppl):S1– S58. 2. U.S. Census Bureau. State and County QuickFacts. 2010. quickfacts.census.gov/qfd/states/00000.html. Accessed October 1, 2016. 3. Steinke M, Fiocchi A, Kirchlechner V, et al. Perceived food allergy in 891
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188. Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. 2008;121(1):183–191. 189. American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics. 2000;106(2 Pt 1):346–349. 190. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008;122(5):984–991. 191. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372(9):803–813. 192. Du Toit G, Sayre PH, Roberts G, et al. Effect of avoidance on peanut allergy after early peanut consumption. N Engl J Med. 2016;374(15):1435– 1443. 193. Fleischer DM, Conover-Walker MK, Matsui EC, et al. The natural history of tree nut allergy. J Allergy Clin Immunol. 2005;116(5):1087–1093. 194. Sampson HA, Scanlon SM. Natural history of food hypersensitivity in children with atopic dermatitis. J Pediatr. 1989;115(1):23–27. 195. Pastorello EA, Stocchi L, Pravettoni V, et al. Role of the elimination diet in adults with food allergy. J Allergy Clin Immunol. 1989;84(4 Pt 1):475– 483. 196. Hourihane JO, Roberts SA, Warner JO. Resolution of peanut allergy: casecontrol study. BMJ. 1998;316(7140):1271–1275. 197. Skolnick HS, Conover-Walker MK, Koerner CB, et al. The natural history of peanut allergy. J Allergy Clin Immunol. 2001;107(2):367–374. 198. Businco L, Benincori N, Cantani A, et al. Chronic diarrhea due to cow’s milk allergy. A 4- to 10-year follow-up study. Ann Allergy. 1985;55(6):844–847. 199. Bock SA. The natural history of adverse reactions to foods. N Engl Reg Allergy Proc. 1986;7(6):504–510. 200. Bock SA. Natural history of severe reactions to foods in young children. J Pediatr. 1985;107(5):676–680. 907
201. Hill DJ, Firer MA, Ball G, et al. Natural history of cows’ milk allergy in children: immunological outcome over 2 years. Clin Exp Allergy. 1993;23(2):124–131. 202. Eggesbo M, Botten G, Halvorsen R, et al. The prevalence of allergy to egg: a population-based study in young children. Allergy. 2001;56(5):403–411. 203. Ford RP, Taylor B. Natural history of egg hypersensitivity. Arch Dis Child. 1982;57(9):649–652. 204. Savage JH, Matsui EC, Skripak JM, et al. The natural history of egg allergy. J Allergy Clin Immunol. 2007;120(6):1413–1417. 205. Host A. Frequency of cow’s milk allergy in childhood. Ann Allergy Asthma Immunol. 2002;89(6 Suppl 1):33–7. 206. Host A, Halken S. A prospective study of cow milk allergy in Danish infants during the first 3 years of life. Clinical course in relation to clinical and immunological type of hypersensitivity reaction. Allergy. 1990;45(8):587–596. 207. Skripak JM, Matsui EC, Mudd K, et al. The natural history of IgEmediated cow’s milk allergy. J Allergy Clin Immunol. 2007;120(5):1172– 1177. 208. Sicherer SH, Munoz-Furlong A, Burks AW, et al. Prevalence of peanut and tree nut allergy in the US determined by a random digit dial telephone survey. J Allergy Clin Immunol. 1999;103(4):559–562. 209. Fleischer DM, Conover-Walker MK, Christie L, et al. The natural progression of peanut allergy: resolution and the possibility of recurrence. J Allergy Clin Immunol. 2003;112(1):183–189. 210. Bock SA, Atkins FM. The natural history of peanut allergy. J Allergy Clin Immunol. 1989;83(5):900–904. 211. Fleischer DM. The natural history of peanut and tree nut allergy. Curr Allergy Asthma Rep. 2007;7(3):175–181. 212. Burks AW, Shin D, Cockrell G, et al. Mapping and mutational analysis of the IgE-binding epitopes on Ara h 1, a legume vicilin protein and a major allergen in peanut hypersensitivity. Eur J Biochem. 1997;245(2):334–339. 213. Stanley JS, King N, Burks AW, et al. Identification and mutational analysis of the immunodominant IgE binding epitopes of the major peanut allergen Ara h 2. Arch Biochem Biophys. 1997;342(2):244–253. 908
214. Fleischer DM, Conover-Walker MK, Christie L, et al. Peanut allergy: recurrence and its management. J Allergy Clin Immunol. 2004;114(5):1195–1201.
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OVERVIEW Asthma is a disease characterized by hyperresponsiveness of bronchi to various stimuli, airways inflammation, and changes in airway resistance, lung volumes, and inspiratory and expiratory flow rates, resulting in symptoms of cough, wheezing, dyspnea, or shortness of breath. There are wide variations of resistance to airflow on expiration (and inspiration) with remarkable transient increases in certain lung volumes, such as residual volume (RV), functional residual capacity (FRC), and total lung capacity. In 1991, a National Institutes of Health (NIH) Expert Panel suggested that asthma was a disease characterized by (a) airway obstruction that is reversible—partially or completely, (b) airway inflammation, and (c) airway hyperresponsiveness (1). In 1997, the Expert Panel 2 Report described asthma as follows: Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with 910
widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. Reversibility of airflow limitation may be incomplete in some patients with asthma (2). The NIH Expert Panel 3 Report of 2007 confirmed this working definition (3). As of 2016, the Global Initiative for Asthma proposed the definition as follows: Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation (4). Asthma, which can be considered intermittent or persistent, has been described or characterized by other designations, including allergic bronchitis, asthmatic bronchitis, allergic asthma, atopic asthma, nonallergic asthma, reactive airways disease, cough equivalent asthma (5–7), and cardiac asthma (8–10). A central feature of asthma from a physiologic viewpoint is bronchial hyperresponsiveness to stimuli, such as histamine or methacholine. In population screening, such nonspecific hyperresponsiveness has been reported as sensitive but not specific. However, caution is required in that in a study of 150 adolescents nearly 18 years of age who were transferred from pediatric to adult care, 29% of those patients with a diagnosis of asthma did not have bronchial hyperresponsiveness (11). Asthma is considered, for most patients, a reversible obstructive airway disease as compared with chronic obstructive pulmonary disease (COPD). Many patients with asthma experience symptom-free periods of days, weeks, months, or years in between episodes, whereas chronic symptoms and fixed dyspnea characterize COPD. When daily symptoms of cough, wheezing, and dyspnea have been present for months in a patient with asthma, bronchodilator nonresponsiveness may be present. However, effective anti-inflammatory therapy, such as with a course of prednisone and/or inhaled corticosteroid (ICS)/long-acting β-adrenergic agonist with or without a leukotriene receptor antagonist or biosynthesis inhibitor or muscarinic antagonist, reduces symptoms and improves the quality of life along with improvement in pulmonary function status. Asthma–COPD overlap syndrome can be suspected when there is a history of asthma and cigarette smoking, and strong bronchodilator response to 911
albuterol (for forced expiratory volume in 1 second [FEV1] ≥ 15% and ≥400 mL) with evidence of obstruction (FEV1/forced vital capacity [FVC] < 0.70) (12). Immunoglobulin E (IgE)-mediated bronchoconstriction can be demonstrated in many patients with asthma, but not all cases of asthma are “allergic.” It is thought that about 80% of patients with persistent asthma have allergic asthma. In the Inner-City Asthma Study of children aged 5 to 11 years, 94% of children reacted to at least one allergen (13). Some evidence does exist for IgE antibodies to respiratory syncytial virus (RSV) (14) and parainfluenza virus (15); however, not all studies are consistent with this mechanistic explanation of antiviral IgEmediated asthma. Alternatively, RSV infection supports TH2 polarization of the immune response with reduced antiviral interferon-γ (IFNγ) production, and rhinovirus infection causes increased interleukin 33 (IL-33) production, the latter supporting TH2 inflammation (16). There is reduced generation of antiviral IFNs when there is activation of the high-affinity receptor for IgE (Fcε RI) by allergen in plasmacytoid dendritic cells (17). In other words, allergen IgE activation of Fcε RI can decrease the innate immunity system’s generation of antiviral IFNs. A clinical analogy of this observation is from a study where omalizumab was administered for 4 months to prevent seasonal exacerbations of asthma. Good responders to omalizumab were characterized by robust increases in in vitro IFNα from peripheral blood mononuclear cells during rhinovirus exposure (18). Furthermore, rhinovirus can increase activity of basophils (19). The heritability (fraction of asthma that can be attributed to genetics aka genetic susceptibility) is 0.54 based on 71 studies of twins (20). Further, there is evidence that heritability of asthma is increasing over time (21,22). In monozygotic twins, there is a stronger correlation between the age of onset of asthma in the first twin with onset in the second (less waiting time) as compared with the sequence in dizygotic twins. There is a greater degree of concordance of severity of asthma in monozygotic compared to dizygotic twins (21). The sudden onset of wheezing dyspnea that occurs within 3 hours of ingestion of aspirin or other nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) (23) is not an IgE-mediated reaction but represents alterations of arachidonic acid metabolism, such as blockage of the cyclooxygenase pathway with shunting of arachidonic acid into the lipoxygenase pathway. Potent lipoxygenase pathway products, such as leukotriene D4 (LTD4), cause acute bronchoconstriction in aspirin- and NSAID–sensitive patients (23–26). Patients with aspirinexacerbated respiratory disease have a “knock-in” condition in that there is 912
increased LTC4 synthase in bronchial and nasal mucosa and elevated urinary concentrations of LTE4, a metabolite of LTD4, even at baseline (23,26). The concentrations of LTE4 rise significantly after ingestion of aspirin or an NSAID in susceptible patients (23,25). Many patients with asthma may have symptoms precipitated by nonspecific, non–IgE-mediated triggers, such as cold air, air pollutants including ozone (27), fine particles ( 18 years, 8.7%) and White non-Hispanic (ages < 18 years, 7.6%; age > 18 years, 7.6%) (95). By socioeconomic status, the prevalence of 920
current asthma is 10.4% if the family is below 100% of the federal poverty level compared with 6.3% if family income is at least 450% of the same level. There is a disportionate rate of hospital discharges for asthma (based on 2010 data) in that for Whites, the rate was 8.7 of 10,000 persons compared with 29.9 of 10,000 in Blacks (95). The rate for hospitalizations for asthma based on the population had remained unchanged during the period from 1980 to 2004 (96) despite vast increments in the knowledge of asthma. These data have been expressed differently in the past 10 years, but the data remain the same on a per population basis. Fatalities from asthma in the United States in 2014 were 3,651 (187 in children and 3,464 in adults (age > 18 years) (95). The rate of fatalities from asthma increased in the United States from 0.8 deaths per 100,000 general population in 1977 to 2.0 in 1989, still 2.0 in 1997 (97). By 2014, the rate had declined to 1.1 per 100,000 population. By race, it was 0.9 per 100,000 for White non-Hispanic, 2.54 per 100,000 for Black non-Hispanic, and 0.8 per 100,000 for Hispanic (95). The World Allergy Organization (WAO) has estimated that 300 million people worldwide have asthma, of which half are in developing countries, and that there are 250,000 premature deaths from asthma (98). By the year 2015, the WAO anticipates that 400 million people would have asthma. Many patients with asthma live in resource-poor countries and have governments who supply albuterol but not controller medications, such as ICS. There is a wide distribution of self-reported symptoms from asthma, such as quite low in Russia, Georgia, and Indonesia to high in the United Kingdom, Australia, and New Zealand (98). Intermittent respiratory symptoms may exist for years before the actual diagnosis of asthma is made in patients, especially those older than 40 years of age. The diagnosis of asthma may be more likely made in women and nonsmokers, whereas men may be labeled as having chronic bronchitis, when in fact they do not have chronic sputum production for 3 months each year for 2 consecutive years. Asthma may have its onset in the geriatric population, and medication nonadherence and polypharmacy are found frequently (99). Asthma may begin during or after an upper respiratory tract infection, and the diagnosis can be delayed or overlooked. Treatment may be more complicated because of comorbidities and impaired cognition (“geriatric overload”). Asthma morbidity can be enormous from a personal and family perspective as well as from the societal aspect. The number of days of school missed from asthma is excessive, as is work absenteeism or presenteeism (present but not 921
fully productive). When children are ill from asthma, the parent may miss work, and the child doesn’t attend school. In the United States, attacks of asthma are frequent because 48.0% of children/adolescents 80%; prophylaxis for exerciseFEV1/FVC normal; induced bronchoconstriction) FEV normal between 1
exacerbations
952
Persistent (mild) ≥2 d a week but not daily/ 3–4 times a ≥2 d a week but not daily month or more than once on a given day
FEV1 > 80%;
Persistent (moderate)
Daily symptoms/daily use >1 night/week but not nightly
FEV1 > 60% but 5%
The severity increases if one of three parameters for a given severity is not met. For example, symptoms 2 days a week and nocturnal awakenings three times a month with FEV1 of 70% means persistent moderate asthma FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.
RECOMMENDED INITIAL/ALTERNATIVE MEDICATIONS BASED ON ASTHMA SEVERITY
DESIGNATION INITIAL
ALTERNATIVES
Intermittent
Short-acting β2adrenergic agonist prn
Mild
Low-dose inhaled corticosteroid
Moderate
Low-dose inhaled Low-dose inhaled corticosteroid + corticosteroid + longleukotriene receptor antagonist, leukotriene acting β2-adrenergic bio-synthesis inhibitor, or theophylline agonist or medium-dose inhaled corticosteroid
Severe
Medium-dose
Cromolyn, leukotriene receptor antagonist, nedocromil, theophylline
Medium or high-dose inhaled
953
corticosteroida + longacting β2-adrenergic agonist
corticosteroida + Leukotriene receptor antagonist, leukotriene biosynthesis inhibitor, theophylline and consider omalizumab, mepolizumab or reslizumab
For intermittent asthma or mild, moderate and severe persistent asthma, the components of patient education, environmental control and management of comorbities are recommended. For patients with mild, moderate or severe persistent allergic asthma, allergen immunotherapy should be considered. a
May require initial oral corticosteroid course to stabilize
Modified from the National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda MD: National Heart, Lung and Blood Institute, National Institutes of Health, U. S. Department of Health and Human Services; 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.
Asthma in children may be classified by age of onset and persistence of wheezing (see Chapter 20). Designations include “transient early wheeze” (wheezing with lower respiratory tract illnesses before age 3 years but not thereafter), “late-onset wheeze” (wheezing beginning at or after age 6 years), and “persistent wheeze” (wheeze with lower respiratory tract illnesses before age 3 years and wheeze at age 6 years) (160,161). In adults, another approach is that of grouping of patients with asthma into clusters using prespecified variables, including induced sputum eosinophil numbers (162). For example, some patients are classified as “concordant disease” because there is a match between symptoms and eosinophilic inflammation, whereas others are either “discordant symptoms” (excessive symptoms with little sputum eosinophilia that could characterize obese subjects or hypervigilant people) or “discordant inflammation” (few symptoms but high levels of sputum eosinophilia) (162). A nuanced approach is the use of endotypes or distinct subtypes of asthma as opposed to phenotypes or observed characteristics (allergic or nonallergic) (163). Endotypes imply particular pathophysiology and examples include ABPA, aspirin-exacerbated respiratory disease, late-onset severe, neutrophilic asthma, and asthma predictive index positive asthma in children (163). A patient whose asthma can be classified as an endotype will also have observable characteristics (phenotypes) of asthma, such as obesity, good adherence, and poor perceiver. 954
Allergic Asthma Allergic asthma is caused by inhalation of allergen that interacts with IgE present in high-affinity receptors (Fcε RI) on bronchial mucosal mast cells. Twenty-four hours after allergen bronchoprovocation challenge, bone marrow examination demonstrates increased numbers of eosinophil/basophil progenitor cells and classic (immunogenic antigen presenting) dendritic cells (164,165). These cells have been identified in both early responders and dual responders (164). The inflammatory progenitors and dendritic cells then can populate the bronchial airways and nasal mucosa (165). Allergic asthma often occurs from ages 2 to 4 to 60+ years and has been recognized in the geriatric population (166,167). The use of the term allergic asthma implies that a temporal relationship exists between respiratory symptoms (clinical reactivity) and allergen exposure and that antiallergen IgE antibodies can be demonstrated or suspected. Approximately 75% to 90% of patients with persistent asthma have clinical reactivity or at least allergic sensitization depending on the study. Respiratory symptoms may develop within minutes or in an hour after allergen exposure; however, they may not be obvious when there is uninterrupted allergen exposure. Common allergens associated with IgEmediated asthma include pollens, such as from trees, grasses, and weeds; fungal spores; dust mites; animal dander; and in some settings, animal urine or cockroach excreta. IgE-mediated occupational asthma is considered under the category of occupational asthma. Allergen particle size must be less than 10 μm to penetrate into deeper parts of the lung because larger particles, such as ragweed pollen (19 μm), impact in the oropharynx. However, submicronic, “subpollen” ragweed particles have been described that could reach smaller airways (168). Particles smaller than 1 μm, however, may not be retained in the airways. Fungal spores, such as Aspergillus species, are 2 to 3 μm in size, and the major cat allergen (Fel d 1) has allergenic activity from 0.4 to >9 μm in size (169). Cat allergen is found in cat saliva, from sebaceous glands, and from skin. Fel d 1 can be present in indoor air, on clothes, and in schoolrooms or in homes where no cats are present (169). The potential severity of allergic asthma should not be minimized because experimentally, after an antigen-induced early bronchial response, bronchial hyperresponsiveness to an agonist such as methacholine or histamine can be demonstrated. This hyperresponsiveness precedes a late (3- to 11-hour) response (170). In addition, fungus-related (mold-related) asthma may result in a need for 955
intensive antiasthma pharmacotherapy, including ICS and even alternate-day prednisone in some patients. Exposure to Aspergillus alternata, a major fungal aeroallergen, was considered an important risk factor for respiratory arrests in 11 patients with asthma (171). The risk of asthma deaths is higher on days with mold spore counts >1,000/mm3 (172). Dust mites and animal danders are important triggers of allergic asthma. Mouse urine and cockroach allergens (feces, saliva, and shedding body parts) are other indoor allergens that can be associated with allergic sensitization and severe asthma (173,174). The diagnosis of allergic asthma should be suspected when symptoms and signs of asthma correlate closely with local patterns of pollinosis and fungal spore recoveries. For example, in the Upper Midwestern United States after a hard freeze in late November, which reduces (but does not eliminate entirely) fungal spore recoveries from outdoor air, patients suffering from mold-related asthma note a reduction in symptoms and medication requirements. When perennial symptoms of asthma are present, potential causes of asthma include animal dander, dust mites, cockroach excreta, mouse urine, and, depending on the local conditions, fungal spores and pollens. Cockroach allergen (Bla g 1) is an important cause of asthma in infested buildings, usually in lowsocioeconomic areas. High indoor concentrations of mouse urine protein (Mus d 1) have been identified with volumetric sampling, and monoclonal antibodies directed at specific proteins suggested additional indoor allergens. The physician should correlate symptoms with allergen exposures, support the diagnosis by demonstration of antiallergen IgE antibodies, and institute measures when applicable to decrease allergen exposure (50). Patients with allergic asthma likely have allergic rhinitis, and uncontrolled allergic rhinitis is associated with less well-controlled asthma (175). It is advised to treat the upper and lower airways (176). Some recommendations for environmental control have been made (1–4,50). There is evidence supporting a multicomponent home-based environmental control program (13). In a study of inner-city children with asthma, where 94% of children had at least one positive skin test to an indoor allergen, the interventions included home visits for teaching; creating a plan of action; allergen-impermeable encasings for the mattress, box spring, and pillows; and a high-efficiency particulate air (HEPA) filtered vacuum cleaner (13). If there were mold or animal sensitization or passive smoking, an HEPA air filter was used. For cockroach exposure and sensitization, professional pest control services were obtained. Twenty percent reduction in symptoms and days of wheeze with intensive environmental control measures was found to be as great 956
as what has been reported in studies of ICS (13). The beneficial effects of environmental control help support the notion of allergic asthma being exacerbated by indoor allergens. Detection of a major cat allergen, Fel d 1, in homes or schools never known to have cat exposure is consistent with transport of Fel d 1 into such premises and sensitivity of immunoassays for cat allergen. The removal of an animal from a home and effectively encasing a mattress and pillow are interventions known to decrease the concentration of allergens below which many patients do not have clinical asthma symptoms. Once a cat is removed from the home and cleaning occurs, it has been reported that it takes 20 to 24 weeks for the concentration of cat allergen to decrease to that found in homes without cats (177). A few homes had persistently high concentrations of Fel d 1 over this period, and sources of residual cat dander were identified subsequently in those houses (177). Although food ingestion can result in anaphylaxis, persistent asthma is not explained by IgE-mediated reactions to ingested food. Food production exposure, such as occurs in bakers (178), egg handlers, flavoring producers, and workers exposed to vegetable gums, dried fruits, teas (179), or enzymes (180), is known to produce occupational asthma mediated by IgE antibodies.
Nonallergic Asthma In nonallergic asthma, IgE-mediated airway reactions to common allergens are not present. Nonallergic asthma occurs at any age range, as does allergic asthma, but the former is generally more likely to occur in subjects younger than 4 years of age or older than 60 years of age. Episodes of nonallergic asthma are triggered by ongoing inflammation or by upper respiratory tract infections, odors or air pollution, purulent rhinosinusitis, or exacerbations of chronic rhinosinusitis (CRS). Most patients have no evidence of IgE antibodies to common allergens. In youngsters, “transient early wheezers” have about a 70% likelihood of not having asthma by ages 9 to 11 years (160,181). In other patients, skin tests or in vitro allergen tests are positive, but despite the presence of IgE antibodies, there is no temporal relationship between exposure and symptoms. Often, but not exclusively, the onset of asthma occurs in the setting of a viral upper respiratory tract infection. Virus infections have been associated with mediator release and bronchial epithelial shedding, which can lead to ongoing inflammation and asthma symptoms. Commonly recovered viruses that are associated with worsening asthma include picornaviruses 957
(rhinoviruses), coronaviruses, RSV, parainfluenza viruses, influenza viruses, and adenovirus. CRS can be identified in some patients with asthma, as can nasal polyps with or without aspirin intolerance (aspirin-exacerbated respiratory disease). Indoor air pollution (3,4) from volatile organic compounds, formaldehyde, wood burning stoves, and cigarette smoking can contribute to asthma of any kind including nonallergic asthma. It is important to consider occupation or hobby-related exposures that may in fact be IgE-mediated in patients with nonallergic asthma. The TH2 (“hygiene hypothesis”) theory of asthma was supported in part by a study finding that protection against developing asthma in children aged 6 to 13 years was associated with day care attendance during the first 6 months of life or with having two or more older siblings at home (182). The “protected” children by age 13 years had a 5% incidence of asthma, compared with 10% in children who had not attended day care or who had one or no sibling (182). Of note is that at 2 years of age, the ultimately protected children had a 24% prevalence of wheezing, compared with 17% in nonprotected children. Overall, the frequent exposure to other children in early childhood, which is likely associated with more viral infections, could result in a TH1 predominance as opposed to a TH2 or allergy profile of CD4+ lymphocytes. Allergen immunotherapy is not indicated and will not be beneficial in patients with nonallergic asthma despite any presence of antiallergen IgE antibodies.
Potentially (Near) Fatal Asthma The term potentially (near) fatal asthma describes the patient who is at high risk for an fatality from asthma (152,154). The initial series of patients with potentially fatal asthma had one or more of the following criteria: (a) respiratory acidosis or failure from asthma, (b) endotracheal intubation from asthma, (c) two or more episodes of acute severe asthma despite use of oral corticosteroids and other antiasthma medications, or (d) two or more episodes of pneumomediastinum or pneumothorax from asthma. Other factors have been associated with a potentially fatal outcome from asthma, and these criteria may not identify all high-risk patients (2,3). The NAEPP summary lists some additional factors associated with exacerbations or deaths including persistent severe airflow obstruction, acute severe airflow obstruction, and being frightened by one’s asthma (3). The physician managing the high-risk patient should be aware of the potential of a fatality and strive to prevent this outcome (152,154). The impossible-to-manage patient who has both severe asthma and 958
nonadherence is referred to as having malignant, potentially fatal asthma (154).
Aspirin-Exacerbated Respiratory Disease (Aspirin-Induced Asthma) Selected patients with asthma, often nonallergic, have acute bronchoconstrictive responses to aspirin and/or nonselective NSAIDs that inhibit cyclooxygenase-1 (23–26,183–189). The onset of acute bronchoconstrictive symptoms after ingestion of such agents can be within minutes (such as after chewing Aspergum) to within 3 hours (187,189). Some physicians accept a respiratory response that occurs within 8 to 12 hours after aspirin or NSAID ingestion; however, a shorter time interval seems more appropriate, such as up to 3 hours. In persistent asthma, variations in expiratory flow rates occur frequently, so that confirming that aspirin produces a reaction at 8 hours requires careful evaluation. The most severe reactions occur within minutes to 2 hours after ingestion. With indomethacin, 1 or 5 mg oral challenges have resulted in acute responses as have aspirin tablets being placed on the tongue to treat sore throat. Cross-reaction exists, such that certain nonselective NSAIDs that inhibit cyclooxygenase-1 (ibuprofen, indomethacin, flufenamic acid, and mefenamic acid) have a higher likelihood of inducing bronchospastic responses in aspirin-sensitive subjects than other NSAIDs. Because fatalities have occurred in aspirin sensitive subjects with asthma, challenges should be carried out only with appropriate explanation to the patient, with obvious need for the challenge (such as presence of rheumatoid arthritis or coronary artery disease), and by experienced physicians. Often, aspirin-sensitive patients can be desensitized to aspirin after experiencing early bronchospastic responses (183,185,187). Subsequent regular administration of aspirin does not cause acute bronchospastic responses. From the historic perspective, the term aspirin-exacerbated respiratory disease (187,188) has replaced the term aspirin triad or Samter triad (189) and refers to aspirin-intolerant patients with asthma who have also chronic nasal polyps and CRS. The onset of asthma often precedes the recognition of aspirin intolerance by years. Approximately one-third to two-thirds of patients have immediate skin reactivity to common allergens. At one time, tartrazine (FD&C Yellow No. 5) was reported to result in immediate bronchospastic reactions in 5% of patients with the aspirin triad. Contrary results in double-blind studies have been reported in that none of the patients responded to the challenge or subsequent avoidance or tartrazine (190). The drugs that produce such immediate respiratory responses share the ability 959
to inhibit the enzyme cyclooxygenase-1, which is known to metabolize arachidonic acid into PGD2, PGF2α, and thromboxanes. Structurally, these drugs are different, but they have a common pharmacologic effect. Data suggest that the blockade of cyclooxygenase-1 diverts arachidonic acid away from production of PGE2, with loss of its “braking effects” on the lipoxygenase pathway. This effect results in unrestrained overproduction of LTC4 and LTD4 (23–26,186,187). The latter is a potent bronchoconstrictive agonist. Patients with aspirin-exacerbated respiratory disease have higher baseline PGF2α concentrations and higher urinary LTE4 concentrations (25) than aspirin-tolerant patients with asthma. After aspirin ingestion, intolerant patients have profound increases in urinary LTE4 compared with aspirin-tolerant subjects (25). When bronchial biopsy specimens were obtained from aspirin-intolerant and aspirintolerant patients with asthma, there were many more cells (primarily activated eosinophils, but also mast cells and macrophages) that expressed LTC4 synthase in the aspirin-intolerant patients (26). This critical finding supports the urinary LTE4 results, which are the marker for the bronchoconstrictor LTD4 that requires LTC4 synthase for generation. In other words, these data support a “knock-in” as opposed to a “knock-out” state. It has been demonstrated that after aspirin or nonselective NSAID ingestion, there is a decline in the protective PGE2, whose main effect is the “brake” on synthesis of 5-lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) (187). The lack of or reduced inhibition of these two key enzymes in the lipoxygenase pathway, allows for excessive generation of LTC4 at baseline and after aspirin or nonselective NSAID ingestion. The overexpression of LTC4 synthase primarily by eosinophils results in profound increases in LTD4 after aspirin or a nonselective cyclooxygenase inhibitor is ingested. Bronchial biopsies have not identified differential staining for cycloxygenase-1, cyclooxygenase-2, 5-LO, LTA4 hydrolase, or FLAP in aspirin-intolerant versus aspirin-tolerant patients (191). The effects of excessive LTD4 production appear to be amplified by increased numbers of its receptor, specifically cysteinyl leukotriene type 1 receptor as compared to cysteinyl leukotriene type 2 receptor (192,193). In addition, there are four receptors for prostaglandin E (E-prostanoids 1-4 designated as EP), yet EP2 is reduced in bronchial and nasal mucosa in patients with aspirinexacerbated respiratory disease (194). EP-2 stimulation results in production of cyclic adenosine monophosphate (AMP), which leads to bronchodilation. This protective response is reduced in aspirin-exacerbated respiratory disease (194).
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Mast cell activation occurs after aspirin challenges as well. There are increases in histamine (and LTC4) in bronchial lavage and nasal fluid after aspirin challenges (195). In some patients, there is an increase in tryptase and PGD2, a potent bronchoconstrictor, vasodilator, and chemoattractant for eosinophils (196). From the practical perspective, in virtually all patients, selective cyclooxygenase-2 inhibitors will be tolerated safely in aspirinintolerant patients (186,187).
Occupational Asthma Occupational asthma has been estimated to occur in 5% to 10% of all patients with asthma (100). Specific industry prevalence of occupational asthma may be even higher (e.g., 15.8% in snow crab processors in Canada) (197). Occupational asthma may or may not be IgE mediated. When it is IgE mediated, longitudinal data support a time of sensitization, followed by development of bronchial hyperresponsiveness and then bronchoconstriction (197). After removal from the workplace exposure, the reverse sequence has been recorded. At the time of removal from exposure, factors associated with persistent asthma include having symptoms for more than 1 year, having abnormal pulmonary function tests, and taking asthma medications. Malo et al. (198) documented that spirometry and bronchial hyperresponsiveness in patients no longer working with snow crabs reached a plateau of improvement by 2 years after cessation of work exposure. In workers with occupational asthma attributable to detergent enzymes such as proteases, amylase, and cellulases, many of the workers continued to report respiratory symptoms 3 years after removal from the workplace (see Chapter 25). Occupational asthma has been recognized among health care professionals (from 4.2% in physicians to 7.3% in nurses) (100,199). It is appreciated that some of the cases are irritant as opposed to allergic. The assessment of patients with possible occupational asthma is discussed in detail in Chapter 25. Some workers have early, late, dual, or irritant bronchial responses, such as occur to trimellitic anhydride, which is used in the plastics industry as a curing agent in the manufacture of epoxy resins. The differential diagnosis of occupational asthma is complex and includes consideration of irritants, smoke, toxic gases, metal exposures, insecticides, organic chemicals and dusts, infectious agents, and occupational chemicals. In addition, one must differentiate true occupational asthma from exposed workers who have coincidental adult-onset asthma not affected by workplace exposure. Some workers have chemical exposure and a compensation syndrome, but no objective asthma despite symptoms and usually a poor response to medications. 961
One must exclude work-related neuroses with fixation on an employer as well as a syndrome of reactive airways dysfunction, which occurs after an accidental exposure to a chemical irritant or toxic gas (200). Atopic status and smoking do not predict workers who will become ill to lower molecular-weight chemicals. Atopic status and smoking are predictors of IgE-mediated occupational asthma to high-molecular-weight chemicals. For example, Western red cedar workers display bronchial hyperresponsiveness during times of exposure, with reductions in hyperresponsiveness during exposure-free periods. The complexity of diagnosing occupational asthma cannot be underestimated in some workers. Respiratory symptoms may intensify when a worker returns from a vacation but may not be dramatic when deterioration occurs during successive days at work. In patients with preexisting asthma, fumes at work may cause an aggravation of asthma without having been the cause of asthma initially. Avoidance measures and temporary pharmacologic therapy can suffice to help confirm a diagnosis in some cases. Resumption of exposure should produce objective bronchial obstruction and clinical changes. The physician must be aware that workers may return serial PEFR measurements that coincide with expected abnormal values during work or shortly thereafter. Such values should be assessed critically because they are effort dependent and may be manipulated. Demonstration of IgE or IgG antibodies to the incriminated workplace allergen or to an occupational chemical bound to a carrier protein has been of value in supporting the diagnosis of occupational asthma from trimellitic anhidride and even in prospective use to identify workers who are at risk for occupational asthma (201). Such assays are not commonly available but are of discriminatory value when properly performed. If a bronchial provocation challenge is deemed necessary, it is preferable to have the employee perform a job-related task that exposes him or her to the usual concentration of occupational chemicals. Subsequent blinding may be necessary as well, and successive challenges may be needed. The PC20 to histamine can decrease after an uneventful challenge, but the next day, when the employee is exposed to the incriminated agent again, a 30% decline in FEV1 can occur, which confirms the diagnosis.
Exercise-Induced Asthma/Bronchoconstriction Exercise-induced asthma occurs in response to either an isolated disorder in patients with intermittent asthma or an inability to complete an exercise program 962
in symptomatic patients with persistent asthma. Control of the latter often permits successful participation in a reasonable degree of exercise. In patients with intermittent asthma, whose only symptoms might be triggered by exercise, the pattern of bronchoconstriction is as follows: during initial exercise, the FEV1 is slightly increased (about 5%), unchanged, or slightly reduced, but no symptoms occur. This is followed by declines of FEV1 and onset of symptoms 5 to 15 minutes after cessation of exercise. The decline of FEV1 is at least 10% (202,203). Airway hyperresponsiveness is present in the patients with asthma, and there is an increase in eNO (204). The term exercise-induced bronchoconstriction (EIB) refers to airway closure that occurs only with exercise, especially common in elite athletes. Not all of these athletes have hyperresponsive bronchi when challenged with histamine or methacholine as direct agonists; some athletes react only to indirect agonists, such as mannitol and hypertonic saline (4.5%) This finding has led to the notion that there may be injury to the airway in elite athletes as opposed to airway inflammation that characterizes asthma. Exercise-induced asthma resulting in a decline in FEV1 of at least 10% is associated with inspiration of cold or dry air. In general, greater declines in spirometry and the presence of respiratory symptoms are directly proportional to the level of hyperventilation and inversely proportional to inspired air temperature and humidity. The mechanism of bronchoconstriction is considered to be related to an increase in osmolarity of the periciliary fluid that accompanies the necessary conditioning of inspired air (202,205). It has been considered that the loss of water is able to increase the osmolarity of the periciliary fluid to over 900 mOsm so that there is bronchoconstriction (205). Another explanation is that postexertional airway rewarming causes increased bronchial mucosal blood flow as a possible mechanistic explanation (206). The evidence for rewarming has been difficult to prove, however. Clinically, it has been recognized that running outdoors while inhaling dry, cold air is a far greater stimulus to asthma than swimming or running indoors while breathing warmer humidified air. It has been argued that the hyperventilation of exercise causes a loss of heat from the airway, which is followed by cooling of the bronchial mucosa. In addition, there are greater declines in FEV1 during exercise when there are higher levels of eosinophils in induced sputum. This finding supports an association between eosinophilic inflammation and exercise-induced asthma. EIB can occur in any form of asthma on a persistent basis but can also be prevented completely or to a great extent by pharmacologic treatment. In 963
prevention of isolated episodes of EIB, medications such as short-acting inhaled β-adrenergic agonists inspired 10 to 15 minutes before exercise often prevent significant exercise-associated symptoms. Long-acting β2-adrenergic agonists are also bronchoprotective but not recommended as stand-alone pretreatment. Cromolyn by inhalation is effective, as to a lesser extent are short-acting muscarinic antagonists and theophylline. Leukotriene receptor antagonists have a positive but more modest protective effect and suggest that LTD4 participates in EIB. Histamine1 antihistamines may provide bronchoprotection in some subjects. For patients with persistent asthma, overall improvement in respiratory status by avoidance measures and regular pharmacotherapy can minimize exercise symptoms. Pretreatment with short- or long-acting β2-adrenergic agonists in addition to scheduled antiasthma therapy can allow asthma patients to participate in exercise activities successfully. ICS can help modify the extent of decline in FEV1 from exercise. The differential diagnosis of EIB includes unexpected dynamic collapse of the bronchi during strenuous exercise. The diagnosis is confirmed by CT examination of the bronchi showing excessive narrowing and with bronchoscopy (207).
Variant Asthma Most patients with asthma report symptoms of coughing, chest tightness, and dyspnea, and the physician can auscultate wheezing or rhonchi on examination. Variant asthma refers to asthma with the primary symptoms of paroxysmal and repetitive coughing or dyspnea in the absence of wheezing (6). The coughing often occurs after an upper respiratory infection, exercise, or exposure to odors, fresh paint, or allergens. Sputum is usually not produced, and the cough occurs on a nocturnal basis. Antitussives, expectorants, antibiotics, and use of intranasal corticosteroids do not suppress the coughing. The chest examination is free of wheezing or rhonchi. McFadden (208) documented increases in large airways resistance, moderate-to-severe reductions in FEV1 (mean, 53%), and bronchodilator responses. The mean RV was 152%, consistent with air trapping. In addition, patients with exertional dyspnea as the prime manifestation of asthma had an FEV1 value still within normal limits but an RV of 236% (208) and not greatly increased airways resistance. Both phenotypes had reduced small airways flow rates. Some patients can be induced to wheeze after exercise or after performing an FVC maneuver. Pharmacologic therapy can be successful to suppress the coughing episodes 964
or sensation of dyspnea. When inhaled, β2-adrenergic agonists have not been effective; the best way to suppress symptoms is with an orally ICS. If using an inhaler produces coughing, a 5- to 7-day course of oral corticosteroids often stops the coughing (6,7). At times, even longer courses of oral corticosteroids and antiasthma therapy are necessary.
Factitious Asthma Factitious asthma presents diagnostic and management problems that often require multidisciplinary approaches to treatment (159,209). The diagnosis may not be suspected initially because patient history, antecedent triggering symptoms, examination, and even abnormal pulmonary physiologic parameters may appear consistent with asthma. Nevertheless, there may be no response to appropriate treatment or, in fact, worsening of asthma despite what would be considered effective care. Some patients are able to adduct their vocal cords during inspiration and on expiration, emit a rhonchorous sound, simulating asthma. Other patients have repetitive coughing paroxysms or “seal barking” coughing fits. A number of patients with factitious asthma are physicians, nurses, or paramedical personnel who have an unusual degree of medical knowledge. Psychiatric disease can be severe, yet patients seem appropriate in a given interview. Factitious asthma episodes do not occur during sleep, and the experienced physician can distract the patient with factitious asthma and temporarily cause an absence of wheezing or coughing. Invasive procedures may be associated with conversion reactions or even respiratory “arrests” from breath-holding.
Vocal Cord Dysfunction and Asthma VCD (also called laryngeal dyskinesia) may coexist with asthma (143,144,210–212) (Fig. 19.4B). In a series of 95 patients with VCD, 53 patients had asthma. The level of medication prescriptions can be very high in patients with VCD with or without asthma (143). Of great concern is the prolonged use of oral corticosteroids for dyspnea that is, in fact, due to VCD and not from asthma. Patients with VCD and asthma may or may not have insight into the VCD. Some patients can be taught by a speech therapist to avoid vocal cord adduction during inspiration. In particular, they can learn abdominal in place of thoracic breathing on inspiration. The diagnosis can be suspected when there is a truncated inspiratory loop on a flow-volume loop, when direct visualization of the larynx identifies vocal cord adduction on inspiration, on CT examination of the neck (143,144, 210–212), or by bedside examination. In the latter case, the 965
patient may have a diagnosis of asthma and be hospitalized. Although symptoms are present, the patient has limited wheezing or a quiet chest, relatively normal blood gases or pulse oximetry, and is unwilling to phonate the vowel “e” for more than 3 seconds. In addition, when prompted, there is no large inspiratory effort made. In the series of 95 patients, many were health care providers and females who were obese (143). GERD was present in 15 of 40 (37.5%) patients who had both VCD and asthma, compared with 11 of 33 (33%) with VCD without asthma (143). In all, 95 patients (38%) had a history of abuse, such as physical, sexual, or emotional (143). VCD should be suspected in difficult-tocontrol patients with severe (typically corticosteroid-dependent asthma) in patients whose symptoms or medical requirements do not concur with the relatively normal spirometric or arterial blood gas findings, and in those who have prolonged hoarseness with dyspnea, wheezing, or coughing, with or without asthma.
Coexistent Asthma and Chronic Obstructive Pulmonary Disease Usually, in the setting of long-term cigarette smoking (at least 30 to 40 packyears), asthma may coexist with COPD. Obviously, the patients with asthma or COPD should not smoke. Multiple medications may be administered in patients with asthma and COPD to minimize signs and symptoms. However, some dyspnea likely will be fixed and not transient because of the underlying COPD. The component of asthma can be significant, perhaps 25% to 50% initially. However, with continued smoking, the reversible component, using oral and ICS, β2-adrenergic agonists, combined ICS/long-acting β2-adrenergic agonist, theophylline, tiotropium, and leukotriene antagonists, diminishes or becomes nonexistent. At that point, the fewest medications possible should be used. When there is no benefit from oral corticosteroids, it is advisable to taper and discontinue them. Initially, such as after hospitalization for asthma, the patient with combined asthma and COPD may benefit from a 2- to 4-week course of oral corticosteroids. The effort to identify the maximal degree of reversibility should be made even when asthma is a modest component of COPD. The lack of bronchodilator responsiveness or peripheral blood eosinophilia does not preclude a response to a 2-week course of prednisone. Long-term care of patients with coexistent asthma and COPD can be successful in improving quality of life and reducing or eliminating disabling 966
wheezing. A combination of ICS and long-acting β2-adrenergic agonist can improve patient outcomes (213,214). However, eventually, patients may succumb to end-stage COPD or coexisting cardiac failure. The asthma–COPD overlap syndrome refers to patients whose response to albuterol is quite large (for FEV1 ≥ 15% and ≥ 400 mL) despite evidence of airways obstruction (FEV1/FVC < 0.70) (12). However, there remains controversy over which criteria are the most useful for the diagnosis (215).
NONANTIGENIC PRECIPITATING STIMULI Hyperresponsiveness of bronchi in patients with asthma is manifested clinically by responses to various nonantigenic triggers. Some airborne triggers include odors, such as cigarette smoke, fresh paint, cooking odors, perfumes, cologne, insecticides, and household cleaning agents (216). In addition, sulfur dioxide, ozone, nitrogen dioxide, carbon monoxide, and other combustion products, both indoors and outdoors, can trigger asthma signs and symptoms. Emergency department visits for asthma in adults in New York City peaked 2 days after increases in ambient air ozone levels (217). The effect was most pronounced in patients who had smoked more than 14 pack-years of cigarettes (217). There was no ozone effect for adult nonsmokers or light smokers (15% improvements in FEV1, whereas others have poor responses (12 years of age and adults with episodes of acute asthma, the
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recommendations of the NAEPP include two to four inhalations from an MDI every 20 minutes up to three times (3).
FIGURE 19.5 A simplified schematic of β2-adrenergic receptor stimulation. β2-Adrenergic agonist stimulation of its receptor causes a conformational change in the guanine nucleotide-binding regulatory protein GS. There is increased guanosine triphosphatase (GTPase) activity and then a transduced signal, resulting in activation of adenylate cyclase. The sequence raises the concentration of cyclic adenosine monophosphate (cAMP). The regulatory protein GS couples β2-adrenergic receptors to adenylate cyclase and calcium channels. GS interacts with the sodium channel, resulting in its inhibition. Levalbuterol is the (R)-enantiomer of albuterol and was approved by the Food and Drug Administration (FDA) in 1999 for the treatment of bronchospasm in patients aged 4 years and older. It is marketed in the United States as Xopenex and is available as an MDI or nebulized solution. The pediatric and adult doses are 0.31 mg and 0.63 to 1.25 mg, respectively, and can be administered every 4 to 6 hours. Levalbuterol is about four times as potent as albuterol with 0.63 mg of levalbuterol providing comparable bronchodilation to 2.5 mg of albuterol (258). For patients who experience tremulousness and palpitations with albuterol, levalbuterol is a useful alternative, but maximal bronchodilation is 984
similar to that achieved with albuterol. Older SABAs Once Used for Asthma In addition to albuterol and levalbuterol, other SABAs include Pirbuterol (Maxair) and Metaproterenol (Alupent). However, these latter two SABAs were phased out of the US market in 2013 and 2010, respectively. Aerosolized Terbutaline (Bricanyl) is currently not available in the United States. Epinephrine directly activates both α- and β-adrenergic receptors and has a potent bronchodilation effect. While most commonly used for the treatment of anaphylaxis, epinephrine was used extensively in the past for treatment of acute asthma. The recommended adult dose is 0.30 mL of a 1:1,000 solution administered intramuscularly. In infants and children, the dose is 0.01 mL/kg, with a maximum of 0.25 mL. The dose may be repeated in 15 to 30 minutes if necessary. Intramuscular epinephrine may still have a place for some patients with acute severe asthma who have not responded to albuterol because they are unable to inspire sufficiently or in patients with acute severe wheezing where it is not clear whether the patient with asthma is experiencing anaphylaxis. Nebulized racemic epinephrine is also effective but is not used unless the patient has an upper airway obstruction (epiglottitis or stridor). Side effects of epinephrine include agitation, tremulousness, tachycardia, and palpitation. Hypertension in the presence of acute asthma often resolves with epinephrine administration. This occurs because of a decrease in bronchospasm and as a result of a decrease in peripheral vascular resistance by stimulation of β2-adrenergic receptors in smooth muscle. Epinephrine must be administered with caution in patients with cardiovascular disease and hypertension but should not be considered contraindicated when bronchoconstriction is significant if albuterol is not being used. The maximum bronchodilator effect of epinephrine given intramuscularly is about equivalent to that of inhaled β2-adrenergic agonists and occasionally in the severely obstructed patient exceeds what can be gained by aerosol therapy. Although epinephrine is an old drug, it is expedient, effective, and rapidly metabolized. Ephedrine also stimulates both α- and β-adrenergic receptors but is less potent than albuterol and epinephrine. It has an onset of action of ˜1 hour with a peak effect between 2 and 3 hours. Ephedrine is an outdated for treatment of asthma but was used for decades because it was effective by oral administration and possessed a long duration of action (3 to 6 hours). It is available without prescription (25 to 50 mg) for asthma and as a stimulant. 985
In summary, short-acting β2-adrenergic agonists currently are recommended as rescue therapy for acute asthma exacerbations and not for daily scheduled use, at least for most patients. These medications, when used properly, can also provide protection against EIB. For patients with uncontrolled asthma despite use of a SABA, a step-up therapy in therapy is indicated and, in the case of moderate-to-severe persistent asthma, the use of a combined ICS and long-acting β2-adrenergic agonist may be indicated. In resource-poor countries or for patients in resource sufficient countries, who are not able to afford controller medications, unfortunately, their monotherapy consists of albuterol. Long-Acting β2-Adrenergic Agonists As the name implies, long-acting β2 agonists (LABAs) have a longer duration of bronchodilator effect (12 to 24 hours) and can inhibit both the early and late phases of the respiratory response following allergen challenge. These medications are recommended for administration concomitantly with an ICS. This is due to findings from a large double-blind placebo controlled trial examining the use of a LABA versus placebo as add-on therapy in patients with asthma. This study showed a small but significant association between LABA use and increased risk of asthma-related death (odds ratio 4.37), particularly among African Americans (259). Important limitations of this study included difficulties in patient enrollment, lack of in-person follow-up in a medical clinic, and no method by which medication compliance was reinforced. Further, patients received individual inhalers (salmeterol and fluticasone) but not salmeterol/fluticasone or did not use an ICS for persistent moderate-to-severe asthma. Given these findings, a subsequent meta-analysis was performed which found an odds ratio of asthma-related death to be 2.7 and 7.3 when a LABA was prescribed with or without an ICS, respectively (260). Additionally, no deaths among 22,600 patients were reported when either a combined ICS/LABA inhaler or a corticosteroid inhaler alone was prescribed (260). In 2016, another large prospective multicenter double-blind study involving 11,679 patients with asthma reported no significantly increased risk of serious asthma-related events between patients who received a combined corticosteroid/LABA inhaler versus a corticosteroid alone (261). Furthermore, this study found those patients taking a combined ICS/LABA had significantly fewer asthma exacerbations than those patients receiving ICS alone (261). Salmeterol is a partial β2-adrenergic receptor agonist with an onset of action 986
within 20 minutes. It is 50 times more potent experimentally than albuterol but provides a similar peak bronchodilation. Salmeterol is currently marketed in the United States as Serevent and is indicated for the treatment of asthma and for the prevention of exercise-induced bronchospasm in patients aged 4 years and older. More commonly, salmeterol is prescribed in combination with the ICS fluticasone and marketed as Advair. The recommended dose of salmeterol is 50 µg twice daily. Formoterol is a full β2-adrenergic agonist with a rapid onset of action within 5 minutes. It has a maximum bronchodilator effect similar to salmeterol or albuterol administered every 6 hours. Until 2016, formoterol was available as a monotherapy inhaler Foradil but has since been withdrawn from the market. However, this LABA is found in combination with the ICS mometasone or budesonide and marketed as Dulera or Symbicort, respectively. The recommended dose of formoterol is 9 to 10 µg twice daily. Although not approved in the United States as a reliever medication, the combined budesonide/formoterol is used in other countries for both acute and maintenance therapy (262–264). The nebulized form of formoterol, Performomist, is not currently approved for the treatment of asthma. The use of a LABA does not preclude the use of a SABA. Responses of FEV1 to albuterol were preserved for 6 hours despite regular use of salmeterol (265). Such patients should receive ICS therapy, but even in its absence, in this study, a diminished response to successive doses of albuterol (or tachyphylaxis) did not occur (265). Thus, patients with moderate or severe persistent asthma may require a scheduled LABA and intermittent albuterol or other SABA to control their disease. In summary, data support the use of regularly scheduled long-acting β2adrenergic agonists with ICS for moderate and severe persistent asthma (266,267). In patients whose asthma is not well controlled on low-dose ICS, studies have shown the combination of an ICS plus 12-hour long-acting β2adrenergic agonist provides better asthma control than solely increasing the dose of the corticosteroid (268). As patients improve, it is possible that less or no β2adrenergic agonist can be used. Alternatively, full control may still not be achievable despite combined ICS/LABA therapy, and additional therapeutic agents should be considered. Ultra-Long-Acting β2 Agonists Ultra-LABAs represent the newest class of β2-adrenergic receptor agonists. 987
These medications are more lipophilic than prior agents and thus have a longer duration of action (24 hours). Similar to LABAs, ultra-LABA monotherapy is not recommended for the treatment of asthma, but select ultra-LABAs (e.g., Indacaterol and Olodaterol) are approved as single maintenance therapy in COPD. Vilanterol is a partial β2-adrenergic receptor agonist with a rapid onset of action within 5 minutes. It has a greater potency than albuterol and salmeterol but is comparable to formoterol (269,270). Vilanterol is available in combination with Fluticasone furoate and marketed in the United States as Breo. This medication is indicated for the treatment of asthma in patients aged 18 years and older and is administered as 1 inhalation (of 25 µg of vilanterol) daily. In summary, an ultra-LABA in combination with ICS provides another treatment option in the management of patients with moderate-to-severe persistent asthma. Although this combined medication can significantly improve FEV1 in patients with asthma compared to placebo, it remains unclear whether it is more efficacious than combined ICS and other LABAs (271). Genetic Polymorphisms and the β2-Adrenergic Receptor As with most clinical observations, there is significant variability in patient responses to β2-adrenergic agonists. This has led to studies of SNPs at the 16 and 27 positions of the gene encoding the β2-adrenergic receptor (located on chromosome 5q31). Most patients with mild asthma have the Glycine/Glycine genotype at the 16th amino acid position of the β2-adrenergic receptor, and such patients have a better response to β2-adrenergic agonist therapy compared with patients who have the Arginine/Arginine genotype (272,273). This finding has not been replicated large studies of patients treated with salmeterol alone or the combinations of either formoterol/budesonide or salmeterol/fluticasone (274,275). Thus, although there are differences in responses to short-acting β2adrenergic agonists, additional investigations are needed to understand therapeutic differences and how to provide “personalized” pharmacotherapy. Adverse Effects of β2-Adrenergic Receptor Therapy The immediate relief of short-acting β2-adrenergic agonists has made them widely acceptable to both patients and physicians. Unfortunately, some patients develop an almost addictive relationship with their inhalers, which results in excessive use and risk of arrhythmias and death (276). Physicians, other health care providers, and pharmacists need to be aware of the potential overuse of 988
MDIs, dry-powder inhalers, and/or nebulizers by patients and the potential “masking” of a deteriorating underlying disease. Unlimited or unsupervised prescription refills cannot be recommended because when asthma is worsening, patient self-management may result in a fatality. As an asthma attack progresses and continued β2-adrenergic agonist therapy is used in the absence of inhaled or oral corticosteroids, there may be development of arterial hypoxemia, carbon dioxide retention, and acidosis not recognized by the patient. Although subjective and objective improvement of airway obstruction is produced by inhaled short-acting β2-adrenergic agonists, the associated hypoxemia of asthma is not improved and may be increased. This phenomenon results from enhancing the already existing V/Q imbalance by either increasing aeration of those alveoli already overventilated in relation to their perfusion or by reestablishing ventilation to nonperfused alveoli. The resultant hypoxemia is usually clinically insignificant, unless the initial PO2 is on the steep portion of the oxygen–hemoglobin dissociation curve (i.e., less than 60 mm Hg). In moderately severe acute asthma, oxygen should be administered to correct the hypoxemia. Another concern with inhaled β2-adrenergic agonists is the occasional paradoxic response of increased bronchial obstruction. With an exacerbation of asthmatic symptoms, these patients may overuse inhalation therapy because of a decreasing response to preceding inhalations. A cycle begins of increasing obstruction with increasing use of the aerosol. This pattern may progress to acute severe asthma or respiratory/cardiac arrest. Patients identified as using β2adrenergic agonist inhalation or nebulizers excessively should have this therapy terminated or monitored more aggressively. The physician should begin a short course of prednisone to control underlying bronchoconstriction and airway inflammation. There remains a public health concern of asthma fatalities that occur in patients with persistent asthma, who rely on short- or long-acting β2adrenergic agonists in the absence of ICS or other controller therapy.
Muscarinic Antagonists Muscarinic receptors are G protein-coupled receptors that bind acetylcholine and play a prominent role in the parasympathetic nervous response. There are five different muscarinic receptors with M1, M2, and M3 being the most common subtypes found in the respiratory tract. M1 and M3 receptors are present on airway smooth muscle and, upon engagement, elicit bronchoconstriction. In 989
contrast, signaling through M2 receptors on airway smooth muscle can inhibit acetylcholine release and thus reduce cholinergic-mediated bronchoconstriction. Thus, the optimal anti-cholinergic drug used for asthma treatment would have a high affinity for M1 and M3 receptors (to block bronchoconstriction) but a low affinity for the M2 receptor (to promote its inhibitory effects). In addition to varying receptor affinities, anticholinergic agents can differ by rate of onset and duration of clinical effect. Short-Acting Muscarinic Antagonists Ipratropium Bromide (Atrovent) is a nonselective antagonist of the M1, M2, and M3 receptors with a duration of effect lasting approximately 2 to 4 hours. However, ipratropium bromide is not recommended as monotherapy for the treatment of acute asthma, given it has a slower onset of action and a smaller clinical effect than β2-adrenergic agonists. Additionally, a large meta-analysis found no clinically significant benefit when using either an anticholinergic agent alone or in combination with a β2-adrenergic agonist for the management of chronic asthma (277). In contrast, separate studies have found the use of an anticholinergic together with a β2-adrenergic agonist to improve lung function and reduce hospitalizations during acute asthma exacerbations (278,279). Dual combined ipratropium bromide plus albuterol is currently available in an MDI (Combivent) and nebulized (Duoneb) formulations. Long-Acting Muscarinic Antagonists Tiotropium Bromide (Spiriva, Spiriva Respimat) is a higher affinity muscarinic receptor antagonist than Ipratropium Bromide. While it binds equally to both the M2 and M3 receptors, tiotropium has a much slower dissociative rate from the M3 receptor, thus prolonging its bronchoprotective effects. This medication is currently indicated in patients aged 12 years and older with a recommended dose of 2.5 µg once daily. In a large, randomized three-way, double-blind crossover study, the additive effect of tiotropium was compared to the additive effect of a LABA as well as to the doubling effect of the corticosteroid dose among patients with uncontrolled moderate persistent asthma taking inhaled glucocorticoids (280). This study found patients who received tiotropium in addition to their glucocorticoid had a significant improvement in lung function and symptoms compared to patients who received an increase in steroid dose alone (280). Additionally, there was a noninferior improvement compared to patients who received both a LABA and 990
glucocorticoid (280). In more recent meta-analyses, the addition of a LAMA was found to improve lung function and reduce the rate of asthma exacerbations among patients taking inhaled glucocorticoids without LABA (280) as well as reduce the need for rescue oral steroids in patients already taking both a LABA + ICS (281,282).
Leukotriene Antagonists and Biosynthesis Inhibitors Cysteinyl leukotrienes are derived from arachidonic acid and include Leukotriene C4 (LTC4) which is converted to LTD4 which is then converted to Leukotriene E4 (LTE4). These lipid mediators, in particular LTC4 and LTD4, are potent inducers of bronchoconstriction and thus are thought to contribute to asthma pathogenesis. There are three cysteinyl leukotriene receptors aptly named cysteinyl leukotriene receptor-1 (CystLT1R), -2 (CystLT2R), and -3 (CystLT3R). Each leukotriene has a different affinity for a given receptor with LTD4 having the highest affinity for the CysLT1R. LTD4 and LTC4 share a similar high affinity for the CysLT2R and LTE4 has the highest affinity for the more recently discovered CysLT3R (283,284). There are currently no FDA– approved antagonists of either CystLT2R or CystLT3R. Leukotriene Antagonists Montelukast (Singulair) and Zafirlukast (Accolate) are both CysLT1 receptor antagonists approved for the prophylaxis and chronic treatment of asthma. Montelukast is indicated for patients aged 12 months and older while Zafirlukast is indicated for patients aged 5 years and older. Both leukotriene antagonists can block declines in FEV1 from exercise, allergen challenge, and aspirin administration and serve as controller medications (285–291). Administration of montelukast or zafirlukast in adults with persistent mild to moderate asthma resulted in a reduction in symptoms and increase in FEV1 by up to 13%, compared with a placebo response of 4.2% (88). Comparable results were reported in children aged 6 to 14 years (88). These findings support the concept that leukotrienes contribute to airway tone. However, there is some patient-to-patient variability in the degree of FEV1 improvement observed with montelukast. Approximately 15% of patients treated with this medication note an improvement in bronchodilation by 18% to 25%, whereas other patients only observe an 8% to 10% increase (88). The effects of leukotriene antagonists in controlling asthma can extend 991
beyond bronchodilator responses (88,287). In one study, montelukast 10 mg (or placebo) was added to beclomethasone dipropionate 200 μg twice daily in adult patients with incompletely controlled asthma. This combination of montelukast and ICS was associated with a significant increase in FEV1, decrease in asthma symptoms, and reduction in number of asthma exacerbations compared to patients treated with placebo plus ICS (291). The leukotriene receptor antagonists can help some patients with persistent asthma lower their dosage of ICS. Leukotriene antagonists are generally well tolerated and effective (292). However, a postmarketing analysis of these medications reported an increase in neuropsychiatric episodes, including mood changes, depression, dream abnormalities, and suicidal ideations, especially among adolescents and the elderly. As a result, patients should be advised of this small, possible risk and closely monitored for any change in behavior. Leukotriene Synthesis Inhibitor Zileuton (Zyflo) is an inhibitor of the 5-LO enzyme and blocks the downstream conversion of arachidonic acid into leukotrienes by ˜26% to 86% (293,294). In a 12-week study of zileuton in patients with asthma, the average FEV1 improved by 20.8% with active treatment compared to 12.7% with placebo (293). Additionally, in another study, the use of zileuton resulted in bronchodilation (14.6% vs. 0% for placebo) 60 minutes following treatment (294). Zileuton is currently indicated for patients with asthma aged 12 years and older. Reversible elevations of alanine aminotransferase, over three times normal limits, occurred in less than 2.5% of patients and 0.5% of controls (293,294). As a result, it is recommended that liver function tests be measured while taking this medication. As with the leukotriene receptor antagonists, mood changes and other neuropsychiatric events have also been associated with Zileuton and patients should be monitored appropriately.
Biological Modifiers Significant advances have been made in defining the cellular and molecular mechanisms contributing to asthma pathogenesis. As discussed in Chapter 1, allergic asthma is characterized by a type 2 inflammatory response with IgE as well as the cytokines IL-4, IL-5, and IL-13 all thought to play important roles. In addition to promoting inflammation, these mediators have also become important therapeutic targets for drug design. It is hypothesized that if the type 2
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inflammatory response could be attenuated, asthma symptoms and exacerbation rates could be improved, and the natural history of the disease potentially altered. Currently, there are three immunomodulatory agents approved by the FDA for the treatment of moderate-to-severe allergic asthma. Additionally, the safety and efficacy of other biological modifiers inducing those that target the IL-4 receptor α chain (295), IL-13 (296), IL-5 (297,298) and TSLP (77,299) are being evaluated in ongoing clinical trials. Anti-IgE Omalizumab is a humanized monoclonal IgG1κ antibody that recognizes the Fc portion of IgE. Upon binding, omalizumab forms a complex with free (or unbound) IgE and prevents the IgE from engaging with its receptor, FcεRI. In a pooled analysis of over 4,300 clinical trial participants with severe asthma, omalizumab was shown to significantly reduce the rate of asthma exacerbations and ER visits by 38% and 47%, respectively (300). Additionally, patients treated with omalizumab noted a significant improvement in quality of life and were more likely to tolerate a reduction in daily ICS than placebo-treated controls (301–303). The clinical effects observed with omalizumab may be secondary to a variety of mechanisms. By forming complexes, omalizumab can both reduce serum levels of free IgE (304) and downregulate FcεRI receptor expression on the surface of mast cells, basophils, and dendritic cells (305–307). Additionally, Omalizumab has been associated with a decrease in the number of eosinophils detected in the blood and sputum (304). Taken together, omalizumab can impair the ability of IgE to bind allergen, to activate basophils and mast cells, and to promote the development of a type 2 inflammatory response. Omalizumab is marketed under the name Xolair in the United States and is indicated for the treatment of moderate-to-severe persistent asthma in patients aged 6 years and older. To qualify for treatment, patients must have at least one positive skin test or in vitro confirmed specific IgE to a perennial allergen and have asthma symptoms that are inadequately controlled with ICS. This medication is administered subcutaneously with the dose (75 to 375 mg) and frequency of administration (every 2 or 4 weeks) determined by the patient’s body weight and total IgE level prior to treatment. Because omalizumab causes serum levels of total IgE (a measurement of both free and bound IgE) to increase (308,309), it is not recommended that total IgE levels be monitored while on treatment (this point applies to some but not all in vitro assays to detect total IgE). 993
Importantly, postmarketing analyses found an increased risk of anaphylaxis occurring in 0.2% of patients receiving omalizumab. Symptoms developed as soon as 90 minutes after the administration of the first dose of omalizumab and as late as 1 year into treatment. Due to these observations, patients should be properly counselled, prescribed auto-injectable epinephrine, and, after receiving omalizumab, monitored closely for 2 hours after the first three injections and 30 minutes after subsequent injections in a health care setting equipped to manage severe allergic reactions (310). Finally, a recent large observational cohort study found no association between omalizumab and an increased risk of malignancy (311). Anti–IL-5 Mepolizumab is a humanized monoclonal IgG1κ antibody that binds to soluble IL-5, thereby preventing IL-5 from engaging with and activating its receptor, the IL-5 receptor. IL-5 is a critical cytokine for eosinophil survival, activation, and proliferation. By antagonizing the effects of IL-5, mepolizumab has been shown to reduce peripheral blood eosinophils (312–314). In phase 3 randomized double-blind placebo controlled trials of patients with asthma, mepolizumab was associated with a significant reduction in clinically significant asthma exacerbations compared to placebo (312,313). However, significant associations between the use of mepolizumab and improvements in either FEV1 or asthma symptoms were variable (312,313). In a separate study, the dose of oral glucocorticoids was 2.39 times more likely to be reduced (and by a median of 50%) in patients with asthma receiving mepolizumab as compared to placebo (315). Importantly, despite the reduction in oral steroids, mepolizumab treated patients still noted a 32% relative reduction in annual rate of exacerbations (315). The mechanisms by which mepolizumab exerts its clinical effects and by which a reduction in eosinophils can lead to a decline in asthma exacerbations remain under investigation. Mepolizumab is marketed under the name Nucala in the United States and is indicated for the treatment of severe persistent asthma in patients aged 12 years and older. To qualify for treatment, patients must have both asthma symptoms that are inadequately controlled with ICS and an eosinophilic phenotype associated with their disease. The peripheral blood eosinophil count should be ≥150 cells/µL within 6 weeks or ≥300 cells/µL within 1 year prior to starting treatment. Mepolizumab is administered subcutaneously at a dose of 100-mg every 4 weeks and is not based upon a patient’s weight (or IgE concentration). To date, there have been no reported episodes of anaphylaxis with mepolizumab 994
but two patients (compared to 0 placebo-treated controls) developed shingles during the course of the clinical trials. Varicella vaccination should be considered, if medically appropriate, prior to starting mepolizumab. Reslizumab is a humanized monoclonal IgG4κ antibody that, like mepolizumab, binds to soluble IL-5, thereby preventing it from engaging with and activating the IL-5 receptor. Large double-blind placebo controlled clinical trials have shown that in patients with moderate-to-severe persistent asthma with uncontrolled disease reported significant reductions in asthma exacerbations as well as improvements in lung function and quality of life with reslizumab compared to placebo (316–318). The clinical efficacy of reslizumab compared to Mepolizumab cannot be evaluated at this time, given that there have been no direct head-to-head clinical studies. Reslizumab is marketed under the name Cinqair in the United States and is indicated for the treatment of severe persistent asthma in patients aged 18 years and older. To qualify for treatment, patients must have asthma symptoms that are inadequately controlled with ICS and have an eosinophilic phenotype associated with their disease. The peripheral blood eosinophil count should be ≥400 cells/ µL in the 3 to 4 weeks prior to starting treatment. Reslizumab is administered intravenously over a period of 20 to 50 minutes at a dose of 3 mg/kg every 4 weeks. Anaphylaxis was reported in 0.3% of patients receiving Reslizumab and occurred as early as during the second infusion. It is thus recommended that patients be properly counselled, prescribed injectable epinephrine for emergency use, and, after receiving Reslizumab, monitored closely in a health care setting equipped to manage severe allergic reactions. Theophylline (1,3-dimethylxanthine) is a methylxanthine drug that remains a third-line treatment option for ambulatory or hospitalized patients with moderate-to-severe persistent asthma. The limited use of this drug is secondary to its narrow therapeutic index, major side effects, and significant interactions with numerous other medication classes (see Chapter 36). The most important pharmacologic action of theophylline is bronchodilation but other properties include central respiratory stimulation, inotropic and chronotropic cardiac effects, diuresis, relaxation of vascular smooth muscles, improvement in ciliary action, and reduction of diaphragmatic muscle fatigue. The molecular mechanisms by which theophylline exerts its clinical effects remain unclear. It has been shown in vitro to increase cAMP concentrations by inhibiting phosphodiesterase, the enzyme that converts 3′5′-cAMP to 5′-AMP. However, the inhibition of phosphodiesterase by theophylline was accomplished 995
with concentrations that would be toxic in vivo; thus, theophylline’s mechanism of action is unlikely attributable to phosphodiesterase inhibition. Possible alternative explanations for bronchodilation induced the antagonism of adenosine receptor, inhibition of the pro-inflammatory cytokine NF-κB, and induction of the anti-inflammatory cytokine, IL-10 (319). Optimal bronchodilation from theophylline is a function of the serum concentration. Maximal bronchodilation is usually achieved with concentrations between 8 and 15 μg/mL. However, some patients achieve adequate clinical improvement with serum theophylline levels at 5 μg/mL or even lower. The explanation for this phenomenon is that the bronchodilator effect of theophylline, as measured by percentage increase in FEV1, is related to and fairly dependent on the logarithm of the serum-level concentration (320,321). In this study, the mean improvement in FEV1 was 19.7% with theophylline concentration 5 μg/mL, 30.9% at 10 μg/mL, and 42.2% at 20 μg/mL. At these concentrations, improvement in pulmonary function occurs in linear manner with the log of the theophylline concentration. However, using an arithmetic scale on the abscissa, improvement in pulmonary function occurs in a hyperbolic manner. Thus, although continued improvement occurs with increasing serum concentrations, the incremental increase with each larger dose decreases. About half of the improvement in FEV1 that is achievable with a theophylline concentration of 20 μg/mL is reached with concentration of 5 μg/mL, and 75% of the improvement is reached with a concentration of 10 μg/mL. Since the introduction of inhaled glucocorticoids, LABAs, and biologic modifiers, theophylline remains an alternative controller medication for use in patients with moderate and severe persistent asthma (3,4). When added to ICS plus β2-adrenergic agonist combinations, theophylline may provide no additional benefit. As a result, theophylline remains indicated only in problem-patients with persistent severe asthma, steroid-phobic patients, patients with asthma and COPD, and perhaps patients who cannot afford ICS/LABA.
Chromones Chromones are distinct chemical compounds with unique pharmacologic properties used in the treatment of various allergic diseases. These compounds stabilize mast cells, thus decreasing the release of inflammatory mediators such as histamine. Chromones also function by inhibiting IgE production and modulating sensory nerves, the latter of which has been shown to reduce the severity of itch. Chromones act directly on the mucosal surfaces but have 996
minimal effect in the skin. These medications are neither systemically absorbed nor metabolized. The two major chromones, Cromolyn and Nedocromil, were once available as inhalers. However, both of these medications were taken off the US market prior to 2014 because they contained chlorofluorocarbons. Currently, cromolyn is available in oral (Gastrocrom), nasal (NasalCrom), and ophthalmic (Opticrom) formulations, whereas nedocromil is available in an ophthalmic solution (Alocril). Although these formulations are indicated for allergic rhinitis, allergic conjunctivitis, and mastocytosis, they are not recommended for treatment of acute or chronic asthma. Formerly, inhaled cromolyn sodium was shown to be effective in preventing bronchospasm from inhaled allergens and exercise with study patients reporting a 28% to 33% reduction in asthma symptoms after administration when compared to placebo (322) (see Chapter 36). However, a Cochrane analysis found little to no improvement over placebo for maintenance therapy in children (323). Additionally, in the Childhood Asthma Management Program, nedocromil and cromolyn (as with budesonide) did not appear to protect against loss of FEV1/FVC in mild-to-moderate asthma (324). However, cromolyn and nedocromil have been of value for prevention or minimization of EIB when inhaled up to 2 hours prior to exercise (325). Preexposure cromolyn by inhalation can help reduce symptoms triggered by animal danders, molds, high dusty environments, odors, and exercise.
Practical Considerations for Asthma Therapies Despite the significant pharmacologic advances in asthma management, no medication will provide significant benefit if used improperly. For example, correct inhaler technique is essential for the appropriate delivery of medication. If not properly educated, patients may fail to fully expire before actuating their inhaler. Alternatively, patients may inhale too rapidly, take a submaximal inspiration, flex the neck during inspiration, and/or not hold their breath for 10 seconds after a full inspiration. In addition to improper breathing techniques, difficulties manipulating the device itself (i.e., forgetting to shake the canister before actuation, activating the inhaler twice for one inhalation, forgetting to remove the cap before inhalation) can also impact drug delivery and explain poor therapeutic responses. To address these concerns, clinicians are encouraged to review proper inhaler techniques at office visits and have the patient in turn demonstrate correct use. 997
A number of devices have been developed in an effort to improve the dynamics of aerosol administration by a pressurized inhaler (see Chapter 37). These devices attempt to minimize aerosol deposition in the oropharynx and increase delivery to the airways. By necessitating a slower inspiration, more drugs may be distributed to obstructed peripheral airways than with a rapid inspiration, which favors central airway deposition at the expense of the peripheral airways. Additionally, these devices can assist when effective synchronization of inhalation with actuation of the air inhaler cannot be corrected. Motor-driven nebulizers do not result in greater bronchodilation than that achieved with pressurized metered-dose aerosol canisters. Drug delivery by motor-driven nebulizers has been considered more efficacious because the patient inhales a relatively large concentration of drug from the nebulizer. For example, the dose of albuterol added to the nebulizer is 5 mg, which is 56 times the dose generated by the MDI (90 μg). However, it was demonstrated that perhaps only 15% to 20% of the drug is actually nebulized during inspiration, and only 10% of the nebulized dose would reach the bronchi. In conclusion, the dose delivered to the lung from the nebulizer may be approximately similar to that given by a pressurized aerosol canister. Nebulizers can still provide benefit especially because they do not necessitate the patient to learn correct inhalation technique as required for inhalers. Physicians and other health care providers should become familiar with the proper use of the different asthma devices available and, when appropriate, consider spacers and/or breath-activated units to improve drug delivery. It is advisable to recheck the patient’s inhaler technique periodically because technical errors can still occur. Additionally, other barriers to medication adherence should be addressed on a more personalized basis (326). Financial costs, social factors, fear of side effects, intensity of the dosage regimen, and the patient’s perception of their disease may all play important roles on how (and when) patients utilize medical therapies for the treatment of their disease.
Drugs to Use Cautiously or to Avoid Monotherapy of persistent mild, moderate, or severe asthma with short- or longacting β2-adrenergic agonists is not recommended (3) and should not be done. Additionally, the use of β2-adrenergic antagonists may enhance or trigger wheezing in overt and latent asthmatic patients. Should selective or nonselective β2-adrenergic antagonists be required in a patient with asthma, cautious 998
increases in dose with close supervision is recommended. Both cardioselective (atenolol and metoprolol) and nonselective (propranolol, carvedilol, lebatalol, and timolol) blockers have been associated with increased numbers of emergency department visits and hospitalizations in patients with asthma (327). Acute bronchospasm has been associated with conjunctival instillation of timolol for glaucoma (328). Bronchoconstriction has also been described for betaxolol, a β1-adrenergic antagonist, which is less likely to cause declines in FEV1 than timolol (329). Occasionally, parasympathomimetic agents, such as pilocarpine, administered in the conjunctival sac can cause bronchospasm. It is advisable to make certain that the patient with persistent asthma is first achieving adequate control of asthma, such as with ICS or β2-adrenergic agonist/ICS or other medications, so that any possible effects from necessary ophthalmic drugs are minimized. Angiotensin-converting enzyme (ACE) inhibitors have been associated with cough and asthma (in addition to pharyngeal or laryngeal angioedema), even after the first dose (330,331). Discontinuation of the ACE inhibitor is associated with resolution of cough over several days or up to a month. ACE inhibitors and angiotensin receptor blockers antagonists are not contraindicated in patients with asthma in the absence of prior adverse reactions, such as cough or acute angioedema. Narcotics analgesics, such as morphine, oxycodone, hydromorphone, and fentanyl, are at least relatively (or absolutely) contraindicated during exacerbations of asthma. Moreover, morphine can activate mast cells to release histamine. Nocturnal reductions in PO2 occur regularly in normal subjects and in patients with asthma. Acute severe asthma (status asthmaticus) is a contraindication for the use of soporific medications. Antidepressants of the tricyclic or serotonin reuptake inhibitor classes can be continued with asthma medications. Antidepressants of the monoamine oxidase inhibitor class can be utilized but are not recommended in a patient who might receive epinephrine because there could be a severe hypertensive crisis. Drugs possessing anticholinesterase properties may potentiate wheezing. This results from their parasympathomimetic-enhancing effect caused by the inhibition of acetylcholine catabolism. These drugs represent the primary drug treatment of myasthenia gravis; if asthma coexists, a therapeutic problem arises. When anticholinesterases are necessary, maximal doses of β2-adrenergic agonists and ICS may be necessary. The addition of oral corticosteroids may be
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indicated for more adequate control of asthma, but it must be remembered that, in some patients, myasthenic symptoms may initially worsen with addition of oral corticosteroids (332).
Nonpharmacologic Treatment Allergen Avoidance For those patients with allergic asthma, specific allergy management must be included in their treatment regimen. In adults, inhalant allergens are the most frequent causative agents. Many, but not all, studies suggest that there is a dose– response relationship between allergen exposure and development of asthma. Moreover, there are suggestions that there are threshold levels of allergen exposure, below which sensitization and, therefore, allergic asthma are unlikely to occur. For a major dust mite allergen Der p 1 it is 2 µg/g dust and for a major cockroach allergen Bla g 1, it is 1 unit/g dust. When one allergen is the primary cause (e.g., animal dander) and can be removed from the environment, symptomatic relief is achieved, often within 1 to 2 months (or longer) if there is thorough cleaning. Most allergic patients, however, are sensitive to more than one allergen, and many allergens cannot be removed completely. As a result, certain strategies are recommended for avoidance of particular agents. To reduce dust mite allergen, certain basic environmental controls in the house are advisable (333). Hypoallergenic pillows are preferred and should be enclosed in impermeable encasings. Box springs and mattresses should similarly be enclosed. Relative humidity inside the home should be between 35% and 50% to decrease dust mite growth. Bedding should be washed weekly in warm water. In some situations, additional cleaning and/or removal of carpets is beneficial because the carpet is a reservoir of dust mite allergen. For the highly dustallergic patient, appropriate filters (i.e., high-efficiency particular air filters) on furnaces and vacuums as well as air cleaners should be used and maintained properly. The use of acaricides to eliminate dust mites, however, has limited efficacy. In patients with perennial symptoms, it is generally advisable that pets (e.g., cats, dogs, and birds) be removed from the house if there are symptoms from contact or if there is a positive skin test. As stated earlier in this chapter, cat dander (Fel d I) antigen may require months for levels to fall below threshold levels (< 8 µg Fed d 1 /mg dust) once 1000
the cat is removed from the household (177). Often, patients will not remove the pet as advised and instead, the physician and patient must rely on pharmacologic therapies. Washing pets weekly can reduce, albeit temporarily, pet allergen levels (334). Other aspects may be considered with regard to the environmental control in the home. Basement apartments, because of increased moisture, are most likely to have higher levels of airborne fungi and mite antigens. Visible molds should be removed and, depending on the severity of asthma or difficulty in achieving adequate control, cleaning of the heating-ventilation-air conditioning ducts should be performed. Measures to reduce exposure to rodent urine and cockroaches should be implemented and likely require continued effort (13,335). Ingestion of foods essentially is never the cause of asthma; an exception occurs when the cause is acute severe bronchoconstriction from anaphylaxis. Patients, however, may attribute their respiratory symptoms to aspartame or monosodium glutamate although such associations are not justified. Exposure to sulfur dioxide from sodium or potassium metabisulfite (used as an antioxidant in foods) can cause acute respiratory symptoms in patients with asthma. However, patients with stable asthma who are managed by anti-inflammatory medications will not be affected significantly by metabisulfite. But air pollution, including smoke and ash that has blown hundreds of miles from the source, can cause worsening control of asthma. Immunotherapy When environmental control is either impossible or insufficient to control symptoms in mono- or polysensitized patients with allergic asthma, subcutaneous allergen immunotherapy should be considered (see Chapter 13). Efficacy in asthma has been documented for pollens, dust mites, and Cladosporium species (336,337), and allergen immunotherapy should be considered in patients with persistent asthma, who are also being treated with pharmacotherapy (3) (Table 19.6). Other than very modest effects, subcutaneous immunotherapy with cat dander extracts has not been impressive in reducing symptoms when the cat remains in the home environment. While some studies have suggested the sublingual immunotherapy (SLIT) may reduce asthma symptoms (338), SLIT is not currently a recommended treatment option for asthma, and additional studies are needed to further investigate this indication. Johnstone and Dutton (339), in a 14-year prospective study of subcutaneous allergen immunotherapy for asthmatic children, reported that 72% of the treated group were free of symptoms at 16 years of age, as compared with only 22% of 1001
the placebo group. This publication occurred in 1968 and, for decades, was treated with healthy skepticism. In 2007, somewhat similar data were reported again, in that children with rhinitis who received allergen immunotherapy had less emergence of asthma those patients who did not receive allergen immunotherapy (340). Bronchial Thermoplasty Bronchial thermoplasty involves the delivery of targeted thermal energy directly into the airways to ablate smooth muscle and thus attenuate bronchoconstriction. The procedure is performed by bronchoscopy and divided into three treatment sessions (bronchoscopy) that specifically target the right lower lobe, then left lower lobe, and finally bilateral upper lobes of the lungs. It is currently approved for the treatment of uncontrolled severe persistent asthma despite ICS/LABA in patients aged 18 years and older. During the bronchial thermoplasty treatment period, a transient worsening of asthma symptoms in some patients occurred (341–343). However, following this period, studies have reported variable clinical outcomes. In one instance, lung function as measured by mean FEV1 was not significantly different between bronchial thermoplasty and controls, but subjective asthma symptoms did improve with the former treatment (342). In a second unblinded trial, bronchial thermoplasty was associated with a significant increase in FEV1 and reduction in rescue inhaler use (341). Finally, in a large double-blind randomized control study, patients who received either bronchial thermoplasty or a sham procedure both noted improvements in asthma symptoms, but only those who received active treatment reported a significant reduction in asthma exacerbations and ER visits (344). Given these findings, there may be certain patients for whom bronchial thermoplasty will be beneficial. Yet, there is currently no biomarker available to predict who these patients may be. Furthermore, the studies above excluded patients with FEV1 less than 50% or had frequent asthma exacerbations, and thus the efficacy of bronchial thermoplasty in patients with severe asthma or those who are corticosteroid-dependent remains unknown. After 5 years, patients who received bronchial thermoplasty had stable lung function but continued to report lower rates of severe asthma exacerbations than prior to treatment (344). These suggest bronchial thermoplasty is well tolerated after the initial treatment period but longer follow-up studies are still indicated to monitor for any adverse effects.
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MANAGING PHENOTYPES OF ASTHMA Nonallergic Asthma Treatment of nonallergic asthma primarily involves the judicious use of pharmacologic therapy as avoidance measures; immunotherapy and immunomodulator treatments are not indicated. The next three paragraphs apply to allergic asthma as well. Convincing evidence is available that virus-induced upper respiratory infections initiate exacerbations of asthma. Important agents for children 0 to 5 years of age include rhinovirus, RSV, parainfluenza virus; for older children and adults, influenza virus, parainfluenza virus, and rhinovirus are important. Adenovirus infection rarely acts to initiate asthma attacks. Additional viruses will be understood better (metapneumoviruses) or identified that are associated with episodes of asthma. Mycoplasma pneumoniae infections may be associated with new-onset asthma (345) or likely exacerbations of established asthma (346). In patients with acute exacerbations of asthma, in which serologic evidence of infection with M. pneumoniae or Chlamydophilia (formerly Chlamydia) pneumoniae was present, the macrolide, telithromycin, reduced symptoms (40% vs. 27%) but did not improve PEFR significantly more than placebo (78 vs. 67 L/minute) (346). It remains to be established whether there will be an indication for macrolides for treatment of asthma, for example, whether there is an anti-inflammatory or antiinfective role because data have been disappointing for cough (347) and asthma (348). Annual influenza vaccination should be administered according to the Centers for Disease Control and Prevention recommendations for children and adults. Treatment of secondary bacterial infections, such as acute (purulent) bronchitis and rhinosinusitis, is desirable. Pneumococcal vaccine can be administered to adults over the age of 50 years with persistent asthma, although pneumococcal pneumonia is an infrequent occurrence.
Aspirin-Exacerbated Intolerant Asthma)
Respiratory
Disease
(Aspirin-
Treatment of aspirin-exacerbated respiratory disease (aspirin-intolerant asthma) includes avoidance measures for patients with IgE-mediated triggers of asthma, anti-inflammatory therapy, and management of CRS. It is important to avoid 1003
aspirin and nonselective NSAIDs, which may also produce serious acute bronchoconstriction. Patients must be informed that numerous proprietary mixtures contain aspirin, and they must be certain to take no proprietary medication that contains acetylsalicylic acid. Acetaminophen may be used as a safe substitute for aspirin in nearly all patients, and other salicylates, such as sodium salicylate, choline magnesium trisalicylate, or salsalate, can be taken safely. Other patients respond with urticaria, angioedema, or anaphylaxis. The mechanisms of acute bronchoconstriction include the blockade of cyclooxygenase-1, reduced production of PGE2, and generation of LTC4 and LTD4. Patients with aspirin-exacerbated respiratory disease have increased baseline urinary concentrations of LTE4, a marker of 5-LO products. After aspirin ingestion, there is even greater increase in urinary LTE4 concentrations, consistent with synthesis of the potent agonist LTD4. Although PGE2 can be thought of as a bronchodilator, it has a major role in “braking” the production of leukotrienes via inhibitory effects on 5-LO and FLAP. PGE2 also stabilizes mast cells, but this protective effect is also reduced after aspirin ingestion. The cyclooxygenase-2 inhibitors are tolerated uneventfully (349). There are very few patients who experience acute bronchoconstriction from both cyclooygenase-1 and cyclooxygenase-2 antagonists. In some situations, provocative dose testing with either aspirin or NSAIDs may be carried out to confirm the diagnosis or to treat underlying aspirinexacerbated respiratory disease. Because the mean provoking dose of aspirin was 62 mg during oral challenges (350), the physician or proficient health care professional should be in attendance at all times because of the explosiveness and severity of these reactions, primarily when the initial dosage is the full dose. The FEV1 should be at least 70% before the challenge. Pulmonary function parameters and vital signs should be measured prospectively because the patient can begin wheezing abruptly and drop the FEV1 by 30% to 40%. Aspirin should be administered in serial doubling doses, beginning with 30 mg (It may be advisable to begin with 3 to 10 mg in some patients. Indeed, the 3 mg dosage could serve as an active placebo in very anxious patients). The dosage is advanced to 60, 100, 150, 325, and 650 mg every 3 hours if there is 2,000 μg/day may cause adrenal suppression or adverse effects on bone health and still not improve asthma. Another approach for moderate and severe asthma is bronchial thermoplasty. It is hoped that there will be tangible clinical benefit from the reduction in the smooth muscle mass. Asthma is a long-term condition with fluctuations. In a study of the natural history of severe persistent asthma in patients who required at least 1 year of prednisone in addition to other pharmacotherapy (β2-adrenergic agonists, theophylline, and high-dose ICS), avoidance measures, and possibly immunotherapy, prednisone-free intervals occurred, even lasting several years, before prednisone was required again (362). It was uncommon to have greater prednisone requirements, although usually, in these cases of persistent severe asthma, prednisone dosages were stable over time, or reductions occurred. The conclusion is that in assessment of novel treatments for persistent moderate, severe, or refractory asthma, adequate “wash-in” periods are needed in studies of such patients; otherwise, credit may be given to a new therapy inappropriately. The term glucocorticoid-resistant has been applied to patients with asthma who do not increase their FEV1 by 12% after 1 week administration of prednisone 40 mg daily (363). Experimentally, glucocorticoid receptor downregulation on T lymphocytes has been identified, suggesting that such patients could have impaired inhibition of activated T lymphocytes in asthma. For example, in cells from corticosteroid-resistant patients, dexamethasone in vitro did not inhibit T-lymphocyte proliferation to the mitogen phytohemagglutinin. Incubation with vitamin D also produced little effect in monocytes from patients with steroid resistant as opposed to steroid-sensitive patients (363). Excessive and harmful allergic inflammation characterizes this form of difficult to treat asthma. In summarizing the discussion of intractable or difficult to treat or refractory asthma, it is worth reconsidering the differential diagnosis of asthma. Some patients will have unrecognized VCD and asthma. Other patients may misrepresent their dosages and use of prednisone. 1014
ACUTE SEVERE ASTHMATICUS)
ASTHMA
(STATUS
Acute severe asthma (status asthmaticus) is defined as severe asthma unresponsive to emergency therapy with β2-adrenergic agonists (see Chapter 21). It is a medical emergency for which immediate recognition and treatment are necessary to avoid a fatal outcome. For practical purposes, acute severe asthma is present in the absence of meaningful response to two aerosol treatments with β2-adrenergic agonists or 1 hour of nebulized albuterol. A number of factors have been shown to be important in inducing acute severe asthma and contributing to the mortality of asthma. About half of patients have an associated respiratory tract infection. Some have overused short-acting β2-adrenergic agonists before developing refractoriness. In the aspirinexacerbated respiratory disease asthmatic patient, ingestion of aspirin or related cyclooxygenase-1 inhibitors may precipitate acute severe asthma. Exposure to animal dander (especially cat dander) in the highly atopic patient may contribute to development of acute severe asthma, particularly when this is associated with an upper respiratory infection. Withdrawal or too sudden reduction of oral or ICS may be associated with the development of acute severe asthma. In many situations, both the patient and physician or health care provider are unaware of the severity of progression of symptoms, and often earlier and more aggressive medical management would have prevented the need for emergency department visit or hospitalization. The inappropriate use of soporific medications in the treatment of acute severe asthma has contributed to the development of respiratory failure. Acute severe asthma requires immediate treatment with high-dose corticosteroids either parenterally or orally. Patients with acute severe asthma must be hospitalized where close observation and ancillary treatment by experienced personnel are available. If respiratory failure occurs, optimal treatment often involves the combined efforts of the emergency department physician, pulmonary disease critical care specialist, and/or anesthesiologist. Initial laboratory studies should include a complete blood count, Gram stain with culture and sensitivity of the sputum, chest radiograph, serum electrolytes, and chemistries; pulse oximetry; and perhaps arterial blood gas studies (Tables 19.12 and 19.13). There may be considerable improvement during treatment of acute severe asthma without improvement in PEFR, FEV1, or FVC. This apparent lack of spirometric improvement occurs even though the hyperinflation 1015
of lung volumes is diminishing in association with a reduction in the elastic work of breathing. The severity of acute asthma is organized into four stages (Table 19.13). Stage I signifies the presence of airway obstruction only. Because of the associated hyperventilation, the PCO2 is low, and the pH is, therefore, slightly alkalotic (respiratory alkalosis). The PO2 in stage I is normal. Spirometric study shows only a decrease in FEV1, with a normal vital capacity. As symptoms progress, obstruction of the airway increases, compliance decreases, and air trapping and hyperinflation develop. As a result of the latter changes, the FRC increases, and the vital capacity is decreased. In stage II, V/Q imbalance with hypoxemia occurs. These changes, however, are not enough to impair net alveolar ventilation; thus, although PO2 is lowered, PCO2 remains low, and an alkalotic pH persists. With progressive severity, net alveolar ventilation decreases, and a transitional period exists (stage III), in which the PCO2 increases and the pH decreases, so that now both values appear to be normal. When the blood gas study shows hypoxemia in the presence of a normal PCO2 and pH, close supervision and frequent determinations of pH and PCO2 are essential to evaluate the adequacy of treatment and the possible progression to respiratory failure characterized by hypoxemia and elevated PCO2 (stage IV). Clinical observation alone is inadequate in determining the seriousness of acute severe asthma. TABLE 19.12 INITIAL TREATMENT OF ACUTE SEVERE ASTHMA 1.Corticosteroid therapy (give immediately in the office or emergency department). Methylprednisolone (Solu-Medrol), 0.5–1.0 mg/kg intravenously every 6 h; or hydrocortisone (Solu-Cortef), 4 mg/kg intravenously every 6 h; or prednisone, 1 mg/kg orally every 6 h (minimum is 80 mg methylprednisolone equivalent/24 h) 2.β-Adrenergic agonists Choice of approaches available: a. Aerosolized therapy; albuterol or levalbuterol Repeat twice at 20-min intervals, then at reduced frequency. May use continuous nebulization of albuterol or levalbuterol. b. Epinephrine, 0.01 mL/kg of 1:1,000 solution, intramuscularly not to exceed 0.3–0.4 mL in adults. May repeat twice at 20-min intervals, then at reduced frequency. c. If a patient does not respond to (a), try (b).
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3.Ipratropium bromide (can be combined with albuterol) 4.Hospitalize 5.Laboratory studies White blood cell count with differential Chest radiograph Pulse oximetry or arterial blood gas Serum electrolytes and chemistries Sputum Gram stain, culture, and sensitivities (some cases) Bedside spirometer may be useful, but not essential Electrocardiogram (some cases) 6.Oxygen therapy; 2–3 L/minute nasal cannula (best guided by arterial blood gas determination) 7.Correct dehydration 8.Aminophylline therapy (controversial because of unclear benefit for many patients). Check theophylline concentration if chronic therapy. Administration is discouraged because efficacy has been questioned during emergency use. 9.Antibiotic therapy. When indicated for bronchitis or exacerbations of rhinosinusitis. 10.Impending or acute respiratory failure. Repeat β2-adrenergic agonists; endotracheal intubation with assisted or controlled ventilation.
TABLE 19.13 SPIROMETRY AND BLOOD GASES IN ASTHMA AS RELATED TO THE STAGE OR SEVERITY
FEV1
VITAL CAPACITY
Po2 Pco2 pH (NORMAL, (NORMAL, (NORMAL, 7.35–7.43 mm 90–100 mm Hg) 35–40 mm Hg) Hg)
Stage I (respiratory alkalosis)
↓
Normal
Normal
↓
>7.43
Stage II (respiratory alkalosis)
↓↓
↓
↓
↓↓
>7.43
Stage III
↓↓↓
↓↓
↓↓
35–40
7.35–7.43
1017
Stage IV (respiratory acidosis)
↓↓↓↓
↓↓↓
↓↓↓
↑↑↑
or = 12 years of age. Intal Study Group. Chest. 1999;116:65–72. 323. van der Wouden JC, Uijen JH, Bernsen RM, et al. Inhaled sodium cromoglycate for asthma in children. Cochrane Database Syst Rev. 2008:CD002173. doi:10.1002/14651858.CD002173.pub2. 324. Strunk RC, Weiss ST, Yates KP, et al. Mild to moderate asthma affects lung growth in children and adolescents. J Allergy Clin Immunol. 2006;118:1040–1047. 325. Kelly K, Spooner CH, Rowe BH. Nedocromil sodium vs. sodium cromoglycate for preventing exercise-induced bronchoconstriction in asthmatics. Cochrane Database Syst Rev. 2000:CD002731. doi:10.1002/14651858.CD002731. 326. Vrijens B, Dima AL, Van Ganse E, et al. What we mean when we talk about adherence in respiratory medicine. J Allergy Clin Immunol Pract. 2016;4:802–812. 327. Brooks TW, Creekmore FM, Young DC, et al. Rates of hospitalizations and emergency department visits in patients with asthma and chronic obstructive pulmonary disease taking beta-blockers. Pharmacotherapy. 2007;27:684–690. 328. Prakash UB, Rosenow EC III. Pulmonary complications from ophthalmic 1054
preparations. Mayo Clin Proc. 1990;65:521–529. 329. Dunn TL, Gerber MJ, Shen AS, et al. The effect of topical ophthalmic instillation of timolol and betaxolol on lung function in asthmatic subjects. Am Rev Respir Dis. 1986;133:264–268. 330. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence-based clinical practice guidelines. Chest. 2006;129:169S– 173S. 331. Lipworth BJ, McMurray JJ, Clark RA, et al. Development of persistent late onset asthma following treatment with captopril. Eur Respir J. 1989;2:586–588. 332. Adams SL, Mathews J, Grammer LC. Drugs that may exacerbate myasthenia gravis. Ann Emerg Med. 1984;13:532–538. 333. Portnoy J, Miller JD, Williams PB, et al. Environmental assessment and exposure control of dust mites: a practice parameter. Ann Allergy Asthma Immunol. 2013;111:465–507. 334. Portnoy J, Kennedy K, Sublett J, et al. Environmental assessment and exposure control: a practice parameter—furry animals. Ann Allergy Asthma Immunol. 2012;108:223.e1–223.e15. 335. Portnoy J, Chew GL, Phipatanakul W, et al. Environmental assessment and exposure reduction of cockroaches: a practice parameter. J Allergy Clin Immunol. 2013;132:802-8 e1–802-8 e25. 336. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2003:CD001186. doi:10.1002/14651858.CD001186. 337. Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011;127:S1–S55. 338. Compalati E, Passalacqua G, Bonini M, et al. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: results of a GA2LEN meta-analysis. Allergy. 2009;64:1570–1579. 339. Johnstone DE, Dutton A. The value of hyposensitization therapy for bronchial asthma in children—a 14-year study. Pediatrics. 1968;42:793– 802. 340. Jacobsen L, Niggemann B, Dreborg S, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year 1055
follow-up on the PAT study. Allergy. 2007;62:943–948. 341. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007;176:1185–1191. 342. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007;356:1327–1337. 343. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181:116–124. 344. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol. 2013;132:1295–1302. 345. Ou CY, Tseng YF, Chiou YH, et al. The role of Mycoplasma pneumoniae in acute exacerbation of asthma in children. Acta Paediatr Taiwan. 2008;49:14–18. 346. Sutherland ER, Martin RJ. Asthma and atypical bacterial infection. Chest. 2007;132:1962–1966. 347. Hodgson D, Anderson J, Reynolds C, et al. The effects of azithromycin in treatment-resistant cough: a randomized, double-blind, placebo-controlled trial. Chest. 2016;149:1052–1060. 348. Wong EH, Porter JD, Edwards MR, et al. The role of macrolides in asthma: current evidence and future directions. Lancet Respir Med. 2014;2:657–670. 349. Celik G, Pas¸aog˘lu G, Bavbek S, et al. Tolerability of selective cyclooxygenase inhibitor, celecoxib, in patients with analgesic intolerance. J Asthma. 2005;42:127–131. 350. Hope AP, Woessner KA, Simon RA, et al. Rational approach to aspirin dosing during oral challenges and desensitization of patients with aspirinexacerbated respiratory disease. J Allergy Clin Immunol. 2009;123:406– 410. 351. Mullarkey MF, Blumenstein BA, Andrade WP, et al. Methotrexate in the treatment of corticosteroid-dependent asthma. a double-blind crossover study. N Engl J Med. 1988;318:603–607. 1056
352. Erzurum SC, Leff JA, Cochran JE. Lack of benefit of methotrexate in severe, steroid-dependent asthma. A double-blind, placebo-controlled study. Ann Intern Med. 1991;114:353–360. 353. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir. 2014;43:343–373. 354. Evans DJ, Cullinan P, Geddes DM. Cyclosporine as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev. 2001; (2):CD002993. doi:10.1002/14651858.CD002993. 355. Muranaka M, Miyamoto T, Shida T, et al. Gold salt in the treatment of bronchial asthma—a double-blind study. Ann Allergy. 1978;40:132–137. 356. Li Y-F, Gauderman J, Avol A, et al. Associations of tumor necrosis factor G-308A with childhood asthma and wheezing. Am J Respir Crit Care Med. 2006;173:970–976. 357. Erin EM, Leaker BR, Nicholson GC, et al. The effects of monoclonal antibody directed against tumor necrosis factor-α in asthma. Am J Respir Crit Care Med. 2006;174:753–762. 358. Salmun LM, Barlan I, Wolf HM, et al. Effect of intravenous immunoglobulin on steroid consumption in patients with severe asthma: a double-blind, placebo-controlled, randomized trial. J Allergy Clin Immunol. 1999;103:810–815. 359. Landwehr LP, Jeppson JD, Katlan MG, et al. Benefits of high-dose IV immunoglobulin in patients with severe steroid-dependent asthma. Chest. 1998;114:1349–1356. 360. Hunt LW, Swedlund HA, Gleich GJ. Effect of nebulized lidocaine on severe glucocorticoid-dependent asthma. Mayo Clin Proc. 1996;71:361– 368. 361. Decco ML, Neeno TA, Hunt LW, et al. Nebulized lidocaine in the treatment of severe asthma in children: a pilot study. Ann Allergy Asthma Immunol. 1999;82:29–32. 362. Dykewicz MS, Greenberger PA, Patterson R, et al. Natural history of asthma in patients requiring long-term systemic corticosteroids. Arch Intern Med. 1986;146:2369–2372. 363. Zhang Y, Leung DY, Goleva E. Anti-inflammatory and corticosteroid1057
enhancing actions of vitamin D in monocytes of patients with steroidresistant and those with steroid-sensitive asthma. J Allergy Clin Immunol. 2014;133:1744–1752. 364. Becker JM, Arora A, Scarfone RJ, et al. Oral versus intravenous corticosteroids in children hospitalized with asthma. J Allergy Clin Immunol. 1999;103:586–590. 365. Levenson T, Greenberger PA, Donoghue ER, et al. Asthma deaths confounded by substance abuse: an assessment of fatal asthma. Chest. 1996;110:604–610. 366. Sabin BR, Greenberger PA. Chapter 13: Potentially (near) fatal asthma. Allergy Asthma Proc. 2012;33(Suppl 1):S44–S46. 367. Tirumalasetty J, Grammer LC. Asthma, surgery, and general anesthesia: a review. J Asthma. 2006;43:251–254. 368. Su FW, Beckman DB, Yarnold PA, et al. Low incidence of complications in asthmatic patients treated with preoperative corticosteroids. Allergy Asthma Proc. 2004;25:327–333. 369. Lange P, Scharling H, Ulrik CS, et al. Inhaled corticosteroids and decline of lung function in community residents with asthma. Thorax. 2006;61:100–104. 370. O’Byrne PM, Pedersen S, Busse WW, et al. Effects of early intervention with inhaled budesonide on lung function in newly diagnosed asthma. Chest. 2006;129:1478–1485. 371. Weiss ST, McGeachie MJ. Decline in lung function in childhood asthma. N Engl J Med. 2016;375:7.
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Recurrent wheezing is a common problem among infants, toddlers, and young children. As a simple starting point, this chapter refers to asthma in children less than 5 years of age with four or more episodes of wheezing. These episodes improve with bronchodilators or anti-inflammatory medications and may or may not be associated with viral infections. In many of these young asthmatics, environmental allergy is already playing an underappreciated role. Scientific advances are slowly being introduced in the identification of asthma in young children. The purpose of this chapter is to review the latest known factors important in the development of asthma in infants and very young children. Also, current difficulties of evaluation and management of wheezing in these children are discussed.
EPIDEMIOLOGY The prevalence rate for asthma in infants and young children is increasing, particularly in westernized countries. An increase in atopy as well as improvements in disease diagnosis may be contributing factors (1). Children under 3 years of age have a significantly higher risk of being diagnosed with asthma now compared to previous years (2). Hospital admission and emergency department (ED) visit rates are highest among children aged 4 years and under as compared to older asthmatic children (3,4). Asthmatic children under 24 months of age are four times more likely to be admitted to the hospital than teenagers with asthma (5). In Norway, 75% of all children hospitalized for asthma are under 4 years of age (6). Although the number of days in the hospital is declining in older children, hospital length of stay for asthmatic infants is not changing (7). In addition, infants are more likely to require emergency room assistance for asthma exacerbations, and they have higher risk of respiratory failure (8,9). The use of the emergency room for treatment is common among uninsured and 1059
minority infants who present with the highest disease burden, and incur increasing economic direct costs (10). Currently, asthma deaths in all age groups have decreased (11). Overall, it appears that hospitalization rates may be improving for older children, but no substantial progress has been made in improving the quality of life of asthmatic infants (12). The daily quality of life of the very young children with asthma is also diminished because these children have more sleep disruptions, limitations in activity and play than older asthmatic children (4).
NATURAL HISTORY Wheezing in infants and young children can be divided into three specific phenotypes: early transient wheezers, late-onset nonatopic wheezers, and persistent atopic wheeze/asthma (12). The early transient wheezers have symptoms primarily with viral infections, do not wheeze in between infectious episodes, and are no longer wheezing by the time they are 6 years of age. They often respond poorly to bronchodilators and asthma-controller medications. The late-onset, nonatopic wheezers will wheeze with viral infections and also under other conditions, such as exercise. Their prevalence peaks between 3 and 6 years of age and then gradually declines and frequently becomes asymptomatic early in the second decade of life. The third phenotype combines wheezing with evidence of immunoglobulin E (IgE)-mediated disease. This atopic phenotype is the group most likely to have persistent wheezing. This phenotype gradually increases until it becomes the most common cause of wheezing by 6 years of age. Most recently, it has been demonstrated that the initial age of asthma diagnosis has been dropping from 4.7 to 2.6 years of age (6). An asthma predictive index (API) (13) was developed to predict infants who were more likely to go on to develop asthma when they were older. It was subsequently modified to include criteria of the child having four or more wheezing episodes with at least one episode being physician diagnosed. In addition, there must be either one major criterion of the following: parental asthma history, physician diagnosed atopic dermatitis or allergic sensitization to at least one aeroallergen, or two minor criteria of allergic sensitization to milk, egg, or peanut, wheezing unrelated to colds and blood eosinophilia ≥4% (14). In a subsequent iteration, the University of Cincinnati API (ucAPI) was developed in a cohort of 3-year-old children subsequently diagnosed with asthma at 7 years of age as defined by positive postbronchodilator testing (forced expiratory volume in 1 second increases ≥12%)/methacholine challenge (PC20 ≤ 4 mg/mL) or by the clinical 1060
need for daily controller therapy (15). Persistent wheezing was defined as physician diagnosed asthma or two or more wheezing episodes in the last 12 months at both 2- and 3-year-old visits. In this study, either persistent wheezing phenotype or a positive ucAPI was associated with meeting criteria of asthma at 7 years of age. Table 20.1 demonstrates the key components of the ucAPI. Either ucAPI or the modified API (mAPI) are acceptable tools for discerning the appropriateness of a diagnosis of asthma in a wheezing toddler. The strength of the University of Cincinnati study was a focus on slightly different criteria which would readily be usable at the initial consultation visit of a wheezing child. The ucAPI has minor criteria investigable with prick skin testing and without a delay required by a blood draw for the identification of eosinophilia as in the mAPI. In addition, the ucAPI has been linked to asthma at 7 years of age. The mAPI has the advantage that remission of asthma in the future is linked to disappearance of blood eosinophilia 7 days. Metapneumovirus causes febrile winter-time asthma exacerbations in children. Children presenting with status asthmaticus had prolonged hospitalizations when infected with metapneumovirus (38). In asthmatic children under 3 years of age, Manoha et al. (39) found that 1063
metapneumovirus and rhinovirus were more significant viral triggers of asthma exacerbations than RSV (39). In addition, pediatric infections with picornaviruses are associated with status asthmaticus admissions to the pediatric intensive care unit (40). Cytomegalovirus infection has been noted to cause wheezing even in immunocompetent infants (41). Enterovirus D68 has been noted to cause wheezing in young children (42).
Allergy Until recently, allergy was not considered a risk factor for the development of wheezing in infants and very young children. In 1970, Bernton and Brown (43) skin-tested allergic children to cockroach allergen and found no child under 4 years of age with a positive skin test. Other early studies also suggested that IgEmediated allergy did not act as a trigger for infantile asthma (44). These studies have formed the groundwork for the case that allergy is unimportant to infantile asthma. Case for Indoor Atopic Sensitization Affecting Asthma in Infants and Toddlers Allergic sensitization now forms a core criterion in asthma predictive indices. The need for allergist input in determining aeroallergen sensitization was recently studied, and the use of clinical features alone without tests was inaccurate at predicting allergic from nonallergic asthma in children (45). In addition, the 2005 to 2006 National Health and Nutrition Examination survey revealed that information of IgE sensitization to cockroach, rat, and mold were associated with an increased risk for ED visits (46). There are multiple regional and age-related factors involved when investigating indoor aeroallergen sources of sensitization. Delacourt et al. (47) reported that 25% of infants with recurrent wheezing had positive skin test results to either dust mites or cat allergen. The prevalence rate for reactivity to one inhalant in a general population of 1- and 6-year-old was 11% and 30%, respectively (48). Wilson et al. (49) evaluated 196 rural children less than 3 years of age diagnosed with infantile asthma for allergy. Forty-five percent of the infants who were tested to indoor inhalant allergens had at least one positive skin test result. For the 49 children who were under 1 year of age, 28.5% had a positive skin test to cockroach and 10.2% to dust mite. Environmental factors in home cooling such as evaporative coolers have been linked to higher sensitization rates in children to dust mite as compared to desert dwellers utilizing central air conditioners (50). Mouse allergy is present in 12% of asthmatic children (51). Sensitization to mouse, presumably from indoor 1064
exposure, has been linked to increased asthma symptoms and hospitalization in very young asthmatic children (52). Cockroach sensitization is linked to previous episodes of wheezing in young children (53). In addition, 30% of rural asthmatic children may have sensitization to flying insects, such as mayfly, housefly, caddis fly, moth, and ant (54). Finally, the usefulness of identifying concurrent indoor aeroallergen sensitization was also demonstrated in the Childhood Asthma Management Program (CAMP) in which nonatopic wheezing preschoolers had remitting asthma at 4 years after study entry (55,56). Case for Aeroallergen Sensitization to Pollen Affecting Asthma in Infants and Toddlers Many pediatricians have been reluctant to test very young children and infants to aeroallergens. However, studies suggest that aeroallergen sensitization in very young children may in fact occur despite “common wisdom.” In a birth cohort study, aeroallergen sensitized 4-year-old children had significant allergic diseases, such as asthma (52). Forty-two percent of children sensitized to grass had asthma. In addition, a majority of children were already sensitized to more than one allergen, and this increased sensitization was associated with an increased risk of asthma. Ogershok et al. (57) found that while no children under 12 months of age had aeroallergen sensitization, 29% of 12- to 24-month-olds with asthma were pollen sensitized (57). In this study, equal numbers of 3-yearold asthmatic infants and toddlers were sensitized to pollen as to indoor allergens. Overall, 40% of asthmatic children between 12 and 36 months of age were noted to be pollen sensitized. In another study, up to 52% of children less than 3 years of age with asthma were sensitized to pollen (58). This early sensitization to pollen in wheezing infants predicted subsequent asthma through adolescence (59). Studies of pediatric asthma have demonstrated that children as young as preschoolers have pollen-associated asthma symptoms, exacerbations, and hospital admissions (60).
EVALUATION OF WHEEZING INFANT
THE
PERSISTENTLY
Infants and young children with repeated episodes of wheezing require a complete history and physical examination. The frequency of hospitalizations and ED visits helps indicate the severity of the problem. Response to bronchodilators or maintenance inhaled corticosteroids (ICS) or use of an API may provide clues supportive of a diagnosis of asthma. Persistent coughing and wheezing associated with triggers other than viral infections strongly suggests 1065
asthma. A history of persistent wheezing, particularly if not associated with a viral infection such as those wheezing episodes associated with exposure to pets, foods, indoor, or outdoor allergens, is an indication for skin testing. Persistently wheezing infants not responding to inhaled or systemic glucocorticosteroids or bronchodilators might need flexible bronchoscopy as suggested by 2016 American Thoracic Society (ATS) clinical practice guidelines (61), albeit this recommendation had a low quality of evidence. Factors important in the history of the coughing or wheezing infant are listed in Table 20.2. In taking an environmental history, one should remember that many infants spend significant amounts of time in more than one household. The differential diagnosis of infantile wheezing may be complex (Table 20.3). Asthma in a child under 1 year of age is a diagnosis of exclusion because congenital defects are more prevalent in this age group. The height and weight should be compared with standard norms to determine the growth pattern. On auscultation, the presence of inspiratory wheezing may indicate extrathoracic obstruction. Wheezing due to asthma occurs throughout the entire expiratory phase. Specifically, expiratory stridor mimicking wheezing will not carry through to the end of expiration. Rales or rhonchi may indicate atelectasis or pneumonia. Unequal breath sounds may suggest diaphragmatic hernia or pneumothorax. TABLE 20.2 IMPORTANT FACTORS IN THE HISTORY OF THE WHEEZING INFANT HISTORY
POTENTIAL ETIOLOGY
Sudden onset
Foreign object
Intubation at birth
Subglottic stenosis, chronic lung disease of prematurity
Maternal papillomatosis
Laryngeal papilloma
Forceps delivery
Vocal cord injury
Difficulty feeding, dysphagia
Congenital heart defect Neurogenic defect
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Eosinophilic esophagitis Irritability, regurgitation, torticollis
Sandifer syndrome (gastroesophageal reflux)
Recurrent pneumonia
Aspiration Tracheoesophageal fistula Cystic fibrosis Ciliary dyskinesia Immunodeficiency Human immunodeficiency virus infection
Formula changes
Milk or soy allergy, GERD
Isolated episode
Tuberculosis Respiratory syncytial virus Adenovirus Histoplasmosis Parainfluenza virus Metapneumovirus Mycoplasma Bocavirus Enterovirus D86
Eczema, urticaria
Atopic diseases associated with asthma
Severe or recurrent infections
Immunodeficiencies
Recurrent wheezing ≥4 episodes
Asthma
GERD, gastroesophageal reflux disease.
Infants under 1 year of age with persistent wheezing and older children with a suggestive history should be evaluated for GER, anatomic abnormalities, and 1067
feeding disorders. An upper gastrointestinal series performed after consultation with a radiologist will provide information about anatomic abnormalities, such as diaphragmatic hernia, gastric volvulus, tracheoesophageal fistulas, and vascular rings, and may provide evidence of GER if it occurs during the examination. Feeding disorders may be diagnosed with a modified barium swallow, and the recent ATS guidelines suggest that video-fluoroscopic swallowing studies, or 24-hour pH monitoring, may be helpful in the discernment of gastrointestinal causes of wheezing (61). Dysphagia and cough with feeding may indicate eosinophilic esophagitis requiring upper endoscopy to diagnose. The most important recommendation in the 2016 ATS guideline is not to perform empiric formula switching (61). The most helpful and accurate study for the evaluation of GER in infants and small children is 24-hour esophageal pH monitoring. Bronchoscopy may also be necessary if the presence of a foreign body, aspiration, ciliary dyskinesia, or evaluation of severe infectious episode for etiologic agent. A chest film should be performed the first time an infant has an acute episode of wheezing. This will assist with evaluating nonasthmatic reasons for wheeze. Repeated radiographs for each subsequent episode of asthmatic wheezing are not necessary. In fact, a recent study demonstrated that chest X-ray in the ED for asthmatic children with exacerbation was not useful when O2 saturations are >92% to 96%, or if afebrile in the ED (62). Other pulmonary causes of wheezing may be investigated with a sweat chloride test to exclude cystic fibrosis should be considered in any infant under 1 year of age with repeated episodes of wheezing or respiratory distress. Wheezing associated with increased numbers of severe or unusual infections should lead to evaluation for an immune deficiency. The use of a rhinoprobe or bronchoscopy may be beneficial in evaluation of infants with situs inversus totalis for primary ciliary dyskinesia (63). Tracheobronchomalacia may be determined by bronchoscopy or multidetector computed tomography as a noninvasive modality. TABLE 20.3 DIFFERENTIAL DIAGNOSIS OF COUGHING AND WHEEZING IN INFANTS AND YOUNG CHILDREN Congenital Disorders
Cystic fibrosis Tracheoesophageal fistula
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Primary ciliary dyskinesia Immunodeficiency Sickle cell disease (acute chest syndrome) Diaphragmatic hernia Chronic lung disease of prematurity α1-Antitrypsin deficiency
Pulmonary lymphangiectasia Carnitine deficiency
Congenital Heart Disease Aberrant left coronary artery Chronic heart failure
Upper Airway Disorders Foreign body (also esophageal) Laryngotracheomalacia Vocal cord dysfunction/paralysis, Charcot-Marie-Tooth disease, Waardenburg syndrome Laryngeal web, papillomatosis, cleft, cyst
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Subglottic or tracheal stenosis Hemangioma Laryngeal paralysis, Chiari malformation Bigeminal choristoma
Lower Airway Disorders Bronchial stenosis, casts Foreign object Hypersensitivity pneumonitis Asthma Bronchomalacia Lobar emphysema, hemosiderosis
Infectious/Postinfectious Epiglottitis Croup Tracheitis Bronchiolitis Diphtheria, atypical mycobacteria, pertussis
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Chlamydia Pneumocystis jiroveci Histoplasmosis, Protozoan infection Bronchiectasis Rhinovirus, sinusitis Retropharyngeal abscess Bronchiolitis obliterans
Compression Syndromes Tuberculosis Lymphadenopathy Vascular ring Pulmonary sling, aortic malformations Mediastinal masses Congenital goiter Thyroglossal duct cyst Teratoma Aspiration syndromes
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Neurogenic
Other Munchausen syndrome by proxy, psychogenic cough, child abuse Neurofibroma GERD, gastric volvulus, eosinophilic esophagitis Pulmonary Langerhans cell histiocytosis GERD, gastroesophageal reflux disease.
ALLERGY EVALUATION AND OTHER TESTS Allergy appears to be a more significant trigger in infants and toddlers than previously appreciated. Skin testing using the prick-puncture technique with relevant indoor and outdoor (≥1 year of age) should be considered in infants and young children with asthma. In fact, a history of recurrent croup (particularly if seasonal) is a nonspecific manifestation of atopy and may also suggest the need for allergy evaluation (64). Appropriate environmental control measures can then be instituted for those who are found to have evidence of atopy. Identification of outdoor aeroallergen sensitization can assist in determining issues of concomitant allergy therapy with asthma therapy and designing a maintenance asthma plan that accounts for peak pollen season. In older preschool-aged children, fractional concentration of exhaled nitric oxide (FeNO) evaluation utilizing breath condensate technology might be useful in office evaluation of asthma. Studies have been performed showing that children as young as 3 to 4 years of age can perform this test (65). Elevated FeNO findings in these children correlated well with those of older children in the diagnosis of asthma and identifying asthma severity and aeroallergen sensitization (66). In fact, in one study of children 5 to 6 years of age, FeNO may be a more sensitive indicator of bronchial hyperresponsiveness than traditional spirometry (67).
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OUTPATIENT TREATMENT OF THE ASTHMATIC INFANT AND TODDLER The treatment of asthmatic infants is similar to that in older children and consists of avoiding identified triggers of wheezing, regular use of an anti-inflammatory medication, and a bronchodilator for symptomatic relief. However, treatment of this age group poses certain challenges. Many medications and delivery systems for asthma have been inadequately tested in this population, or there is conflicting data concerning their use. Monitoring the effectiveness of treatment in infants is more difficult owing to a lack of clinical availability of pulmonary function testing. Compliance with daily treatment is difficult because of the poor cooperation inherent in this age group as well as the reluctance of parents to have their children on medications when they are asymptomatic. Fortunately, the newer medications for asthma in infants promise better control of wheezing with improved safety and convenience. A summary of current asthma medications for infants is listed in Table 20.4. The 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines emphasize the need for assessment of both impairment and risk (68). Impairment includes both functional limitations experienced by the patient or frequent or intense exacerbations. Functional limitations in infants can include coughing/wheezing/breathlessness during daytime, nighttime, or with play; feeding difficulties or posttussive emesis or use of short-acting β-adrenergic agonist >2 times/week lasting greater than 4 weeks. Possible risks to be prevented include limited lung growth or recurrent exacerbations of asthma with ED visit, hospitalization, and oral glucocorticosteroid use. The most difficult group to determine maintenance medication for is the infants with severe exacerbations, but no perceivable daily symptoms between episodes. The NHBLI guidelines note that children with ≥4 episodes/year that last longer than a day and affect sleep and have a positive asthma risk profile (API) should have daily long-term control therapy. Other groups of infants requiring long-term controller therapy include those with a history of two oral corticosteroid bursts for exacerbations in 6 months or children who require β-adrenergic agonist treatment for >2 days/week lasting longer than 4 weeks. If, at any point, a notable clinical response is not observed with asthma-specific medications, alternative diagnoses should be considered. Alternative diagnoses to asthma should be considered in children with failure to thrive, very early onset in neonatal period, vomiting, clubbing, continuous wheezing not responsive to controller therapy, hypoxia unrelated to viral illness, and no association of 1073
symptoms with when triggers such as viral upper respiratory infection is present (68).
β-Adrenergic Agonists β-Adrenergic agonists are clearly effective in infants and young asthmatic children for acute wheezing. Side effects of these medications may include tremors, irritability, sleep disturbances, and behavioral problems. At higher doses, tachycardia, agitation, hypokalemia, and hyperglycemia may also be seen. It has been subsequently determined that infants do have functioning βadrenergic receptors, and studies in infants specifically diagnosed with asthma suggest that β-adrenergic agonists decrease wheezing as well as improve pulmonary functions (69). This improvement is noted both for nebulized medications and metered-dose inhalers with face mask spacer devices (70). Infants with true asthma should be given inhaled β-adrenergic agonists as needed for wheezing during acute exacerbations of their disease.
Anticholinergics Ipratropium bromide is a quaternary isopropyl derivative of atropine available as a nebulizer solution. A pediatric asthma consensus group suggests that ipratropium may be useful as a second- or third-line medication in severe infantile asthma exacerbations. A meta-analysis of clinical trials of ipratropium for wheezing in children under 2 years of age concluded that there is not enough evidence to support the routine use of anticholinergic therapy for wheezing infants (71). A current NHLBI consensus statement notes that data suggest that ipratropium is appropriate to use during severe exacerbations in infants as addon therapy when there is a perceived eventual need for intensive care unit admission (68). Further benefit of ipratropium treatment during the remainder of the hospitalization has not been noted.
Leukotriene Antagonists Leukotrienes are very potent chemical mediators that produce bronchospasm, eosinophilia, stimulate mucus secretion, and increase vascular permeability, all critical features of asthma. Leukotriene antagonists block these inflammatory effects. So far, these medications appear to have a good safety profile and are well tolerated (72). Montelukast has been reported to decrease asthma exacerbations in children 10 months to 5-year-olds with intermittent asthma (73). In head-to-head comparisons to inhaled steroids in children with mild persistent asthma, both montelukast and inhaled steroids improved symptom control, but 1074
those patients on inhaled steroids utilized less oral corticosteroid rescue (74). NHLBI asthma treatment guidelines list iICSs as preferred first-line treatment for asthma as a result of these studies. Montelukast is noted by the NIHBI guidelines to be alternative therapy or add-on therapy for mild persistent to more severe asthma (68). These recommendations do not reflect that parents of mild infantile asthmatics perceive montelukast as a particularly attractive long-term controller medication because it can be taken as a tablet once daily, it has a relatively high safety profile, and it is not a corticosteroid. TABLE 20.4 EXAMPLES OF OFFICE-BASED MEDICATIONS FOR THE TREATMENT OF INFANTILE ASTHMA MEDICATION
DOSAGE
Short-Course Systemic Steroids Prednisolone (5 mg/5 mL or 15 mg/5 mL) 1–2 mg/kg/d orally; maximum 20 mg 352 μg/d
a
2007 NHBLI guidelines specifically note that blow by technique for nebulized aerosol delivery is inadequate. b
2007 NHBLI guidelines specifically note doubling the dose of inhaled steroid during exacerbations is not effective. c
2007 NHBLI guidelines note that HFA use with spacer and face mask may reduce lung delivery by 50%. DPI, dry-powder inhaler; HFA, hydrofluoroalkane; ICU, intensive care unit; pMDI, metered-dose inhaler.
Corticosteroids Corticosteroids are potent anti-inflammatory medications that have profound effects on asthma. They decrease inflammatory mediators, reduce mucus production, decrease mucosal edema, and increase β-adrenergic responsiveness. Clinically, corticosteroids improve lung function, reduce airway hyperreactivity, and modify the late-phase asthmatic response. The efficacy of steroids in treating 1076
true infantile asthma is well known. For acute exacerbations, asthmatic infants treated with steroids have a significantly reduced need for hospitalization, reduced length of stay once hospitalized, and reduced asthma medications (75,76). Maintenance inhaled steroids provide many of the beneficial antiinflammatory properties of corticosteroids without numerous unwanted side effects. Young children with severe asthma treated with inhaled nebulized or hydrofluoroalkane (HFA)-driven corticosteroids have markedly decreased symptoms and days of oral corticosteroid use (77). Inhaled glucocorticosteroids have been demonstrated to improve pulmonary function tests, decrease β agonist use, and improve symptoms in the youngest children with asthma (6 canisters/year) (80) as compared to two separate canisters of medication. Most outcomes favor fixed-dose combination of drug usage over increasing to high-dose–inhaled steroid as suggested in NHLBI step 4 therapy for older children. This class of medication is still not a standard recommendation of the NHLBI guidelines ≤4 years of age due to lack of studies supporting efficacy.
Allergen Avoidance Dust mite avoidance measures have been noted to have a modest treatment effect in infants and possibly reduce the prevalence of asthma in a prevention strategy devised for high-risk infants (81,82). Reduced levels of cockroach allergen have been associated with decreasing number of cockroaches by utilizing better eradication efforts (83). However, a study linking decreased cockroach levels in the dwelling with improved asthma symptoms in infants has not been reported. 1077
Clearly, more studies are required to determine best treatment options, including allergen avoidance.
Monitoring for Obesity Given the importance of obesity as an exacerbating factor to asthma severity, following growth charts for BMI ≥ 85% seems reasonable. Those at particular risk may be those children with repetitive oral steroid bursts (84). Those children receiving inhaled steroids can also be evaluated for longitudinal growth. Early dietary intervention with either the pediatrician or nutritionist assistance and maximized asthma care to allow for exercise may be useful strategies to prevent development of obesity in at-risk infants. In addition, encouraging breastfeeding continuation may assist in obesity risk reduction.
Allergy Immunotherapy Potential deleterious outcomes of childhood asthma have been convincingly shown to develop despite the use of inhaled steroids. The increasingly apparent role of aeroallergens in the progression of infant wheezing to clinical long-term asthma has suggested that allergen immunotherapy might provide a more permanent disease-modifying outcome after the treatment is discontinued. In children older than 3 years of age, a 3-year course of subcutaneous immunotherapy with standardized allergen extracts has shown long-term clinical effects, including the prevention of the development of asthma in children with allergic rhinoconjunctivitis (85). This clinical effect was noted up to 7 years after treatment (84). However, subcutaneous immunotherapy in very young children is problematic because of their immaturity and inability to verbalize or cooperate. Sublingual immunotherapy might be better tolerated in young children. Data demonstrates that children as young as age 3, utilizing sublingual immunotherapy with standardized extracts might reduce symptom scores and rescue medication use in allergic asthma compared with placebo (86). Further studies are needed to determine the role of immunotherapy in altering the natural history of asthma in young children. REFERENCES 1. Shamssain MH, Shamsian N. Prevalence and severity of asthma, rhinitis, and atopic eczema: the north east study. Arch Dis Child. 1999;81:313–317. 2. Radhakrishnan DK, Dell SD, Guttmann A, et al. Trends in the age of diagnosis of childhood asthma. J Allergy Clin Immunol. 2014;134:1057– 1062. 1078
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60. Vicendese D, Abramson MJ, Dharmage SC, et al. Trends in asthma readmissions among children and adolescents over time by age, gender and season. J Asthma. 2014;51(10):1055–1060. 61. Ren CL, Esther CR Jr, Debley J, et al. Official American Thoracic Society Clinical Practice Guidelines: diagnostic evaluation of infants with recurrent or persistent wheezing. Am J Respir Crit Care Med. 2016;194:356–373. 62. Narayanan S, Magruder T, Walley SC, et al. Relevance of chest radiography in pediatric inpatients with asthma. J Asthma. 2014;51(7):751–755. 63. Welch JE, Hogan MB, Wilson NW. Ten-year experience using a plastic, disposable curette for the diagnosis of primary ciliary dyskinesia. Ann Allergy Asthma Immunol. 2004:93(2):189–192. 64. Arslan Z, Cipe FE, Ozmen S, et al. Evaluation of allergic sensitization and gastroesophageal reflux disease in children with recurrent croup. Pediatr Int. 2009;51(5):661–665. 65. Sayão LB, de Britto MC, Burity E, et al. Exhaled nitric oxide as a diagnostic tool for wheezing in preschool children: a diagnostic accuracy study. Respir Med. 2016;113:15–21. 66. Beigleman A, Mauger DT, Phillips BR, et al. Effect of elevated exhaled nitric oxide levels on the risk of respiratory tract illness in preschool-aged children with moderate-to-severe intermittent wheezing. Ann Allergy Asthma Immunol. 2009;103(2):108–113. 67. Lee JW, Shim JY, Kwon JW, et al. Exhaled nitric oxide as a better diagnostic indicator for evaluating wheeze and airway hyperresponsiveness in preschool children. J Asthma. 2015;52(10):1054–1059. 68. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Expert Panel Report 3. Guidelines for the diagnosis and management of asthma. Full Report 2007, National Institutes of Health, 2007. Available at: https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf. 69. Prendiville A, Green S, Silverman M. Airway responsiveness in wheezy infants: evidence for functional beta adrenergic receptors. Thorax. 1987;42:100–104. 70. Bentur L, Canny GJ, Shields MD, et al. Controlled trial of nebulized albuterol in children younger than 2 years of age with acute asthma. 1084
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INTRODUCTION Each year in the United States, acute severe asthma (ASA) accounts for approximately 2.0 million emergency department (ED) visits, 480,000 hospitalizations, and 3,400 deaths (1). Although the rate of asthma death has decreased each year since 2000, African Americans and older patients with comorbid conditions remain at particular risk (2–5). Table 21.1 lists additional risk factors for near-fatal or fatal asthma. Treatment of an acutely ill patient with asthma involves targeted strategies to improve airway obstruction and decrease work of breathing. For most patients, short-acting β agonists (with or without a short-acting anticholinergic) and a burst of systemic corticosteroids are sufficient. Patients with acute respiratory failure require supplemental oxygen and supported ventilation by mask or endotracheal tube (5–7). Adherence with evidence-based asthma guidelines for hospitalized patients has improved over recent years, although substantial interhospital variability exists, and this has improved outcomes (8). Comprehensive management of this patient group includes education, vaccinations, controller agents, and follow-up appointments with an asthma specialist.
PATHOPHYSIOLOGY OBSTRUCTION
OF
ACUTE
AIRFLOW
The speed with which ASA develops varies (9). A sudden attack that leads to severe obstruction in less than 3 hours is termed sudden asphyxic asthma. This type of attack represents a more pure form of smooth muscle–mediated bronchospasm and may respond quickly to bronchodilators (10,11). Triggers of sudden attacks include medications, such as nonselective nonsteroidal antiinflammatory agents and β-blockers in susceptible patients, allergen or irritant exposure, sulphites, and inhalation of illicit drugs (12,13). Respiratory tract infection is not a common cause (14).
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TABLE 21.1 RISK FACTORS FOR NEAR-FATAL OR FATAL ASTHMA Frequent emergency department visits Frequent hospitalization Intensive care unit admission Intubation Hypercapnia Barotrauma Psychiatric illness Medical noncompliance Illicit drug abuse Low socioeconomic status Inadequate access to medical care Inadequate asthma control/the use of more than two canisters per month of inhaled β2adrenergic agonist Poor patient perception of airflow obstruction Comorbidities such as coronary artery disease Sensitivity to Alternaria species
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More commonly, exacerbations evolve over 24 hours or more with progressive airway wall inflammation, accumulation of intraluminal mucus, and bronchospasm. Mucus, which consists of sloughed epithelial cells, eosinophils, fibrin, and other serum components that have leaked through the denuded airway epithelium, obstructs large and small airways and predicts a more protracted course. Patients with slower onset exacerbations have time to intervene with corticosteroids, an opportunity that is too often missed, resulting in the need for emergency services. Triggers of slower exacerbations include viral infections and allergic and nonspecific irritant exposures. Regardless of tempo, severe airflow obstruction increases work of breathing and interferes with gas exchange. The higher mechanical cost of breathing in these patients is because of greater amounts of resistive work from narrowed airways and elastic work from lung hyperinflation. Whereas bronchospasm and inflammation underlie airway narrowing, inadequate expiratory time and incomplete exhalation cause lung hyperinflation. A patient with a respiratory rate in the 20s or 30s has 1 or 2 seconds for exhalation. This amount of time is inadequate to exhale tidal breaths in the setting of airflow obstruction. Lung volumes increase, and tidal breathing occurs at higher lung volumes (even near total lung capacity in severe cases) where the compliance of the lung is low. This dynamic lung hyperinflation (DHI) may be self-limiting because hyperinflation increases lung elastic recoil pressure and airway diameter to increase expiratory flow. At the end of exhalation, incomplete gas emptying elevates alveolar volume and pressure, a state referred to as auto–positive end-expiratory pressure (auto-PEEP). To affect inspiratory flow, patients must be able to overcome autoPEEP. Their ability to do so is adversely affected by DHI, which places the diaphragm in an unfavorable position for force generation. Fatiguing muscles and respiratory acidosis further decrease respiratory muscle strength (15). In the end, the combination of diminished respiratory muscle strength and inordinate resistive and elastic loads can cause hypercapnic respiratory failure and respiratory arrest. Airway narrowing further decreases ventilation (V) relative to perfusion (Q) in alveolar-capillary units, resulting in hypoxemia (16). Asthma generally does not cause intrapulmonary shunt physiology, which is defined by a V/Q of zero in alveolar-capillary units. Common causes of shunt are pneumonia, pulmonary edema, alveolar hemorrhage, and atelectasis. When significant, patients with shunt are difficult to oxygenate. Asthma drops V/Q, but not to zero, and therefore, patients with asthma usually respond to supplemental oxygen, and refractory hypoxemia suggests other diagnoses. Although there is a rough 1089
correlation between the hypoxemia and the severity of airflow obstruction, hypoxemia may occur sooner and/or resolve later than measures of obstruction (i.e., peak flow or spirometry) (17). Cardiovascular complications of ASA include accentuation of the normal inspiratory reduction in stroke volume and blood pressure, termed the pulsus paradoxus (PP). The vigorous inspiratory efforts required to overcome autoPEEP drop pleural pressure and increase blood return to the right ventricle (RV). The RV fills early in inspiration and shifts the intraventricular septum leftward, causing diastolic dysfunction of the left ventricle (LV) and incomplete LV filling. Large negative pleural pressures further impair LV emptying by increasing LV afterload (18). Rarely, these effects cause pulmonary edema. During forced exhalation, positive pleural and intrathoracic pressures decrease venous return to the RV. These swings in pleural pressure and cyclical changes in venous return underlie widened PP and signal a severe attack. However, the absence of a widened PP does not ensure a mild attack because PP decreases in the fatiguing patient unable to generate large swings in pleural pressure. Further complicating severe attacks is the potential for DHI to increase total pulmonary vascular resistance, pulmonary artery pressures, and cause right heart strain (19).
CLINICAL PRESENTATION, DIFFERENTIAL DIAGNOSIS, AND SEVERITY ASSESSMENT Analysis of multiple factors, including the history, physical examination, measures of airflow obstruction, response to therapy, arterial blood gases, and chest radiography, is important in the assessment and management of acutely ill patients (20,21).
Differential Diagnosis “All that wheezes is not asthma” is a fitting clinical saw worth considering during the initial evaluation. An extensive smoking history suggests chronic obstructive pulmonary disease and a more fixed form of expiratory airflow obstruction. Congestive heart failure may present with wheezing (termed cardiac asthma) that responds to bronchodilators (22). Myocardial ischemia should be considered in patients at risk for coronary artery disease, particularly those receiving subcutaneous or intramuscular epinephrine, because ASA can incite an imbalance between myocardial oxygen supply and demand (23). Aspiration and foreign body obstruction occasionally mimic asthma, and should be considered in the very young and old, in patients with altered mental status or
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neuromuscular disease, and when symptoms occur after eating or dental work. Localized wheeze and, rarely, asymmetric hyperinflation on chest radiography are clues to foreign body aspiration. Upper airway obstruction, including vocal cord dysfunction (VCD), can present with respiratory distress and “wheezes.” In contrast to asthma, classic upper airway (extrathoracic) obstruction flattens the inspiratory portion of the flow-volume loop and is associated with prolongation of inhalation and stridor. Other clues to the presence of VCD include normal oxygenation, lack of response to bronchodilators, and normal airway pressures after intubation (24). Significant response to helium–oxygen mixtures (heliox) suggests upper airway obstruction, although heliox response occurs in some patients with asthma and does not reliably distinguish upper from lower airway obstruction. Tracheal stenosis should be considered in patients with a history of intubation, trauma or radiation to the throat or chest, sarcoidosis, granulomatosis with polyangiitis, amyloidosis, and benign or malignant tumors. Whereas mycobacterial and viral infections can present with wheezing, bacterial pneumonia is an unusual cause of wheezing. Antibiotics are frequently prescribed for patients with asthma with increased sputum production alone, but have not been shown to improve outcome (25,26). Wheezing has been reported in pulmonary embolism (27); pulmonary embolism should be considered in a patient with risk factors for venous thromboembolism, particularly in the absence of known asthma.
Physical Examination The general appearance of the patient (posture, speech, positioning, and alertness) provides a quick guide to severity, response to therapy, and need for intubation. Patients assuming the upright position have a higher heart rate, respiratory rate, and PP, and a significantly lower partial pressure of arterial oxygen (PaO2) and peak expiratory flow rate (PEFR) than patients who are able to lie supine (28). Diaphoresis is associated with an even lower PEFR. Accessory muscle use indicates a severe attack, but is not always present (29). An altered mental status and bradycardia suggest impending arrest and are indications for intubation (21). The mouth and neck should be inspected for evidence of previous surgery, malignancy, and angioedema. Prolongation of inspiration and stridor suggest upper airway obstruction. Tracheal deviation, asymmetric breath sounds, mediastinal crunch, and subcutaneous emphysema suggest barotrauma and the need for a stat chest X-ray.
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Chest auscultation typically reveals expiratory-phase prolongation and wheezing that is more pronounced during exhalation than inhalation. However, wheezing is not a reliable indicator of severity (30). A silent chest indicates severely decreased air exchange and possible impending respiratory arrest. (In this situation, increased wheezing signals improvement.) Localized wheezing or crackles may represent mucus plugging and atelectasis, but should prompt consideration of pneumonia, pneumothorax, endobronchial lesions, and foreign body. Tachycardia is common (31). Heart rate generally decreases in improving patients, but can remain elevated despite clinical improvement because of β2adrenergic agonists. The usual rhythm is sinus tachycardia, but supraventricular and ventricular arrhythmias occur; bradycardia is an ominous sign (21).
Measurement of Airflow Obstruction Measuring PEFR or forced expiratory volume in 1 second (FEV1) helps assess the severity of airflow obstruction. Objective measures are important because physician estimates of severity are often wrong—with errors equally distributed between overestimates and underestimates of the actual PEFR. However, PEFRs should not be measured in severely ill patients because they rarely alter management, and the required maneuver can worsen bronchospasm even to the point of respiratory arrest (32). According to the Expert Panel Report 3 of the National Institutes of Health, mild attacks are characterized by PEFR > 70% of predicted or personal best, moderate attacks by PEFRs between 40% and 69%, severe attacks by PEFR < 40%, and life-threatening attacks by PEFR < 25% (21). Measuring the change in PEFR or FEV1 is a valid predictor of the need for hospitalization. Several studies have demonstrated that inconsequential changes or deterioration after 30 to 60 minutes of therapy predict a more severe course and need for hospitalization, whereas a robust response typically allows for discharge (33).
Arterial Blood Gases Arterial blood gases document the degree of hypoxemia and allow for acid–base analysis. In the early stages of ASA, mild hypoxemia and respiratory alkalosis are common. As the severity of airflow obstruction increases, PaCO2 generally increases, and therefore, eucapnia and hypercapnia are worrisome findings. Hypercapnia alone is not an indication for intubation because these patients may still respond adequately to pharmacotherapy and/or noninvasive mechanical 1092
ventilation (NIV) (34,35). Conversely, the absence of hypercapnia does not rule out a life-threatening attack (36). Arterial blood gases are not required in all patients, especially patients who respond clinically to initial treatment, and in an attempt to limit the complications of arterial puncture, venous blood gases are commonly used in EDs to screen for arterial hypercapnia. Data suggest that arterial hypercapnia is extremely unlikely when the venous PCO2 is ≤45 mm Hg (37). Patients with respiratory alkalosis lasting days compensate by wasting serum bicarbonate, which may manifest as a normal anion gap metabolic acidosis (referred to as posthypocapnic metabolic acidosis). Metabolic acidosis with an elevated anion gap typically results from lactic acidosis secondary to increased work of breathing, tissue hypoxia, or intracellular alkalosis. Lactic acidosis indicates a severe exacerbation and occurs more commonly in men and in patients receiving parenteral β2-adrenergic agonists (38). Serial blood gases are not necessary to determine clinical course. In most cases, valid judgments follow serial examinations with attention to patient posture, accessory muscle use, diaphoresis, chest auscultation, pulse oximetry, and PEFR measurements. Patients who deteriorate on these grounds are candidates for intubation regardless of PaCO2. Conversely, intubation is not indicated in patients improving by multifactorial assessment despite hypercapnia. Serial blood gases help guide management in mechanically ventilated patients.
Chest Radiography In classic cases of ASA, chest X-rays rarely alter management (39). In one study reporting radiographic abnormalities in one-third of cases, the majority of findings were attributable to common asthma features of airway wall thickening and intraluminal mucus (40). Chest radiography is indicated for patients with localizing signs or symptoms and when the diagnosis is in question. In mechanically ventilated patients, chest radiography further confirms proper endotracheal tube position and helps to exclude barotrauma.
EMERGENCY DEPARTMENT MANAGEMENT Patients with mild-to-moderate attacks responding well to initial therapy may be considered for discharge. Observation in the ED for at least 60 minutes after the last β2-adrenergic agonist treatment ensures suitability for discharge (21). 1093
Patients should invariably be discharged on inhaled and/or systemic steroids and receive written medication instructions, a written asthma action plan, and instructions for follow-up. Patients presenting with a mild exacerbation that completely resolves after bronchodilators may be discharged on inhaled steroids or the combination of a long-acting β2-adrenergic agonist and inhaled steroid, particularly if they were not previously on controller therapy. Patients with incomplete responses or attacks of greater severity should receive a course of intramuscular or oral steroids. When considering hospitalization, health care providers should err on the side of admission when there is a risky home environment or noncompliance favors directly observed therapy. Patients with severe attacks who do not respond (or actually deteriorate) in the face of initial bronchodilator therapy should receive systemic steroids and be admitted to the hospital. Indications for intensive care unit admission include respiratory arrest, progressive hypercapnia, NIV and invasive mechanical ventilation, altered mental status, arrhythmias, myocardial injury, and need for frequent bronchodilator treatments (21).
PHARMACOLOGIC THERAPY Oxygen Supplemental oxygen by low-flow nasal cannula or facemask should be titrated to maintain arterial oxygen saturations greater than 92% (>94% with pregnancy and ischemic heart disease). Adequate oxygenation is generally not difficult to achieve with low-flow supplementation and is important for delivery of oxygen to tissues, including the exercising respiratory muscles, heart, and brain. Supplemental oxygen further protects against hypoxemia resulting from β2adrenergic agonist–induced pulmonary vasodilation and increased blood flow to low V/Q units (41).
β2-Adrenergic Agonists Inhaled short-acting β2-adrenergic agonists are the primary treatment of smooth muscle–mediated bronchoconstriction. Approximately two-thirds of patients with ASA respond convincingly to this therapy in the ED. The other third requires prolonged treatment in the ED or admission to hospital. In a study by Rodrigo and Rodrigo, 67% of patients improved significantly and were discharged from the ED after 2.4 mg albuterol by metered-dose inhaler (MDI) (42). Half of the responders in this study met discharge criteria after receiving 12 1094
puffs (1.2 mg) of albuterol. Similarly, Strauss and co-workers found that twothirds of patients with acute asthma could be discharged after three 2.5-mg doses of albuterol by nebulization every 20 minutes (43). The optimal dose of albuterol in ASA has yet to be firmly established. McFadden and colleagues compared two 5.0-mg nebulized treatments of albuterol over 40 minutes with the standard approach of three 2.5-mg albuterol every 20 minutes in 160 ED patients (44). Although both approaches were effective, the 5.0-mg regimen increased lung function quicker and to a greater extent than standard-dose therapy. The higher dose strategy resulted in patients achieving discharge criteria more rapidly and leaving the ED with PEFRs closer to normal, and a trend toward fewer hospitalizations. On the other hand, Emerman and colleagues compared the effects of three doses of 2.5 or 7.5 mg of albuterol every 20 minutes in 160 acutely ill patients with asthma and found no differences in spirometry or admission rates (45). These data generally support the standard recommendation of administering 2.5-mg albuterol by nebulization every 20 minutes during the first hour of treatment (i.e., three doses) (21). MDIs are also effective. Also, 4 to 12 puffs by MDI with a spacing device achieves the same degree of bronchodilation as one 2.5-mg nebulized treatment of albuterol (46). MDIs with spacers are less expense and faster; hand-held nebulizers require fewer instructions, less supervision, and less coordination. Continuous or repetitive doses of albuterol are indicated until there is convincing improvement or side effects limit further administration (Table 21.2) (47). Fortunately, high doses of inhaled β2-adrenergic agonists are generally well tolerated. Tremor and tachycardia are common, but significant cardiovascular morbidity is rare (48). Clinical response and side effects further inform the dosing schedule after the first hour of management. Racemic albuterol consists of equal amounts of R- and S-albuterol. The R isomer confers bronchodilator effects, whereas the S isomer is either inert or proinflammatory, which provides the rationale for using the R isomer alone. The R isomer levalbuterol compares favorably to albuterol, but is not superior (49,50). Long-acting β2-adrenergic agonists are not indicated in the initial treatment of ASA, although formoterol (which has acute onset of action) is safe and effective in this setting (51). The combined inhalers containing long-acting β2-adrenergic agonists and inhaled corticosteroids (ICSs) can be initiated or continued in hospitalized patients receiving rescue therapy, and will generally be required to 1095
achieve adequate control in the outpatient setting (52). TABLE 21.2 COMMON DRUGS USED IN TREATMENT OF ACUTE ASTHMA IN ADULTS
THE
INITIAL
Albuterol
2.5 mg in 2.5 mL normal saline by nebulization every 20 min three times over the first hour; or four to eight puffs by MDI with spacer every 20 min three times; for intubated patients, titrate to physiologic effect and side effects.
Ipratropium bromide
0.5 mg by nebulization every 20 min three times in combination with albuterol, or four to eight puffs by MDI with spacer every 20 min for three doses.
Epinephrine
0.3 mL of a 1:1,000 solution subcutaneously every 20 min three times as needed
Corticosteroids
Prednisone or methylprednisolone 40–80 mg/d in 1 or 2 divided doses until PEFR reaches 70% of predicted or the patient’s personal best.
MDI, metered-dose inhaler; PEFR, peak expiratory flow rate.
There is no advantage to parenteral administration of β2-adrenergic agonists in the initial management of ASA unless the patient is unable to comply with inhaled therapy (such as those with altered mental status and impending cardiopulmonary arrest). However, lack of response to several hours of inhaled β2-adrenergic agonist therapy is an indication for subcutaneous or intramuscular epinephrine, which is generally well tolerated (53,54). Intravenous (IV) β2adrenergic agonists are not recommended, with the possible exception of patients in cardiac arrest. They are less effective and more toxic than their inhaled counterparts (55).
Ipratropium Bromide The bronchodilating properties of ipratropium bromide are modest, precluding its use as a single agent in ASA. However, data support adding ipratropium to albuterol in the initial management of severe cases of ASA. In these cases, combination therapy decreases time in the ED, albuterol dose requirements, and hospitalization rates (56–59). The benefits of combination therapy do not extend 1096
to patients with mild-to-moderate exacerbations (59–62). The current recommendation is to mix 0.5 mg of ipratropium bromide with 2.5 mg of albuterol in the same nebulizer and deliver three treatments over the first hour to patients in severe exacerbation (21). A similar strategy is available by MDI with spacer. Once the patient is admitted, there are no data to support continued combination therapy, and albuterol can be used alone as required (63,64).
Corticosteroids Systemic corticosteroids are indicated in patients with ASA except for the rare patient demonstrating a robust and durable response to inhaled β2-adrenergic agonists alone. Corticosteroids treat inflammation by promoting new protein synthesis, and their effects are delayed, underlining the importance of early initiation. This delay may explain the results of select studies demonstrating that corticosteroid use in the ED does not improve lung function acutely or decrease hospitalization rates (65). A number of other studies have demonstrated that given early systemic steroids decrease hospitalization rates (66–68), speed the rate of recovery, and decrease the chance of relapse after discharge (69–72). Different routes of administration and dosing regimens have been studied (73–77), and debate continues regarding the optimal strategy. Oral steroids are as effective as parenteral steroids (77). For hospitalized adults, the Expert Panel Report 3 recommends 40 to 80 mg/day of prednisone, methylprednisolone, or prednisolone in 1 or 2 divided doses until PEFR reaches 70% of predicted or the patient’s personal best (21). For outpatients, a common strategy is to use prednisone, 40 mg/day for 5 to 10 days, with early follow-up to judge clinical response and optimize the outpatient regimen (74). Recently, a single 12-mg dose of oral dexamethasone was shown to be noninferior to 60 mg/day of prednisone for 5 days (75). Alternatively, a single dose of triamcinolone diacetate 40 mg intramuscularly has also been reported to be as effective as prednisone 40 mg/day for 5 days (76). There is no established role for use of high-dose ICSs in acute asthma in patients receiving systemic steroids (78). However, ICSs play a pivotal role in achieving outpatient asthma control, and patients with ASA discharged from the ED or hospital should be on an ICS–based treatment program.
Theophylline and Aminophylline Overall, the data do not support the use of theophylline or aminophylline in ASA. Nair et al. (79) conducted a meta-analysis for the Cochrane Review and 1097
concluded that the use of IV aminophylline does not result in additional bronchodilation in adults compared to standard therapy with inhaled short-acting β2-adrenergic agonists and that the frequency of adverse effects was higher with aminophylline use. The Expert Panel Report 3 does not recommend the use of theophylline for adults or children in the ED or hospital setting (21). Serum levels should be checked on arrival in patients taking theophylline as an outpatient before additional drug is prescribed. If the serum level is therapeutic and adverse effects have not been identified, then theophylline may be continued orally or by continuous infusion.
Magnesium Sulfate Prospective trials and meta-analyses have yielded conflicting results regarding the efficacy of magnesium sulfate (MgSO4) in ASA. A recent meta-analysis of the safety and efficacy of IV MgSO4 in adults treated in the ED for ASA demonstrated that a single infusion of 1.2 or 2 g IV MgSO4 over 15 to 30 minutes reduces hospital admissions and improves lung function in patients who had not responded to supplemental oxygen, β agonists, and IV corticosteroids (80). There is no established role for inhaled MgSO4 in acute asthma (81).
Leukotriene Modifiers Limited data support the use of leukotriene receptor antagonists in ASA. The most compelling study is a randomized, double-blinded, parallel group trial by Camargo et al. (82) in 201 acutely ill patients with asthma. When added to standard therapy, IV montelukast (which is not available in the United States) improved FEV1 over the first 20 minutes compared to placebo. Effects were seen within 10 minutes and lasted for 2 hours. There is no benefit to adding oral montelukast to conventional therapy (83).
Heliox Heliox consists of 20% oxygen and 80% helium (30%:70% mixtures are also available). It is a low-density gas that can be delivered by face mask in an attempt to decrease work of breathing or as a driving gas for albuterol nebulization. Rarely, experienced clinicians may use heliox in intubated patients with refractory and life-threatening exacerbations. The data have demonstrated mixed but disappointing results with heliox, and methodologic differences, small patient numbers, and failure to control for upper airway obstruction have confounded these studies (84–86). Overall, the data do not support the routine 1098
use of heliox in ASA; however, it is reasonable to consider its use in severe cases (84,87).
Antibiotics The Expert Panel does not recommend antibiotics for most patients with acute asthma unless necessary to treat comorbid conditions, such as pneumonia or bacterial sinusitis (21). In the recently published randomized Azithromycin for Acute Exacerbations of Asthma trial, azithromycin was no better than placebo regarding symptoms, quality of life, or lung function (26). The main reason for nonrecruitment in this study was receipt of antibiotics in almost half of screened patients, suggesting that clinicians are not adhering to guideline recommendations in many cases.
MECHANICAL VENTILATION Noninvasive Positive Pressure Ventilation Despite the increasing use of NIV in patients with acute asthma managed in EDs and intensive care units, limited data are available to inform its use in this setting. A recent meta-analysis on the use of NIV for ASA demonstrated decreased fatigue, improved gas exchange, and decreased risk of intubation (34), and NIV is now approximately as common as invasive ventilation for initial ventilator support (88). Mortality from asthma is less in patients receiving NIV compared to patients requiring intubation, but there is concern about increased mortality in the small subgroup of patients failing NIV and subsequently requiring intubation. This may stem in part from delayed recognition of the need for intubation (88). NIV should be considered only in alert, cooperative, and hemodynamically stable patients. It should be used only by experienced staff in a highly monitored setting, allowing for early identification of failing patients. Reasonable initial settings are inspiratory positive airway pressure (IPAP) 8 to 10 cm H2O and expiratory positive airway pressure (EPAP) 0 to 5 cm H2O delivered by full face mask. Depending on the patient’s initial clinical response, IPAP can be increased to 12 to 15 cm H2O and EPAP to 5 cm H2O to decrease respiratory rate, work of breathing, and dyspnea.
Intubation Despite optimal use of medications and NIV, a small proportion of patients with 1099
ASA require intubation for respiratory arrest and impending respiratory arrest (e.g., extreme exhaustion, a quiet chest, bradycardia, or altered mental status).
Postintubation Hypotension The immediate postintubation period can be challenging, and considerable care must be taken to stabilize the patient through the thoughtful use of sedatives, bronchodilators, fluids, and ventilator settings. One immediate concern in the postintubation period is the potential for hypotension (89). Hypotension occurs for several reasons, including sedation, loss of sympathetic activity, and hypovolemia from increased insensible losses and decreased oral fluid intake. Overzealous Ambu-bag ventilation or inappropriately set respiratory rates on the ventilator also result in dangerous levels of DHI and elevated airway pressures. This decreases venous return to the RV, decreases LV filling, stroke volume, and cardiac output. When this occurs, a 30- to 60-second trial of hypopnea (2 to 3 breaths/minute) or apnea in a preoxygenated patient is both diagnostic and therapeutic (89). This maneuver prolongs expiratory time and deflates the lung to improve hemodynamics. Failure of a trial of deflation to improve hemodynamic stability mandates consideration of tension pneumothorax and tube thoracostomy. Hemodynamic improvement with deflation does not completely exclude tension pneumothorax, requiring careful inspection of the postintubation chest X-ray.
Initial Ventilator Settings and Dynamic Hyperinflation Expiratory time, tidal volume, and severity of airflow obstruction determine the level of DHI (89). Because airflow obstruction is generally refractory in this subgroup of patients, expiratory time and tidal volume are the key manipulable variables during ventilator management. Expiratory time is determined by minute ventilation (respiratory rate × tidal volume) and inspiratory flow rate (90,91). When minute ventilation is increased, expiratory time is decreased and DHI increases. To avoid dangerous levels of DHI, the initial minute ventilation should not exceed 7 to 8 L/minute in a 70-kg weighing patient (92). To this end, we recommend a respiratory rate of 12 to 14 breaths/minute and a tidal volume of 7 to 8 mL/kg. High inspiratory flow rates can further prolong expiratory time, but in patients breathing over the set ventilator rate, increasing the inspiratory flow rate can increase respiratory rate, mandating a close watch on measures of lung inflation (93). During volume-controlled mechanical ventilation (VCV), we favor an inspiratory flow rate of 60 L/minute, using a square flow pattern (i.e., a constant 1100
flow rate). A decelerating flow strategy with an average flow of >40 L/minute is an acceptable alternative in many patients, and may be better tolerated. There is no consensus as to which ventilator mode should be used in patients with asthma. In paralyzed patients, synchronized intermittent mandatory ventilation and assist-controlled ventilation are equivalent. VCV is more commonly used than pressure-controlled ventilation (PCV), but theoretically, PCV may deliver more uniform distribution of ventilation than VCV. On the other hand, the delivered Vt is more variable during PCV and is affected by changes in the degree of lung inflation and bronchoconstriction. Ventilator-applied PEEP is not recommended in sedated and paralyzed patients because it may increase lung volume if used excessively (94). In spontaneously breathing patients, small amounts of ventilator-applied PEEP (e.g., 5 cm H2O) decrease inspiratory work of breathing by decreasing the pressure gradient required to overcome auto-PEEP and are safe.
Assessing Lung Inflation Determination of the severity of DHI is central to risk assessment and adjustment of ventilator settings. Numerous methods have been proposed to measure DHI. The volume at end-inspiration, termed Vei, is determined by collecting expired gas from total lung capacity to functional residual capacity during 40 to 60 seconds of apnea in a paralyzed patient. A Vei greater than 20 mL/kg has been correlated with barotrauma (92). Indeed, Vei is the only measure of DHI that has been shown to predict barotrauma (even though it may underestimate the degree of air trapping with very slowly emptying air spaces). The limitation with this measure is that it is impractical in clinical practice, and most clinicians and respiratory therapists are unfamiliar with expiratory gas collection. Surrogate measures of lung inflation include the single-breath plateau pressure (Pplat) and auto-PEEP. Accurate measurements of these pressures require patient–ventilator synchrony and absence of patient effort. Even when measured accurately, neither pressure has been proved to predict complications. Pplat is an estimate of average end-inspiratory alveolar pressures determined by stopping flow at end-inspiration. Pplat is affected by the entire respiratory system, including lung tissue and chest wall; thus, significant variations in DHI may occur from patient to patient at the same pressure. For example, an obese patient will likely have a higher Pplat than a thin patient for the same degree of DHI. Common recommendations are to seek a Pplat < 30 cm H2O.
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Auto-PEEP is the lowest average alveolar pressure achieved during the respiratory cycle. It is obtained by measuring airway-opening pressure during an end-expiratory hold maneuver. In the presence of auto-PEEP, airway-opening pressure increases by the amount of auto-PEEP present. Persistence of expiratory gas flow at the beginning of inspiration (which can be detected by auscultation or monitoring of flow tracings) also suggests auto-PEEP. Auto-PEEP may underestimate the severity of DHI (95). This occurs when severe airway narrowing limits the communication between the alveolus and mouth so that during an end-exhalation hold maneuver, airway-opening pressure fails to increase. Without supporting data, a common goal in clinical practice is to seek an auto-PEEP of less than 15 cm H2O.
Ventilator Adjustments With the above considerations in mind, we offer the following algorithm for ventilator adjustment. This algorithm relies on Pplat as the measure of DHI and arterial pH as a marker of ventilation. If initial ventilator settings result in Pplat of more than 30 cm H2O, respiratory rate should be decreased until this goal is achieved. Hypercapnia may ensue, but fortunately, this is generally well tolerated (96). Anoxic brain injury and myocardial dysfunction are contraindications to permissive hypercapnia because hypercapnia causes cerebral vasodilation, decreased myocardial contractility, and pulmonary vasoconstriction (97). If hypercapnia results in a blood pH of less than 7.15 (and respiratory rate cannot be increased because of the Pplat limit), we consider a slow infusion of sodium bicarbonate, although this has not been shown to improve outcome. If Pplat is less than 30 cm H2O and pH is less than 7.20, respiratory rate can be safely increased to lower PaCO2 and elevate arterial pH until Pplat nears the threshold pressure. Commonly, patients can be ventilated to a pH of more than 7.20 with a Pplat of less than 30 cm H2O, particularly as they improve and near extubation. Whether the above strategy improves outcomes is unknown. One study of barotrauma in patients mechanically ventilated with limited tidal volumes and airway pressures included 79 patients with asthma; five of these patients developed barotrauma (98). There were no reported differences in tidal volumes and airway pressures between patients with and without barotrauma.
Sedation and Paralysis Sedation is indicated to improve comfort, safety, and patient–ventilator 1102
synchrony. This is particularly true when hypercapnia stimulates respiratory drive. Some patients (such as those with sudden asphyxic asthma) may be extubated within hours. In these patients, propofol is attractive because it can be rapidly titrated to a deep level of sedation and still allow for quick awakening after discontinuation (99). Time to awakening is less predictable with benzodiazepines, and benzodiazepines increase the risk of delirium. To provide the best combination of amnesia, sedation, analgesia, and suppression of respiratory drive, we typically add fentanyl to propofol. Consideration should be given to holding sedatives and analgesics in calm patients to avoid accumulation (100). Ketamine, an IV anesthetic with sedative, analgesic, and bronchodilating properties, is generally reserved for intubated patients with severe bronchospasm precluding safe mechanical ventilation (101). Ketamine must be used with caution because of its sympathomimetic effects and association with delirium. Short-term paralysis is indicated when safe and effective mechanical ventilation cannot be achieved by sedatives and analgesics. Cis-atracurium is the preferred agent because it is essentially free of cardiovascular effects, does not release histamine, and does not require hepatic and renal function for clearance. Paralytics may be given intermittently by bolus or continuous IV infusion. Continuous infusions require a nerve stimulator or withholding the drug every 4 to 6 hours to avoid accumulation and prolonged paralysis. Paralytic agents should be minimized whenever possible because of increased risk of deep vein thrombosis, pneumonia, and myopathy (102).
Administration of Bronchodilators during Mechanical Ventilation Many questions remain regarding the optimal administration of inhaled bronchodilators during mechanical ventilation. Manthous et al. (103) compared the efficacy of albuterol delivered by MDI via a simple inspiratory adapter (no spacer) to nebulized albuterol in mechanically ventilated patients. Using the peak-to-pause pressure gradient at a constant inspiratory flow to measure airway resistance, they found no effect (and no side effects) from the administration of 100 puffs (9.0 mg) of albuterol; whereas albuterol delivered by nebulizer to a total dose of 2.5 mg reduced inspiratory flow-resistive pressure by 18%. Increasing the nebulized dose to a total of 7.5 mg reduced airway resistance further in most patients, but caused side effects in half of these patients. When MDIs are used during mechanical ventilation, they must be delivered by a 1103
spacing device on the inspiratory limb of the ventilator (104). In general, nebulizers should be placed close to the ventilator, and in line humidifiers stopped during treatments. Inspiratory flow should be reduced to approximately 40 L/minute during treatments to minimize turbulence, although this strategy has the potential to worsen lung hyperinflation and must be time limited. Patient– ventilator synchrony is crucial to optimize drug delivery. In either case (MDI with spacer or nebulizer), higher drug dosages are required. Dose should also be titrated to achieve a decrease in the peak-to-pause airway pressure gradient. If no measurable decrease in airway resistance occurs, other causes of elevated airway resistance, such as a plugged endotracheal tube, should be considered.
Other Considerations Rarely, the above strategies are unable to stabilize the ventilated patient, and consideration should be given to the use of other strategies. Halothane and enflurane are general anesthetic bronchodilators that can reduce airway pressures and PaCO2 (105), but these agents cause myocardial depression, arterial vasodilation, and arrhythmias, and their benefits do not last after drug discontinuation. Heliox delivered through the ventilator circuit may also decrease airway pressures and PaCO2 (106). However, safe use of heliox in ventilated patients requires significant institutional expertise and careful planning. Ventilator flow meters that are gas density dependent must be recalibrated to low-density gas, and a spirometer should be placed on the expiratory port of the ventilator during heliox administration to measure tidal volume. Finally, extracorporeal life support is a viable option in many centers for patients with life-threatening ASA despite optimal pharmacologic and ventilator management.
Extubation Although some patients with labile asthma respond to therapy within hours, more typically patients require 24 to 48 hours of bronchodilator and antiinflammatory therapy before they are candidates for extubation. Although weaning and extubation criteria have not been validated in ASA, a reasonable approach is to offer a spontaneous breathing trial to alert or easily arousable patients who have (1) minimal oxygen requirements, (2) normalized their PaCO2, (3) require infrequent suctioning, and (4) hemodynamically stable. If pneumonia, anoxic brain injury, or muscle weakness has not complicated the patient’s course, progression to spontaneous breathing should be prompt. Patients successfully completing a 30- to 120-minute spontaneous breathing trial 1104
can evaluated for extubation. A cuff leak test helps assess patency of the upper airway at the time of extubation. After extubation, observation in the intensive care unit is recommended for an additional 12 to 24 hours, and attention appropriately shifts to optimizing outpatient control and preventing future attacks. REFERENCES 1. Moorman JE, Akinbami LJ, Bailey CM, et al. National Surveillance of Asthma: United States, 2001–2010. National Center for Health Statistics. Vital Health Stat 3. 2012;(35):1–58. 2. Krishnan V, Diette GB, Rand CS, et al. Mortality in patients hospitalized for asthma exacerbations in the United States. Am J Respir Crit Care Med. 2006;174:633–638. 3. Getahun D, Demissie K, Rhoads GG. Recent trends in asthma hospitalization and mortality in the United States. J Asthma. 2005;42:373– 378. 4. Dougherty RH, Fahy JV. Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype. Clin Exp Allergy. 2009;39:193–202. 5. Lugogo NL, Macintyre NR. Life-threatening asthma: pathophysiology and management. Respir Care. 2008;53(6):726–739. 6. Corbridge T, Hall JB. The assessment and management of status asthmaticus in adults. Am J Respir Crit Care Med. 1995;151:1296–1316. 7. McFadden ER Jr. Acute severe asthma: state of the art. Am J Respir Crit Care Med. 2003;168:740–759. 8. Hasegawa K, Tsugawa Y, Clark S, et al. Improving quality of acute asthma in US hospitals: changes between 1999–2000 and 2012–2013. Chest. 2016;150:112–122. 9. Barr RG, Woodruff PG, Clark S, et al. Sudden-onset asthma exacerbations: clinical features, response to therapy, and 2-week follow-up. Multicenter Airway Research Collaboration (MARC) investigators. Eur Respir J. 2000;15;266–273. 10. Wasserfallen JB, Schaller MD, Feihl F, et al. Sudden asphyxic asthma: a distinct entity? Am Rev Respir Dis. 1990;142:108–111. 11. Sur S, Crotty TB, Kephart GM, et al. Sudden-onset fatal asthma: a distinct 1105
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50. Jat KR, Khaira H. Levalbuterol versus albuterol for acute asthma: a systematic review and meta-analyis. Pulm Pharmacol Ther. 2013;26:239– 248. 51. Rodrigo GJ, Neffen H, Colodenco FD, et al. Formoterol for acute asthma in the emergency department: a systematic review with meta-analysis. Ann Allergy Asthma Immunol 2010;104:247–252. 52. Peters JI, Shelledy DC, Jones AP, et al. A randomized, placebo-controlled study to evaluate the role of salmeterol in the in-hospital management of asthma. Chest. 2000;118:313–320. 53. Appel D, Karpel JP, Sherman M. Epinephrine improves expiratory airflow rates in patients with asthma who do not respond to inhaled metaproterenol sulfate. J Allergy Clin Immunol. 1989;84:90. 54. Cydulka R, Davison R, Grammer L, et al. The use of epinephrine in the treatment of older adult asthmatics. Ann Emerg Med. 1990;17:322–326. 55. Salmeron S, Brochard L, Mal H, et al. Nebulized versus intravenous albuterol in hypercapnic acute asthma: a multicenter, double-blind, randomized study. Am J Respir Crit Care Med. 1994;149:1466–1470. 56. Zorc JJ, Pusic MV, Ogborn CJ, et al. Ipratropium bromide added to asthma treatment in the pediatric emergency department. Pediatrics. 1999;103:748–752. 57. Qureshi F, Pestian J, Davis P, et al. Effect of nebulized ipratropium on hospitalization rates of children with asthma. N Engl J Med. 1998;339:1030–1035. 58. Rodrigo GJ, Rodrigo C. First-line therapy for adult patients with acute severe asthma receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the emergency department. Am J Respir Crit Care Med. 2000;161:1862–1868. 59. Stoodley RG, Aaron SD, Dales RE. The role of ipratropium bromide in the emergency management of acute asthma exacerbation: a meta-analysis of randomized clinical trials. Ann Emerg Med. 1999;34:8–18. 60. Weber EJ, Levitt A, Covington JK, et al. Effect of continuously nebulized ipratropium bromide plus albuterol on emergency department length of stay and hospital admission rates in patients with acute bronchospasm. Chest. 1999;115:937–944.
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Fitzgerald JM, Grunfeld A, Pare PD, et al; and the Canadian Combivent 61. Study Group. The clinical efficacy of combination nebulized anticholinergic and adrenergic bronchodilators vs nebulized adrenergic bronchodilator alone in acute asthma. Chest. 1997;111:311–315. 62. Ducharme FM, Davis GM. Randomized controlled trial of ipratropium bromide and frequent low doses of salbutamol in the management of mild and moderate acute pediatric asthma. J Pediatr. 1998;133:479–485. 63. Craven D, Kercsmar CM, Myers TR, et al. Ipratropium bromide plus nebulized albuterol for treatment of hospitalized children with acute asthma. J Pediatr. 2001;138:51–58. 64. Goggin N, Macarthur C, Parkin PC. Randomized trial of the addition of ipratropium bromide to albuterol and corticosteroid therapy in children hospitalized because of an acute asthma exacerbation. Arch Pediatr Adolesc Med. 2001;115:1329–1334. 65. Rodrigo G, Rodrigo C. Corticosteroids in the emergency department therapy of acute asthma: an evidence-based evaluation. Chest. 1999;116:285–295. 66. Rowe BH, Spooner C, Ducharme F, et al. Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database Syst Rev. 2001(1):CD002178. doi:10.1002/14651858.CD002178. 67. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med. 1986;314:150. 68. Lin RY, Pesola GR, Bakalchuk L, et al. Rapid improvement of peak flow in asthmatic patients treated with parenteral methylprednisolone in the emergency department: a randomized controlled study. Ann Emerg Med. 1999;33:487. 69. Connett GJ, Warde C, Wooler E, et al. Prednisolone and salbutamol in the hospital treatment of acute asthma. Arch Dis Child. 1994;70:170–173. 70. Scarfone RJ, Fuchs SM, Nager AL, et al. Controlled trial of oral prednisone in the emergency room treatment of children with acute asthma. Pediatrics. 1993;2:513–518. 71. Rowe BH, Spooner C, Ducharme F, et al. Corticosteroids for preventing relapse following acute exacerbations of asthma. Cochrane Database Syst Rev. 2007;(3):CD000195. doi:10.1002/14651858.CD000195.pub2. 1110
72. Manser R, Reid D, Abramson MJ. Corticosteroids for acute severe asthma in hospitalised patients. Cochrane Database Syst Rev. 2001;(1):CD001740. doi:10.1002/14651858.CD001740. 73. Emerman CL, Cydulka RK. A randomized comparison of 100-mg vs 500mg dose of methylprednisolone in the treatment of acute asthma. Chest. 1995;107:1559–1563. 74. Cydulka RK, Emerman CL. A pilot study of steroid therapy after emergency department treatment of acute asthma: is a taper needed? J Emerg Med. 1998;16:15–19. 75. Rehrer MW, Liu B, Rodriguez M, et al. A randomized controlled noninferiority trial of single dose oral dexamethasone versus 5 days of oral prednisone in acute adult asthma. Ann Emerg Med. 2016;68:608–613. 76. Schuckman H, DeJulius DP, Blanda M, et al. Comparison of intramuscular triamcinolone and oral prednisone in the outpatient treatment of acute asthma: a randomized controlled trial. Ann Emerg Med. 1998;31:333–338. 77. Engel T, Dirksen A, Frolund L. Methylprednisolone pulse therapy in acute severe asthma. A randomized, double-blind study. Allergy. 1990;45:224– 230. 78. Guttman A, Afilalo M, Colacone A, et al. The effects of combined intravenous and inhaled steroids (beclomethasone dipropionate) for the emergency treatment of acute asthma. The Asthma ED Study Group. Acad Emerg Med. 1997;4:100–106. 79. Nair P, Milan SJ, Rowe BH. Addition of intravenous aminophylline to inhaled beta2-agonists in adults with acute asthma. Cochrane Database Syst Rev. 2012;(12):CD002742. doi:10.1002/14651858.CD002742.pub2. 80. Kew KM, Kirtchuk L, Michell CI. Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department. Cochrane Database Syst Rev. 2014;(5):CD010909. doi:10.1002/14651858.CD010909.pub2. 81. Powell C, Dwan K, Milan SJ, et al. Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database Syst Rev. 2012; (12):CD003898. doi:10.1002/14651858.CD003898.pub5. 82. Camargo CA Jr, Smithline HA, Malice MP, et al. A randomized controlled trial of intravenous montelukast in acute asthma. Am J Resp Crit Care Med. 2003;167:528–533. 1111
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106. Gluck EH, Onorato DJ, Castriotta R. Helium-oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis. Chest. 1990;98:693–698.
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Clinical trials are the gold standard to prove efficacy of new therapies and management approaches for any disease. These trials take place after several years of preclinical development of new drugs designed to interfere with disease pathogenesis. Drugs vary widely from low-molecular-weight molecules to large recombinant compounds, such as monoclonal antibodies. Once a candidate drug is selected for development, it undergoes several toxicology tests before the Food and Drug Administration (FDA) approves it for investigational studies in humans. Under FDA supervision, clinical development takes place through phases I, II, and III studies to learn the pharmacokinetics (PK), pharmacodynamics (PD), and clinical efficacy of the new drug, respectively, while accumulating safety data all along. Several drugs have been developed for asthma, targeting airway inflammation and relaxation of airway smooth muscle. As our understanding of asthma pathogenesis evolves, new drugs are being developed to manage a disease that affects 24 million Americans and 334 million worldwide.
DRUG DEVELOPMENT A drug undergoes several phases of development until it is marketed (Fig. 22.1) (1). New drugs are initially developed based on our understanding of the essential biologic processes in disease pathogenesis based on human studies and animal models of human disease. One approach to develop a drug is to model a critical step of a pathway in an in vitro system (e.g., biologic response to a cytokine receptor) and test several compounds to identify those that affect the pathway. Pharmaceutic industries have libraries with thousands of natural and synthetic chemicals, peptides, nucleic acids, and other organic molecules which can be screened in high-throughput assay systems to test their biologic activity. Another approach is to design new compounds based on crystallography threedimensional structure of the target molecule (e.g., a receptor) and computerdesign and synthetize a drug, atom by atom, creating a three-dimensional 1115
molecule that will interact with the target (e.g., disrupt ligand-receptor binding). These designed drugs are then tested in biologic systems for their activities. A third approach is to use biotechnology to produce recombinant molecules that act as agonists (e.g., a cytokine) or antagonists (e.g., monoclonal antibodies, soluble receptors) in the targeted pathway. In the case of monoclonal antibodies, they were initially produced in mouse cell systems, but later biotechnologic advances allowed humanization of these antibodies by changing murine immunoglobin G (IgG) antibody protein sequences to human IgG sequences except for the principal amino acids responsible for binding to the target epitope (10% murine and 90% human amino acid sequence). This humanization of the antibody minimizes immunogenicity while sparing specificity and biologic activity (e.g., omalizumab [anti-IgE], mepolizumab and reslizumab [anti-IL-5], lebrikizumab [anti-IL13], and benralizumab [anti-IL5 receptor α]) (2–4). More recently, human cell hybridoma systems have allowed direct production of fully human monoclonal antibodies for therapeutic use (e.g., dupilumab [anti-IL-4 receptor α]) (4). Besides antibodies, biotechnology has produced recombinant human molecules for asthma trials, such as interleukin (IL) 4 soluble receptor (5), interferon γ (6), IL-12 (7), and others (4). Newer approaches to develop biologic treatments include genetic alteration of animals to produce human molecules (e.g., making goats secrete human growth hormone in their milk), DNA-based therapies (8), virus vectors for human gene therapy, epigenetic tools (e.g., small interfering RNAs) (9), stem cell (10), and genome-editing technologies (e.g., using CRISPR/Cas9) (11). A drug is usually developed together with several chemically similar counterparts. These similar compounds are tested in biologic systems in vitro and in animal models of human disease for their biologic activities to eventually identify a single or a few compound(s) for further development. These compounds may undergo chemical modifications to improve their eventual clinical application based on extensive understanding of the organic chemical characteristics necessary for resistance to gastrointestinal digestion and successful oral absorption (bioavailability), to prolong half-life by affecting distribution and metabolism, and to avoid toxicity. After in vitro testing, the drug is tested in animals for bioavailability, biologic activity, specificity of action, and toxicity. After a lead compound is selected, the pharmaceutic company files for a patent to obtain exclusive rights to market it for 20 years. Next, the drug enters the preclinical phase of development to establish an extensive safety profile of the drug in standard animal and cell culture systems. This phase includes in vitro and animal experiments to assess dose range, lethal dose 50% (dose that kills 1116
50% of exposed animals), acute and chronic toxicity, teratogenesis, mutagenesis, carcinogenesis, effects on pregnancy, and so on. During this phase, the pharmaceutic company discusses with the FDA about safety data in animals that will be required to start human studies. Once these requirements are fulfilled, the pharmaceutic company works closely with the FDA to design the first human study with the new drug, aiming at assessing PK in humans. This study is submitted to the FDA as an Investigational New Drug (IND) application. Only after the FDA approval, the IND can begin the first clinical trial, initiating the clinical phase (human studies) of drug development.
FIGURE 22.1 Phases of drug development. IND, Investigational New Drug approval; NDA, New Drug Application approval; PD, pharmacodynamics; PK, pharmacokinetics; RCTs, randomized clinical trials. The clinical development of a drug to attain FDA approval for marketing involves three phases of clinical studies. All studies in these phases are designed by the pharmaceutic company with continuous discussions and oversight from the FDA. In phase I studies, the drug is administered to few humans (e.g., n = 10) for the first time after completion of preclinical safety studies. The main aim of phase I studies is to understand drug’s PK, determining the maximum tolerated dose, time to peak serum level, bioavailability, half-life, metabolism, volume distribution, and route of elimination. Secondary aims include initial
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safety assessment (adverse effects) and measuring biomarkers of drug activity. Based on the dose that worked in animal studies and on PK data in humans, phase II studies are designed to assess PD, that is, to determine whether the drug causes the expected biologic effects for the targeted human disease. Two kinds of studies are usually conducted in this phase: proof-of-concept and dose-finding studies. In proof-of-concept studies, the biologic effect of the drug on the disease of interest is assessed in small randomized clinical trials where usually the maximal tolerated dose is administered to determine whether the new drug has the expected biologic activity in humans. In asthma, a common proof-of-concept study is to assess the inhibitory effect of the drug on the early airway response (EAR) and late airway response (LAR) to inhaled allergen challenge. Often, pharmaceutic companies conduct a couple of proof-of-concept studies that are considered “go” or “no-go” trials; that is, depending on the presence or absence of signs of biologic activity, the drug will or will not proceed in further clinical development, respectively. In a dose-finding trial, a few hundred subjects are randomized to placebo or two or more different dose regimens in a double-blind manner to determine what doses improve disease-related outcomes (e.g., forced expiratory volume in 1 second [FEV1] in asthma). Surrogate biologic markers of efficacy are often used to enable these trials to be short and thus less costly. Such secondary outcomes may include assays in patients’ samples to determine whether the drug had the expected biologic effects in the targeted pathway. For example, in trials of omalizumab, a neutralizing anti-IgE antibody, besides asthma clinical outcomes, serum-free IgE concentration was also measured as a surrogate marker of drug efficacy, which was achieved when free IgE was lowered to undetectable levels. At the end of phase II trials, researchers know the dose that affects important disease physiologic outcomes and have additional safety data in hundreds of individuals. This information is then used to plan and design phase III clinical trials to assess clinical efficacy and to obtain additional safety data to apply for FDA approval to market the drug. Phase III studies are large double-blind, placebo-controlled, randomized clinical trials designed to determine whether the drug improves clinically relevant outcomes selected by the pharmaceutic company and FDA. For asthma, some of the main outcomes to establish efficacy are airway obstruction (pulmonary function test), symptoms, quality of life (QOL) and frequency of exacerbations (see Table 22.1). The FDA usually requires more than one phase III trial demonstrating efficacy. If phase III trials are successful, the pharmaceutic company submits to the FDA a New Drug Application (NDA) to obtain approval for marketing. This application contains all data available on the 1118
drug since its preclinical development, as well as data from clinical studies in 3,000 to 5,000 patients. The FDA takes on average 6 months to approve or deny an NDA (range: 3 months to years) and may seek input from outside experts. Once approved, the pharmaceutic company can market the drug with exclusivity until the patent expires, at which point other companies can start producing and marketing the drug without having to pay a fee to the patent holder. After approval, new phase III studies can be undertaken to expand indications to different age groups (e.g., pediatrics) and new diseases, which can help extend duration of patents. After FDA approval, phase IV studies are designed to monitor safety aiming at identifying severe and rare side effects, such as those occurring at a rate of 1:10,000 or rarer. Examples of rare adverse events discovered in this phase include liver toxicity caused by telithromycin, cardiovascular events caused by rofecoxib, progressive multifocal leukoencephalopathy caused by JC virus in those receiving rituxan (anti-CD20), tendon rupture in patients taking quinolones, and, possibly, increased risk of asthma-related death in patients taking long-acting bronchodilators, particularly in African Americans not taking inhaled corticosteroids (ICSs). Besides phase IV trials, these rare serious events can be captured through the FDA surveillance system for medications’ adverse events called MedWatch (http://www.fda.gov/safety/medwatch/default.htm), which allows health care professionals to report adverse events directly to the FDA online. Rare serious adverse events related to a drug lead to “black box warnings” in the drug’s package insert, limitations of FDA–approved indications based on new risk and benefit ratio assessments, and even drug withdrawal from the market. The costly development of new drugs is a risky business. It is estimated that the cost to bring a new drug to market can reach over $1.5 billion. Many drugs fail during clinical development, and only 30% of marketed drugs return the costs for their development. New drugs can fail even after marketing in phase IV studies because of rare life-threatening adverse events, leading to restrictions in use or withdrawal from the market. Although patent protects marketing of new drugs for 20 years, it usually takes 8 to 10 years to obtain FDA approval to market a drug, leaving 10 or fewer years for the pharmaceutic company to profit from a drug. This profit should not only cover the expenses incurred to develop the drug itself but it should also fund research and development of new drugs to keep the pharmaceutic company in business. Successful drugs can be highly profitable such as atorvastatin (Lipitor) with over $12 billion in annual sales during 2005 to 2008, or fluticasone-salmeterol inhaler (Advair) with almost $8 1119
billion in sales in 2008 and over $4 billion annually from 2011 to 2013, omalizumab (Xolair) over $1 billion annually from 2011 to 2014 and over $2 billion in 2015, and adalimumab (Humira) $14 billion in 2015. TABLE 22.1 OUTCOMES IN ASTHMA CLINICAL TRIALS
MEASUREMENT
ASTHMA PROCEDURE REQUIRED ASSESSED
Allergy to airborne allergens
Allergy skin testing or specific serum IgE
COMPONENT
Atopy or IgE sensitization
FEV1 or FEV1/FVC ratio Spirometry
Airway obstruction
Post-bronchodilator FEV1 Spirometry pre– and post–short-acting bronchodilator
Reversible bronchospasm component
Best achievable FEV1 or Spirometry after Possibly a measure of remodeling maximum asthma therapy FEV1/FVC ratio for 1 wk Peak expiratory flow rate Portable PEFR meter (PEFR)
Frequent monitoring of airway obstruction
Provocative concentration Methacholine challenge to decline FEV1 by 20% (PC20)
Airway hyperresponsiveness
Early and late airway responses to allergen
Whole lung inhalation allergen challenge
IgE-mediated response to allergen in lower airways
Lavage of allergenchallenged segmental bronchus
Bronchoscopy
Induction of Th2 inflammation in a segment of lower airways
Bronchial mucosal biopsy Bronchoscopy
Airway inflammation and remodeling
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Sputum eosinophils
Sputum induction
Airway inflammation
Blood eosinophils
Blood draw
Airway inflammation
Fractional exhaled nitric Exhaling into NO oxide (FeNO) analyzer
Airway inflammation
Exhaled breath condensate
Measure small molecular Airway inflammation inflammatory markers and pH
Symptom diary
Complete diary forms
Symptoms
Asthma quality of life questionnaire
Complete questionnaire
Impact of asthma on own life (patient’s perspective)
Asthma control questionnaire
Complete questionnaire
Ongoing severity of asthma (physician’s perspective)
Asthma utilization
Complete questionnaire
Asthma impact on school/work and social activities
FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; IgE, immunoglobin E; NO, nitric oxide.
POSTMARKETING TRIALS After FDA approval to market a drug, postmarketing studies (phase IV trials) may be undertaken for a variety of purposes. If adverse events are a concern, the FDA may mandate additional monitoring of specific adverse events. For example, studies of safety of long-acting β agonist (LABA) inhalers (12), and the EXCELS study which thus far has shown no increase in risk of cancer in patients receiving omalizumab for asthma (13), although omalizumab may increase risk for arterial thromboembolic events (14). Additional phase IV clinical trials can also be designed to compare efficacy and safety of the new drug with those of existing drugs, to determine the best step therapy to use the new drug, and to evaluate safety and efficacy in children or in other disease 1121
indications. Moreover, analyses of combined data from multiple trials and new stratified trials can identify and prospectively validate biomarkers and clinical features that characterize best responders to the new drug, allowing personalized asthma care (15–17). These aforementioned phase IV clinical trials are efficacy trials where carefully selected patients are enrolled, close monitoring ensure high treatment compliance, and several outcomes are frequently measured. Another category of postmarketing studies is effectiveness trials where performance of a treatment is compared to a control treatment in the real world, generally in primary care clinics. In these trials, inclusion and exclusion criteria are less stringent, study visits minimized, and few clinically relevant outcomes measured. Another category of trials is patient-centered outcomes research trials where multilevel interventions with known efficacious treatments are compared in the community, at home, or in health care system setting to optimize implementation of management guidelines. Intervention involves education of patients, family, physicians (e.g., primary care doctors, emergency department doctors) as well as community agencies that can undertake home visits to teach home disease management, and/or to identify and reduce exposure to potential home environmental disease exacerbators (18).
OUTCOMES IN ASTHMA TRIALS Outcomes measured in asthma trials have evolved as has our knowledge on asthma pathogenesis, clinical trial design, and technology to measure biomarkers. In the early 1900s, pathologic and clinical evidence already indicated that asthma pathogenesis involved bronchoconstriction, eosinophilic bronchitis, and natural allergen exposure triggering asthma and hay fever symptoms. The advent of pulmonary function testing in the 1940s to 1950s led to demonstration of reversible airway obstruction and airway hyperresponsiveness in patients with asthma. In the 1970s, inhalation allergen challenges allowed the experimental observation of early and late airway bronchospastic responses associated with increased blood eosinophilia. In the 1980s, bronchoscopic biopsies of bronchial mucosa revealed chronic airway inflammation even in patients with mild disease, which is characterized mainly by eosinophilic bronchitis, and increased CD4+ T cells. In the 1990s, remodeling was described, which entails alterations in the resident structural cells resulting from chronic airway inflammation driven by infiltrating leukocytes. Remodeling includes goblet cell hyperplasia, smooth muscle cell hyperplasia, collagen
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deposition in the subepithelial reticular membrane, increased innervation and vasculature, among other changes (19). Currently, research continues to focus on mechanisms of inflammation, heterogeneity of airway inflammation (endotypes of asthma), innate response, interactions between resident cells and leukocytes, and inflammatory changes during asthma exacerbations which are mainly triggered by respiratory viral infections. The number and variety of clinical outcomes measured in asthma trials expanded based on our understanding of pathogenesis of airway disease as aforementioned (20). Pulmonary function tests (21) assess airway physiology such as spirometry to measure FEV1 to evaluate changes in airway flows, a function of airway caliber. Portable peak expiratory flow (PEF) meters allow patients to monitor airway flow at home. More recently, electronic portable devices can measure and record PEF, FEV1, and forced vital capacity (FVC) of 6 seconds, greatly expanding our ability to monitor variability in airway obstruction, a hallmark of asthma. Airway hyperresponsiveness to nonspecific stimuli is also measured in asthma trials because it is an important feature of asthma (22,23) and because it correlates with airway inflammation. It is commonly measured as the provocative concentration of methacholine or histamine to cause a 20% decline in FEV1 (PC20). Airways of individuals with asthma undergo excessive bronchoconstriction upon inhalation of methacholine or histamine, which act directly on smooth muscles causing contraction. Airway hyperactivity is defined as a PC20 < 8 mg/mL for these two direct agents (24). ICS therapy simultaneously improves both hyperresponsiveness and airway inflammation. Indirect agents are used less often to assess PC20. They cause bronchoconstriction indirectly by stimulating mast cells to release bronchospastic mediators, including histamine, cysteinyl leukotrienes, and prostaglandin D2. Examples of indirect agents to assess airway responsiveness include exercise, inhalation of adenosine, or inhalation of osmotic stimulants, such as cold dry air, distilled water, hypertonic saline, or mannitol (25). PC20 using indirect agents can correlate more closely with airway inflammation than PC20 using direct agents (methacholine and histamine). Airway hyperresponsiveness can also occur in medical conditions other than asthma, including allergic rhinitis without asthma, up to 6 weeks after respiratory virus infections, and in smokers with chronic obstructive pulmonary disease (24) (see Table 19.3).
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The realization that IgE sensitization and inhalation of a relevant allergen causes reproducible EAR and LAR led to the development of a widely used proof-of-concept asthma study model. In this model, subjects inhale increasing amounts of allergen—to which they react in allergy skin testing—to determine the concentration of allergen that causes a 20% decline in FEV1. Then, the subject receives placebo and/or drug therapy for a period of time and returns for a repeat allergen challenge using the same allergen and dose as the initial challenge to determine whether the drug attenuates airway responses to the allergen. Because EAR and LAR are very reproducible, only 10 to 12 patients are needed per group to assess whether a drug attenuates any response by 30% or more. Almost all currently available asthma drugs attenuate EAR or LAR or both (2,3,26–41), making this study model a common phase II trial to determine whether a new drug works for asthma (Fig. 22.2). Drugs that inhibit mast cell activation and bronchoconstriction should attenuate EAR, whereas drugs that inhibit delayed production of mediators or airway influx or function of leukocytes (e.g., eosinophils, dendritic cells, and lymphocytes) can inhibit LAR. This model of inhalation allergen challenge that induces 20% decline in FEV1 also increases airway hyperresponsiveness and sputum eosinophilia 24 hours after the challenge, allowing researchers to assess the effects of new drugs in these outcomes as well. The presence of LAR seems to be driven by T cells because studies of peptide immunotherapy revealed isolated late-phase reactions to injections without acute reactions (42). Peptides are too small to cross-link IgE and stimulate mast cells, but they do bind to human leukocyte antigens and stimulate T cells. Lastly, EAR and LAR responses in the lower airways are not unique to patients with asthma. They can also be present in nonasthmatic allergic rhinitic patients after rhinovirus colds (43), raising the hypothesis that a spectrum of disease progression in the lower airways may occur, such as IgE sensitization, bronchial hyperresponsiveness, bronchial EAR and LAR to allergen challenge, and finally full-blown asthma.
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FIGURE 22.2 Inhalation allergen challenge causing biphasic airway response in patients with asthma. Graph showing percentage changes in mean FEV1 and SEM from baseline to 7 hours postchallenge. Changes are reproducible between inhalation challenges performed 4 weeks apart (traced and continuous lines). Bronchoconstriction occurs within minutes and improves in 2 hours (EAR) mostly as a consequence of smooth cell contraction. Then, 3 to 8 hours after challenge, bronchoconstriction recurs as a consequence of increased influx of leukocytes, particularly eosinophils, Th2 lymphocytes, and basophils (LAR). Listed are medications that inhibit EAR and LAR (top line) when administered before the challenge. Anti-IL5 antibodies (mepolizumab and reslizumab) do not alter EAR or LAR. The effects of dupilumab and of long-acting muscarinic antagonists (LAMA) on allergen airway responses in humans have not been published. FEV1, forced expiratory volume in 1 second; EAR, early airway response; LAR, late airway response; anti-CysLTR1, antagonists of cysteinyl leukotriene receptor 1 (e.g., montelukast, zafirlukast); anti-5LO, antagonist of 5lipoxygenase (e.g., zileuton); anti-IgE, antibody anti-IgE (e.g., omalizumab); ICSs, inhaled corticosteroids; LABA, long-acting β2 receptor agonist bronchodilators (e.g., salmeterol, formoterol); SABA, short-acting β2 receptor 1125
agonist bronchodilators (e.g., albuterol, terbutaline). Another common proof-of-concept study design used in phase II trials to assess efficacy of new asthma controllers rather than acute relievers of bronchospasm, is the corticosteroid withdrawal model. In this model, subjects with moderate-to-severe asthma enter a run-in period on inhaled plus or minus oral corticosteroid therapy that is (are) titrated to the minimum corticosteroid dose necessary to control symptoms, at which point subjects are randomized to placebo or the new drug as an add-on therapy. Then, after a period on corticosteroid therapy and study medication (either new drug or placebo), corticosteroid therapy is tapered to determine whether the new drug is more efficacious than placebo in maintaining asthma control. In this kind of study, patients need to be monitored very closely, and protocols for action plan need to be in place to rescue patients when their asthma deteriorates. The corticosteroid withdrawal study is a model of loss of asthma control caused by worsening airway inflammation. It is not a model to study asthma exacerbations because acute exacerbations are caused by common colds in up to 80% of the episodes (44,45). Exacerbations occur when virus-induced inflammation superimposes to chronic allergen–driven inflammation. Studies evaluating asthma exacerbations recruit patients who have exacerbated in the previous year and follow them for a long period (e.g., 12 months) to capture new episodes of acute asthma deterioration requiring a short course of systemic corticosteroid therapy. Asthma exacerbation rate has increasingly become a primary outcome in asthma clinical trials evaluating new drugs because current available therapies are very efficacious in controlling symptoms, airway function, QOL, and other asthma outcomes. The recognition that asthma is a chronic inflammatory airway disease led to implementation of measurements of inflammation in clinical trials (see Table 22.1) (46). Blood eosinophilia is a marker to select patients with allergic inflammation for biologic therapies targeting eosinophils and Th2 inflammation. Bronchoalveolar lavage and bronchial mucosal biopsy reliably assess luminal and tissue inflammatory infiltrates, but necessitate bronchoscopy which precludes their use in large clinical trials. In the 1990s, sputum induction using hypertonic saline solution started to be used in asthma studies as a noninvasive technique to assess lower airway inflammation, but it remains a research tool. Sputum eosinophilia (>2% of nonsquamous cells) is characteristic of allergic asthma, increases after allergen challenge (47) and decreases with therapy, including systemic (48) or ICS (49), leukotriene antagonists, (50) and biologic immunomodulators targeting mediators of allergic inflammation, (4) such as IgE 1126
(omalizumab) (51–53), IL-5 (mepolizumab (54–56) and reslizumab (57,58)), and IL-5 receptor α subunit (benralizumab) (59,60). Biologicals targeting IL-5 reduce blood and sputum eosinophils and are efficacious in patients with asthma and eosinophilia (61). Anti-IL-13 antibodies (e.g., lebrikizumab and tralokinumab) can increase blood eosinophil count (62) and have had modest clinical efficacy in asthma trials (63,64). An anti-IL-4 receptor α (dupilumab) may also increase blood and sputum eosinophilia (65), but improves asthma outcomes (66). Mast cell stabilizers (cromolyn and nedocromil) improve symptoms of asthma and airway function, but have mild and inconsistent antiinflammatory effects as measured by eosinophil count or eosinophil products in airways and blood (67–70). It is noteworthy that sputum eosinophilia is not pathognomonic of asthma and can also occur in patients with eosinophilic bronchitis or chronic eosinophilic pneumonia. In addition, sputum neutrophilia, not eosinophilia, can be found in some patients with asthma, particularly those with nonatopic or more severe disease (71–73). Because of the risk of severe bronchospasm with inhalation allergen challenge, other models have been developed to study the effects of drugs in allergic airway inflammation. In one model, allergen is infused into a bronchial tree segment to induce localized airway allergic inflammation, the so-called segmental allergen challenge model (74). An equal amount of saline is infused in another segmental bronchus in the contralateral lung as a control challenge. Subsequent bronchoscopies are then performed to collect bronchoalveolar lavages of the same segments to evaluate early and late local inflammatory responses. Yet another model to induce mild airway inflammation of lower airways is the repeated low-dose inhalation allergen challenge model (75,76), in which subjects inhale the allergen dose calculated to cause only 5% decline in FEV1, based on a baseline allergen challenge. The same dose is inhaled daily for 5 or more days to induce airway eosinophilia, worsen hyperresponsiveness, and to cause none-to-mild short-living asthma symptoms, thus reproducing many features of asthma while avoiding the risk of severe bronchoconstriction associated with high-dose inhalation allergen challenges to induce EAR and LAR. Both the segmental and the repeated low-dose allergen challenge models are not widely used owing to the need for bronchoscopy and labor. Bronchoscopy with mucosal biopsy, however, has been used in clinical trials to assess the effect of therapy on airway inflammation (51) and remodeling (e.g., subepithelial collagen deposition (77,78)). An approach to indirectly measure airway remodeling is to administer a short course of maximal therapy. Because it is not practical to perform 1127
bronchoscopy for mucosal biopsy to histologically measure remodeling in large trials, researchers have used a short course of maximal therapy to reduce inflammation and bronchospasm and measure “the best achievable” FEV1 (79). In this study model, before and after an intervention, patients undergo a week of oral corticosteroid, maximal dose of ICS–long-acting bronchodilator (ICS + LABA) combination and a leukotriene antagonist treatment. At the end of the week of maximal asthma therapy, FEV1 is measured before and after maximal bronchodilation with administration short-acting bronchodilator (short-acting β2 agonists [SABA]). This best achievable FEV1 is considered by some to be a measurement of remodeling, which is assumed to be the irreversible component of airway obstruction after maximal therapy to reverse bronchospasm and to improve any reversible component of bronchial inflammation. However, this assumption has not been validated by comparing best achievable FEV1 (or FEV1/FVC ratio) with bronchial biopsy measures of remodeling (e.g., goblet and gland cell volume, smooth muscle volume, and subepithelial reticular membrane thickening). Noninvasive measurements of airway inflammation were developed in the 1990s and 2000s and include fractional exhaled nitric oxide (FeNO) and EBC. Nitric oxide (NO) can be measured as a gas in exhaled air. It is produced by the action of nitric oxide synthases (NOS) on L-arginine. In the lungs, NOS are found in airway epithelial and endothelial cells. Airway epithelial cells express inducible NOS (aka iNOS or NOS2) upon stimulation by several inflammatory pathways, including interferons (via signal transducer and activator of transcription [STAT]-1), Toll-like receptors (via nuclear factor kappa B), and IL4 (via STAT-6) which are activated both in respiratory infections and allergic inflammation. NO has several roles, including vasodilation, bronchodilation, and innate defense by inflicting nitrosative distress via nitration, nitrosation, and nitrosylation of molecules. Guidelines have been devised on how to measure FeNO because several factors can alter its concentration, such as food intake, contamination with upper airway NO, air flow, and other diseases besides asthma (80). Normal levels are Mon > Pbo al. (130) 1999 efficacy of ICS y old. three arms: in improving (Beclomethasone• FEV 50%–• Pbo FEV1, symptoms, 1 [Bec]) versus QOL, and 85% • Mon 10 mg qd reducing LTA (Montelukast • Bec 200 μgexacerbations. [Mon]) in bid asthma. Duration: 12 wk.
Bec is superior to Mon, which is better than Pbo to treat moderate-tosevere asthma. Hallmark study showing great variability in individual responses to drugs.
CAMP (131) (Childhood Asthma Management Program research group) 2000
To compare N = 1,041, 5– long-term 12 y old. efficacy and • Mild-tosafety of moderate nedocromil asthma (Ned) versus ICS therapy in childhood asthma.
Pauwels et al. (132) START (Inhaled Steroid Treatment as Regular Therapy in early asthma study) 2003
To determine N = 7,241, 5– • Bud 400 (200Bud reduced in Bud reduces long-term 66 y old. if Ned Pbo for chronic • Ned 8 mg bid > Pbo in providingtherapy of • Bud 200 μggreater benefits in childhood symptoms, AHR, asthma. Bud bid exacerbation rate, decreased All used albuterol growth by 1.1 and rescue Alb (Alb) prn. cm in the first use. year only. Duration: 4–6 y.
Patients homozygous for Arg in the 16th amino acid of the B2AR have worse asthma
acid of the B2AR respond differently to Alb.
for rescue phase. of Alb. Alb therapy, Washout of 8 wk. Gly/Gly patients but < 56 did better on Alb puffs/wk. Ipratropium (Ipra) than on Pbo. prn. • Treated with SABA only.
Morgan WJ To N = 937, 5–11 y Randomized to Real et al. (134) determine old. real versus intervention 2004 whether mock successfully • Allergen tailored reduced skin testintervention allergen tailored to amount of showing avoidance decrease allergens in allergy to improves home dust aeroallergensallergen and asthma in tobacco samples. It (dust, rat, inner-city exposure. also reduced mouse, pediatric cockroach, Education and symptoms, population. mold, pets). implementation. missed Duration: 2 y. school days, and unscheduled doctor’s visits for asthma.
while taking Alb regularly four times a day.
Tailored environmental intervention to reduce exposure to allergens and tobacco in children with asthma improves symptoms and reduces exacerbations.
O’Byrne et To N = 2,760, 4–80 Randomized to Bud/For bid Bud/For can al. (135). determine y old. three arms: + prn reduced be used as SMART whether exacerbation both • FEV1 =• Bud/For (Symbicort Bud/For can 80/4.5 μgrisk by 45% maintenance 60%–100% MAintenance be used as and rescue bid +and and Reliever maintenance • Receiving Terbutaline symptoms, medication. Therapy) and rescue 200–1,000 (Ter) prn. and improved For is a fast2005 medications lung function acting LABA, μg ICS • Bud 320 μg for asthma. compared improving • ≥12% bid + Ter with the other lung function reversibility prn two groups. within 5 min. • Using SABA• Bud/For prn almost 80/4.5 μg daily. bid + prn. Duration: 2 y. Boushey et al. (79) IMPACT
To evaluate N = 225, 18–65 Randomized to Daily Bud daily versus y old. three arms: better prn ICS for • Pbo bid improved
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It may be possible to treat mild
(IMProving mild Asthma persistent Control asthma. Trial) 2005
Guilbert et al. (136) PEAK (Prevention of Early Asthma in Kids) 2006
(intermittent baseline persistent Bud). asthma with FEV1, prn ICS. sputum • ≥ 12%• Bud 200 μg eosinophils, Although bid reversibility PC20, and intermittent or PC20 < 16 • Zafirlukast (Zaf) 20 mgFeNO than ICS mg/mL. the other two controlled bid. • Mild treatments. well QOL and persistent All groups: prn symptoms, its QOL, asthma inBud 800 μg bid ability to run-in phase. for 10–14 d, or symptoms prevent severe Prednisone for and FEV1 exacerbations 5 d if asthma after 1 wk of and deaths are maximal worsened. unknown. therapy did Duration: 12 not differ mo. among groups, suggesting no deterioration of remodeling. • FEV1 70%.
≥
To N = 285, 2–3 y Fluticasone determine old. (Flu) 88 μg or whether ICS • Positive Pbo bid for 2 y, prevents the 1 y of asthma asthma in predictive follow-up off high-risk index (≥4study young wheezing medication. children. episodes + atopy markers).
During the 2 Two years of y of ICS in young treatment, children at Flu improved high risk to symptoms, develop reduced asthma did exacerbations not prevent and need for asthma. But rescue ICS medications. controlled In the third well asthmayear, there like were no symptoms. differences between groups.
Papi et al. (137) To N = 455, 18– Randomized to ExacerbationPatients with BEST determine 65 y old. four arms: rate was mild (BEclomethasonewhether lower in persistent • FEV1 ≥ • A: Pbo bid + plus Salbutamol rescue rescue prngroup A thanasthma can be 75%. [albuterol] therapy with group B, but treated with Bec/Alb Treatment) 2007 combined • ≥12% symptom250/100 μg similar
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Alb + Bec is better than Alb alone in mild persistent asthma.
reversibility• or PC20 < 8 mg/mL. •
B: Pbo bid +among driven rescue Albgroups A, C, ICS/SABA 100 μg prn and D. therapy prn instead of C: Bec 250Group A regular ICS μg bid +received the daily therapy. rescue Alblowest 100 μg prn cumulative • D: Bec/AlbICS dose 250/100 μg over the 6 bid + rescuemo. Alb 100 μgGroup A prn was consistently Duration: 6 mo. better in improving lung function, symptoms, and use of rescue inhaler.
Cox et al. (138) AIR (Asthma Intervention Research trial) 2007
To N = 112, 18– Randomized to BT reduced BT done in determine 65 y old. • Bronchial by 50% loss three the effect of • Bec ≥ 200 thermoplastyof control bronchoscopy bronchial during 2-wk sessions can μg + LABA • Continued LABA thermoplasty per day. improve medical (BT) on the holding control of • FEV therapy. control of periods at 3, patients with 1 moderate or moderate-to60%–85%. Duration: 12 6, and 12 severe mo, and severe asthma • PC20 < 8mo. persistent improved and AHR mg/mL. asthma. AM PEFR during step(˜7.5%), down therapy. • Alb prn ≤ 4 AQLQ, Small sample puffs/d. ACQ, size to assess • Worsening symptoms effect on control and need for exacerbations. after rescue holding SABA use. LABA.
Sorkness et al. (139) PACT (Pediatric Asthma
To compare N = 285, 6–14 Controllers: Flu Flu and three y old. 100 μg, Sal 50 Flu/Sal controller • FEV provided ≥ μg, Mon 5 1 regimens for mg/dose. better and
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Flu bid and Flu/Sal best controlled asthma, but
80%. Controller Trial) children 2007 with mild• PC20 to-moderate 12.5 asthma. mg/mL.
Randomized to comparable Flu bid three arms: asthma improved the < control than most markers • Flu bid Mon. Flu of airway • Flu/Sal best inflammation. qAM, Sal improved qPM lung • Mon qPM function and FeNO. Duration: 48 wk.
Peters et al. (140) To N = 500, ≥6 y Randomized to Treatment SteppingLOCSS determine old. three arms: failure rate down patients (Leukotriene or whether • Controlled • Continued was similar with wellCorticosteroid or patients with on Flu 100 Flu bid between Flu controlled Corticosteroid– asthma well bid and Flu asthma on μg bid. • Flu 100 μg + Salmeterol) 2007 controlled + Sal groups ICS bid to ≥ Sal 50 μg(20%), and ICS + LABA on ICS bid • FEV1 qPM. can be worst in the qPM is better 80%. stepped Mon group than to Mon • PC20 1 y. IgE) SC (24.5%
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Add-on Oma reduced symptoms and Fall seasonal peak in asthma exacerbations.
based therapy.
Zeiger et al. (146) MIST (Maintenance and Intermittent Inhaled Corticosteroids in Wheezing Toddlers) 2011
• If on SABA every 2–reduction) only: not 4 wk and well exacerbations. • Pbo controlled. • Added to • If on current controller: asthma not well therapy. controlled or exacerbation Duration: in previous60 wk. year.
Comparison N = 278, 1–4.5 y RandomizedDaily and prn Preschoolers of daily old. to three Bud groups with recurrent versus arms: had similar wheezing and • Positive intermittent at risk for modified • Bud neb rates of (prn for API. 1 mg bidexacerbations developing RTI) ICS asthma can be prn foras well as • ≥ 4 wheezing therapy for treated with RTI for 7symptom episodes in preschoolers severity, time ICS prn for d the previous with to first RTI, resulting year. • Bud neb recurrent exacerbation, in less 0.5 mgand adverse exposure to wheezing • 1–6 and at risk events. Prn ICS. exacerbations qPM for Bud group needing oral • All developing corticosteroid subjects had 70% asthma. lower annual therapy in the could previous take AlbICS dose. year. neb qid prn. Duration: 1 y
Martinez et al. To assess (147) TREXA the efficacy (Beclomethasoneof rescue as rescue (prn) ICS treatment for versus lowchildren with dose daily mild persistent ICS therapy asthma) for children with mild 2011 persistent asthma.
N = 288, 6–18 y RandomizedExacerbation old. to four rates were arms: 31%, 28%, • Mild persistent • Bec bid 35%, and asthma for plus prn 49%; and ≥2 y. Bec + treatment failures were Alb • If on a (Combo) 5.6%, 2.8%, controller 8.5%, and medication, • Bec bid 23%, have well plus prn respectively. controlled Alb (Bec Bec bid
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Mild persistent asthma is best treated with Bec bid + Alb prn. Bec + Alb prn may be an effective step down for those well controlled on
provided the daily ICS, and best it does not • If not on a• Pbo bid outcomes, but slow growth. controller, plus prn similar to have either Bec + those of the uncontrolled Alb (Bec Combo asthma, or prn) group. Only have had 1–2• Pbo bid Combo and exacerbations plus prn Bec bid in the Alb (Alb caused 1.1 cm previous prn) decrease in year. growth. Bec: 40 asthma.
bid)
μg/dose. Duration: 44 wk Calhoun et al. (148) BASALT (Best Adjustment Strategy for Asthma in the Long Term) 2012
To determine N = 342, ≥18 y Randomized No All three whether old. to three arms differences in modes of adjusting ICS • Mild-toto adjust ICS treatment therapy dose based on dose based failure rates: provided moderate FeNO, or day- asthma. on: 22%, 20%, similar to-day outcomes. • Physician: and 15%, symptoms, is • Controlled respectively. Neither ICS adjusted on low-dose superior to adjusted by q6wks No ICS, Bec 80 guidelinebased on significant symptoms, μg bid. informed, asthma differences nor ICS physician adjusted by • FEV1 ≥ 70% guidelines. between adjustment in FeNO was guideline • PC20 < 8• Symptoms: preventing versus FeNO,superior to Bec 40 μg treatment mg/mL or or between physician taken with failure in adjustments FEV1 ≥ 12% guideline rescue Alb adults with based on versus reversibility prn. mild-toguidelines. symptom. after SABA. moderate • FeNO: ICS asthma. dose adjusted q6wks to keep FeNO 22– 35 ppb. Duration: 9 mo.
Kerstjens et al. (149)
To examine N = 912, 1–4.5 y Randomized Tio increased Addition of the efficacy of old. to two arms: Tio in
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• PrimoTinA- tiotropium asthma (Tio) for (Tiotropium patients with for asthma asthma poorly • poorly controlled on controlled on ICS + LABA. ICS + LABA) • 2012
Not • Tio 5 μgFEV1 by at patients controlled on qd least 85 mL, uncontrolled ICS + LABA prolonged on ICS + • Pbo qd time to first LABA PostAlb Duration: 48 exacerbation provides FEV1 ≤ 80%.wk by 25%, and modest ≥1 severe reduced risk improvement in lung exacerbation of severe in previous exacerbationsfunction and reduced 12 mo. by 21% compared to severe exacerbations. Pbo.
Bacharier et To evaluate N = 607, 1–6 y Randomized Azi reduced Among al. (150) whether early old. to two arms: by 36% the preschoolers APRIL Azithromycin • 1–4 • Azi 12risk of severe with recurrent (Azithromycin (Azi) therapy severe lower wheezing mg/kg/d RTI for for RTI requiring RTIs, the episodes with for 5 d PRevention of reduces Oral early use of RTI that • Pbo Severe lower progression to corticosteroidAzi during required Oral respiratory lung RTI corticosteroidAlb neb prn (from 8% to RTI reduced tract ILlnesses requiring oral 5%). the need for in previousqid. in corticosteroids year. Induction of Oral Duration: 18 Azi bacterial corticosteroid Preschoolers) therapy in preschoolers • Or use ofmo resistance therapy. 2015 controller for with recurrent was rare. ≤ 8 mo in wheezing. previous year. Wechsler et To compare al. (151) the BELT (Blacks effectiveness and and safety of Exacerbations Tio versus on LABA LABA added versus to ICS in Tiotropium) Black adults with asthma. 2015
N = 1,070, 18– Randomized There were Tio or LABA 75 y old. to two arms: no addition to • Physician- • Tio 18 μg differences ICS provides between ICS similar diagnosed qd + Tio versus effectiveness asthma. • LABA ICS + LABA in Black • On ICS + (Sal 50 μgin time to individuals LABA, or on or For 9first with asthma. ICS with μg) bid exacerbation, uncontrolled Continue ICS. exacerbation asthma. rate, FEV1, Duration: 18 ACQ, and in • FEV1 ≥ 40%. mo. patients with different B2AR genotypes.
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Sheehan et al. To evaluate N = 300, 1–5 y Randomized to There were no Among (152) AVICA whether old. two arms: differences preschoolers (Acetaminophenacetaminophen• Mild with asthma, • Acetaminophenbetween versus used prn for there were no persistent 15 mg/kg prngroups on Ibuprofen in fever or pain number of differences in asthma. qid for fever or Children with causes worse doses taken, asthma pain. • On ICS Asthma) asthma exacerbation outcomes daily, prn or• Ibuprofen 9.4 rates, rate of between those outcomes 2016 on Mon. mg/kg prn qidasthma control using compared to for fever ordays, use of acetaminophen prn ibuprofen • Physicianpain. in preschoolers diagnosed rescue inhaler, versus with mild asthma. Both were grape- unscheduled ibuprofen prn persistent for fever or flavored syrups. health care asthma. utilization pain. Duration: 48 wk. visits, and adverse events. Stempel et al. To evaluate N = 11,679, Randomized to Rate of serious Flu + Sal did (153) AUSTRI the risk of ≥12 y old. two arms: asthma-related not increase (Serious combined ICS • Moderate- • Flu 100, 250,event (death, risk for a Asthma Events + LABA and to-severe or 500 μg bid. endotracheal serious with Fluticasone Flu + Sal intubation, or asthma-related physician• Sal 50 μg with plus Salmeterol versus ICS Flu diagnosed hospitalization)event, and it Flu 100, 250,was similar in did reduce rate versus alone in asthma for or 500 μg bid. both groups. of severe Fluticasone patients with >1 y. Alone) moderate-toFlu + Sal asthma Diskus inhaler • Severe severe asthma. reduced by exacerbations device. 2016 exacerbation 21% the rate of from 10% to in the Duration: 26 wk. severe asthma 8%. previous exacerbations. year. • On daily controller. Stempel et al. (154) VESTRI (Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma) 2016
To evaluate N = 6,208, 4– Randomized to Rate of serious Flu + Sal did the risk of 11 y old. two arms: asthma-related not increase combined ICS • Moderate- • Flu 100 or 250event (death, risk for a + LABA and endotracheal serious to-severe μg bid. Flu + Sal intubation, or asthma-related physician • Sal 50 μg with versus ICS Flu diagnosed hospitalization)event, and it Flu 100 or 250was similar in did reduce rate alone in asthma for μg bid. children with both groups. of severe ≥1 y. moderate-toFlu + Sal asthma Diskus inhaler severe asthma. • Severe reduced by exacerbations device.
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exacerbationDuration: 26 wk. 14% the rate of from 10% to in the severe asthma 8.5%. No previous exacerbations. difference in year. growth rate. • On daily controller. ACQ, asthma control questionnaire; AHR, airway hyperresponsiveness; AM, morning; API, asthma predictive index (155); AQLQ, asthma quality of life questionnaire; bid, twice a day; BT, bronchial thermoplasty; ED, emergency department; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroids; LABA, long-acting β2 agonist; LTA, leukotriene antagonist; Neb, nebulization; OCS, oral corticosteroid; Pbo, placebo; PC20, provocation concentration of methacholine that causes a 20% drop in FEV1; PEFR, peak expiratory flow rate; q6wks, every 6 weeks; qAM, every morning; qid, four times per day; QOL, quality of life; qPM, every evening; RTI, respiratory tract illness; SABA, short-acting β2 agonist; Sal, salmeterol; Tri, triamcinolone.
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2603. 112. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004;170(8):836–844. 113. Rabe KF, Atienza T, Magyar P, et al. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet. 2006;368(9537):744–753. 114. Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129(1):15–26. 115. Lemanske RF Jr, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010;362(11):975–985. 116. Wechsler ME, Castro M, Lehman E, et al. Impact of race on asthma treatment failures in the asthma clinical research network. Am J Respir Crit Care Med. 2011;184(11):1247–1253. 117. Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011;154(9):573–582. 118. Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with highdosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2115–2127. 119. FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an antiinterleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128–2141. 120. Hanania NA, Noonan M, Corren J, et al. Lebrikizumab in moderate-tosevere asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015;70(8):748–756. 121. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365(12):1088–1098.
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Piper E, Brightling C, Niven R, et al. A phase II placebo-controlled study 122. of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41(2):330–338. 123. ATS. Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med. 2000;162(6):2341–2351. 124. Lange P, Parner J, Vestbo J, et al. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med. 1998;339(17):1194–1200. 125. Pillai P, Chan YC, Wu SY, et al. Omalizumab reduces bronchial mucosal IgE and improves lung function in non-atopic asthma. Eur Respir J. 2016;48(6):1593–1601. 126. Chung KF. Asthma phenotyping: a necessity for improved therapeutic precision and new targeted therapies. J Intern Med. 2016;279(2):192–204. 127. Ciprandi G, Tosca MA, Silvestri M, et al. Inflammatory biomarkers in asthma endotypes and consequent personalized therapy. Expert Rev Clin Immunol. 2017;13:715–721. 128. Kupczyk M, ten Brinke A, Sterk PJ, et al. Frequent exacerbators—a distinct phenotype of severe asthma. Clin Exp Allergy. 2014;44(2):212– 221. 129. Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med. 1997;337(20):1405–1411. 130. Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Montelukast/Beclomethasone Study Group. Ann Intern Med. 1999;130(6):487–495. 131. CAMP. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343(15):1054–1063. 132. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361(9363):1071–1076. 133. Israel E, Chinchilli VM, Ford JG, et al. Use of regularly scheduled 1157
albuterol treatment in asthma: genotype-stratified, randomised, placebocontrolled cross-over trial. Lancet. 2004;364(9444):1505–1512. 134. Morgan WJ, Crain EF, Gruchalla RS, et al. Results of a home-based environmental intervention among urban children with asthma. N Engl J Med. 2004;351(11):1068–1080. 135. O’Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med. 2005;171(2):129–136. 136. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354(19):1985–1997. 137. Papi A, Canonica GW, Maestrelli P, et al. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. 2007;356(20):2040–2052. 138. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007;356(13):1327–1337. 139. Sorkness CA, Lemanske RF Jr, Mauger DT, et al. Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial. J Allergy Clin Immunol. 2007;119(1):64–72. 140. Peters SP, Anthonisen N, Castro M, et al. Randomized comparison of strategies for reducing treatment in mild persistent asthma. N Engl J Med. 2007;356(20):2027–2039. 141. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008;122(6):1127.e8–1135.e8. 142. Ducharme FM, Lemire C, Noya FJ, et al. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med. 2009;360(4):339–353. 143. Wechsler ME, Kunselman SJ, Chinchilli VM, et al. Effect of beta2adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebocontrolled, crossover trial. Lancet. 2009;374(9703):1754–1764.
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Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up 144. therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363(18):1715–1726. 145. Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;364(11):1005–1015. 146. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365(21):1990–2001. 147. Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377(9766):650–657. 148. Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA. 2012;308(10):987–997. 149. Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012;367(13):1198–1207. 150. Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314(19):2034–2044. 151. Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs longacting beta-agonist in combination with inhaled corticosteroids in black adults with asthma: The BELT randomized clinical trial. JAMA. 2015;314(16):1720–1730. 152. Sheehan WJ, Mauger DT, Paul IM, et al. Acetaminophen versus ibuprofen in young children with mild persistent asthma. N Engl J Med. 2016;375(7):619–630. 153. Stempel DA, Raphiou IH, Kral KM, et al. Serious asthma events with fluticasone plus salmeterol versus fluticasone alone. N Engl J Med. 2016;374(19):1822–1830. 154. Stempel DA, Szefler SJ, Pedersen S, et al. Safety of adding salmeterol to 1159
fluticasone propionate in children with asthma. N Engl J Med. 2016;375(9):840–849. 155. Guilbert TW, Morgan WJ, Krawiec M, et al. The Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network. Control Clin Trials. 2004;25(3):286–310.
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Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a multifaceted immunologically mediated pulmonary disease with associated constitutional symptoms as a result of sensitization and then repeated inhalation of a wide variety of inhaled organic dusts. It is characterized by non– immunoglobulin E (IgE)-mediated inflammation of the pulmonary interstitium, terminal airways, and alveoli. This syndrome occurs in both atopic and nonatopic individuals and may present in several clinical forms depending on the duration, frequency, and intensity of antigen exposure; the antigenicity of the offending agent; and the patient’s age and immunologic responsiveness. Most cases occur in occupational and agricultural settings. However, various hobbies and medications are also associated with HP. Despite the many antigens recognized to cause HP, the clinical, immunologic, and pathophysiologic findings are generally comparable.
ALLERGENS PNEUMONITIS
OF
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HYPERSENSITIVITY
HP was recognized by Ramazzini (1) in 1713 in grain workers. Because awareness of this pulmonary disease has increased, there has been identification of new antigens implicated in the disease currently encompassing over 200 different agents (2). Although the immunopathophysiology of the disease is becoming clarified, there continue to be cases of HP in which the specific antigen has not been defined. The primary exposures for the development of HP are occupational, agricultural, and those related to hobbies. To reach the terminal airways and alveoli, the allergenic particles must be smaller than 3 to 5 μm. The variety of causative antigens includes airborne microbial antigens, animal or plant products, and low-molecular-weight chemicals (Table 23.1). Many of these same antigens, such as diisocyanates, mammalian and insect proteins, and wood dusts, can also induce IgE–mast cell-mediated allergic responses, including asthma. Thermophilic actinomycetes were recognized as the causative agent in farmer’s lung in 1932 in England (3). These bacteria thrive at temperatures of 70°C and can be found in high concentrations in compost piles or in silos where animal fodder is stored and becomes a culture medium for the organism. Identification and clarification of the responsible antigens has been described by a number of investigators (4,5). Increased awareness of the environmental factors favoring disease and changes in farming techniques have reduced the incidence of this disorder (6). TABLE 23.1 SOME PNEUMONITIS ANTIGENS
ANTIGENS
OF
SOURCE OF ANTIGEN
HYPERSENSITIVITY
DISEASE NAME
Bacteria Thermophilic actinomycetes Moldy hay, compost, silage, (Saccharopolyspora grain, moldy sugarcane rectivirgula, Thermoactinomyces vulgaris)
Farmer’s lung, mushroom picker’s lung, bagassosis
Bacillus, Klebsiella, Cytophaga
Ventilation pneumonitis, humidifier lung
Air conditioner, humidifier
Pseudomonas, Acinetobacter Contaminated metal-working Machine operator’s lung
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fluids Bacillus subtilis
Enzyme dust
Mycobacterium
Hot tub, metal-working fluids Hot tub lung
Enzyme/detergent worker’s lung
Fungi Aspergillus
Moldy brewing malt, stucco, Malt worker’s lung, compost, soy sauce, home stipatosis, compost lung contamination
Alternaria, Pullaria
Moldy redwood, wood dust
Wood worker’s lung, sequoiosis
Cephalosporium
Moldy wood floors or basement, sewer water
Floor finisher’s lung
Epicoccum, Rhodotorula
Cellar, bathroom and shower walls
Penicillium
Moldy cheese, cork dust, hay, Cheese worker’s/washer’s wood dust, salami seasoning, lung, suberosis, compost residential composter’s lung
Penicillium, Monocillium
Moldy peat moss
Peat moss processor’s lung
Cryptostroma corticale
Moldy maple bark
Maple bark disease
Trichosporum
Moldy homes in Japan
Summer pneumonitis
Pleurotus, Hypsizigus, Indoor mushroom cultivation Mushroom Lyphyllum, Cortinus shiitake, picker’s/worker’s lung
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Pholiota Candida
Moldy reed
Saxophonist’s lung
Pezizia, Penicillium, Fusarium
Moldy home
El Niño lung
Cladosporium
Contaminated water, moldy home
Hot tub lung/sauna taker’s lung
Rhizopus, Mucor
Moldy wood trimmings
Wood trimmer’s disease
Contaminated humidifier/ventilation
Ventilation pneumonitis
Amebae Naegleria, Acanthamoeba
Animal Protein Avian proteins (pigeon, duck, Droppings, feather bloom goose, turkey, chicken, dove, parakeet, parrot, lovebird, owl, canary, pheasant)
Bird/pigeon breeder’s lung/disease, bird fancier’s disease, budgerigar disease, plucker’s lung, duck fever
Rodent urine/serum protein
Rat or gerbil urine or serum
Lab worker’s lung, gerbil keeper’s lung
Pearl oyster/mollusk shell protein
Shell dust
Oyster shell lung/sericulturist lung
Animal fur dust (e.g., cat)
Animal pelts, fur
Furrier’s lung
Insect (grain weevil, silk worm)
Sitophilus granarius, silk worm larvae
Wheat weevil disease
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Drugs/Medications Amiodarone, chlorambucil, clozapine, cyclosporin, gold, β-blocker, sulfonamide, nitrofurantoin, minocycline, procarbazine, leflunomide, methotrexate
HMG-CoA reductase Drug-induced inhibitor, fluoxetine, hypersensitivity roxithromycin, lenalidomide, pneumonitis loxoprofen, mesalamine, sirolimus, tocainamide, trofosfamide, hydroxyurea, nasal heroin, infliximab, rituximab
Chemicals Isocyanates (TDI, HDI, MDI) Paint/chemical catalyst, Bathtub refinisher’s varnish, lacquer, polyurethane disease, paint refinisher’s foam plasticizer, spandex disease, plastic worker’s fibers, polyurethane lung, chemical worker’s elastomers lung Phthalic anhydride
Heated epoxy resin, dyes, insecticides
Dimethyl phthalate or styrene Chemicals used in manufacture of yachts
Epoxy resin lung
Yacht-maker’s lung
Methylmethacrylate
Dental prosthesis making
Others
Tobacco leaves
Tobacco grower’s lung
Insecticide
Pyrethrum lung
Coffee bean and tea leaf dust Coffee worker’s lung, tea grower’s lung Sawdust (pine, Cabreuva wood)
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Wood worker’s lung
Fish meal extract
Fish meal worker’s lung
Veterinary feed containing soybean hulls HDI, hexamethylene diisocyanate; HMG-CoA, 3-hydroxy-3-methyl-glutaryl–coenzyme A; MDI, methylene diphenyl diisocyanate; TDI, toluene diisocyanate.
Both commercial and residential exposures to mold-contaminated materials have been implicated in a number of cases of HP with the descriptive names of many of these diseases reflecting the source of exposure. For example, ventilation pneumonitis, caused by contaminated heating or cooling units, is probably the most common building-related form of HP (7,8). This syndrome may occur as a result of the inhalation of aerosols-containing antigens found in small home ultrasonic humidifiers to large industrial air handling units (9). Over the past decade, respiratory illness related to inhalation of metal-working fluids (MWFs) containing Gram-negative bacteria has been reported; this finding has far-reaching consequences for industry (10–12). While fungal exposure is ubiquitous outdoors, indoor exposure in water-damaged environments is less well characterized, but many case reports incriminate fungi as the cause of the disease in both adults and children (13). The role of fungal fragments in initiating human disease has yet to be clarified, but it provides a new paradigm for fungal exposure (14). Workers cultivating mushrooms in indoor facilities have been identified as another occupation with many affected individuals (15,16). Pigeon breeders and bird fanciers have long been recognized to develop HP to inhaled antigens in dried avian droppings and feather bloom (17,18). A variety of exotic, wild, and domestic birds have also been identified as causing bird breeder’s disease, including parakeets, cockatiels, doves, geese, and turkeys (19–21). Exposures to down feather pillows and comforters are also another culprit (22). Because new cases of HP are recognized, measures to identify the antigen and decrease antigen exposure can be implemented. This recognition, as well as changes in exposure, has resulted in some hypersensitivity diseases such as smallpox handler’s lung and pituitary snuff taker’s lung (porcine and bovine allergens) being of historical interest only (23). Occupational exposures recently recognized include the manufacture of yacht hulls where inhalation of fumes from heated chemicals in rolling fiberglass has been implicated (24). Kiln-dried 1166
wood heavily contaminated with Paecilomyces has affected workers in a hardwood floor processing plant (25). Inhalation of the coolant HFC134a used during laser removal of body hair has been reported to trigger HP symptoms with peripheral blood and bronchial biopsy eosinophilia (26). Cases of HP because of wind instruments contaminated with either mycobacteria or fungi have also been published (27,28). Medications are also an important cause of pulmonary disease that resembles HP. Among the implicated medications are nitrofurantoin, amiodarone, minocycline, roxithromycin, lenalidomide, nadolol, and sulphasalazine (29–34). Intranasal heroin has also been reported to cause the syndrome (35). Because the use of biologic agents become more common, we also have seen drug-induced pneumonitis from tumor necrosis factor α (TNF-α) blockers (e.g., infliximab and etanercept) (36,37) and monoclonal antibodies, such as rituximab, an anti-CD20 IgG1 monoclonal antibody (38). Specific syndromes of HP occur in different parts of the world. For example, esparto grass is used in the production of rope, matting, paper pulp, and plaster in Mediterranean countries. Individuals such as stucco workers have developed HP to Aspergillus fumigates-contaminated esparto fiber dust in their workplace environments (39). Workers in Eastern Canada who are employed in peat moss processing plants are frequently exposed to loose dry material which may contain many microorganisms, of which molds have been implicated in causing HP (40). Summer-type HP caused by Trichosporon is an important example of a disease not found in the United States, but is the most prevalent form of HP in Japan (41). In the Midwestern United States, of 85 patients with HP identified from 1997 to 2002, the most common causes were avian-related (34%), hot tub lung (21%), farmer’s lung (11%), household mold exposure (9%), and unidentified antigen (25%) (42). Controversy surrounds the classification of “hot tub lung” as HP versus infection with nontuberculous mycobacteria.
EPIDEMIOLOGY The exact incidence of HP is unknown, but it has been identified in 2% to 8% of farmers (43) and in 6% to 21% of pigeon breeders (44). Of 36 cases of chronic HP identified by a hospital survey in Japan, reported etiologies were summertype HP (10 cases), other home-related causes (5 cases), bird fancier’s disease (7 cases), isocyanate (5 cases), farmer’s lung (4 cases), and five miscellaneous cases (45). In Ireland, as haymaking methods were revolutionized in the 1980s and between 1997 and 2002, a marked decline in HP was observed (46). In the 1167
United Kingdom, however, the overall incidence of HP is one to two cases per million workers each year. From reviewing the cases from January 1996 to December 2015, contaminated water-based MWF is the most commonly suspected culprit (35%) for occupational HP reported in the United Kingdom, compared to farming (17%) and birds (11%). Occupations reported to have been associated with HP owing to avian exposures included poultry farming and domestic bird breeding. Between 1996 and 2000, there was only one case of MWF contamination reported (47). The majority of reported cases of MWF-HP have occurred in workers manufacturing components for cars and airplanes. In the United States, the “healthy worker effect” and high employee turnover may be partly responsible for the underreporting or underrecognition of work-related cases of HP.
DIAGNOSTIC FEATURES
CRITERIA
AND
CLINICAL
The criteria for the diagnosis of HP consist of recognizing the clinical features with supporting exposure history, laboratory, pulmonary function, and radiographic characteristics (Fig. 23.1) (48). Although there is no single confirmatory test for HP, not even lung biopsy, six significant predictors were identified that provide a 95% confidence interval. These include (a) exposure to a known offending allergen; (b) positive precipitating antibodies to the offending antigen; (c) recurrent episodes of symptoms; (d) inspiratory crackles on lung auscultation; (e) symptoms occurring 4 to 8 hours after exposure, and (f) weight loss (49). The clinical presentation follows repeated exposure and can vary from sudden and explosive systemic and respiratory symptoms to an insidious, progressive course of dyspnea, fatigue, and weight loss. Based on these clinical presentations, HP has been divided into acute, subacute, and chronic forms (50).
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FIGURE 23.1 Evaluation of hypersensitivity pneumonitis. IgA, immunoglobin A; IgG, immunoglobin G. The patient with the acute form presents with nonproductive cough, dyspnea, 1169
sweating, myalgia, and malaise occurring 4 to 12 hours after intense exposure to the inciting allergen. Acute viral or bacterial infections may mimic this presentation, leading to treatment with antibiotics. With avoidance of the allergen, the symptoms spontaneously resolve over 18 to 24 hours, with complete resolution within days. This is in contrast to viral infections. On repeat exposure, the symptoms recur with either more severe and progressive symptoms or less intense and nonprogressive symptoms. The patient may recognize this pattern and try to minimize their exposure. The chronic form is characterized by the insidious onset of dyspnea that especially occurs with exertion. Other symptoms include productive cough, fatigue, and anorexia with weight loss. Fever is not typical unless there is a high-dose allergen exposure superimposed on the chronic symptoms. This form is usually related to continuous low-level antigen exposure and is not often recognized, resulting in a delay in the correct diagnosis. An antigen exposure history could be the only clue to the diagnosis. The subacute form is characterized by symptoms intermediate to the acute and chronic form with progressive lower respiratory symptoms. The acute and subacute forms may overlap clinically, just as the subacute and chronic forms may. Lacasse et al. in 2009 published a study looking at dividing the forms into two clusters, acute and chronic HP. Lacasse et al. (51) hypothesized that the subacute form may be a variant of acute HP. In this study, nodular opacities were seen on high-resolution computed tomography (CT) in both clusters (acute versus chronic).
PHYSICAL EXAMINATION The physical examination may be normal in the asymptomatic patient between widely spaced episodes of acute HP. Fine, dry crackles may be present, depending on the degree of lung disease present and the timing following the most recent exposure. Wheezing is not a prominent symptom. An acute flare-up of HP is associated with an ill-appearing patient in respiratory distress with temperature elevation up to 40°C for 6 to 12 hours after antigen exposure. Rash, lymphadenopathy, or rhinitis should prompt investigation for causes other than HP. With extensive fibrosis that occurs in the chronic form of the disease, dry crackles and decreased breath sounds predominate. Some patients with end-stage disease may have digital clubbing (52).
PULMONARY FUNCTION TESTS The classic pulmonary function abnormality in the acute form is restriction with 1170
decreased forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) occurring 6 to 12 hours after exposure to the offending antigen (Fig. 23.2). A biphasic obstructive response similar to that seen in the early and late phases of asthma has been observed in patients who develop both occupational asthma and HP as a result of sensitization to the same antigen. Peripheral airways obstruction as determined by decreased FEV1 and/or forced midrange flow measurements (FEF25%–75%) has frequently been reported. Decreased gas transfer across the alveolar wall as measured by the diffusion capacity of the lungs for carbon monoxide (DLCO) is often detected. This is in contrast to asthma, a disease in which an elevated DLCO commonly occurs. Although hypoxemia at rest may be observed with severe lung damage, hypoxemia with exercise is common and can be documented by pre- and postexercise arterial blood gas measurements. Bronchial hyperresponsiveness as determined by methacholine challenge is present in a majority of patients with HP and is likely caused by the inflammatory response of the airways. In subacute and chronic HP, there is usually a demonstrable combination of obstruction and restriction.
FIGURE 23.2 Graphic representation of changes in acute hypersensitivity pneumonitis. DLCO, diffusion capacity of the lungs for carbon monoxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; WBC, white blood cell.
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RADIOGRAPHIC FEATURES Chest Radiographs Radiographic abnormalities may be transient or permanent depending on the form or stage of disease. Transient radiographic changes occur primarily in the acute form with patchy, peripheral, bilateral interstitial infiltrates with a fine, reticulonodular pattern similar to acute pulmonary edema (53) as seen in Fig. 23.3. There may be bilateral ground-glass opacities in the middle to lower lung fields that are indistinguishable from other interstitial lung disorders. Central lymphadenopathy may also be present. These changes usually resolve spontaneously with avoidance or with corticosteroid therapy. Between acute attacks, the chest radiograph is usually normal.
Figure 23.3 Chest radiograph of a patient with hypersensitivity pneumonitis demonstrating bilateral lower-lobe patchy infiltrates and a reticulonodular pattern. In the subacute form, nodular, patchy, or diffuse infiltrates with bilateral ground-glass opacities; poorly defined small centrilobular nodules; and lobular areas of decreased attenuation, vascularity on inspiration, and of air-trapping on expiration have been observed (54). In the chronic form, fibrotic changes with patchy or random reticulation, traction bronchiectasis, and areas of emphysema may be seen superimposed on acute or subacute changes, typically sparing the lung bases. Less commonly, subpleural honeycombing is found (54). Findings not characteristic of HP include calcification, cavitation, atelectasis, solitary pulmonary nodules, pneumothorax, and pleural effusions.
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Computed Tomography Scans High-resolution chest CT scans may be helpful when vague parenchymal changes are present on plain chest radiographs. Findings include ground-glass opacification and diffuse consolidation suggestive of alveolar disease. A normal chest CT scan does not rule out acute HP because the sensitivity of this technique may be only 55% (55). In subacute disease, 1- to 3-mm ill-defined centrilobular nodules with superimposed areas of ground-glass opacity may be seen (56). The CT findings of the chronic form are honeycombing, pulmonary fibrosis, and traction bronchiectasis. CT features to suggest HP are predominantly middle lung involvement, extensive ground-glass opacities, and small nodules often in the central and peripheral compartments. The role of magnetic resonance imaging has been limited because of respiratory and cardiac motion artifact. Similarly, gallium lung scan and the clearance rate from the alveolar epithelium using a technetium label are being investigated in the early detection of inflammation or damage to the alveolar capillary unit, respectively, in infiltrative lung diseases, but studies specifically in HP are lacking (57).
LABORATORY Routine laboratory studies are typically normal in the asymptomatic patient. In the acute form, leukocytosis with a white blood cell count to 25,000 mm3 and a left shift, an elevated erythrocyte sedimentation rate, and decreased DLCO are common. Eosinophilia is uncommon. Total serum IgE levels are normal unless the patient has coexisting atopic disease (58). Quantitative immunoglobulin measurements are normal, or at times, serum IgG may be elevated. The characteristic immunologic feature of HP is the presence of high titers of precipitating IgG and other classes of antibodies directed against the offending antigen demonstrated in the sera of affected patients (59). Serum precipitating antibodies, as detected by the Ouchterlony double-gel immunodiffusion technique, indicate antigen exposure, but not necessarily disease (Fig. 23.4). In pigeon breeders, as many as 50% of similarly exposed but asymptomatic individuals may have detectable precipitins (60). False-negative precipitin panels could result from omission of the responsible antigen from the test panel. Enzyme-linked immunosorbent assays and complement fixation techniques for antibody measurements may be too sensitive. However, a small study using an automated solid-phase indirect enzyme assay with fluorimetry was shown to be more sensitive in detecting symptomatic bird fanciers using antibody level of 10 mg/L in contrast to precipitin formation which detects antibody at over 40 mg/L. 1173
The assay was rapid and may be able to differentiate between pigeon breeders who have subacute or insidious onset of chronic avian HP (61). Compared to double diffusion, electrosyneresis (electrophoresis on cellulose acetate sheets) demonstrated value to detect mold antigens in symptomatic patients, but only if the appropriate antigens were selected (62). If these tests are negative despite a suggestive history, additional testing with antigens specifically prepared from the suspect environment may be necessary. The absence of serum precipitins does not rule out HP. Routine precipitins panel may have false-negative tests, even if the correct antigen is included. Depending on the exposure, an airborne mist, fluid, dust, or soil sample from the original source may be obtained and cultured for contaminating microorganisms. This cultured material can then be used as an antigen in gel diffusion reactions.
SKIN TESTING In contrast to asthma and other IgE–mast cell-mediated diseases, immediate wheal-and-flare skin reactivity to allergens is not useful because the immunopathogenesis of HP does not involve IgE. Skin testing with antigens that cause HP has been associated with late-onset skin reactions that histologically resemble Arthus-type reactions with mild vasculitis. On occasion, necrosis has also been observed. When differentiating IgE–mast cell-mediated occupational asthma from HP, skin testing can aid in the diagnosis. Both asthma and HP may occur in the same individual; in that case, both immediate and late reactions to antigens used in cutaneous testing may occur.
BRONCHOALVEOLAR LAVAGE Pulmonary consultation to conduct bronchoscopy and bronchoalveolar lavage (BAL) may be indicated when other studies are normal or other diagnoses, such as tuberculosis, pulmonary sarcoidosis, alveolar proteinosis, or idiopathic pulmonary fibrosis, are entertained. Bronchoalveolar lavage fluid (BALF) is helpful in the diagnosis of HP because there is a lymphocytosis with preponderance of CD8+ T lymphocytes over CD4+ T cells (63). It appears to be characterized by the CD3+/CD8+/CD56+/CD57+/CD10– phenotype. The density of these phenotypic markers in BALF T lymphocytes is greater than in sarcoidosis, cryptogenic organizing pneumonia, or healthy controls (64). In addition, mast cells (greater than 1% of recovered white cells) associated with a BAL lymphocytosis may support the diagnosis of HP. The mast cells may also help in monitoring exposure because they are usually increased with acute exposure (65). An elevated lymphocyte count may not always be demonstrated 1174
in the chronic form. In contrast to the subacute and chronic forms of HP, increased alveolar macrophages are observed in the acute form. Lymphocytosis with a normal CD4/CD8 ratio correlated with more severe interstitial disease on high-resolution CT (66). Recently, elevated levels of albumin in BALF using eriochrome cyanine R in fluorimetric determination was found in patients with HP (67). Cultures of BALF can help exclude infectious disorders.
Figure. 23.4 Precipitin bands detected by the Ouchterlony double-gel immunodiffusion technique.
PATHOLOGIC FEATURES If a biopsy is deemed necessary, open lung biopsy is recommended to obtain an adequate tissue sample. Studies of transbronchial biopsy results suggest that the sample may not be adequate. Lung biopsy findings depend on the form of the disease and extent of lung damage that has occurred. The cells specifically are activated “foamy” macrophages, and have a marked predominance of lymphocytes, plasma cells, and neutrophils (68). The acute form has a marked neutrophilic infiltration in the alveoli and respiratory bronchioles with diffuse alveolar damage. Specimens of the subacute form classically reveal a triad of cellular bronchiolitis, patchy chronic interstitial lymphocytic pneumonitis, and scattered small alveolar noncaseating granulomas (54) (Fig. 23.5). The granulomas differ from pulmonary sarcoidosis in that they appear smaller, dispersed in interstitial fibrosis, loosely arranged, poorly formed, and are distributed away from bronchioles and vessels. Immunoglobulin or complement has only rarely been demonstrated in pulmonary biopsies. In the later stages of chronic HP, interstitial fibrosis with collagen-thickened bronchiolar walls and less prominent lymphocytic alveolitis is common. In chronic bird fancier’s lung, nonspecific interstitial pneumonia or usual interstitial pneumonia patterns may be seen (54), compared to farmers with chronic HP develop emphysema (69).
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Figure 23.5 Light microscopy view of lung biopsy revealing a lymphocytic infiltrate with small noncaseating granulomas.
SPECIFIC INHALATION CHALLENGE Although purposeful inhalation challenge is not required for diagnosis, it can be helpful in situations in which the history is convincing, but other data are lacking and the diagnosis is unclear. An allergen challenge can be performed in two ways. First, the patient can return to the workplace or the suspect environment where the antigen is present. In conjunction with pulmonary function and laboratory studies, this approach can implicate the suspect environment, but it will not necessarily identify the allergen. In evaluating these individuals, vital signs (hypoxemia), including temperature (fever), spirometry (decreased FVC), diffusing capacity, and white blood cell counts with differentials (peripheral neutrophilia), should be monitored before exposure and at intervals up to 12 hours later. An inhalation challenge can also be performed in the hospital pulmonary function laboratory. In this situation, vital signs, including temperature, spirometry, and complete blood count, should be monitored before, during, and after a controlled antigen exposure. Unfortunately, there is generally no specified concentration of allergen or commercially available allergen preparations for this use. The concentration of antigen used can be determined by using air sampling data, which reflects usual exposure. Nonspecific antigen should also be used as a control challenge. This inhalation test requires careful observation by trained personnel because severe systemic febrile and respiratory reactions requiring intervention with corticosteroids may occur.
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DIFFERENTIAL DIAGNOSIS HP should be considered in any patient with acute or chronic respiratory distress with or without systemic symptoms or interstitial pneumonia (Table 23.2). Like other occupational respiratory diseases, a detailed knowledge of the work and home environment is required. Documentation of cross-shift lung function changes can be detected in some individuals. It should be noted that HP is limited to the lung, and involvement of extrapulmonary tissues has not been described. The acute form of HP is commonly confused with atypical, communityacquired pneumonia. A group of conditions referred to as organic dust toxic syndrome (ODTS) is also often confused with HP (70). ODTS occurs in the agricultural setting, presents in individuals exposed to grain, silage, or swine materials, and primarily affects younger age groups and those without prior sensitization to offending agents. In contrast to HP, ODTS is thought to be caused by inhalation of endotoxin and other phlogistic agents. Diseases such as humidifier fever can also occur in outbreaks and may be related to inhalation of endotoxin from Gram-negative bacteria that contaminate ventilation and humidification systems (71). TABLE 23.2 CLINICAL PRESENTATION OF HYPERSENSITIVITY PNEUMONITIS FEATURES
ACUTE
SUBACUTE
CHRONIC
Fever, chills
+
−
−
Dyspnea
+
+
+
Cough
Nonproductive
Productive
Productive
Malaise, myalgia
+
+
+
Weight loss
−
+
+
Rales
Bibasilar
Diffuse
Diffuse
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Chest X-ray, HRCT
Nodular infiltrates
Nodular infiltrates
Fibrosis
PFTs
Restrictive
Mixed
Mixed
DLCO
Decreased
Decreased
Decreased
DLCO, diffusion capacity of the lungs for carbon monoxide; HRCT, high-resolution computed tomography; PFTs, pulmonary function tests. Adapted from Grammer LC. Occupational allergic alveolitis. Ann Allergy Asthma Immunol. 1999;83:602–606; with permission.
Hairi et al. describe a case series of acute onset or exacerbation of HP, which includes the presence of intra-alveolar fibrin deposition in the cases, which resembled acute fibrinous and organizing pneumonia (AFOP). Given the findings by Hairi et al., (72) acute HP should be included in the differential of patients with unexplained neutrophilic capillaritis (72). Hairi et al. also supported that HP should be considered in the differential of the histologic pattern of AFOP. The differential diagnosis of the subacute form of HP includes chronic bronchitis, recurrent episodes of influenza, and idiopathic pulmonary fibrosis. “Hot tub lung” refers to a noncaseating granulomatous lung disease with nontuberculous mycobacteria (usually Mycobacterium avium-intracellulare) from exposure to hot water aerosols from hot tubs or spas, showers, and indoor swimming pools (73). Immunologic pathogenesis has resulted in treatment with corticosteroids although mere abstinence from hot tubs has been successful in some cases. Whereas the chest CT scan findings are similar to HP, the histopathologic features are distinct (74,75). Like hot tub lung, nontuberculous Mycobacterium (most often Mycobacterium immunogenum) has been implicated with MWFs. However, detection of M. immunogenum in MWF is difficult. Unlike hot tub lung, mycobacteria are not cultured from BALF, and measurement of M. immunogenum antigens by enzyme-linked immunosorbent assay have recently been described (76). The chronic form of HP must be differentiated from many chronic interstitial lung diseases, including idiopathic pulmonary fibrosis, chronic eosinophilic pneumonia, collagen vascular disorders (dermatomyositis), emphysema, lymphogenous spread of carcinoma, sarcoid, desquamative interstitial pneumonia, and Hamman–Rich syndrome (Table 23.3). Morell et al. (77) found 1178
that 43% in the study initially meeting 2011 idiopathic pulmonary fibrosis criteria were finally diagnosed with HP at a later timepoint. Extrapulmonary findings of liver or spleen enlargement, generalized or local lymphadenopathy, severe sinusitis, or myositis are not consistent with HP.
PATHOGENESIS Although the mechanisms of inflammation are complex and still not fully clarified, the Gell and Coombs type III immune complex and IV cell-mediated reactions are the best paradigm for explaining the immunologic mechanisms, resulting in HP. Several animal models and many animal studies have been conducted to elucidate the complexity of the immune inflammation-inducing disease (78–81). Unfortunately, the findings do not appear to directly parallel the inflammatory process seen in human disease. Also, there is difficulty evaluating exposed but asymptomatic animals, as can be done in human studies. Animal models suggest that HP is facilitated by the overproduction of interferon γ (IFNγ), a helper T-cell type 1 (TH1) response (82). This is supported by observations that interleukin 10 (IL-10), a TH1 suppressor molecule, ameliorates the severity of the disease. TABLE 23.3 EVALUATING CHRONIC INTERSTITIAL LUNG DISORDERS IN LUNG DISORDERS IN THE DIFFERENTIAL DIAGNOSIS OF CHRONIC HYPERSENSITIVITY PNEUMONITIS
BAL
LUNG BIOPSY
DISEASE
ETIOLOGY BLOOD
Pulmonary sarcoidosis
Unknown
↑ACE level, CD4+ ↑IgG, alveolitis ↑Calcium
Diffuse uniform granulomas
Chronic bronchitis
Tobacco smoke
Normal
Centrilobular emphysema
Byssinosis
Cotton, flax, Normal or hemp dust
Histiocytosis,
Unknown
PMNs increased
Inflammation NA
Normal
OTHER
Hilar adenopathy, skin test anergy, gallium scan
Reversible obstruction
Cytoplasmic Pneumothorax
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X/eosinophilic, granuloma
Birbeck granules
Coal worker’s Coal dust pneumoconiosis
Normal
Focal emphysema “dust macules”
Pulmonary alveolar proteinosis
Unknown
Normal
Chronic eosinophilic pneumonia
Unknown
Eosinophilia Eosinophilia Eosinophils
Saline lavage PAS staining PAS material can improve alveolar in sputum function material, no interstitial changes
α1-Antitrypsin Genetic deficiency deficiency
Pi typing-ZZ NA phenotype
Alveolar wall Panacinar destruction emphysema
Sick building syndrome
Irritants
Normal
Normal
Normal
Idiopathic pulmonary fibrosis
Unknown
Normal
Lymphocytes Fibrosis
Drug reactions Drug
Eosinophils Eosinophils, Variable lymphs, PMNs
Chronic Tuberculosis Normal granulomatous infections
Positive AFB Caseating culture granulomas
Inorganic Berylliosis, BeLPT respiratory dust silicosis syndromes
CD4+ alveolitis, BeLPT
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Granulomas, nodular silica deposits
Positive PPD
Chronic aspergillosis
Aspergillus Precipitating Few species antibody, degenerating eosinophilia, eosinophils elevated total and fungal and specific hyphae IgE
Exudative Positive SPT, bronchiolitis, positive marked sputum eosinophils, culture, central asthma saccular bronchiectasis
ACE, angiotensin-converting enzyme; AFB, acid fast bacteria; BAL, bronchoalveolar lavage; BeLPT, beryllium lymphocyte proliferation test; IgE, immunoglobin E; IgG, immunoglobin G; NA, not available; PAS, periodic acid-Schiff stain; PMNs, polymorphonuclear cells; PPD, purified protein derivative; SPT, skin puncture test.
Human studies are more difficult to perform, relying on patients who have already experienced symptoms and, therefore, not truly evaluating the course of inflammation from the onset. The relative contributions of cellular versus humoral immunity in the pathogenesis are not entirely defined. A case report of a patient with hypogammaglobulinemia and HP supports the central role of cellular immunity in mediating the disease (83). The study data are frequently based on BAL findings compared with biopsy or peripheral blood. The data suggest that the most important elements in the inflammatory process are the activation of alveolar macrophages, CD8+ cells, and TH1 lymphocytes. The hypothesized mechanism for HP is depicted in Fig. 23.6. When antigens 2 to 10 μm in size are inhaled, they are engulfed and processed by activated alveolar macrophages that can be detected by an increase in surface IL-2R (CD25). The activated macrophages release pro-inflammatory cytokines, such as IL-1 and TNF-α (84). This in turn activates endothelial cells to increase adhesion molecules by upregulating intracellular adhesion molecule type 1 (ICAM-1) and e-selectin (85). Antigens may also combine with antibodies, forming immune complexes that directly activate complement releasing C3a and C5a, which promote chemotaxis of neutrophils. The neutrophils release superoxide anions, hydroxyl radicals, and toxic oxygen radicals, which contribute to the inflammation. Alveolar macrophages have cognate interaction with regulatory CD8+ T lymphocytes through the T-cell receptor in the presence of B7 costimulatory molecules CD80 and CD86 on macrophages, which act as an accessory signal (86). In healthy subjects, alveolar macrophages have a normal suppressive activity. In contrast, the activated alveolar macrophages in HP increase the 1181
antigen-presenting capacity through the increased expression of CD80 and CD86, thus enhancing the lymphocytic alveolitis. Cigarette smoking may provide a protective effect from HP by decreasing the expression of B7 costimulatory molecules, whereas viral infections could enhance HP by increasing B7 expression (87). BALF CD8+ T lymphocytes release multiple TH1 cell type cytokines, including IL-2, IL-8, IL-12, IL-16, and IFN-γ. These cytokines are associated with an intense inflammatory process. In direct contrast to asthma, there is an imbalance of IL-10 and IL-12. Stimulated by TNF-α, IL-10 normally functions to inhibit ICAM-1 and B7 molecule expression to prevent the alveolar macrophage from interacting with the T cell, thus preventing activation. In HP, there is a decreased production of IL-10, leading to activated macrophages and ongoing inflammation. Gene polymorphisms for TNF-α, IL10, and TGF-β examined by restriction fragment length polymorphism analysis did not support an association between genetic control of cytokine production and disease susceptibility in 61 patients with HP compared to 101 healthy controls (88).
Figure 23.6 Immunopathogenesis of hypersensitivity pneumonitis. IFNγ, interferon gamma; MCP, monocyte chemoattractant protein-1; MIF, macrophage inhibitory factor; MnSOD, manganese superoxide dismutase; NGF, 1182
nerve growth factor; PMN, polymorphonuclear leukocyte; TNF-α, tumor necrosis factor-alpha. While HP has been classified as a Th1 disease, recent studies support that IL17 and IL-22 secreting TH17 cells are involved in HP. Simonian et al. (89) showed that with chronic exposure to Saccharopolyspora retivirgula (such as in farmer’s lung), CD4+ T cells were not polarized to TH1 but rather to TH17 with differential expression of IL-17A and IL-22. This study also supports a role for TH17 cells in the subsequent development of lung fibrosis. Joshi et al. (90) showed that either genetic deletion or antibody-mediated depletion of IL-17 resulted in decreased inflammation and protection against HP. BALF T cells from patients with HP have high levels of functioning IL-12R compared with peripheral blood T cells. When stimulated with recombinant IL12, lung T cells significantly increased IFN-γ production (91). T lymphocytes along with mast cells can both produce and respond to nerve growth factor (NGF). This neurotrophic cytokine not only contributes to the development and survival of sympathetic and sensory neurons but is associated with cough and found in higher levels in asthmatics and correlates with IgE levels. In asymptomatic pigeon fanciers, serum concentrations of NGF were normal, but increased in parallel with serum CRP as a marker of inflammation. In vitro studies using mitogen-induced production of NGF by lymphocytes was higher than normal (92). Natural killer T cells are a distinct subset of αβ T cells and are characterized by the co-expression of surface markers of both these cell types and release large amounts of IL-4 and IFN-γ, thus regulating the innate and adaptive immune response by modulating the TH1/TH2 balance. In mice, these cells can attenuate HP by suppressing the IFN-γ producing neutrophils (93). Increased expression of the integrin αEβ7 on the surface of T cells function as mucosal homing receptors for the selective retention of T lymphocytes in lung mucosa (94). The chemokines IL-8 and monocyte chemoattractant protein1/monocyte chemotactic and activating factor are significantly increased in BALF, suggesting a role in the accumulation of cells such as neutrophils, lymphocytes, and monocyte/macrophages into the alveoli of patients with HP (95). Arachidonic acid metabolites are released from many cell types. Along with hydrolytic enzymes, these further contribute to inflammation. Surfactant is responsible for the regulatory activities of lung lymphocytes and alveolar macrophages. Alveolar macrophages from patients with HP enhance 1183
phytohemagglutinin-induced peripheral blood mononuclear cell (PBMC) proliferation, whereas normal alveolar macrophages suppress this proliferation. Surfactant from normal individuals decreases mitogen-induced proliferation of PBMC greater than surfactant from patients with HP in the presence of alveolar macrophages (96). Thus, the alveolitis in HP may also be caused in part by alteration in the surfactant immunosuppressive effect. Viruses, including influenza A, have been demonstrated by polymerase chain reaction in the lower airways of patients with acute HP. In experimental murine models infected with respiratory syncytial virus, both the early and late inflammatory responses are augmented in HP. Avian circoviruses can be detected in the T lymphocytes of respiratory organs of free-ranging and captive birds worldwide. These viruses may be potential triggers in avian-induced HP (97). Further studies are required to clarify the nature of this relationship between viral infection and the modulation of pulmonary immune response (98,99). Recent studies have also linked Toll-like receptors (TLRs) to HP. TLRs are expressed on immune cells and recognize most antigens. In HP, when specific TLRs are activated, it is through an intracellular pathway, known as the MyD88 pathway, to release many pro-inflammatory cytokines and mediators. Nance et al. (100) have demonstrated that in mice, exposure to S. rectivirgula, activates MyD88, through TLR2, to initiate a cytokine and chemokine cascade, resulting in neutrophil recruitment. This has also been observed with M. avium-induced hypersensitivity responses, similar to the reaction found in hot tub lung (101).
MANAGEMENT Avoidance The most important element of management, as in any allergic lung disease, is avoidance of the offending antigen. This can occur in two ways: removal of the individual from the antigen or removal of the antigen exposure from the individual’s environment. Workplace reassignment is a reasonable means of managing affected employees. Although this straightforward approach is simple to recommend, adherence by patients can be more difficult. For example, farmers afflicted with farmer’s lung may be unable to change careers. Machinists with MWF–induced lung disease may be unable to work in other capacities. Pigeon breeders frequently continue intermittent pigeon exposure. Although elimination of the antigen seems essential for a long-term solution to the problem, continued antigen exposure may not lead to clinical deterioration for 1184
some persons (102). Depending on the source of the antigen and the conditions surrounding its generation, various industrial hygiene measures have been proposed. For instance, reducing the humidity in silos has resulted in a decline in the prevalence and incidence of farmer’s lung. Other measures include alterations in plant management, increased automation, improved exhaust ventilation, and personal protective face masks. Design of new facilities should reduce stagnant water prone to microbial overgrowth. Humidity of facilities should be maintained below 60%. If a facility is prone for dampness, carpeting should be avoided. Water in ventilation and air-conditioning systems should not be recirculated. Frequently, assays for the presence of the material in the environment are lacking, or the minimum concentration to provoke symptoms or initiate sensitization is not known.
Pharmacologic Treatment Few data exist on the various pharmacologic treatments for HP. Corticosteroid therapy should be instituted in the acute and subacute forms because this has been reported to reduce symptoms and detectable inflammation and improve pulmonary function. Oral corticosteroids are recommended for acute disease starting at prednisone doses of 40 to 80 mg daily until clinical and laboratory improvements are observed, then decreased stepwise to 5 to 10 mg every other day for 6 weeks. Although indefinite corticosteroid therapy is not necessary, individualized treatment is recommended. Unfortunately, the long-term outcome of patients treated with a course of prednisone for acute farmer’s lung has not always been complete recovery (103). Ongoing follow-up visits should include pulmonary function studies, not peak flow measurements, because they are not sensitive enough. Inhaled corticosteroid therapy is not as effective as oral drug therapy. If obstructive pulmonary function changes are present, then treatment with bronchodilators can be attempted. Steroid-sparing agents in the treatment of chronic progressive HP are unproven. Drugs that have shown potential in vitro include thalidomide because it reduces IL-18, IL-8, and TNF-α release from alveolar macrophages in interstitial lung disease. However, unfavorable side effect profiles limit current use (104). Garcia et al. (105) have demonstrated a significant increase in circulating fibrocytes in patients with HP compared to healthy individuals. However, antifibrotic agents such as nintedanib, an oral tyrosine kinase inhibitor that targets several growth factor receptors, and pirfenidone, an oral pyridine analogue that inhibits cytokines such as TNF-α and TGF-β, have not been studied in chronic HP patients.
PREVENTION AND SCREENING 1185
The presence of occupational lung disease in a worker usually represents a sentinel event. As in other occupational lung diseases, a systematic evaluation and investigation of the work environment and exposed cohort is recommended, although not mandated by law or always conducted (106). The investigation for additional cases may include a screening questionnaire survey with positive responses undergoing chest radiographs, serum precipitins, and lung function testing. Questionnaire surveys can be used to screen for further cases of disease, and to compare rates of symptoms between different locations in the same plant. If possible, the numbers of workers on medical leave should be reviewed. Survey questions should include demographics, risk factors, and protective factors in the home and workplace, including tobacco use and the presence of a humidifier and/or dehumidifier. Industrial hygiene surveys should include reviewing building maintenance records, visual inspection for standing water, mold growth, stained ceiling tile or carpet, roof drainage patterns, measurement of temperature and humidity, and measurement and culture of airborne, soil, or water microorganisms. In 1998, the National Institute for Occupational Safety and Health published recommended exposure limits for MWF fluids (0.4 mg/m3 as a time-weighted average for up to 10 hours) designed to prevent respiratory disorders (107). Unfortunately, companies may not strictly enforce this exposure limit or provide specific medical surveillance programs for employees exposed to higher levels. Changes in agricultural processes, such as haymaking, can reduce the microbiologic concentrations, including fungus (108).
PROGNOSIS There have been limited studies on the factors determining prognosis of HP. Factors identified as having predictive value in the likelihood of recovery from pigeon breeder’s disease and farmer’s lung include age at diagnosis, duration of antigen exposure after onset of symptoms, and total years of exposure before diagnosis. The effect of other factors, including the nature of the allergen, especially its inflammatory potential, host susceptibility, severity of lung function at diagnosis, and form of the disease, are not well clarified. Although most cases of acute disease improve, those patients with ongoing exposure continue to experience symptoms, and have abnormal lung function and abnormal chest radiographs. The mortality rates from HP range from 1% to 29% with agricultural industries closely associated with mortality. Farmer’s lung deaths accounted for 40% of all HP deaths. A population-based study of 26 states using data from the National Institute for Occupational Safety and Health found Wisconsin to have the highest mortality rate at 1.04 per million and the 1186
death rate increasing over the period 1980 to 2002 (109). It is unclear what factors account for this increase, making additional epidemiologic and surveillance research a priority in an effort to implement regional prevention and control strategies. The presence of pulmonary fibrosis is an important predictor of mortality (110). Deaths from pigeon breeder’s disease have also been reported (111). The findings of fibrosis at lung biopsy or high-resolution CT indicate a poor prognosis, and the patient may die within a few years after diagnosis (112).
CONCLUSION The diagnosis of HP requires a high index of suspicion, because the primary focus of treatment is avoidance of the offending allergen even if the specific allergen is not identified. Efforts are needed to prevent recurrent and progressive disease in individuals already sensitized and prevent potential epidemics in occupational settings. Because the diagnosis is difficult and occupational evaluation complex, a team approach, including the collaborative efforts of allergists, pulmonologists, occupational physicians, industrial hygienists, and microbiologists, is important. REFERENCES 1. Ramazzini B. De Morbus Artificum Diatriba (originally published 1713). Chicago: University of Chicago Press, 1940. 2. Mohr LC. Hypersensitivity pneumonitis. Curr Opin Pulm Med. 2004;10:401–411. 3. Campbell JM. Acute symptoms following work with hay. BMJ. 1932;2:1143–1144. 4. Dickie HA, Rankin J. Farmer’s lung: an acute granulomatous interstitial pneumonitis occurring in agricultural workers. JAMA. 1958;167:1069– 1076. 5. Emanuel DA, Wenzel FJ, Bowerman CI, et al. Farmer’s lung: clinical, pathologic and immunologic study of twenty-four patients. Am J Med. 1964;37:392–401. 6. Ranalli G, Grazia L, Roggeri A. The influence of hay-packing techniques on the presence of Saccharopolyspora rectivirgula. J Appl Microbiol. 1999;87:359–365. 7. Fink JN, Banaszak EF, Thiede WH, et al. Interstitial pneumonitis due to hypersensitivity to an organism contaminating a heating system. Ann 1187
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2007;131:1572–1574. 34. Chew GY, Hawkins CA, Cherian M, et al. Roxithromycin induced hypersensitivity pneumonitis. Pathology. 2006;38:475–477. 35. Suresh K, D’Ambrosio C, Einarsson O, et al. Hypersensitivity pneumonitis induced by intranasal heroin use. Am J Med. 1999;107:392–395. 36. Perez-Alvarez R, Perez-de-Lis M, Diaz-Lagares C, et al. Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases. Semin Arthritis Rheum. 2011;41(2):256–264. 37. Roubille C, Haraoui B. Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum. 2014;43(5):613–626. 38. Naqibullah M, Shaker SB, Bach KS, et al. Rituximab-induced interstitial lung disease: five case reports. Eur Clin Respir J. 2015;2. doi:10.3402/ecrj.v2.27178. 39. Quirce S, Hinojosa M, Blanco R, et al. Aspergillus fumigatus is the causative agent of hypersensitivity pneumonitis caused by esparto dust. J Allergy Clin Immunol. 1998;102:147–148. 40. Cormier Y, Israil-Assayag E, Bedard G, et al. Hypersensitivity pneumonitis in peat moss processing plant workers. Am J Respir Crit Care Med. 1998;158:412–417. 41. Kawai T, Tamura M, Murao M. Summer type hypersensitivity pneumonitis: a unique disease in Japan. Chest. 1984;85:311–317. 42. Hanak V, Golbin JM, Ryu JH. Causes and presenting features in 85 consecutive patients with hypersensitivity pneumonitis. Mayo Clin Proc. 2007;82:812–816. 43. Madsen D, Kloch LE, Wenzel FJ, et al. The prevalence of farmer’s lung in an agricultural population. Am Rev Respir Dis. 1976;113:171–174. 44. Lopez M, Salvaggio JE. Epidemiology of hypersensitivity pneumonitis/allergic alveolitis. Monogr Allergy. 1987;21:70–86. 45. Yoshizawa Y, Ohtani Y, Hayakawa H, et al. Chronic hypersensitivity pneumonitis in Japan: a nationwide epidemiologic survey. J Allergy Clin Immunol. 1999;103:315–320. 46. Arya A, Roychoudhury K, Bredin C. Farmer’s lung is now in decline. Ir
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Med J. 2006;99:203–205. 47. Barber CM, Wiggans RE, Carder M, et al. Epidemiology of occupational hypersensitivity pneumonitis; reports from the SWORD scheme in the UK from 1996 to 2015. Occup Environ Med. 2017;74(7):528–530. 48. Richerson HB, Berstein IL, Fink JN, et al. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. J Allergy Clin Immunol. 1989;84:839–844. 49. Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2003;168:952– 958. 50. Fink JN, Sosman AJ, Barboriak JJ, et al. Pigeon breeder’s disease: a clinical study of a hypersensitivity pneumonitis. Ann Intern Med. 1968;68:1205–1219. 51. Lacasse Y, Selman M, Costabel U, et al. HP Study Group. Classification of hypersensitivity pneumonitis: a hypothesis. Int Arch Allergy Immunol. 2009;149(2):161–166. 52. Sansores R, Salas J, Chapela R, et al. Clubbing in hypersensitivity pneumonitis. Arch Intern Med. 1990;150:1849–1851. 53. Unger JD, Fink JN, Unger GF. Pigeon breeder’s disease: roentgenographic lung findings in a hypersensitivity pneumonitis. Radiology. 1968;90:683– 687. 54. Silva CI, Churg A, Muller NL. Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic findings. AJR Am J Roentgenol. 2007;188:334–344. 55. Lynch DA, Rose CS, Way D, et al. Hypersensitivity pneumonitis: sensitivity of ARCT in a population based study. AJR Am J Roentgenol. 1992;159:469–472. 56. Buschman DL, Gamsu G, Waldron JA, et al. Chronic hypersensitivity pneumonitis: use of CT in diagnosis. AJR Am J Roentgenol. 1992;159:957–960. 57. Uh S, Lee SM, Kim HT, et al. The clearance rate of alveolar epithelium using 99mTc-DTPA in patients with diffuse infiltrative lung diseases. Chest. 1994;106:161–165. 58. Patterson R, Fink JN, Pruzansky JJ, et al. Serum immunoglobulin levels in 1191
pulmonary allergic aspergillosis and certain other lung diseases, with special reference to immunoglobulin E. Am J Med. 1973;54:16–22. 59. Moore VL, Fink JN, Barboriak JJ, et al. Immunologic events in pigeon breeder’s disease. J Allergy Clin Immunol. 1974:53:319–328. 60. Fink JN, Schlueter DP, Sosman AJ, et al. Clinical survey of pigeon breeder’s. Chest. 1972;62:277–281. 61. McSharry C, Dye GM, Ismail T, et al. Quantifying serum antibody in bird fanciers’ hypersensitivity pneumonitis. BMC Pulm Med. 2006;6:16. 62. Fenoglio CM, Reboux G, Sudre B, et al. Diagnostic value of serum precipitins to mould antigens in active hypersensitivity pneumonitis. Eur Respir J. 2007;29:706–712. 63. Leatherman JW, Michael AF, Schwartz BA, et al. Lung T-cells in hypersensitivity pneumonitis. Ann Intern Med. 1984;100:390–392. 64. Satake N, Nagai S, Kawatani A, et al. Density of phenotypic markers on BAL T-lymphocytes in hypersensitivity pneumonitis, pulmonary sarcoidosis and bronchiolitis obliterans with organizing pneumonia. Eur Respir J. 1993;6:477–482. 65. Semenzato G, Bjermer L, Costabel U, et al. Clinical guidelines and indications for bronchoalveolar lavage (BAL): extrinsic allergic alveolitis. Eur Respir J. 1990;3:945–946, 961–969. 66. Sterclova M, Vasakova M, Dutka J, et al. Extrinsic allergic alveolitis: comparative study of the bronchoalveolar lavage profiles and radiological presentation. Postgrad Med J. 2006;82:598–601. 67. Sato T, Saito Y, Chikuma M, et al. Fluorimetric determination of trace amounts of albumin in bronchoalveolar lavage fluid with eriochrome cyanine R. Biol Pharm Bull. 2007;30:1187–1190. 68. Kawanami O, Basset F, Barrios R, et al. Hypersensitivity pneumonitis in man. Light and electron microscope studies of 18 lung biopsies. Am J Pathol. 1983;110:275–289. 69. Lalancette M, Carrier G, Lavioleete M, et al. Farmer’s lung. Long-term outcome and lack of predictive value of bronchoalveolar lavage fibrosing factors. Am Rev Respir Dis. 1993;148(1):216–221. 70. Parker JE, Petsonk LE, Weber SL. Hypersensitivity pneumonitis and organic dust toxic syndrome. Immunol Allergy Clin North Am. 1192
1992;12:279–290. 71. Rylander R, Haglind P. Airborne endotoxins and humidifier disease. Clin Allergy. 1984;14:109–112. 72. Hariri LP, Mino-Kenudson M, Shea B, et al. Distinct histopathology of acute onset or abrupt exacerbation of hypersensitivity pneumonitis. Hum Pathol. 2012;43:660–668. 73. Lumb R, Stapledon R, Scroop A, et al. Investigation of spa pools associated with lung disorders causes by Mycobacterium avium complex in immunocompetent adults. Appl Environ Microbiol. 2004;70(8):4906–4910. 74. Sood A, Sreedhar R, Kulkarni P, et al. Hypersensitivity pneumonitis-like granulomatous lung disease with nontuberculous mycobacteria from exposure to hot water aerosols. Environ Health Perspect. 2007;115:262– 266. 75. Hartman TE, Jensen E, Tazelaar H, et al. CT findings of granulomatous pneumonitis secondary to Mycobacterium avium-intracellulare inhalation: “hot tub lung.” AJR Am J Roentgenol. 2007;188:1050–1053. 76. Roussel S, Rognon B, Barrera C, et al. Immuno-reactive proteins from Mycobacterium immunogenum useful for serodiagnosis of metalworking fluid hypersensitivity pneumonitis. Int J Med Microbiol. 2011;301(2):150– 156. 77. Morell F, Villar A, Montero MA, et al. Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study. Lancet Respir Med. 2013;1:685–694. 78. Fink JN, Hensley GT, Barboriak JJ. An animal model of hypersensitivity pneumonitis. J Allergy. 1970;46:156–161. 79. Moore VL, Hensley GT, Fink JN. An animal model of hypersensitivity pneumonitis in the rabbit. J Clin Invest. 1975;56:937–944. 80. Takizawa H, Ohta K, Horiuchi T, et al. Hypersensitivity pneumonitis in athymic nude mice. Am Rev Respir Dis. 1992;146:479–484. 81. Bice DE, Salvaggio J, Hoffman E. Passive transfer of experimental hypersensitivity pneumonitis with lymphoid cells in the rabbit. J Allergy Clin Immunol. 1976;58:250–262. 82. Denis M, Ghadirian E. Murine hypersensitivity pneumonitis: bidirectional role of interferon-gamma. Clin Exp Allergy. 1992;22:783–792. 1193
83. Schkade PA, Routes JM. Hypersensitivity pneumonitis in a patient with hypogamma-globulinemia. J Allergy Clin Immunol. 1996;98:710–712. 84. Denis M. Interleukin-1 (IL-1) is an important cytokine in granulomatous alveolitis. Cell Immunol. 1994;157:70–80. 85. Pforte A, Schiessler A, Gais P, et al. Expression of the adhesion molecule ICAM-1 on alveolar macrophages and in serum in extrinsic allergic alveolitis. Respiration. 1993;60:221–226. 86. Israël-Assayag E, Dakhama A, Lavigne S, et al. Expression of costimulatory molecules on alveolar macrophages in hypersensitivity pneumonitis. Am J Respir Crit Care Med. 1999;159:1830–1834. 87. Blanchet MR, Israël-Assayag E, Cormier Y. Inhibitory effect of nicotine on experimental hypersensitivity pneumonitis: histopathological patterns and survival. Respir Med. 2009;103(4):508–515. 88. Kondoh K, Usui Y, Ohtani Y, et al. Proinflammatory and antiinflammatory cytokine gene polymorphisms in hypersensitivity pneumonitis. J Med Dent Sci. 2006;53:75–83. 89. Simonian PL, Roark CL, Wehrmann F, et al. Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis. J Immunol. 2009;182(1):657–665. 90. Joshi AD, Fong DJ, Oak SR, et al. Interleukin-17-mediated immunopathogenesis in experimental hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2009;179(8):705–716. 91. Yamasaki H, Ando M, Brazer W, et al. Polarized type 1 cytokine profile in bronchoalveolar lavage T cells of patients with hypersensitivity pneumonitis. J Immunol. 1999;163:3516–3523. 92. McSharry CP, Fraser I, Chaudhuri R, et al. Nerve growth factor in serum and lymphocyte culture in pigeon fanciers’ acute hypersensitivity pneumonitis. Chest. 2006;130:37–42. 93. Hwang SJ, Kim S, Park WS, et al. IL-4 secreting NKT cells prevent hypersensitivity pneumonitis by suppressing IFN-γ producing neutrophils. J Immunol. 2006;177:5258–5268. 94. Lohmeyer J, Friedrich J, Grimminger F, et al. Expression of mucosarelated integrin αEβ7 on alveolar T cells in interstitial lung diseases. Clin Exp Immunol. 1999;116:340–346. 1194
95. Sugiyama Y, Kasahara T, Mukaida N, et al. Chemokines in bronchoalveolar lavage fluid in summer-type hypersensitivity pneumonitis. Eur Respir J. 1995;8:1084–1090. 96. Israël-Assayag E, Cormier Y. Surfactant modifies the lymphoproliferative activity of macrophages in hypersensitivity pneumonitis. Am J Physiol. 1997;273:L1258–L1264. 97. Bougiouklis PA. Avian circoviruses of the genus Circovirus: a potential trigger in pigeon breeder’s lung (PBL)/bird fancier’s lung (BFL). Med Hypotheses. 2007;68:320–323. 98. Dakhama A, Hegele RG, Laflamme G, et al. Common respiratory viruses in lower airways of patients with acute hypersensitivity pneumonitis. Am J Respir Crit Care Med. 1999;159:1316–1322. 99. Gudmundsson G, Monick MM, Hunninghake GW. Viral infection modulates expression of hypersensitivity pneumonitis. J Immunol. 1999;162:7397–7401. 100. Nance SC, Yi AK, Re FC, et al. MyD88 is necessary for neutrophil recruitment in hypersensitivity pneumonitis. J Leukoc Biol. 2008;83:1207– 1217. 101. Daito H, Kikuchi, Sakakibara T, et al. Mycobacterial hypersensitivity pneumonitis requires TLR9-MyD88 in lung CD11b+ CD11c+ cells. Eur Respir J. 2011;38(3):688–701. 102. Cuthbert OD, Gordon MF. Ten year follow-up of farmers with farmer’s lung. Br J Ind Med. 1983;40:173–176. 103. Kokkarinen JI, Tukiainen HO, Terho EO. Effect of corticosteroid treatment on the recovery of pulmonary function in farmer’s lung. Am Rev Respir Dis. 1992;145:3–5. 104. Ye Q, Chen B, Tong Z, et al. Thalidomide reduces IL-18, IL-8 and TNF-α release from alveolar macrophages in interstitial lung disease. Eur Respir J. 2006;28:824–831. 105. García de Alba C, Buendia-Roldán I, Salgado A, et al. Am J Respir Crit Care Med. 2015;191(4):427–436. 106. Weltermann BM, Hodgson M, Storey E, et al. Hypersensitivity pneumonitis: a sentinel event investigation in a wet building. Am J Ind Med. 1998;34:499–505. 1195
107. Cohen H, White EM. Metalworking fluid mist occupational exposure limits: a discussion of alternative methods. J Occup Environ Hyg. 2006;3:501–507. 108. Reboux G, Reiman M, Roussel S, et al. Impact of agricultural pracitices on microbiology of hay, silage, and flour on Finnish and French farms. Annal Agric Environ Med. 2006;13:267–273. 109. Bang KM, Weissman DN, Pinheiro GA, et al. Twenty-three years of hypersensitivity pneumonitis mortality surveillance in the United States. Am J Ind Med. 2006;49:997–1004. 110. Vourlekis JS, Schwarz MI, Cherniack RM, et al. The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am J Med. 2004;116:662–668. 111. Greenberger PA, Pien LC, Patterson R, et al. End-stage lung and ultimately fatal disease in a bird fancier. Am J Med. 1989;86:119–122. 112. Pérez-Padilla R, Salas J, Chapela R, et al. Mortality in Mexican patients with chronic pigeon breeder’s lung compared with those with usual interstitial pneumonia. Am Rev Respir Dis. 1993;148(1):49–53. *Michael C. Zacharisen and Jordan N. Fink contributed previously to this chapter.
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INTRODUCTION Allergic bronchopulmonary aspergillosis (ABPA) is characterized by immunologic reactions to antigens of Aspergillus fumigatus (A. fumigatus) that are present in the bronchial tree and result in pulmonary infiltrates, mucus plugging, and proximal bronchiectasis. ABPA initially was described in England in 1952 in patients with asthma who had recurrent episodes of fever, roentgenographic infiltrates, peripheral blood and sputum eosinophilia, and sputum production containing A. fumigatus hyphae (1). The first adult with ABPA in the United States was described in 1968 (2), and the first childhood case was reported in 1970 (3). Since then, the recognition of ABPA in children (4–11), adults (12–15), corticosteroid-dependent asthmatic patients (16–18), patients with cystic fibrosis (CF) (19–32), and patients with allergic fungal rhinosinusitis (33–37) and in well-controlled HIV (38) is the result of the increasing awareness by physicians and health care professionals of this complication of asthma or CF. The diagnosis has been helped by serologic tests such as total serum immunoglobulin E (IgE) (39,40), serum IgE and IgG antibodies to A. fumigatus (14,15,41–44), precipitating antibodies (45), and familiarity with chest radiography and high-resolution computed tomography (CT) findings, including high-attenuation mucus (46–53). In addition, when a patient presents with an unexplained radiographic opacification, thought from a neoplasm with postobstructive pneumonia, and the lesion clears with systemic steroids, this observation can lead to the diagnosis of ABPA (54). Some atypical patients seemingly have no documented history of asthma and present with chest roentgenographic infiltrates, lobar collapse, peripheral blood eosinophilia, and elevated total IgE concentration (55,56).
PREVALENCE The prevalence of ABPA in patients with asthma is affected by the clinical
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setting, geographic location, and aggressiveness of diagnostic testing. The prevalence in specialty clinics has been reported as high as 12.9% (57) and 15.8% (53) or higher. In a study published in 1991, it was estimated that the prevalence was 6.0% of 531 patients in Chicago at the Northwestern University Allergy-Immunology Service with asthma and immediate cutaneous reactivity to an Aspergillus mix (58). In comparison, the prevalence was 28% of such patients in Cleveland (41). These high-prevalence figures were generated from the ambulatory setting of allergist-immunologist practices where screening began with skin testing that identified Aspergillus-positive patients with asthma. Using data from Northwestern University that was accumulated from 2000 to 2010, the prevalence was 4.8% for patients evaluated by my five colleagues and 23.5% for patients evaluated by this author (14). The literature suggests that the overall prevalence of ABPA in patients with persistent asthma is 1% to 2.5% (58,59). ABPA has been identified on an international basis, and because of its destructive potential, it should be confirmed or excluded in all patients with persistent asthma.
CHARACTERISTICS AND ,ASPERGILLUS SPECIES
RESPONSES
TO
Aspergillus species are aerobic, ubiquitous, thermotolerant, and can be recovered on a perennial basis (60–62). Spores (conidia) measure 2 to 3.5 μm and can be cultured on Sabouraud’s agar slants incubated at 37°C to 40°C. Growth at this warm temperature is a somewhat unique property of A. fumigatus. Aspergillus hyphae may be identified in tissue by hematoxylin and eosin staining, but identification and morphology are better appreciated with silver methenamine or periodic acid-Schiff stains. Hyphae are 7 to 10 μm in diameter, septate, and classically branch at 45-degree angles. Aspergillus spores, which are often green, are inhaled from outdoor and indoor air and can reach terminal airways. They then could grow as hyphae. Airway epithelial cells phagocytose spores (63), but it is the alveolar macrophages that ingest and kill the spores (conidia) (63–65). Polymorphonuclear leukocytes (PMNs) do not ingest hyphae but bind to them and kill the hyphae by damaging their cell walls with a powerful, oxidative burst (63–66). Protection against invasive aspergillosis occurs owing to multiple factors, but most crucial is the presence of sufficient, functioning PMNs because prolonged neutropenia (417 kU/mL) Elevated serum IgE-Af and/or IgG-Af antibodies
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FOR
ALLERGIC
Serum precipitating antibodies to Af Proximal bronchiectasis Peripheral blood eosinophilia (≥1,000/mm3)
MINIMAL ESSENTIAL CRITERIA FOR ABPA-CBa
Asthma Immediate cutaneous reactivity to Aspergillus Elevated total IgE concentration Elevated serum IgE-Af and or IgG-Af antibodies Proximal bronchiectasis
a
Suitable for diagnosis of ABPA in cystic fibrosis.
ABPA, allergic bronchopulmonary aspergillosis; Af, Aspergillus fumigatus; CB, central bronchiectasis; IgE, immunoglobin E.
Patients with ABPA manifest multiple allergic conditions. For example, only one of the initial 50 patients diagnosed and managed at the Northwestern University Feinberg School of Medicine had isolated cutaneous reactivity to A. fumigatus (91). Other atopic disorders (rhinitis, urticaria, atopic dermatitis, and drug allergy) may be present in patients with ABPA (91). The severity of asthma ranges from intermittent asthma to mildly persistent, to severe prednisonedependent persistent asthma. Occasionally, patients deny developing wheezing or dyspnea on exposure to raked leaves, moldy hay, or damp basements, but they noted nonimmunologic triggering factors, such as cold air, infection, or weather changes. The findings in these patients emphasize that ABPA may be present in patients who appear to have no obvious IgE-mediated asthma. Such patients can present with mucoid impactions and tenacious sputum and then have the
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diagnosis of ABPA made. The number of diagnostic criteria vary depending on the classification (ABPA-CB or ABPA-S) and stage of ABPA. Furthermore, prednisone therapy causes clearing of the chest roentgenographic infiltrates, decline of the total serum IgE concentration, disappearance of precipitating antibodies, peripheral blood or sputum eosinophilia, and absence or reduction of sputum production.
PHYSICAL EXAMINATION The physical examination in ABPA may be completely unremarkable in the asymptomatic patient, or the patient may have crackles, bronchial breathing, or wheezing, depending on the degree and quality of lung disease present. An acute exacerbation of ABPA may be associated with temperature elevation to 103°F (although this is most uncommon), with malaise, dyspnea, wheezing, and sputum production. In some cases of ABPA, extensive pulmonary consolidation on roentgenography may be accompanied by few or no clinical symptoms, in contrast to the usual manifestations of a patient with a bacterial pneumonia and the same degree of consolidation. When extensive pulmonary fibrosis has occurred from ABPA, post-tussive crackles will be present. ABPA has been associated with collapse of a lung from a mucoid impaction, and it was associated with a spontaneous pneumothorax (88). The physical examination yields evidence for these diagnoses. When ABPA infiltrates affect the periphery of the lung, pleuritis may occur, and it may be associated with restriction of chest wall movement on inspiration and a pleural friction rub. Some patients with endstage ABPA (fibrotic stage V) have digital clubbing and cyanosis (89,90). The latter findings should suggest concomitant CF as well.
RADIOLOGY Chest roentgenographic changes may be transient or permanent (Figs. 24.1 to 24.6) (46,47). Transient roentgenographic changes, which may clear with or without oral corticosteroid therapy, appear to be the result of parenchymal infiltrates, mucoid impactions, or secretions in damaged bronchi. These nonpermanent findings include (a) perihilar infiltrates simulating adenopathy; (b) air–fluid levels from dilated central bronchi filled with fluid and debris; (c) massive consolidation that may be unilateral or bilateral; (d) roentgenographic infiltrates; (e) “toothpaste” shadows resulting from mucoid impactions in damaged bronchi; (f) “gloved-finger” shadows from distally occluded bronchi filled with secretions; and (g) “tramline” shadows, which are two parallel hairline shadows extending out from the hilum. The width of the transradiant 1204
zone between the lines is that of a normal bronchus at that level (46). Tramline shadows, which represent edema of the bronchial wall, may be seen in asthma without ABPA, in CF, and in left ventricular failure with elevated pulmonary venous pressure. Permanent roentgenographic findings related to proximal bronchiectasis have been shown to occur in sites of previous infiltrates, which are often, but not exclusively, in the upper lobes. This is in contrast to postinfectious bronchiectasis, which is associated with distal abnormalities and normal proximal bronchi. When permanent lung damage occurs to large bronchi, parallel line shadows and ring shadows are seen. These do not change with oral corticosteroids. Parallel line shadows are dilated tramline shadows that result from bronchiectasis; the transradiant zone between the lines is wider than that of a normal bronchus. These shadows are believed to be permanent, representing bronchial dilation. The ring shadows, 1 to 2 cm in diameter, are dilated bronchi en face. Pulmonary fibrosis may occur and likely is irreversible. Late findings in ABPA include cavitation, contracted upper lobes, fibrosis, and localized emphysema. When bullous changes are present, a spontaneous pneumothorax may occur (88).
FIGURE 24.1 An 11-year-old boy with far-advanced allergic bronchopulmonary aspergillosis. Presentation chest radiograph showing massive 1205
homogeneous consolidation in left upper lobe. (Reprinted from Mintzer RA, Rogers LF, Kruglick GD, et al. The spectrum of radiologic findings in allergic bronchopulmonary aspergillosis. Radiology. 1978;127:301, with permission.)
FIGURE 24.2 Magnified view of the left upper lobe showing massive homogeneous consolidation (narrow arrowhead), parallel lines (open broad arrowheads), and ring shadows (closed broad arrowhead). (Reprinted from Mintzer RA, Rogers LF, Kruglick GD, et al. The spectrum of radiologic findings in allergic bronchopulmonary aspergillosis. Radiology. 1978;127:301, with permission.)
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FIGURE 24.3 A 31-year-old man with far-advanced allergic bronchopulmonary aspergillosis. Presentation chest radiograph. Note massive homogeneous consolidation (large arrowhead) and air–fluid level (small arrowhead). (Reprinted from Mintzer RA, Rogers LF, Kruglick GD, et al. The spectrum of radiologic findings in allergic bronchopulmonary aspergillosis. Radiology. 1978;127:301, with permission.)
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FIGURE 24.4 Bronchogram showing classic proximal bronchiectasis with normal peripheral airways in a 25-year-old woman with allergic bronchopulmonary aspergillosis. (Reprinted from Mintzer RA, Rogers LF, Kruglick GD, et al. The spectrum of radiologic findings in allergic bronchopulmonary aspergillosis. Radiology. 1978;127:301, with permission.)
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FIGURE 24.5 Post-tussive films after bronchography. Air–fluid levels (large arrowheads) are present in several partially filled ectatic bronchi. A bronchus in the left upper lobe is filled after the tussive effort, confirming that a portion of the density seen in this area is in fact a filled ectatic proximal bronchus (small arrowheads). (Reprinted from Mintzer RA, Rogers LF, Kruglick GD, et al. The spectrum of radiologic findings in allergic bronchopulmonary aspergillosis. Radiology. 1978;127:301, with permission.) With high clinical suspicion of ABPA (asthma, high total serum IgE concentration, immediate cutaneous reactivity to A. fumigatus) and a negative chest roentgenogram, central bronchiectasis may be demonstrated by highresolution CT (48,50,51,53). This examination should be performed as an initial radiologic test beyond the chest roentgenogram (Figs. 24.7 through 24.9). If
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findings are normal, studies should be repeated in 1 to 2 years for highly suspicious cases.
FIGURE 24.6 Magnified view of the left upper lung of the patient shown in Figs. 24.4 and 24.5 demonstrating parallel lines (long arrows) and toothpaste shadows (arrowheads). Perihilar infiltrates (pseudohilar adenopathy) and a gloved-finger shadow are also seen (small arrows). (Reprinted from Mintzer RA, Rogers LF, Kruglick GD, et al. The spectrum of radiologic findings in allergic bronchopulmonary aspergillosis. Radiology. 1978;127:301, with permission.) High-resolution CT using 1.5-mm section cuts has proved valuable in detecting bronchiectasis in ABPA (48–53). The thin-section cuts were obtained every 1 to 2 cm from the apex to the diaphragm. The use of high-resolution CT examinations has identified areas of cylindrical bronchiectasis in patients with asthma. However, the areas are localized, and the patients do not have sufficient other criteria to make the diagnosis of ABPA. For example, bronchial dilatation was present in 41% of lung lobes in eight ABPA patients compared with 15% of lobes in patients with asthma without ABPA. From the axial perspective, 1210
proximal bronchiectasis is present when it occurs in the inner two-thirds of the lung. Bronchiectasis in ABPA may be cylindrical, cystic, or varicose (48–50). When high-resolution CT using 1 to 3 mm of collimation (thin sections) was performed in 44 patients with ABPA and compared with 38 patients with asthma without ABPA, bronchiectasis was identified in both patient groups (50). Bronchiectasis was present in 42 patients (95%) with ABPA compared with 11 patients (29%) with asthma. The CT scans revealed bronchiectasis in 70% of lobes examined in ABPA versus 9% of lobes from patients with asthma (50). Some 86% of ABPA patients had three or more bronchiectatic lobes, whereas 91% of the patients with asthma had bronchiectasis in one or two lobes. In the ABPA patients, bronchiectasis was varicose in 41% of patients, cystic in 34% of patients, and cylindrical in 23% of patients. Consolidation was identified in 59% of ABPA patients, primarily being located peripherally, whereas consolidation was present in 9% of patients with asthma (50). In another study, bronchiectasis, typically cylindrical, was identified in Aspergillus-skin test positive patients with asthma who did not have sufficient criteria for ABPA (48). These findings provide foundation for the accepted evidence of bronchial wall remodeling from airways inflammation in asthma.
FIGURE 24.7 Computed tomography scan of a 42-year-old woman demonstrating right upper lobe and left lower lobe infiltrates, the latter not seen on the posteroanterior and lateral radiographs. Dilated bronchioles are present in areas of infiltrates (arrows).
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FIGURE 24.8 Dilated bronchi from an axial longitudinal orientation (arrow) consistent with bronchiectasis (same patient as in Fig. 24.7).
FIGURE 24.9 Cystic (dilated) bronchi and bronchioles (same patient as in Fig. 24.7).
STAGING Five stages of ABPA have been identified (12) namely, are acute, remission, exacerbation, corticosteroid-dependent asthma, and fibrotic. The acute stage (stage I) is present when all the major criteria of ABPA can be documented. These criteria are asthma, immediate cutaneous reactivity to A. fumigatus, precipitating antibody to A. fumigatus, elevated serum IgE concentration, which is over the upper limit of normal adults (>417 kU/L), peripheral blood 1212
eosinophilia, history of or presence of roentgenographic infiltrates, and proximal bronchiectasis, unless the patient has ABPA-S. If measured, sera from stage I patients have elevated serum IgE and IgG antibodies to A. fumigatus compared with sera from patients with asthma and immediate cutaneous reactivity to A. fumigatus but not sufficient criteria for ABPA. After therapy with prednisone, the chest roentgenogram clears and the total serum IgE concentration declines substantially (12,15,39,40). Remission (stage II) is defined as clearing of the roentgenographic lesions and decline in total serum IgE for at least 6 months. Exacerbation (stage III) of ABPA is present when, after the remission that follows prednisone therapy, the patient develops a new roentgenographic infiltrate, total IgE concentration rises over baseline, and the other criteria of stage I appear. Corticosteroid-dependent asthma (stage IV) includes patients whose prednisone cannot be terminated without occurrence of persistent moderate-to-severe allergic asthma requiring oral corticosteroids for control or new roentgenographic infiltrates. Despite prednisone administration, most patients have elevated total serum IgE concentrations, precipitating antibody, and elevated serum IgE and IgG antibodies to A. fumigatus. Roentgenographic infiltrates may or may not occur. Stage V ABPA is present when extensive cystic or fibrotic changes are demonstrated on the chest roentgenogram (89,90). Patients in the fibrotic stage have some degree of irreversible obstructive flow rates on pulmonary function testing. A reversible obstructive component requires prednisone therapy, but high-dose prednisone does not reverse the roentgenographic lesions of irreversible obstructive disease. At the time of the initial diagnosis, the stage of ABPA may not be defined, but it becomes clear after several months of observation and treatment. Patients with ABPA-S can be in stages I through IV, but not stage V (13). Patients with ABPA and CF are often in stage III (recurrent exacerbation) but may be in any stage.
LABORATORY AND TEST FINDINGS All patients exhibit immediate cutaneous reactivity (wheal and flare) to A. fumigatus antigen. Because of the lack of standardized A. fumigatus antigens for clinical testing, differences in skin reactivity have been reported by different researchers (Table 24.2) (86,92–94). Approximately 25% of patients with asthma without ABPA demonstrate immediate skin reactivity to A. fumigatus, and about 10% show precipitating antibodies against A. fumigatus. Conversely, a nonreactive skin test (prick and intradermal) to reactive extracts of A. fumigatus essentially excludes the diagnosis of ABPA (14). Some commercial mixes of 1213
Aspergillus species contain little or no A. fumigatus; it is advised to skin test with a reactive extract of A. fumigatus. Some ABPA patients display a biphasic skin response to the intradermal injection of A. fumigatus antigen. This consists of a typical immediate wheal and flare (erythema) seen within 20 minutes, which subsides, to be followed in 4 to 8 hours by erythema and induration that resolves in 24 hours. Initially, IgG, IgM, IgA, and C3 had been identified on biopsies of these late, cutaneous reactions, consistent with features of an Arthus (type III) immune response (95). IgE antibodies subsequently were found to participate in the late reactions with little evidence of immunoglobulin, complement, or immune complexes (96). Furthermore, some of the edema and induration can be attributable to the potent vasodilator, calcitonin gene-related peptide, and permeability factor, vascular endothelial growth factor that have been found during late-phase cutaneous reactions (to pollen, cat, and dust mite allergens) (97). Few ABPA patients treated at the Northwestern University Feinberg School of Medicine have biphasic skin reactivity despite the presence of anti-A. fumigatus IgE antibodies and precipitating antibodies. Conversely, few patients are tested by intradermal injection, because skin-prick test results are positive in nearly all patients. As shown in Table 24.2, precipitating antibody to A. fumigatus is not uncommon in patients without ABPA and likely represents previous exposure to A. fumigatus antigens. In ABPA, however, these antibodies may be important in the pathogenesis of the disease, or at least a manifestation of very high levels of antiA. fumigatus IgG antibody production. TABLE 24.2 INCIDENCE OF IMMUNOLOGIC REACTIONS TO ASPERGILLUS FUMIGATUS
PATIENTS STUDIED
IMMEDIATE SKIN REACTIVITYPRECIPITINS (%) (%)
Normal population
1–4
0–3
Hospitalized patients Asthma without aspergillosis
2.5–6 12–38
Asthma without aspergillosisa
1214
9–25
London
23
10.5
Cleveland
28
7.5
ABPA
100
100b
Aspergilloma
25
100
Cystic fibrosis
39
31
a
Similar antigenic material used for both groups.
b
May be negative at times.
Data from Hoehne JH, Reed CE, Dickie HA. Allergic bronchopulmonary aspergillosis is not rare. Chest. 1973;63:177; Longbottom JL, Pepys J. Pulmonary aspergillosis: diagnostic and immunologic significance of antigens and C-substance in Aspergillus fumigatus. J Pathol Bacteriol. 1964;88:141; Reed C. Variability of antigenicity of Aspergillus fumigatus. J Allergy Clin Immunol. 1978;61:227; Rosenberg M, Patterson R, Mintzer R, et al. Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med. 1977;86:405; and Schwartz HJ, Citron KM, Chester EH, et al. A comparison of the prevalence of sensitization to Aspergillus antigens among asthmatics in Cleveland and London. J Allergy Clin Immunol, 1978;62:9.
A. fumigatus extracts are mixtures containing well over 400 distinctive proteins and additional glycoproteins, polysaccharides, and other metabolites with biologic functions (98–100). This has led to attempts at utilization of recombinant allergens for diagnosis (98,99,101–104). There is marked heterogeneity of immunoglobulin and lymphocyte binding on stimulation with A. fumigatus allergens (98). From the historic perspective regarding methodology, after rocket immunoelectrophoresis of A. fumigatus mycelia and addition of A. fumigatus antisera raised in rabbits, 35 different bands could be detected. Immunoblotting then resulted in identification of 100 proteins (glycoproteins) that bind to immunoglobulins (98). As of now, it can be stated that the even larger number of proteins, glycoproteins, polysaccharides, and metabolic products with biologic function is a testament to the challenges of identifying critical immunodominant peptides and allergens that would be useful in diagnosis (105). 1215
One characterized polypeptide is Asp f 1 and has a molecular weight of 18,000 Da. It is generated from a culture filtrate that was found to react with IgE and IgG antibodies and was toxic to lymphocytes (63). Asp f 1 is a member of the mitogillin family, which demonstrates ribonuclease (ribotoxic) activity. Sera from ABPA patients react with several ribotoxins, and far greater quantities of IgE and IgG antibodies to ribotoxins from Aspergillus are present in patients with ABPA as compared with nonatopic patients with asthma (63). In diagnosis, utilizing assays for both anti-IgE antibodies to Asp f 1 and Asp f 2 shows some discrimination from asthma (106). Some peptides (12 to 16 amino acids from Asp f 1) induce TH1, and others produce TH2 cytokine responses. Peptides that are three to seven amino acids long have been obtained from the IgE-binding region of Asp f 2 and evaluated for IgE binding with sera from ABPA patients. Overall, just a few amino acids of Asp f 2 provide the conformation to react with IgE, whereas these short IgE-specific peptides did not react with IgG antibodies (103,105). These results emphasize the just a few of the complexities to be addressed in the future in terms of developing diagnostic tests. Reactive epitopes of A. fumigatus are under investigation for use in skin testing and in vitro assays. It is hoped that more precise skin testing and in vitro test results using recombinant, molecularly based allergens will lead to more accurate diagnoses. However, such an approach, at least with even with ragweed proteins for allergic rhinitis, was unsuccessful in that a particular “immunologic fingerprint” did not occur as hypothesized. The genotypes were different for the “hay fever” phenotype. In the double-gel diffusion technique, most patients’ sera have at least one to three precipitin bands to A. fumigatus. Some sera must be concentrated five times to demonstrate precipitating antibody. A precipitin band with no immunologic significance may be seen, caused by the presence of C-reactive protein in human sera that cross-reacts with a polysaccharide antigen in A. fumigatus. This false-positive band can be avoided by adding citric acid to the agar gel. It is not essential to require the presence of precipitating antibodies for the diagnosis of ABPA (14). Because of the high incidence of cutaneous reactivity and precipitating antibodies to A. fumigatus in patients with CF and transient roentgenographic infiltrates attributed to A. fumigatus, there is concern that A. fumigatus bronchial colonization or ABPA itself could contribute to the ongoing lung damage of CF. Nevertheless, this notion has produced conflicting results (107,108). The use of high-dose tobramycin by nebulization might favor the growth of A. fumigatus in the bronchial mucus of CF patients. The question has also been raised whether 1216
ABPA might be a variant form of CF. Genetic testing has identified the ΔF508 mutation in one allele of some ABPA patients or other variant patterns (30,109). Eleven patients with ABPA who had normal sweat electrolytes (≤40 mM) had extensive genetic analysis of the coding region for the CF transmembrane regulator. Five patients had one CF mutation (ΔF508 in four and R117H in one), whereas another patient had two CF mutations (ΔF508/R347H). In comparison were 53 patients with chronic bronchitis, none of whom had the ΔF508 mutation, demonstrating clear-cut differences and suggesting that ABPA in some patients includes CF heterozygosity. In a study of 16 patients with ABPA, six patients (37.5%) were homozygous for ΔF508 and six were heterozygous with other mutations in four patients (28). In our patient population, all but one patient tested had normal sweat chloride concentrations in the absence of CF. Nevertheless, there is consistent evidence that ABPA can complicate CF, and it must be considered in that population because about 8.9% (range 3% to 25%) of patients with CF have ABPA (110). The prevalence of sensitization to A. fumigatus, by skin testing or in vitro measurement in CF, is even higher with a pooled prevalence of 39.1% (range 20% to 65%) (110). Serum IgE concentrations in patients with ABPA are elevated, but the degree of elevation varies markedly. In most patients, the total serum IgE concentration is greater than 417 kU/L (417 IU/mL or 1,000 ng/mL) (1 kU/L = 1 IU/mL = 2.4 ng/mL). It has been demonstrated that A. fumigatus growing in the respiratory tract without tissue invasion, as in ABPA, can provide a potent stimulus for production of total “nonspecific” serum IgE (111). When serum IgE or serum IgG antibodies, or both, against A. fumigatus are elevated compared with sera from skin-prick–positive asthmatic patients without evidence for ABPA, ABPA is highly probable or definitely present (14,15,42,43). With prednisone therapy and clinical improvement, the total IgE concentration and IgE–A. fumigatus decrease, although at different rates. Seemingly, this decrease is associated with a decrease in the number of A. fumigatus organisms in the bronchi and suppression of CD4TH2 allergic inflammation. It is possible, but unlikely, that the reduction in IgE concentration is directly because of prednisone without an effect on A. fumigatus in the lung, because in other conditions, such as atopic dermatitis and asthma, corticosteroids did not lower total serum IgE concentrations significantly (112,113). Because of the wide variation of total serum IgE concentrations in atopic patients with asthma, some difficulty exists in differentiating the patient with ABPA from the patient with asthma and cutaneous reactivity to A. fumigatus, with or without precipitating antibody to A. fumigatus and a history of an 1217
abnormal chest roentgenogram. Detection of elevated serum IgE and IgG antibodies to A. fumigatus has proved useful to identify patients with ABPA (14,15,42,43). Sera from patients with ABPA have at least twice the level of antibody to A. fumigatus than do sera from patients with asthma with skin-prick– positive reactions to A. fumigatus. During other stages of ABPA, the indices have diagnostic value if results are elevated, but are not consistently positive in all patients. In patients with suspected ABPA, sera should be obtained and serodiagnosis should be attempted before prednisone therapy is started so that the total IgE concentration is at its peak. Hyperimmunoglobulinemia E should raise the possibility of ABPA in any patient with asthma, although other causes besides ABPA include atopic dermatitis, hyper-IgE syndrome, chronic granulomatous disease (if ABPA is present), other immune deficiency, eosinophilic granulomatosis with polyangiitis (formerly Churg–Strauss syndrome), allergic bronchopulmonary mycosis (ABPM), parasitism, and, remotely, IgE myeloma. Lymphocyte transformation to A. fumigatus is present in some cases but is not a diagnostic feature of ABPA or consistently elevated during exacerbations (86). Delayed hypersensitivity (type IV) reactions occurring 48 hours after administration of intradermal A. fumigatus antigens typically are not seen (114). T- and B-cell analysis of selected patients with ABPA has not shown abnormal numbers of B cells, CD4 (helper), or CD8 (suppressor) cells. However, some patients have evidence for B-cell activation (CD19+ CD23+) or T-cell activation (CD3+ CD25+). T-cell clones from peripheral blood from three ABPA patients, two of whom had been in remission, were generated and analyzed (115). The clones were specific for Asp f 1 and were reported to be HLA class II molecules restricted to HLA-DR2 or HLA-DR5 alleles. Furthermore, the T-cell clones produced high quantities of IL-4 and little IFNγ, consistent with helper Tcell type 2 (TH2 subtype of CD4+ cells). Additional experiments explored major histocompatibility complex (MHC) class II restriction in 15 additional ABPA patients to determine whether specific HLA class II molecules were likely associated with A. fumigatus presentation (116). Of 18 patients (88.8%) overall, 16 were either HLA-DR2 or HLA-DR5 compared with 42.1% frequency in normal individuals (116). Using polymerase chain reaction techniques to investigate HLA-DR subtypes, it was determined that three HLA-DR2 alleles (identified as subtypes DRB1 1501, 1503, and 1601) and three HLA-DR5 alleles (identified as subtypes DRB1 1101, 1104, and 1202) were recognized by T cells in their activation (116). In other words, T-cell activation after binding to Asp f 1
1218
was restricted to certain subtypes of class II molecules HLA-DR2 or HLA-DR5, raising the possibility that selective HLA-DR alleles might provide the genetic disadvantage that permits T-cell activation and, possibly, ABPA to evolve. Because not all patients with these genotypes have ABPA, additional insight is attributable to gain of function polymorphisms for IL-4 in ABPA (81). Using CD20 (B cells), incubation with IL-4 increases the number of CD23 (FcεRII) molecules on the CD20 cells, being greater in ABPA than non-ABPA cell populations (81). This process could facilitate antigen presentation by B cells. Genetic susceptibilities affecting surfactant proteins and TLR9 have been described (18). Circulating immune complexes with activation of the classic pathway during an acute flare-up of ABPA has been described (117). Although Clq precipitins were present in patient sera, it was not proven that A. fumigatus antigen was present in these complexes. ABPA is not considered to be characterized by circulating immune complexes as in serum sickness. But it has been demonstrated that A. fumigatus can convert C3 proactivator to C3 activator, a component of the alternate pathway (118). It is known that secretory IgA can activate the alternate pathway, and that A. fumigatus in the bronchial tract can stimulate IgA production (119). In vitro basophil histamine release resulted from exposure to an Aspergillus mix, anti-IgE, and other fungi in patients with ABPA and fungi-sensitive asthma (with immediate cutaneous reactivity to A. fumigatus) (120). There was much greater histamine release to Aspergillus and anti-IgE from basophils of patients with ABPA than there was from fungi-sensitive asthmatic patients without ABPA. Furthermore, patients with stage IV and stage V ABPA demonstrated greater histamine release to A. fumigatus than did patients in stage I, II, or III. There was greater histamine release to other fungi from cells taken from ABPA patients than there was from other patients with asthma. These data document a cellular difference in ABPA patients when compared with fungi-sensitive asthmatic patients. There was no difference between ABPA patients and patients with asthma in terms of cutaneous endpoint titration using a commercially available Aspergillus mix (120). With flow cytometry, basophil reactivity to A. fumigatus has been reported in patients with CF who have ABPA or are sensitized to A. fumigatus without having ABPA (121,122). When basophils are positive for the surface activation marker CD203c after incubation with A. fumigatus, they are considered upregulated. The basophil marker, CD63, which has kinetics similar to histamine, can also be stimulated by A. fumigatus but did not add to discrimination in addition to testing for CD203c (122). The stimulated 1219
basophils from patients with CF and ABPA show much higher activation (CD203c levels) than stimulated basophils from patients who are sensitized to A. fumigatus but do not have ABPA (121). There was a negative correlation between CD203c levels of stimulated basophils and FEV1 in A. fumigatus sensitized patients (but not in nonsensitized patients) (121). Basophils are surrogates for mast cells, which primarily reside in tissue. The basophil stimulation test may provide an extension of what it means to be sensitized beyond positive immediate skin test and in vitro detection of anti-allergen IgE. A positive sputum culture for A. fumigatus is a helpful, but not pathognomonic, feature of ABPA. Repeated positive cultures may be significant. Whereas some patients produce golden brown plugs or “pearls” of mucus containing Aspergillus mycelia, others produce no sputum at all, even in the presence of roentgenographic infiltrates. Sputum eosinophilia is usually found in patients with significant sputum production, but is not essential for diagnosis and clearly is not specific. Peripheral blood eosinophilia is common in untreated patients, but need not be extremely high, and is often about 10% to 25% of the differential in patients who have not received oral corticosteroids. Bronchial inhalational challenges with A. fumigatus are not required to confirm the diagnosis and are not without risk. Nevertheless, a dual reaction usually occurs after bronchoprovocation. An immediate reduction in flow that resolves, to be followed in some cases by a recurrence of obstruction after 4 to 10 hours, has been described (95). Pretreatment with β-adrenergic agonists prevents the immediate reaction; pretreatment with one dose of inhaled corticosteroids reduces the extent of the late reaction; and cromolyn sodium has been reported to prevent both. Inhalational challenge with A. fumigatus in a most skin test positive patients with asthma produces the immediate response only. Aspergilloma patients may respond only with a late pattern.
LUNG BIOPSY Because of the increasing recognition of ABPA, the need for lung biopsy in confirming the diagnosis appears unnecessary unless other diseases must be excluded. Bronchiectasis in the affected lobes in segmental and subsegmental bronchi, with sparing of distal branches, characterizes the pattern of proximal or central bronchiectasis (123–125). Bronchi are tortuous and very dilated. Histologically, bronchi contain tenacious mucus, fibrin, Curschmann spirals, Charcot–Leyden crystals (eosinophil-derived lysophospholipase), and 1220
inflammatory cells (mononuclear cells and eosinophils) (123–126). Fungal hyphae can be identified in the bronchial lumen, and A. fumigatus can be isolated in culture. Except for a few unusual case reports, no evidence exists for invasion of the bronchial wall, despite numerous hyphae in the lumen. Bronchial wall damage is associated with the presence of mononuclear cells and eosinophils, and in some cases with granulomata. Organisms of Aspergillus may be surrounded by necrosis, or acute or chronic inflammation. In other areas, there is replacement of submucosa with fibrous tissue. It is not known why bronchial wall destruction is focal with uninvolved adjacent areas. A variety of morphologic lesions have been described in patients meeting criteria of ABPA (123–125). These include A. fumigatus hyphae in granulomatous bronchiolitis, exudative bronchiolitis, A. fumigatus hyphae in microabscess, eosinophilic pneumonia, lipid pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, pulmonary vasculitis, and pulmonary fibrosis. Some patients with ABPA may show pathology consistent with bronchocentric granulomatosis. Mucoid impaction related to ABPA may cause proximal bronchial obstruction with distal areas of bronchiolitis obliterans. Examples of a cavitary mass (Figs. 24.10 and 24.11) and microscopic sections are shown in Figs. 24.12 and 24.13.
FIGURE 24.10 Computed tomography scan demonstrating a cavitary mass in the right lower lobe in a 56-year-old man. The total serum IgE was 4,440 ng/mL. His only symptom was a mild nonproductive cough.
1221
FIGURE 24.11 The same patient as in Fig. 24.10. The computed tomography scan at the level of the carina demonstrating cystic bronchiectasis (arrow).
FIGURE 24.12 Typical microscopic appearance representing eosinophilic pneumonia. The collapsed alveolus contains a predominance of large mononuclear cells, few lymphocytes, plasma cells, and clumps of eosinophils; similar cells infiltrate the alveolar walls. Superior segment of the upper lobe was resected for a cavitary and infiltrative lesion. (Reprinted from Imbeau SA, Nichols D, Flaherty D, et al. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1978;62:243, with permission. Photographs from the specimen collection of Enrique Valdivia; magnification × 120, hematoxylin and eosin stain.)
PATHOGENESIS
1222
On a historic basis, in some asthma patients who had a normal bronchogram before they developed ABPA, bronchiectasis has been found to occur at the sites of roentgenographic infiltrates. This phenomenon has been confirmed by repeated CT examinations as well. It is thought that inhaled spores grow in the patient’s tenacious mucus and release antigenic glycoproteins and perhaps other reactants that activate bronchial mast cells, lymphocytes, macrophages, dendritic cells, and eosinophils, and generate antibodies, cytokines, and chemokines, followed by tissue damage that is associated with subsequent bronchiectasis or roentgenographic infiltrates. Aspergillus spores are thermophilic and aerobic; therefore, growth is feasible in bronchi. It is possible that spores are trapped in the viscid mucus, or alternatively, that they have a special ability (virulence) to colonize the bronchial tree and result in the development of tenacious mucus. The latter is such that during bronchoscopy, the mucoid material may remain impacted after 30 minutes of attempted removal. In contrast, in patients with CF without ABPA, such difficulty is not encountered. Proteolytic enzymes and presumably gliotoxins and ribotoxins produced by A. fumigatus growing in the bronchial tree may contribute to lung damage on a nonimmunologic or immunologic basis. Some strains of conidia of A. fumigatus have adhesive proteins that bind to fibrinogen, which itself functions as a substrate for the binding of pathogens to damaged epithelium and macrophages (127). It has been proposed that Asp f 2 can bind to fibrinogen as well (102). Immunologic injury could occur because the release of antigenic material is associated with production of IgE, IgA, and IgG antibodies and activation of the pulmonary immune response with a panoply of harmful pro-inflammatory effects.
FIGURE 24.13 Right lower lobectomy. The lung has prominent cellular 1223
infiltration and an area of early bronchocentric granulomatosis, with leukocytes and a crown of epithelioid cells. Aspergillus was demonstrated in the center of the lesions with special stains. (Reprinted from Imbeau SA, Nichols D, Flaherty D, et al. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1978:62:243, with permission. Photographs from the specimen collection of Enrique Valdivia; magnification × 240, hematoxylin and eosin stain.) Although peripheral blood lymphocytes from stable ABPA patients have not been reported to form excess IgE in vitro compared with nonatopic patients at the time of an ABPA flare-up, these cells produced significantly increased amounts of IgE (128). This suggests that during an ABPA flare-up, IgE-forming cells are released into the systemic circulation, presumably from the lung. The biphasic skin reaction requires IgE and, possibly, IgG, and it has been suggested that a similar reaction occurs in the lung. Nevertheless, the lack of immunofluorescence in vascular deposits is evidence against an immune complex vasculitis as a cause of bronchial wall damage. Instructive experiments have been carried out in monkeys (129). The passive transfer of serum-containing IgG and IgE antibodies from a patient with ABPA to a monkey, followed by bronchial challenge with A. fumigatus, has been associated with pulmonary lesions in the monkey. First, monkeys were immunized with A. fumigatus and generated IgG antibodies. Then, normal human serum was infused into both immunized and nonimmunized monkeys, and allergic human serum from a patient with ABPA (currently without any precipitating antibody) was infused into other monkeys, immunized and nonimmunized (129). All animals were challenged with aerosolized A. fumigatus, and lung biopsy samples were obtained on the fifth day. Only the monkey with precipitating antibody (IgG) to A. fumigatus who received human allergic serum (IgE) showed biopsy changes consistent with ABPA (129). Mononuclear and eosinophilic infiltrates were present, with thickening of alveolar septa, but without evidence of vasculitis. These findings confirm that IgE and IgG directed against A. fumigatus are necessary for the development of pulmonary lesions. Similarly, a murine model of ABPA was developed that resulted in blood and pulmonary eosinophilia using A. fumigatus particulates, which simulate spores (130). Intranasal inoculation of A. fumigatus particulates resulted in perivascular eosinophilia, as well as pulmonary lymphocytes, plasma cells, histocytes, and eosinophils consistent with ABPA. In contrast, if A. fumigatus in alum was injected into the peritoneal cavity, anti-A. fumigatus-IgG1 and total IgE 1224
concentrations increased, but pulmonary and peripheral blood eosinophilia did not occur. A true model of ABPA where animals develop spontaneously occurring pulmonary infiltrates has yet to be described. It is established that CD4+-TH2 lymphocytes produce IL-4 (and IL-13) and IL-5 to support IgE synthesis and eosinophilia, respectively. Elevated soluble IL2 receptors suggest CD4+ lymphocyte activation (131), and CD4+-TH2 type clones have been produced from ABPA patients (82). The presentation of Asp f 1 is restricted to certain class II MHC molecules, HLA-DR2 and HLA-DR5 (82), and an increasing number of genetic susceptibilities have been described in preliminary studies (18). The demonstration of hyperreleasability of mediators from basophils of patients with stages IV and V ABPA (120) is consistent with the hypothesis that a subgroup of patients may be most susceptible to immunologic injury if peripheral blood basophils are representative bronchial mast cells. The fact that basophils from patients with any stage of ABPA have increased in vitro histamine release as compared with basophils from A. fumigatus skin-prick–positive patients with asthma suggests that mast cell mediator release to various antigens (fungi) may contribute to lung damage in ABPA if these findings can be applied to bronchial mast cells. Analysis of bronchoalveolar lavage from stages II and IV ABPA patients who had no current chest roentgenographic infiltrates revealed evidence for local antibody production of IgA–A. fumigatus and IgE–A. fumigatus compared with peripheral blood (132). Bronchial lavage IgA–A. fumigatus was 96 times that of peripheral blood, and IgE–A. fumigatus in lavage was 48 times that found in peripheral blood. Although total serum IgE was elevated, there was no increase in bronchial lavage total IgE corrected for albumin. These results suggest that the bronchoalveolar space is not the source of the markedly elevated total IgE in ABPA (132). Perhaps pulmonary interstitium or nonpulmonary sources (tonsils or bone marrow) serve as sites of total IgE production in ABPA. In a serial analysis of serum IgA–A. fumigatus in 10 patients, there were sharp elevations over baseline before (five cases) or during (five cases) roentgenographic exacerbations of ABPA for IgA1–A. fumigatus (133). Serum IgA2–A. fumigatus was elevated before the exacerbation in two cases and during the exacerbation in five cases. With immunoblotting of sera and staining with antibodies to IgE, IgA, and IgG, there were heterogeneous polyclonal antibody responses to seven different molecular weight bands of A. fumigatus. (133). Band intensity increased during ABPA exacerbations, and patient’s sera often had broader reactivity with A. fumigatus bands from 24- to 90-kDa molecular 1225
weights during disease flare-ups. Some patients had immunoblot patterns consistent with increases in IgE, IgG, or IgA antibodies binding to different A. fumigatus antigens but no consistent binding to a particular A. fumigatus band (133). A summary of immunopathogenesis includes genetic susceptibility and powerful virulence factors, including proteases and enzymes from A. fumigatus, that can damage epithelium and interfere with surfactant, adhesive proteins, generation of tenacious eosinophil-rich mucoid impactions, a brisk CD4 TH2 response with its characteristic cytokines and chemokines, activation of CD20 B cells and upregulation of CD23 (the low-affinity IgE receptor that binds allergen–IgE complexes) by IL-4, remarkable amounts of isotypic antibody production in the bronchoalveolar space and presumably interstitium, genetic restriction of HLA-DR2 and HLA-DR5 and gain of function polymorphisms for IL-4, eosinophil upregulation and activation, mast cell activation, basophil hyperreleasability and activation, and chemokines such as thymus- and activation-regulated chemokine and B-cell activating factor (134). The immunopathogenesis also includes allergic inflammation that is responsive to systemic but not inhaled corticosteroids and poorly responsive to intensive antifungal therapies.
DIFFERENTIAL DIAGNOSIS The differential diagnosis of ABPA includes disease states associated primarily with transient or permanent roentgenographic lesions, asthma, peripheral blood or sputum eosinophilia, and increased total serum IgE concentration. The asthma patient with a roentgenographic infiltrate may have atelectasis or middle lobe collapse from inadequately controlled asthma. Bacterial, viral, or fungal pneumonias must be excluded in addition to Mycobacterium tuberculosis and the many other causes of roentgenographic infiltrates. Eosinophilia may occur with parasitism, M. tuberculosis, eosinophilic granulomatosis with polyangiitis, pulmonary infiltrates from drug allergies, neoplasm, eosinophilic pneumonia, and, rarely, avian-hypersensitivity pneumonitis. Mucoid impaction of bronchi may occur without ABPA. All patients with a history of mucoid impaction syndrome or with collapse of a lobe or lung, however, should have ABPA excluded. Similarly, although the morphologic diagnosis of bronchocentric granulomatosis is considered by some to represent an entity distinct from ABPA, ABPA must be excluded in such patients. Although the sweat test for CF is within normal limits in ABPA patients, unless concomitant CF is present, the patient with CF and asthma or changing roentgenographic infiltrates should have 1226
ABPA excluded or confirmed. Genetic testing and assessment of pancreatic function for CF would be indicated. Some patients with asthma who develop pulmonary infiltrates with eosinophilia are likely to have ABPA or ABPM. Some patients will have mucus plugging (tree-in-bud) from atypical Mycobacteria (135). In the patient without a history of roentgenographic infiltrates, ABPA should be suspected on the basis of (a) a positive, immediate cutaneous reaction to A. fumigatus or presence of in vitro anti-A. fumigatus IgE; (b) elevated total serum IgE (>417 kU/L); (c) increasing severity of asthma; (d) abnormalities on chest roentgenogram or CT; (e) repeatedly positive sputum cultures for Aspergillus species; or (f) bronchiectasis (14,15,18). A rare patient with asthma, roentgenographic infiltrates, and bronchiectasis or a history of surgical resection for such may present with peripheral eosinophilia, elevated total serum IgE concentration, but other negative serologic results for ABPA. Some other species of Aspergillus may be responsible, such as A. oryzae, Aspergillus ochraceus, or A. niger (15,78). Perhaps a different ABPM may be present (15,78). For example, illnesses consistent with allergic bronchopulmonary candidiasis, curvulariosis, dreschleriosis, stemphyliosis, fusariosis, and pseudallescheriasis have been described (15,136–138). Positive sputum cultures, precipitating antibodies, or in vitro assays for a fungus other than Aspergillus or for different Aspergillus species could suggest a causative source of the ABPM. The presence of bronchiectasis from ABPA has been associated with colonization of bronchi by nontuberculous mycobacteria (135). It appears that the identification of nontuberculous mycobacteria in the sputum of patients with asthma should at least raise the possibility of ABPA. Similarly, bronchiectatic airways may become colonized by Pseudomonas aeruginosa in ABPA patients who do not have CF.
NATURAL HISTORY Although most patients are diagnosed before the age of 40 years, and an increasing number are diagnosed before the age of 20 years, one must not overlook the diagnosis of ABPA in older patients previously characterized as having persistent asthma or chronic bronchiectasis. Some patients as old as 80 have had the diagnosis of ABPA made. Late sequelae of ABPA include irreversible pulmonary function abnormalities, symptoms of chronic bronchitis, and pulmonary fibrosis (89,90). Death results from respiratory failure and cor 1227
pulmonale (89,90). ABPA has been associated with respiratory failure in the second or third decade of life. Most patients who have ABPA do not progress to the end-stage disease, especially if there is early diagnosis and appropriate treatment. Patients who present in the acute stage (stage I) of ABPA may enter remission (stage II), recurrent exacerbation (stage III), or may develop corticosteroid-dependent asthma (stage IV). One patient who had a single roentgenographic infiltrate when her ABPA was diagnosed entered a remission stage that lasted for 8 years until an exacerbation occurred (139). Thus, a remission does not imply permanent cessation of disease activity. This patient may be the exception, but serves to emphasize the need for longer term observation of patients with ABPA. Patients who have corticosteroid-dependent asthma (stage IV) at the time of diagnosis may evolve into having pulmonary fibrosis (stage V). Because prednisone does not reverse bronchiectasis or the pulmonary fibrotic changes in the lung, every effort should be made by physicians and health care professionals managing patients with asthma to suspect and confirm cases of ABPA before significant structural damage to the lung has developed. In managing patients with ABPA, there can be a lack of correlation between clinical symptoms and chest roentgenographic lesions. Irreversible lung damage, including bronchiectasis, may occur without the patient seeking medical attention. In Great Britain, ABPA exacerbations were reported to occur between October and February during elevations of fungal spore counts (45). In Chicago, 38 of 49 (77.5%) ABPA exacerbations (new roentgenographic infiltrate with elevation of total serum IgE concentration) occurred from June through November in association with increased outdoor fungal spore counts (140). Acute and chronic pulmonary function changes have been studied in a series of ABPA cases, during which time all patients received corticosteroids and bronchodilators (141). There appeared to be no significant correlation between duration of ABPA (mean follow-up period, 44 months), duration of asthma, and diffusing capacity of the lungs for carbon monoxide, total lung capacity, vital capacity, forced expiratory volume in 1 second (FEV1), and FEV1%. In six patients with acute exacerbations of ABPA, a significant reduction in total lung capacity, vital capacity, FEV1, and diffusing capacity of the lungs for carbon monoxide occurred, which returned to baseline during steroid treatment. Thus, early recognition and prompt effective treatment of flare-ups appear to reduce the likelihood of irreversible lung damage. Other patients may have reductions in FEV1 and FEV1% consistent with an obstructive process during an ABPA 1228
exacerbation. The prognosis for stage V patients is less favorable than for patients classified into stages I through IV (90). Although prednisone has proven useful in patients with end-stage lung disease, 6 of 17 stage V patients, observed for a mean 4.9 years, died. When the FEV1 was 0.8 L or less after aggressive initial corticosteroid administration, the outcome was poor (90). In contrast, when stage IV patients are managed effectively, deterioration of respiratory function parameters or status asthmaticus has not occurred. Prednisone remains the most effective treatment. Other treatments, including high-dose inhaled corticosteroids or antifungals (whether azoles or inhaled amphotericin), have not been more than adjunctive interventions. First published in 1973, from a 5-year follow-up of ABPA cases, it was reported that a daily prednisone dose of 7.5 mg was required to maintain clinical improvement and roentgenographic clearing in 80% of patients; of those treated with either cromolyn or bronchodilators alone, only 40% had radiologic clearing (142). In a study of patients from Northwestern University Feinberg School of Medicine, who had periodic blood sampling, both immunologic and clinical improvement occurred with prednisone therapy. Individuals with ABPA have high presentation (stages I and III) total serum IgE concentrations, and those patients previously never requiring oral steroids for control of asthma have the highest concentrations. Treatment with prednisone causes roentgenographic and clinical improvement, as well as decreases in total serum IgE. Total serum IgE and IgE–A. fumigatus may increase before and during a flare-up, but the serum IgE–A. fumigatus does not fluctuate to the extent that total serum IgE concentration does. Prognostic factors remain to be established that may identify patients at risk for developing stage IV or V ABPA. The roentgenographic findings at the time of diagnosis do not appear to provide prognostic data about long-term outcome unless the patient is stage V. The effect of untreated ABPA exacerbations has produced stage V ABPA. In addition, at least some patients with CF who develop ABPA have a worse prognosis. Lastly, the effect of allergic fungal rhinosinusitis (Table 24.3) on the natural history of ABPA is unknown.
TREATMENT Prednisone is the drug of choice but need not be administered indefinitely (Table 24.4). Multiple agents have been tried, including intrabronchial instillation of amphotericin B (143,144), oral nystatin (144), natamycin (144), azoles (144) 1229
itraconazole, ketoconazole, voriconazole, and posaconazole, high-dose inhaled corticosteroids (145), and omalizumab (146–150). Itraconazole (151–155) or voriconazole or other antifungals may have an adjunctive role, but prednisone therapy typically eliminates or diminishes sputum plug production. Although the exact pathogenesis of ABPA is unknown, oral corticosteroids have been demonstrated to reduce the clinical symptoms, incidence of positive sputum cultures, and roentgenographic infiltrates. Oral corticosteroids may be effective by decreasing sputum volume, by making the bronchi a less suitable culture media for Aspergillus species, and by inhibiting many of the Aspergillus– pulmonary immune system interactions. The total serum IgE concentration declines by at least 35% within 2 months of initiating prednisone therapy (40). Failure to observe this reduction suggests noncompliance of patients or a continuing exacerbation of ABPA. TABLE 24.3 CRITERIA FOR DIAGNOSIS OF ALLERGIC FUNGAL SINUSITIS Chronic sinusitis—at least 6 mo duration with nasal polyposis Allergic mucin (histologic examination with eosinophils and fungal hyphae and “putty” material by rhinoscopy) Computed tomography of sinuses shows opacification, and magnetic resonance imaging shows fungal findingsa Absence of invasive fungal disease, diabetes mellitus, HIV
a
T1-weighted imaging reveals isointense or hypointense findings of mucin in sinuses; T2-weighted imaging demonstrates a “signal void” where there is inspissated mucin.
TABLE 24.4 TREATMENT OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS 1.Prednisone is drug of choice; 0.5 mg/kg daily for 2 wk, then on alternate days for 6–8 wk, then attempt tapering by 5 mg on alternate days every 2 wk. 2.Repeat chest roentgenogram and/or high-resolution computed tomography of lung at 2–4 wk to document clearing of infiltrates.
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3.Serum IgE concentration at baseline and at 4 and 8 wk, then every 8 wk for first year to establish range of total IgE concentrations (a 100% increase can identify a silent exacerbation). 4.Baseline spirometry or full pulmonary function tests depending on the clinical setting. 5.Environmental control for fungi and other allergens at home or work. 6.Determine whether prednisone-dependent asthma (stage IV ABPA) is present; if not, manage asthma with anti-inflammatory medications and other medications as indicated. 7.Future ABPA exacerbations may be identified by a. Asymptomatic sharp increases in the total serum IgE concentration b. Increasing asthma symptoms or signs c. Deteriorations in FVC and/or FEV1
d. Cough, chest pain, new production of sputum plugs, dyspnea not explained by other causes e. Chest roentgenographic or high-resolution computed tomography findings (patient may be asymptomatic) 8.Document in record that prednisone side effects were discussed and address bone density issues (e.g., adequate calcium and vitamin D, exercise, and antiosteopenia medication if indicated). 9.Persistent sputum expectoration should be cultured to identify Aspergillus fumigatus, Staphylococcus aureus, Pseudomonas aeruginosa, nontuberculous mycobacteria, etc. 10.If new ABPA exacerbations occur, repeat step 1.
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ABPA, allergic bronchopulmonary aspergillosis; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; IgE, immunoglobin E;
Our current treatment regimen is to clear the roentgenographic infiltrates with daily prednisone, usually at 0.5 mg/kg. Most infiltrates clear within 2 weeks, at which time the same dose, given on a single alternate-day regimen, is begun and maintained for 2 months until the total serum IgE, which should be followed up every 4 to 8 weeks for the first year, has reached a baseline concentration. The baseline total serum IgE concentration can remain elevated despite clinical and radiographic improvement. Slow reductions in prednisone, at no faster than 10 mg/month, can be initiated once a stable baseline of total IgE has been achieved. Acute exacerbations of ABPA are often preceded by a 100% increase in total serum IgE and must be treated promptly with increases in prednisone and reinstitution of daily steroids. Certainly, the physician must exclude other causes for roentgenographic infiltrates. Pulmonary functions should be measured yearly or as necessary for stages IV and V and as required for asthma. If prednisone can be discontinued, the patient is in remission (stage II), and perhaps only an inhaled corticosteroid will be needed for management of asthma. Alternatively, if the patient has asthma that cannot be managed without prednisone despite avoidance measures and maximal anti-inflammatory medications, alternate-day prednisone will be necessary. The dose of prednisone required to control asthma and to prevent ABPA radiologic exacerbations is usually less than 0.5 mg/kg on alternate days. For corticosteroid-dependent patients (stage IV or V) with ABPA, an explanation of prednisone risks and benefits is indicated, as is the discussion that untreated ABPA infiltrates result in bronchiectasis and irreversible fibrosis. Specific additional recommendations regarding adequate calcium and vitamin D ingestion, bone density measurements, bronchial hygiene, and physical fitness should be considered. In a two track study, the Northwestern regimen (prednisone 0.5 mg/kg/day for 2 weeks, then alternate days for 8 weeks; then reduce by 5 mg on alternate days every 2 weeks: discontinue after 3 to 5 months) was compared with a longer and initially higher course of daily prednisone (first 6 weeks 0.75 mg/kg/day, next 6 weeks, 0.5 mg/kg/day, taper by 5 mg every 6 weeks: discontinue after 8 to 10 months) (156). Both treatments were similar in clinical outcomes. The main difference was more side effects from oral corticosteroids in the latter arm (156). In ABPA patients receiving prednisone, itraconazole, 200 mg twice daily or placebo, was administered for 16 weeks (151). A response was defined as (a) at 1232
least a 50% reduction in oral corticosteroid dose and (b) a decrease of 25% or more of the total serum IgE concentration and at least one of three additional parameters: a 25% improvement in exercise tolerance or similar 25% improvement in pulmonary function tests or resolution of chest roentgenographic infiltrates if initially present with no subsequent new infiltrates, or if no initial chest roentgenographic infiltrates were present, no emergence of new infiltrates. Oral corticosteroids were tapered during the study, although it was not certain that all patients had an attempt at steroid tapering. With that consideration, itraconazole administration was associated with a response as defined. Unfortunately, less than 25% of patients had chest roentgenographic infiltrates at the beginning of the study. More responders (60%) occurred in patients without bronchiectasis (ABPA-S) versus ABPA-CB (31%), compared with 8% in placebo-treated patients (151). Eleven isolates from sputum cultures were analyzed for antifungal susceptibility, and five were susceptible to intraconazole (151). None of the patients whose isolates of A. fumigatus were resistant or intolerant in vitro to itraconazole had responses to treatment. The conclusions from this study were that patients with ABPA “generally benefit from concurrent itraconazole” (151). The difficulties and complexities in such studies are apparent, and ideally the drug would be of value in patients with ABPA-CB, who are the patients more frequently seen in the office. Itraconazole has antiinflammatory effects and reduces eosinophils in induced sputum and lowers the total IgE concentration (154). Itraconazole and posaconazole’s absorption (but not voriconazole’s) is reduced if there is gastric hypochlorhydria (157), so it should be ingested 1 hour before or 2 hours after meals. It slows hepatic metabolism of drugs that use the CYP 3A4 pathway, including methylprednisolone and dexamethasone (but not prednisolone), inhaled budesonide and fluticasone, statins, coumadin, oral hypoglycemics, tacrolimus, cyclosporines, and benzodiazepines, as examples. Itraconazole itself is potentiated by clarithromycin and some protease inhibitors used for human immunodeficiency virus infection. Voriconazole can cause skin rash/photosensitivity (not prevented by skin protection) (157). Antifungal agents have been administered for 50 years to ABPA patients and are not a substitute for oral corticosteroids. Unfortunately, they remain adjunctive at best. The primary pharmacologic therapy remains prednisone, which, if the patient is in stage IV or V, often can be administered on an alternate-day basis. Perhaps itraconazole has anti-inflammatory effects or a delaying effect on corticosteroid elimination. If so, then its effects might resemble those of the macrolide troleandomycin, delaying the metabolism of 1233
methylprednisolone. I have seen failures of itraconazole and voriconazole and excessive reliance on it without clearing of chest roentgenographic infiltrates. Nevertheless, as adjunctive therapy in patients who have susceptible strains of A. fumigatus or continue to produce mucus plugs despite prednisone, azoles can be considered in ABPA. Some studies have reported reductions in daily prednisone use and clearance of A. fumigatus from sputum. In CF patients with ABPA, itraconazole was reported to result in a 47% reduction in oral steroid dose and a 55% reduction in ABPA exacerbations (29). The study group was composed of 16 patients (9%) from a pool of 122 CF patients. Itraconazole was administered to 12 of the 16 patients, who also received inhaled corticosteroids and prednisone and treatment for CF. Elevated serum aspartate aminotransferase or alanine aminotransferase results of greater than three times the upper limit of normal were contraindications to the use. It has been thought that subcutaneous immunotherapy (SCIT) with Aspergillus species should not be administered in patients with ABPA, but examples of adverse effects aside from injection reactions have not been reported. It is known that SCIT with Aspergillus extracts would not result in immune complex formation. Immunotherapy can be administered with pollens and mites and other fungi, but not those in the Aspergillus genus. Nevertheless, this remains an area suitable for investigation, and inclusion of Aspergillus in the treatment is not absolutely contraindicated. Inhaled corticosteroids should be used in an effort to control asthma, but one should not depend on them to prevent exacerbations of ABPA. Similarly, the leukotriene D4 antagonists have antieosinophil actions in vitro and theoretically might be of value for use in ABPA patients. They can be administered for a trial of 1 to 3 months or continued for treatment of persistent asthma. The immunobiologic omalizumab has potential benefit in treatment of patients with ABPA in asthma or CF (146–150). As with other treatments, if improvement (fewer exacerbations of asthma or reduction in prednisone) doesn’t occur, the treatment should be discontinued after an initial trial of 6 to 12 months. There is no published information regarding the anti-IL-5 immunobiologics, mepolizumab and reslizumab, in ABPA. One could speculate that these treatments will be beneficial in treatment of patients with ABPA. The exact role of environmental exposure of Aspergillus spores in the pathogenesis of ABPA remains unknown, primarily because of lack of firm evidence. Nevertheless, Aspergillus spores are found regularly in crawl spaces,
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68. Abad A, Fernández-Molina JV, Bikandi J, et al. What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis. Rev Iberoam Micol. 2010;27:155–182. 69. Morrison BE, Park SJ, Mooney JM, et al. Chemokine-mediated recruitment of NK cells is a critical host defense mechanism in invasive aspergillosis. J Clin Invest. 2003;112:1862–1870. 70. Bozza S, Gaziano R, Spreca A, et al. Dendritic cells transport conidia and hyphae of Aspergillus fumigatus from the airways to the draining lymph nodes and initiate disparate Th responses to the fungus. J Immunol. 2002;168:1362–1371. 71. Bozza S, Campo S, Arseni B, et al. PTX3 binds MD-2 and promotes TRIFdependent immune protection in aspergillosis. J Immunol. 2014;193:2340– 2348. 72. Morris MP, Fletcher OJ. Disease prevalence in Georgia turkey flocks in 1986. Avian Dis. 1988;32:404–406. 73. Quirce S, Cuevas M, Diez-Gomez ML, et al. Respiratory allergy to Aspergillus-derived enzymes in bakers’ asthma. J Allergy Clin Immunol. 1992;90:970–978. 74. Houba R, Heederik DJ, Doekes G, et al. Exposure-sensitization relationship for alpha-amylase allergens in the baking industry. Am J Respir Crit Care Med. 1996;154:130–136. 75. Rosenberg IL, Greenberger PA. Allergic bronchopulmonary aspergillosis and aspergilloma: long-term followup without enlargement of a large multiloculated cavity. Chest. 1984;85:123–125. 76. Binder RE, Faling LJ, Pugatch RE, et al. Chronic necrotizing pulmonary aspergillosis: a discreet clinical entity. Medicine. 1982;151:109–124. 77. Barth PJ, Rossberg C, Kock S, et al. Pulmonary aspergillosis in an unselected autopsy series. Pathol Res Pract. 2000;196:73–80. 78. Knutsen AP, Bush RK, Demain JG, et al. Fungi and allergic lower respiratory tract diseases. J Allergy Clin Immunol. 2012;129:280–291. 79. Agbetile J, Bourne M, Fairs A, et al. Effectiveness of voriconazole in the treatment of Aspergillus fumigatus-associated asthma (EVITA3 study). J Allergy Clin Immunol. 2014;134:33–39. 80. Knutsen AP, Noyes B, Warrier MR, et al. Allergic bronchopulmonary 1241
aspergillosis in a patient with cystic fibrosis: diagnostic criteria when the IgE level is less than 500 IU/mL. Ann Allergy Asthma Immunol. 2005;95:488–493. 81. Knutsen AP, Kariuki B, Consolino JD, et al. IL-4 alpha chain receptor (IL4Ralpha) polymorphisms in allergic bronchopulmonary aspergillosis. Clin Mol Allergy. 2006;4:3. 82. Chauhan B, Santiago L, Hutcheson PS, et al. Evidence for the involvement of two different MHC class II regions in susceptibility or protection in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 2000;106:723–729. 83. Katzenstein AL, Sale SR, Greenberger PA. Allergic Aspergillus sinusitis: a newly recognized form of sinusitis. J Allergy Clin Immunol. 1983;72:89– 93. 84. Montone KT. Pathology of fungal rhinosinusitis: a review. Head Neck Pathol. 2016;10:40–46. 85. Sher TH, Schwartz HJ. Allergic Aspergillus sinusitis with concurrent allergic bronchopulmonary Aspergillus: report of a case. J Allergy Clin Immunol. 1988;81:844–846. 86. Rosenberg M, Patterson R, Mintzer R, et al. Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med. 1977;86:405–414. 87. Patterson R, Greenberger PA, Halwig JM, et al. Allergic bronchopulmonary aspergillosis: natural history and classification of early disease by serologic and roentgenographic studies. Arch Intern Med. 1986;146:916–918. 88. Ricketti AJ, Greenberger PA, Glassroth J. Spontaneous pneumothorax in allergic bronchopulmonary aspergillosis. Arch Intern Med. 1984;144:181– 182. 89. Greenberger PA, Patterson R, Ghory AC, et al. Late sequelae of allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1980;66:327– 335. 90. Lee TM, Greenberger PA, Patterson R, et al. Stage V (fibrotic) allergic bronchopulmonary aspergillosis: a review of 17 cases followed from diagnosis. Arch Intern Med. 1987;147:319–323.
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1800. 103. Banerjee B, Greenberger PA, Fink JN, et al. Immunologic characterization of Asp f 2, a major allergen from Aspergillus fumigatus associated with allergic bronchopulmonary aspergillosis. Infect Immun. 1998;66:5175– 5182. 104. Arruda LK, Mann BJ, Chapman MD. Selective expression of a major allergen and cytotoxin, Asp f I, in Aspergillus fumigatus. Implications for the immunopathogenesis of Aspergillus-related diseases. J Immunol. 1992;149:3354–3359. 105. Gautam P, Sundaram CS, Madan T, et al. Identification of novel allergens of Aspergillus fumigatus using immunoproteomics approach. Clin Exp Allergy. 2007;37:1239–1249. 106. Fukutomi Y, Tanimoto H, Yasuedo H, et al. Serological diagnosis of allergic bronchopulmonary mycosis: progress and challenges. Allergol Internat. 2016;65:30–36. 107. Kraemer R, Deloséa N, Ballinari P, et al. Effect of allergic bronchopulmonary aspergillosis on lung function in children with cystic fibrosis. Am J Respir Crit Care Med. 2006;174:1211–1220. 108. Sequeiros IM, Jarad N. Factors associated with a shorter time until the next pulmonary exacerbation in adult patients with cystic fibrosis. Chron Respir Dis. 2012;9:9–16. 109. Weiner Miller P, Hamosh A, Macek M Jr, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in allergic bronchopulmonary aspergillosis. Am J Hum Genet. 1996;59:45–51. 110. Maturu VN, Agarwal R. Prevalence of Aspergillus sensitization and allergic bronchopulmonary aspergillosis in cystic fibrosis: systematic review and meta-analysis. Clin Exp Allergy. 2015;45:1765–1778. 111. Patterson R, Rosenberg M, Roberts M. Evidence that Aspergillus fumigatus growing in the airway of man can be a potent stimulus of specific and nonspecific IgE formation. Am J Med. 1977;63:257–262. 112. Gunnar S, Johansson O, Juhlin L. Immunoglobulin E in “healed” atopic dermatitis and after treatment with corticosteroids and azathioprine. Br J Dermatol. 1970;82:10–13. 113. Settipane GA, Pudupakkam RK, McGowan JH. Corticosteroid effect on 1244
immunoglobulins. J Allergy Clin Immunol. 1978;62:162–166. 114. Slavin RG, Hutcheson PS, Knutsen AP. Participation of cell-mediated immunity in allergic bronchopulmonary aspergillosis. Int Arch Allergy Appl Immunol. 1987;83:337–340. 115. Knutsen AP, Mueller KR, Levine AD, et al. Characterization of Asp f1 CD4+ T cell lines in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1994;94:215–221. 116. Chauhan B, Santiago L, Kirschmann DA, et al. The association of HLADR alleles and T cell activation with allergic bronchopulmonary aspergillosis. J Immunol. 1997;159:4072–4076. 117. Geha RS. Circulating immune complexes and activation of the complement sequence in acute allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1977;60:357–359. 118. Marx JJ, Flaherty DK. Activation of the complement sequence by extracts of bacteria and fungi associated with hypersensitivity pneumonitis. J Allergy Clin Immunol. 1976;57:328–334. 119. Apter AJ, Greenberger PA, Liotta JL, et al. Fluctuations of serum IgA and its subclasses in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1989;84:367–372. 120. Ricketti AJ, Greenberger PA, Pruzansky JJ, et al. Hyperreactivity of mediator releasing cells from patients with allergic bronchopulmonary aspergillosis as evidenced by basophil histamine release. J Allergy Clin Immunol. 1983;72:386–392. 121. Mirković B, Lavelle GM, Azim AA,, et al. The basophil surface marker CD203c identifies Aspergillus species sensitization in patients with cystic fibrosis. J Allergy Clin Immunol. 2016;137:436–443. 122. Gernez Y, Waters J, Tirouvanziam R, et al. Basophil activation test determination of CD63 combined with CD203c is not superior to CD203c alone in identifying allergic bronchopulmonary aspergillosis in cystic fibrosis. J Allergy Clin Immunol. 2016;138:1195–1196. 123. Chan-Yeung M, Chase WH, Trapp W, et al. Allergic bronchopulmonary aspergillosis. Chest. 1971;59:33–39. 124. Imbeau SA, Nichols D, Flaherty D, et al. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 1978;62:243–255. 1245
125. Bosken CH, Myers JL, Greenberger PA, et al. Pathologic features of allergic bronchopulmonary aspergillosis. Am J Surg Pathol. 1988;12:216– 222. 126. Panchabhai TS, Mukhopadhyay S, Sehgal S, et al. Plugs of the air passages: a clinicopathologic review. Chest. 2016;150:1141–1157. 127. Upadhyay SK, Gautam P, Pandit H, et al. Identification of fibrinogenbinding proteins of Aspergillus fumigatus using proteomic approach. Mycopathologia. 2012;173:73–82. 128. Ghory AC, Patterson R, Roberts M, et al. In vitro IgE formation by peripheral blood lymphocytes from normal individuals and patients with allergic bronchopulmonary aspergillosis. Clin Exp Immunol. 1980;40:581– 585. 129. Slavin RG, Fischer VW, Levin EA, et al. A primate model of allergic bronchopulmonary aspergillosis. Int Arch Allergy Appl Immunol. 1978;56:325–333. 130. Kurup VP, Mauze S, Choi H, et al. A murine model of allergic bronchopulmonary aspergillosis with elevated eosinophils and IgE. J Immunol. 1992;148:3783–3788. 131. Brown JE, Greenberger PA, Yarnold PR. Soluble serum interleukin 2 receptors in patients with asthma and allergic bronchopulmonary aspergillosis. Ann Allergy Asthma Immunol. 1995;74:484–488. 132. Greenberger PA, Smith LJ, Hsu CC, et al. Analysis of bronchoalveolar lavage in allergic bronchopulmonary aspergillosis: divergent responses in antigen-specific antibodies and total IgE. J Allergy Clin Immunol. 1988;82:164–170. 133. Bernstein JA, Zeiss CR, Greenberger PA, et al. Immunoblot analysis of sera from patients with allergic bronchopulmonary aspergillosis: correlation with disease activity. J Allergy Clin Immunol. 1990;86:532– 539. 134. Nayak DA, Greenberger PA, Watkins DW. Measurements of B-Cell Activating Factor (BAFF) of tumor necrosis factor family in patients with allergic bronchopulmonary aspergillosis (ABPA) and asthma. J Allergy Clin Immunol. 2015;135:AB20. 135. Greenberger PA, Katzenstein A-LA. Lipoid pneumonia with atypical mycobacterial colonization in allergic bronchopulmonary aspergillosis: a 1246
complication of bronchography and a therapeutic dilemma. Arch Intern Med. 1983;143:2003–2005. 136. Greenberger PA. Allergic bronchopulmonary aspergillosis and funguses. Clin Chest Med. 1988;9:599–608. 137. Miller MA, Greenberger PA, Palmer J, et al. Allergic bronchopulmonary pseudallescheriasis in a child with cystic fibrosis. Am J Asthma Allergy Pediatr. 1993;6:177–179. 138. Miller MA, Greenberger PA, Amerian R, et al. Allergic bronchopulmonary mycosis caused by Pseudoallescheria boydii. Am J Respir Crit Care Med. 1993;148:810–812. 139. Halwig JM, Greenberger PA, Levin M, et al. Recurrence of allergic bronchopulmonary aspergillosis after seven years of remission. J Allergy Clin Immunol. 1984;74:738–740. 140. Radin R, Greenberger PA, Patterson R, et al. Mold counts and exacerbations of allergic bronchopulmonary aspergillosis. Clin Allergy. 1983;13:271–275. 141. Nichols D, Dopico GA, Braun S, et al. Acute and chronic pulmonary function changes in allergic bronchopulmonary aspergillosis. Am J Med. 1979;67:631–637. 142. Safirstein BH, D’Souza MF, Simon G, et al. Five-year follow-up of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis. 1973;108:450–459. 143. Ram B, Aggarwal AN, Dhooria S, et al. A pilot randomized trial of nebulized amphotericin in patients with allergic bronchopulmonary aspergillosis. J Asthma. 2016;53:517–524. 144. Moreira AS, Silva D, Ferreira AR, et al. Antifungal treatment in allergic bronchopulmonary aspergillosis with and without cystic fibrosis: a systematic review. Clin Exp Allergy. 2014;44:1210–1227. 145. Imbeault B, Cormier Y. Usefulness of inhaled high-dose corticosteroids in allergic bronchopulmonary aspergillosis. Chest. 1993;103:1614–1617. 146. Zirbes JM, Milla CE. Steroid-sparing effect of omalizumab for allergic bronchopulmonary aspergillosis and cystic fibrosis. Pediatr Pulmonol. 2008;43:607–610. 147. van der Ent CK, Hoekstra H, Rijkers GT. Successful treatment of allergic 1247
bronchopulmonary aspergillosis with recombinant anti-IgE antibody. Thorax. 2007;62:276–277. 148. Kanu A, Patel K. Treatment of allergic bronchopulmonary aspergillosis (ABPA) in CF with anti-IgE antibody (omalizumab). Pediatr Pulmonol. 2008;43:1249–1251. 149. Voskamp AL, Gillman A, Symons K, et al. Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol Pract. 2015;3:192–199. 150. Jat KR, Walia DK, Khairwa A. Anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database Syst Rev. 2015;(11):CD010288. doi: 10.1002/14651858.CD010288.pub3. 151. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med. 2000;342:756– 762. 152. Denning DW, Van Wye JE, Lewiston NJ, et al. Adjunctive therapy of allergic bronchopulmonary aspergillosis with itraconazole. Chest. 1991;100:813–819. 153. Leon EE, Craig TJ. Antifungals in the treatment of allergic bronchopulmonary aspergillosis. Ann Allergy Asthma Immunol. 1999;82:511–517. 154. Wark PA, Hensley MJ, Saltos N, et al. Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: a randomized controlled trial. J Allergy Clin Immunol. 2003;111:952–957. 155. Elphick HE, Southern KW. Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database Syst Rev. 2016;11:CD002204. 156. Agarwal R, Aggarwal AN, Dhooria S, et al. A randomised trial of glucocorticoids in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Eur Respir J. 2016;47:490–498. 157. Burgel P-R, Paugam A, Hubert D, et al. Aspergillus fumigatus in the cystic fibrosis lung: pros and cons of azole therapy. Infect Drug Resist. 2016;9:229–238.
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INTRODUCTION The most common immunologically mediated respiratory diseases caused by occupational exposure are occupational asthma (OA) and occupational rhinitis (OR) (1). High-molecular-weight (HMW) occupational agents can cause those diseases as well and hypersensitivity pneumonitis (HP) (2) which is covered in Chapter 23. Low-molecular-weight (LMW) agents, such as acid anhydrides, can cause OA, OR, and HP as well as less common occupational immunologic lung disease (OILD), such as pulmonary disease anemia syndrome and late respiratory systemic syndrome (Table 25.1).
DEFINITIONS OA is one of two forms of work-related asthma (WRA) (3,4). The other form is work-exacerbated asthma in which the individual has preexisting asthma made worse by exposures in the workplace. OA can be subdivided into allergic or nonallergic, also called OA with or without latency, respectively (5). The most widely recognized nonallergic OA is reactive airways dysfunction syndrome (RADS) that occurs after a high-level irritant exposure to an agent, such as chlorine gas (Table 25.2). Allergic OA can be further subdivided into diseases caused by HMW agents that are mediated by immunoglobin E (IgE) and diseases caused by LMW agents that can be mediated by IgE, but other mechanisms also occur. A parallel classification occurs with rhinitis. There is work-related rhinitis (WRR) that is comprised of work-exacerbated rhinitis and OR that can be allergic or nonallergic (6,7). Nonallergic OR has no latency and can occur with high exposure to an irritant-like ammonia gas, giving rise to reactive upper airway dysfunction syndrome. Allergic OR can be caused by HMW or LMW agents and is generally IgE mediated. LWM agents can precipitate a disorder called work-associated irritable larynx 1250
syndrome (WILS) that is characterized by chronic cough, laryngospasm, and globus (8). Along with WRR and WRA, WILS is a cause of cough in the workplace (9).
EPIDEMIOLOGY The epidemiology of OILD and OR is difficult to assess for several reasons. First, there is often a high turnover rate in jobs associated with OILD and OR, thus selecting workers who have not become sensitized. In one study of an electronics industry, a substantial proportion of workers who left reported respiratory disease as the reason (10). Second, occupationally related diseases generally are underreported. For instance, although the incidence of work-related illness is thought to be upward of 20 per 100, only 2% of these illnesses were recorded in employers’ logs, as required by the Occupational Safety and Health Administration (OSHA) (11). Finally, the incidence of disease varies with the antigen exposure involved. For example, the incidence of OA among animal handlers is estimated at 8%, whereas that of workers exposed to proteolytic enzymes can be up to 45% which is significantly higher (12). A recent literature review, primarily from Canada and Europe, suggests that the prevalence of OA may be decreasing (13). TABLE 25.1 TRIMELLITIC ANHYDRIDE–INDUCED RESPIRATORY DISEASES AND IMMUNOLOGIC CORRELATES DISEASE
MECHANISM
IMMUNOLOGIC TESTS
Asthma or rhinitis
IgE
Immediate skin test IgG against TM–protein conjugate
Late respiratory systemic syndrome
IgG and IgA
IgG, IgA, or total antibody against TM– protein conjugate
Pulmonary disease, anemia syndrome
Complement-fixing antibodies
Complement-fixing antibodies against TM cells
IgA, immunoglobulin A; IgE, immunoglobulin E; IgG, immunoglobulin G; TM, trimellityl.
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TABLE 25.2 CRITERIA FOR REACTIVE AIRWAYS DYSFUNCTION SYNDROME 1. No history of bronchospastic respiratory disease 2. Onset of symptoms follows a high-level exposure to a respiratory irritant 3. Onset of symptoms is abrupt, within minutes to hours 4. Symptoms must persist for at least 3 mo 5. Methacholine challenge is positive 6. The symptoms are asthma like, such as cough and wheeze 7. Other respiratory disorders have been excluded
It has been estimated that 2% of all cases of asthma in industrialized nations are occupationally related. In US surveys, 9% to 15% of adult asthma cases were classified as occupational in origin. The European Community Respiratory Health Survey Study Group reported the highest risk for asthma was in farmers (odds ratio, 2.62), painters (2.34), plastic workers (2.20), cleaners (1.97), and spray painters (1.96) (14). In one American study of WRA in California, Massachusetts, Michigan, and New Jersey, the most common industries where OA occurred were transportation manufacturing equipment (19.3%), health services (14.2%), and educational services (8.7%) (15).
MEDICOLEGAL ASPECTS Most sensitizing agents that have been reported to cause OA are proteins of plant, animal, or microbial derivation and are, therefore, not specifically regulated by OSHA. Some of the LMW sensitizers, such as isocyanates, anhydrides, and platinum, are regulated by OSHA; published standards for airborne exposure can be found in the Code of Federal Regulations (CFR 29.1927-1999) (16). OSHA, a division of the US Department of Labor, is responsible for determining and enforcing these legal standards. The National Institute of Occupational Health and Safety, a division of the US Department of 1252
Health and Human Services, is responsible for reviewing available research data on exposure to hazardous agents and providing recommendations to OSHA, but has no regulatory or enforcement authority. More than 400 different substances have been reported to act as respiratory sensitizers and causes of OA and OR, and new sensitizers continue to be reported (17). The Hazard Communication Standard, also called “worker right-to-know” legislation at the federal, state, and local levels, was passed in the United States about four decades ago (18). Substances that are capable of inducing respiratory sensitization are generally considered hazardous, and thus workers exposed to such substances are covered in most legislation. The common elements that exist in most hazard communication legislation are (a) that the employer apprise a governmental agency relative to its use of hazardous substances; (b) that the employer inform the employee of the availability of information on hazardous substances to which the employee is exposed; (c) that alphabetized material safety data sheets for hazardous substances in the workplace be available to the employee; (d) that there be labeling of containers of hazardous substances; and (e) that training be provided to employees relative to health hazards, methods of detection, and protective measures to be used in handling hazardous substances. This hazard communication legislation may make workers more aware of the potential that exists to develop respiratory sensitization and OR or OILD syndromes as a result of certain exposures. Legal and ethical aspects of management of individuals with OA are major problems. Guidelines for assessing impairment and disability from OA continue to evolve (19,20). The American Thoracic Society has proposed criteria based on a possible four points for each of the following: forced expiratory volume in 1 second, methacholine challenge, and medication. After totaling the points, the degree of impairment can be determined (20). Depending on the occupation, disability can then be assessed.
OCCUPATIONAL ASTHMA AND RHINITIS Pathophysiology The pathophysiology of asthma and rhinitis is reviewed in Chapters 19 and 26. The major pathophysiologic abnormalities of asthma, occupational, or otherwise, are bronchoconstriction, excess mucus production, and bronchial wall inflammatory infiltration, including activated T cells, mast cells, and eosinophils. Neutrophilic OA has also been described (21). There is evidence that these abnormalities may be at least in part explained by neurogenic mechanisms and 1253
release of inflammatory mediators and cytokines, such as interleukins and interferons. Type I hypersensitivity involving cross-linking of IgE on the surface of mast cells and basophils, resulting in release of mediators such as histamine and leukotrienes, is believed to be the triggering mechanism in most types of immediate-onset asthma and rhinitis. There is increasing evidence that cellular mechanisms are very important in asthma, especially in delayed types (21). An updated paradigm of the Gell and Coombs classification is improving our understanding of some of those cellular mechanisms (22). There are now four types of type IV, or cellular, mechanisms, including type IVa2, which involves TH2 cells and is probably responsible for late asthmatic responses.
Reaction Patterns A number of patterns of asthma may occur after a single inhalation challenge, as shown in Table 25.3 (3,4). The immediate reaction is mediated by IgE, occurs within minutes of challenge, presents as large airway obstruction, and is preventable with cromolyn and reversible by bronchodilators. The late response occurs several hours after inhalation challenge, presents as small airway obstruction in which wheezing may be mild and cough and dyspnea may predominate, lasts for several hours, is usually preventable with steroids (23) or cromolyn, and is only partly reversed by most bronchodilators. The dual response is a combination of the immediate and late asthmatic responses. It is partially prevented by steroids or bronchodilators. After a single challenge study with certain antigens like Western red cedar, the patient may have repetitive asthmatic responses occurring over several days. This repetitive asthmatic response can be reversed with bronchodilators. Other atypical patterns —square wave, progressive, and progressive and prolonged immediate—have been described after diisocyanate challenges; the mechanisms resulting in these patterns have not been elucidated (24).
Etiologic Agents Most of the 400 agents that have been described to cause OA and OR are HMW (>1 kDa) heterologous proteins of plant, animal, or microbial origin. LMW chemicals can act as irritants and aggravate preexisting asthma. They may also act as allergens if they are capable of haptenizing autologous proteins in the respiratory tract. Numerous reviews of OA have information on etiologic agents (25,26). A representative list of agents and industries associated with OILD can be found in Table 25.4. 1254
TABLE 25.3 TYPES OF INHALATION CHALLENGE
RESPIRATORY
RESPONSE
TO
ASTHMA
IMMEDIATE
LATE
REPETITIVE
Onset
10–20 min
4–6 h
Periodic after initial attack
Duration
1–2 h
2–6 h
Days
Abnormality
FEV1
FEV1
FEV1
Immune mechanism Type I (IgE)
Type IVa2
Type IVb CD8?
Symptoms
Wheezing
Wheezing, dyspnea
Recurrent wheezing
Therapy
Bronchodilators
Bronchodilators, corticosteroids
Bronchodilators
FEV1, forced expiratory volume in 1 second; IgE, immunoglobulin E; IgG, immunoglobulin G.
Etiologic Agents of Animal Origin Proteolytic enzymes are known to cause asthmatic symptoms on the basis of type I immediate hypersensitivity. Examples are pancreatic enzymes, hog trypsin used in the manufacture of plastic polymer resins, Bacillus subtilis enzymes (27) incorporated into laundry detergents, and subtilisin. Papain, which is a proteolytic enzyme of vegetable origin used in brewing beer and manufacturing meat tenderizer, has been noted to cause similar symptoms by IgE-mediated mechanisms (28). Several enzymes have been described as new causes of OA and OR: savinase, a genetically engineered amylase, and a microbial transglutaminase (17). TABLE 25.4 EXAMPLES OF OCCUPATIONAL ALLERGENS AGENT
INDUSTRIES AND OCCUPATIONS
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Animal Proteins
Proteolytic enzymes
Detergent industry; pharmaceutic industry; meat tenderizer manufacturing; beer clearing
Animal dander, saliva, urine
Lab researchers; veterinarians; grooms; breeders; pet shop owners; farmers
Avian protein
Poultry breeders; bird fanciers; egg processors
Insect scales
Beekeepers; insect control workers; bait handlers; mushroom workers; entomologists
Vegetable Proteins
Latex
Health care workers
Flour or contaminants (insects, molds)
Bakers
Green coffee beans, tea, garlic, other spices, soybeans
Workers in processing plants
Grain dust
Farmers; workers in processing plants
Castor beans
Fertilizer workers
Guar gum
Carpet manufacturing
Wood dusts: boxwood, mahogany, oak, redwood, Western red cedar
Carpenters; sawyers, wood pulp workers; foresters; cabinet makers
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Penicillium caseii
Cheese workers
Orris root, rice flour
Hairdressers
Thermophilic molds
Mushroom workers
Chemicals
Antibiotics
Hospital and pharmaceutic personnel
Other drugs; piperazine hydrochloride, α- Hospital and pharmaceutic personnel methyldopa, amprolium hydrochloride Platinum
Workers in processing plants; production of cisplatin
Nickel chromium, cobalt, and zinc
Workers using those metals
Anhydrides (TMA, PA, TCPA)
Workers in manufacture of curing agents, plasticizers, anticorrosive coatings
Azo dyes
Dye manufacturers
Ethylenediamine
Shellac and lacquer industry workers
Isocyanates
Production of paints, surface coatings, insulation polyurethane foam
Soldering fluxes, colophony
Welders
Chloramine-T
Sterilization
PA, phthalic anhydride; TCPA, tetrachlorophthalic anhydride; TMA, trimellitic anhydride.
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Animal dander can cause asthma in a variety of workers, including veterinarians, laboratory workers, grooms, shepherds, breeders, pet shop owners, farmers, and jockeys (3,4). This can even be a problem for people whose work takes them to homes of clients who have pets, such as real estate agents, interior designers, and domestic workers. Immediate asthmatic reactions and late interstitial responses have been reported after inhalation challenge with avian proteins in people who raise poultry and in workers exposed to egg products in egg processing facilities. Positive skin test results and in vitro IgE antibody have been demonstrated as well (3,4). A variety of insect scales have been associated with asthma. Occupational exposure to insect scales occurs in numerous circumstances (3,4). Bait handlers can become sensitized to mealworms used as fishing bait. Positive skin test results, in vitro IgE antibody, and positive inhalation challenges have been demonstrated to mealworms. Positive skin test results have been shown in various workers who have asthma upon insect exposure to screw worm flies in insect control personnel, to moths in fish bait workers, and to weevils in grain dust workers. Asthma has been reported in workers who crush oyster shells to remove the meat. On the basis of skin tests to various allergens, the authors determined that the allergen was actually the primitive organisms that attached to the oyster shell surface. Similarly, asthma may occur from sea squirt body fluids in workers who gather pearls and oysters and in snow crab workers (29). Etiologic Agents of Vegetable Origin In terms of plant protein antigens, exposure to latex antigens, particularly those dispersed by powder in exam gloves, has become an important cause of OA in the health care setting. People working in a number of other occupations, including seamstresses, may develop latex hypersensitivity (30). In the baking industry, flour proteins are well recognized to cause OA (31). Numerous other plant foodstuff proteins, including tea, garlic, coffee beans, spices, soybeans, vegetable gums, castor bean, guar gum, grain dust, wood dust, and dried flowers, have been described to cause OA (3,4). In addition to the plant-derived proteins enumerated above, a variety of microbial proteins have been reported to be sensitizing agents in OA, including those from Alternaria, Aspergillus, and Cladisporium species (3,4). Wood dust from Western red cedar is a well recognized cause of OA, but the antigen appears to be the LMW chemical, plicatic acid, not an HMW plant protein (32). 1258
Chemicals Asthma has been described in pharmaceutic workers and hospital personnel exposed to pharmacologic products. Numerous antibiotics, including ampicillin, penicillin, spiramycin, and sulfas (3,4), are known to cause asthma, positive skin test results, and/or specific IgE antibody. Other pharmaceutic, including amprolium hydrochloride, α-methyldopa, and piperazine hydrochloride, have been reported to cause asthma on an immunologic basis. Workers in platinum-processing plants may have rhinitis, conjunctivitis, and asthma (33). Positive bronchial challenges and specific IgE have been demonstrated in affected workers. Another metal, nickel sulfate, has also been reported to cause IgE-mediated asthma (34). Other metals reported to cause OA and OR include chromium, cobalt, vanadium, and zinc (3,4). The manufacture of epoxy resins requires a curing agent, usually an acid anhydride or a polyamine compound. Workers may thus be exposed to acid anhydrides in the manufacture of curing agents, plasticizers, and anticorrosive coating materials. Studies have reported that three different patterns of immunologic respiratory response may occur (Table 25.1). Initially, it was presumed that the antibody in affected workers was directed only against the trimellityl (TM) haptenic determinant. However, studies of antibody specificity have demonstrated that there is antibody directed against both hapten and TM–protein determinants that are considered new antigen determinants. Other acid anhydrides that have been described to cause similar respiratory hypersensitivity reactions include phthalic anhydride (PA), hexahydrophthalic anhydride (HHPA), and maleic anhydride (3,4). HHPA has also been described to cause hemorrhagic rhinitis via an immunologic mechanism (35). Isocyanates are required catalysts in the production of polyurethane foam, vehicle spray paint, and protective surface coatings. It is estimated that about 5% to 10% of isocyanate workers develop asthma from exposure to subtoxic levels after a variable period of latency (36). The isocyanates that have been described to cause OA include toluylene diisocyanate, hexamethylene diisocyanate, and diphenylmethyl diisocyanate (36). The histology of bronchial biopsy specimens from workers with isocyanate asthma appears very similar to that from patients with immunologic asthma and thus is suggestive of an immunologic mechanism. Compared with those isocyanate workers with negative bronchial challenges, workers with positive challenges have a higher prevalence and level of antibody against isocyanate–protein conjugates. However, in most studies, isocyanate 1259
workers with positive challenges did not have detectable specific IgE in their serum. In one study, it is speculated that some isocyanate asthma is mediated by IgE, but more than half is not (37). HP (38) and hemorrhagic pneumonitis (39) as a result of isocyanates have been reported to be caused by immunologic mechanisms. Formaldehyde, a respiratory irritant at ambient concentrations of 1 ppm or more, is sometimes cited as a cause of OA; however, documented instances of formaldehyde-induced IgE-mediated asthma are almost nonexistent (40). A bifunctional aldehyde, glutaraldehyde, has been reported to cause OA (41). Ethylenediamine, a chemical used in shellac and photographic developing industries, has been reported to cause OA and OR (42). Chloramine T (43), reactive azo dyes (44), and dimethyl ethanolamine are other chemicals that have also been reported to be causes of OA (45).
HYPERSENSITIVITY PNEUMONITIS The signs, symptoms, immunologic features, pulmonary function abnormalities, pathology, and laboratory findings of HP are reviewed in Chapter 23. No matter what the etiologic agent, the presentation follows one of three patterns. In the acute form, patients have fever, chills, chest tightness, dyspnea without wheezing, and nonproductive cough 4 to 8 hours after exposure. The acute form resolves within 24 hours. In the chronic form, which results from prolonged lowlevel exposure, patients have mild coughing, dyspnea, fatigue, pulmonary fibrosis, and weight loss. There is also a subacute form, which presents as a clinical syndrome of productive cough, malaise, myalgias, dyspnea, and nodular infiltrates on chest film. Any form can lead to severe pulmonary fibrosis with irreversible change; thus, it is important to recognize this disease early so that significant irreversible lung damage does not occur. A variety of organic dusts from fungal, bacterial, or serum protein sources in occupational settings have been identified as etiologic agents of HP (2) (Table 25.5). Several chemicals, including anhydrides and isocyanates, as discussed previously, have been reported to cause HP; others include organochlorine and carbamate pesticides (2).
DIAGNOSIS The diagnosis of OILD is not difficult in the individual worker if symptoms appear at the workplace shortly after exposure to a well-recognized antigen. However, the diagnosis can be challenging in patients whose symptoms occur 1260
many hours after exposure, for instance, late asthma from trimellitic anhydride. Because of the increasing importance of OILD, it has become essential to evaluate patients with respiratory syndromes for a possible association between their disease states, their pulmonary function test results, and their exposures in the work environment. In some cases, rhinoconjunctivitis precedes OA (46,47). In the case of a well-established OILD syndrome, a careful history and physical examination with corroborative immunology and spirometry will suffice (3). The history and physical examination findings in asthma, rhinitis, and HP are discussed in Chapters 19, 26, and 23. Immunologic evaluations may provide important information about the cause of the respiratory disease. Skin tests, with antigens determined to be present in the environment, may detect IgE antibodies and suggest a causal relationship (3). Haptens may be coupled to carrier proteins, such as human serum albumin, and used in skin tests (45) or immunoassays. In cases of HP, double gel immunodiffusion techniques may be used to determine the presence of precipitating antibody, which would indicate antibody production against antigens known to cause disease (2). It may be necessary to attempt to reproduce the clinical features of asthma or interstitial lung disease by bronchial challenge, followed by careful observation of the worker. Challenge may be conducted by natural exposure of the patient to the work environment with pre- and postexposure pulmonary functions, compared with similar studies on nonwork days. Another technique used for diagnosis of OILD is controlled bronchoprovocation in the laboratory with preand postexposure pulmonary function measurements (3,48). It is important that the intensity of exposure not exceed that ordinarily encountered on the job and that appropriate personnel and equipment be available to treat respiratory abnormalities that may occur. Some advocate the use of peak flow monitoring, whereas others find it less reliable (3). Evaluating induced sputum eosinophils has been reported to be a potentially useful technique to diagnose OA (49). TABLE 25.5 PNEUMONITIDES
OCCUPATIONAL
HYPERSENSITIVITY
DISEASE
EXPOSURE
SPECIFIC INHALANT
Farmer’s lung
Moldy hay
Saccharopolyspora rectivirgula Thermoactinomyces vulgaris
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Malt worker’s disease
Fungal spores
Aspergillus clavatus Aspergillus fumigatus
Maple-bark stripper’s disease
Moldy logs
Cryptostroma corticale
Wood pulp worker’s disease
Moldy logs
Alternaria and Rhizopus species
Sequoiosis
Moldy redwood sawdust Graphium species; Aureobasidium pullulans Moldy cork
Suberosis (cork worker’s lung)
Penicillium glabrum, Chrysonilia sitophila, A. fumigatus Humidifier/air conditioner disease Fungal spores
Thermophilic actinomycetes Naegleria gruberi
Bird breeder’s disease
Avian dust
Avian serum
Bagassosis
Moldy sugarcane
Thermoactinomyces vulgaris
Mushroom worker’s disease
Mushroom compost
S. rectivirgula T. vulgaris
Isocyanate disease
Isocyanates
Toluene diisocyanate Diphenylmethane diisocyanate
Metal worker’s lung
Contaminated metal working fluid
Mycobacterium immunogen
Cheese worker’s lung
Mold used in cheese production
Penicillium roqueforti
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If the analysis of OILD is not for an individual patient but rather for a group of workers afflicted with a respiratory illness, the approach is somewhat different. The initial approach to an epidemiologic evaluation of OILD is usually a cross-sectional survey using a well-designed questionnaire (50). The questionnaire should include a chronologic description of all past job exposures, symptoms, chemical exposures and levels, length of employment, and protective respiratory equipment used. Analysis of the survey can establish possible sources of exposure. All known information about the sources of exposure should be sought in the form of previously reported toxic or immunologic reactions. Ultimately, immunologic tests and challenges may be done selectively.
PROGNOSIS Unfortunately, many workers with OA do not completely recover, even though they have been removed from exposure to a sensitizing agent (4,51). Prognostic factors that been examined include specific IgE, duration of symptoms, pulmonary function testing, and nonspecific bronchial hyperreactivity (BHR). An unfavorable prognosis has been reported to be associated with a persistent high level of specific IgE, long duration of symptoms (>1 to 2 years), abnormal pulmonary function test results, and a high degree of BHR (51). The obvious conclusion from these studies is that early diagnosis and removal from exposure are requisites for the goal of complete recovery. In workers who remain exposed after a diagnosis of OA is made, further deterioration of lung function and increase in BHR have been reported (4). It must be appreciated that lifethreatening attacks and even deaths have been reported when exposure continued after diagnosis (3,4).
TREATMENT The management of OILD consists of controlling the worker’s exposure to the offending agent. This can be accomplished in various ways. Sometimes, the worker can be moved to another station; efficient dust and vapor extraction can be instituted; or the ventilation can be improved in other ways, so that a total job change is not required (52). Consultation with an industrial hygienist familiar with exposure levels may be helpful in this regard. It is important to remember that the levels of exposure below the legal limits that are based on toxicity may still cause immunologic reactions. Face masks of the filtering type are not especially efficient or well tolerated. Ideally, the working environment should be designed to limit the concentration of potential sensitizers to safe levels. Thus, avoidance may well entail retraining and reassigning an employee to another job 1263
(53). Pharmacologic management of OILD is rarely helpful in the presence of continued exposure. Certainly, in acute HP, a short course of oral corticosteroids is useful in conjunction with avoidance. However, chronic administration of steroids for occupational HP is not recommended. Asthma resulting from contact with occupational exposures responds to therapeutic agents, such as β-adrenergic receptor agonists, leukotriene modifiers, and inhaled and oral corticosteroids. As exposure continues, sensitivity may increase, thereby making medication requirements prohibitive. Immunotherapy has been used with various occupational allergens causing asthma, including treatment of laboratory animal workers, bakers, and oyster gatherers, with reported success. To date, there are no double-blind placebocontrolled trials. Immunotherapy may be feasible in rare cases, with certain occupational allergens of the same nature as the common inhalant allergens.
PREVENTION The key principle in OILD is that prevention, rather than treatment, must be the goal (54). Such preventative measures as improved ventilation and adhering to threshold limits, as discussed under section “Treatment,” would be helpful to this end. There should be efforts to educate individual workers and managers in highrisk industries so that affected workers can be recognized early. Currently, there are no preemployment screening criteria that have been shown to be useful in predicting the eventual appearance of OILD. There is conflicting evidence as to whether HLA studies are useful in predicting isocyanate asthma or anhydride asthma. It has been reported that atopy is a predisposing factor for a worker to develop IgE-mediated disease (46), but there is at least one conflicting study (55). Whether or not cigarette smoking is a risk factor for OILD is unclear. Prospective studies of acid anhydride workers, such as those of Zeiss et al. (56), Baur et al. (57), and Newman-Taylor et al. (58), have reported that serial immunologic studies are useful in predicting which workers are likely to develop immunologically mediated diseases. At the first sign of OA, those workers then could be removed from the offending exposure and retrained before permanent illness develops. Multiple studies have reported that decreasing the airborne levels will reduce disease prevalence (54). This appears to be the best approach to preventing OILD and OR. In one study, medical surveillance studies with cost–benefit analyses have been reported to reduce cases of permanent OA (59). 1264
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and other industrialized areas: a population-based study. Lancet. 1999;353:1750–1754. 15. Jajosky RA, Harrison R, Reinisch F, et al. Surveillance of work-related asthma in selected U.S. states using surveillance guidelines for state health departments—California, Massachusetts, Michigan, and New Jersey, 1993–1995. Morb Mortal Wkly Rep. 1999;48:1–20. 16. Office of the Federal Register National Archives and Records Administration. Code of Federal Regulations Title 29, Labor Subtitle B; Chapter XVII OSHA Parts 1927–1999. Washington, DC: Federal Register; 2015. 17. Cartier A. New causes of immunologic occupational asthma, 2012–2014. Curr Opin Allergy Clin Immunol. 2015;15(2):117–123. 18. Howard J. OSHA and the regulatory agencies. In: Rom WN, ed. Environ Occup Med. 3rd ed. Philadelphia, PA: Lippincott-Raven; 1998:1671–1679. 19. Rondinelli RD, ed. Guides to the Evaluation of Permanent Impairment. 6th ed. Chicago: American Medical Association, 2007. 20. Miller A. Guidelines for the evaluation of impairment/disability in patients with asthma. Am J Respir Crit Care Med. 1994;149:834–835. 21. Leigh R, Hargreave FE. Occupational neutrophilic asthma. Can Respir J. 1999;6:194–196. 22. Kay AB. Concepts of allergy and hypersensitivity. In: Kay AB, Bousquet J, Holt PG, Kaplan AP, eds. Allergy and Allergic Diseases. 2nd ed. Oxford: Wiley-Blackwell Science; 2008:23–35. 23. Boschetto P, Fabbri LM, Zocca E, et al. Prednisone inhibits late asthmatic reactions and airway inflammation induced by toluene diisocyanate in sensitized subjects. J Allergy Clin Immunol. 1987;80:261–267. 24. Malo JL, Tarlo SM, Sastre J, et al; ATS ad hoc committee on Asthma in the Workplace. An official American Thoracic Society Workshop Report: presentations and discussion of the fifth Jack Pepys Workshop on Asthma in the Workplace. Comparisons between asthma in the workplace and nonwork-related asthma. Ann Am Thorac Soc. 2015;12(7):S99–S110. 25. Vandenplas O, Dressel H, Nowak D, et al; ERS Task Force on the Management of Work-related Asthma. What is the optimal management option for occupational asthma? Eur Respir Rev. 2012;21(124):97–104. 1266
26. Maestrelli P, Schlünssen V, Mason P, et al; ERS Task Force on the Management of Work-related Asthma. Contribution of host factors and workplace exposure to the outcome of occupational asthma. Eur Respir Rev. 2012;21(124):88–96. 27. Lemiere C, Cartier A, Dolovich J, et al. Isolated late asthmatic reaction after exposure to a high-molecular-weight occupational agent, subtilisin. Chest. 1996;110:823–824. 28. Novey HS, Keenan WJ, Fairshter RD, et al. Pulmonary disease in workers exposed to papain: clinicophysiological and immunological studies. Clin Allergy. 1980;10:721–731. 29. Weytjens K, Cartier A, Malo J-L, et al. Aerosolized snow-crab allergens in a processing facility. Allergy. 1999;54:892–893. 30. Weytjens K, Labrecque M, Malo J-L, et al. Asthma to latex in a seamstress. Allergy. 1999;54:290–291. 31. Blanco Carmona JG, Juste Picon S, Garces Sotillos M. Occupational asthma in bakeries caused by sensitivity to alpha-amylase. Allergy. 1991;46:274–276. 32. Frew A, Chang JH, Chan H, et al. T lymphocyte responses to plicatic acidhuman serum albumin conjugates in occupational asthma caused by Western red cedar. J Allergy Clin Immunol. 1998;101:841–847. 33. Cromwell O, Pepys J, Parish WE, et al. Specific IgE antibodies to platinum salts in sensitized workers. Clin Allergy. 1979;9:109–117. 34. Malo J-L, Cartier A, Doepner M, et al. Occupational asthma caused by nickel sulfate. J Allergy Clin Immunol. 1982;69:55–59. 35. Grammer LC, Shaughnessy MA, Lowenthal M. Hemorrhagic rhinitis. An immunologic disease due to hexahydrophthalic anhydride. Chest. 1993;104(6):1792–1794. 36. Lefkowitz D, Pechter E, Fitzsimmons K, et al. Isocyanates and workrelated asthma: findings from California, Massachusetts, Michigan, and New Jersey, 1993–2008. Am J Ind Med. 2015;58(11):1138–1149. 37. Redlich CA, Bello D, Wisnewski AV. Isocyanate exposures and health effects. In: Rom WN, Markowitz SB, eds. Environmental and Occupational Medicine. 4th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2007:502–516. 1267
38. Walker CL, Grammer LC, Shaughnessy MA, et al. Diphenylmethan diisocyanate hypersensitivity pneumonitis: a serologic evaluation. J Occup Med. 1989;31:315–319. 39. Patterson R, Nugent KM, Harris KE, et al. Case reports: immunologic hemorrhagic pneumonia caused by isocyanates. Am Rev Respir Dis. 1990;141:225–230. 40. Dykewicz MS, Patterson R, Cugell DW, et al. Serum IgE and IgG to formaldehyde-human serum albumin: lack of relation to gaseous formaldehyde exposure and symptoms. J Allergy Clin Immunol. 1991;87:48–57. 41. Chan-Yeung M, McMurren T, Catonio-Begley F, et al. Clinical aspects of allergic disease: occupational asthma in a technologist exposed to glutaraldehyde. J Allergy Clin Immunol. 1993;91:974–978. 42. Lam S, Chan-Yeung M. Ethylenediamine-induced asthma. Am Rev Respir Dis. 1980;121:151–155. 43. Blasco A, Joral A, Fuente R, et al. Bronchial asthma due to sensitization to chloramine T. J Invest Allergol Clin Immunol. 1992;2:167–170. 44. Nilsson R, Nordlinder R, Wass U, et al. Asthma, rhinitis, and dermatitis in workers exposed to reactive dyes. Br J Ind Med. 1993;50:65–70. 45. Vallieres M, Cockcroft DW, Taylor DM, et al. Dimethyl ethanolamineinduced asthma. Am Rev Respir Dis. 1977;115:867–871. 46. Grammer LC, Ditto AM, Tripathi A, et al. Prevalence and onset of rhinitis and conjunctivitis in subjects with occupational asthma caused by trimellitic anhydride (TMA). J Occup Environ Med. 2002;44(12):1179– 1181. 47. Piirilä P, Estlander T, Hytönen M, et al. Rhinitis caused by ninhydrin develops into occupational asthma. Eur Respir J. 1997;10:1918–1921. 48. Tarlo SM. The role and interpretation of specific inhalation challenges in the diagnosis of occupational asthma. Can Respir J. 2015;22(6):322-323. 49. Vandenplas O, Ghezzo H, Munoz X, et al. What are the questionnaire items most useful in identifying subjects with occupational asthma? Eur Resp J. 2005;26:1056–1063. 50. Wilken D, Baur X, Barbinova L, et al; ERS Task Force on the Management of Work-related Asthma. What are the benefits of medical 1268
screening and surveillance? Eur Respir Rev. 2012;21(124):105–111. 51. Marabini A, Siracusa A, Stopponi, et al. Outcome of occupational asthma in patients:a 3-year study. Chest. 2003;124:2372–2376. 52. Merget R, Schulte A, Gebler A, et al. Outcome of occupational asthma due to platinum salts after transferral to low-exposure areas. Int Arch Occup Environ Health. 1999;72:33–39. 53. Vandeplas O, Dressel H, Wilken D, et al. Management of occupational asthma: cessation or reduction of exposure? A systematic review of available evidence. Eur Respir Rev. 2011;38:804–811. 54. Heederik D, Henneberger PK, Redlich CA; ERS Task Force on the Management of Work-related Asthma. Primary prevention: exposure reduction, skin exposure and respiratory protection. Eur Respir Rev. 2012;21(124):112–124. 55. Calverley AE, Rees D, Dowdeswell RJ. Allergy to complex salts of platinum in refinery workers: prospective evaluations of IgE and Phadiatop[SC] status. Clin Exp Allergy. 1999;29:703–711. 56. Zeiss CR, Wolkonsky P, Pruzansky JJ, et al. Clinical and immunologic evaluation of trimellitic anhydride workers in multiple industrial settings. J Allergy Clin Immunol. 1982;70:15–18. 57. Baur X, Stahlkopf H, Merget R. Prevention of occupational asthma including medical surveillance. Am J Ind Med. 1998;34:632–639. 58. Baker RD, van Tongeren MJ, Harris JM, et al. Risk factors for sensitization and respiratory symptoms among workers exposed to acid anhydrides: a cohort study. Occup Environ Med. 1998;55:684–691. 59. Phillips VL, Goodrich MA, Sullivan TJ. Health care worker disability due to latex allergy and asthma: a cost analysis. Am J Public Health. 1999;89:1024–1028.
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INTRODUCTION AND DEFINITIONS The clinical definition of allergic rhinitis (AR) is a symptomatic disorder of the nose induced by an immunoglobulin E (IgE)-mediated inflammatory reaction after allergen exposure of the membranes lining the nose (1). The symptoms that characterize the disorder are rhinorrhea, nasal congestion, sneezing, nasal pruritus, postnasal drainage, and, at times, pruritus of the eyes, ears, and throat. General symptoms such as fatigue, impaired concentration, and reduced productivity are also associated with AR. Previously, AR was subdivided, based on the time of exposure into either a seasonal or a perennial disorder. Perennial allergic rhinitis (PAR) is the most frequently caused by indoor allergens, such as dust mites, mold spores, animal dander, and cockroaches. Seasonal allergic rhinitis (SAR) is related to a wide variety of pollens and molds. However, it became evident that a new classification system was required because of several clinical observations (2): • In many areas of the world, pollens and molds are perennial allergens (e.g., the weed Parietaria pollen allergy in the Mediterranean area (3) and grass pollen allergy in southern California and Florida) (4). 1270
• Symptoms of PAR may not always be present throughout the year. • Many patients who are sensitive to pollen and also allergic to mold may have difficulty defining a pollen season (5). • The majority of patients are sensitized to several allergens and, therefore, manifest symptoms not only seasonally but throughout the year (6). The priming effect on the nasal mucosa induced by low levels of pollen allergens (7) and persistent inflammation of the nose in asymptomatic AR patients may result in rhinitis symptoms not confined to the specific allergy season (8). The 2012 AR and its Impact on Asthma workshop guidelines for the classification and treatment of AR (2) have led to the definitions of allergic nasal disease as intermittent or persistent, and mild or moderate-severe category (2). Intermittent rhinitis is defined on the basis of symptoms that are present for fewer than 4 days/week or fewer than 4 weeks (2). When symptoms are present for more than 4 days/week and are present for more than 4 weeks, it is defined as persistent rhinitis. Mild symptoms do not affect sleep, impair participation in daily activities, sports, and leisure, or interfere with work or school and are not considered bothersome (2). Conversely, moderate-severe symptoms result in abnormal sleep, interfere with daily activities, sports, and leisure, impair work and school activities, and are considered troublesome. Any one of the designators classifies AR into the moderate-severe category (2).
EPIDEMIOLOGY Although AR may have its onset at any age, the incidence of onset is greatest in children at adolescence, with a decrease in incidence seen in advancing age. It effects up to 60 million people in the United States annually. Up to 30% of adults and up to 40% of children self-report AR (9). Surveys which require a physician-confirmed diagnosis of AR report a 14% prevalence in US adults, 13% of children, 7% of Latin American adults, and 9% of Asian-Pacific adults (10). Although it has been reported in infants (10), in most cases, an individual requires two or more seasons of exposure to a new antigen before exhibiting the clinical manifestations of AR. Children with a bilateral family history of atopy may develop symptoms more frequently and at a younger age than those with a unilateral family history (11,12). Infants born to atopic families are sensitized to pollen aeroallergens more frequently than indoor aeroallergens in the first year of life (13).
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The prevalence of SAR is higher in children and adolescents, whereas PAR has a higher prevalence in adults (14). Older children have a higher prevalence of AR than younger ones, with a peak occurring in children aged 13 to 14 years. Approximately 80% of individuals diagnosed with AR will develop symptoms before the age of 20 years (15). Boys tend to have an increased incidence of AR in childhood, but females are more commonly affected in adulthood. Epidemiology studies suggest that the prevalence of AR in the United States and around the world is increasing and more than 40% in many populations in the United States and Europe (16). However, accurate estimates of AR are difficult to obtain secondary to variability of geographic pollen counts, misinterpretation of symptoms by patients, and inability of the patient and physician to recognize the disorder. Climate change has resulted in a change in the duration of allergy seasons and the geographic pollen counts during different seasons. Although there is an increased prevalence of AR, the cause for this increase is unknown. Risk factors associated with development of AR include family history, (17) higher socioeconomic status (18), atmospheric pollution (19), ethnicity other than white (20), late entry into daycare (21), lack of other siblings (22), birth during a pollen season (23), heavy maternal smoking during the first year of life (24), exposure to high concentrations of indoor allergens, such as mold spores, dust mites, and animal dander (25), higher serum IgE (>100 IU/mL before the age of 6 years) (24), the presence of positive allergen skinprick tests (26), early introduction of foods or formula (24), and a trend toward sedentary lifestyles (27).
Burden of Disease According to 1997 survey data from primary care physicians, there were 16.9 million office visits for symptoms suggestive of AR (28). In 2000, more than $6 billion was spent on prescription medications for this condition, and over-thecounter medications were at least twice that amount (29). Compared with matched controls, patients with AR have an approximately twofold increase in medication costs and a 1.8-fold increase in the number of visits to a health care practitioner (30). In Europe, the total societal cost of persistent AR and its comorbidities in 2002 were estimated at €355.05 per patient month (31). Employer and societal costs may be substantially reduced with appropriate therapy of AR. Unfortunately, the lack of treatment, undertreatment, and nonadherence to treatment has been shown to increase direct and indirect costs (32). In addition to the characteristic nasal and ocular symptoms of AR, patients can experience fatigue, headache, disrupted sleep patterns, and declines in 1272
cognitive processing, psychomotor speed, verbal learning, and memory (33). Hidden direct costs include the treatment of asthma, upper respiratory infection, chronic sinusitis, otitis media, nasal polyposis, and obstructive sleep apnea (34). Surveys report that 38% of patients with AR have coexisting asthma, and as many as 78% of patients with asthma also have AR (35). Asthma and AR are often thought of as conditions that characterize different points on a continuum of inflammation within one common airway (36). Evidence suggests a common pathophysiology for these allergen-induced disorders and supports the observation that treatment of AR reduces the incidence and severity of asthma (37). Asthma patients with AR experience incomplete asthma control and have higher medical resource use, including acute asthma exacerbations, emergency department visits, unscheduled physician office visits, and prescription medication use when compared to asthma patients without concomitant AR (38–40). Allergy has been linked as a contributing factor in 40% to 80% of cases of chronic rhinosinusitis (41). Approximately 21% of children with nasal allergies experience otitis media with effusion (OME). Children with an OME have a 35% to 50% incidence of allergy (42,43). In patients with AR, an allergen challenge induces expression of intercellular adhesion molecule 1 (ICAM-1), the receptor for 90% of human rhinoviruses (41), thus increasing the susceptibility for an upper respiratory infection. In turn, rhinovirus can accentuate the pattern of airway reactivity in patients with AR (44). Although the link between AR and nasal polyps does not appear to be causal, the recurrence rate of nasal polyps in patients with AR is higher than for patients who are nonallergic (45). The indirect costs of AR, such as absenteeism and presenteeism (decreased productivity while at work), are also substantial. AR results in impaired productivity and/or missed work in 52% of patients (46). In a survey of 8,267 US employees, 55% experienced AR symptoms for an average of 52.5 days, were absent from work for 3.6 days/year because of their condition, and were unproductive 2.3 hours/work day when experiencing symptoms. The mean total productivity (absenteeism and presenteeism) losses were $593 per employee per year (47). In total, AR results in an estimated 3.5 million lost work days and 2 million lost school days (32). Approximately 10,000 children are absent from school on any given day secondary to AR (32). Depending on a child’s age, absence from school may also affect parents’ productivity or absence from work. The impact of AR on patient-perceived health status is substantial. When compared to patients without AR, nearly twice as many AR patients rated their health as only fair/poor/very poor. Almost twice as many patients with AR compared with adults without nasal allergies say that their health limited them in 1273
daytime physical indoor activities and outdoor activities (48). In one Spanish study, the negative impact on daily activities for patients with AR was greater than for patients with type 2 diabetes mellitus and hypertension (49). Patient evaluations of disease severity have shown that patients rate their disease more persistent and severe than physicians (50). Quality of life surveys have evaluated the impairment secondary to AR. In the Medical Outcomes Study Short-Form Health Survey, of 36 items administered to patients with AR and asthma (51), patients with AR had similar impairment with asthma when evaluating energy/fatigue, general health perception, physical role limitations as well as emotional role limitations—mental health, pain, and change in health. Patients with AR actually had significantly lower scores than asthma patients in the area of social functioning. These surveys clearly demonstrate the overall morbidity of the disorder, and therefore, the symptoms of these patients should not be trivialized.
GENETICS The development of AR entails a complex interaction between environmental exposure and genetic predisposition to implicated allergens. The hereditary nature of AR and other atopic diseases has been frequently demonstrated in families and twins (52). In a series of 8,633 of 5-year old twins in which the prevalence of rhinitis was 4.4%, there was a 93% correlation in full-term monozygotic twins and a 53% correlation in dizygotic twins having rhinitis. Atopy has also been linked to multiple genetic loci on chromosomes 2, 5, 6, 7, 11, 13, 16, and 20 (53). More recent genomic searches have shown a close association of AR involving chromosomes 2, 3, 4, and 9 (Table 26.1) (54–60). Risk factors for SAR include male sex, atopic parents with SAR, first-born child, early sensitization to food, and atopic dermatitis (61). A family history is a major risk factor for AR. In a study by Tang et al. (62), the development of atopic disease in the absence of parental family history was only present in 17%, whereas the risk increased to 29% when one parent or sibling was atopic. When both parents were atopic, the risk for developing an atopic disorder was 47% in the next generation. Studies have also shown that single nucleotide polymorphisms (SNPs), variations in DNA sequence seen in over 1% of the population that result from a single base change, have also been implicated in the pathogenesis of AR. Genome-wide association studies use reduced sets of SNPs to allow genotyping across the genome. These SNPs are then associated with the phenotype in AR in either a family-based or a case–control study design (63). Many of these SNP studies have been carried out in Asian populations, 1274
especially in Korea and Japan. SNPs have been reported in molecules, including chemokines and their receptors; interleukins and their receptors; angiotensinconverting enzyme inhibitor and angiotensinogen genes; and eosinophil peroxidase and leukotrienes (60). A number of studies have also investigated polymorphisms in different genes. Polymorphisms in the CD14 gene have been associated with the severity of AR (64). Different polymorphisms of ADAM33 have been correlated to Japanese cedar pollinosis (65). Additionally, polymorphisms and haplotypes of FOXJ1 and the FcgRIIa gene have been associated with AR (66,67). In European-pooled analyses, SNPs within the tolllike receptor 4 (TLR-4) and tumor-necrosis factor (TNF) genes may increase the risk of AR in children (61). Furthermore, a large European study identified chromosome 11 open reading frame 30 (C11orf30) as a genome-wide significant locus for AR. A meta-analysis of genome-wide association studies with cat, dust mite and pollen allergies among Europeans identified 16 shared susceptibility loci, of which eight have been previously associated with asthma (63). TABLE 26.1 GENOMIC SEARCHES CONDUCTED IN ALLERGIC RHINITIS ASSOCIATED REGIONS
CHROMOSOMAL
POPULATION
SAMPLE
Danish
424 individuals from 100 families, Principal association: 4q24-q27. of which selection was made of 33 Other candidate regions: 2q12families with at least two siblings q33, 3q13, 4p15-q12, 5q13-q15, diagnosed with AR 6p24-p23, 12p13, 22q13, y Xp21
Japanese
48 Japanese families (188 members) with at least two siblings with AR due to Dactilys glomerata
1p36.2, 4q13.3 y 9q34.3 Weak linkage to 5q33.1
Danish
424 individuals from 100 families Region 4q32.2
French
295 families with at least one asthmatic
Swedish
250 families initially included in Most intense association: 3q13, an atopic dermatitis linkage study 4q34-35 y 18q12
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2q32, 3p24-p14, 9p22 and 9q22q34 with RA 1p31 p with asthma and AR
Weakest association: 6p22-24, 9p11-q12, 9q33.2-34.3 y 17q11.2 Danish
Three independent populations 3q13.31 with a total of 236 families, including 125 sibling couples with rhinitis
AR, allergic rhinitis. Adapted from Dávila I, Mullol J, Ferrer M, et al. Genetic aspects of allergic rhinitis. J Investig Allergol Clin Immunol. 2009;19(1):25–31.
Genetics alone cannot explain the increasing prevalence of AR, and this highlights the importance of environmental factors and epigenetic mechanisms in the pathology of AR (68). Epigenetics is the study of potentially heritable changes in gene expression that does not involve changes to the underlying DNA sequence. It may involve processes such as histone acetylation or DNA methylation which alters mRNA expression, modifies chromatin structure, and may either facilitate or prevent binding of transcription factors to promoter regions. DNA methylation may be a useful biomarker for phenotyping of AR and has useful diagnostic potential because it is more stable and easier to measure than mRNA and proteins (68). One study suggests the beneficial effects of allergen immunotherapy may be because of reduced DNA methylation of the FoxP3 promoter region in regulatory T cells. Additionally, several mouse model studies of SAR demonstrated DNA methylation changes expressed in CD4+ T cells (69). Gene–environment interaction may also play a role in the epidemic rise of allergic diseases. One theory that has garnered much worldwide attention using gene expression measurements is the hygiene hypothesis which states that environmental exposures to high levels of microbial components, such as seen in traditional farms, may prevent sensitization to inhalant allergens and development of allergic diseases by upregulating expression of TLRs as well as regulatory cytokines, such as interleukin 10 (IL-10) and transforming growth factor β (70,71). Additionally, there is evidence that protection of AR from farm exposures could be effective during pregnancy. Pregnant women exposed to farm stables have an increased expression of receptors involved in innate immunity, including TLR-2, TLR-4, and CD14 (72).
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Pollen and mold spores are the allergens responsible for intermittent AR or SAR; Chapters 6 and 7 discuss the importance of these seasonal allergens in detail. Occasionally, PAR may be the result of exposure to an occupational allergen. Symptoms tend to be perennial but not constant because there is a clear, temporal association with workplace exposure. Some causes of occupational rhinitis include laboratory animals (rats, mice, guinea pigs, etc.), grains (bakers and agricultural workers), medications such as psyllium or penicillium, wood dust, particularly hard woods (mahogany, Western red cedar, etc.), latex, and chemicals (acid anhydrides, platinum salts, glues, and solvents) (73). Occupational immunologic diseases, including rhinitis, are discussed in detail in Chapter 25. Although some clinicians believe that food allergens may be significant factors in the cause of persistent AR, a direct immunologic relationship between ingested foods and persistent rhinitis symptoms has been difficult to establish. Rarely, hypersensitivity to dietary proteins may induce the symptoms of nonSAR. Double-blind food challenges almost never confirm such reactions (74). Cow’s milk is often the food suspected of precipitating or aggravating upper respiratory symptoms. Usually, however, the overwhelming majority of patients with proven food allergies do not have isolated nasal symptoms; instead, they exhibit other symptoms, including gastrointestinal disturbances, urticaria, angioedema, asthma, and anaphylaxis, in addition to rhinitis, after ingestion of the specific food. Cross-reactive allergens between food and inhalant allergens are common. Patients with AR owing to birch and, to a lesser extent, other Betulaceae (hazel, alder) pollen frequently develop oral allergic symptoms to tree nuts, fruits, and vegetables, including apples, carrots, celery, and potatoes (75). Most patients develop mild symptoms, but anaphylaxis may occur very rarely from these cross-reacting foods. Some birch or hazel pollen allergens cross-react with those of fresh apples, especially those located just beneath the skin. Baked apples are tolerated as apple sauce (76). Ragweed-sensitive individuals may experience symptoms when eating banana or melon. Latex-sensitive individuals may develop symptoms when ingesting avocado, banana, chestnut, kiwi fruit, or other foods (77). Nonspecific irritants and infections may influence the course of persistent (perennial) AR. Children with this condition appear to have a higher incidence of respiratory infections that tend to aggravate the condition and may lead to the development of complications. Irritants such as pool chlorine, glues, hairsprays, laundry detergent, perfumes, tobacco smoke, and air pollutants (sulfur dioxide, volatile organic compounds, particulate matter, ozone, diesel 1277
exhaust particles, and nitrogen dioxide) can aggravate the symptoms (78). Cold drafts, chilling, and sudden changes in ambient temperature are also implicated in symptom exacerbation, and these features indicate that the patient has concurrent nonallergic rhinitis (NAR).
CLINICAL FEATURES The major symptoms of AR are sneezing, rhinorrhea, nasal pruritus, and nasal congestion, although patients may not have the entire symptom complex. When taking a history, one should record the specific characteristics of the symptoms, as follows: • Define the onset and duration of symptoms and emphasize any relationship to seasons or life events, such as changing residence or occupation, or acquiring a new pet. • Define the current symptoms, including secretions, degree of congestion, sneezing, and nasal itching, or sinus pressure and pain. Obtain a history regarding ocular symptoms, such as itching, lacrimation, puffiness, and chemosis; pharyngeal symptoms of a mild sore throat, throat clearing, and itching of the palate and throat; and associated systemic symptoms of malaise, fatigue, or sleep disturbances. • Identify exacerbating factors, such as seasonal or perennial allergens and nonspecific irritants (e.g., cigarette smoke, illicit drug use, chemical fumes, cold air, etc.). • Identify other associated allergic diseases, such as asthma or atopic dermatitis, or a family history of allergic diathesis. • Obtain a complete medication history, including both prescription and overthe-counter medications. Drug history is important because several medications can provoke or exacerbate rhinitis symptoms. These include antihypertensive medications, aspirin, or other nonsteroidal anti-inflammatory drugs (NSAIDs) oral contraceptives, and in particular, topical sympathomimetics/nasal decongestants which can provoke rhinitis medicamentosa (RM) if used for extended periods of time without the use of intranasal corticosteroids (79,80). Obtain a careful occupational history. The occupational history may be relevant either as a direct cause of AR or because of workplace triggers that exacerbate preexisting rhinitis (81). It is important to recognize occupational rhinitis because it usually precedes the development of occupational asthma, and 1278
therefore, these patients should be more closely monitored to prevent the development of occupational asthma. Professions most at risk for occupational asthma include bakers, furriers, and animal laboratory workers (82). Identify patients with pollen-food syndrome or oral allergy syndrome. Patients with AR can develop oral symptoms to raw fruits and vegetables. It is characterized by an immediate, IgE reaction induced by prior sensitization to pollen rather than primary sensitization to a food allergen. Cross-reactivity depends on specific epitopes shared by food allergens and pollen (83). Sneezing is the most characteristic symptom, and occasionally, one may have paroxysms of 10 to 20 sneezes in rapid succession. Sneezing episodes may arise without warning, or they may be preceded by an uncomfortable itching or irritated feeling in the nose. Sneezing attacks result in tearing of the eyes because of activation of the nasal-lacrimal reflex. During the pollen season, nonspecific factors, such as particulate exposure, sudden drafts, air pollutants, or noxious irritants, may also trigger violent sneezing episodes. The rhinorrhea is typically a thin discharge, which may be quite profuse and continuous. Because of the copious nature of the rhinorrhea, the skin covering the external nose and the upper lip may become irritated and tender. Purulent discharge is never seen in uncomplicated AR, and its presence usually indicates secondary infection. Nasal congestion resulting from swollen turbinates is a frequent complaint. Early in the season, the nasal obstruction may be more troublesome in the evening and at night, only to become almost continuous as the season progresses. If the nasal obstruction is severe, interference with aeration and drainage of the paranasal sinuses or the eustachian tube may occur, resulting in complaints of headache or earache. The headache is of the so-called vacuum type, presumably caused by the development of negative pressure when air is absorbed from the obstructive sinus or middle ear. Patients also complain that their hearing is decreased and that sounds seem muffled. Patients may also notice a crackling sensation in the ears, especially when swallowing. Nasal congestion alone, particularly in children, occasionally may be the major or sole complaint. With continuous severe nasal congestion, the senses of smell and taste may be lost. Itching of the nose may also be a prominent feature, inducing frequent rubbing of the nose, particularly in children. Eye symptoms (pruritus, erythema, and lacrimation) often accompany the nasal symptoms. Patients with severe eye symptoms often complain of photophobia, inability to wear contact lenses, and sore, tired eyes. Conjunctival injection and chemosis often occur. There is marked itching of the ears, palate, throat, or face, which may be extremely annoying. Because of irritating sensations in the throat and the posterior drainage of the nasal 1279
secretions, a hacking, nonproductive cough may be present. Lower respiratory tract symptoms, including cough, wheeze, and exertional dyspnea, may be associated with AR even in the absence of overt asthma. Bronchial hyperreactivity can be induced by changes in histamine/methacholine bronchial provocation doses after seasonal allergy exposure in atopic patients (84). Disorders of the upper and lower respiratory tract often coexist; most asthmatics have rhinitis or rhinosinusitis (85), whereas a significant minority of individuals with AR have coexistent asthma (86). Rhinitis/rhinosinusitis may impair asthma control and should always be considered in the assessment of patients with poorly controlled asthma (87). Some patients have systemic symptoms of SAR. Complaints may include weakness, malaise, irritability, fatigue, and anorexia. Certain patients relate that nausea, abdominal discomfort, and poor appetite appear to occur with swallowing excess mucous. A characteristic feature of the symptom complex is the periodicity of its appearance. Symptoms usually recur each year for many years in relation to the duration of the pollinating season of the causative plant. The most sensitive patients exhibit symptoms early in the season, almost as soon as the pollen appears in the air. The intensity of the symptoms tends to follow the course of pollination, becoming more severe when the pollen concentration is highest and waning as the season ends, when the amount of pollen in the air decreases. In some patients, symptoms disappear suddenly when the pollination season is over, whereas in others, symptoms may disappear gradually over a period of 2 to 3 weeks after the pollination season is completed. There may be an increased reactivity of the nasal mucosa after repeated exposure to the pollen. This local and nonspecific increased reactivity has been termed the priming effect (88). Under experimental conditions, a patient may respond to an allergen, not otherwise considered clinically significant if they were not exposed or primed to a clinically significant allergen. The nonspecificity of this effect may account for the presence of symptoms in some patients beyond the termination of the pollinating season because an allergen not clinically important by itself may induce symptoms in the primed nose. For example, a patient with positive skin tests to mold antigens and ragweed and no symptoms until August may have symptoms until late October, after the ragweed-pollinating season is over. The symptoms persist because of the presence of molds in the air, which affect the primed mucous membrane. In most patients, however, this does not appear to occur (89). The presence of a secondary infection or the effects of nonspecific irritants on inflamed nasal membranes may also prolong and influence the 1280
degree of rhinitis symptoms beyond the specific pollinating season. Some nonspecific irritants include tobacco smoke, paints, newspaper ink, and laundry soap/detergent. Rapid atmospheric changes may aggravate symptoms in predisposed patients. Nonspecific air pollutants may also potentiate the symptoms of AR, such as sulfur dioxide, ozone, carbon monoxide, and nitrogen dioxide. These symptoms of AR may exhibit periodicity within the season. Many patients tend to have more intense symptoms in the morning because most windborne pollen is released in greatest numbers between sunrise and 9:00 AM. Some specific factors such as rain may decrease symptoms of rhinitis because rain can clear pollen from the air. Also, dry windy days may increase symptoms because higher concentrations of pollen may be distributed over larger areas. The symptoms of PAR are similar to seasonal rhinitis. The decreased severity of symptoms seen in some patients may lead them to interpret their symptoms as resulting from sinus trouble or frequent colds. Nasal congestion may be the dominant symptom, particularly in children, in whom the passageways are relatively small. Sneezing, clear rhinorrhea, and itching of the eyes, ear, nose, and throat accompanied by lacrimation may also occur. The presence of itching in the nasopharyngeal and ocular areas is consistent with an allergic cause of the chronic rhinitis. The chronic nasal obstruction may cause mouth breathing, snoring, almost constant sniffing, and a nasal twang to the voice. The obstruction may worsen or be responsible for the development of obstructive sleep apnea. Because of the constant mouth breathing, patients may complain of a dry, irritated, or sore throat. Anosmia may occur in patients with marked chronic nasal obstruction. Protracted sneezing episodes on awakening or in the early morning hours are a complaint. Because the chronic edema involves the opening of the eustachian tube and the paranasal sinuses, dull frontal headaches and ear symptoms, such as decreased hearing, fullness, and popping of the ears are common. In children, there may be recurrent episodes of serous otitis media. Chronic nasal obstruction may lead to eustachian tube dysfunction. Persistent, low-grade nasal pruritus leads to almost constant rubbing of the nose and nasal twitching. In children, recurrent epistaxis may occur because of the friability of the mucous membranes, sneezing episodes, forceful nose blowing, or nose picking. After exposure to significant levels of an allergen, such as close contact with a pet or when dusting the house, the symptoms may be as severe as in the acute stages of SAR. Constant, excessive postnasal drainage of secretions may be associated with a chronic cough or a continual clearing of the throat.
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Physical Examination Most abnormal physical findings are present during the acute stages of disease, whether patients are having PAR or SAR. The physical findings commonly recognized include: • Nasal obstruction and associated mouth breathing. • Pale to bluish nasal mucosa and enlarged (boggy) inferior turbinates. • Clear nasal secretions (whitish secretions may be seen in patients experiencing severe AR). • Clear or white secretions along the posterior wall of the nasopharynx. • Conjunctival erythema, lacrimation, and puffiness of the eyes. The physical findings, which are usually confined to the nose, ears, and eyes, aid in the diagnosis. Rubbing of the nose and mouth breathing are common findings. Some children will rub the nose in an upward and outward direction, which has been termed the allergic salute. The eyes may exhibit excessive lacrimation. The sclera and conjunctivae may be reddened, and chemosis is often present. The conjunctivae may be swollen and may appear granular, and the eyelids are often swollen. The skin above the nose may be reddened and irritated because of the continuous rubbing and blowing. Examination of the nasal cavity discloses a pale, wet, edematous mucosa, frequently bluish in color. A clear, thin nasal secretion may be seen within the nasal cavity. Swollen turbinates may completely occlude the nasal passageway and severely affect the patient. Occasionally, there is fluid in the middle ear, resulting in decreased hearing. The pharynx may have streaks of lymphoid tissue, sometimes called “cobblestoning” because of the appearance. The nose and eye examination is normal during asymptomatic intervals in those with SAR. In patients with PAR, the physical examination may aid in the diagnosis, particularly in a child, who may constantly rub his nose or eyes. These include a gaping appearance because of the constant mouth breathing, and a broadening of the midsection of the nose. There may be a transverse nasal crease across the lower third of the nose where the soft cartilaginous portion meets the rigid bony bridge. This is the result of the continual rubbing and pushing of the nose to relieve itching. The mucous membranes are pale, moist, and boggy, and may have a bluish tinge. The nasal secretions are usually clear and watery, but may be more mucoid and microscopically may show large numbers of eosinophils. Dark circles under the eyes, known as allergic shiners, appear in some children. These 1282
are presumed to be due to venous stasis secondary to constant nasal congestion. The conjunctiva may be injected or may appear granular. In children affected with PAR early in life, narrowing of the arch of the palate may occur. These children may develop facial deformities, such as dental malocclusion or gingival hypertrophy. The throat is usually normal on examination, although the posterior pharyngeal wall may exhibit prominent lymphoid follicles.
PATHOPHYSIOLOGY The nose has the following six major functions: an olfactory organ, a resonator for phonation, a passageway for airflow in and out of the lungs, a means of humidifying and warming inspired air, a filter of noxious particles from inspired air, and a part of the immunologic responses of the nose and sinuses (90,91). Allergic reactions in the nasal mucous membranes may markedly affect the nose’s major functions. AR is an IgE-mediated disease characterized by an eosinophilic inflammatory response with manifestations of nasal congestion, rhinitis, pruritus, and sneezing in response to inhaled allergens in a previously sensitized subject (92–94). Symptoms normally involve an early phase that clears within 1 to 2 hours, followed by a late phase that may last up to 12 to 24 hours (95). IgE antibodies bind to high-affinity receptors (FcεRI) on mast cells and basophils and to low-affinity receptors (FcεRII or CD23) on other cells, such as monocytes, eosinophils, B cells, and platelets (91). Upon exposure of the allergen into the respiratory tract, the allergen is first internalized by antigenpresenting cells (APCs), which include macrophages, CD1+ dendritic cells, B lymphocytes, and epithelial cells (96). After the allergen is taken up by the APC, it is then processed to a small peptide that binds to specific major histocompatibility complex (MHC) class II molecules via CD4+ T lymphocytes (97). Nasal allergen provocation has been associated with increased HLA-DR and HLA-DQ (these are αβ heterodimers of class II MHC molecules that function as cell surface receptor proteins on antigen presenting cells) positive cells in the lamina propria and epithelium in allergic subjects (98). The MHC class II–peptide complex is then expressed on the cell surface where it is recognized by the TH0 receptor and other co-stimulatory molecules, resulting in differentiation into TH2 CD4+ lymphocytes that produce cytokines like IL-4, IL5, and IL-13. This is the crucial early event in allergic sensitization and the key to the development of allergic inflammation via TH2 induction. Anergy of the TH2 differentiation pathway may occur if there is a lack of a second cell-to-cell 1283
contact between CD80 or CD86 on APCs and CD28 on T cells (99). After IgE antibodies specific for a certain allergen are synthesized and secreted, they bind to high-affinity FcεRI IgE receptors on the surface of mast cells. Mast cells are abundant in the epithelial compartment of the nasal mucosa in AR subjects and may be easily activated upon re-exposure to the allergen. On nasal re-exposure to allergen, the allergen cross-links the specific cell-bound IgE antibodies on the mast cell surface in a calcium-dependent process, resulting in mast cell degranulation and release of a number of preformed and newly synthesized mediators of inflammation. These mediators include histamine, leukotrienes, prostaglandins, proteases, proteoglycans, platelet-activating factor, bradykinin, cytokines, and chemokines (91). These mediators are responsible for mast cell–mediated allergic reactions, resulting in immediate-type rhinitis symptoms, including edema, increased vascular permeability, and nasal discharge. Histamine, the major mediator of AR, stimulates the secretion of mucus and nasal discharge, as well as the sensory nerve endings of the trigeminal nerve to induce sneezing and pruritus. Histamine, leukotrienes, and prostaglandins may also act on blood vessels and cause nasal congestion (91). The normal nasal submucosa contains approximately 7,000/mm3 mast cells, but only 50/mm3 mast cells are in the nasal epithelium (91). However, the superficial nasal epithelium contains 50-fold more mast cells and basophils in AR compared to NAR subjects (100). Nasal mast cells are predominantly connective tissue mast cells located in the nasal lamina propria, although 15% are epithelial mucosal mast cells. Mucosal mast cells express tryptase without chymase and may proliferate in AR under the influence of TH2 cytokines. Mast cells and their mediators are important components of the early-phase response given mast cell degranulation in the nasal mucosa and detection of histamine, leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) in nasal washings (91). Additionally, the early-phase response may also be associated with an increase in neuropeptides such as calcitonin gene-related peptide (cGRP), substance P, vasoactive intestinal peptide (VIP) and increasing numbers of cytokines, including IL-1, IL-3, IL-4, IL-5, IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF), and TNF-α (101–105). These mast cell– derived cytokines promote further IgE production and mast cell and eosinophil growth, survival, and chemotaxis. IL-1, IL-5, and TNF-α promote eosinophil movement by increasing the expression of endothelial adhesion molecules. Eosinophils may secrete a plethora of cytokines, including IL-3, IL-4, IL-5, IL10, and GM-CSF, resulting in mast cell growth and TH2 proliferation. 1284
Eosinophils may also act in an autocrine manner and produce IL-3, IL-5, and GM-CSF that are important in hematopoiesis, differentiation, and survival of eosinophils (91). There is an accumulation of CD4+ lymphocytes, eosinophils, neutrophils, and basophils during an allergic inflammatory process (106). Eosinophils release oxygen-free radicals and proteins, including eosinophil major basic protein, eosinophil cationic protein (ECP), and eosinophil peroxidases, which may disrupt the respiratory epithelium and promote further mast cell mediator release and hyperresponsiveness (107,108). Eosinophils also increase during seasonal exposure, and the number of eosinophil progenitors in the nasal scrapings increases after exposure to allergens, thus correlating with the severity of seasonal disease. Almost 4 to 6 hours after allergen stimulation, the early-phase may be followed by the late-phase response which may last anywhere from 18 to 24 hours. The late-phase response is characterized by a prolongation of sneezing, rhinorrhea, and a sustained nasal congestion. The late-phase response may also trigger a systemic inflammation that may augment inflammation in the upper and lower airways, suggesting a link to asthma. The late-phase response is characterized by infiltration of T lymphocytes, basophils, eosinophils, and neutrophils in the nasal submucosa. In those who undergo nasal challenge, the late-phase reaction occurs in greater than 50% of AR subjects (91). Unlike the early-phase response, PGD2 and tryptase are not detected in the late-phase response. The absence of these mediators during the late-phase response is consistent with basophil-derived histamine release rather than mast cell involvement. Basophils are significantly increased in nasal lavage fluid 3 to 11 hours after allergen challenge, suggesting their role in late-phase reactions (109).
LABORATORY FINDINGS The diagnosis of AR is based on both clinical history and diagnostic studies. In vitro allergen-specific IgE (sIgE) testing is advantageous in a number of clinical settings where skin-prick testing cannot be performed, such as urticaria with dermatographism, severe eczema/allergic contact dermatitis (making interpretation challenging), or use of medications, such as histamine1/histamine-2 antagonists, tricyclic antidepressants, or β-blockers. It may also be advantageous to perform in vitro testing in infants and young children. There is no risk of anaphylaxis with in vitro testing. Conversely, in vitro testing offers a lower sensitivity as compared to skin-prick testing at a higher cost, and the results are not readily available to both the clinician and the patient.
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In chronic rhinitis, the presence of large numbers of eosinophils suggests an allergic cause, although NAR with eosinophilia syndrome (NARES) certainly occurs. The absence of nasal eosinophilia does not exclude an allergic cause, especially if the test is performed during a relatively quiescent period of the disease, or in the presence of bacterial infection when large numbers of polymorphonuclear neutrophils obscure the eosinophils. Peripheral blood eosinophilia of (absolute eosinophil count > 500/µL) may or may not be present in active SAR. A significantly elevated concentration of serum IgE may occur in some patients with AR, but many other conditions (including racial factors) may increase the serum levels of total IgE, such as concomitant atopic dermatitis. Thus, the measurement of total serum IgE is barely predictive for allergy screening in rhinitis and should not be used as a diagnostic tool (1).
DIAGNOSIS The diagnosis of SAR (intermittent) usually presents no difficulty by the time the patient has had symptoms severe enough to seek medical attention. The seasonal nature of the condition, the characteristic symptom complex, and the physical findings should establish a diagnosis in almost all cases. If the patient is first seen during the initial or second season, or if the major symptom is conjunctivitis, there may be a delay in making the diagnosis from the history alone. Additional supporting evidence is a positive history of allergic disorders in the immediate family and a collateral history of other allergic disorders in the patient. After the history is taken and the physical examination is performed, skin tests should be performed to determine the reactivity of the patient against the suspected allergens. For the proper interpretation of a positive skin test, it is important to remember that patients with AR may exhibit positive skin tests to allergens other than those that are clinically important. In SAR, it has been demonstrated that prick testing with standardized extracts is adequate for diagnostic purposes in many patients if standardized extracts are used. Intradermal testing when positive may not always correlate with allergic disease (110,111). Skin testing should be performed and interpreted by trained personnel because results may be altered by the distance placed between allergens (112), the application site (back versus arm), the type of device used for testing (113), the season of the year tested (114), and the quality of extracts used for testing (115). The first immunoassay used to accurately measure serum sIgE was the radioallergosorbent test (RAST) (116–118). Newer immunoassays use enzymelabeled anti-IgE; they have been employed as a diagnostic aid in some allergic 1286
diseases. Immunoassays of circulating sIgE can be used instead of skin testing when high-quality extracts are not available, when a control skin test with a diluent is consistently positive, when antihistamine therapy cannot be discontinued, or widespread skin disease is present. Initially, RAST, then enzyme-based anti-IgE assays appear to correlate fairly well with other measures of sensitivity, such as skin tests, endpoint titration, histamine release, and provocation tests. The frequency of positive reactions obtained by skin testing is usually greater than that found with serum or nasal RAST or enzyme assay. In view of these findings, the serum assays may be used as a supplement to skin testing. Skin testing is the diagnostic method of choice to demonstrate IgE antibodies. When the skin test is positive, there is little need for other tests. When the skin test is dubiously positive, the in vitro diagnostic test will, as a rule, be negative. Therefore, the information obtained by measuring serum sIgE usually adds little to that gleaned from critical evaluation of skin testing with high-quality extracts.
DIFFERENTIAL DIAGNOSIS The diagnosis of AR must be established carefully because an incorrect diagnosis could result in expensive treatments and major alterations in a patient’s lifestyle and environment. Several medical conditions may be confused with persistent AR (Table 26.2). The main causes of persistent nasal congestion and discharge include RM, drugs, pregnancy, nasal foreign bodies, other bony abnormalities of the lateral nasal wall, concha bullosa (air cell within the middle turbinate), enlarged adenoids, nasal polyps, cerebrospinal fluid (CSF) rhinorrhea, tumors, hypothyroidism, ciliary dyskinesia from cystic fibrosis, primary ciliary dyskinesia, Kartagener syndrome, granulomatous diseases (e.g., sarcoidosis, granulomatosis with polyangiitis, midline granuloma), nasal mastocytosis, congenital syphilis, gustatory rhinitis, gastroesophageal reflux, atrophic rhinitis, eosinophilic granulomatosis with polyangiitis (formerly known as Churg–Strauss vasculitis), allergic fungal sinusitis, and NARES.
Rhinitis Medicamentosa A condition that may enter into the differential diagnosis is RM or rebound nasal congestion. RM is a drug-induced, nonallergic form of rhinitis in which the nasal mucosa is induced or aggravated by the excessive or improper use of nasal decongestants (119). The pathophysiology of RM is not well understood and is thought to be a dysregulation of sympathetic/parasympathetic tone, resulting in increased parasympathetic activity, vascular permeability, and edema formation 1287
by altering vasomotor tone, thus creating the rebound congestion (120). Sympathomimetic amines, such as pseudoephedrine, phenylephrine, and ephedrine, activate sympathetic nerves through release of endogenous norepinephrine causing vasoconstriction (121). Imidazolines (e.g., xylometazoline, oxymetazoline, clonidine) cause vasoconstriction primarily through α2-adrenoreceptors (122). In patients with RM, discontinuation of the offending agent along with a course of oral corticosteroids is recommended. TABLE 26.2 DIFFERENTIAL DIAGNOSIS OF NONALLERGIC RHITINIS Associated drugs • Topical α-adrenergic agonists • Oral estrogens • Ophthalmic and oral β-blockers Infections • Chronic sinusitis • Tuberculosis • Syphilis • Fungal infection Systemic conditions • Cystic fibrosis • Immunodeficiencies • Immotile cilia syndrome • Hypothyroidism • Rhinitis of pregnancy
Structural abnormalities • Marked septal deviation • Concha bullosa • Nasal polyps • Adenoidal hypertrophy • Foreign body
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Neoplasms • Squamous cell carcinoma • Nasopharyngeal carcinoma Granulomatous diseases • Granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis) • Sarcoidosis • Midline granuloma • Eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg–Strauss vasculitis) Other • Atrophic rhinitis • Gustatory rhinitis • Allergic fungal sinusitis • Gastroesophageal reflux disease • Nonallergic rhinitis with eosinophilia syndrome (NARES)
Drugs A number of different drugs may cause nasal congestion. Examples include antihypertensive medications such as reserpine, hydralazine, guanethidine, methyldopa, prazosin, doxazosin, reserpine, and chlorothiazide; β-adrenergic blockers such as nadolol and propranolol; phosphodiesterase-5 inhibitors such as sildenafil, vardenafil, tadalafil, oral contraceptives and exogenous hormones; antidepressants/antipsychotics; cocaine; and NSAIDs. Discontinuation of these drugs for a few days results in marked symptomatic improvement. Cyclic changes in rhinitis intensity may be related to the changes in relative concentrations of the complex mix of hormones during the menstrual cycle. In nasal provocation experiments, allergic patients on oral contraceptives having grass challenges had less nasal congestion at day 14 of the menstrual cycle and more sneezing at the end of the cycle (123). Thus, oral contraceptives affect nasal reactivity in complex ways and usually can be continued in patients with AR. Cocaine sniffing is often associated with congestion, rhinorrhea, diminished 1289
olfaction, and septal perforation (124). Aspirin and other NSAIDs commonly induce rhinitis. In a population-based random sample, aspirin intolerance was more frequent in subjects with AR than those without AR (125). In about 10% of adult patients with asthma, aspirin and other NSAIDs that inhibit cyclooxygenase (COX) enzymes precipitate asthmatic attacks and nasal reactions (126). This distinct clinical syndrome, called aspirin-exacerbated respiratory disease (AERD), is characterized by an atypical sequence of symptoms, intense eosinophilic inflammation of the nasal and bronchial tissues, combined with an overproduction of cysteinyl leukotrienes. After ingestion of aspirin or other NSAIDs, an acute asthma attack occurs within 3 hours, usually accompanied by profuse rhinorrhea, conjunctival injection, periorbital edema, and sometimes a scarlet flushing of the head and neck. The inflammatory cell populations in the nasal mucosa of aspirin-sensitive rhinitis patients have been studied. In comparison to normal subjects, there is an increase in eosinophils, mast cells, and activated T cells. Marked increases in the numbers of IL-5 mRNA+ cells and lower numbers of IL-4 mRNA+ cells are observed in aspirinsensitive patients. No differences are recognized for either IL-2 or IFN-γ. The predominance of macrophages, and the disproportionate increase in IL-5 compared to IL-4 mRNA expression suggest that factors other than allergic mechanisms may be important in this disease (105,127). A similar increase in IL-5, an overexpression of LTC4 synthetase, and increase in cysteinyl leukotriene 1 receptor numbers have been noted in the bronchi or cells of patients with AERD (127,128).
Pregnancy Rhinitis of pregnancy has been attributed to increasing concentrations of female hormones during pregnancy, and the need for swollen mucosae with mucous hypersecretion for protection of the vagina and cervix (129). It is estimated to impact up to 10% to 30% of pregnant women and is limited to the gestational period (130). The rhinitis characteristically begins at the end of the first trimester and then disappears immediately after delivery (131). It has been reported that increased nasal congestion occurs in 22% to 72% of gravidas with asthma (132). The course of rhinitis of pregnancy is variable, and although many patients remain unchanged, approximately one-third may actually have a worsening of their condition during pregnancy similar to the pattern of asthma in pregnancy (133).
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On rare occasions, a patient with a foreign body in the nose may be thought to have chronic rhinitis. Foreign bodies usually present as unilateral nasal obstruction accompanied by a foul, purulent nasal discharge. Children may place foreign bodies into the nose, most commonly peas, beans, buttons, and erasers. Nasal foreign bodies resulting in chronic rhinitis, however, are rarely seen in adults and are usually the result of trauma or comorbid mental illness (134). Sinusitis is often misdiagnosed if the nose is not examined properly. Examination is best done after secretions are removed so that the foreign body may be visualized. Common symptoms of nasal foreign body include nasal discharge, congestion, pain, and/or malodorous, mucopurulent discharge (135).
Physical Obstruction Careful physical examination of the nasal cavity should be performed to exclude septal deviation, enlarged adenoids, choanal atresia, concha bullosa, and nasal polyps as a cause of nasal congestion.
Cerebrospinal Fluid Rhinorrhea CSF rhinorrhea may rarely mimic AR (136). The majority of CSF rhinorrhea cases are the result of trauma (137). Cases of spontaneous (nontraumatic) CSF rhinorrhea may be a high or normal pressure leak, and can persist for months to years. There are reports of meningitis in 19% of patients with persistent CSF leak (138). The CSF is clear and watery in appearance, and may be either unilateral or bilateral (139). Obtaining β-2 transferrin levels from the nasal discharge establishes the diagnosis. The β-2 transferrin is only present in the CSF, perilymph, and aqueous humor. When present in nasal discharge, it is highly specific for CSF rhinorrhea (140). After localization of the leak with magnetic resonance or computed tomography (CT) cisternography or highresolution CT examination, surgical repair is required to prevent meningitis (140).
Tumor Several neoplasms may occur in the nasopharyngeal area. The most important are encephalocele, inverted papilloma, squamous cell carcinoma, sarcoma, and angiofibroma. Encephaloceles are generally unilateral. They usually occur high in the nose and occasionally within the nasopharynx. They increase in size with straining, lifting, or crying. Some have a pulsating quality. CSF rhinorrhea, or even meningitis, may develop as a complication of biopsy of these lesions.
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Inverted papillomas have a somewhat papillary appearance. They are friable and more vascular than nasal polyps, and bleed more readily. They occur either unilaterally or bilaterally, and frequently involve the nasal septum as well as the lateral wall of the nose. A biopsy is necessary to confirm the diagnosis. Angiofibromas are the most common tumors in preadolescent boys (141). They arise in the posterior choana (choanae osseae) of the nasopharynx. They have a polypoid appearance but are usually reddish-blue in color. They do not pit on palpation. Angiofibromas are highly vascular tumors that bleed excessively when injured or when a biopsy is done. Larger tumors may invade bone and extend into adjacent structures (141). Carcinomas and sarcoma may simulate nasal polyps. They are generally unilateral, may occur at any site within the nasal chamber, are firm, and usually bleed with manipulation. As the disease progresses, adjacent structures become involved.
Hypothyroidism In patients with hypothyroidism, an increase in thyroid-stimulating hormone results in edema of the nasal turbinates. Therefore, a careful review of systems and thyroid function studies are important to exclude hypothyroidism as a cause of nasal congestion.
Syphilis In up to 70% of infants infected with syphilis, there is mucocutaneous involvement of the nasal passages causing rhinitis that is either present at birth or develops within first 3 months of life (142). Saddle nose deformity occurs secondary to ulceration of the nasal mucosa and cartilage.
Ciliary Disorders With the dyskinetic cilia syndrome, patients may experience rhinitis symptoms secondary to abnormalities of mucociliary transport. The criteria for diagnosis include (a) absence or near absence of tracheobronchial or nasal mucociliary transport and (b) total or nearly total absence of dynein arms of the cilia in the nasal or bronchial mucosa. On electron microscopy, one may see defective radial spokes or transposition of a peripheral microtubular doublet to the center of the axoneme. The last criterion is (c) clinical manifestations of chronic upper and lower respiratory tract infections (i.e., sinusitis, bronchitis, and bronchiectasis) (143). Rare patients may have the triad of bronchiectasis, sinusitis, and situs inversus (Kartagener syndrome) (144). In some patients, cilia, although abnormal in structure, may be motile. The cilia in patients with this syndrome 1292
can be distinguished from those in patients with asthma, sinusitis, chronic bronchitis, and emphysema, who may have nonspecific abnormalities in cilia structure.
Perennial Nonallergic Rhinitis PAR comprises a heterogeneous group of at least seven subgroups. These include NARES, drug-induced rhinitis, gustatory rhinitis, hormone-induced rhinitis, atrophic rhinitis, rhinitis of the elderly, and idiopathic rhinitis. NARES is characterized by nasal eosinophilia, but there is currently no consensus on the degree of eosinophilia required because a range for 5% to 20% has been reported to be consistent with the condition (145,146). Because the pathophysiology of NARES is unknown, it has been equated to idiopathic rhinitis, local allergic rhinitis (LAR), a local inflammatory response induced by irritants, or as a precursor to AERD because NARES patients frequent have eosinophilic nasal polyps, bronchial hyperreactivity, and nonallergic asthma. NARES patients demonstrate perennial symptoms of sneezing, itching, rhinnorhea, nasal obstruction, and, occasionally, a loss of the sense of smell. The condition may occur in children and adults and usually has a favorable response to intranasal corticosteroids. Idiopathic rhinitis, sometimes referred to as vasomotor or intrinsic rhinitis, is the most prevalent type of NAR. Its pathophysiology is unrelated to allergy or underlying systemic disease and usually not associated with nasal eosinophilia. In these patients, nasal symptoms, although similar to that of AR, are usually precipitated by nonspecific stimuli, such as smoke, perfume, strong odors, and barometric pressure changes. Although the pathophysiology of idiopathic rhinitis is unknown, some forms of idiopathic rhinitis may be disorders of the nonadrenergic, noncholinergic, or peptidergic neural system (147,148). Nasal peptidergic neurons (mainly sensory C fibers) are activated by those nonspecific stimuli, resulting in antidromic and orthodromic release of inflammatory neuropeptides which can exert side effects on the blood vasculature and mucous secreting glands and lead to the symptoms of idiopathic rhinitis (149). These fibers are thought to be primarily activated by the transient response potential (TRP) calcium ion channels whose ligands are demonstrated to be affected by temperature, mechanical, or osmotic stimuli, or as a spectrum of chemical irritants. The TRPV1 is activated by hot temperatures and has been shown to be a specific ligand for capsaicin. An acute exposure to capsaicin can activate TRPV1, whereas continuous exposure to capsaicin can desensitize this receptor (150). TRPA1 and TRPM8 channels may be stimulated by cold air (151) and 1293
may be attenuated by capsaicin (152). Similar TRP pathways may play a significant role in gustatory rhinitis, (153) acute viral rhinosinusitis (154,155), rhinitis of the elderly, or even AR.
Atrophic Rhinitis Primary atrophic rhinitis is a type of rhinitis that is more prevalent in lower socioeconomic populations in the developing world and characterized by progressive atrophy of the nasal mucosa and underlying bone, resulting in a nasal cavity that is widely patent but full of copious foul-smelling crusts (156). The infection may be attributed to Klebsiella pneumoniae sp. ozaenae, although its role as a primary pathogen is not fully documented. Symptoms usually consist of severe nasal congestion, hyposmia, and a constant smell. Decreased blood flow to the nasal mucosa contributes to the local atrophy and leads to the enlargement of the nasal space with paradoxic nasal congestion (157). Atrophic rhinitis can overlap in patients with NAR or AR. It must be distinguished from secondary atrophic rhinitis associated with radiation, trauma, excessive nasal surgery, and chronic granulomatous conditions.
Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) can be associated with rhinitis and recurrent otitis media, especially in children (158–160). The prevalence is thought to increase with age, and up to 22% of elderly individuals have GERD (161,162). A recent 10-year prospective cohort study found that those with nocturnal GERD were 60% more likely to develop rhinitis symptoms (163). Another recent study also found a link between GERD and rhinitis symptoms in patients even up to 75 years of age (164). The exact underlying mechanisms of the GERD–rhinitis association and whether treatment of GERD will improve rhinitis in different age groups merits further study.
Allergic Fungal Rhinosinusitis The fungi responsible for allergic fungal rhinosinusitis (AFS) are predominantly of the Dematiaceae family (Aspergillus spp., Rhizopus spp., Alternaria spp., Curvularia spp., and Bipolaris spicifera) (165). AFS primarily occurs in atopic patients who develop an IgE-mediated response to the fungus, resulting in nasal polyps (166). The sinus mucosa shows a characteristic eosinophilic inflammation, with allergic mucin filling the sinuses. Elevated total IgE and fungal-specific IgG and IgE antibodies are commonly found (167). AFS is unilateral in more than 50% of patients but may involve several sinuses with 1294
associated bone erosion. On CT scan, involved sinuses demonstrate the presence of an expandable lesion commonly with bone thinning and/or erosion, but bony invasion is not seen (168). The CT findings also included heterogeneous opacities, with areas of hyperattenuation (i.e., increased density on a CT scan, magnetic resonance imaging shows T2 hypointensity) (168). In areas where erosion/expansion has not occurred, the surrounding bone may appear thickened or osteitic from the chronic inflammation as compared to the uninvolved areas. Although often described as being calcific, the density of these opacities is actually a combination of the various metals (e.g., iron, magnesium, and manganese) concentrated by the fungal organisms, as well as the low-water and high-protein content of the mucin (168). One study reported that when used in combination with the presence of nasal polyps and Aspergillosis sIgE, the sensitivity and specificity of CT imaging is up to 70% and 100%, respectively (169). Treatment usually includes surgical intervention with polypectomy and marsupialization of the involved sinuses. Medical management involves longterm intranasal glucocorticosteroids with the use of systemic corticosteroids for more difficult cases (170). Several studies have reported that immunotherapy is helpful in AFS as adjunct treatment. These studies report better quality of life (170–173) with reduced corticosteroid requirements and need for repeat surgery. However, the studies have suffered from the absence of well-characterized controls, and doubt has been raised given the poor outcomes of fungal immunotherapy when used for other conditions, such as AR and asthma (174).
LOCAL ALLERGIC RHINITIS LAR is a clinical entity characterized by symptoms suggestive of AR owing to a localized allergic response in the nasal mucosa in the absence of systemic atopy assessed by conventional diagnostic tests such as skin-prick test or determination of sIgE in serum (175). The prototypical LAR patient is a young female, nonsmoker with a family history of atopy and a history consistent with AR. Most LAR patients usually have moderate-to-severe symptoms that tend to worsen over time. Although LAR is more common in adults, 36% of subjects develop it in childhood (176–178). More than 30% of subjects with LAR also report asthmatic symptoms (177–179). IgE may play an important role in nonatopic asthma, and may be produced locally as in the nasal mucosa of LAR patients (180). Several studies have demonstrated the local synthesis of IgE in the bronchial mucosa of atopic and nonatopic asthmatics, with increased expression of the IgE ε heavy chain germline and mature gene transcripts (ε chain mRNA) and local IgE class 1295
switching (181,182). The characterization of LAR has generated important clinical questions as to whether it develops into AR with systemic atopy or is a risk factor for asthma. The results of the first longitudinal study revealed that LAR has a low rate of conversion to AR that is similar to healthy controls (6.25% versus 5%) after 5 years of evaluation. This study periodically evaluated a cohort of 149 LAR patients and 130 control subjects using questionnaires, skin-prick tests, serum sIgE, lung function, and nasal allergen provocation test (177). LAR patients worsened over time, with impairment in quality of life, an increase in rhinitis persistence and severity, and new associations with conjunctivitis and asthma. The diagnosis of LAR starts with the demonstration of an allergen-specific nasal response by means of nasal allergen provocation test and/or sIgE in nasal secretions or tissue (183). Nasal allergen provocation testing is considered the gold standard for LAR diagnosis. The nasal allergen provocation testing has a higher sensitivity than sIgE measurement in nasal secretions, because the measurement of sIgE in nasal secretions can vary depending on the technique used (184,185). The treatment of LAR is similar to AR and includes education, allergen avoidance measures, pharmacologic treatment with intranasal corticosteroids, oral and intranasal antihistamines, and allergen immunotherapy (180,186).
COURSE AND COMPLICATIONS The course of patients with AR is variable (187); one study reported 39% improved, 39% remained unchanged, and in 21%, the symptoms became worse (188). In another study, 8% of those with AR had remissions for at least 2 years’ duration (187). In a study published in the 1970s, a chance for remission was better in those with SAR and if the disease was present for less than 5 years (189). The possibility of developing asthma as sequelae to AR may worry the patient(s). AR and positive allergy skin tests are significant risk factors for developing new asthma (190). A 10-year prognosis study for childhood AR found that asthma or wheezing developed in 19% of cases and was more common among those with PAR than those with SAR (191). Individuals with either of these diagnoses are about three times more likely to develop asthma than negative controls. However, upper and lower airway symptoms may develop simultaneously in about 25% of patients. Patients with AR may develop complications because of chronic nasal inflammation, including recurrent otitis media with hearing loss, impaired speech development, acute and chronic 1296
sinusitis, recurrence of nasal polyps, abnormal craniofacial development, sleep apnea with its related complications (191,192), aggravation of asthma, and increased propensity to develop asthma. In patients with AR, a continuous allergen exposure results in persistent inflammation that upregulates expression of ICAM-1 and VCAM-1 in the inflamed epithelium (193). Because ICAM-1 is the ligand for almost 90% of rhinoviruses, its upregulation may be responsible for the increased prevalence of rhinovirus recovery in these patients. Poorly controlled symptoms of AR may contribute to sleep loss, secondary daytime fatigue, learning impairment, decreased overall cognitive functioning, decreased long-term productivity, and decreased quality of life. The symptoms of AR and skin test reactivity tend to wane with increasing age. In most patients, however, skin tests remain positive despite symptomatic improvement; therefore, symptomatic improvement does not necessarily correlate with skin test conversion to negative.
TREATMENT There are three types of management of SAR or PAR: (a) avoidance therapy, (b) symptomatic therapy (pharmacologic treatment), and (c) immunotherapy. Aeroallergen avoidance and immunotherapy are reviewed in Chapter 13.
Overview of Pharmacologic Treatment The current treatment strategy for AR consists of a stepwise approach based on symptom duration, severity, and associated comorbid conditions, such as conjunctivitis or asthma. Medical therapies are targeted at blocking symptoms from either the histamine-mediated early-phase response within the target tissue or the late-phase response. Pharmacotherapy in AR is generally divided into two broad classes—topical or oral agents. For the management of mild intermittent AR, the suggested initial pharmacologic therapy consists of an oral antihistamine, an intranasal antihistamine, or an oral decongestant. An oral nonsedating second-generation H1-receptor antihistamine is recommended over a first-generation H1-receptor antihistamine which is normally associated with more adverse effects, including sedation, impaired motor coordination, and excessive drying (194). When intermittent disease is moderate or severe, intranasal steroids provide an alternative to the aforementioned agents (91). For persistent moderate or severe AR, intranasal corticosteroids should be the first class of medications employed, with intranasal antihistamines as an alternative agent.
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Investigation into the presence of allergic conjunctivitis should also take place because topical ocular H1 antihistamines with mast cell stabilizing properties (i.e., cromolyn, nedocromil, olopatadine, azelastine, pemirolast) may be necessary to achieve better control of ocular symptoms in AR subjects who do not experience control of allergic conjunctival symptoms with the use of intranasal corticosteroids (195). Despite individual improvement seen in subjects with increased sneezing, pruritus, or conjunctival symptoms, clinical studies have demonstrated little benefit of adding oral antihistamines or a leukotrienemodifying agent like montelukast to an intranasal corticosteroid for treatment of moderate or severe AR (196). With all grades of severity, appropriate follow-up should occur in a reasonable period with therapy stepped down or intensified as tolerated. Specific drugs for the treatment of AR and other allergic diseases are covered in Chapters 33 to 38.
Intranasal Corticosteroids Intranasal corticosteroids are the single most effective first-line therapy for moderate-to-severe AR. They are generally considered the most effective medications at managing the inflammatory component and relieving all four primary nasal symptoms of AR, including nasal congestion, rhinorrhea, pruritus, and sneezing. In addition, these agents may relieve oropharyngeal pruritus, cough associated with AR, itchy, watery eyes associated with allergic conjunctivitis, and improvement of asthma (197). The concept of delivering steroids intranasally was to minimize potential side effects of using systemic corticosteroids. In most studies, intranasal corticosteroids were shown to be more effective than the combined antihistamines and leukotriene antagonists in the treatment of SAR. Additionally, in most patients who are unresponsive or noncompliant with intranasal corticosteroids, other viable alternatives include using an antihistamine in combination with a leukotriene antagonist or a decongestant (198). The onset of therapeutic efficacy of intranasal corticosteroids normally occurs between 3 and 12 hours. Corticosteroids are lipid soluble and exert their effect by binding to the cytoplasmic glucocorticoid receptors before being translocated to the nucleus. After entering the cell nucleus, the activated corticosteroid receptor attaches as a dimer to specific sites on DNA in the promoter region of steroid-responsive genes to either induce or suppress gene transcription patterns and downregulate the inflammatory response (199). The mRNA transcripts induced during this process then undergo posttranscriptional processing and are transported to the cytoplasm for translation by ribosomes with reduced production of pro-inflammatory proteins 1298
(91). After posttranslational processing, the new proteins are either released extracellularly or retained by the cell for intracellular activity. Additionally, the activated glucocorticoid receptors may interact directly with other transcription factors in the cytoplasm and alter the steroid responsiveness of the target cell (91). Corticosteroids have specific effects on inflammatory cells and chemical mediators. Intranasal glucocorticoids inhibit the uptake and/or processing, but not the presentation of antigen by airway Langerhans cells that reduces the secondary inflammatory response and symptoms of AR (200,201). Intranasal corticosteroids reduce eosinophils and their products, resulting in decreased eosinophil survival. Corticosteroids may also reduce the influx of basophils and mast cells in the epithelial layers of the nasal mucosa (91). Corticosteroids inhibit T-cell activation and reduce the production of pro-inflammatory cytokines, including IL-2, IL-3, IL-4, IL-5, and IL-13 and their receptors, resulting in reduced vascular permeability and decreased blood flow (202,203). Corticosteroids may also reduce the release of preformed and newly generated mediators, such as histamine, tryptase, prostanoids, and leukotrienes (204–206). Corticosteroids also inhibit local IgE production and granulocyte levels in the mucosa (207). With the exception of their sterol D rings, all intranasal corticosteroids have common structural elements used in the treatment of inflammation. At the present time, there are several nasal corticosteroids available to treat AR. These include beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. All intranasal steroids are US Food and Drug Administration (FDA) approved for the treatment of AR over 6 years of age. All intranasal steroids were pregnancy category C, with the exception of budesonide, which was FDA pregnancy category B (208). In 2015, the FDA stopped using letter grades for pregnancy recommendations. Intranasal corticosteroids offer improved efficacy over other classes of medications for AR, and despite variations in their sensory attributes (e.g., taste or smell), there is no evidence of superior clinical response of one agent over another (209,210). With the exception of beclomethasone dipropionate, all other intranasal corticosteroids are quickly metabolized to less active metabolites, have minimal systemic absorption, and have been associated with few systemic side effects (91). The total bioavailability of intranasal mometasone is 0.1% and that of fluticasone propionate is 2% (211). The bioavailability of fluticasone furoate 1299
is 0.5% (212). The bioavailabilities of intranasal triamcinolone acetonide and beclomethasone dipropionate are unknown at this time. Unlike other intranasal corticosteroids, beclomethasone dipropionate is metabolized to active and relatively inactive metabolites, beclomethasone-17-monopropionate and beclomethasone-21 monopropionate and beclomethasone, respectively (213,214). Ciclesonide is a prodrug that is enzymatically converted to the active molecule desciclesonide that has an affinity for the glucocorticoid receptor that is 120 times higher than the parent compound (91). Desciclesonide is 99% protein bound, and there is a high first-pass effect that contributes to desciclesonide’s undetectable bioavailability (215). There have also been promising results using combined therapy of intranasal corticosteroid and intranasal antihistamine. A novel formulation contains azelastine hydrochloride and fluticasone propionate and is delivered as a single nasal spray (216). It is indicated for the treatment of moderate-to-severe SAR and PAR when monotherapy with either an intranasal antihistamine or an intranasal corticosteroid is not sufficient. This combination has shown superior efficacy compared to intranasal antihistamine or intranasal corticosteroid monotherapy for both nasal and ocular symptom relief in AR patients, regardless of disease severity. Additionally, it provided more effective and rapid symptom relief compared with azelastine hydrochloride or fluticasone propionate monotherapy when delivered in the same formulation and device (217). Recommended doses of intranasal corticosteroids are generally not associated with clinically significant systemic side effects. Studies in children and adults have not demonstrated clinically relevant effects from intranasal corticosteroids on the hypothalamic–pituitary–adrenal (HPA) axis, ocular pressure or cataract formation or bone density. Studies with intranasal beclomethasone demonstrate no effect on the HPA function in adults (218). In children, growth effect may be a better indicator of systemic effect than HPA axis suppression. When compared with placebo, osteocalcin, a marker of bone turnover, and eosinophilia were unaffected by a variety of intranasal corticosteroids, suggesting an insignificant systemic glucocorticoid burden (219). Also, there was no increased risk of bone fracture in octogenarians using intranasal corticosteroids regardless of the dose (220). There is insufficient data to draw definitive conclusions about the effects of intranasal corticosteroids in the eyes. Intranasal steroids should be used with caution in individuals with glaucoma or cataracts because they may increase risk for exacerbations (221). There have been reports of a possible association 1300
between the development of posterior subcapsular cataracts and the use of intranasal or inhaled corticosteroids in older patients, but this was not confirmed by other studies with intranasal corticosteroids (222,223). A retrospective chart review study of 12 patients showed an increase in intraocular pressure with the use of intranasal corticosteroids, and there were significant reductions in intraocular pressures after discontinuing these topical steroids (224). Another study showed similar effects on intraocular pressure with the use of intranasal or inhaled beclomethasone dipropionate (225). In children, concerns arose about possible adverse effects of intranasal corticosteroids on growth rate. When beclomethasone was given at twice the recommended dosage, growth suppression was detected in children with PAR (226). Similar studies with fluticasone propionate, mometasone furoate, triamcinolone, and budesonide demonstrated no growth suppression in children when compared with placebo (226–229). A recent study also showed that fluticasone furoate administered over 52 weeks in prepubescent children resulted in a small reduction in growth velocity compared with placebo (230). Long-term use of intranasal corticosteroids does not appear to cause significant risk for adverse morphologic effects in the nasal mucosa. In a 1-year study of patients with perennial rhinitis treated with mometasone, nasal biopsy specimens showed a decrease in focal metaplasia, no change in epithelial thickness, and no sign of atrophy (231). In another study of intranasal corticosteroid treatment in 90 patients with perennial rhinitis, nasal biopsy specimens revealed normalization of the nasal mucosa at the end of the 12month study period (232). The major side effects of intranasal corticosteroids include local dryness or irritation in the form of stinging, burning, or sneezing (91). Local adverse effects of long-term topical intranasal corticosteroids include mucosal irritation that causes discomfort, mild bleeding, dryness, or rarely septal perforation, warranting periodic examination of the nasal cavity (233). Hemorrhagic crusting and perforation of the nasal septum are more common in patients who improperly point the spray toward the septal wall. Patients should be instructed to direct sprays away from the nasal septum to avoid these side effects. This complication may be reduced by tilting the head downward, using a mirror when spraying into the nose, using the new actuators for nasal sprays, and having the right hand spray the device into the left nostril and the left hand spray the device into the right nostril (91). The risk of perforation is usually greatest during the first 12 months of treatment, and the majority of cases involve young women 1301
(234). The development of aqueous formulations has reduced the incidence of local irritation with intranasal corticosteroids, resulting in greater use in children (91). Initially, some patients may require topical decongestants before administering intranasal corticosteroids. In some cases, a 3- to 5-day course of oral steroids is required to allow delivery of the intranasal corticosteroids in subjects with severe nasal congestion (91). Unlike decongestant nasal sprays, intranasal corticosteroids may be used prophylactically because the maximum benefit is not immediate and may take weeks. Although intranasal corticosteroids may have a delayed onset of action, many patients may have a clinically evident onset of action during the first day of administration (235–237). Intranasal fluticasone dipropionate delivered on an as-needed basis has been shown to be more effective than as-needed H1-receptor antagonists in the treatment of SAR (238). Although some studies suggest using intranasal corticosteroids on an as-needed basis, optimal effectiveness for patients may be achieved only with regular use (239,240).
Intranasal Corticosteroid Injection The first report of intranasal corticosteroid injections was in 1951 (241). Intranasal corticosteroid injections are occasionally used in the management of patients with common allergic and nonallergic nasal conditions, such as nasal polyposis; they are not indicated for AR (91). In 2007, a study by Becker et al. (242) demonstrated that intrapolyp steroid injections are associated with a significantly lower rate of complications than surgical excision of sinonasal polyps and may decrease the need for further surgical intervention for polyps. However, this technique has decreased in recent years with the advent of newer and safer topical intranasal steroids and because of possible systemic effects from steroid injections. Two major adverse effects that are seen in turbinate steroid injections but not with intranasal corticosteroid sprays include adrenal suppression secondary to absorption of the steroid and absorption of steroid emboli, which may lead to transient or permanent loss of vision (91).
Systemic Corticosteroids Oral corticosteroids have greater potency than topical corticosteroids and are an effective treatment for AR. Although AR is not life threatening, it may seriously impair the quality of life, and some patients may only be able to respond to corticosteroids. In addition, oral corticosteroids may be indicated when topical corticosteroids are not adequately distributed in AR patients with marked nasal 1302
obstruction or nasal polyposis. In such cases, a short 5- to 7-day burst of systemic corticosteroids may be indicated, but should be limited to sporadic use. The dose is up to 0.5 mg/kg/day of prednisone or its equivalent. The improvement in nasal symptoms may then be maintained with daily topical intranasal corticosteroids. Oral corticosteroids should be limited in long-term use for AR because of side effects and potential complications associated with its prolonged use (198). Patients who have long-term, systemic dosing of oral corticosteroids often require bone density and blood glucose monitoring and ophthalmic examinations (208). It is essential for clinicians and patients to weigh the risks and benefits of oral corticosteroid use in deciding systemic dosing frequency, amount, and treatment duration. Antihistamines Antihistamines are useful for the management of intermittent AR, mild AR, SAR, or PAR. Antihistamines are most useful in controlling the symptoms of sneezing, rhinorrhea, and pruritus that occur in AR. Antihistamines are compounds of varied chemical structure that have the property of antagonizing some of the actions of histamine. The first-generation antihistamines (e.g., chlorpheniramine, diphenhydramine, tripelennamine, and clemastine fumarate) are effective H1-receptor antagonists. Problems associated with their use relate to side effects, which are numerous and can be severe in some patients. The most common and most important effects are anticholinergic, including dry mouth and eyes, urinary retention, and central nervous system (CNS) effects (primarily sedation, and impairment of motor and cognitive functions). The patient may not be aware of having reduced cognitive ability, because it can occur independently of sedation (243). Recent metaanalyses found significant overuse of anticholinergic agents, including antihistamines in cognitively impaired individuals, preventing them from attending memory clinic. Therefore, special care should be taken when prescribing sedating antihistamines to elderly patients, especially if they are at risk for cognitive impairment (244–248). Large doses of first-generation antihistamines, such as diphenhydramine, are rarely reported to cause torsades de pointes. Populations that require caution are those taking more than one antihistamine, patients with hypertension who require a diuretic, patients with hypokalemia or hypomagnesemia, and patients taking antiarrhythmic agents (248). The CNS side effects can be problematic in any patient, particularly those who need to drive motor vehicles or operate complex machinery, or pay attention and learn in school. Often underrecognized are the potentiating effects 1303
of alcohol and other CNS depressing drugs, such as sedatives, hypnotics, and antidepressants. Because the newer second-generation antihistamines do not appreciably penetrate the blood–brain barrier, most studies show a lack of sedation. These medications are free of anticholinergic side effects, such as dry mouth, constipation, difficulty voiding, and blurry vision. Older patients, who may have benign prostatic hypertrophy or xerostomia, usually tolerate these drugs. Because fatal cardiac arrhythmias occurred when terfenadine and astemizole were given concomitantly with erythromycin (a macrolide antibiotic), imidazole antifungal agents (ketoconazole and itraconazole), or medications that inhibit the cytochrome P450 system (249,250), these drugs have been removed from the US market. The other second-generation antihistamines, such as loratadine, desloratadine, fexofenadine, cetirizine, and levocetirizine, have not been associated with cardiac toxicity. The second-generation antihistamines have a rapid onset of action that allows them to be taken as needed (91). Azelastine, available as a nasal spray, is a selective H1-receptor antagonist with structural and chemical differences that distinguish it from currently available antihistamines (91). Azelastine is 10 times more potent than chlorpheniramine at the H1-receptor site (251). In addition to this H1-blocking action, azelastine has demonstrated an inhibitory response on cells and chemical mediators of the inflammatory response. Azelastine prevents leukotriene generation from mast cells and basophils, and modulates the activity of eosinophils and neutrophils, macrophages, and cytokines (91). Azelastine has a low incidence of somnolence and does not seem to result in psychomotor impairment. Azelastine is indicated for both SAR and PAR and can be considered first-line treatment for mild SAR and PAR because the medication has a rapid onset of action of approximately 30 minutes. Azelastine also has efficacy in moderate-to-severe AR (91). Combined therapy of intranasal azelastine and fluticasone has been shown to be more effective than either monotherapy alone. A recent study found that intranasal azelastine had comparable efficacy to intranasal fluticasone in the treatment of moderate-tosevere SAR (252). Olopatadine nasal spray is a selective H1-receptor antagonist and, like azelastine, has a fast onset of action (253), and has shown efficacy in SAR. An unpleasant taste is the most common side effect of both azelastine and olopatadine, but overall, they are well tolerated (254). Sympathomimetic Agents Sympathomimetic drugs are used as vasoconstrictors for the nasal mucous 1304
membranes and may be used in combination with oral antihistamines; however, studies failed to show improved benefit compared to either as monotherapy (255). Pseudoephedrine is generally reported to be more effective than phenylephrine. The adverse effect profile of decongestants includes insomnia, anorexia, and irritability. Oral decongestants should be avoided in children less than 4 years of age, elderly adults, and any patient with a history of cardiovascular disease or hyperthyroidism. RM may occur within 3 days of intranasal vasoconstrictor use although in some patients may not develop until 6 weeks of use (256). The recommendation is to limit use to less than 3 days. Leukotriene-Receptor Antagonists Leukotrienes are newly formed mediators that have been found to be important in allergic disease. The inhibition of LTC4, LTCD4, and LTCE4 or 5lipoxygenase has been an important strategy for management of AR and asthma. Leukotriene-receptor antagonists, montelukast and zafirlukast, have been reported to be effective for the treatment of AR. Studies have demonstrated similar efficacy of montelukast to a second-generation oral antihistamine, and in certain patients, there might be an additive effect when combined with an antihistamine (257–261). A meta-analysis demonstrated that, as compared with placebo, montelukast induced a moderate but significant reduction in scores for daily symptoms of rhinitis. In comparison, nasal corticosteroids induced a significant and substantial reduction in symptom scores (259). Thus, the role of montelukast is generally as an adjunct in the treatment of a patient who does not have an adequate response to an antihistamine or a nasal corticosteroid or both. However, there are no clear data demonstrating that leukotriene-receptor antagonists combined with either antihistamines or nasal corticosteroids reduce symptom scores more than the antihistamines or corticosteroids alone. Leukotriene-receptor antagonists, however, have shown efficacy in aspirinsensitive rhinitis (262) and in patients who have the combination of SAR and mild asthma (263). Anticholinergics Parasympathetic fibers originate in the superior salivatory nucleus of the brainstem, and relay in the sphenopalatine ganglion before distributing to the nasal glands and blood vessels. Parasympathetic stimulation causes a watery secretion, mediated by the classical autonomic transmitter acetylcholine, and a vasodilatation of blood vessels serving the glands. The muscarinic receptors of the seromucinous glands can be blocked by the anticholinergic drug, ipratropium bromide. Ipratropium bromide, a quaternary derivative of isopropyl noratropine, 1305
is poorly absorbed by the nasal mucosa because of a low-lipid solubility and does not cross the blood–brain barrier. Ipratropium bromide is effective in controlling watery nasal discharge, but it does not affect sneezing or nasal congestion in both PAR and NAR. The drug is effective for the treatment of common cold (264), gustatory rhinitis, and rhinorrhea in elderly patients. One study demonstrated that atropine sulfate, a nonselective muscarinic receptor antagonist, improved severe rhinorrhea in patients with PAR, whereas the other nasal symptoms were not improved significantly (265). Topical side effects, caused by anticholinergic action, are uncommon and usually dose dependent in their severity. Nasal dryness, irritation, and burning are the most prominent effects, followed by a stuffy nose, dry mouth, and headache. Because patients with perennial rhinitis usually suffer also from nasal congestion, itching, and sneezing, other drugs are preferable as first-line agents to ipratropium in the vast majority of cases of AR. Ipratropium combined with an intranasal glucocorticosteroid or an H1 antihistamine may be considered in patients where rhinorrhea is the predominant symptom, or in patients with rhinorrhea who are not fully responsive to other therapies. Intranasal Cromolyn In the United States, cromolyn nasal spray is available without prescription, has minimal systemic absorption, and is very safe for chronic use without evidence of tachyphylaxis (150). The main clinical disadvantage of intranasal cromolyn is the need for administration four to six times per day for ongoing treatment effect (92). The proposed mechanism of action of cromolyn in AR is to stabilize mast cell membranes, apparently by inhibiting calcium transmembrane flux and thereby preventing antigen-induced degranulation. It is effective in the management of both SAR and PAR. Cromolyn can be effective in reducing sneezing, rhinorrhea, nasal pruritus, and in a limited number of patients with nasal polyps. It has little effect on mucociliary transport. Cromolyn often prevents the symptoms of both SAR and PAR, and diligent prophylaxis can significantly reduce both immediate and late symptoms after allergen exposures. Adverse effects are rare and mostly include sneezing, nasal stinging, nasal burning, transient headache, and an unpleasant aftertaste. For management of seasonal rhinitis, treatment should begin 2 to 4 weeks before contact with the offending allergens, and should be continued throughout the period of exposure. Because cromolyn has a delayed onset, concurrent antihistamine therapy is usually necessary to control symptoms. It is essential for the patient to understand the rate and extent of response to be expected from intranasal 1306
cromolyn, and that because the product is prophylactic, it must be used on a regular basis for maximum benefit.
Capsaicin Nasal Spray Capsaicin is a pungent agent derived from red peppers that is known for desensitizing peptidergic sensory C fibers and reducing nasal hyperreactivity. It is most well studied in NAR and is available without a prescription (147). In a randomized study of 42 patients with AR and NAR, intranasal capsaicin and eucalyptol were used twice daily for 2 weeks compared with placebo (266). There was a statistically greater reduction in total nasal symptom score, with greatest improvements in nasal congestion, sinus pressure, and headache. There was no reduction in sneezing, rhinorrhea, and postnasal drip between the active and placebo groups. New agents targeting these same nasal sensory receptors may potentially control nasal hyperreactivity that underlies AR and NAR.
Complementary and Alternative Therapies Acupuncture Acupuncture is a component of traditional Chinese medicine that works on the principle of redistribution of Qi, the life energy. Acupuncture may exert its antiinflammatory effect through the HPA axis or by the sympathetic and parasympathetic nervous systems. Additionally, other anti-inflammatory properties include a histamine antagonist effect and downregulation of proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6, and IL-10), pro-inflammatory neuropeptides (e.g., substance P), cGRP, VIP, neurotrophins (e.g., nerve growth factor [NGF] and brain-derived neuronal factor [BDNF]), and the expression of COX-1, COX-2, and nitric oxide synthase (267). A recent systematic review of 13 studies evaluated 2,365 AR patients (1,126 treated versus 1,239 placebo). The group receiving acupuncture experienced a significant reduction in nasal symptom scores. A nonsignificant trend was found for relief medication scores, and no effect was observed for the rhinitis quality of life questionnaire (RQLQ). No serious adverse effects were observed for the acupuncture treatment group (268). An additional trial reported that 175 patients who received acupuncture had decreased sneezing and pruritic symptom scores and improvement in RQLQ scores (269). Acupuncture is a reasonable option for individuals with mild AR disease who wish to minimize pharmacologic therapy. However, although acupuncture may cause small improvement in symptom quality of life, it is very expensive and may not be a cost-effective treatment of AR (270).
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Acupressure Acupressure is similar to acupuncture without involvement of needles. In an Australian trial, 63 SAR patients were randomly assigned to real (n = 31) and sham (n = 32) ear acupoint groups for a total of 8 weeks. Total nasal symptoms score and regular activities at home and work were significantly improved in the real compared with the sham ear acupoint groups (271). A follow-up study investigated 245 PAR patients randomized to receive real or sham ear acupressure treatment once weekly for 8 weeks with a 12-week follow-up period. There was a small, statistical improvement in sneezing and quality of life along with additional improvements in most measures of nasal symptoms at the end of the follow-up period in the acupressure group compared to the sham group (272). These studies demonstrate a significant effect of ear acupressure on AR. Additional studies will be required to make more definitive recommendations about the utility of this therapy. Rhinophototherapy Similar to phototherapy that treats various inflammatory skin diseases, including atopic dermatitis, rhinophototherapy may also act as an immunosuppressive agent to treat AR. A randomized, double-blind, placebo-controlled study was conducted to assess the effect of rhinophototherapy in 49 ragweed SAR patients during their peak season, using a combination of ultraviolet (UV)-B (5%), UV-A (25%), and visible light (70%). Rhinophototherapy resulted in a significant improvement in total nasal symptoms score, sneezing, rhinorrhea, and nasal itching compared to the control group. Additionally, the nasal lavage studies revealed a significantly reduced number of eosinophils, ECP, and IL-5 (273). Two months after completion of therapy, cytology samples showed that any UV damage to the nasal mucosa induced by intranasal phototherapy is resolved (274). In an uncontrolled study, the addition of phototherapy to mometasone resulted in improvement of symptom and RQLQ symptom scores compared to the mometasone monotherapy group (275). Despite no direct data on the effect of phototherapy in AR, there is limited data that point to a reduction of symptoms and eosinophil counts in AR. Intranasal Carbon Dioxide (CO2) Intranasal CO2 may inhibit trigeminal neuronal activation and suppress the release of cGRP that are both increased in rhinitis. A randomized, double-blind, placebo-controlled study evaluated two 60-second intranasal treatments with CO2 which resulted in rapid (within 10 minutes) and sustained (up to 24 hours) 1308
relief of SAR symptoms (276).
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mRNA expression in seasonal allergic rhinitis induced by natural allergen exposure: effect of topical corticosteroids. J Allergy Clin Immunol. 1998;102:610–615. 203. Al Ghamdi K, Ghaffar O, Small P, et al. IL-4 and IL-13 expression in chronic sinusitis: relationship with cellular infiltrate and effect of topical corticosteroid treatment. J Otolaryngol. 1997;26:160–166. 204. Pipkorn U, Proud D, Lichtenstein LM, et al. Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids. N Engl J Med. 1987;316:1506–1510. 205. Scadding GK, Darby YC, Austin CE. Effect of short-term treatment with fluticasone propionate nasal spray on the response to nasal allergen challenge. Br J Clin Pharmacol. 1994;38:447–451. 206. Wang D, Smitz J, DeWaele M, et al. Effect of topical applications of budesonide and azelastine on nasal symptoms, eosinophil count and mediator release in atopic patients after nasal allergen challenge during the pollen season. Int Arch Allergy Immunol. 1997;114:185–192. 207. Meltzer EO. The role of nasal corticosteroids in the treatment of rhinitis. Immunol Allergy Clin North Am. 2011;31:545–560. 208. Platt M. Pharmacotherapy for allergic rhinitis. Int Forum Allergy Rhinol. 2014;4(Suppl 2):S35–S40. 209. Benninger M, Farrar JR, Blaiss M, et al. Evaluating approved medications to treat allergic rhinitis in the United States: an evidence-based review of efficacy for nasal symptoms by class. Ann Allergy Asthma Immunol. 2010;104:13–29. 210. Blaiss MS. Safety update regarding intranasal corticosteroids for the treatment of allergic rhinitis. Allergy Asthma Proc. 2011;32:413–418. 211. Daley-Yates PT, Kunka RL, Yin Y, et al. Bioavailability of fluticasone propionate and mometasone furoate aqueous nasal sprays. Eur J Clin Pharmacol. 2004;60:265–268. 212. Allen A, Down G, Newland A, et al. Absolute bioavailability of intranasal fluticasone furoate in healthy subjects. Clin Ther. 2007;29:1415–1420. 213. Falcoz C, Kirby SM, Smith J, et al. Pharmacokinetics and systemic exposure of inhaled beclomethasone dipropionate. Eur Respir J. 1996;9(Suppl 23):162S. 1325
214. Daley-Yates PT, Price AC, Sisson JR, et al. Beclomethasone dipropionate: absolute bioavailability, pharmacokinetics, and metabolism following intravenous, oral, intranasal, and inhaled administration in man. Br J Clin Pharmacol. 2001;51:400–409. 215. Nave R, Wingertzahn MA, Brookman S, et al. Safety, tolerability and exposure of ciclesonide nasal spray in healthy and asymptomatic subjects with seasonal allergic rhinitis. J Clin Pharmacol. 2006;46:461–467. 216. Surda P, Fokkens WJ. Novel, alternative, and controversial therapies of rhinitis. Immunol Allergy Clin North Am. 2016;36:401–423. 217. Bousquet J, Bachert C, Bernstein J, et al. Advances in pharmacotherapy for the treatment of allergic rhinitis; MP29-02 (a novel formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system) fills the gaps. Expert Opin Pharmacother. 2015;16(6):913–928. 218. Ratner PH, Miller SD, Hampel FC, et al. Once-daily treatment with beclomethasone dipropionate nasal aerosol does not affect hypothalamicpituitary-adrenal axis function. Ann Allergy Asthma Immunol. 2012;109:336–341. 219. Wilson AM, Sims EJ, McFarlane LC, et al. Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis. J Allergy Clin Immunol. 1998;102:598–604. 220. Suissa S, Baltzan M, Kremer R, et al. Inhaled and nasal corticosteroid use and the risk of fracture. Am J Respir Crit Care Med. 2004;169:83–88. 221. Blaiss MS. Safety considerations of intranasal corticosteroids for the treatment of allergic rhinitis. Allergy Asthma Proc. 2007;28:145–152. 222. Ozturk F, Yuceturk AV, Kurt E, et al. Evaluation of intraocular pressure and cataract formation following the long-term use of nasal corticosteroids. Ear Nose Throat J 1998;77:846–848, 850–851. IIb 403. 223. Ernst P, Baltzan M, Deschenes J, et al. Low-dose inhaled and nasal corticosteroid use and the risk of cataracts. Eur Respir J. 2006;27:1168– 1174. 224. Bui CM, Chen H, Shyr Y, et al. Discontinuing nasal steroids might lower intraocular pressure in glaucoma. J Allergy Clin Immunol. 2005;116:1042– 1047.
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medications in the use of high-risk medications in the elderly and potentially harmful drug-disease interactions in the elderly quality measures. J Am Geriatr Soc. 2015;63(12):e8–e18. 247. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175(3):401–407. 248. Weiler JM, Bloomfield JR, Woodworth GG, et al. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. Ann Intern Med. 2000;132:354–363. 249. Taglialatela M, Castaldo P, Pannaccione A, et al. Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity. Clin Exp Allergy. 1999;29:182–189. 250. Simons FE. Advances in H1-anthihistamines. N Engl J Med. 2004;351:2203–2217. 251. Casale TB. The interaction of azelastine with human lung histamine H1, beta, and muscarinic receptor-binding sites. J Allergy Clin Immunol. 1989;83:771–776. 252. Bernstein JA. Azelastine hydrochloride: a review of pharmacology, pharmacokinetics, clinical efficacy and tolerability. Curr Med Res Opin. 2007;23:2441–2452. 253. Patel D, Garadi R, Brubaker M, et al. Onset and duration of action of nasal sprays in seasonal allergic rhinitis patients: olopatadine hydrochloride versus mometasone furoate monohydrate. Allergy Asthma Proc. 2007;28:592–599. 254. Fairchild CJ, Meltzer EO, Roland PS, et al. Comprehensive report of the efficacy, safety, quality of life, and work impact of olopatadine 0.6% and olopatadine 0.4% treatment in patients with seasonal allergic rhinitis. Allergy Asthma Proc. 2007;28:716–723. 255. Sussman GL, Mason J, Compton D, et al. The efficacy and safety of fexofenadine HCl and pseudoephedrine, alone and in combination, in seasonal allergic rhinitis. J Allergy Clin Immunol. 1999;104(1):100–106. 256. Lockey RF. Rhinitis medicamentosa and the stuffy nose. J Allergy Clin Immunol. 2006;118:1017–1018. 257. Patel P, Philip G, Yang W, et al. Randomized, double-blind, placebo1329
controlled study of montelukast for treating perennial allergic rhinitis. Ann Allergy Asthma Immunol. 2005;95(6):551–557. 258. van Adelsberg J, Philip G, Pedinoff AJ, et al. Montelukast improves symptoms of seasonal allergic rhinitis over a 4-week treatment period. Allergy. 2003;58(12):1268–1276. 259. Wilson AM, O’Byrne PM, Parameswaren K. Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med. 2004;116(5):338–344. 260. Chen ST, Lu KH, Sun HL, et al. Randomized placebo-controlled trial comparing montelukast and cetirizine for treating perennial allergic rhinitis in children aged 2–6 yr. Pediatr Allergy Immunol. 2006;17(1):49–54. 261. Keshin O, Alyamac E, Tuncer A, et al. Do the leukotriene receptor antagonists work in children with grass pollen-induced allergic rhinitis? Pediatr Allergy Immunol. 2006;17(4):259–268. 262. Parnes SM. The role of leukotriene inhibitors in patients with paranasal sinus disease. Curr Opin Otolaryngol Head Neck Surg 2003;11:184–191. 263. Baena-Cagnani CE, Berger WE, DuBuske LM, et al. 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. 2003;130:307–313. 264. Borum P, Olsen L, Winther B, et al. Ipratropium nasal spray: a new treatment for rhinorrhea in the common cold. Am Rev Respir Dis. 1981;123:418–420. 265. Georgitis JW. Nasal atropine sulfate. Arch Otolaryngol Head Neck Surg. 1998;2:916–920. 266. Bernstein JA, Davis BP, Picard JK, et al. A randomized, double-blind, parallel trial comparing capsaicin nasal spray with placebo in subjects with a significant component of nonallergic rhinitis. Ann Allergy Asthma Immunol. 2011;107:171. 267. McDonald JL, Cripps AW, Smith PK, et al. The anti-inflammatory effects of acupuncture and their relevance to allergic rhinitis: a narrative review and proposed model. Evid Based Complement Alternat Med. 2013;2013:591796. 268. Feng S, Han M, Fan Y, et al. Acupuncture for the treatment of allergic 1330
rhinitis: a systematic review and meta-analysis. Am J Rhinol Allergy. 2015;29(1):57–62. 269. Xue CC, Zhang AL, Zhang CS, et al. Acupuncture for seasonal allergic rhinitis: a randomized controlled trial. Ann Allergy Asthma Immunol. 2015;115(4):317.e1–324.e1. 270. Reinhold T, Roll S, Willich SN, et al. Cost-effectiveness for acupuncture in seasonal allergic rhinitis: economic results of the ACUSAR trial. Ann Allergy Asthma Immunol. 2013;111:56. 271. Xue CC, Zhang CS, Yang AW, et al. Semi-self-administered ear acupressure for persistent allergic rhinitis: a randomized sham-controlled trial. Ann Allergy Asthma Immunol 2011;106(2):168–170. 272. Zhang CS, Xia J, Zhang AL, et al. Ear acupressure for perennial allergic rhinitis: a multicenter randomized controlled trial. Am J Rhinol Allergy. 2014;28(4):e152–e157. 273. Koreck AI, Csoma Z, Bodai L, et al. Rhinophototherapy: a new therapeutic tool for the management of allergic rhinitis. J Allergy Clin Immunol. 2005;115(3):541–547. 274. Koreck A, Szechenyi A, Morocz M, et al. Effects of intranasal phototherapy on nasal mucosa in patients with allergic rhinitis. J Photochem Photobiol B. 2007;89(2–3):163–169. 275. Tatar EC, Korkmaz H, Surenoglu UA, et al. Effects of rhinophototherapy on quality of life in persistent allergic rhinitis. Clin Exp Otorhinolaryngol. 2013;6(2):73–77. 276. Casale TB, Romero FA, Spierings EL. Intranasal noninhaled carbon dioxide for the symptomatic treatment of seasonal allergic rhinitis. J Allergy Clin Immunol. 2008;121(1):105–109.
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NASAL POLYPS Nasal polyps have been recognized and treated since ancient times. The occurrence of nasal polyps in association with asthma and aspirin sensitivity, sometimes known as the “aspirin triad,” was first identified in 1911 (1). The aspirin triad is now called aspirin-exacerbated respiratory disease (AERD) (2). Nasal polyps are associated with chronic mucosal inflammation—a condition often referred to as chronic hyperplastic rhinosinusitis. In most cases, nasal polyps arise from the mucosa of the middle meatus and clefts of the ethmoid region (2,3). Polyp tissue is generally characterized by chronic, eosinophilic infiltration, but plasma cells, lymphocytes, and mast cells are also typically present (4,5). Polypoid tissue is rich in ground substance-containing acid mucopolysaccharide (6). The prevalence of nasal polyposis in the general population is estimated at 2% to 4% (7,8). A large population-based study did not reveal any gender differences, but there are reports of male predominance (2,9). Nasal polyps are diagnosed more often during the third and fourth decades of life. Most clinical data indicate that there is no greater prevalence of nasal polyps among atopic compared with normal populations; however, the coexistence of allergic rhinitis may render symptom control more challenging (10,11). In a study of an adult allergy clinic population, 4.2% of patients had nasal polyps; 71% of polyp patients had asthma, and 14% had aspirin intolerance (12). Nasal polyps are less common in children. The discovery of nasal polyps in a child, especially in association with nasal colonization by Pseudomonas species, should prompt an evaluation for cystic fibrosis (CF), in which the prevalence of nasal polyps is 6.7% to 48% (13–15). Nasal polyps are also reported to affect 37% of adults with CF (16).
Clinical Presentation 1332
Patients with nasal polyposis present with perennial nasal congestion, rhinorrhea, and anosmia (or hyposmia). Nasal and ostiomeatal obstruction may result in purulent nasal discharge and chronic sinusitis. Enlargement of nasal polyps may lead to broadening of the nasal bridge. Rarely, encroachment into the orbit can occur, resulting in compression of ocular structures and unilateral proptosis, falsely suggesting an orbital malignancy (17,18). A thorough nasal examination, preferably with a nasal speculum, is necessary for identification of nasal polyps. More complete visualization can be accomplished by flexible rhinoscopy. Nasal polyps appear as bulbous translucent to opaque growths, often extending from the middle and inferior nasal turbinates, causing partial or complete obstruction of the nasal canals. Frontal, ethmoidal, and maxillary tenderness with purulent nasal discharge from the middle meatus indicate concurrent acute or chronic paranasal sinusitis. Sinus imaging studies are rarely needed to identify nasal polyps. Common imaging changes include widening of the ethmoid labyrinths, mucoceles or pyoceles within the paranasal sinuses, and generalized loss of translucence in the maxillary, ethmoid, and frontal sinuses (17). Sinus imaging is reviewed in detail in Chapter 10.
Causes Although multiple theories regarding the etiology of nasal polyposis have been proposed, the pathogenesis remains poorly defined. Allergic mechanisms have been investigated, but no consistent association has been established between atopy and nasal polyposis. Patients with nasal polyps are less likely to be sensitized to perennial allergens than those diagnosed with allergic rhinitis (19). Mast cells and mast cell mediators are abundant in polyp tissue. TH2-directed inflammation is suggested by the presence of abundant eosinophils in 70% to 90% of cases (4). CD8+ T cells are increased in polyp tissue when compared with healthy controls (20). Growth factors and cytokines that can stimulate in vitro proliferation of basophils, mast cells, innate lymphoid type 2 cells, and eosinophils are present in nasal polyp tissue (21–23). The potential roles of TH1 (T-helper cell type 1) and TH2 (T-helper cell type 2) cytokines are under investigation (24). Total immunoglobin E (IgE) and interleukin 5 (IL-5) levels are higher in nasal tissue of patients with chronic rhinosinusitis (CRS) and nasal polyps, compared with CRS patients without polyps (25). Overproduction of thymic stromal lymphopoietin may enhance TH2 inflammation in nasal polyp tissue (23). The pathophysiology of CF-related polyp disease may be different from that of non– 1333
CF-related polyps. For example, myeloperoxidase and IL-8 are increased in polyp tissue from CF patients, whereas eosinophilic cation protein, eotaxin, and IgE are frequently elevated in nasal polyps of patients without CF, especially in those with aspirin sensitivity and/or asthma (26,26a). Microbial pathogens have been postulated to play roles in the pathogenesis of nasal polyps by promoting inflammation. In particular, Staphylococcus aureus– derived toxins may act as conventional allergens, leading to the production of specific IgE (sIgE), or as superantigens that can nonspecifically activate T cells (27). Treatment with antibiotics effective against S. aureus has shown some efficacy (28). The role of oxidative stress has also been investigated. Free oxygen radicals have been identified in nasal polyp tissue. Increased severity of nasal polyposis and bronchial hyperresponsiveness correlate with levels of free oxygen radicals in polyp tissue (29,30). AERD is generally associated with severe nasal polyposis and chronic sinusitis that is less responsive to treatment (31,32). The link between aspirin sensitivity, asthma, and nasal polyps has been attributed to reduced prostaglandin E2 and enhanced the production of leukotrienes from arachidonic acid. Patients with nasal polyposis generally have elevated levels of urinary leukotriene E4 (LTE4) at baseline (33). Aspirin-sensitive patients demonstrate increased levels of urinary LTE4 after oral aspirin challenge (34). In addition, LTC4 synthase is overexpressed in nasal polyps of patients with AERD (35).
Treatment Intranasal glucocorticoids are the treatment of choice for nasal polyposis and are more effective long term than surgical polypectomy (36). Intranasal steroids significantly reduce polyp size, nasal congestion, rhinorrhea, and increase nasal airflow (37–39). Aggressive treatment of nasal polyps with intranasal corticosteroids has also been shown to reduce the need for surgery (40). The effectiveness of intranasal steroids on improving olfactory dysfunction is variable (41,42). Optimal results may require a short course of oral corticosteroids (30 to 35 mg of prednisone daily for 5 to 7 days), followed by maintenance therapy with intranasal steroids (43–45). In a controlled trial, a course of oral steroids significantly reduced hyposmia and size of nasal polyps (44). Patients should be instructed to avoid the nasal septum when administering nasal steroids in order to limit irritation. Higher doses of intranasal corticosteroids may be more effective, although a recent Cochrane Database 1334
Review found insufficient evidence that one type of nasal steroid is superior to another (46,47). Fluticasone propionate administered as 400 μg twice daily was more effective than 400 μg once daily in improving nasal inspiratory flow and reducing polyp size (38). Coexistent sinus infections, which may reduce responsiveness to intranasal steroids, should be treated appropriately. Leukotriene antagonists may provide a modest benefit as an adjunctive treatment along with nasal steroids. In a double-blind study of 40 postoperative patients with nasal polyps, there was no difference in the recurrence rate of polyps between patients treated with montelukast versus nasal beclomethasone for 1 year (48). However, intranasal steroids exhibited superiority in treating olfactory deficits and nasal congestion. Another small, double-blind study found significant improvement in Health-related-Quality-of-Life in polyps patients on montelukast versus placebo for 4 weeks (49). A small study suggested that Zileuton, a 5-lipoxygenase inhibitor, may be more effective than other leukotriene antagonists for nasal polyps, but larger, controlled trials are needed (50). Surgical treatment for nasal polyposis should be considered when optimal medical therapy has failed. Simple polypectomy may be indicated for complete nasal obstruction, which causes extreme discomfort. If nasal polyps are associated with persistent ethmoid sinusitis with obstruction of the ostiomeatal complex, a more extensive surgical procedure may be considered. Several randomized controlled trials have shown equivalent outcomes at 1 year of follow-up after surgical versus medical management of nasal polyps (51,52). Nasal polyps frequently recur after simple surgical polypectomy, and long-term recurrence rates may be as high as 60% following functional endoscopic sinus surgery (FESS) for severe disease (53). Although further studies evaluating the role of long-term nasal steroids after surgery are needed, their administration in this setting should be considered to prevent recurrence (54,55). Outcomes of FESS are generally less favorable among aspirin triad patients compared with patients with chronic sinusitis who are aspirin insensitive (56,57). In a retrospective study, patients with aspirin triad had more extensive sinus disease based on radiologic findings, and 39% required surgical revisions versus 9% of sinusitis patients without aspirin sensitivity (56). The addition of aspirin following surgery may improve long-term outcomes in selected patients with nasal polyposis and AERD (58–61). Long-term aspirin desensitization has been reported to reduce the number of episodes of acute sinusitis, corticosteroid use, and requirement for polypectomies and sinus surgery (34,62). Because of the 1335
risk of provoking severe asthmatic attacks, this procedure should be performed exclusively by an experienced practitioner in an appropriate setting, and considered only in aspirin-sensitive patients refractory to conventional therapies (63). In recent years, research on biologics for nasal polyposis has begun to emerge. Omalizumab, an anti-IgE monoclonal antibody, has beneficial effects in treating nasal polyps, and it can be considered if more conservative medical and surgical treatment are not effective (8,28,64). Although only approved by the Food and Drug Administration for severe eosinophilic asthma, anti-IL-5 monoclonal antibodies, such as mepolizumab and reslizumab, have shown benefit for nasal polyps as well (65,66).
Rhinosinusitis The term sinusitis is used interchangeably with the term rhinosinusitis (RS), with the later recently accepted as the preferred terminology. RS is classified as acute rhinosinusitis (ARS) (symptoms 12 weeks) (8). CRS can be divided into those with nasal polyps (CRSwNP) and those without nasal polyps (CRSsNP). RS affects approximately 13% to 14% of the population, with 20,000 cases of acute bacterial sinusitis each year (8,67,68). The estimated annual health care costs for acute sinusitis exceed $3.5 billion annually, and the annual costs of CRS are estimated at $8 billion (8,69,70). RS is an inflammatory disorder of the mucosal lining of the nose and paranasal sinuses that may be initiated by infectious or noninfectious factors. Viral upper respiratory infections often precede acute bacterial sinus infections. Given that most viral infections resolve within 7 to 10 days, acute bacterial sinusitis is typically suspected when symptoms persist or worsen beyond 10 days with facial pain, postnasal drip, and purulent discharge (8,71). Noninfectious triggers for RS include environmental exposures to fumes or chemical vapors. ARS has long been considered a complication of seasonal or perennial allergic rhinitis (72–74). Individuals with exposure to tobacco smoke and those with nonallergic rhinitis are also more susceptible to recurrent or chronic sinusitis (75–77). Regardless of initiating events, the four physiologic derangements that contribute to the evolution of infectious sinusitis are: (a) reduced patency of the sinus ostia; (b) a decrease in the partial pressure of oxygen within the sinus cavities; (c) diminished mucociliary transport; and (d) compromise of 1336
microcirculation blood flow in the mucosa (78,79). Edematous obstruction of the sinus ostia is a consistent finding in both acute and chronic sinusitis; this condition causes a low-oxygen environment within the sinus cavity, which results in decreased mucociliary transport and favors the growth of common bacterial pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, and anaerobic bacteria (80,81). Studies suggest there are different CRS phenotypes or endotypes based on the presence or absence of infection or predominance of neutrophils or eosinophils; characterization of patient phenotypes may in the future guide treatment strategies (82,83). Patients presenting with noninfectious CRS (with or without AERD) and nasal polyposis exhibit predominant eosinophilic infiltration associated with increased expression of type 2 mediators, including IL-5, IL-13, and eotaxin-2, as compared to CRS patients without nasal polyps (84). The eosinophilia associated with nasal polyps may be more common in those of European descent; neutrophilia may be predominant in nasal polyp tissue of Asians (82).
Causative Microorganisms Microbial pathogens implicated in ARS have been studied extensively. Identification of bacterial pathogens by endoscopically directed middle meatal cultures closely approximates results obtained via needle puncture of the maxillary sinus (85,86). Cultures obtained by middle meatal sampling or maxillary sinus puncture for acute bacterial sinusitis in adults revealed that the most common pathogens are S. pneumoniae, H. influenzae, S. aureus, and Moraxella catarrhalis (87). Another study of 339 adult patients with acute sinusitis found that viruses were cultured from 8% of aspirates, whereas 15% to 40% of antral aspirates were sterile. Common isolates included rhinovirus, influenza type A, and parainfluenza viruses (88). In children with acute maxillary sinusitis, S. pneumoniae, H. influenzae, and M. catarrhalis have been identified as the predominant pathogens (89). Since the introduction of the pneumococcal conjugate vaccine (PCV13), the proportion of sinusitis caused by S. pneumoniae has declined, whereas that caused by H. influenzae has increased (8,90,91). Viruses were isolated from 4% of pediatric patients in one study, and 20% of cultured aspirates were sterile (88). Anaerobic bacteria play a large role in CRS in adults, but are rarely identified in children. There is also increasing concern for drug-resistant Gram-negative organisms in chronic sinusitis, particularly Pseudomonas aeruginosa (92,93).
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Immunocompromised individuals may develop invasive forms of fungal sinusitis involving unusual or opportunistic organisms. Invasive fungal RS should be suspected with opacified sinuses with soft tissue infiltration and/or osseous destruction (8). Mucormycotic sinusitis is caused by fungi of the family Mucoraceae (Mucor), which are zygomycetes, and may be isolated from the throat and stools of normal individuals (94). Mucormycotic sinusitis is potentially fatal in diabetic, leukemic, or otherwise immunosuppressed patients (95). Invasive aspergillosis involving the sphenoid sinus is particularly difficult to treat, even in immunocompetent patients, and can result in severe neurologic complications (96). Rarely, tuberculosis can cause infectious sinusitis, particularly in immunocompromised patients (97). Atypical mycobacteria have been reported to cause sinusitis in patients with acquired immunodeficiency syndrome (98). Allergic fungal sinusitis is an increasingly recognized syndrome occurring in immunocompetent atopic patients with hypertrophic rhinitis and nasal polyps. Abundant mucin found within the sinuses demonstrates numerous eosinophils and Charcot–Leyden crystals; fungal stains reveal the presence of noninvasive hyphae (99,100). The disease occurs primarily in adults, but should be considered in atopic children with refractory sinus disease (101). Although Aspergillus species are frequently involved, dematiaceous fungi have also been implicated. In particular, Bipolaris spicifera plays a prominent role in the Southwest region of the United States (102). Patients generally exhibit high total serum IgE levels and have positive skin tests to fungal allergens (100,103).
Clinical Presentation Episodes of bacterial ARS are most commonly preceded by symptoms suggestive of viral upper respiratory tract infections or other environmental stimuli, which can cause mucosal inflammation, hypertrophy, and obstruction of the sinus ostia. Common presenting symptoms include frontal or maxillary head pain, fever, and mucopurulent or bloody nasal discharge lasting longer than 7 to 10 days. Other clinical features include general malaise, cough, hyposmia, mastication pain, and changes in the resonance of speech. Pain cited as coming from the upper molars may represent an early symptom of acute maxillary sinusitis. Children with acute maxillary sinusitis present most often with cough, nasal discharge, and fetid breath; fever is less common (89). Symptoms associated with CRS are less fulminant; facial pain, headache, and postnasal discharge are common symptoms (8). The clinician should be aware
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that chronic maxillary sinusitis may result from primary dental infections (i.e., apical granuloma of the molar teeth, periodontitis) (88). Pain associated with temporomandibular dysfunction may be incorrectly diagnosed as chronic sinusitis. Individuals with sinusitis may experience severe facial pain associated with rapid changes in position (e.g., lying supine or bending forward) or with rapid changes in atmospheric pressure that occur during air travel. Episodes of ARS or CRS may be manifestations of other underlying problems. Local obstruction by a deviated nasal septum, nasal polyps, or occult benign or malignant neoplasm may explain recurrent sinus infections. Patients presenting with frequent CRS exacerbations or recurrent ARS that responds poorly to antibiotics or surgical treatment should be examined for primary or acquired immunodeficiency states (8). Humoral immune deficiencies that should be considered include specific antibody deficiency, common variable immune deficiency, rare complement deficiencies, and selective IgA deficiency in combination with IgG subclass deficiency (104–106). Disorders of ciliary dysmotility may occur in male patients. Kartagener syndrome is characterized by recurrent sinusitis, nasal polyps, situs inversus, infertility, and bronchiectasis (107). Nasal mucosal biopsy and electron microscopic examination to identify abnormalities in ciliary structure should be done in suspected cases. Granulomatosis with polyangiitis is a necrotizing vasculitis that presents with epistaxis, refractory sinusitis, serous otitis, nodular pulmonary infiltrates, and focal necrotizing glomerulonephritis (108). Chronic sinusitis or otitis media can precede pulmonary and renal manifestations for years before full expression of the disease. Early diagnosis and treatment of this systemic vasculitis before development of renal disease can be lifesaving. Eosinophilic granulomatosis with polyangiitis is another disease in the differential of severe CRSwNP (8).
Diagnosis Palpable tenderness, erythema, and warmth may be appreciated over inflamed frontal, ethmoid, or maxillary sinuses. Persistent purulent rhinorrhea and facial pain predict a high likelihood of bacterial ARS. Sinus imaging should be reserved for patients suspected of acute complication of ARS unresponsive to antibiotics, or patients with CRS for whom anatomic abnormalities are suspected and/or surgical intervention is being considered. Magnetic resonance imaging (MRI) is recommended for patients with persistent symptoms of unilateral CRS to exclude a tumor or soft tissue mass extending to the orbit or into the cranium (8,109). Rhinoscopy can be useful in identifying purulent discharge in the middle meatus compatible with acute maxillary sinusitis (8). Computed 1339
tomography (CT) is particularly useful for defining abnormalities in the anterior ethmoid and middle meatal areas (ostiomeatal unit), which cannot be visualized well on sinus roentgenograms. The CT coronal views (Fig. 27.1) are much less costly than a complete sinus CT and are adequate for determining the patency of the ostiomeatal complex, which includes the ethmoid and maxillary ostia and infundibulum. Demonstration of ostiomeatal obstruction is essential for assessing the need for surgical intervention in patients with CRS (110).
Complications In the age of antibiotics, severe life-threatening complications of acute sinusitis are relatively uncommon. However, the clinician must be able to recognize clinical manifestations of potentially fatal complications of sinusitis so that medical and surgical treatments can be initiated in a timely manner.
FIGURE 27.1 Computed tomographic image of the paranasal sinuses. A coronal section exhibits significant sinus disease on the left with a relatively normal appearance on the right. The left middle meatus (MM) and maxillary ostium (O) are obstructed by inflamed tissue, causing significant obstruction of the left ethmoid (ES) and maxillary (MS) sinuses.
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Serious complications of frontal sinusitis may be attributed to the proximity of the frontal sinus to the roof of the orbit and anterior cranial fossa. Osteomyelitis can result from acute frontal sinusitis and may present as a localized subperiosteal abscess (Pott’s puffy tumor) (111). Intracranial complications of frontal sinusitis include extradural, subdural, and brain abscesses as well as meningitis and cavernous sinus thrombosis (112,113). CT scans may be adequate to diagnose some complications of sinusitis, but MRI is superior to evaluate intracranial findings. Acute ethmoiditis is encountered most commonly in children. Extension of inflammation into the orbit can result in unilateral orbital and periorbital swelling with cellulitis. This presentation can be distinguished from cavernous sinus thrombosis by the lack of focal cranial neurologic deficits, absence of retro-orbital pain, and no meningeal signs. Patients with orbital cellulitis usually respond to antibiotics, and surgical drainage is rarely necessary. Cavernous sinus thrombosis is a complication of acute or chronic sinusitis that demands immediate diagnosis and treatment. The cavernous sinuses communicate with the venous channels draining the middle one-third of the face. Cavernous sinus thrombosis often arises from a subcutaneous infection in the face or paranasal sinuses. Vital structures that course through the cavernous sinus include the internal carotid artery and the third, fourth, fifth, and sixth cranial nerves. Symptoms of venous outflow obstruction caused by cavernous sinus thrombosis include retinal engorgement, retrobulbar pain, and visual loss. Impingement of cranial nerves in the cavernous sinus can result in extraocular muscle paralysis and trigeminal sensory loss. If not treated promptly with high doses of parenteral antibiotics, septicemia and central nervous system involvement can lead to a fatal outcome (114). Surgical intervention may be required. Acute sphenoid sinusitis is difficult to diagnose. A high index of suspicion and radiologic imaging with CT scan or MRI, are essential (115,116). Affected patients report occipital and retro-orbital pain, or the pain distribution may be nonspecific. Because of the posterior location of the sphenoid sinus, diagnosis of sphenoiditis may be delayed until serious complications are recognized. Extension of infections to contiguous structures may result in ocular palsies, orbital cellulitis, subdural abscess, meningitis, or hypopituitarism. It has long been recognized that chronic or recurrent sinusitis may exacerbate asthma. There is a strong correlation between sinus mucosal thickening and biomarkers of bronchial inflammation (e.g., sputum eosinophils, exhaled nitric 1341
oxide) in severe asthmatics (117). Surgical treatment of CRS may improve control in patients with difficult or refractory asthma (28,56,118,119).
Treatment of Acute Sinusitis The primary goal of treatment should be facilitation of drainage of affected sinuses and elimination of causative organisms. Gwaltney et al. studied 31 patients who presented with upper respiratory infection with significant CT abnormalities consistent with sinusitis (120). CT abnormalities spontaneously resolved in most patients 2 weeks later without antibiotics, suggesting that antibiotics are used unnecessarily in many patients. Judicious use of antibiotics is essential, especially in light of increasing problems with antibiotic resistance. Topical nasal vasoconstrictors (e.g., oxymetazoline) used prudently over the initial 2 to 3 days of treatment of acute sinusitis can facilitate drainage. Oxymetazoline and saline lavage used in combination for acute sinusitis have been shown to improve mucociliary clearance (121). The use of nasal steroids either as monotherapy or in combination with antibiotics for acute sinusitis has been advocated (8). A meta-analysis involving patients with radiographic or endoscopically diagnosed acute sinusitis who were not on antibiotics found that nasal steroids were more effective than placebo at relieving symptoms, with greater benefit seen at higher doses (122). Antibiotics should be considered in those who fail the aforementioned drainage measures, or who have persistent symptoms for more than 7 to 10 days. The emergence of penicillin-resistant strains must be recognized. For treating bacterial ARS, amoxicillin-clavulanate given for 14 days is recommended as the empiric antibiotic of choice in both adult patients and children (91). For those suspected of penicillin allergy, doxycycline (in adults), levofloxacin, and moxifloxacin are recommended as alternative agents (91). Owing to concerns over antibiotic resistance, macrolide antibiotics are no longer recommended for bacterial ARS. Treatment failures for acute sinusitis are not uncommon. Parenteral antibiotics should be instituted if local extension of infection (i.e., cellulitis or osteomyelitis) occurs, or if the infection is suspected to have spread to vital ocular or central nervous system structures. Surgical drainage of infected sinuses may be indicated when fever, facial pain, and sinus imaging changes persist, and for complicated cases of acute sinusitis. FESS may be superior to open techniques, depending on the specifics of a particular case (123). For patients with acute maxillary sinusitis who do not respond to conservative (medical) drainage measures and aggressive antibiotic therapy, antral puncture and irrigation may be indicated; ostial dilatation with a balloon is an alternative 1342
approach (8). Similar principles apply to the treatment of frontal, ethmoid, or sphenoid sinusitis.
Treatment of Chronic Rhinosinusitis The treatment approach to CRS and recurrent exacerbations should begin with identifying modifiable factors, such as allergic rhinitis, deviated nasal septum, nasal polyps, concha bullosa, exposure to tobacco smoke, toxic irritants at work, and other environmental factors. Acute exacerbations of CRS can be treated with short-term antibiotics, but there is no good evidence to support chronic antibiotic treatment for CRS (8). A course of oral steroids alone or combined with antibiotics may be effective in treating worsening CRS symptoms, especially in CRSwNP. One study showed improvements in nasal symptoms and nasal inspiratory flow in CRS patients treated with intranasal budesonide for 20 weeks (124). Chronic treatment with daily nasal irrigation is a very useful adjunctive treatment for CRS. Intranasal glucocorticoids are particularly effective in those with coexisting allergic rhinitis (124,125). Daily maintenance therapy with oral or topical decongestants is not considered beneficial for CRS (8); however, use of topical decongestants (oxymetazoline) in combination with nasal steroids may be a useful adjunctive treatment for CRS, and may be safe for up to 4 weeks (126–129). Treatment of predisposing conditions is more likely to be effective than multiple rounds of increasingly more broad-spectrum antibiotics. If indicated, prolonged treatment (3 to 6 weeks) with antibiotics is thought to be more effective than shorter courses (130). When incomplete resolution of exacerbations occurs, endoscopic or surgically obtained cultures can be helpful to guide antibiotic choices, particularly when broad-spectrum antibiotics such as fluoroquinolones are being considered (92). When all attempts at pharmacologic management have failed, surgery may be required as adjunctive treatment for chronic or recurrent sinusitis when associated with chronic ostiomeatal obstruction (8). FESS has supplanted older surgical procedures, such as maxillary Caldwell–Luc antrostomy. The basic principle of endoscopic techniques is to resect the inflamed tissues that obstruct the ostiomeatal complex and the anterior ethmoids, and thus directly interfere with normal physiologic drainage (131). Because nasal endoscopic surgery is less invasive, postoperative morbidity has been reduced markedly in comparison with formerly used surgical techniques. Multiple studies have demonstrated short-term improvements in symptoms after surgery for CRS or recurrent
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sinusitis (55). A prospective study of 82 patients who underwent endoscopic surgery after failing medical management reported significant initial improvements in self-reported symptoms; however, there was a trend toward recurrence of presenting complaints by 3 years (119). Those patients with AERD were less likely to experience long-term benefits from surgery.
Nonallergic Rhinitis Symptoms of nonallergic rhinitis are often indistinguishable from those associated with perennial allergic rhinitis. Nonallergic rhinitis is defined as inflammation of the nasal mucosa that is not because of IgE-mediated sensitization. Lack of allergic causation should be proven by the absence of skin test reactivity to a panel of common aeroallergens. A community-based Danish study of over 1,000 adults found that approximately 25% of chronic rhinitis sufferers had nonallergic rhinitis (132). Women were more likely to have nonallergic rhinitis than men, and symptom severity was indistinguishable between allergic and nonallergic rhinitics. Onset after 40 to 50 years of age is more likely with nonallergic versus allergic rhinitis; however, nonallergic rhinitis occurs in children as well (133,134). As many as 40 million Americans have nonallergic rhinitis, or a combination of nonallergic rhinitis and allergic rhinitis (135). Table 27.1 presents a classification for the nonallergic nasal disorders, which includes the differential diagnosis for conditions that may mimic rhinitis (136). Evaluation begins with a careful history and nasal examination, preferably with a nasal speculum. Nasal septal deviation is usually obvious. Pale, boggy nasal turbinates characteristic of allergic rhinitis may also be seen in a patient with nonallergic rhinitis with eosinophilia syndrome (NARES) or nasal polyps. The nasal mucosa appears beefy red or hemorrhagic in patients with rhinitis medicamentosa. Cytologic examination of a nasal mucus smear may reveal an abundance of neutrophils, which is suggestive of infectious rhinitis (137). Nasal eosinophils are consistent with allergic rhinitis, NARES, or nasal polyposis (138,139). Vasomotor rhinitis or idiopathic nonallergic noninfectious rhinitis is the most common of these disorders, excluding viral upper respiratory infections. Symptoms include perennial nasal congestion, rhinorrhea, and postnasal discharge. Ocular symptoms can be present in nonallergic rhinitis, although they tend to be more prominent in allergic rhinitis (140). Typically, nasal symptoms are triggered by irritants in tobacco smoke, chemical fumes, perfumes, or various 1344
scents and noxious odors. Symptoms are classically triggered by rapid changes in temperature. Although the pathophysiology of this condition is not well understood, it has been postulated that environmental factors may trigger neurogenic reflex responses or that symptoms are a consequence of an imbalance in parasympathetic and sympathetic tone (141). Transient receptor potential ion channels on sensory nerve endings on nasal mucosa may act as primary irritant sensors; activation of these channels leads to neuropeptide release with subsequent vasodilation and increase in transudation (142). Gustatory rhinitis is a form of vasomotor rhinitis in which clear rhinorrhea is provoked by eating, particularly when eating hot or spicy foods (143). Other subtypes of vasomotor rhinitis are listed in Table 27.1. TABLE 27.1 NONALLERGIC NASAL DISORDERS CONDITIONS THAT MAY SUBTYPES OF NONALLERGIC RHINITIS SYMPTOMS OF RHINITIS
Vasomotor rhinitis
Nasal polyps
Gustatory rhinitis
Structural/mechanical factors
MIMIC
Irritant triggered (e.g., chlorine)
Deviated septum/septal wall anomalies
Cold air
Adenoidal hypertrophy
Exercise (e.g., running)
Trauma
Undetermined or poorly defined triggers
Foreign bodies
Nonallergic rhinitis with eosinophilia syndrome (NARES)
Nasal tumors Benign
Atrophic rhinitis Rhinitis medicamentosa (topical vasocontrictors) Drug-induced rhinitis (oral medications) Hormonally induced rhinitis Pregnancy rhinitis Menstrual cycle related Infectious rhinitis Acute Chronic
Malignant Choanal atresia Cleft palate Pharyngonasal reflux Acromegaly (excess growth hormone) Rhinitis associated with inflammatoryimmunologic disorders Granulomatous infections Granulomatosis with polyangiitis (Wegener syndrome) Sarcoidosis Midline granuloma
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Eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) Relapsing polychondritis Amyloidosis Cerebrospinal fluid rhinorrhea Ciliary dyskinesia syndrome
Adapted from the Joint Council of Allergy, Asthma & Immunology. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol. 2008;122(6):1237.
NARES is an inflammatory nasal disorder in which eosinophils are detectable on a nasal smear (>5% to >20% nasal eosinophils), but skin tests to relevant aeroallergens are negative (144–146). The cause of this condition is unknown. NARES may be a precursor to the development of nasal polyposis and aspirin intolerance (147). Primary atrophic rhinitis is a disorder of unknown origin, which is characterized by formation of thick, malodorous, dry crusts that obstruct the nasal cavity (148,149). Secondary atrophic rhinitis is more common in the Western world, and is associated with granulomatous disease, nasal irradiation, trauma, and prior sinonasal surgery. Removal of the middle and/or inferior turbinates in particular may predispose to development of secondary atrophic rhinitis (150). Rhinitis medicamentosa can result from the chronic use or abuse of topical decongestants, or from cocaine use. Excessive use of topical vasoconstrictor agents, such as neosynephrine or oxymetazoline, can result in epistaxis, “rebound” nasal congestion, and rarely cause nasal septal perforation (151). Intranasal cocaine use can result in the same signs and symptoms. Benzalkonium chloride, a preservative commonly used in over-the-counter and prescription aqueous products, might play a causative role in rhinitis medicamentosa (152). Drug-induced rhinitis occurs as an adverse effect of certain oral medications (see Table 27.2) (153). In particular, angiotensin-converting enzyme inhibitors have been reported to cause rhinorrhea and vasomotor symptoms in association with chronic cough, which resolve after withdrawal of the drug (154). Other oral medications associated with drug-induced rhinitis include phosphodiesterase type 5 inhibitors (e.g., sildenafil), nonsteroidal anti-inflammatory drugs, certain 1346
psychotropic medications, gabapentin, and α-antagonists used for benign prostatic hypertrophy (153,155). Nasal congestion and rhinorrhea are common during pregnancy. This may be related to underlying allergic rhinitis, sinusitis, rhinitis medicamentosa, or may be due to vasomotor rhinitis of pregnancy (“pregnancy rhinitis”). “Pregnancy rhinitis” occurs in approximately one-fifth of pregnant women and manifests primarily as nasal congestion that starts before the last 6 weeks of pregnancy and resolves within 2 weeks of delivery (156). It may be due to progesterone or estrogen-induced nasal vasodilation and enhancement of mucus secretion, or possibly to placental growth hormone (157). TABLE 27.2 CAUSATIVE AGENTS FOR DRUG-INDUCED RHINITIS Antihypertensives
Psychotropic agents
Amiloride
Chlordiazepoxide-amitryptyline
ACE inhibitorsa
Chlorpromazine
ARBsb
Risperidone
β-Blockers
Thioridazine Ovarian hormonal agents
Chlorothiazine Clonidine
Oral contraceptivesd
Hydralazine
Exogenous estrogens Pain relievers
Hydrochlorothiazide
Aspirin
Methyldopa
Nonsteroidal anti-inflammatory drugs
α-Adrenergic antagonistsc
Miscellaneous
Prazosin Doxazosin
Cocainee
Phentolamine
Gabapentin
Terazosin Tamsulosin Phosphodiesterase type 5 inhibitors Sildenafil Tadalafil Verdenafil a
Angiotensin-converting enzyme inhibitors.
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b
Angiotensin receptor blockers (177).
c
Used for hypertension or benign prostatic hypertrophy depending on specific drug.
d
May not apply to modern oral contraceptives (178).
e
Mechanism may be similar to other topical vasoconstrictors.
Adapted from Ramey JT, Bailen E, Lockey RF. Rhinitis medicamentosa. J Investig Allergol Clin Immunol. 2006;16(3):148–155.
Local allergic rhinitis is caused by local production of sIgE (158). Skin tests and serum sIgE are negative, but sIgE can be measured in nasal lavage and nasal provocation tests are positive. The prevalence of this condition has not been reported. Conditions that mimic rhinitis must be considered in the differential diagnosis. A grossly deviated nasal septum, nasal tumors, or a foreign body can be the source of unilateral nasal obstruction refractory to medical treatment. Cerebral spinal fluid (CSF) rhinorrhea is characterized by clear nasal discharge. It occurs in 5% of all basilar skull fractures but can be present in patients with no history of trauma. Detection of β-2 transferrin in the CSF is useful in confirming the diagnosis (159,160).
Treatment Selection of therapy for vasomotor rhinitis is empiric, and there are variable responses to different regimens. Azelastine hydrochloride is a topical antihistamine that has been shown to decrease nasal congestion and postnasal drip associated with vasomotor rhinitis in multiple randomized controlled trials (161–164). Olopatadine hydrochloride nasal spray has shown similar efficacy to azelastine for vasomotor rhinitis (165). Intranasal steroids are beneficial for some cases of vasomotor rhinitis (166,167). The combination of azelastine with intranasal steroids (fluticasone proprionate) provides greater symptom relief than either agent alone (161,168). When not contraindicated by coexisting medical conditions, oral decongestants are often effective for congestion caused by vasomotor rhinitis when given as 12-hour slow-release preparations (e.g., pseudoephedrine) (169). Nasal ipratropium, an anticholinergic agent, is proven to be effective in treating rhinorrhea associated with nonallergic rhinitis, and is the treatment of choice for gustatory and cold air–induced rhinitis (143,170,171). A recent Cochrane Database Review of four studies including 302 patients concluded that intranasal capsaicin may be a treatment option for vasomotor rhinitis (172). Environmental triggers, such as tobacco smoke and irritants, encountered at home or work should be avoided. 1348
The syndrome of NARES responds best to intranasal glucocorticoids (167). Atrophic rhinitis is treated chronically with saline irrigation, with topical and systemic antibiotics prescribed for acute infections (150). Patients with rhinitis medicamentosa should discontinue offending medications. Intranasal glucocorticoids may be of considerable benefit in these patients in decreasing mucosal edema (173). For rhinitis of pregnancy, medication use should be minimized. Saline rinses and mechanical alar dilators may be appropriate. If necessary, nasal steroids (i.e., intranasal budesonide) may be safe and effective for controlling chronic allergic rhinitis symptoms encountered during pregnancy, but do not have proven efficacy for treating pure pregnancy rhinitis (156,174,175). Nasal ipratropium could also be considered to treat associated rhinorrhea (170,176). Nasal obstruction caused by a severely deviated septum requires septoplasty. Some patients with CSF rhinorrhea recover spontaneously, or with medical treatment alone. When persistent, intravenous antibiotics should be started to prevent meningitis, and endoscopic or open surgery often is required to repair a dural tear (8). REFERENCES 1. Jenneck C, Juergens U, Buecheler M, et al. Pathogenesis, diagnosis, and treatment of aspirin intolerance. Ann Allergy Asthma Immunol. 2007;99(1):13–21. 2. Stevens WW, Schleimer RP, Kern RC. Chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol Pract. 2016;4(4):565–572. 3. Andrews AE, Bryson JM, Rowe-Jones JM. Site of origin of nasal polyps: relevance to pathogenesis and management. Rhinology. 2005;43(3):180– 184. 4. Lou H, Meng Y, Piao Y, et al. Cellular phenotyping of chronic rhinosinusitis with nasal polyps. Rhinology. 2016;54(2):150–159. 5. Kim JW, Hong SL, Kim YK, et al. Histological and immunological features of non-eosinophilic nasal polyps. Otolaryngology Head Neck Surg. 2007;137(6):925–930. 6. Weisskopf A, Burn HF. Histochemical studies of the pathogenesis of nasal polyps. Ann Otol Rhinol Laryngol. 1959;68(2):509–523. 7. Johansson L, Akerlund A, Holmberg K, et al. Prevalence of nasal polyps in adults: the Skovde population-based study. Ann Otol Rhinol Laryngol. 1349
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hyperplasia. Cochrane Database Syst Rev. 2003(1):CD002081. 156. Ellegard EK. The etiology and management of pregnancy rhinitis. Am J Respir Med. 2003;2(6):469–475. 157. Ellegard EK. Clinical and pathogenetic characteristics of pregnancy rhinitis. Clin Rev Allergy Immunol. 2004;26(3):149–159. 158. Campo P, Salas M, Blanca-Lopez N, et al. Local allergic rhinitis. Immunol Allergy Clin North Am. 2016;36(2):321–332. 159. Meurman OH, Irjala K, Suonpaa J, et al. A new method for the identification of cerebrospinal fluid leakage. Acta Otolaryngol. 1979;87(3– 4):366–369. 160. Ryall RG, Peacock MK, Simpson DA. Usefulness of beta 2-transferrin assay in the detection of cerebrospinal fluid leaks following head injury. J Neurosurg. 1992;77(5):737–739. 161. Bernstein JA. Azelastine hydrochloride: a review of pharmacology, pharmacokinetics, clinical efficacy and tolerability. Curr Med Res Opin. 2007;23(10):2441–2452. 162. Banov CH, Lieberman P. Efficacy of azelastine nasal spray in the treatment of vasomotor (perennial nonallergic) rhinitis. Ann Allergy Asthma Immunol. 2001;86(1):28–35. 163. Gehanno P, Deschamps E, Garay E, et al. Vasomotor rhinitis: clinical efficacy of azelastine nasal spray in comparison with placebo. ORL J Otorhinolaryngol Relat Spec. 2001;63(2):76–81. 164. Lieberman PL, Settipane RA. Azelastine nasal spray: a review of pharmacology and clinical efficacy in allergic and nonallergic rhinitis. Allergy Asthma Proc. 2003;24(2):95–105. 165. Lieberman P, Meltzer EO, LaForce CF, et al. Two-week comparison study of olopatadine hydrochloride nasal spray 0.6% versus azelastine hydrochloride nasal spray 0.1% in patients with vasomotor rhinitis. Allergy Asthma Proc. 2011;32(2):151–158. 166. Pipkorn U, Berge T. Long-term treatment with budesonide in vasomotor rhinitis. Acta Otolaryngol. 1983;95(1–2):167–171. 167. Webb DR, Meltzer EO, Finn AF Jr, et al. Intranasal fluticasone propionate is effective for perennial nonallergic rhinitis with or without eosinophilia. Ann Allergy Asthma Immunol. 2002;88(4):385–390. 1362
168. Kaliner MA. A novel and effective approach to treating rhinitis with nasal antihistamines. Ann Allergy Asthma Immunol. 2007;99(5):383–390; quiz 391–392, 418. 169. Corey JP, Houser SM, Ng BA. Nasal congestion: a review of its etiology, evaluation, and treatment. Ear Nose Throat J. 2000;79(9):690–693, 696, 698 passim. 170. Grossman J, Banov C, Boggs P, et al. Use of ipratropium bromide nasal spray in chronic treatment of nonallergic perennial rhinitis, alone and in combination with other perennial rhinitis medications. J Allergy Clin Immunol. 1995;95(5 Pt 2):1123–1127. 171. Bonadonna P, Senna G, Zanon P, et al. Cold-induced rhinitis in skiers— clinical aspects and treatment with ipratropium bromide nasal spray: a randomized controlled trial. Am J Rhinol. 2001;15(5):297–301. 172. Gevorgyan A, Segboer C, Gorissen R, et al. Capsaicin for non-allergic rhinitis. Cochrane Database Syst Rev. 2015;(7):CD010591. 173. Ferguson BJ, Paramaesvaran S, Rubinstein E. A study of the effect of nasal steroid sprays in perennial allergic rhinitis patients with rhinitis medicamentosa. Otolaryngology Head Neck Surg. 2001;125(3):253–260. 174. Ellegard EK, Hellgren M, Karlsson NG. Fluticasone propionate aqueous nasal spray in pregnancy rhinitis. Clin Otolaryngol Allied Sci. 2001;26(5):394–400. 175. Berard A, Sheehy O, Kurzinger ML, et al. Intranasal triamcinolone use during pregnancy and the risk of adverse pregnancy outcomes. J Allergy Clin Immunol. 2016;138(1):97.e107–104.e107. 176. Namazy J, Schatz M. The treatment of allergic respiratory disease during pregnancy. J Investig Allergol Clin Immunol. 2016;26(1):1–7; quiz 2p following 7. 177. Samizo K, Kawabe E, Hinotsu S, et al. Comparison of losartan with ACE inhibitors and dihydropyridine calcium channel antagonists: a pilot study of prescription-event monitoring in Japan. Drug Saf. 2002;25(11):811–821. 178. Wolstenholme CR, Philpott CM, Oloto EJ, et al. Does the use of the combined oral contraceptive pill cause changes in the nasal physiology in young women? Am J Rhinol. 2006;20(2):238–240.
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THE EYE The allergic eye diseases are contact dermatoconjunctivitis, acute allergic conjunctivitis, vernal conjunctivitis, and atopic keratoconjunctivitis (allergic eye diseases associated with atopic dermatitis). Several other conditions mimic allergic disease and should be considered in any patient presenting with conjunctivitis. These include the blepharoconjunctivitis associated with staphylococcal infection, seborrhea and rosacea, acute viral conjunctivitis, chlamydial conjunctivitis, keratoconjunctivitis sicca, herpes simplex keratitis, giant papillary conjunctivitis, vasomotor (perennial chronic) conjunctivitis, and the “floppy eye syndrome.” Each of these entities is discussed in relationship to the differential diagnosis of allergic conjunctivitis. The allergic conditions themselves are emphasized. In addition to the systematic discussion of these diseases, because the chapter is written for the nonophthalmologist, an anatomic sketch of the eye (Fig. 28.1) is included.
Diseases Involving the Eyelids There are two conditions to be considered when the eyelids are involved. They are contact dermatitis and atopic keratoconjunctivitis. Contact Dermatitis and Dermatoconjunctivitis Because the skin of the eyelid is thin (0.55 mm), it is particularly prone to develop both immune and irritant contact dermatitis. When the causative agent has contact with the conjunctiva and the lid, a dermatoconjunctivitis occurs.
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FIGURE 28.1 Transverse section of the eye. (From Brunner L, Suddarth D. Textbook of Medical-Surgical Nursing. 4th ed. Philadelphia: JB Lippincott, 1980, with permission.) Clinical Presentation Contact dermatitis and dermatoconjunctivitis affect women more commonly than men because women use cosmetics more frequently. Vesiculation may occur early, but by the time the patient seeks care, the lids usually appear thickened, red, and chronically inflamed. Peeling and scaling of the eyelids also occur with chronic exposure. If the conjunctiva is involved, there is erythema and tearing. A papillary response with vasodilation and chemosis occurs. Pruritus is the cardinal symptom; a burning sensation may also be present. Rubbing the eyes intensifies the itching. Tearing can occur. An erythematous blepharitis is common, and in severe cases, keratitis can result. Causative Agents Contact dermatitis and dermatoconjunctivitis can be caused by agents directly applied to the lid or conjunctiva, aerosolized or airborne agents contacted by chance, and cosmetics applied to other areas of the body. In fact, eyelid dermatitis occurs frequently because of cosmetics (e.g., nail polish, hair spray) applied to other areas of the body (1). However, agents applied directly to the eye are the most common causes. Contact dermatitis can be caused by eye makeup, including eyebrow pencil and eyebrow brush-on products, eye shadow, eye liner, mascara, artificial lashes, and lash extender. These products contain 1366
coloring agents, lanolin, paraben, sorbitol, paraffin, petrolatum, and other substances such as vehicles and perfumes (1). Brushes and pads used to apply these cosmetics can also produce dermatitis. In addition to agents applied directly only to the eye, soaps and face creams can produce a selective dermatitis of the lid because of the thin skin in this area. Cosmetic formulations are frequently altered (1). Therefore, a cosmetic previously used without ill effect can become a sensitizing agent. Any medication applied to the eye can produce a contact dermatitis or dermatoconjunctivitis. Ophthalmic preparations contain several sensitizing agents, including benzalkonium chloride, chlorobutanol, chlorhexidine, ethylenediaminetetraacetate acid (EDTA), and phenylmercuric salts. EDTA cross-reacts with ethylenediamine, so that patients sensitive to this agent are subject to develop dermatitis as a result of several other medications. Today, antibiotics, antivirals, and antiglaucoma drugs are probably the major causes of iatrogenic contact dermatoconjunctivitis. Several other topically applied medications, however, have been shown to cause dermatoconjunctivitis. These include antihistamines, such as antazoline, as well as atropine, pilocarpine, phenylephrine, epinephrine, and topical anesthetics. Of continuing importance is the conjunctivitis associated with the wearing of contact lenses, especially soft lenses. Reactions can occur to the lenses themselves or to the chemicals used to treat them. Both toxic and immune reactions can occur to contact lens solutions. Thimerosal, a preservative used in contact lens solutions, has been shown to produce classic, cell-medicated contact dermatitis (2). Other substances found in lens solutions that might cause either toxic or immune reactions are the bacteriostatic agents (methylparaben, chlorobutanol, and chlorhexidine) and EDTA, which is used to chelate lens deposits. With the increasing use of disposable contact lenses, the incidence of contact allergy to lenses and their cleansing agents appears to be declining. Dermatitis of the lid and conjunctiva can also result from exposure to airborne agents. Hair spray, volatile substances contacted at work, and the oleoresin moieties of airborne pollens have all been reported to produce contact dermatitis and dermatoconjunctivitis. Hair preparations and nail enamel frequently cause problems around the eye while sparing the scalp and the hands. Finally, Rhus dermatitis can affect the eye, producing unilateral periorbital edema, which can be confused with angioedema. Diagnosis and Identification of Causative Agents The differential diagnosis includes seborrheic dermatitis and blepharitis, 1367
infectious eczematous dermatitis (especially chronic staphylococcal blepharitis), and rosacea. Seborrheic dermatitis can usually can differentiated from contact dermatitis on the basis of seborrheic lesions elsewhere and the lack or pruritus. Also, pruritus does not occur in staphylococcal blepharitis or rosacea. If the diagnosis is in doubt, an ophthalmology consultation should be obtained. In some instances, the etiologic agent may be readily apparent. This is usually the case in dermatitis caused by the application of topical medications. However, many cases present as chronic dermatitis, and the cause is not readily apparent. In such instances, an elimination-provocation procedure and patch tests can identify the offending substance. The elimination-provocation procedure requires that the patient stop using all substances under suspicion. This is often difficult because it requires the complete removal of all cosmetics, hair sprays, spray deodorants, and any other topically applied substances. It should also include the cessation of visits to hair stylists and day spas during the course of the elimination procedure. The soaps and shampoo should be changed. A bland soap (e.g., Basis) and shampoo free of formalin (e.g., Neutrogena, Ionil) should be employed. In recalcitrant cases, the detergent used to wash the pillowcases should also be changed. The elimination phase of the procedure should continue until the dermatitis subsides, or for a maximum of 1 month. When the illness has cleared, cosmetics and other substances can be returned at a rate of 1 every week. On occasion, the offending substances can be identified by the recurrence of symptoms upon the reintroduction of the substance in question. Patch tests can be helpful in establishing a diagnosis (3,4). However, the skin of the lid is markedly different from that of the back and forearm, and drugs repeatedly applied to the conjunctival sac concentrate there, producing high local concentrations of the drug. Thus, false-negative results from patch tests are common (1). Testing should be performed, not only to substances in standard patch test kits but also to the patient’s own cosmetics. In addition to the cosmetics themselves, tests can be performed to applying agents, such as sponges and brushes. Both open- and closed-patch tests are indicated when testing with cosmetics (1). Fisher (4) describes a simple test consisting of rubbing the substances into the forearm three times daily for 4 to 5 days and then examining the sites. Because of the difficulty involved in establishing the etiologic agent with standard patch test kits, an ophthalmic patch test tray (Table 28.1) has been suggested (3). Therapy The treatment of choice is removal of the offending agent. On occasion, this can 1368
be easily accomplished. An example of this is the switch from chemically preserved to heat-sterilized systems in patients with contact lens-associated contact conjunctivitis. The offending agent, however, frequently cannot be identified, regardless of the diagnostic procedures applied. In these instances, chronic symptomatic therapy, possibly in conjunction with an ophthalmologist, is all that can be offered to the patient. Symptomatic relief can be obtained with topical corticosteroid creams, ointments, and drops. Corticosteroid drops should be employed only under the direction of the ophthalmologist. Cool tap-water soaks and boric acid eye baths may help. Atopic Dermatitis Ocular Involvement Manifestations of atopic involvement of the eyelids are similar to immune and irritant contact dermatitis of the lids. Chronic scaling, pruritus, and lichenification of the lids are most commonly due to these two disorders, and both should be considered in the differential diagnosis. The features that distinguish atopic dermatitis of the lid from contact and irritant dermatitis are the following: • The presence of atopic dermatitis manifestations elsewhere and concomitant existence of allergic respiratory disease. • Pruritus is usually more common and intense in atopic dermatitis. • Madarosis (lash loss) and trichiasis (lash misdirection) are more common in atopic dermatitis. • Involvement of the eye itself is also present in most cases of atopic dermatitis of the lid. • The ocular findings are conjunctival erythema and swelling, limbal papillae, keratoconus (see below), anterior and posterior subcapsular cataracts, and occasionally corneal erosion with ulcers, neovascularization, and scarring. • A family history of atopic disease is usually noted. Dermatitis infecting the lids can present with a myriad of manifestations. The hallmark is intense bilateral itching and burning of the lids with scaling. There is often accompanying tearing and photophobia. Like vernal conjunctivitis, patients with ocular manifestations as well can exhibit a thick, ropy discharge. The lids are edematous, scaly, and thickened. There is a wrinkled appearance of the skin. Lichenification occurs with chronic involvement. Eyelid 1369
malpositions are common. Because of the chronic itching, the patient’s rubbing and scratching of their lids leads to further changes such as fissures, which occur commonly near the lateral canthus (5). Periorbital features of allergic disease have also been described. The classic “Dennie–Morgan” fold is a crease extending from the inner canthus laterally to the mid-pupillary line of the lower lid. There is often periorbital darkening referred to as “the allergic shiner.” The lateral eyebrows are often absent (Hertoghe sign). Eyelid margin (blepharitis) involvement is characteristic. The findings resemble those of chronic bacterial blepharitis (see below), and indeed these findings may be because of bacterial overgrowth occurring with atopy. There is hyperemia and an exudate with crusting in the morning. TABLE 28.1 SUGGESTED OPHTHALMIC TRAY FOR PATCH TESTING
COMPOUND
PATCH TEST CONCENTRATION (%) VEHICLE
Preservatives Benzalkonium chloride
0.1
aq
Benzethonium chloride
1
aq
Chlorhexidine gluconate
1
aq
Cetalkonium chloride
0.1
aq
Sodium EDTA
1
aq
Sorbic acid
2.5
pet
Thimerosal
0.1; 1
pet
1370
β-Adrenergic Blocking Agents
Befunolol
1
aq
Levobunolol HCI
1
aq
Metipranolol
2
aq
Metoprolol
3
aq
Timolol
0.5
aq
Atropine sulfate
1
aq
Epinephrine HCI
1
aq
Phenylephrine HCI
10
aq
Scopolamine hydrobromide
0.25
aq
Bacitracin
5
pet
Chloramphenicol
5
pet
Gentamicin sulfate
20
pet
Kanamycin
10
pet
Mydriatics
Antibiotics
1371
Neomycin sulfate
20
pet
Polymyxin B sulfate
20
pet
Idoxuridine
1
pet
Trifluridine
5
pet
Antiviral Drugs
Antihistamines or Antiallergic Drug Chlorpheniramine maleate
5
pet
Sodium cromoglycate
2
aq
Benzocaine
5
pet
Procaine
5
aq
Oxybuprocaine
0.5
aq
Proxymetacaine
0.5
aq
1
pet
Anesthetics
Enzymatic Cleaners Papain
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Tegobetaine
1
aq
Pilocarpine
1
aq
Tolazoline
10
aq
Echothiophate iodide
1
aq
1
aq
Miotics
Other Epsilon aminocaproic acid
aq, aqueous; EDTA, ethylenediaminetetraacetic acid; pet, petrolatum. From Mondino B, Salamon S, Zaidman G. Allergic and toxic reactions in soft contact lens weavers. Surv Ophthalmol. 1982;26:337–344, with permission.
Owing to misdirection of the lashes, there is often contact of the lash with the conjunctivae, and this can be particularly bothersome to patients. As noted, bacterial colonization is not uncommon. Staphylococcal aureus is probably the most common organism involved. Presumably, Staphylococcus colonizes the eye through contact with the hands. The phenotype of the Staphylococcus growing in the eye correlates with that of overgrowth on the skin in the majority of instances (6). Therapy Therapy of the lids in atopic dermatitis is similar to that of allergic disease in general. Known environmental exacerbants should, of course, be avoided. Cool compresses and bland moisturizers are helpful. Vaseline and Aquaphor (Beiersdorf, Norwalk, Connecticut) are examples in this regard. Periodic exacerbations of lid inflammation can be treated with low-dose topical corticosteroid ointments. An example is fluorometholone 0.1% ophthalmic ointment. Care must be taken, however, because long-term administration can thin the skin of the eyelid and produce permanent cosmetic changes because 1373
vessels begin to show through the thin skin. The lowest dose for the shortest period of time should be employed. Tacrolimus and pimecrolimus topical preparation can also be helpful as in atopic dermatitis in general. Pathophysiology The pathogenesis of eye involvement in atopic dermatitis, like the pathophysiology underlying abnormalities in the skin, is complex. It certainly involves immunoglobulin E (IgE)-mediated mechanisms, but clearly other inflammatory pathways are also active. Patients with atopic keratoconjunctivitis have elevated tear levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNFα), interleukin 2 (IL-2), IL-4, IL-5, and IL-10, thus indicating a combined TH1 and TH2 response (7). However, at least in animal models, there is a clear predominance of the TH2 phenotype in terms of T cells. The characteristic ocular eosinophilia appears to be dependent upon the presence of this T-cell population (8). The active role of T cells in allergic disorders of the eye clearly explain the beneficial effect of cyclosporin in these diseases (9). Acute Allergic Conjunctivitis Pathophysiology Acute allergic conjunctivitis is the most common form of allergic eye disease (10). Seasonal allergic conjunctivitis and perennial allergic conjunctivitis are estimated to affect 15% to 45% of the US population (10). Seasonal and perennial allergic conjunctivitis represent 25% to 95% of the total cases of ocular allergy (10,11). And, the incidence of this condition is probably underestimated because the percentage of undiagnosed allergic conjunctivitis in patients presenting with rhinitis may range from 25% to 60% (12). Allergic conjunctivitis is produced by IgE-induced mast cell and basophil degranulation (11,13). As a result of this reaction, histamine, kinins, leukotrienes, prostaglandins, interleukins, chemokines, IL-4, IL-5, and eosinophilic cationic protein, eotaxin, and other mediators are released in the eye (14–17). Patients with allergic conjunctivitis have elevated amounts of total IgE in their tears (18–20), and tear fluid also contains IgE specific for seasonal allergens (21). Eosinophils are found in ocular scrapings (22–24). These eosinophils are activated, releasing contents such as eosinophil cationic protein from their granules. These contents appear in tear fluid as well (24). Ocular challenge with pollen produces both an early- and 1374
a late-phase ocular response (25). In humans, the early phase begins within 20 minutes after challenge. The late phase is dose dependent, and large doses of allergen cause the initial inflammation to persist and progress (25). The late phase differs from that which occurs in the nose and lungs in that it is often continuous and progressive rather than biphasic (25). It is characterized by the infiltration of inflammatory cells, including neutrophils, eosinophils, and lymphocytes. The eosinophil is the predominant cell (25). In addition, during the late-phase reaction, mediators are continually released, including histamine, leukotrienes, and eosinophil contents (26). Subjects with allergic conjunctivitis demonstrate a typical TH2 (allergic) profile of cytokines in their tear fluid showing excess production of IL-4 and IL5 (27–29). If the illness becomes chronic, however, there may be a shift in cytokine profile to a TH1 pattern with excess production of IFN-γ, as seen in atopic keratoconjunctivitis (29,30). Subjects with allergic conjunctivitis have an increased number of mast cells in their conjunctivae (31), and mast cell numbers increase during the allergy season. In addition, the phenotype is modified as mucosal mast cells increase to a greater degree than connective tissue mast cell (11). Patients with allergic conjunctivitis are hyperresponsive to intraocular histamine challenge (32). Of interest is the fact that there is evidence of complement activation. Elevated levels of C3a des-Arg appear in tear fluid (28). The consequences of this immune reaction are conjunctival vasodilation and edema. The clinical reproducibility of the reaction is dependable. Instillation of allergen into the conjunctival sac was once used as a diagnostic test (33). Clinical Presentation Acute allergic conjunctivitis is usually recognized easily. Intense itching is the dominant feature (34). Rubbing the eyes intensifies the symptoms. The illness is almost always bilateral. However, unilateral acute allergic conjunctivitis can occur secondary to manual contamination of the conjunctiva with allergens, such as foods and animal dander. Ocular signs are usually minimal despite significant symptoms. The conjunctiva may be injected and edematous. In severe cases, the eye may be swollen shut. These symptoms of allergic conjunctivitis may be so severe as to interfere with the patient’s sleep and work. Allergic conjunctivitis rarely occurs without accompanying allergic rhinitis. Nevertheless, the eye symptoms may be more prominent than nasal symptoms and can be the patient’s major complaint. However, if symptoms or signs of 1375
allergic rhinitis are totally absent, the diagnosis of allergic conjunctivitis is doubtful. Allergic conjunctivitis also exists in a chronic, perennial form. Symptoms are usually less intense. As in acute allergic conjunctivitis, ocular findings on physical examination may not be impressive. Diagnosis and Treatment The diagnosis of allergic conjunctivitis can usually be made on the basis of history. Usually, there is an atopic personal or a family history; the disease is usually seasonal. At times, the patient may be able to define the offending allergen accurately. Skin tests are confirmatory. Stain of the conjunctival secretions may show numerous eosinophils, but the absence of eosinophils does not exclude the condition (35). Normal individuals do not have eosinophils in conjunctival scrapings; therefore, the presence of one eosinophil is consistent with the diagnosis (35). The differential diagnosis should include other forms of acute conjunctivitis, including viral and bacterial conjunctivitis, contact dermatoconjunctivitis, conjunctivitis sicca, and vernal conjunctivitis. Treating allergic conjunctivitis is the same as for other atopic illness: avoidance, symptomatic relief, and immunotherapy, in that order. When allergic conjunctivitis is associated with respiratory allergic disease, the course of treatment is usually dictated by the more debilitating respiratory disorder. Avoiding ubiquitous aeroallergens is impractical, but avoidance measures outlined elsewhere in this text can be employed in the treatment of allergic conjunctivitis. Effective symptomatic therapy for allergic conjunctivitis can usually be achieved with topical medications. The most significant change in the management of allergic eye disorders since the last edition of this text is the release of new topical agents to treat these disorders. Six classes of topical agents are now available: vasoconstrictors, “classic” antihistamines, “classic” mast cell stabilizers, new agents with multiple “antiallergic” activities, nonsteroidal antiinflammatory agents, and corticosteroids. Selected examples of these agents are noted in Table 28.2. Corticosteroids are not discussed here because, as a result of their well-known side effects, patients should use them only when prescribed by the ophthalmologist. TABLE 28.2 REPRESENTATIVE TOPICAL AGENTS USED TO TREAT ALLERGIC EYE DISORDERS REPRESENTATIVE
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DRUG CLASS
TRADE EXAMPLES
NAME DOSAGE
COMMENTS
Vasoconstrictors Tetrahydrozoline, phenylephrine, oxymetazoline, naphazoline
Naphcon, Vasocon, 1–2 drops every 4 h Only helpful for eye Visine prn (not more than redness. Does not qid) relieve itch. Available without prescription. Some concern about “rebound.” Contraindicated in narrow-angle glaucoma.
Antihistamines Levocabastine
Livostin
1 drop qid
Emedastine
Emadine
1 drop qid
Effective for itching. Available by prescription only. May be more potent than antihistamines available without prescription.
Combination Vasoconstrictor Plus Antihistamine Antazoline, naphazoline
Vasocon-A
1 drop qid
Effective for eye redness and itch. Available without prescription.
Lodoxadine
Alomide
1 drop qid
Cromolyn
Crolom, Opticrom
1 drop qid
Best when initiated before onset of symptoms.
Mast Cell Stabilizers
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Nedocromil
Allocril
1 drop qid
Pemirolast
Alamast
1 drop qid
Nonsteroidal Anti-inflammatory Drugs Ketorolac
Acular
1 drop qid
Indicated for itching
Drugs with Multiple “Antiallergic” Activities Such as Antihistamine, Mast Cell Stabilizing, and Antieosinophil Effects Olopatadine preparations
Patanol (0.1%)
1 drop bid
Prescription required
Pataday (0.2%)
1 drops qd
Prescription required
Pazeo (0.7%)
1 drop qd
Prescription required
Ketotifen
Zaditor
1 drop every 12 h
Available without prescription
Epinastine
Elestat
1 drop every 12 h
Prescription required
Azelastine
Optivar
1 drop every 12 h
Prescription required
Acaftadine
Lastacraft
1 drop qd
Prescription required
Bepotastine
Bepreve
1 drop qd
Prescription required
bid, two times a day; prn, as needed; qd, once a day; qid, four times a day.
Several preparations contain a mixture of a vasoconstrictor combined with an antihistamine (Table 28.2). These drugs can be purchased over the counter. The antihistamine is most useful not only for itching but also reduces vasodilation. Vasoconstrictors only diminish vasodilation and have little effect on pruritus. They have relatively short duration of action, are subject to tachyphylaxis (36), and can cause rebound vasodilatation. Three frequently employed decongestants are naphazoline, oxymetazoline, and phenylephrine. The two most common antihistamines available in combination products are antazoline and pheniramine maleate. 1378
Levocabastine (Livostin) is an H1 antihistamine available only by prescription. Levocabastine was specifically designed for topical application. In animal studies, it is 1,500 times more potent than chlorpheniramine on a molar basis (37). It has a rapid onset of action (37), is effective in blocking intraocular allergen challenge (38), and appears to be as effective as other agents, including sodium cromoglycate (39,40) and provides excellent compliance (41). Emedastine (Emadine) is also a high-potency selective H1 antagonist with a receptor-binding affinity even higher than levocabastine (42). It has rapid onset of action (within 10 minutes) and a duration of activity of 4 hours (42). As a rule, vasoconstrictors and antihistamines are well tolerated. However, antihistamines may be sensitizing. In addition, each preparation contains several different vehicles that may produce transient irritation or sensitization. Just as vasoconstrictors in the nose can cause rhinitis medicamentosa, frequent use of vasoconstrictors in the eye results in conjunctivitis medicamentosa. As a rule, however, these drugs are effective and well tolerated (43). Four mast cell stabilizers are available for therapy, namely, cromolyn sodium, nedocromil sodium, lodoxamide, and pemirolast. All are efficacious and usually well tolerated (44–48). They are more effective when started before the onset of symptoms and used regularly four times a day (46), but they can relieve symptoms if given shortly before ocular allergen challenge (47). Thus, they are also useful in preventing symptoms caused by isolated allergen challenge such as occurs when visiting a home with a pet or mowing the lawn. In these instances, they should be administered immediately before exposure. Ketorolac tromethamine (Acular) is a nonsteroidal anti-inflammatory agent that is most effective in controlling itching but also ameliorates other symptoms (49). Its effect results from its ability to inhibit the formation of prostaglandins, especially prostaglandin E2 which causes itching when applied to the conjunctiva (50). Four agents for the treatment of allergic eye disorders have broad-based antiallergic or anti-inflammatory effects in addition to their antihistamine activity, such as azelastine (Optivar), olopatadine (Patanol and Pataday), ketotifen (Zaditor), and epinastine (Elestat). They prevent mast cell degranulation, reduce eosinophil activity, and downregulate the expression of adhesion molecules as well as inhibit the binding of histamine to the H1 receptor (51–54). Because of the efficacy and low incidence of side effects, these agents have become the most frequently prescribed class of drugs to treat allergic 1379
conjunctivitis. Allergen immunotherapy can be helpful in treating allergic conjunctivitis. Subcutaneous immunotherapy (SCIT) for allergic rhinitis demonstrated improvement in ocular allergy symptoms (55). SCIT has been demonstrated to reduce the sensitivity to ocular challenge with grass pollen (56). Sublingual immunotherapy reduces ocular symptoms as well (57). Vernal Conjunctivitis Clinical Presentation Vernal conjunctivitis is a chronic, bilateral, catarrhal inflammation of the conjunctiva most commonly arising in children during the spring and summer. It can be perennial in severely affected patients. It is characterized by an intense itching, burning, and photophobia. The illness is usually seen during the preadolescent years and often resolves at puberty. Male patients are affected about three times more often than female patients when the onset precedes adolescence, but when there is a later onset, female patients predominate. In the later onset variety, the symptoms are usually less severe. The incidence is increased in warmer climates. It is most commonly seen in the Middle East and along the Mediterranean Sea. Vernal conjunctivitis presents in palpebral and limbal forms. In the palpebral variety, which is more common, the tarsal conjunctiva of the upper lid is deformed by thickened, gelatinous vegetations produced by marked papillary hypertrophy. This hypertrophy imparts a cobblestone appearance to the conjunctiva, which results from intense proliferation of collagen and ground substance along with a cellular infiltrate (57). The papillae are easily seen when the upper lid is everted. In severe cases, the lower palpebral conjunctiva may be similarly involved. In the limbal form, a similar gelatinous cobblestone appearance occurs at the corneal–scleral junction. Trantas’ dots—small, white dots composed mainly of eosinophils—are often present. Usually, there is a thick, stringy exudate full of eosinophils. This thick, ropy, white or yellow mucous discharge has highly elastic properties and produces a foreign body sensation. It is usually easily distinguished from the globular mucus seen in seasonal allergic conjunctivitis or the crusting of infectious conjunctivitis. The patient may be particularly troubled by this discharge, which can string out for more than 2.5 cm (1 inch) when it is removed from the eye. Widespread punctate keratitis may be present. Severe cases can result in epithelial ulceration with scar formation. 1380
Pathophysiology and Cause The cause of and pathophysiologic mechanisms underlying vernal conjunctivitis remain obscure (58–76). Several features of the disease, however, suggest that the atopic state is related to its pathogenesis. The seasonal occurrence, the presence of eosinophils, and the fact that most of the patients have other atopic disease (58) are circumstantial evidence supporting this hypothesis. In addition, several different immunologic and histologic findings are consistent with an allergic etiology. Patients with vernal conjunctivitis have elevated levels of total IgE (61), allergen-specific IgE (61), histamine (60,62), and tryptase (62) in the tear film. In addition, histologic studies support an immune origin. Patients with vernal conjunctivitis have markedly increased numbers of eosinophils, basophils, mast cells, and plasma cells in biopsy specimens taken from the conjunctiva (62). The mast cells are often totally degranulated (62). Elevated levels of major basic protein are found in biopsy specimens of the conjunctiva (64). Also, in keeping with the postulated role of IgE-mediated hypersensitivity is the pattern of cytokine secretion and T cells found in tears and on biopsy specimens. A TH2 cytokine profile with increased levels of IL-4 and IL-5 has been found (70). In addition, in animal models, a clear role for T-helper cells type 2 (but not type 1) has been demonstrated. It has been shown that TH2 cells play a critical role in inducing conjunctival eosinophilic infiltration in this regard. Finally, ocular shields, designed to prevent pollen exposure, have been reported to be therapeutically effective (68). A role for cell-mediated immunity has also been proposed and is supported by the findings of increased CD4+/CD29+ helper T cells in tears during acute phases of the illness (65). Also, in keeping with this hypothesis is the improvement demonstrated during therapy with topical cyclosporine (66,67). Fibroblasts appear to be operative in the pathogenesis as well. They may be activated by T-cell or mast cell products. When stimulated with histamine, fibroblasts from patients with vernal conjunctivitis produce excessive amounts of procollagen I and II (69). In addition, they appear to manufacture constitutively increased amounts of transforming growth factor-β, IL-1, IL-6, and TNF-α in vitro. The increased levels of cytokines noted in vitro are accompanied by increased serum levels of IL-1 and TNF-α as well (70). This overexpression of mediators both locally and systemically probably accounts for the upregulation of adhesion molecules (71) on corneal epithelium noted in this disorder. Also of interest is the hypothesis that complement, perhaps activated by IgG– allergen immune complexes, plays a role in producing vernal conjunctivitis. 1381
Pollen-specific IgG antibodies (72) and complement activation products (C3 desArg) occur in tears of patients with vernal conjunctivitis (73). The specific IgG antipollen found in the tear film may not be acting through the complement system; however, because much of it appears to be IgG4 (72), a noncomplement-fixing subclass with putative reaginic activity. Also, patients with vernal conjunctivitis have decreased tear lactoferrin, an inhibitor of the complement system (76). The eosinophilic cellular infiltrate in vernal conjunctivitis may contribute to corneal complications. Eosinophils secrete gelatinase B and polycationic toxic proteins, such as major basic protein and eosinophilic cationic protein. In vitro these can cause epithelial damage with desquamation and cellular separation (64). Enzymatic activity may also play a role in pathophysiology of vernal conjunctivitis. Elevated levels of urokinase and metalloproteinases have been seen in vernal conjunctivitis (74). Vasomotor complications can occur in this disorder and perhaps produce a hyperreactivity of the conjunctivae. Increased expression of muscarinic and adrenergic receptors and neural transmitters have been shown to occur in vernal conjunctivitis. These abnormalities could possibly result in hypersecretion and corneal hyperreactivity (75). Diagnosis and Treatment Vernal conjunctivitis must be distinguished from other conjunctival diseases that present with pruritus or follicular hypertrophy. These include acute allergic conjunctivitis, conjunctivitis and keratoconjunctivitis associated with atopic dermatitis, the giant papillary conjunctivitis associated with soft contact lenses and other foreign bodies, the follicular conjunctivitis of viral infections, and trachoma (rarely found in the United States). In most instances, the distinction between acute allergic conjunctivitis and vernal conjunctivitis is not difficult. However, in the early phases of vernal conjunctivitis or in mild vernal conjunctivitis, giant papillae may be absent. In such instances, the distinction may be more difficult because both conditions occur in atopic individuals, and pruritus is a hallmark of each. However, in vernal conjunctivitis, the pruritus is more intense, the tear film contains a significantly greater concentration of histamine and greater amounts of eosinophils, and the conjunctival epithelium has more abundant mast cells (63). Also, the cornea is not involved in acute allergic conjunctivitis. 1382
The conjunctivitis and keratoconjunctivitis associated with atopic dermatitis can be similar to vernal conjunctivitis. In atopic dermatitis, the conjunctivitis can produce hypertrophy and opacity of the tarsal conjunctiva (77). A form of keratoconjunctivitis with papillary hypertrophy and punctate keratitis can occur (78,79). Many of these patients have signs and symptoms typical of vernal conjunctivitis, including giant follicles and pruritus. In addition, vernal conjunctivitis and atopic dermatitis can occur together in the same patient. However, because the treatment of both conditions is similar, the distinction, except for its prognostic value, may not be essential. The giant papillary conjunctivitis caused by wearing of soft contact lenses is similar to that of vernal conjunctivitis. Patients complain of itching, mucous discharge, and a decreasing tolerance to the lens. Symptoms usually begin 3 to 36 months after lenses are prescribed (80). The syndrome can occur with hard and soft lenses and can be seen with exposed sutures (80) and plastic prostheses (81). Thus, chronic trauma to the lid appears to be the common inciting agent. Several features distinguish this entity from vernal conjunctivitis. Lensassociated papillary conjunctivitis causes less intense itching and shows no seasonal variation. It resolves with discontinuation of lens use. Viral infections can be distinguished from vernal conjunctivitis by their frequent association with systemic symptoms and the absence of pruritus. A slitlamp examination can produce a definitive distinction between these two entities. Patients with mild vernal conjunctivitis can be treated with cold compresses and topical vasoconstrictor-antihistamine preparations. Levocabastine has been shown to be effective in a double-blind, placebo-controlled trial of 46 patients over a period of 4 weeks (82). Oral antihistamines may be of modest help. Cromolyn sodium and lodoxamide have been used effectively not only for milder but also for more recalcitrant, chronic forms of the condition (83–87). Cromolyn has been shown to decrease conjunctival injection, punctate keratitis, itching, limbal edema, and tearing when administered regularly. It may be more effective in patients who are atopic (85). In a multicenter, double-blind 28-day study, another mast cell stabilizer, lodoxamide, was found to be more effective than cromolyn sodium (87). Aspirin (88,89) has been found to be helpful in a dose of 0.5 to 1.5 g daily. Ketorolac tromethamine has not been approved for use in vernal conjunctivitis, but based on the studies of aspirin, it might be an effective agent in this regard. Acetylcysteine 10% (Mucomyst) has been suggested as a means of counteracting 1383
viscous secretions. In severe cases, cyclosporine has been used (90). None of the above medications is universally effective, however, and topical corticosteroids often are necessary. If topical corticosteroids are needed, the patient should be under the care of an ophthalmologist. Fortunately, spontaneous remission usually occurs at puberty. Perhaps a more appropriate name for this disorder would be vernal keratoconjunctivitis because corneal involvement is common and can be severe. Corneal complications are as a result of uncontrolled inflammation and can be site threatening (91). Other Eye Manifestations Associated with Atopic Dermatitis Atopic dermatitis is associated with several manifestations of eye disease (92–98). These include lid dermatitis, blepharitis, conjunctivitis, keratoconjunctivitis, keratoconus, cataracts, and a predisposition to develop ocular infections, especially with herpes simplex and vaccinia viruses (92). Lid involvement has been discussed in detail previously. Atopic dermatitis patients with ocular complications can be distinguished from those without ocular disease in that they have higher levels of serum IgE and more frequently demonstrate IgE specific to rice and wheat. Those with associated cataract formation have the highest levels of IgE. Patients with ocular complications also have increased tear histamine and leukotriene B4 levels compared with atopic dermatitis subjects without ocular complications (93). As with other allergic eye conditions, subjects with atopic keratoconjunctivitis have cells in ocular tissue that exhibit a TH2 cytokine profile with increased expression of messenger RNA for IL-4 and IL-5. Subjects with allergic keratoconjunctivitis, however, are different from those with vernal conjunctivitis in that they also express increased levels of IFN-γ and IL-2, indicating that in later stages of this disease, an element of delayed hypersensitivity is involved in the pathogenesis. Lid involvement can resemble contact dermatitis. The lids become thickened, edematous, and coarse; the pruritus may be intense. Conjunctivitis may vary in intensity with the degree of skin involvement of the face (76). It resembles acute allergic conjunctivitis and to some extent resembles vernal conjunctivitis. It actually may be allergic conjunctivitis occurring with atopic dermatitis. Atopic keratoconjunctivitis usually does not appear until the late teenage 1384
years. The peak incidence is between 30 and 50 years of age. Male patients are affected in greater numbers than female patients. Atopic keratoconjunctivitis is bilateral. The major symptoms are itching, tearing, and burning. The eyelids may be red, thickened, and macerated. There is usually erythema of the lid margin and crusting around the eyelashes. The palpebral conjunctiva may show papillary hypertrophy. The lower lid is usually more severely afflicted and more often involved. Punctate keratitis can occur, and the bulbar conjunctiva is chemotic. Atopic keratoconjunctivitis must be differentiated from chronic blepharitis of nonallergic origin and vernal conjunctivitis. This may be difficult in the case of blepharitis. Indeed, staphylococcal blepharitis often complicates this disorder. Vernal conjunctivitis is usually distinguished from atopic keratoconjunctivitis by the fact that it most often involves the upper rather than lower lids and is more seasonal. It also occurs in a younger age group. The papillae in vernal conjunctivitis are larger. Cromolyn sodium is helpful in treating atopic keratoconjunctivitis (95). Topical corticosteroids often are needed, however. Their use should be under the direction of the ophthalmologist. Keratoconus occurs less frequently than conjunctival involvement. The cause of the association between atopic dermatitis and keratoconus is unknown, but there appears to be no human leukocyte antigen haplotype that distinguishes atopic dermatitis patients with keratoconjunctivitis from patients without it or from controls (77). The incidence rate of cataract formation in atopic dermatitis has been reported to range from 0.4% to 25% (77). These cataracts may be anterior or posterior in location, as opposed to those caused by administering corticosteroids, which are usually posterior. They have been observed in both children and adults. They may be unilateral or bilateral. Their presence cannot be correlated with the age of onset of the disease, its severity, or its duration (96). The pathophysiology involved in the formation of cataracts is unknown, but patients with atopic cataracts have higher serum IgE levels (96) and have elevated levels of major basic protein in aqueous fluid and the anterior capsule, which is not found in senile cataracts (97). Eyelid disorders may be the most common ocular complaint in patients with atopic dermatitis (98). Dermatitis of the lid produces itching with lid inversion. The skin becomes scaly, and the skin of the eyes around the lid may become more wrinkled. The skin is extremely dry. The lesion is pruritic, and the disorder can be confused with contact dermatitis of the lid. 1385
Herpes keratitis is more common in patients with atopic dermatitis. This condition may be recurrent, and recalcitrant epithelial defects can occur (98). As with vernal keratoconjunctivitis, atopic keratoconjunctivitis can be site threatening (99). Blepharoconjunctivitis (Marginal Blepharitis) Blepharoconjunctivitis (marginal blepharitis) refers to any condition in which inflammation of the lid margin is a prominent feature of the disease. Conjunctivitis usually occurs in conjunction with the blepharitis. Three illnesses are commonly considered under the generic heading of blepharoconjunctivitis: bacterial (usually staphylococcal) blepharoconjunctivitis, seborrheic blepharoconjunctivitis, and rosacea. They often occur together. Blepharoconjunctivitis accounts for 4.5% of all ophthalmologic problems presenting to the primary care physician (100). Staphylococcal Blepharoconjunctivitis The staphylococcal organism is probably the most common cause of conjunctivitis and blepharoconjunctivitis. The acute bacterial conjunctivitis is characterized by irritation, redness, and mucopurulent discharge with matting of the eyelids. Frequently, the conjunctivitis is present in a person with low-grade inflammation of the eyelid margins. In the chronic form, symptoms of staphylococcal blepharoconjunctivitis include erythema of the lid margins, matting of the eyelids on awakening, and discomfort, which is usually worse in the morning. Examination frequently shows yellow crusting of the margin of the eyelids, with collarette formation at the base of the cilia, and disorganized or missing cilia. If the exudates are removed, ulceration of the lid margin may be visible. Fluorescein staining of the cornea may show small areas of dye uptake in the inferior portion. It is believed that exotoxin elaborated by Staphylococcus organisms is responsible for the symptoms and signs. Because of the chronicity of the disease and the subtle findings, the entity of chronic blepharoconjunctivitis of staphylococcal origin can be confused with contact dermatitis of the eyelids and contact dermatoconjunctivitis. The absence of pruritus is the most important feature distinguishing staphylococcal from contact dermatoconjunctivitis. Seborrheic Dermatitis of the Lids Staphylococcal blepharitis can also be confused with seborrheic blepharitis. Seborrheic blepharitis occurs as part of seborrheic dermatitis. It is associated 1386
with oily skin, seborrhea of the brows, and usually scalp involvement. The scales, which occur at the base of the cilia, tend to be greasy, and if these are removed, no ulceration is seen. There is no pruritus. Rosacea Rosacea involving the eyes can be severe even if the skin involvement is minor. Patients present with an angry, erythematous chronic conjunctivitis. The eyelid margin is involved with erythema and meibonium gland dysfunction. The glands are dilated, and their orifices plugged. The pressure on the eyelids below the gland openings will often produce a toothpaste-like secretion. Chronic inflammation can result in loss of secretion and conjunctivitis sicca. Complications include hordeola, chalazia, and telangiectasia. Of course, there are cutaneous manifestations of telangiectasia with flushing as well. The blepharitis is manifested by collarettes, loss of lashes, discoloration, and whitening and misdirection of the lashes. There is usually marked erythema of the lid margin. Vessels that are telangiectasia can be seen crossing the eyelid margin. Patients often present with these manifestations thinking they are allergy related, and therefore, this condition must always be kept in mind when making a differential diagnosis. It is important to be aware of the disorder because it can result in corneal erosions with neovascularization, and there can be an associated episcleritis and iritis. Diagnosis and Treatment of Blepharoconjunctivitis In all three forms of blepharoconjunctivitis, the cardinal symptoms are burning, redness, and irritation. True pruritus is usually absent or minimal. The inflammation of the lid margin is prominent. The discharge is usually mucopurulent, and matting in the early morning may be an annoying feature. In the seborrheic and rosacea forms, cutaneous involvement elsewhere is present. All three forms are usually chronic and are often difficult to manage. In staphylococcal blepharoconjunctivitis, lid scrubs using a cotton-tipped applicator soaked with baby shampoo and followed by the application of a steroid ointment may be helpful. Commercially available lid scrubs specifically designed to treat this condition are also available. Control of other areas of seborrhea is necessary. Tetracycline or doxycycline can be beneficial in the therapy of rosacea. Ophthalmologic and dermatologic consultation may be needed. Infectious Conjunctivitis/Keratitis 1387
Viral Conjunctivitis Viral conjunctivitis is the most common cause of red eye. It has several characteristics that distinguish it from allergic and bacterial disease. They include: • Profuse watery discharge without purulence. • Usually occurs during an upper respiratory tract infection (latter stages). • May have palpable preauricular node. • There is no itching. Viral conjunctivitis is usually of abrupt onset, frequently beginning unilaterally and involving the second eye within a few days. Conjunctival injection, slight chemosis, watery discharge, and enlargement of a preauricular lymph node help to distinguish viral infection from other entities. Clinically, lymphoid follicles appear on the conjunctiva as elevated avascular areas, which are usually grayish. These correspond to the histologic picture of lymphoid germinal centers. Viral conjunctivitis is usually of adenoviral origin and is frequently associated with a pharyngitis and low-grade fever in pharyngoconjunctival fever. Epidemic keratoconjunctivitis presents as an acute follicular conjunctivitis, with a watery discharge and preauricular adenopathy. This conjunctivitis usually runs a 7- to 14-day course and is frequently accompanied by small corneal opacities. Epidemic keratoconjunctivitis can be differentiated from allergic conjunctivitis by the absence of pruritus, the presence of a mononuclear cellular response, and a follicular conjunctival response. The treatment of viral conjunctivitis is usually supportive, although prophylactic antibiotics are frequently used. If significant corneal opacities are present, the application of topical steroid preparations has been suggested. Acute Bacterial Conjunctivitis The most prominent distinguishing feature of acute bacterial conjunctivitis is purulent discharge. Patients may also have a sensation mimicking a foreign body in the eye, and lid edema is not uncommon. The most common culprits are Staphylococcal pneumonia, Haemophilus influenzae, S. aureus, and Moraxella catarrhalis. Gonococcal conjunctivitis bears special mention because of the fact that it can be invasive and cause permanent damage. In gonococcal conjunctivitis, the typical symptoms are usually far more pronounced. There is often a very copious purulent discharge. 1388
Treatment consists of warm compresses and ocular antibiotics. A follow-up visit within 2 days should be scheduled to check for progress. Chlamydial (Inclusion) Conjunctivitis In adults, inclusion conjunctivitis presents as an acute conjunctivitis with prominent conjunctival follicles and a mucopurulent discharge. There is usually no preceding upper respiratory infection or fever. This process occurs in adults who may harbor the chlamydial agent in the genital tract, but with no symptoms referable to this system. A nonspecific urethritis in men and a chronic vaginal discharge in women are common. The presence of a mucopurulent discharge and follicular conjunctivitis, which lasts more than 2 weeks, certainly suggests inclusion conjunctivitis. A Giemsa stain of a conjunctival scraping specimen may reveal intracytoplasmic inclusion bodies and helps to confirm the diagnosis. The treatment of choice is systemic tetracycline for 10 days. Herpes Simplex Keratitis Up to 500,000 cases of ocular herpes simplex are seen in the United States each year (100). A primary herpetic infection occurs subclinically in many patients. However, acute primary keratoconjunctivitis may occur with or without skin involvement. The recurrent form of the disease is seen most commonly. Patients usually complain of tearing, ocular irritation, blurred vision, and occasionally photophobia. Fluorescein staining of the typical linear branching ulcer (dendrite) of the cornea confirms the diagnosis. Herpetic keratitis is treated with antiviral compounds or by debridement. After the infectious keratitis has healed, the patient may return with a geographic erosion of the cornea, which is known as metaherpetic (trophic) keratitis. In this stage, the virus is not replicating, and antiviral therapy is usually not indicated. If the inflammation involves the deep corneal stroma, a disciform keratitis may result and may run a rather protracted course, leaving a corneal scar. The exact cause of disciform keratitis is unknown, but it is thought that immune mechanisms play an important role in its production (101,102). It is important to distinguish herpetic keratitis from allergic conjunctivitis. The absence of pruritus and the presence of photophobia, blurred vision, and a corneal staining area should alert the clinician to the presence of herpetic infection. Using corticosteroids in herpetic disease only spreads the ulceration and prolongs the infectious phase of the disease process (103). Herpes Zoster Herpes zoster can occur typically with the appearance of ocular symptoms as the 1389
first manifestation, prior to the onset of skin involvement. Therefore, the diagnosis should always be kept in mind. The ocular symptoms occur when the ophthalmic division of the trigeminal nerve is involved. The presence of a vesicle at the tip of the nose (Hutchinson sign) may appear as a sentinel lesion. Like herpes infection, zoster also produces a dendritic keratitis. The distinction between the two, therefore, may be dependent on the typical skin lesions. Keratoconjunctivitis Sicca Keratoconjunctivitis sicca is a chronic disorder characterized by a diminished tear production. This is predominately a problem in menopausal or postmenopausal women and may present in patients with connective tissue disease, particularly rheumatoid arthritis. Although keratoconjunctivitis sicca may present as an isolated condition affecting the eyes only, it may also be associated with xerostomia (Sjögren syndrome). Symptoms may begin insidiously and are frequently confused with a mild infectious or an allergic process. Mild conjunctival injection, irritation, photophobia, and mucoid discharge are present. Corneal epithelial damage can be demonstrated by fluorescein or rose Bengal staining, and hypolacrimation can be confirmed by inadequate wetting of the Schirmer test strip. Frequent application of artificial tears can be helpful. Cyclopsorin eye drops (Restasis) are indicated in patients not adequately responding to artificial tears. Giant Papillary Conjunctivitis Giant papillary conjunctivitis, which is characterized by the formation of large papillae (larger than 0.33 mm in diameter) on the upper tarsal conjunctiva, has been associated with the wearing of contact lenses, prostheses, and sutures (104). Although it is most commonly caused by soft contact lenses (105), it can also occur with gas-permeable and rigid lenses. Patients experience pruritus, excess mucus production, and discomfort when wearing their lenses. There is decreased lens tolerance, blurred vision, and excessive lens movement (frequently with lens displacement). Burning and tearing are also noted. The patient develops papillae on the upper tarsal conjunctiva. These range from 0.3 mm to greater than 1 mm in diameter. The area involved correlates with the type of contact lens worn by the patient (105). The mechanism of production of giant papillary conjunctivitis is unknown. One hypothesis is that the reaction is caused by an immunologic response to deposits on the lens surface. Deposits consist not only of exogenous airborne antigens but also of products in the tear film, such as lysozyme, IgA, lactoferrin, 1390
and IgG (106,107). However, the amount of deposits does not clearly correlate with the presence of giant papillary conjunctivitis, and all lenses develop deposits within 8 hours of wear (107,108). More than two-thirds of soft lens wearers develop deposits within 1 year of wear. Evidence suggesting an immune mechanism in the production of giant papillary conjunctivitis is based on several observations. The condition is more common in atopic subjects. Patients with giant papillary conjunctivitis have elevated, locally produced tear IgE (109). Eosinophils, basophils, and mast cells are found in giant papillary conjunctivitis in greater amounts than in acute allergic conjunctivitis (109–113). There are elevated levels of major basic protein in conjunctival tissues of patients with giant papillary conjunctivitis (110) and elevated levels of leukotriene C4, histamine, and tryptase in their tears (109–113). Further evidence for an IgEmediated mechanism is the observation that ocular tissues from patients with giant papillary conjunctivitis exhibit increased messenger RNA for IL-4 and IL-5 (110) and have increased levels of major basic protein and eosinophilic cationic protein in tears (106–108). Non-IgE-mediated immune mechanisms have also been incriminated in the production of this disorder. In fact, because the condition clearly occurs in nonallergic patients, other mechanisms must be a cause. For example, the tear cytokine profile in giant papillary conjunctivitis differs considerably from that found in vernal keratoconjunctivitis. It is clear, therefore, that microtrauma of the conjunctivitis is the major causative factor in this condition. Although eosinophils appear to play a strong role in vernal conjunctivitis and atopic keratoconjunctivitis, they seem to be less important in giant papillary conjunctivitis (110). IgG levels are elevated, but the IgG is blood borne rather than locally produced (114). There is also evidence for complement activation, and there is decreased lactoferrin in the tears of patients with giant papillary conjunctivitis (108,114). Neutrophil chemotactic factor is present in tear fluids in amounts exceeding levels found in nonaffected soft contact lens wearers (112). Treatment of giant papillary conjunctivitis is usually carried out by the ophthalmologist. Early recognition is important because discontinuation of lens wear early in the stage of the disease and prescription of appropriate lens type and edge design can prevent recurrence. It is also important to adhere to a strict regimen for lens cleaning and to use preservative-free saline. Enzymatic cleaning with papain preparations is useful to reduce the coating of the lenses by antigens. Disposable lenses may also be beneficial. Both cromolyn sodium and 1391
nedocromil sodium have been found to be helpful (113). Floppy Eye Syndrome Floppy eye syndrome is a condition characterized by lax upper lids and a papillary conjunctivitis resembling giant papillary conjunctivitis. Men older than 30 years of age constitute the majority of patients. The condition is thought to result from chronic traction on the lax lid produced by the pillow at sleep. It may be unilateral or bilateral (115). Vasomotor (Perennial Chronic) Conjunctivitis Vasomotor, perennial, chronic conjunctivitis is a poorly defined condition not mediated by IgE. It refers to a conjunctivitis characterized by “vasomotor” instability. The term has been used to apply to patients who have chronic conjunctival findings exacerbated by irritant, and perhaps weather, stimulants in whom other disorders of the eye have been ruled out. It has been estimated that vasomotor stimuli may be involved in 25% of chronic conjunctivitis cases (116). It can be considered the ocular analogue of “vasomotor” rhinitis.
Approach to the Patient with an Inflamed Eye The physician seeing a patient with acute or chronic conjunctivitis should first exclude diseases (not discussed in this chapter) that may be acutely threatening to the patient’s vision. These include conditions such as acute keratitis, uveitis, acute angle-closure glaucoma, and endophthalmitis. The two most important symptoms pointing to a threatening condition are a loss in visual acuity and pain. These are signs that the patient could have an elevated intraocular pressure, keratitis, endophthalmitis, or uveitis. On physical examination, the presence of unreactive pupils and/or circumcorneal hyperemia (dilatation of the vessels adjacent to the corneal edge or limbus) are warning signals that indicate a potentially threatening problem, and require immediate ophthalmologic consultation. These findings, especially circumcorneal hyperemia, are present in four threatening conditions: keratitis, uveitis, acute angle-closure glaucoma, and endophthalmitis. This contrasts with the pattern of vasodilation seen in acute allergic conjunctivitis, which produces erythema that is more pronounced in the periphery and decreases as it approaches the cornea. If the physician believes that the patient does not have a threatening eye disease, the next step is to differentiate between allergic and nonallergic diseases of the eye (Table 28.3). The differential diagnosis between allergic and nonallergic diseases of the eye can usually be made by focusing on a few key 1392
features. The following five cardinal questions should be asked in this regard: 1. Does the eye itch? This is the most important distinguishing feature between allergic and nonallergic eye disorders. All allergic conditions are pruritic. Nonallergic conditions usually do not itch. The physician must be certain that the patient understands what is meant by itching because burning, irritated, “sandy feeling” eyes are often described as “itchy” by the patient. 2. What type of discharge, if any, is present? A purulent discharge with early morning matting is not a feature of allergic disease and points toward infection. 3. Is the lid involved? Lid involvement indicates the presence of atopic dermatitis, contact dermatitis, or occasionally seborrhea or rosacea. Often, the patient complains of “eye irritation,” which may mean the lid or conjunctiva or both. The physician should be careful to ascertain which area of the eye is involved. 4. Are other allergic manifestations present? Examples include atopic dermatitis, asthma, and rhinitis. 5. Are there other associated nonallergic conditions? Nonallergic conditions include dandruff and rosacea.
THE EAR: OTIC MANIFESTATIONS OF ALLERGY The most common otologic problem related to allergy is otitis media with effusion (OME). The potential role of allergic disease in the pathogenesis of OME is explored in the following discussion. Otitis media is a general term defined as any inflammation of the middle ear with or without symptoms and usually associated with an effusion. It is one of the most common medical conditions seen in children by primary care physicians (117). In 1996, it was estimated that total (direct + indirect) costs for otitis media in the United States approximated $5 billion (118). The classification of otitis media can be confusing. The First International Symposium on Recent Advances in Middle Ear Effusions includes the following types of otitis media: (a) acute purulent otitis media, (b) serous otitis media, and (c) mucoid or secretory otitis media. Chronic otitis media is a condition displaying a pronounced, retracted tympanic membrane with pathologic changes in the middle ear, such as cholesteatoma or granulation tissue. The acute phase of otitis media occurs during the first 3 weeks of the illness, the subacute phase between 4 and 8 weeks, and the chronic phase begins after 8 weeks. For this 1393
review, acute otitis media (AOM) applies to the classic ear infection, which is rapid in onset and associated with a red, bulging, and painful tympanic membrane. Fever and irritability usually accompany AOM. The presence of middle ear fluid without signs or symptoms of acute infection is OME. In many of these patients, hearing loss (HL) accompanies the condition. Other commonly used names for OME are ear fluid, serous, secretory, or nonsuppurative otitis media. Chronic OME is persisting of OME for 3 months from the date of onset (if known) or from the date of diagnosis (if onset is unknown). Middle ear effusion is defined as fluid in the middle ear from any cause. Middle ear effusion is present with both OME and AOM, and may persist for weeks or months after the signs and symptoms of AOM resolve. In the United States, there are about 2.2 million diagnosed episodes of OME occur annually in the United States at a cost of $4.0 billion (119). This condition results in the one of the most commonly performed surgeries in the United States: tympanostomy tube placement (118). OME is of major importance in children because the effusion can lead to a mild-to-moderate conductive HL of 20 dB or more (120). It has been theorized that chronic conductive HL in the child may lead to poor language development and learning disorders. When children aged 5 to 6 years in primary school were screened for OME, about one in eight were found to have fluid in one or both ears (121). There are many epidemiologic factors in the development of recurrent and chronic OME in children, with age at first episode being a major risk factor (122) (Table 28.4). Other risk factors include male sex, bottle feeding, day care attendance, allergy, race (Native American and Inuit), lower socioeconomic status, pacifier use, prone sleep position, winter season, and passive smoke exposure (118,123). In addition, diseases of the antibody-mediated immune system, primary ciliary dyskinesia, Down syndrome, and craniofacial abnormalities, especially cleft palate, can all contribute to chronic OME. In evaluation of the patient with recurrent or chronic OME, each of these conditions needs to be considered. TABLE 28.3 DIFFERENTIAL FEATURES TO BE CONSIDERED IN DIAGNOSING ALLERGIC EYE DISEASE
CLINICAL FEATURE
SKIN OF LIDS SCRATCHY AND/OR (SANDY) MARGIN SEASONALITCHING IRRITATIONINVOLVEDBILATERAL
Acute allergic conjunctivitis Yes
ProminentNot usual
1394
No
Yes
Vernal conjunctivitis
Yes
ProminentNot usual
No
Yes
Conjunctivitis sicca
No
No
Prominent
No
Yes
Acute viral conjunctivitis
Variable, No usually is not
Variable
No
Variable
Acute bacterial conjunctivitisNo
No
Variable
Matting, lid Variable edema
Contact
Yes
No
Variable
No
1395
Usually
dermatoconjunctivitis
Blepharoconjunctivitis No (bacterial/seborrheic/rosacea)
No
No
Yes
Usually
These conditions are to be considered in the absence of significant pain, photophobia, vision loss or blurring, poorly reactive pupils, and/or a limbal flush (circum corneal hyperemia). Any of these manifestations can indicate an elevated intraocular pressure or the presence of uveitis or other threatening ocular conditions (see text).
Pathogenesis of Otitis Media with Effusion It appears that multiple factors influence the pathogenesis of OME. Most studies link OME with eustachian tube dysfunction, viral and bacterial infections, abnormalities of mucociliary clearance, immature immune system, allergy, or as an inflammatory response following AOM, most often between 6 months and 4 years of age (Table 28.4). Eustachian Tube Anatomy and Physiology The nasopharynx and middle ear are connected by the eustachian tube. The production of middle ear effusions appears to be related to functional or anatomic abnormalities of this tube. Under normal conditions, the eustachian tube has three physiologic functions: (a) ventilation of the middle ear to equilibrate pressure and replenish oxygen; (b) protection of the middle ear from nasopharyngeal sound pressure and secretions; and (c) clearance of secretions produced in the middle ear into the nasopharynx. The eustachian tube of the infant and the young child differs markedly from that of the adult. These anatomic differences predispose infants and young children to middle ear disease. In infancy, the tube is wide, short, and more horizontal in orientation. As growth occurs, the tube narrows, elongates, and 1396
develops a more oblique course (Fig. 28.2). Usually, after the age of 7 years, these physical changes lessen the frequency of middle ear effusion (118). In the normal state, the middle ear is free of any significant amount of fluid and is filled with air. Air is maintained in the middle ear by the action of the eustachian tube. This tube is closed at the pharyngeal end except during swallowing, when the tensor veli palatini muscle contracts and opens the tube by lifting its posterior lip (Fig. 28.3A). When the eustachian tube is opened, air passes from the nasopharynx into the middle ear, and this ventilation system equalizes air pressure on both sides of the tympanic membrane (Fig. 28.3B). TABLE 28.4 RISK FACTORS FOR CHRONIC AND RECURRENT OTITIS MEDIA WITH EFFUSION (OME) 1.Age—children with OME in the first year of life have increased incidence of recurrence 2.Males > females 3.Bottle-fed infants 4.Passive smoking exposure 5.Allergy 6.Lower socioeconomic status 7.Race—Native Americans and Eskimos > whites > African Americans 8.Day care centers 9.Season—winter > summer 10.Genetic predisposition—if siblings have OME, higher risk 11.Down syndrome
1397
12.Primary immunodeficiency disorders 13.Primary and secondary ciliary dysfunction 14.Craniofacial abnormalities
FIGURE 28.2 Illustration showing difference in angles of eustachian tubes in infants and adults. When the eustachian tube is blocked by either functional or anatomic defects, air cannot enter the middle ear, and the remaining air is absorbed. This results in the formation of negative pressure within the middle ear and subsequent retraction of the tympanic membrane (Fig. 28.3C). High negative pressure associated with ventilation may result in aspiration of nasopharyngeal secretions into the middle ear, producing acute OME (Fig. 28.3D). Prolonged negative pressure causes fluid transudation from the middle ear mucosal blood vessels (Fig. 28.3E). With chronic OME, there is infiltration of lymphocytes and macrophages, along with production of different inflammatory mediators. Also, there is an increased density of goblet cells in the epithelium of the eustachian tube. It is thought that many children with middle ear effusions, without a demonstrable cause of eustachian tube obstruction, have a growth-related inadequate action of the tensor veli palatini muscle. Another possibility is functional obstruction from persistent collapse of the tube owing to increased 1398
tubal compliance. Nasal obstruction, either from adenoid hypertrophy or from infectious or allergic inflammation, may be involved in the pathogenesis of middle ear effusion by the Toynbee phenomenon (124). Studies have reported that, when the nose is obstructed, there is an increased positive nasopharyngeal pressure followed by a negative nasopharyngeal pressure on swallowing. The increased positive nasopharyngeal pressure may predispose to insufflation of secretions into the middle ear, and the secondary negative pressure in the nasopharynx may further be a factor in the inadequate opening of the eustachian tube, thereby causing obstruction.
FIGURE 28.3 Proposed pathogenic mechanisms of middle ear effusion. EC, external canal; ET, eustachian tube; Mast., mastoid; TM, tympanic membrane; ME, middle ear; NP, nasopharynx; TVP, tensor veli palatini muscle. (From Bluestone CD. eustachian tube function and allergy in otitis media. Pediatrics 1978;61:753, with permission.) Infection Respiratory bacterial and viral infections are significant contributors to the pathogenesis of otitis media. Bacteria have been cultured in about 70% of middle 1399
ear effusions during tympanocentesis for otitis media in children (125). The three most common bacterial isolates in AOM and OME are Streptococcus pneumoniae, nontypeable H. influenzae (NTHI), and M. catarrhalis (118). S. pyogenes and anaerobic cocci are isolated in less than 5% of the patients with AOM. In 1999, Alloiococcus otitis was noted to be a significant bacterial pathogen in relationship with OME (126). The predominant anaerobes are Grampositive cocci, pigmented Prevotella and Porphyromonas species, Bacterioides species, and Fusobacterium species. The predominant organisms isolated from chronic otitis media are Staphylococcus aureus, Pseudomonas aeruginosa, and anaerobic bacteria. In neonates, group B streptococci and Gram-negative organisms are common bacterial pathogens causing otitis media. Most patients with chronic OME have sterile middle ear effusions. Post and associates used a polymerase chain reaction (PCR) to detect bacterial DNA in middle ear effusions in children who had failed multiple courses of antibiotics and, therefore, were undergoing myringotomy and tube placement (127). Of the 97 specimens, 75 (77.3%) were PCR positive for one or more of the following bacteria: S. pneumoniae, NTHI, and M. catarrhalis. This suggests that active bacterial infection may be occurring in many children with chronic OME. Viral agents are not commonly cultured from middle ear effusions. Most studies report positive viral cultures in less than 5% of the aspirates from the middle ear, with respiratory syncytial virus (RSV) being the most common isolate (128). However, using molecular techniques such as PCR, viral RNA can be detected in about 75% of children with AOM; common isolates include rhinovirus, coronavirus, and RSV (129,130). Mucociliary Dysfunction Mucociliary dysfunction from either a genetic defect or an acquired infectious or environmental condition can lead to OME. Investigations suggest that the mucociliary transfer system is an important defense mechanism in clearing foreign particles from the middle ear and the eustachian tube (131). Goblet and secretory cells provide a mucous blanket to aid ciliated cells in transporting foreign particles toward the nasopharynx for phagocytosis by macrophages, or to the lymphatics and capillaries for clearance. Respiratory viral infections are associated with transient abnormalities in the structure and function of cilia (132). Primary ciliary dyskinesia, an autosomal recessive syndrome, has been linked to more than 20 different structural defects in cilia, which lead to ciliary dysfunction (133). Both of these conditions can lead to inefficient ciliary 1400
transport, which results in mucostatics and can contribute to eustachian tube obstruction and the development of middle ear effusion. Allergy and Immunology There is considerable debate about whether allergic disorders are a factor in the pathogenesis of OME. Many investigators believe that allergic disorders play a prominent role, either as a cause or contributory factor; whereas others state that there is no convincing evidence that allergy leads to otitis media. Allergy has been implicated as a causative factor in OME by (a) double-blind placebocontrol nasal challenge studies with histamine and allergens; (b) studies on allergic children; and (c) studies on randomly selected children with OME referred to specialty clinics (134,135). Kraemer (136) compared risk factors of OME among children with tympanostomy tubes compared with controls matched for age and reported atopy as a risk factor. In a series of 488 new patients referred to a pediatric allergy clinic, 49% had documented middle ear dysfunction (137). In a prospective study, Bierman and Furukawa (138) have demonstrated that allergic children have a high incidence of OME with conductive HL. Half of their patients developed chronic OME or AOM in a 6month follow-up. Tomonaga et al. evaluated 605 children with allergic rhinitis and found 21% with OME. They also determined that 50% of 259 children with diagnosed OME had allergic rhinitis (139). Bernstein and Reisman reviewed the clinical course of 200 randomly selected children with OME who had at least one tympanostomy with tube insertion (140). Twenty-three percent were considered allergic by history, physical examination, and allergy skin testing. In human studies, Friedman et al. evaluated eight patients, aged 18 to 29 years, with seasonal rhinitis but no middle ear disease. Patients were blindly challenged with the pollen to which the patient was sensitive or to a control. Nasal function was determined by nasal rhinomanometry and eustachian tube function by the nine-step-deflation tympanometric test. The results from this and other studies (141) showed that eustachian tube dysfunction can be induced by allergen and histamine challenge (141), although no middle ear effusions occurred. Osur evaluated 15 children with ragweed allergy and measured eustachian tube dysfunction before, during, and after a ragweed season (142). There was a significant increase in eustachian tube dysfunction during the pollen season, but it did not lead to OME. It appears that other variables need to be present for effusion to develop. Work by Hurst et al. has provided the most conclusive evidence of the role of allergy in OME. These researchers evaluated 89 patients for allergy who 1401
required the placement of tympanostomy tubes because of persistent effusion. Radioallergosorbent test, serum IgE levels, and skin tests were performed. Atopy was present in 97% of the patients with OME by skin testing. Significant levels of eosinophil cationic protein and eosinophils were found in the effusions, suggesting allergic inflammation in the middle ear (143). These investigators also determined that IgE in middle ear effusion is not a transudate but more likely reflects an active localized process in atopic patients (144) and that tryptase, a reflection of mast cell activity, is found in most ears of patients with chronic effusion who were atopic (145). These findings and others (146) support the hypothesis that middle ear mucosa is capable of an allergic response and that the inflammation within the middle ear of most OME patients is allergic in nature. AOM and chronic suppurative otitis media are commonly part of a primary or secondary immunodeficiency syndrome. The middle ear is usually one of many locations for infection in immunodeficient patients. Of the primary immunodeficiency conditions, otitis media is more common in the humoral or Bcell disorders, such as X-linked hypogammaglobulinemia, common variable immunodeficiency, and selective IgA deficiency. A patient’s incapacity to produce antibodies against pneumococcal polysaccharide antigens and a related IgG2 subclass deficiency has been associated with the development of recurrent otitis media in children (147).
Diagnosis AOM usually presents with fever, otalgia, vomiting, diarrhea, and irritability. In young children, pulling at the ear may be the only manifestation of otalgia. Otorrhea, discharge from the middle ear, may occur if spontaneous perforation of the tympanic membrane occurs. It is not uncommon for AOM to be preceded by an upper respiratory infection. The pneumatic otoscope is an important tool for making accurate diagnosis of AOM. Classically, the tympanic membrane is erythemic and bulging without a light reflex or the ossicular landmarks visualized. Pneumatic testing fails to elicit any movement of the tympanic membrane on applying positive and negative pressures. Most children with OME do not have symptoms. Others may complain of stopped-up or popping ears or a feeling of fullness in the ear. Older children may even note an HL. Their teachers and parents detect the condition in many younger children because they are noted to be inattentive, loud talkers, and slow learners. Other children may be discovered with OME in screening tests done for 1402
hearing at school. When middle ear effusions become chronic, there may be significant diminution of language development and auditory learning, with resultant poor academic achievement. On pneumatic otoscopic examination of patients with OME, the tympanic membrane may appear entirely normal. At other times, air–fluid levels and bubbles may be apparent. There is often retraction of the tympanic membrane, and the malleus may have a chalky appearance. As the disease progresses, the tympanic membrane takes on an opaque amber or bluish gray color. Alteration of the light reflex is commonly present. Mild retraction of the tympanic membrane may indicate only negative ear pressure without effusion. In more severe retraction, there is a prominent lateral process of the malleus with acute angulation of the malleus head. Tympanic membrane motility is generally poor when positive and negative pressures are applied by the pneumatic otoscopy. Tympanometry is commonly used as a confirmatory test for OME. It is a tool for indirect measuring of the compliance or mobility of the tympanic membrane by applying varying ear canal pressure from 200 to 400 mm H2O. Patients with OME have a flat (type B) curve because of failure of the tympanic membrane to move with the changing pressure. Audiometric examination in OME often discloses a mild-to-moderate degree of conduction hearing impairment of 20 to 40 dB. The guidelines for the treatment of OME in young children from the Agency for Health Care Policy and Research recommend that an otherwise healthy child with bilateral OME for 3 months should have a hearing evaluation (148). According to a recent update on the clinical practice guidelines by the American Academy of Otolaryngology—Head and Neck Surgery Foundation (AAOHNSF), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP), the physician should obtain an ageappropriate hearing test if OME persist for 3 months or longer or for OME of any duration in an at-risk child (149). Counsel families of children with bilateral OME and documented HL about the potential impact on speech and language development is also recommended. Physician should follow up a child with chronic OME at 3 to 6 months’ interval until the effusion is no longer present. Acoustic reflectometry, a test that involves a tone sweep in the patient’s ear and measuring reflected sound pressure to assess effusion, and tuning fork tests can also be used in the diagnosis and evaluation of OME. The physical examination of the patient with OME should not stop at the tympanic membrane. Craniofacial anomalies, such as Down syndrome, submucous cleft palate, and bifid uvula, may be present that predispose to OME. 1403
Stigmata of an allergic diathesis should be sought in each patient. Eye examination may illustrate injected conjunctiva seen in patients with allergic conjunctivitis. Pale, boggy turbinates with profuse serous rhinorrhea are commonly found with allergic rhinitis. When chronic middle ear effusions are associated with the signs and symptoms of allergic disease, a standard allergic evaluation is indicated. A nasal smear for eosinophils, peripheral eosinophil count, and cutaneous tests for specific allergens may be of diagnostic importance. In patients with recurrent or chronic otitis media in whom middle ear disease is just one of many sites of infection, screening of the immune system should be considered. Laboratory studies, such as IgG, IgA, and IgM, naturally occurring antibodies such as isohemagglutinins, and specific antibody titers to antigens previously given in vaccines, such as tetanus, are useful in evaluation of humoral immune status. Measuring specific antibody levels before and after administration of a pneumococcal polyvalent vaccine is an effective mean of evaluating humoral immune function. Another possible condition to consider in children with multiple sites of recurrent infection is primary ciliary dyskinesia. Examination of the cilia by electron microscopy can illustrate abnormalities of the cilia ultrastructure, which can lead to ciliary dysfunction and its related chronic otitis.
Management Management of the patient with OME requires appropriate pharmacologic and surgical intervention. It is important to understand the natural history of AOM and OME. Usually, the symptoms of AOM resolve in 48 to 72 hours if the organism is sensitive to the prescribed antibiotic. Two weeks into treatment, 70% of patients have a middle ear effusion. One month after treatment, 40% continue to have effusion, but after 3 months, only 10% of patients continue to have a persistent effusion (118). In patients with OME in which allergy may be a contributing factor, appropriate allergy treatment of avoidance of particular allergens, medication, and immunotherapy may be indicated. Pharmacotherapy Antimicrobial agents are the first-line therapy in AOM and may be beneficial in OME because bacteria are found in many cases. Amoxicillin is recommended as the first-line agent to treat uncomplicated AOM. For clinical treatment failures after 2 to 3 days of amoxicillin, recent use of amoxicillin in the last 30 days, concurrent purulent conjunctivitis, or with a history of recurrent AOM 1404
unresponsive to amoxicillin, the AAP Clinical Practice Guidelines recommend antimicrobial agents with additional β-lactamase coverage, including oral amoxicillin/clavulanate, cefuroxime axetil, cefprozil, cefpodoxime proxetil, and intramuscular ceftriaxone (150). Intramuscular ceftriaxone should be reserved for severe cases or patients in whom noncompliance is expected. Tympanocentesis for identification of pathogens and susceptibility to antimicrobial agents is recommended for selection of third-line agents (150). Resistant bacteria are an increasing problem in the management of children with otitis media. Sutton et al. reported penicillin resistance in the middle ear fluid of 38.2% of S. pneumoniae cultures at the time of tympanostomy tube surgery (151). β-Lactamase production was found in 65.1% and 100% of H. influenzae and M. catarrhalis specimens, respectively, in that study. In a recent review van Zon et al. reviewed 23 studies to evaluate the benefit of antibiotics use for the treatment of OME. The reviewers reported only a small advantage of antibiotics with complete resolution of the effusion (152). There was no significant impact on HLs or the rate of subsequent tympanostomy tube insertion. As a conclusion, antibiotics are not recommended to treat OME, because of the small benefits that are offset by adverse events, bacterial resistance, and lack of impact on HLs or future surgery (152). In some circumstances, like acute bacterial sinusitis or group A streptococcal infection, antibiotic therapy can be beneficial. A recent review by Venekamp et al., which involved 23 trials, evaluated the benefits and harms of antibiotics in treatment of OME. The evidence shows that oral antibiotics are associated with an increased chance of complete resolution of OME at various time points, but the results indicate that antibiotic use is associated with adverse events, such as diarrhea, vomiting, or skin rash. There is no short-term hearing benefit, no change in frequency of ventilation tube insertions, and no benefit on other outcomes such as speech, language and cognitive development, or quality of life (153). Another management option advocated for OME is observation of the patient for up to 4 months because of the natural history of resolution of OME in most patients. In patients with recurrent episodes of otitis media, a prophylactic antibiotics is no longer recommended, rather a tympanostomy tube can be offered to a patient with three episodes in 6 months or four episodes in 1 year (with one episode in the preceding 6 months) (150,154). Another therapeutic modality prescribed in patients with OME is oral corticosteroids. Many studies have evaluated corticosteroids alone and in combination with antibiotics in clearing of middle ear effusions. The recent clinical practice guidelines from the AAO-HNS, AAP, and AAFP indicate that 1405
systemic corticosteroid therapy is not effective in treating these children (149). In a recent systematic review to evaluate the benefit of an oral steroid and intranasal steroid, either alone or in combination with antibiotics in management of OME, Simpson et al. conclude that oral steroids, especially when used in combination with an oral antibiotic, lead to a quicker resolution of OME in the short term (155). However, there was no evidence of longer term benefit and no impact on relieve symptoms of HL. There was also no significant evidence of benefit from topical intranasal steroids, alone or in combination with an antibiotic, either at short- or longer-term follow up (155). Williamson et al. evaluated the benefit of topical intranasal corticosteroids for bilateral OME in a double-blind randomized control trial. The study included 127 children aged 4 to 11 years, The results showed no difference in the resolution of effusion or HL over 3 months between children treated with nasal mometasone 50 μ in each nostril or placebo (156). In patients with allergic rhinitis complicated by OME, topical nasal steroids can be beneficial, because of the anti-inflammatory effect on allergic rhinitis, which may be a contributing factor to OME (157). In a systematic review of randomized controlled trials, to evaluate the short- and long-term benefit of antihistamines and/or decongestants for treating OME, Griffin and Flynn (158) concluded that there was no significant benefit on OME resolution. Schoem et al. evaluated the role of montelukast in treatment of OME in a prospective randomized placebo-controlled double-blind study, involving children aged 2 to 6 years with one or bilateral OME. Early results shows no advantage of montelukast versus placebo in clearance of middle ear effusion (159). Another study by Ertugay et al. evaluated the use of montelukast, 4 mg, with or without the H1 antihistamine, levocetirizine, 2.5 mg/5 mL, in 120 children with OME in a randomized prospective double-blind placebocontrolled, four treatment arm, trial. The results showed significant improvement in otoscopic sign scores for subjects using both therapies. Improvement in bilateral tympanometry findings was not significant (160). At present, the data do not support the use of systemic corticosteroids, intranasal corticosteroids, antihistamines, or decongestants in the management of OME as discussed earlier. Environmental Control When allergic rhinitis is associated with OME, environmental control of allergens and irritants should be advised. The most significant irritant is cigarette smoke. The parents must be urged to avoid exposure of their children to cigarette smoke in the home, car, restaurant, and day care facilities. Environmental inhalant allergens are more important to younger children because of the greater 1406
time spent in the home. Specific instructions for the avoidance of house dust mites, cockroaches, animal dander, and house mold spores should be given when indicated. Vaccination The heptavalent pneumococcal conjugate vaccine has been effective in significantly decreasing the number of episodes of otitis media in children. Black et al. demonstrated that children who received the pneumococcal conjugate vaccine were 20.1% less likely to require insertion of tympanostomy tubes than were controls (161). It is estimated to prevent up to 1,000,000 episodes of AOM per year, leading to cost savings of $160 per otitis media episode prevented (162). Similar results have been reported by Canadian investigators (163). Surgical Treatment Refractory cases that continue to have middle ear fluid after a 3- to 6-month trial of observation or medical management often need surgical intervention. Chronic middle ear effusion has been associated with the development of cholesteatomas, atrophy of the tympanic membrane, facial paralysis, and retention pockets. The Agency of Health Care Policy and Research Guidelines recommend myringotomy with the insertion of tympanostomy tubes for children with OME between 1 and 3 years of age who have bilateral HL of at least 20 dB for 4 to 6 months. This procedure is effective in removing the effusion and restoring normal hearing in the child. A number of studies (118,164) have demonstrated the beneficial effect of tympanostomy tubes in OME. It is usually recommended that tympanostomy tubes remain in place for 6 to 18 months. The longer the tube remains in the tympanic membrane, the greater the chance of complications. These include tympanosclerosis, persistent perforation, otorrhea, and occasionally cholesteatoma. Adenoidectomy has been suggested in the treatment of OME to remove blockage of the eustachian tube and improve ventilation. The Agency of Health Care Policy and Research Guidelines do not recommend adenoidectomy for children between 1 and 3 years of age with OME, although older children may benefit from the surgery. The AAOHNSF, AAP, and AAFP clinical practice guidelines recommend tympanostomy tubes when surgery is performed for OME in a child less than 4 years of age (149). Adenoidectomy should not be performed unless a distinct indication, such as nasal obstruction or chronic adenoiditis, exists. For a child older than 4 years of age, tympanostomy tubes or adenoidectomy or both are recommended when surgery is performed for OME. The primary benefits of adenoidectomy are to reduce failure rates, reduce time with middle ear effusion, and decrease the need for repeat surgery or future 1407
tubes. Gates et al. demonstrated that adenoidectomy improved and reduced recurrence of OME in children older than 4 years of age (165). They reported that the size of the adenoids did not relate to improvement of OME with adenoidectomy. One study showed that the use of CO2 laser myringotomy was more efficacious than incisional myringotomy with adenoidectomy in OME (166). Tonsillectomy is not recommended in the management of children with OME (118,167). Immunotherapy Subcutaneous or sublingual immunotherapy has been proved to be effective in the therapy for allergic rhinitis, when avoidance of the allergen is not possible or the symptoms are uncontrolled by medication. Many have the clinical impression that SCIT may be of help in OME in children with allergic rhinitis. However, there have been no controlled studies to verify this clinical impression. In conclusion, the prognosis in OME is usually good. As the child gets older, the incidence of OME tends to decrease. The medical and surgical intervention outlined for OME helps to control the condition until the child “outgrows” this disease. REFERENCES 1. Bashir SJ, Maibach HI. Compound allergy: an overview. Contact Dermatitis. 1997;36:179–183. 2. Marsh R, Towns S, Evans K. Patch testing in ocular drug allergies. Trans Ophthalmol Soc U K. 1978;98:278–280. 3. Mondino B, Salamon S, Zaidman G. Allergic and toxic reactions in soft contact lens wearers. Surv Ophthalmol. 1982;26:337–344. 4. Fisher AA, ed. Contact Dermatitis. 3rd ed. Philadelphia, PA: Lea & Febiger, 1986. 5. Eiseman AS. The ocular manifestations of atopic dermatitis and rosacea. Curr Allergy Asthma Rep. 2006;6:292–298. 6. Inoue Y. Ocular infections in patients with atopic disease. Int Ophthalmol Clin. 2002;42:55–69. 7. Leonardi A, De Dominicis C, Motterle L. Immunopathogenesis of ocular allergy: a schematic approach to different clinical entities. Curr Opin Allergy Clin Immunol. 2007;7:429–435. 8. Fukushima A. Roles of T-cells in the development of allergic conjunctival 1408
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management of acute otitis media. Pediatrics. 2013;131(3):e964–e999. 151. Sutton DV, Derkay CS, Darrow DH, et al. Resistant bacteria in middle ear fluid at the time of tympanotomy tube surgery. Ann Otol Rhinol Laryngol. 2000;109(1):24–29. 152. van Zon A, van der Heijden GJ, van Dongen TMA, et al. Antibiotics for otitis media with effusion in children. Cochrane Database Syst Rev. 2012;9:CD009163. 153. Venekamp RP, Burton MJ, van Dongen TM, et al. Antibiotics for otitis media with effusion in children. Cochrane Database Syst Rev. 2016; (6):CD009163. 154. Teele DW, Klein JO, Word BM, et al; Greater Boston Otitis Media Study Group. Antimicrobial prophylaxis for infants at risk for recurrent acute otitis media. Vaccine. 2000;19 (Suppl 1):S140–S143. 155. Simpson SA, Lewis R, van der Voort J, et al. Oral or topical nasal steroids for hearing loss associated with otitis media with effusion in children. Cochrane Database Syst Rev. 2011;5:CD001935. 156. Williamson I, Benge S, Barton S, et al. A double-blind randomized placebo-controlled trial of topical intranasal corticosteroids in 4- to 11year-old children with persistent bilateral otitis media with effusion in primary care. Health Technol Assess. 2009;13:1–144. 157. Lack G, Caulfield H, Penagos M. The link between otitis media with effusion and allergy: a potential role for intranasal corticosteroids. Pediatr Allergy Immunol. 2011;22:258–266. 158. Griffin G, Flynn CA. Antihistamines and/or decongestants for otitis media with effusion (OME) in children. Cochrane Database Syst Rev. 2011;9:CD003423. 159. Schoem SR, Willard A, Combs JT. A prospective, randomized, placebocontrolled, double-blind study of montelukast’s effect on persistent middle ear effusion. Ear Nose Throat J. 2010;89:434–437. 160. Ertugay CK, Cingi C, Yaz A, et al. Effect of combination of montelukast and levocetirizine on otitis media with effusion: a prospective, placebocontrolled trial. Acta Otolaryngol. 2013;133:1266–1272. 161. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in 1420
children. Pediatr Infect Dis J. 2000;19:187–195. 162. Lieu T, Ray A, Black S, et al. Projected cost-effectiveness of pneumococcal conjugate vaccination of healthy infants and young children. JAMA. 2000;283(11):1460–1468. 163. McClure CA, Ford MW, Wilson JB, et al. Pneummococcal conjugate vaccination in Canadian infants and children younger than five years of age; recommendations and expected benefits. Can J Infect Dis Med Microbiol. 206;17:19–26. 164. Rosenfeld R, Bhyer M, Bower C, et al. Impact of tympanostomy tubes on child quality of life. Arch Otolaryngol Head Neck Surg. 2000;126(5):585– 592. 165. Gates G, Avery C, Prihoda T, et al. Effectiveness of adenoidectomy and tympanostomy tubes in the treatment of chronic otitis media with effusion. N Engl J Med. 1987;317(23):1444–1451. 166. Szeremeta W, Parameswaran M, Isaacson G. Adenoidectomy with laser or incisional myringotomy for otitis media with effusion [In process citation]. Laryngoscope. 2000;110(3 Pt 1):342–345. 167. Stewart I. Evaluation of factors affecting outcome of surgery for otitis media with effusion in clinical practice. Int J Pediatr Otorhinolaryngol. 1999;49(Suppl 1):S243–S245.
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INTRODUCTION Atopic dermatitis (AD) is a common chronic inflammatory skin disease in children and adults (1). The disease is characterized by skin dryness, itch, flexural involvement in older children and adults, and facial/extensor involvement in infants (Fig. 29.1). Infections are a major morbidity of AD. These infections are caused by Staphylococcus aureus, Streptococcus pyogenes, herpes simplex virus (eczema herpeticum [EH]), enterovirus (eczema coxsackium [EC]), and smallpox vaccinia virus vaccine (eczema vaccinatum [EV]). They may lead to life-threatening complications that require urgent care visits and hospitalizations. Chronic AD negatively impacts the quality of life of patients, particularly in those with moderate-to-severe disease. Patients are affected by sleep disturbances and fatigue (2). Parents of AD children are among the most affected parents who take care of children with chronic illness in terms of sleep disturbances and stress (3,4). Sleep deprivation and fatigue lead to poor school or work performance, social isolation, anxiety, and depression in both patients and parents. The national annual cost of AD has been estimated to be $5.3 billion/year (5). There have been significant advances in our understanding of 1422
the pathogenesis and treatment of AD in recent years. This chapter outlines the current treatment approach and potential new managements in the prevention and treatment of AD.
EPIDEMIOLOGY AND NATURAL HISTORY The prevalence of AD is increasing around the world in different regions in the United States. AD prevalence in children ranges from 9% to 18% among states and districts (6). About 30% of these children have allergic rhinitis, whereas 25% have asthma. Although AD is primarily a childhood disease, it also has significant impact on adults. Recent estimate of the prevalence of adult AD in the United States is about 7% (5). The majority (80%) of these adult AD patients have childhood-onset AD, but 20% have adult-onset AD. More than 50% of AD patients have onset before a year, and most AD patients (80%) have onset by 7 years. The majority of children with AD have no more AD by 11 years; however, a significant 35% continues to have AD. Early age of onset and moderate-to-severe disease are the major risk factors for the persistence of AD (7).
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FIGURE 29.1 Facial and extensor distribution of infantile atopic dermatitis.
PATHOGENESIS The pathogenesis of AD involves a combination of skin barrier defects, immune dysregulation, and infectious agents (1). Although AD has been linked to filaggrin mutations, a protein that has skin barrier functions, only a minority of AD patients carries these mutations. In addition, more than half of individuals with filaggrin mutations do not have AD. These observations suggest that other skin barrier genes or variants in the immune response are responsible for the pathogenesis of AD. Genetic variants of thymic stromal lymphopoietin (TSLP) have been associated with AD and EH (8). TSLP is an important cytokine that induces TH2 responses. Importantly, expression of TSLP in infant skin precedes development of clinical AD (9). It is produced by keratinocytes. Together with 1424
interleukin (IL)-33 and IL-25, it activates type 2 innate lymphoid cells that produce IL-4, IL-5, and IL-13. These cytokines lead to further downstream activation of TH2 cells and amplification of IL-4, IL-5, and IL-13 production. These cytokines and IL-31, a cytokine that induces itch, are expressed in acute AD lesions. In addition to these cytokines, adults with chronic AD lesions are characterized by increased expression of IL-22 (10). IL-22 leads to hyperplasia of keratinocytes and further skin barrier defects. IL-4 and IL-13 have also been known to suppress the expression of filaggrin, leading to skin barrier defects (8). Genetics may also be a predispositing factor for AD patients to have increased infections. Multiple genetic variants in the type I and II interferon pathways have been associated with an increased risk for EH (8). S. aureus is a known trigger for AD symptoms. This bacteria is capable of producing multiple toxins, including α/δ cytolysins and enterotoxins (superantigens), which induce TH2 inflammation in AD. A reduced skin innate immunity and the presence of myeloid-derived suppressor cells, which suppress T-cell immunity (11), further contribute to the increased risk of skin infections in AD.
DIAGNOSIS AD consists of many phenotypes. In the future, it may be possible to use genetic testing or biomarkers to identify these phenotypes. However, currently, the diagnosis of AD is based on clinical assessment. Itch must be present. In addition, dry skin, flexural (or facial/extensor in infants) distribution of eczema, and the presence of personal or family history of atopy are important features of the diagnosis (see Table 29.1). The presence of multiple food allergies or specific food immunoglobulin E (IgE) sensitization in young children with eczema is consistent with the diagnosis of AD. In patients with adult-onset AD, they may have atypical features, including nummular dermatitis, seborrheic dermatitis, hand/face/neck dermatitis, and lichenified eczema on the trunk. However, if eczema is generalized or unresponsive to therapy, a skin biopsy or other diagnostic work-up should be considered to rule other skin diseases, such as cutaneous T-cell lymphoma or immunodeficiency. Table 29.2 shows the differential diagnosis of AD. TABLE 29.1 DIAGNOSTIC CRITERIA FOR ATOPIC DERMATITIS The presence of itchy skin in the past 12 mo, plus three of more of the following: 1. Onset of the skin condition under 2 y (not used in children under 4 y)
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2. History of itchy skin involving flexural areas (elbows, behind the knees, front of ankles, or around the neck) 3. History of generalized dry skin 4. Personal history of asthma or allergic rhinitis (for children under 4 y, history of atopic disease in a first-degree relative may be included) 5. Visible flexural dermatitis
Williams HC, Burney PG, Pembroke AC, et al. The U.K. Working Party’s diagnostic criteria for atopic dermatitis. III. Independent hospital validation. Br J Dermatol. 1994;131:406–416.
TABLE 29.2 DERMATITIS
DIFFERENTIAL
DIAGNOSES
OF
ATOPIC
Dermatologic Diseases Seborrheic dermatitis, irritant or allergic contact dermatitis, psoriasis, nummular dermatitis, lichen simplex chronicus, pityriasis rosea, ichthyos Neoplastic Diseases Cutaneous T-cell lymphoma (mycosis fungoides, Sézary syndrome), Letterer–Siwe disease (Langerhans cell histocytosis), necrolytic migratory erythema associated with pancreatic tumor
Immunodeficiencies Hyper-IgE syndrome, Dock 8 deficiency, Wiskott–Aldrich syndrome, severe combined immunodeficiency, Omenn syndrome, IPEX (immune dysregulation, polyendocrinopathy, enteropathy X-linked) syndrome
Infectious Diseases Human immunodeficiency virus–associated eczema, scabies, candidiasis, tinea versicolor
Congenital and Metabolic Disorders Netherton syndrome, phenylketonuria, acrodermatitis enteropathica, essential fatty acid
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deficiency, biotin deficiency, infantile-onset multiple carboxylase deficiency
Krol A, Krafchik B. The differential diagnosis of atopic dermatitis in childhood. Dermatol Ther. 2006;19:73–82.
CLINICAL EVALUATION AND MANAGMENT Evaluation of Severity In the clinical setting, the severity of AD is graded based on history and physical examination. Patients with generalized eczema, history of hospitalization or urgent care visits for AD, history of requirement for systemic corticosteroids or immunosuppressants, recurrent infections or EH, and involvement of face, hands, or eyes are generally considered to have moderate-to-severe AD. Most validated scoring systems for AD severity, such as SCOring of Atopic Dermatitis (SCORAD) and Eczema Area and Severity Index, may be too time-consuming to be used in the clinical setting. However, clinicians may consider the simpler Three Item Severity score (Table 29.3) or Patient-Oriented Eczema Measures, which are based on a simplified version of SCORAD and patient-based symptoms, respectively, for more objective measurement of AD severity. Another patient-based AD severity measurement is Patient-oriented SCORAD, which is available on phone apps for use by clinicians and patients. An accurate assessment of AD severity is crucial for assessing treatment progress and may dictate the management; for example, for moderate-to-severe AD patients, treatment with at least a mid-potency topical corticosteroid (TCS), referral to specialists, or work-up for food allergy (in young children) should be considered. TABLE 29.3 THREE ITEM SEVERITY (TIS) SCORE
Total score
MILD
MODERATE
SEVERE
0–2
3–5
6–9
The TIS is the sum of the three items (3 “e”s): erythema, edema, and excoriations (scored on a scale from 0 to 3); each item should be scored on the most representative lesion, that is, a lesion which represents the average severity.
Willemsen MG, van Valburg RW, Dirven-Meijer PC, et al. Determining the severity of atopic dermatitis in children presenting in general practice: an easy and fast method.
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Dermatol Res Pract. 2009;2009:357046.
Routine Daily Skin Care Skin hydration and daily application of moisturizers are recommended as a preventive treatment in most AD guidelines. However, there is no consensus on the method and frequency of skin hydration. Our clinical experience and past studies (12,13) have shown that daily bath or shower for 15 to 20 minutes followed by application of topical moisturizer and/or medications is an effective method of skin hydration. Such preventive care is crucial to restoring skin barrier function in AD patients.
Topical Corticosteroids TCS remain first-line treatment for AD. Table 29.4 shows some of the common TCS in different potencies. For mild AD, low-potency TCS (groups VI and VII) may suffice. But for moderate-to-severe AD, mid-potency TCS (e.g., groups IV and V) should be prescribed in adequate quantity. Concerns for the side effects of TCS and noncompliance are a main reason for treatment failure in AD. In spite of numerous studies showing the efficacy and safety of TCS in AD (14–16), adherence with TCS remains poor. These problems often arise from unfounded fears for the side effects of TCS (17). Recent concern for TCS “withdrawal” (or “addiction”) has resulted in patients’ or parents’ refusal to use TCS. This has led to AD flare, skin infections, and hospitalization. This poorly defined condition has been reported mostly in adults on the face and genital areas after prolonged use of moderate to high-potency TCS (18). Skin lesions caused by TCS withdrawal and AD are indistinguishable based on histologic examination. In addition, there may be overlapping features between TCS withdrawal and rosacea. In spite of the low quality of evidence for the existence of this condition, only 0.3% has been reported in patients younger than 3 years. Patients should be educated on the difference between systemic corticosteroids versus TCS and their side effects. Most patients and parents are confused on how much TCS to apply. The fingertip unit method offers a practical and reassuring guide for patients and parents to apply TCS (Table 29.5 and Fig. 29.2). Patients are educated on applying TCS on affected areas twice daily as needed. Select AD patients may benefit from a proactive approach by applying TCS on unaffected areas that previously flared or of potential flare twice weekly. This approach has been shown to reduce the overall flare and need for TCS in AD (19).
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Management of Itch, Pain, and Sleep Itch and sleep problem remain to be a major morbidity of AD. These problems often persist in many AD patients even years after they have outgrown AD. The first-generation antihistamines, such as diphenhydramine and hydroxyzine, do not stop the itch in AD. Their main effect is sedation. They are, therefore, best used before sleep. Nonsedative second-generation antihistamines, such as loratadine or cetirizine, have not been proven to be effective in AD, although they can be helpful in the 10% AD with chronic urticaria. There is anecdotal evidence that oral doxepin at low dose may improve the itch and sleep of AD patients, but further studies are needed to validate this. Pain not associated with fissures, skin cracks, or infection is an emerging problem in AD (20). AD patients may complain of pain, burning, and stinging on unaffected areas. Further studies are needed to clarify the mechanisms of these symptoms and whether medications, such as gabapentin or pregabalin, are beneficial. Because there are overlapping mechanisms between itch and pain, systemic and topical µ opiod receptor antagonists have been studied in AD, but have been met with mixed results. On the other hand, κ opiod receptor agonists are potential treatment for the itch of AD. This medication has been approved for use in Japan for itch associated with renal disease and is currently in phase 2 clinical trials for AD. Other potential anti-itch medications include monoclonal antibody against IL-31, which is produced by TH2 cells and has been shown to be an important mediator of itch. TABLE 29.4 TOPICAL CORTICOSTEROID POTENCIES GROUP I (most potent) Betamethasone dipropionate 0.05% (Diprolene) (cream, ointment) Diflorasone diacetate 0.05% (Psorcon) (ointment) Clobetasol propionate 0.05% (Temovate) (cream, ointment) Halobetasol dipropionate 0.05% (Ultravate) (cream, ointment) GROUP II
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Amcinonide 0.1% (Cyclocort) (ointment) Betamethasone dipropionate 0.05% (Diprosone) (cream, ointment) Mometasone furoate 0.1% (Elocon) (ointment) Halcinonide 0.1% (Halog) (cream) Fluocinonide 0.05% (Lidex) (gel, cream, ointment) Desoximetasone (Topicort) (0.05% gel, 0.25% cream, ointment) GROUP III Fluticasone propionate 0.005% (Cutivate) (ointment) Amcinonide 0.1% (Cyclocort) (lotion, cream) Diflorasone diacetate 0.05% (Florone) (cream) Betamethasone valerate 0.1% (Valisone) (ointment) GROUP IV Mometasone furoate 0.1% (Elocon) (cream) Triamcinolone acetonide 0.1% (Kenalog) (cream) Fluocinolone acetonide 0.025% (Synalar) (ointment) GROUP V Fluticasone propionate 0.05% (Cutivate) (cream)
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Fluocinolone acetonide 0.025% (Synalar) (cream) Desonide 0.05% (Tridesilon) (ointment) Betamethasone valerate 0.1% (Valisone) (cream) Hydrocortisone valerate 0.2% (Westcort) (cream) GROUP VI Alclometasone dipropionate 0.05% (Aclovate) (cream, ointment) Flucinolone acetonide 0.01% (Synalar) (solution, cream) Desonide 0.05% (Tridesilon) (cream and aqueous gel) GROUP VII (least potent) Hydrocortisone 1%/2.5% (Hytone) (lotion, cream, ointment)
Stoughton RB. Vasoconstrictor assay—specific applications. In: Maibach HI, Surber C, eds. Topical Corticosteroids. Basel, Switzerland: Karger, 1992:42–53.
Evaluation and Management of Food Allergies In all, 30% to 40% of children with moderate-to-severe AD are affected by one or more food allergies (21); therefore, evaluation for food allergy is warranted in these patients. Offending food allergens may cause allergic reactions that lead to itch/scratch cycle and worsening of AD. The most implicated food allergens are egg, cow’s milk, peanut, wheat, and soy. The diagnosis of food allergy in AD patients should be based on a combination of history, skin tests, serum-specific IgE tests, and oral food challenge. Owing to the high risk of developing peanut allergy, moderate-to-severe AD infants have been the subject of the recently published Learning Early About Peanut study (22). The study showed that infants with moderate-to-severe AD who maintained an ingestion of peanut 1431
allergens for the first 5 years have developed significantly less peanut allergy, as compared to those who avoided peanut. Referral of these high-risk infants to allergists for peanut skin tests and oral challenge is recommended (23). TABLE 29.5 FINGERTIP UNIT (FTU) APPLICATION OF TOPICAL CORTICOSTEROIDS NUMBER OF FTUs
FACE/NECK ARM/HAND LEG/FOOT
TRUNK BACK/BUTTOCK (FRONT)
AGE
3–6 mo
1
1
1.5
1
1.5
1–2 y
1.5
1.5
2
2
3
3–5 y
1.5
2
3
3
3.5
6–10 y
2
2.5
4.5
3.5
5
Long CC, Mills CM, Finlay AY. A practical guide to topical therapy in children. Br J Dermatol. 1998;138:293–296.
FIGURE 29.2 A fingertip unit is equivalent to the amount of cream/ointment squeezed from a typical tube with 5 mm nozzle onto an adult index finger up to 1432
the distal interphalangeal joint.
The Role of Aeroallergens There is evidence that direct skin contact with house dust mites (HDMs) or furry animals may exacerbate AD (24). Therefore, HDM control and avoidance of furry animals are recommended in sensitized AD patients. More recently, a double-blind, placebo-controlled study using an environmental challenge chamber showed that direct skin contact with pollens significantly exacerbates eczema in pollen-sensitized AD patients (25). It may be beneficial for pollensensitized AD patients to cover their affected areas or areas of potential flare when they are outdoors, especially during pollen season. There is evidence that subcutaneous or sublingual allergen immunotherapy may benefit certain subsets of AD patients. Further studies are needed to confirm these findings.
Management of Infections More than 95% of AD lesions can be colonized by S. aureus. Therefore, routine treatment with antibiotics when there is no sign of infection is not recommended. Signs of skin infections in AD include pain, swelling, mucopurulent discharge, or impetiginous (“honey crusted”) lesions. For small, localized areas of skin infections, topical mupirocin should be considered. If the skin infection is widespread, an oral antibiotic such as cephalexin may be given. As methicillinresistant S. aureus is more prevalent in AD patients, a wound culture with antibiotic susceptibility should be considered in cases of treatment failure. Patients who have persistent fever, joint swelling, or focal bone pain should raise the possibility of invasive bacterial infections. Bacteremia is the most common invasive infection in young children with AD. Osteomyelitis and septic arthritis are not uncommon in patients with uncontrolled moderate-to-severe AD. A potential rare invasive infection in severe AD patients is endocarditis. Careful auscultation for heart murmur may be warranted for AD patients with persistent fever. S. pyogenes is another common cause of bacterial infections in AD. Routine daily skin care can improve skin barrier functions and decrease the number of bacteria on the skin. Consistent use of TCS on AD lesions decreases inflammation, which is a predisposing factor for bacterial colonization and infection. The use of diluted bleach bath may benefit a subset of patients with recurrent bacterial skin infections. Placebo-controlled studies are needed to evaluate whether diluted bleach bath can improve eczema severity in AD patients without skin infections. EH is a potentially life-threatening infection in AD. Patients commonly 1433
present with fever and painful vesicular or punched-out rash that superimposes on acute eczematous lesions. Serious complications of EH include viremia, keratoconjunctivitis, and meningitis. On clinical suspicion, oral acyclovir or admission to the hospital for intravenous acyclovir should be initiated. In such cases, viral swab for herpes simplex virus polymerase chain reaction (PCR) should be obtained from the vesicular lesions. In patients with ophthalmic involvement or lesions near the eyes, an urgent ophthalmology consultation should be obtained. For EH patients with disseminated infections, supportive care include intravenous fluids to manage fluid losses, symptomatic management of pain and pruritus, and treatment for secondary bacterial infections. EC, which is caused by Coxsackie virus, may be confused with EH, because it presents with vesicles. The presence of EC lesions on the buttocks may be a distinguishing feature. In addition, AD patients with EC may present with the typical hand-foot-mouth lesions. A lesional swab for enterovirus PCR may be considered if the diagnosis is still not clear. The management of EC is symptomatic with continuation of routine AD treatments. EV is caused by live smallpox vaccine (vaccinia virus), which is generally contraindicated in AD patients. EV lesions are characterized by umbilicated pustules and vesicles. Since 911, due to the threat that smallpox virus may be used as a biologic weapon by terrorists, mass vaccinations with smallpox vaccine in military personnel and first responders have been carried out in the United States. With careful screening and exclusion of AD patients from getting this live vaccine, only rare cases of EV have since been reported. However, clinicians should continue to be vigilant of potential EV in this high-risk population and their close contacts.
Other Treatment Options Topical Calcineurin Inhibitors Tacrolimus ointment (Protopic, Astellas) 0.03% and pimecrolimus cream (Elidel, Valeant) 1% are approved for children aged 2 years and older with AD, and tacrolimus ointment 0.1% for patients aged 16 years and older. They are both second-line therapies for AD. Tacrolimus ointment is indicated for moderate-to-severe AD and pimecrolimus cream for mild-to-moderate AD. Both products have a Food and Drug Administration (FDA) black box warning of cancer risk. More recent studies have indicated that these medications are safe and effective in children and infants (500–1,000
Ciclesonide (HFA) (80, 160)
80
>80–160
>160
Flunisolide (HFA) (80)
80
>80–160
>160
Fluticasone furoate (DPI) (100, 200)
NA
100
Fluticasone propionate (DPI) (50, 100–200 100, 250) 110–220 (HFA) (44, 110, 220)
>200– 400
Mometasone furoate (DPI) (110, 220)
≥220– 1,000
200
>400 >440
>220– 440 ≥440 >400
200–400
Children 4 y and Younger Beclomethasone dipropionate HFA
100
NA
NA
Budesonide pMDI + spacer
200
NA
NA
Budesonide nebulized
500
NA
NA
Fluticasone propionate HFA
100
NA
NA
Ciclesonide
160
NA
NA
a
High doses of inhaled corticosteroids are not recommended for use in young children and infants. DPI, dry powder inhaler; HFA, hydrofluoroalkane; MDI, metered-dose inhaler; NA, not
1603
available.
Delivery Devices The type of delivery device plays an important role in determining the amount of drug delivered to the lungs and subsequently the clinical benefit; Chapter 37 reviews delivery devices in more detail. Lung deposition is influenced by the inhalation device, propellant, particle size, that is, mass mean aerodynamic diameter, and by whether the solution is an aerosol or a suspension. Commonly used devices for GC inhalation are the MDI, DPI, and the nebulizer. The dose of drug delivered to the lungs differs between MDIs and DPIs and among devices delivering different ICSs (Table 35.5), so clinicians should consider these differences when choosing a device. Ease of use, cost, and less-frequent dosing are important factors to consider, because they lead to better compliance. In MDIs, which may be either breath activated or pressurized, hydrofluoroalkane (HFA) propellants have replaced chlorofluorocarbon propellants owing to a worldwide mandate. A spacer may be used with HFA-propelled MDIs to reduce oropharyngeal deposition, minimize local side effects, and improve distal drug distribution in the lungs (68). This mechanism, with possible attachment of a face mask, is the delivery method of choice for children (69). Aerosol particle size is also a key determinant of lung deposition and regional distribution of inhaled drugs. Using a pMDI with extra-fine particles can also improve lung deposition. Nebulizers are used for individuals, such as for infants, young children, and the elderly, who cannot use an MDI owing to coordination, cooperation, or breathing patterns. Compared with MDI or DPI inhalers, nebulizers deliver relatively low doses of GC to the lungs. The characteristics of the face mask, the seal, and the breathing pattern all affect the amount of drug delivered (68).
Dose–Response Considerations Drug deposition in the lungs may be required for clinical response, but the dose– effect relationship for inhaled GC therapy is not linear. In fact, taking into account individual variability, most of the clinical benefit from inhaled GC therapy is achieved by submaximal doses in adults and children (70–72). That is, patients with mild-to-moderate asthma gain the most benefit from using a low- to moderate-dose ICS. However, there may be a dose-related favorable response of bronchial hyperresponsiveness (73). There is a much steeper dose–response curve for systemic effects, however, so the smaller proportional additional benefits of higher doses must be weighed against the risks in individual patients. 1604
One must also consider the severity of the patient’s asthma. Patients with very mild asthma have relatively minimal airflow obstruction and little room for improvement; so low doses potentially provide maximal improvement. Patients with unstable or more severe asthma have significantly greater airflow obstruction and therefore may show a greater response to increasing doses. Similarly, those with severe, steroid-dependent asthma may benefit from highdose ICS as a systemic steroid-sparing agent (74). TABLE 35.5 COMPARISON OF DRUG DEPOSITION IN THE LUNGS AMONG INHALER DEVICES
DRUG
FORMULATION
MMAD (μ–M)
PULMONARY DEPOSITION (% ACTUATION DOSE)
BDP/BMP
MDI-HFA
1.1
53
BUD
DPI
3.7
34
nebulized suspension
2.9
10–20
CIC
MDI-HFA
1.1
52
FLN
MDI-HFA
1.2
68
FF
DPI
4.0
22
FP
DPI
5.4
16
MDI-HFA
2.4–3.2
13–18
DPI
2.2
NA
MDI-HFA
3.7
MF
OF
BDP, beclomethasone dipropionate; BUD, budesonide; CIC, ciclesonide; DPI, dry powder inhaler; FF, fluticasone furoate; FLN, flunisolide; FP, fluticasone propionate; HFA, hydrofluoroalkane; MDI, metered-dose inhaler; MF, mometasone furoate; MMAD, mass mean aerodynamic diameter; NA, not available.
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Systemic Glucocorticoid Therapy for Acute Exacerbations of Asthma The EPR-3 recommends classifying asthma exacerbations as mild, moderate, and severe. These guidelines emphasize early recognition of an asthma exacerbation, use of home-based action plans for initiating therapy with shortacting inhaled β2 agonists, and initiation of systemic GC therapy for asthma exacerbations that are not promptly responsive to therapy with the rescue drugs (68). Higher dose inhaled GCs may benefit children with asthma exacerbations (75). For individuals with more profound symptoms or lung function decline consistent with moderate-to-severe exacerbations, systemic GC treatment should be initiated immediately after recognition of an exacerbation. Systemic GC therapy reduces hospitalization rates, inhaled β2 agonist requirement, and prevents relapses (76,77), especially in patients at high risk for fatal asthma. Administration can be via oral, IV, or intramuscular routes; there is no clear evidence to suggest superiority of route of administration. In addition, lower doses (≤80 mg methylprednisolone equivalent) of systemic GC seem as effective as higher doses for initial management of acute asthma (78,79). Oral GCs may be utilized in the outpatient or emergency department setting for treatment of acute exacerbations. Commonly utilized dosing regimens include prednisone 40 to 80 mg/day (1 to 2 mg/kg/day in children, max 60 mg/day) in 1 to 2 divided doses or equivalent doses of an alternate GC (68). The duration of therapy for an exacerbation can be individualized based on severity of exacerbation and patientspecific factors. In general, an asthma exacerbation may require a 3- to 14-day course of systemic GCs (with 5 to 10 days recommended by expert parameters (68)). Tapering is not necessary for courses of GC at or less than 14 days duration. Intramuscular depot injections of GC can be used for individuals with risk of noncompliance. For individuals requiring prolonged treatment for more severe or refractory exacerbations, alternate-day dosing can be utilized to reduce the risk of systemic side effects. The clinician should frequently re-evaluate patients on prolonged steroid courses and attempt to reduce the dose by 5 to 10 mg every 2 weeks until the lowest clinically effective dose is reached. The goal is to discontinue systemic GC therapy if possible. IV GCs are commonly administered in the emergency department setting, and may include hydrocortisone, betamethasone, methylprednisolone, and dexamethasone. Methylprednisolone, because of its anti-inflammatory potency, lower MC activity, and lower price by comparison with hydrocortisone, may be
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the drug of choice for IV therapy. For acutely, critically ill asthmatic adults, IV dosing of methylprednisolone, 60 to 125 mg IV every 6 hours (or its equivalent) may be appropriate (79). Dosing intervals depend on the clinical condition of the acutely ill asthmatic and pharmacokinetic properties of the GC. However, intervals may begin at every 4 to 6 hours. Treatment can be maintained for 48 hours depending on the clinical response. When signs and symptoms improve, doses can be tapered to twice daily, then to a single morning daily dose. Patients who require IV GCs can be switched to oral GCs once stable. The total duration of IV therapy is dependent on both subjective and objective improvement in respiratory status.
Steroid-Resistant or Steroid-Dependent Asthma GC sensitivity can be affected by bioavailability of the GC preparation, and variability of GC receptors (GCR) and GC receptor transcriptional activity (80). Specifically, reduced numbers of GCRs, altered affinity for the ligand for GCRs, reduced ability of the GCRs to bind DNA, or increased expression of inflammatory transcription factors that compete for DNA binding can reduce cellular responses to GCs. The balance of GCR splice variants may also impact GC sensitivity. GCR-β will not bind to GCs but does interfere with the movement of GCR-α to the nucleus and with gene activation. Increased expression of GR-β has been noted in fatal asthma and nocturnal asthma (81). In asthmatics, steroid insensitivity is defined as persistent lack of control despite GC therapy, or worsening of asthma on reduction or discontinuation of GCs, and may be driven by some or all of these factors. Insensitivity to GCs may be induced by chronic inflammatory cytokine exposure, or by chronic exposure to corticosteroids (82). Further, some virus-induced inflammatory pathways may induce GC resistance, thereby affecting the ability of GCs to prevent or treat viral-induced asthma exacerbations (83,84). Common characteristics of asthmatics, such as obesity, smoking, and vitamin D deficiency have all been associated with steroid insensitivity in adults (85). Asthma with predominant type 2 inflammation, characterized by eosinophilia and/or atopy, responds to GC treatment better than asthma without type 2 inflammation (63). Ex vivo measurements of cellular responses to GCs have identified decreased reactivity of peripheral blood mononuclear cells of severe asthmatics, related to histone deacetylase activity (86). Differential responses of alveolar macrophages (87,88) and airway smooth muscle cells (46) to GCs may also contribute to GC insensitivity in severe asthma.
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Complete resistance to GCs in asthma is rare. Resistance can be identified by failure to significantly improve forced expiratory volume in 1 second or peak expiratory flow after treatment with prednisone 40 to 60 mg daily for 2 to 3 weeks, or equivalent systemic doses. Intramuscular dosing can address concerns of medication noncompliance. It is also important to determine that the patient has asthma and not another disease, such as chronic obstructive pulmonary disease, which may not respond to GC treatment. The clinician should also investigate the possibility of comorbidities or contributing factors, such as aeroallergen exposure, other medications, or psychologic problems that could increase the severity of asthma and its resistance to treatment. Some asthma treatments are the so-called “corticosteroid-sparing” drugs because they may reduce GC requirements through addressing additional inflammatory or physiologic effects of asthma. These include immunosuppressants, biologics (anti-IgE (89) and anti-IL-5 (90)), macrolide antibiotics (91), and bronchial thermoplasty (92). These treatments are discussed in Chapters 19, 22, and 38.
Intranasal Glucocorticoids and Allergic Rhinitis Guidelines for the treatment of both perennial and seasonal allergic rhinitis recommend intranasal GCs as safe and effective therapy. These antiinflammatory medications have prolonged local action, few local side effects, and few, if any, systemic effects (13). All intranasal GCs act directly on nasal inflammation to reduce the symptoms of allergic rhinitis, including nasal congestion, itching, sneezing, and rhinorrhea. They reduce fluid exudation and the number of circulating inflammatory cells, including basophils, lymphocytes, mast cells, eosinophils, neutrophils, and macrophages. Treatment with intranasal steroids also usually improves ocular symptoms, including redness, itching, and watering. This benefit likely reflects both an overall decrease in the inflammatory mediators and inhibition of ipsilateral and contralateral neural reflex arcs from the nose to the eye (93). Intranasal GC preparations have rapid onsets, short half-lives, and rapid first-pass hepatic metabolism consistent with the ICS. Intranasal GC therapy is recommended as first-line treatment and the most effective monotherapy for treating perennial and seasonal allergic rhinitis (94). Combination therapy of allergic rhinitis with concomitant use of intranasal GCs with oral antihistamines, intranasal antihistamines, and/or oral leukotriene antagonists may achieve improved symptom control and is therefore common in
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clinical practice. Treatment with intranasal GCs is best begun days before allergen exposure when possible—usually about 2 weeks before the beginning of allergy season—and may be maintained for another 2 weeks after the end of the season to control residual mucosal hyperreactivity. However, the onset of action of intranasal steroids may be as early as 3 to 4 hours in some individuals, and is estimated at approximately 12 hours in others. Therefore, some individuals may benefit significantly from as-needed treatment. Others require daily treatment for full benefit. Guidelines recommend tapering the dose to the lowest level required to maintain symptom relief after reaching initial control (94). Currently, there are multiple intranasal ICS preparations available for treatment of allergic rhinitis in the United States for children and adult (Table 35.6). All have similar safety profiles, and all are similarly efficacious in controlling symptoms. Patient preference for and clinical benefit from intranasal GC may vary among preparations because of mechanism of delivery (spray versus mist versus aerosol), formulation (aqueous versus alcohol), scent, and volume of solution delivered. The nasal spray pump—available with BUD, CIC, FL, FP, MF, and TA—provides solution directly to the nasal cavity, with most solution coating the inferior turbinates (95). Intranasal GC sprays are now available for over-the-counter purchase. A nasal misting device of FF can provide less volume and may be better tolerated by those averse to dripping. Two intranasal aerosol preparations are available in the United States by prescription—CIC and beclomethasone—and were developed to improve the intranasal deposition profile. Patient instructions for use of intranasal steroid preparations share the same general principles across devices. The patient should blow his or her nose to clear residual mucus. The head should be positioned forward or slightly downward. The administration device should be positioned into each nare with the nozzle directed toward the ipsilateral lateral wall, in the general direction of the ear. This minimizes septal deposition of medication and subsequently the risk of septal irritation. A gentle sniff is allowed, but patients are taught not to inhale strongly as to reduce the rate of posterior oropharyngeal deposition and clearance by swallowing. Most adverse effects are mild and do not warrant discontinuation of treatment. Epistaxis occurs in 5% to 8% of patients and is usually self-limiting. Atrophy or thinning of the nasal tissue with long-term use is not a problem with the newer intranasal GCs. Oral candidiasis has been reported rarely. The potential for systemic absorption and HPA axis suppression remains a concern 1609
for children and adults. However, studies have generally found no difference between intranasal GCs and placebo in their effects on HPA axis function in either children or adults (96,97). Anticipatory clinical monitoring should be utilized, however, particularly for individuals with a history of HPA axis dysfunction, hepatic dysfunction, or use of medications affecting hepatic metabolism, and those on other topical or systemic steroid preparations.
Corticosteroids for Other Allergic Diseases Nasal Polyposis Topical and systemic GCs are accepted medical therapy for patients who have nasal polyposis (98,99). Many patients suffering from nasal polyposis will respond to systemic GC treatment with improvement in symptom scores, polyp scores, and imaging scores. The duration of benefit varies. This so-called “medical polypectomy” may be achieved with a 2-week treatment of oral prednisone, 30 to 50 mg daily with tapering after the first 4 days of treatment. The simultaneous and subsequent use of intranasal steroids is common in clinical practice. Maintenance therapy with intranasal GC preparations, including BDP, BUD, CIC, FL, FP, MF, and TA, have been shown to variably reduce polyp size and prevent regrowth after surgical polypectomy (98). TABLE 35.6 INTRANASAL STEROID (AVAILABLE IN THE UNITED STATES)
DRUG (US BRAND DELIVERY NAME) TYPE
DOSE SPRAY
PREPARATIONS
USUAL PEDIATRICUSUAL ADULT ADMINISTRATION,ADMINISTRATION, SPRAY(S) PERSPRAY(S) PER PERNOSTRIL NOSTRIL (AGE, YEARS) (AGE, YEARS)
Beclomethasone QNASL
Aerosol
40 μg
1 daily (4–11)
—
80 μg
—
2 daily (≥12)
64 μg
1–2 bid (≥6)
1–2 bid (≥12)
Budesonide Rhinocort
Spray
1610
Aqua
Ciclesonide Omnaris
Spray
50
2 daily (≥6)
2 daily (≥12)
Zetonna
Aerosol
37
1 daily (≥12)
1 daily (≥12)
Spray
29
1 tid or 2 bid (6–14) 2 bid or 2 tid (≥14)
27.5
1 daily (2–11)
2 daily (≥12)
Spray
50
1 daily (4–11)
1–2 daily (≥12)
Spray
50
1 daily (2–11)
2 daily (≥12)
Spray
55
1–2 daily (≥2)
1–2 daily (≥12)
Flunisolide Nasarel
Fluticasone Furoate Veramyst
Mist spray
Fluticasone Propionate Flonase
Mometasone Nasonex
Triamcinolone Nasacort
bid, twice daily; tid, three times daily.
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Atopic Dermatitis and Allergic Contact Dermatitis The use of high-potency topical GCs has led to improved treatment for dermatologic conditions that have an inflammatory etiology, such as AD and contact dermatitis (Chapters 29 and 30). AD is a chronic, pruritic, inflammatory skin condition. Management of AD centers on a regimen of excellent skin care (hydration and emollients), antipruritic medications, anti-inflammatory medications, antibacterial treatments, and avoidance of triggers such as allergens or irritants. It is critical for clinicians treating patients with AD to address and emphasize each of these treatment realms (100). For many patients with AD, skin care and allergen avoidance will control their disease. Topical steroids are used on a temporary basis to treat flares of AD in these patients. Other patients will require regular use of topical steroids to maintain adequate control of AD. There are seven classes of topical corticosteroid, ranked according to potency with class 1 being the most potent. The choice of topical corticosteroid potency depends on the severity and distribution of AD lesions, taking into account surface area and degree of systemic absorption that could lead to HPA axis suppression. Whereas using less potent corticosteroid treatments minimizes side effects, under treatment of the skin inflammation may result in persistence or worsening of AD. A more effective strategy may be to use a stepped approach starting with a mid-potency preparation (except for eczema involving the face, axillae, or groin) and, with clinical improvement, switching to a lower potency preparation for maintenance treatment. Frequent clinical reevaluation is warranted. High-potency corticosteroids may be needed for severe hand and foot eczema, or for short periods of time on other areas of the body, and should not be used on the face, genitalia, or in skin folds. Only mild-to-moderate potency steroid preparations should be used in children. In severe cases of AD, oral GC may be used sparingly. Topical and systemic immunomodulators can be used as steroid-sparing therapy or for those refractory to treatment (100). Contact dermatitis is a delayed hypersensitivity reaction to topically exposed antigens. Identification and avoidance of the offending antigen is required for management of contact dermatitis (101). In the acute phase, topical and/or systemic GCs can be used to reduce skin inflammation. Severe allergic contact dermatitis that fails to respond to topical treatment may improve with once-daily, then alternate-day oral prednisone at doses of 30 to 60 mg for 1 to 2 weeks (102). Ocular Allergy Topical antihistamines and mast cell stabilizers are the typical treatments for 1612
mild-to-moderate allergic conjunctivitis, but in severe cases, topical corticosteroids—preferably those with reduced side effects—may be necessary for temporary use to achieve control of disease or in rare cases, for long-term control (93). Loteprednol etabonate has been found effective for treating ocular allergy and inflammation, and with addition of an ester group to the structure, has an improved safety profile with less impact on intraocular pressure and cataract formation (103). Loteprednol etabonate eye drops are available as either 0.5% or 0.2% suspensions. Several randomized trials confirm that the lower dose is effective in reducing redness and itching without causing significant changes in intraocular pressure, even with long-term use (104). GCs are also use to treat vernal keratoconjunctivitis, a severe but transient form of ocular allergy, and atopic keratoconjunctivitis, which is a severe allergic conjunctivitis with AD. Both of these disorders have potential for corneal complications and are treated accordingly. Treatments include loteprednol etabonate, fluorometholone 0.1%, and in severe cases, topical immunomodulators such as cyclosporine and tacrolimus (103). Idiopathic Anaphylaxis and Urticaria and Angioedema Idiopathic anaphylaxis (IA) is a diagnosis of exclusion that can affect both adults and children. As with other cases of anaphylaxis, treatment of acute attacks of IA includes emergent epinephrine administration with adjunctive antihistamines and systemic GCs. For individuals with frequent episodes of IA, defined as at least two episodes in the preceding 2 months or at least six episodes in the preceding year, systemic GC therapy is used to induce remission. Patients are instructed to take both a daily antihistamine and prednisone 40 to 60 mg by mouth daily for 1 to 2 weeks, until symptom control is achieved. After this time, prednisone can be switched to alternate-day dosing and tapered slowly, by 5 mg every other day, every 1 to 2 weeks. If prednisone dose not achieve symptom control, the diagnosis of IA should be questioned (105). Acute and chronic urticaria are common conditions. Management of acute and chronic spontaneous urticaria typically includes H1 and H2 antihistamines, and in many cases, symptoms can be controlled with these treatments. In the case of acute severe urticaria, or for refractory cases of chronic spontaneous urticaria that persist despite high-dose antihistamine treatment, additional antiinflammatory measures are needed to control symptoms. Systemic GC therapy can be used for short periods of time to give relief. Initial therapy with GC may start with 30 to 40 mg of prednisone to control symptoms, and if needed for longer term control, alternate-day therapy with a taper as clinically indicated and 1613
tolerated. Omalizumab or systemic immunosuppressants (cyclosporine, tacrolimus, and azathioprine) can be used to control urticaria, as steroid-sparing agents (see Chapter 31). Unique among subtypes of urticaria, delayed pressure urticaria may respond more favorably to topical corticosteroids to control local disease (106). Eosinophilic Esophagitis Eosinophilic esophagitis is a chronic, antigen-driven inflammatory disorder characterized by eosinophilic inflammation of the esophagus with resultant esophageal dysfunction. Symptoms can vary and include feeding refusal, abdominal pain, reflux, dysphagia, and food impaction. Although empiric or testing-guided food avoidance measures improve this disease for a significant proportion of patients, some will require medical therapy. A short course of systemic GC therapy can be used in the setting of acute severe symptoms. Topical GC may utilized in this setting to reduce eosinophilia, epithelial fibrosis, and remodeling. Viscous BUD (1 mg for children, 2 mg for adolescents and adults; divided twice daily) and FP (440 to 880 µg for children, 880 to 1,760 µg for adults; divided twice daily) have been studied for this indication (107,108). Patients are instructed to swallow the treatment after a meal, with avoidance of subsequent eating or drinking for 30 minutes (109).
CONCLUSIONS GC therapy is widely used for treatment of allergic inflammatory disease because of the wide range of mechanistic targets and clear therapeutic benefits. Because of the tissue specific and systemic side effects of GCs with regular or high-dose use, health care providers must utilize topical preparations when possible, minimize use to lowest effective dose, and carefully monitor patients for the development of side effects. REFERENCES 1. Addison T. On the Constitutional and Local Effects of Disease of the Suprarenal Capsules. London: Samuel Higley, 1855. 2. Hench PS, Kendall EC, Slocumb CH, et al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin. 1949;24(8):181–197. 3. Hench PS, Kendall EC, Slocumb CH, et al. Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain other 1614
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Database Syst Rev. 2007;(3):CD000195. 78. Manser R, Reid D, Abramson M. Corticosteroids for acute severe asthma in hospitalised patients. Cochrane Database Syst Rev. 2001;(1):CD001740. 79. Fiel SB, Vincken W. Systemic corticosteroid therapy for acute asthma exacerbations. J Asthma. 2006;43(5):321–331. 80. Quax RA, Manenschijn L, Koper JW, et al. Glucocorticoid sensitivity in health and disease. Nat Rev Endocrinol. 2013;9(11):670–686. 81. Goleva E, Li LB, Eves PT, et al. Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. Am J Respir Crit Care Med. 2006;173(6):607–616. 82. Rodriguez JM, Monsalves-Alvarez M, Henriquez S, et al. Glucocorticoid resistance in chronic diseases. Steroids. 2016;115:182–192. 83. Papi A, Contoli M, Adcock IM, et al. Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor kappaB and c-Jun N-terminal kinase activation. J Allergy Clin Immunol. 2013;132(5):1075.e1076–1085.e1076. 84. Jackson DJ, Sykes A, Mallia P, et al. Asthma exacerbations: origin, effect, and prevention. J Allergy Clin Immunol. 2011;128(6):1165–1174. 85. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343–373. 86. Hew M, Bhavsar P, Torrego A, et al. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am J Respir Crit Care Med. 2006;174(2):134–141. 87. Bhavsar P, Hew M, Khorasani N, et al. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma. Thorax. 2008;63(9):784–790. 88. Lea S, Harbron C, Khan N, et al. Corticosteroid insensitive alveolar macrophages from asthma patients; synergistic interaction with a p38 mitogen-activated protein kinase (MAPK) inhibitor. Br J Clin Pharmacol. 2015;79(5):756–766. 89. Normansell R, Walker S, Milan SJ, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;1:CD003559.
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90. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–1197. 91. Carr TF, Kraft M. Chronic infection and severe asthma. Immunol Allergy Clin North Am. 2016;36(3):483–502. 92. Pretolani M, Bergqvist A, Thabut G, et al. Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: clinical and histopathological correlations. J Allergy Clin Immunol. 2017;139(4):1176– 1185 93. Bielory L, Katelaris CH, Lightman S, et al. Treating the ocular component of allergic rhinoconjunctivitis and related eye disorders. MedGenMed. 2007;9(3):35. 94. Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol. 2008;122(2 Suppl):S1–S84. 95. Tay SY, Chao SS, Mark KT, et al. Comparison of the distribution of intranasal steroid spray using different application techniques. Int Forum Allergy Rhinol. 2016;6(11):1204–1210. 96. Boner AL. Effects of intranasal corticosteroids on the hypothalamic– pituitary–adrenal axis in children. J Allergy Clin Immunol. 2001;108(1 Suppl):S32–S39. 97. Galant SP, Melamed IR, Nayak AS, et al. Lack of effect of fluticasone propionate aqueous nasal spray on the hypothalamic–pituitary–adrenal axis in 2- and 3-year-old patients. Pediatrics. 2003;112(1 Pt 1):96–100. 98. Peters AT, Spector S, Hsu J, et al. Diagnosis and management of rhinosinusitis: a practice parameter update. Ann Allergy Asthma Immunol. 2014;113(4):347–385. 99. Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl. 2012;(23):1–298. 100. Schneider L, Tilles S, Lio P, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol. 2013;131(2):295.e1-e27–299.e1e27. 101. Fonacier L, Bernstein DI, Pacheco K, et al. Contact dermatitis: a practice parameter-update 2015. J Allergy Clin Immunol Pract. 2015;3(3 1622
Suppl):S1–S39. 102. Jacob SE, Castanedo-Tardan MP. Pharmacotherapy for allergic contact dermatitis. Expert Opin Pharmacother. 2007;8(16):2757–2774. 103. Shaker M, Salcone E. An update on ocular allergy. Curr Opin Allergy Clin Immunol. 2016;16(5):505–510. 104. Sheppard JD, Comstock TL, Cavet ME. Impact of the topical ophthalmic corticosteroid loteprednol etabonate on intraocular pressure. Adv Ther. 2016;33(4):532–552. 105. Fenny N, Grammer LC. Idiopathic anaphylaxis. Immunol Allergy Clin North Am. 2015;35(2):349–362. 106. Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133(5):1270–1277. 107. Konikoff MR, Noel RJ, Blanchard C, et al. A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology. 2006;131(5):1381–1391. 108. Dohil R, Newbury R, Fox L, et al. Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial. Gastroenterology. 2010;139(2):418–429. 109. Sampson HA, Aceves S, Bock SA, et al. Food allergy: a practice parameter update-2014. J Allergy Clin Immunol. 2014;134(5):1016.e1043– 1025.e1043.
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OVERVIEW This chapter summarizes the pharmacology, efficacy, and safety parameters of cromolyn and nedocromil, collectively known as cromones; antileukotrienes; anticholinergics; and theophylline. Antihistamines, corticosteroids, and β agonists are discussed elsewhere in this book.
CROMOLYN AND NEDOCROMIL Cromolyn and nedocromil are chemically dissimilar drugs with similar pharmacologic and therapeutic properties. They are weak anti-inflammatory drugs without significant adverse effects. These drugs have been replaced by more potent anti-inflammatory drugs as first-line therapy (1,2), but may play an adjunctive role in the treatment of asthma, allergic rhinitis, and conjunctivitis (Tables 36.1 and 36.2).
Pharmacology Cromolyn and nedocromil have low oral bioavailability, and all of their pharmacologic effects results from topical deposition in the lung or on mucosal surfaces. Cromolyn has a very short plasma half-life of 11 to 20 minutes (3). Nedocromil has a longer half-life of 1.5 to 2 hours (4). There are no significant drug interactions with the cromones (3,4). Neither drug relieves bronchospasm, both should be used preventatively, as maintenance therapy, or prior to exercise or allergen exposure (1–3).
Mechanism of Action The cromones block chloride transport channels in airway epithelial cells, neurons, and mucosal mast cells that appear to result in their anti-inflammatory 1624
effects (5–8). Cromolyn and nedocromil have been shown to inhibit mediator release from mast cells (7,8), immunoglobulin E synthesis (9,10), and to suppress eosinophil chemotaxis and survival (11) as well as neutrophil activation and migration (12). They also cause release of Annexin A1 (13). Inhalation challenge studies have determined that cromones equally inhibit both the early- and late-phase asthmatic reactions when administered prior to allergen challenge (14–17). The cromones do not inhibit bronchospasm induced by histamine or methacholine (18–20). TABLE 36.1 MAINTENANCE DRUGS LISTED IN NHLBI/NAEPP 2007, GINA 2016 REPORTS
AGE (y)
MEDICATIONS: ALTERNATIVES TO INHALEDALTERNATIVES TO LABA AS CORTICOSTEROIDS ADD-ON THERAPY
0–4
Cromolyn, montelukast
Montelukast
5–11
Cromolyn, nedocromil, LTRA, theophylline
LTRA, theophylline
>11
Cromolyn, nedocromil, LTRA, theophylline
LTRA, theophylline, zileuton, tiotropiuma
GINA, Global Initiative for Asthma; LABA, long-acting β agonist; LTRA, leukotriene antagonist; NAEPP, National Asthma Education and Prevention Program; NHLBI, National Heart, Lung, and Blood Institute. a
Tiotropium approved for age 18 years and older in the United States.
TABLE 36.2 CHARACTERISTICS OF OTHER ANTIALLERGIC DRUGS
DRUG
Cromolyn
DOSING: ADULTS (A) CHLDREN DRUG (C) INTERACTIONS
MECHANISM OF ACTION SAFETY
EFFICACY
Blocks chloride
Inhibits early A and C: 1 None reported and late phase ampule (20
Virtually no known side
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transport channels in mast cells
effects
of allergic asthma Nonallergic asthma Exerciseinduced asthma
mg) qid By nebulizer; 1 ampule (100 mg) 4 times daily
Systemic 4% solution mastocytosis to be used 1 drop in Allergic conjunctivitis, each eye 4– 6 times a vernal conjunctivitis, day giant papillary 5.2 conjunctivitis mg/spray 1 spray in Allergic each nostril rhinitis 3–6 times a day Nedocromil Blocks chloride transport
None known
Allergic 2% solution None reported conjunctivitis 1 drop in each eye 2 times a day
MontelukastBlocks cysteinyl leukotriene receptor
Associated with Asthma eosinophilic Exercisegranulomatosis induced with asthma polyangiitis (EGPA)/Churg–Allergic rhinitis Strauss syndrome (rare)
C: 6 mo–5 None reported y 4 mg granules to be taken at bedtime; 2– 5 y 4 mg chewable tablets; 5– 15 y 5 mg chewable tablets. A: 15 y and older 10 mg tablets
Zafirlukast Blocks cysteinyl leukotriene
EGPA (rare)
Asthma
Hepatic dysfunction
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C: 5–11 y Increases 10 mg bid warfarin halfAges 12 y life and INR
receptor
Zileuton
(rare)
and older: 20 mg bid
Inhibits 5Increases liver Asthma lipoxygenase enzymes in 3%; activity monitoring of liver enzymes required
C: older Increases serum than 12 and levels of A: 600 mg warfarin, qid; theophylline, Sustained- cymbalta, and propranolol released 600 mg 2 bid
Ipratropium Anticholinergic
Dry mouth, Acute asthma MDI/HFA None known bad taste; exacerbationsA: (17 mcg) 2 urinary in inhalations 4 retention, combination times a day as uncommon; with short- needed for glaucoma, acting β COPD blurred agonists; for Nebulizer vision, relief of solution dilated asthma pupil, symptoms in C: 13 y and A: 1 ampule (3 mL) every 20 minutes for 3 doses for acute exacerbations, then every 4– 6 h as needed Combination with albuterol (Respimat) A:1 inhalation every 4 hours as needed for COPD Nasal spray 0.03% and 0.06% C >5 and A; 2 sprays in each nostril 2–4 times a day for rhinorrhea Tiotropium Anticholinergic
Dry mouth; Asthma urinary COPD retention, ocular effects
Dry powder None known inhaler 18 μg qid MDI 1.25, 2 inhalations qid for asthma MDI 2.5, 2 inhalations qid for COPD
TheophyllineNot known Inhibits
Narrow Asthma therapeutic COPD
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All ages: Many dosage must (including,
phosphodiesterases, index antagonizes Nausea and adenosine headache receptors, relaxes common smooth muscle Serious adverse effects, including seizures and arrhythmias, causing death have been reported
be but not individualized limited to): based on adenosine, monitoring allopurinol, peak serum cimetidine, theophylline ciprofloxacin, levels erythromycin, estrogen, fluconazole, fluvoxamine, interferon, lithium, mifepristone, phenobarbital, phenytoin, propranolol, rifampin, ticlopidine, riociguat, verapamil
bid, twice a day; COPD, chronic obstructive pulmonary disease; INR, international normalized ratio; MDI, metered-dose inhaler; qid, once daily.
Efficacy Cromones are an alternative initial therapy for mild persistent asthma (1,2). Their excellent safety profile may be very appealing to parents or patients who are concerned about side effects of inhaled corticosteroids. Both cromolyn and nedocromil have been reported to improve clinical outcomes and lung function when started early in the course of therapy (17). Cromones are less efficacious than corticosteroids in the treatment of asthma (18) and have a very limited role in the long-term treatment of asthma (1,2). Although the National Asthma Education Prevention Program 2007 (NAEPP) and Global Initiative for Asthma 2016 (GINA) guidelines suggest that cromones may be useful as prophylaxis prior to exercise or allergen exposure (1,2), cromolyn is only available in the United States as a nebulizer solution for asthma, and nedocromil is not available in any form for inhalation in the United States.
Safety and Drug Interactions Cromolyn and nedocromil have no known drug interactions, toxicity, or 1629
clinically significant adverse effects.
Dosing and Preparations Cromolyn is available in 20 mg/mL ampoules for nebulization to be administered four times daily, or 10 to 60 minutes prior to allergen exposure for ages 2 years and older. Cromolyn is available as a 100-mg ampoule to be taken orally for gastrointestinal symptoms of systemic mastocytosis for infants, children, and adults; the recommended dosage for mastocytosis is discussed elsewhere in this book. Cromolyn is available as a nasal spray for ages 2 years and older to be used as one spray in each nostril three to six times a day. Cromolyn is available as a 4% ophthalmic preparation to be used four to six times a day for allergic conjunctivitis, giant papillary conjunctivitis, vernal keratitis, and vernal keratoconjunctivitis. Nedocromil is available as a 2% ophthalmic preparation approved to be used twice a day for allergic conjunctivitis.
ANTILEUKOTRIENES The leukotrienes C4, D4, and E4, previously identified as the “slow reacting substance of anaphylaxis,” are potent mediators of inflammation in asthma. The antileukotrienes available in the United States are montelukast, zileuton, and zafirlukast. The GINA and NAEPP guidelines suggest antileukotrienes as an alternative “STEP 2” to low-dose inhaled corticosteroid therapy for children and adults with asthma (1,2). The NAEPP guidelines suggest antileukotrienes as an alternative “STEP 2” in asthmatic smokers (1).
Leukotriene Formation and Biologic Activity of the Leukotrienes The leukotrienes are formed from arachidonic acid. The initial steps in this process are catalyzed by an enzyme complex containing 5-lipoxygenase (5-LO). Separate pathways lead to production of leukotriene B4 (LTB4) or the cysteinyl leukotrienes, such as leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4) (20). The cysteinyl leukotrienes have a common receptor that is distinct from the
1630
LTB4 receptor. The cysteinyl leukotrienes are potent mediators of bronchoconstriction, airway hyperresponsiveness, microvascular permeability, and mucus secretion. LTB4 is a chemoattractant for neutrophils in the lung (21). The leukotrienes are important mediators of aspirin-exacerbated respiratory disease. Aspirin-sensitive asthmatics have increased baseline levels of leukotrienes compared with nonaspirin-sensitive asthmatics, and develop markedly enhanced levels of leukotrienes in their lungs, nasal secretions, and urine following aspirin challenge (22).
Mechanism of Action of Antileukotrienes Zileuton directly inhibits the catalytic activity of 5-LO and inhibits production of LTB4 as well as the cysteinyl leukotrienes. Zafirlukast and montelukast are competitive antagonists of the cysteinyl leukotriene receptor and, therefore, inhibit the activity of LTC4, LTD4, and LTE4 (21). The antileukotrienes have been shown to inhibit influx of eosinophils into the airways and reduce blood eosinophil levels (22–24). Montelukast and zafirlukast have demonstrated bronchodilator activity (21,23). Montelukast and zafirlukast inhibit both the early- and late-phase response to allergen (25,26). Zileuton does not significantly inhibit airway response to allergen (27). The antileukotrienes have demonstrated protective effects against exercise-induced bronchoconstriction (28). Zafirlukast and zileuton inhibit bronchoconstriction induced by cold dry air (29,30). Zafirlukast inhibits sulfur dioxide-induced bronchospasm (31). Zileuton and montelukast have been shown to inhibit aspirin-induced bronchospasm in aspirin-exacerbated asthma (32).
Efficacy The antileukotrienes result in fewer asthma symptoms and exacerbations, decreased use of rescue inhalers and oral corticosteroids compared to placebo. They are less efficacious than inhaled corticosteroids (21,32,33), but may be suitable as monotherapy for selected patients or as add-on therapy to inhaled corticosteroids (1,2). Antileukotrienes may result in improved asthma control as additional therapy in patients not adequately controlled by inhaled corticosteroids. Most of the data from randomized trials show that long-acting β agonists are superior to antileukotrienes as add-on therapy to inhaled corticosteroids for asthma (34). Montelukast and zafirlukast have been shown to be similar in efficacy and 1631
tolerability to antihistamines for allergic rhinitis (35,36). Fluticasone propionate has been shown to be superior to montelukast for the treatment of allergic rhinitis (37).
Safety and Drug Interactions The antileukotrienes are generally safe and well tolerated. Zileuton can cause hepatotoxicity as well as elevated transaminases, hepatitis, and death from liver disease. The manufacturer’s surveillance studies have reported elevated transaminases occurring in 1.8% to 3.2% of patients. Patients should have baseline alanine transaminase measured and then monthly for 3 months, then every 2 to 3 months for the first year, and at the doctor’s discretion thereafter (38). Montelukast and zafirlukast do not have known hepatotoxicity at recommended doses. Montelukast and zafirlukast have been associated with the development of eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg–Strauss syndrome. Many of the patients who developed EGPA were severe asthmatics who had previously received oral steroids, and the manifestations of vasculitis developed after systemic steroids were reduced or discontinued (39). However, a study of 24 EGPA patients revealed that the six patients who developed EGPA while taking montelukast were taking oral steroids when signs of EGPA developed (40). Zileuton and zafirlukast may prolong the international normalized ratio in patients taking warfarin. Zileuton significantly inhibits the hepatic metabolism of theophylline, and may result in theophylline toxicity; zafirlukast may also increase theophylline serum levels. Zileuton has many drug interactions, and caution is advised when prescribing it along with other drugs that are metabolized by the liver (38,41).
Dosage and Preparation Zileuton is approved for individual aged 12 years and older and is available as a 600-mg tablet to be taken four times daily, or a 600-mg sustained-release tablet to be taken as two tablets twice daily with food. Zafirlukast is approved for ages 5 years and older; it is available in 10 mg tablets for ages 5 to 11 and 20 mg tablets for ages 12 and older to be taken every 12 hours. Montelukast is available as 4 mg granules for ages 6 months to 5 years, 4 and 5 mg chewable tablets for ages 2 to 6 and ages 6 to 15 years, respectively, and 10 mg tablets for ages 15 years and older. Montelukast is administered once a day, in the evening or 2 1632
hours prior to exercise. Zileuton is approved for ages 12 years and older; it is available as 600 mg tablets to be taken 1, four times daily or as a 600-mg sustained-release tablet to be taken 2 twice daily.
ANTICHOLINERGICS The naturally occurring anticholinergic alkaloids, such as atropine, have been recognized for centuries to have beneficial effects in asthma. The toxicity of atropine gave rise to the mnemonic: red as a beet; hot as a hare; dry as a bone; blind as a bat; and mad as a hatter. The useful properties of atropine led to the development of inhaled anticholinergics with minimal systemic absorption and side effects. Ipratropium was the first anticholinergic to be approved by the Food and Drug Administration for relief of acute asthma symptoms and is also available as a nasal spray. Tiotropium is approved as a maintenance treatment for asthma.
Cholinergic Mechanisms in the Airways The vagus nerve supplies autonomic innervation to the large- and medium-sized airways. Release of acetylcholine from the parasympathetic postganglionic fibers acting on muscarinic receptors, results in smooth muscle contraction and release of secretions from submucosal glands. The activity of cholinergic fibers results in a constant low level of tonic activity of the airways. A variety of stimuli, including irritants, exercise, cold dry air, histamine, and allergens, can trigger irritant receptors of vagal afferent nerves, resulting in almost immediate reflex bronchoconstriction and mucus hypersecretion (42).
Mechanism of Action of Anticholinergics The anticholinergic agents compete with acetylcholine at muscarinic receptors. Because muscarinic receptors are found primarily in the central airways, anticholinergic bronchodilatation occurs mostly in the larger airways. The anticholinergics provide virtually complete protection against bronchoconstriction by methacholine. Anticholinergics provide varied protection against bronchoconstriction induced by other stimuli, including histamine, irritants, exercise, and allergens (43).
Pharmacology Atropine is well absorbed from mucosal surfaces and reaches peak serum levels within 1 hour. The bronchodilatory effects last for 3 to 4 hours. Atropine relaxes 1633
smooth muscle in the airway, gastrointestinal tract, iris, and peripheral vasculature. It inhibits relaxation of the urinary sphincter. It causes bradycardia at low doses and tachycardia at high doses. It reduces salivary secretions and mucociliary clearance in the airways. Atropine crosses the blood–brain barrier and can cause significant central nervous system side effects (44). Ipratropium and tiotropium are quaternary ammonium derivatives of atropine. The quaternary structure allows for poor absorption across respiratory and other membranes and results in fewer systemic side effects than atropine. Ipratropium starts to work within 15 to 30 minutes after inhalation, but maximum bronchodilatation may not result until 90 minutes; effects last up to 6 hours (45). Tiotropium has a peak onset of dilatation within 1 to 3 hours and effects last for more than 24 hours (46).
Efficacy Anticholinergics are less effective bronchodilators and have a much slower onset of action than albuterol which has its peak effect within 5 to 15 minutes (46). Current guidelines do not recommend anticholinergic medications as standalone treatment for asthma (1,2). Ipratropium may be useful as a bronchodilator in patients who are intolerant to short-acting β agonists (47). Tiotropium has been shown to improve symptoms and lung function when used as add-on therapy in patients with difficult to control asthma (48,49). Ipratropium has been shown to reduce hospital admissions when added to short-acting β agonists in the acute treatment of asthma exacerbations (47). Ipratropium is recommended for the treatment of bronchospasm caused by β blockers (1). Anticholinergics are included in NAEPP and GINA guidelines to be used in addition to short-acting β agonists for the treatment of acute, severe asthma exacerbations (1,2). Ipratropium bromide nasal spray relieves rhinorrhea associated with allergic or nonallergic rhinitis (50,51) as well as rhinorrhea caused by viral upper respiratory infections (52).
Safety and Drug Interactions Atropine causes significant side effects, even at therapeutic doses. Dry mouth, warmth and flushing of the skin, impairment of mucociliary clearance, gastroesophageal reflux, and urinary retention are common. Central nervous system effects ranging from irritability to hallucinations, and coma may occur. Tachyarrhythmias may occur at low doses, and atrioventricular association may occur at high doses. Atropine may trigger acute angle-closure glaucoma. 1634
Because of the availability of drugs with superior safety and efficacy, there is no longer a role for the use of atropine in the treatment of asthma; it is used to treat bradycardia and organophosphate poisoning (44). Ipratropium bromide is very well tolerated and has little toxicity because it is so poorly adsorbed. Rare cases of blurred vision, papillary dilatation, and angleclosure glaucoma have been reported when the drug has had direct contact with the eye. Urinary retention may occur, particularly in men with prostatic hyperplasia. Dry mouth and a bad taste are common side effects with anticholinergics. Paradoxic bronchospasm has rarely been reported (46). Tiotropium is also generally safe and well tolerated, but because its half-life is long, ocular and urinary side effects may occur. There is a concern that the mist formulation of tiotropium, but not the dry powder formulation, may be associated with increased mortality (46,53), but a recent large multicenter trial comparing the two devices failed to demonstrate increased deaths in patients using the mist device (54).
Dosage and Preparation Ipratropium is available as a metered-dose inhaler to be used up to four times a day. It is available as a 0.25-mg nebulizer solution for children younger than 6 years or a 0.5-mg solution for individuals aged 6 years and older to be administered every 4 to 6 hours, or every 20 minutes for three doses in combination with a β agonist for acute asthma exacerbations. Ipratropium is also available in 2.5 mg solution in combination with 0.5 mg of albuterol for the treatment of adults and children with acute asthma exacerbations. Ipratropium is also available as a nasal spray 0.03% for allergic or nonallergic rhinitis and 0.06% for colds to be used two to three times a day. Tiotropium is available in two devices for adults aged 18 years and older. An 18-mg dry powder capsule is administered once daily by the Handihaler device. A metered-dose inhaler is available in 1.25 and 2.5 µg formulations per actuation to be administered two inhalations once a day. Only the 1.25-dose is approved for the treatment of asthma.
THEOPHYLLINE Theophylline was initially used as a diuretic; it was first used to treat acute asthma in the 1930s and was one of the first drugs to be used as maintenance therapy for asthma. Emphasis on the treatment of inflammation in asthma as well as the development of drugs with similar or superior safety and efficacy and 1635
improved safety and tolerability has led to a decline in the use of theophylline (55). Theophylline is listed as an alternative maintenance drug and as add-on therapy in the NAEPP and GINA guidelines (1,2).
Pharmacology Theophylline is a methylxanthine, similar in to the naturally occurring xanthenes caffeine and theobromine. The solubility of methylxanthines is low unless they form salts or complexes with other compounds such as ethylenediamine (as in aminophylline). Theophylline is rapidly absorbed after oral or rectal administration and maximum serum levels occur 2 hours after ingestion on an empty stomach. Food generally slows the rate, but not the amount of absorption (55). The elimination rate of theophylline varies widely among individuals depending on age, genetic and environmental factors as well as underlying disease. It is metabolized by the cytochrome P450 system of the liver, and serum levels are altered by many medications, which are discussed in detail later in this chapter. High-protein, low-carbohydrate diets and diets high in charcoal-grilled foods as well as smoking tobacco and marijuana increase theophylline clearance and may decrease theophylline levels. Pregnancy, fever, advanced age, liver disease, congestive heart failure, and chronic obstructive pulmonary disease (COPD) with hypoxia may increase theophylline levels (56).
Mechanism of Action The mechanism of action of theophylline is not clearly understood. Theophylline inhibits cyclic adenosine monophosphate–specific phosphodiesterases at high concentrations, but this effect is negligible at therapeutic doses (55). Antagonism of adenosine receptors has also been proposed as mechanism of action of theophylline, and may account for its severe adverse effects, including seizures and arrhythmias. Theophylline activates histone deacetylases, an effect that is most pronounced when their activity is reduced by oxidative stress. This effect is most important in patients with COPD (55). The clinical effects of theophylline are relaxation of smooth muscle in airways, increased respiratory drive, decreased fatigue of respiratory muscles, increased mucociliary clearance, and decreased microvascular leakage into airways (55). Theophylline has been shown have modest anti-inflammatory effects: it reduces the influx of eosinophils and activated CD4+ and CD8+ T cells into airways (57,58) and reverses steroid resistance in COPD (59).
1636
Theophylline inhibits bronchial hyperresponsiveness to methacholine; it inhibits the early-phase but not the late-phase response to inhaled allergen (1,57).
Efficacy Theophylline is similar in efficacy but less well tolerated than long-acting inhaled β agonists for the treatment of asthma (60). Comparison studies of theophylline with the long-acting β agonists, formoterol and salmeterol, showed that theophylline provided similar improvement in forced expiratory volume in 1 second, but less improvement in morning and evening peal flow rates and use of rescue inhalers. There were also more adverse events associated with use of theophylline than with use of formoterol or salmeterol (60). A study comparing the leukotriene antagonist zileuton with theophylline found that zileuton was as effective as theophylline and had fewer side effects (61). Theophylline may be an option for asthmatic smokers who do not respond well to inhaled corticosteroids (55).
Safety and Drug Interactions Theophylline is a drug with very narrow margin of safety. Serum concentrations should be monitored and maintained between 5 and 15 µg/mL; many patients will obtain clinical benefit at serum levels in the low therapeutic range (46). Many common drugs can double or triple serum theophylline levels. Fatal toxicity can occur when levels exceed 25 µg/mL. In a 10-year prospective study of the Massachusetts Poison Control Center, there were 356 cases in which the theophylline level was greater than 30 µg/mL. In all, 74 patients had arrhythmias, 29 had seizures, and 15 subjects died (62). Other toxic effects of theophylline include hypokalemia, hyperglycemia, encephalopathy, hyperthermia, and hypotension (55). Theophylline has also unpleasant side effects that many patients find intolerable. Headache, irritability, nausea, and insomnia may occur even when serum levels are within the therapeutic range. Drugs that significantly elevate theophylline levels include clarithromycin, erythromycin, most of the quinolone antibiotics, cimetidine, disulfiram, estrogen, fluvoxamine, interferon-α, pentoxifylline, propafenone, propranolol, tacrine, ticlopidine, thiabendazole, verapamil, and zileuton. Theophylline may decrease the effects of adenosine, diazepam, flurazepam, lithium, and pancuronium. Carbamazepine, phenobarbital, phenytoin, rifampin, and sulfinpyrazone may decrease theophylline levels (55,56). 1637
Preparations and Dosing Theophylline is usually prescribed in long-acting tablets or capsules, which come in a number of different dosages, to be administered once or twice a day. It is also available as uncoated tablets, encapsulated sprinkles, in suspension, and as a rectal suppository. The dosage of theophylline is based on the body weight. For children older than 6 months and adults, the starting dose should be 10 mg/kg up to a maximum initial dose of 300 mg/day. The dosage may be increased every 3 days, if tolerated, up to 16 mg/kg with a maximum dose of 600 mg/day. A serum level should be measured after at least 3 days at the maximum dose. The peak serum level occurs 8 to 13 hours after the sustained-release preparations and should be 5 to 15 μg/mL. Dosage requirements generally maintain stable, but concomitant medications and acute or chronic illness may alter serum levels (55). REFERENCES 1. National Heart, Lung, and Blood Institute. Expert Panel Report 3. Guidelines for the Diagnosis and Management of Asthma 2007. Bethesda, MD: National Institutes of Health, 2007. NIH Publication 07-4051. 2. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. 2016. Available at: http://www.ginasthma.org. 3. Zhang T, Finn DF, Barlow JW, et al. Mast cell stabilisers. Eur J Pharmacol. 2016;778:158–168. 4. Parish RC, Miller L. Nedocromil sodium. Ann Pharmacol. 1993;27:599– 606. 5. Alton EW, Kingsleigh-Smith DJ, Munkonge FM, et al. Asthma prophylaxis agents alter the function of an airway epithelial chloride channel. Am J Respir Cell Mol Biol. 1996;14:380–387. 6. Norris AA, Alton EW. Chloride transport and the action of sodium cromoglycate and nedocromil sodium in asthma. Clin Exp Allergy. 1996;26:250–253. 7. Okayama Y, Benyon RC, Rees PH, et al. Inhibition profiles of sodium cromoglycate and nedocromil sodium on mediator release from mast cells of human skin, lung, tonsil, adenoid and intestine. Clin Exp Allergy. 1992;22:401–409. 8. Bissonette EY, Enisco JA, Befus AD. Inhibition of tumor necrosis factor 1638
release from mast cells by the anti-inflammatory drugs sodium cromoglycate and nedocromil sodium. Clin Exp Immunol. 1995;102:78– 84. 9. Roca-Ferrer J, Mullol J, Lopez E, et al. Effect of topical anti-inflammatory drugs on epithelial cell-induced eosinophil survival and GM-CSF secretion. Eur Respir J. 1997;10:1489–1495. 10. Hoshino M, Nakamura Y. The effect of inhaled sodium cromoglycate on cellular infiltration into the bronchial mucosal and the expression of adhesion molecules in asthmatics. Eur Respir J. 1997;10:858–865. 11. Matsuse H, Shimoda T, Matsuo N, et al. Sodium cromoglycate inhibits antigen-induced cytokine production by peripheral blood mononuclear cells from atopic asthmatics in vitro. Ann Allergy Asthma Immunol. 1999;83(Pt 1):522–525. 12. Loh RK, Jabara HH, Geha RS. Mechanisms of inhibition of IgE synthesis by nedocromil sodium: nedocromil sodium inhibits deletional switch recombination in human B cells. J Allergy Clin Immunol. 1996;97:1141– 1150. 13. Yazid S, Sinniah A, Solito E, et al. Anti-allergic cromones inhibit histamine and eicosanoid release from activated human and murine mast cells by releasing Annexin A1. PLoS One. 2013;8(3):e58963. 14. Calhoun WJ, Jarjour NN, Gleich GJ, et al. Effect of nedocromil sodium pretreatment on the immediate and late responses of the airway. J Allergy Clin Immunol. 1996;98(5 Pt 2):S46–S50. 15. del Bufalo C, Fasano L, Patalano F, et al. Inhibition of fog-induced bronchoconstriction by nedocromil sodium and sodium cromoglycate in intrinsic asthma: a double-blind, placebo controlled study. Respiration. 1989;55:181–185. 16. Griffin MP, Macdonald N, McFadden ER. Short- and long-term effect of cromolyn sodium on the airway of asthmatics. J Allergy Clin Immunol. 1983;71:331–338. 17. Konig P. The effects of cromolyn sodium and nedocromil sodium in early asthma prevention. J Allergy Clin Immunol. 2000;105(Pt 2):575–581. 18. Guevara JP, Ducharme FM, Keren R, et al. Inhaled corticosteroids versus sodium cromoglycate in children and adults with asthma. Cochrane Database Syst Rev. 2006;(2):CD003558. 1639
doi:10.1002/14651858.CD003558.pub2. 19. Sridhar AV, McKean M. Nedocromil sodium for chronic asthma in children. Cochrane Database Syst Rev. 2006;(3):CD004108. doi:10.1002/14651858.CD004108.pub2. 20. Peters-Golden M, Henderson WR. Leukotrienes. N Engl J Med. 2007;357(18):1841–1854. 21. Green RH, Pavord ID. Leukotriene antagonists and symptom control in chronic persistent asthma. Lancet. 2001;357:1991–1992. 22. Cowburn AS, Sladek K, Soja J, et al. Overexpression of leukotriene C4 synthetase in bronchial biopsies from patients with aspirin-intolerant asthma. J. Clin Invest. 1998;101:834–846. 23. Diamant Z, Grootendorst DC, Veseli-Charvat M, et al. The effect of montelukast (MK-0476), a cysteinyl leukotriene antagonist, on allergeninduced airway responses and sputum cell counts in asthma. Clin Exp Allergy. 1999;2:42–51. 24. Pizzichini E, Leff JA, Reiss TF, et al. Montelukast reduces airway eosinophilic inflammation in asthma. Eur Respir J. 1999;14:12–18. 25. Volvovitz B, Tabachnik E, Nussinovitch M, et al. Montelukast, a leukotriene receptor antagonist, reduces the concentration of leukotrienes in the respiratory tract of children with persistent asthma. J Allergy Clin Immunol. 1999;104:1162–1167. 26. Munoz NM, Douglas I, Mayer D, et al. Eosinophil chemotaxis inhibited by 5-lipoxygenase blockade and leukotriene antagonism. Am J Respir Crit Care Med. 1997;155:1398–1403. 27. Pyasi K, Tufvesson E, Moitra S. Evaluating the role of leukotrienemodifying drugs in asthma management: are their benefits ‘losing in translation’? Pulm Pharmacol Ther. 2016;41:52–59. 28. Dryden DM, Spooner CH, Stickland MK, et al. Exercise-induced bronchoconstriction and asthma. Evid Rep Technol Assess (Full Rep). 2010;(189):1–154. 29. Richter K, Jorres RA, Magnussen H. Efficacy and duration of the antileukotriene zafirlukast on cold air-induced bronchoconstriction. Eur Respir J. 2000;15:693–699. 30. Israel E, Demakarian R, Rosenberg M, et al. The effects of a 51640
lipoxygenase inhibitor on asthma induced by cold dry air. N Engl J Med. 1990;323:1140–1144. 31. Lazarus SC, Wong HH, Watts MJ, et al. The leukotriene receptor antagonist zafirlukast inhibits sulfur dioxide–induced bronchoconstriction in patients with asthma. Am J Respir Crit Care Med. 1997;156:1725–1730. 32. Morina N, Bocari G, Iljazi A, et al. Maximum time of the effect of antileukotriene—zileuton in treatment of patients with bronchial asthma. Acta Inform Med. 2016;24:16–19. 33. Altman LC, Munk Z, Seltzer J, et al. A placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene-receptor antagonist. Montelukast Asthma Study Group. J Allergy Clin Immunol. 1998;102:50– 56. 34. Ducharme FM, Lassersson TJ, Cates CJ. Long-acting beta2-agonists versus antileukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev. 2006;(4):CD0031137. 35. Nayak A, Langdon R. Montelukast in the treatment of allergic rhinitis: an evidence-based review. Drugs. 2007;67(6):887–901. 36. Rodrigo GJ, Yanez A. The role of antileukotriene therapy in seasonal allergic rhinitis: a systematic review of randomized trials. Ann Allergy Asthma Immunol. 2006;96(6):779–786. 37. Martin BG, Andrews CP, van Bavel JH, et al. Fluticasone propionate is superior to montelukast for allergic rhinitis while neither affects overall asthma control. Chest. 2005;128(4):1910–1920. 38. Zyflo CR. Manufacturer’s prescribing information. Chiesi USA. 2015. 39. DuMouchel W, Smith ET, Beasley R, et al. Association of asthma therapy and Churg–Strauss syndrome: an analysis of post marketing surveillance data. Clin Ther. 2004;26(7):1092–1104. 40. Giusti Del Giardino L, Cavallaro T, Anzola GP, et al. Neuropathy in eosinophilic granulomatosis with polyangiitis: a comparison study of 24 cases with or without prior leukotriene antagonist exposure. Eur Ann Allergy Clin Immunol. 2014;46(6):201–209. 41. Adkins JC, Brogden RN. Zafirlukast: a review of its pharmacology and therapeutic potential in the management of asthma. Drugs. 1998;55:121– 144. 1641
42. Jartti T. Asthma, asthma medication and autonomic nervous system dysfunction. Clin Physiol. 2001;21:260–269. 43. Morris HG. Review of ipratropium bromide in induced bronchospasm in patients with asthma. Am J Med. 1986;81:36–44. 44. Brown JH, Taylor P. Muscarinic receptor agonists and antagonists. In: Hardman JG, Gilman AG, Limbird LE, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill, 2007. 45. Scullion JE. The development of anticholinergics in the management of COPD. Int J Chron Obstruct Pulmon Dis. 2007;2(1):33–40. 46. Cazzola M, Page CP, Calzetta L, et al. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev. 2012;64(3):450–504. 47. Rodrigo GJ, Castro-Rodrriguez JA. Anticholinergics in treatment of children and adults with acute asthma: a systemic review with meta analysis. Thorax. 2005;60(9):740–746. 48. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step up therapy for adults with uncontrolled asthma. N Engl J Med. 2010;363(18):1715–1726. 49. Kerstens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012;367(13):1198–1207. 50. Kaiser HB, Findlay SR, Georgitis JW, et al. Long-term treatment of perennial allergic rhinitis with ipratropium bromide nasal spray 0.06%. J Allergy Clin Immunol. 1995;95(Pt 2):1128–1132. 51. Georgitis JW, Banov C, Boggs PB, et al. Ipratropium bromide nasal spray in non-allergic rhinitis: efficacy, nasal cytological response and patient evaluation on quality of life. Clin Exp Allergy. 1994;24:1049–1055. 52. Hayden FG, Diamond L, Wood PB, et al. Effectiveness and safety of intranasal ipratropium bromide in common colds. A randomized, doubleblind, placebo-controlled trial. Ann Intern Med. 1996;125:89–97. 53. Singh D, Loke YK, Enright PL, et al. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: a systematic review and meta analysis of randomized controlled trials. BMJ. 2011;342:d3215. 1642
54. Wise RA, Anzuto A, Cotton D, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369(16):1491–501. 55. Barnes P J. Theophylline. Am J Resp Crit Care Med. 2013;188(8):901– 906. 56. Jusko WJ, Gardner MJ, Mangione A, et al. Factors affecting theophylline clearances: age, tobacco, marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives, benzodiazapines, barbiturates, and ethanol. J Pharm Sci. 1979;68:1358–1366. 57. Rabe KF, Magnussen H, Dent G. Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. Eur Respir J. 1995;8:637–642. 58. Aizawa H, Iwanaga T, Inoue H, et al. Once-daily theophylline reduces serum eosinophil levels in induced sputum of asthmatics. Int Arch Allergy Immunol. 2000;121:123–128. 59. To Y, Ito K, Kizawa Y, et al. Targeting phosphoinosotide-3-kinase-d with theophylline reverses corticosteroid insensitivity in COPD. Am J Resp Crit Care Med. 2010;182:897–904. 60. Tee AK, Koh MS, Gibson PG, et al. Long-acting beta-agonists versus theophylline for maintenance treatment of asthma. Cochrane Database Syst Rev. 2007;(3):CD001201. 61. Schwartz HJ, Petty T, Dube LM, et al. A r0andomized controlled trial comparing zileuton with theophylline in moderate asthma. Arch Intern Med. 1998;158:141–148. 62. Shannon M. Life-threatening events after theophylline overdose: a ten year prospective analysis. Arch Int Med. 1999;159(9):989–994.
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Inhalation of drugs provides direct delivery for local treatment of bronchial diseases, with more rapid onset of effect and less potential unwanted systemic effects than oral administration. It is estimated that over 450 million inhaler devices are used annually worldwide (1). This chapter primarily focuses on issues relevant to inhalation delivery devices utilized in the treatment of asthma in the United States.
HISTORY OF INHALATION THERAPY Inhalation therapy for bronchial disorders has been used since ancient times. Centuries ago, the stramonium (a botanically derived antimuscarinic agent) cigarette was described as a treatment for acute asthma (2,3). In the 19th century, inhalation devices were developed primarily for use in the treatment of various conditions including tuberculosis, including atomizers which utilized pressure pumps or steam to disperse liquid medication. A UK patent was filed for the first known dry powder inhaler (DPI) in 1864 (4). Antecedents of contemporary inhalation therapy for asthma are grounded in the early part of the 20th century with invention of hand-powered (5) and electrical (6) devices for nebulization of adrenal extract, later, adrenalin solutions. Inhalation therapy subsequently was revolutionized by the introduction of pressurized metered-dose inhaled (pMDIs) containing isoproterenol or epinephrine into clinical practice in the 1950s (7). The first modern DPI, containing cromolyn sodium, was launched in 1967; pMDIs containing albuterol were first marketed in Europe in 1969, followed by beclomethasone dipropionate in 1972 (4,8). pMDIs utilized Freon chlorofluorocarbon (CFC) propellants until the mid-2000s, when these were eliminated because of their roles in depletion of the stratospheric ozone layer (1,9). The phaseout of CFCs stimulated research in innovative aerosol delivery techniques culminating in the development of new propellants and improved 1644
pMDI designs as well as novel DPIs (10,11). Inhalation devices in use today include conventional pMDIs (used with or without spacer devices), DPIs, and nebulizers. The SoftMist Inhaler (Boehringer Ingelheim), a unique spring-powered device which quickly aerosolizes metered doses of concentrated medications (12), represents an additional category of inhaler device recently launched in the United States.
AEROSOL PARTICLE CHARACTERISTICS An understanding of the fundamentals of particle behavior in inhalation therapy is required for informed use of aerosol devices in the clinical management of asthma. Deposition of aerosolized particles occurs primarily as a result of inertial impaction, sedimentation, and diffusion; in some instances, turbulent mixing, interception, and electrostatic precipitation may also be additional significant factors (Table 37.1) (13). Figure 37.1, based on scintigraphic data from human subjects for 1.5 mm to 6.0 µm particle sizes (extrapolated for smaller particle sizes) and Fig. 37.2, based on mathematical models, demonstrate the relationship between aerodynamic size of inhaled particles and sites of deposition. Spatial distribution of deposited particles is strongly affected by particle size. Large particles (>6 µm) tend to mainly deposit in the upper airway, limiting the amount of drugs that can be delivered to the lung, and in the case of corticosteroid preparations, contribute to oropharyngeal adverse effects; when drugs with gastrointestinal (GI) absorption are used, the portion swallowed after deposition in the upper airways also contributes to undesired systemic effects (13). Most submicron (3 Y OLD (CLINICIAN AND CAREGIVER SHOULD DETERMINE WHETHER CHILD CAN PERFORM THIS TECHNIQUE CORRECTLY)
1–4. Same as above for spacer with face mask. 5.Place the mouthpiece of the spacer in the patient’s mouth with the teeth over the mouthpiece and the lips sealed around it. 6.Actuate one dose into the chamber of the spacer. 7.The patient should breathe (inhale and exhale) normally through the spacer for at least 5 breathsa.
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8.If another dose is required, repeat steps 4–7. D. pMDI + SPACER WITH MOUTHPIECE: FOR PATIENTS ≥6 Y OLD (CLINICIAN AND CAREGIVER SHOULD DETERMINE WHETHER A CHILD CAN PERFORM THIS TECHNIQUE CORRECTLY) 1–4. Same as above for spacer with face mask. 5.Place the mouthpiece of the spacer in the patient’s mouth with the teeth over the mouthpiece and the lips sealed around it. 6.The patient should exhale slowly, as far as comfortable (to empty their lungs). 7.Actuate one dose into the chamber of the spacer and start to inhale slowly through the mouthpiece. Some spacers will make a whistling noise if inspiration is too fast. 8.Maintain a slow and deep inhalation through the mouth, until the lungs are full of air. This should take a child 2–3 s and an adult 5 s. 9.At the end of the inhalation, take the inhaler out of the mouth and close the lips. 10.Continue to hold the breath for as long as possible for up to 10 s before breathing out. 11.Breathe normally. 12.If another dose is required, repeat steps 1–11. E. DPIs: FOR PATIENTS ≥ 5–6 Y OLD (CLINICIAN AND CAREGIVER SHOULD DETERMINE WHETHER A CHILD CAN PERFORM THIS TECHNIQUE CORRECTLY)
1.Take the cap off (some do not have a cap). 2.Follow the dose preparation instructions in the Patient Information leaflet.
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3.Do not point the mouthpiece downwards once a dose has been prepared for inhalation because the dose could fall out. 4.Exhale slowly, as far as comfortable (to empty the lungs). Do not exhale into the DPI. 5.Start to inhale forcefully through the mouth from the very beginning. Do not gradually build up the speed of inhalation. 6.Continue inhaling until the lungs are full. 7.At the end of the inhalation, take the inhaler out of the mouth and close the lips. Continue to hold the breath for as long as possible, or up to 10 s. 8.Breathe normally. 9.If another dose is required, repeat steps 1–8. F. JET NEBULIZERS: FOR PATIENTS OF ANY AGE WHO CANNOT USE A pMDI WITH A VALVED HOLDING CHAMBER, WITH OR WITHOUT A FACE MASK, OR IF THE DRUG IS ONLY AVAILABLE AS NEBULIZER LIQUID
1.Assemble the tubing, nebulizer cup, and mouthpiece (or mask). 2.Pour the medication solution into the nebulizer cup. 3.Do not exceed the fill volume recommended by the manufacturer. 4.Connect to power source; flow of 6–8 L/min, or compressor. 5.Place the mouthpiece in the mouth and close the lips around it (or cover the nose and mouth with an appropriate face mask). 6.Keep the nebulizer vertical during treatment.
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Inhale and exhale using normal (tidal) breaths, with occasional deep breaths, until 7.the nebulizer starts to sputter or no more aerosol is produced. 8.If the treatment must be interrupted, turn off the unit to avoid waste. 9.At the completion of the treatment, take the mouthpiece out of the mouth. 10.Dismantle and clean nebulizer following the manufacturer’s instructions. 11.With technology that differs from that of a traditional jet nebulizer, clinicians should thoroughly review operating instructions prior to patient use and instruction. Rinse mouth after use of all preparations containing inhaled corticosteroids. Devices should be cleaned periodically according to instructions in the Patient Information leaflet. a
With some spacers, the inhalations and exhalations can be monitored by observing the movement of the valves or other components of the device. Adapted from Laube BL, Janssens HM, de Jongh FH, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J. 2011;37:1308– 1331.
TABLE 37.4 ERRORS IN PATIENT USE OF METERED-DOSE INHALER (MDI) % OF PATIENTS
Breath-hold too short
44
Excessively rapid inspiratory flow rate
34
Incomplete inhalation
23
Device not actuated at the beginning of inhalation
19
Multiple actuations with one inhalation
19
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Actuation at the end of inhalation
18
Nasal inhalation after actuating MDI into mouth
12
Wrong position of inhaler
7
No inhalation
6
Failure to remove cap
0.4
Adapted from Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. Eur Respir J. 2002;19:246–251.
SPACER DEVICES: ADJUNCTS TO METEREDDOSE INHALERS Spacer devices are inhalation aids designed for use with pMDIs to overcome coordination difficulties, enhance aerosol deposition in the lower airways, and minimize oropharyngeal deposition (Fig. 37.5). Reduction in oropharyngeal deposition occurs in all patients while improvement in lung deposition is an effect primarily significant in patients with poor pMDI technique or during exacerbations. Although many types of spacer devices are available, the spacer devices most commonly utilized currently are 120 to 200 mL valved holding chambers. Larger sized chambers used more frequently in the past provide no advantage over smaller devices when used with current HFA propellant inhalers (33). These holding chambers remove virtually all particles greater than 5 µm in size (33). A mouthpiece attachment with standard inhalation technique for pMDIs is utilized for older children and adults who can control their respiration (Table 37.3D); tidal respiration through a valved holding chamber with mouthpiece may be appropriate for some younger children who can seal their lips around the mouthpiece but who cannot fully control their respiration. A face mask attachment and tidal respiration is utilized in other situations (Table 37.3B). It has been shown in vitro that even a small air leak in the face mask can dramatically reduce the efficiency of drug delivery; lung dose was higher with leaks near the chin than for leaks near the nose (34,35). Aerosolized drug delivery with face mask may increase facial and eye deposition of aerosol with potential for local adverse effects. However, actual occurrence of such effects 1657
has been minimal in children (36). Delivery of drug by mouthpiece is more efficient than by face mask; patients should be transitioned to mouthpiece as early as possible (37). A proportion of drug particles emitted by a pMDI carries an electrostatic charge. Static electricity accumulates on some plastic spacer devices, which may attract and bind these drug particles on the device’s surface, thus producing variability in the dose of drug delivered; prewashing with detergent was proposed to deal with this issue (38). Metal chambers and most current plastic chambers manufactured with antistatic materials may be used out of the package without prewashing (39). Holding chambers should be cleaned and eventually replaced periodically in accordance with the manufacturers’ recommendations and labeling.
FIGURE 37.5 Scintigraphic images obtained utilizing radiolabeled flunisolide; spacer used with pressurized metered-dose inhaler (MDI) results in increased pulmonary delivery of aerosol with reduced oropharyngeal and gastric (swallowed drug) deposition; capture of aerosol particles on the walls of the spacer is noted. Images were obtained from the same subject on different days. Pressurized MDI alone (A) and MDI with 250 mL tube spacer (B). (Adapted from Newman SP, Steed KP, Reader SJ, et al. Efficient delivery to the lungs of flunisolide aerosol from a new hand-held portable multidose nebulizer. J Pharm Sci. 1996;85:960–964.) It was recognized shortly after introduction of spacers into clinical practice that, as a result of reduced oropharyngeal deposition (Fig. 37.5), local adverse effects of candidiasis and hoarseness from inhaled corticosteroids are minimized significantly (40). When moderate or high dosages of inhaled corticosteroids are administered via pMDI, it is usual practice to routinely prescribe a spacer device. As compared to use of pMDI without spacer, systemic bioavailability of 1658
fluticasone (minimal GI bioavailability) increased as a result of increased pulmonary deposition with use of the spacer (41), whereas systemic bioavailability of beclomethasone (absorbed from the GI tract in contrast to fluticasone) is diminished with spacer use because the reduction in swallowed drug resulting from decreased oropharyngeal deposition overshadows the effect of increased pulmonary deposition (42,43). Because of these considerations, results of clinical trials defining safety and efficacy of an inhaled medication formulation used without spacer devices cannot necessarily be generalized to use of the same formulation when used in conjunction with a spacer device. Routine use of spacers in accordance with Table 37.3 instructions is recommended in the following clinical scenarios: • Children ≤6 years of age using pMDIs (44); • pMDIs are used during acute asthma exacerbations (45); • When moderate or high doses of inhaled corticosteroids are administered via pMDI (downward dosage adjustment may be need to be considered and may be facilitated), and in those patients utilizing lower dosages of inhaled corticosteroids who develop hoarseness, candidiasis, or other oropharyngeal adverse effects (40). • Patients using pMDIs who have not been documented to show excellent inhaler coordination technique, including many adult patients (25). Despite the demonstrated benefits, simplicity, and low cost of spacers, use of these devices transforms the pMDI into a more bulky device which is difficult to transport and use discreetly, and is the inhalation method least preferred by patients (46).
Considerations for pMDI/Spacer Device Use in Infants and Young Children The use of valved holding chambers with mask to deliver medications to infants and toddlers via tidal breathing differs considerably from the considerations that apply to the usual administration to older children and adults. Based on radionuclide studies conducted by Tal et al, in this situation, only around 2% of the dose placed into the holding chamber is deposited into the patient’s lungs, a roughly 10-fold reduction from what is typically observed in older patients (47). However, if the patient is crying during the administration of the aerosol, lung deposition of less than 0.35% was observed. Ideally inhalation should be administered when the patient is calm or asleep. The mask should remain sealed 1659
over the patient’s face for 20 to 30 seconds of tidal breathing after actuation of the MDI. Tal et al. (using a plastic spacer without special precautions to reduce electrostatic charge) found longer periods of time to be useless because the aerosol adhered to the spacer after 30 seconds. Because of the expected 10-fold reduction in pulmonary deposition, the full adult dose of aerosol medication, typically at least two puffs, is administered (47). It may be appropriate to start with several puffs, a dose larger than would be typically used in older children and adults, then to reduce the dose once it is clear that the treatment is effective (48). The SootherMask is a novel approach which can deliver inhaled medication to sleeping infants. The nipple of the infant’s pacifier is inserted through a slot in the anterior wall of the mask. The infant, sucking on the pacifier mask, keeps the mask sealed to its face by means of subatmospheric pressure, and can nasally inhale the medication generated from an pMDI plus valved holding chamber attached to the pacifier mask (49).
BREATH-ACTUATED METERED-DOSE INHALERS The breath-actuated devices are alternatives to holding chambers developed to improve coordination of actuation of conventional pMDIs with inhalation. These devices are designed to actuate the MDI automatically with a spring mechanism as the patient inhales. Although these devices are of little additional benefit to patients with good inhaler coordination, use of a breath-actuated inhaler in those with poor coordination increased the deposition of radiolabeled CFC bronchodilator aerosol into the lungs from a mean of 7.2% with a conventional MDI to a mean of 20.8% with a breath-actuated inhaler; there was a corresponding dramatic improvement in FEV1 after breath-actuated inhaler use as compared with that measured after conventional pMDI in these patients (50). Dependence on inspiratory flow is a theoretical drawback of the breathactuated inhaler. At least one case has been described in which a patient experiencing acute severe airway obstruction was not able to generate sufficient inspiratory flow to activate the device (51), suggesting that, in rare instances, this issue may be clinically significant, especially when rescue bronchodilators are incorporated into breath-actuated inhalers.
DRY POWDER INHALERS An alternative to the pMDI (used alone or in conjunction with spacer or breathactuated devices) is the DPI. In general, DPIs are easier to use effectively than MDIs because they are inherently breath actuated. The current routinely available DPIs require an inspiratory flow rate of at least 60 L/minute for 1660
optimal dispersion of the powdered medication into respirable particles (52); below 30 L/minute, the fine particle output may be reduced by as much as 50% (53). Consequently, concerns have been raised regarding possible inadequacy of drug delivery to the airways from DPIs during severe exacerbations; however, studies of DPI-delivered β-agonists in acute worsening of asthma in older children and adults have not borne out such concerns (54). Because of inspiratory flow dependency, small children as well as adults with cognitive impairment may not be able to use DPIs effectively. In one study, only 40% of preschool children with acute wheezing could generate an inspiratory flow rate exceeding 28 L/minute, although around 75% could exceed this inspiratory flow rate during periods of stable asthma (55). Overall pulmonary deposition from DPIs is similar to that of a suspension formulation (non–extra-fine particle) pMDI with spacer; fine particle mass is around 20% with the available DPIs at the usual inspiratory flow rates (52,53). Hoarseness and other undesirable oropharyngeal effects are common with highdose inhaled corticosteroid preparations delivered via DPI but typically are not problematic with low-dose inhaled corticosteroids administered in this way. Currently available DPIs may be categorized into the following three groups. 1. Single-dose DPI: In a single-dose device, each dose is loaded into the device before use. The drug is supplied in an individual single-dose capsule which is placed into the inhaler and is pierced by spears or severed by a twisting action; the powder is then inhaled by the patient. After use, the remains of the capsule are removed. The Aerolizer device supplied with formoterol (Schering Corporation) and the HandiHaler device supplied with tiotropium (Boehringer Ingelheim Pharmaceuticals, Inc.) are single-dose DPIs. 2. Multiple-dose reservoir DPI: The first such inhaler to be developed was the Turbuhaler (Fig. 37.6), still utilized in many parts of the world but now replaced in the United States by a similar device, the Flexhaler (AstraZeneca). It contains a bulk supply of powdered drug without a carrier from which individual doses are released with each actuation. The Pressair (known as Genuair in several other countries) (AstraZeneca) is a novel multiple-dose reservoir device (56) currently available in the United States for delivery of aclidinium bromide, a long-acting muscarinic antagonist agent labeled for treatment of chronic obstructive pulmonary disease. The Respiclick inhaler, marketed in the United States by Teva as a delivery device for albuterol, is similar to the Spiromax inhaler (Fig. 37.7) used in Europe. It is a multipledose reservoir DPI that utilizes an air pump to transfer drug powder from the 1661
reservoir to the dosing cup when the cap is opened, a cyclone technology to deagglomerate the drug particles from the lactose carrier prior to inhalation, and is designed to externally resemble a conventional pMDI (57). Patients should be reminded that the inhalation technique to be used with the Respiclick is the rapid forceful inhalation appropriate for a DPI.
FIGURE 37.6 Turbuhaler is a cylindrical, multiple-dose reservoir dry powder inhaler device. Dosing is achieved by twisting the turning grip back and forth followed by deep inhalation. (From Vaswani SK, Creticos PS. Metered dose inhaler: past, present, and future. Ann Allergy Asthma Immunol. 1998;80:11–21; with permission.) 3. Multiple unit-dose DPI: These devices utilize individually prepared and sealed doses of drug. The Diskus device shown in Fig. 37.8 contains a coiled 1662
strip of 60 double foil-wrapped individual doses. The patient operates the inhaler by sliding a lever which moves the next dose containing blister into place with simultaneous peeling apart of two layers of foil, exposing the dose ready for inhalation (58). The more recently developed Ellipta device also utilizes coiled strips of individual doses. For a combination therapy Ellipta product, the inhaler is supplied in the two-strip configuration with two 30dose blisters that contain separate drug formulations (Fig. 37.9); one blister from each strip is delivered simultaneously during a single inhalation to provide a single dose of the combination therapy (59).
FIGURE 37.7 Configuration of the Spiromax multidose dry powder inhaler, externally resembling a metered-dose inhaler.
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FIGURE 37.8 Diskus is a disk-shaped, pocket-size, multiple unit-dose dry powder inhaler device. During inhalation, air is drawn through the device delivering the dose via the mouthpiece. It contains 60 metered doses and has a built-in dosage counter. (From Vaswani SK, Creticos PS. Metered dose inhaler: past, present, and future. Ann Allergy Asthma Immunol. 1998;80:11–21; with permission.) General instructions for use of DPIs are provided in Table 37.3. Electronic DPIs incorporating features such as dose delivery confirmation, adherence monitoring, and dosing reminders into portable inhalers are under active investigation (60,61). Although DPIs are believed to be less likely to be misused than pMDIs, serious errors remain frequent and significant. Westerik reported that 55% of patients made ≥1 serious error with a multi-use DPI. The most common errors were the failure to exhale before inhalation, insufficient breath-hold at the end of inhalation, and inhalation that was not forceful from the start; these errors correlated with adverse outcomes, including asthma hospitalization and poor asthma control, and correlated with no inhaler technique review within the past year (62). Error rates exceeding 80% in use of routinely available DPIs have been documented in elderly patients with severe airway obstruction who have not received any training in use of these devices (63). 1664
SOFT MIST INHALER The Respimat Soft Mist Inhaler (SMI) (Fig. 37.10), a device similar in size to a pMDI, utilizes a unique method of generating aerosolized droplets. A 15-µL aliquot of drug formulation solution is forced through a two-channel filter/nozzle glass and silicon system (the “uniblock”), causing it to be accelerated and split into two converging jets which collide at a carefully controlled angle; this results in the drug solution’s disintegration into inhalable droplets (12). Before each actuation, the patient tensions the spring by twisting the device at 180°. The fine particle fraction for most formulations is around 75%, significantly higher than DPIs and pMDI aerosols. The velocity of the aerosol cloud is 3 to 10 times slower than the speed of release from a pMDI. The lower velocity is expected to reduce oropharyngeal deposition and increase the fraction of the emitted dose which reaches the airways (12). The spray duration of the Respimat SMI is 1.2 seconds, significantly longer than 0.15 to 0.36 second spray duration of pMDI mists (64). The long spray duration of the soft mist allows the patient a better chance of coordinating the inhalation maneuver with drug release. In one study, the mean lung deposition of a drug formulation delivered via SMI was 37% of the emitted dose in untrained subjects and 53% in subject who received training, versus 21% for both trained and untrained subjects with a pMDI HFA suspension formulation (12). Scintigraphic imaging generally has demonstrated relatively uniform pulmonary deposition of aerosols generated by the SMI (Fig. 37.11). The major shortcoming of the SMI is the currently limited number of drug formulations available with this device.
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FIGURE 37.9 View of coiled blister strips within the inhaler chassis and mouthpiece/manifold assembly of the Ellipta inhaler.
FIGURE 37.10 Schematic illustration of the spring-powered Respimat (Boehringer Ingelheim) inhaler with “uniblock” designed to emit aerosols with enhanced pulmonary deposition. (From Dennis JR, Nerbrink O. New nebulizer technology. In: Bisgaard H, O’Callaghan C, Smaldone G. Drug Delivery to the Lung. New York, NY: Marcel Dekker, 2001:320; with permission.)
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FIGURE 37.11 Scintigraphic scans from one individual showing the deposition of radiolabeled aerosol in the lungs immediately after administration of a single dose of 250 µg flunisolide delivered via Respimat inhaler, pressurized metered-dose inhaler (MDI) or pressurized MDI plus spacer, on each of three study days. (From Dalby R, Spallek M, Voshaar T. A review of the development of Respimat SoftMist Inhaler. Int J Pharm. 2004;283:1–9; with permission).
CONCURRENT USE OF DPI AND PMDI INHALERS The slow and deep inhalation technique optimal with pMDIs differs from the forceful and fast technique which is advantageous with DPIs. It has been demonstrated that patients make fewer errors (65,66) with improvement of asthma control and significant reduction in exacerbations (67) when exclusively utilizing one type of inhaler in contrast to mixing of the pMDI and DPI devices. Therefore, whenever possible, the inhalers prescribed for a patient’s concurrent use should be of the same type (25,68). Congruity of rescue inhaler with DPI controller inhalers has recently become possible for many patients in the Unites States with the recent launch of a DPI albuterol inhaler labeled for use in older children and adults. Another undesirable occurrence is therapeutic substitution of one inhaler for another of a different type without patient instruction and assessment of proficiency with the newly introduced type of inhaler (69). Because the inhalation technique used with the SMI is similar to that used with pMDIs, the concurrent use of these devices would not be expected to be problematic; however, this issue has not been specifically investigated.
NEBULIZERS 1667
A device that simply sprays gas through a liquid resulting in aerosolization is termed an atomizer. In contrast, nebulizers are more complex devices which, by the incorporation of baffles, selectively remove particles that are too large to enter the lower airways. Many types of nebulizers are available for various applications (25,27). Nebulizers most commonly used in aerosol drug therapy are jet nebulizers driven by air compressors. In the jet nebulizer, the compressed air moves through a narrow hole known as a venturi. Negative pressure pulls liquid up to the venturi by the Bernoulli effect; at the venturi, the liquid is subsequently atomized. Many of the droplets initially atomized are much larger than the 5-μm maximum necessary for them to enter the smaller lower airways. These large particles impact on the nebulizer’s baffles or the internal wall of the nebulizer and return to the reservoir for renebulization. Details of the baffle design have a major effect on the sizes of the particles produced. The traditional jet nebulizer design (Fig. 37.12) most commonly used provides continuous flow of gas from the compressor into the nebulizer; the rate of aerosol outflow from the nebulizer is equal to the inflow rate from the compressor and does not change with the phases of respiration. Typically, only 7% to 25% of medication placed into the nebulizer is delivered to the patient’s airway (70,71). For drugs that are relatively inexpensive and have a high therapeutic index such as bronchodilators, it is simple and effective to compensate for this loss by placing a large dose of medication into the nebulizer; provided that the dosage delivered to the patient is within the flat range of the dose–response curve, the precision and efficiency of delivery may not be a critical issue. However, these factors may become meaningful when medications that are expensive and/or have a greater potential for significant dose-dependent adverse effects, such as corticosteroids, are used. Breath-assisted open vent nebulizers are a modification in which the vent is designed to be open only during inspiration, enhancing aerosol generation only during the inspiratory phase. Aerosol generation continues as a result of the continuous gas flow from the compressor during expiration, but is not enhanced by the vent, which is closed during expiration (Fig. 37.13). The primary advantages of this nebulizer design include significantly improved delivery of the drug placed into the nebulizer into the airway and shorter time required for its nebulization; other benefits include the generation of a greater fraction of smaller particles caused by increased evaporation from droplets owing to the additional airflow, and the need for less powerful compressors (70). General instructions for use of jet nebulizers are provided in Table 37.3F. For a single drug preparation, various nebulizers may provide widely 1668
differing drug delivery that further varies depending on the patient’s tidal volume during nebulization. In models of nebulization of budesonide suspension, using various nebulizer devices and tidal volumes ranging from 75 to 600 mL, the estimated percentage of the dosage placed into the nebulizer that is inhaled varied over a wide range depending on these factors (71).
FIGURE 37.12 Conventional nebulizer design. Air from the compressor passes through a small hole (venturi). Rapid expansion of air causes a negative pressure, which sucks fluid up the feeding tube system, where it is atomized. Larger particles impact on baffles and the walls of the chamber and are returned for renebulization. Small aerosol particles are released continuously from the nebulizer chamber. On expiration, the nebulizer continues to generate aerosol, which is wasted. (From O’Callaghan C, Barry PW. The science of nebulized drug delivery. Thorax. 1997;52[Suppl 2]:31–44; with permission.)
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FIGURE 37.13 An example of an open vent nebulizer, the Pari LC Jet Plus. On inspiration, the valve located at the top of the chamber opens, allowing extra air to be sucked through the vent. The main effect of this is to pull more aerosol from the nebulizer on inspiration, increasing the dose to the patient. On expiration, the vent closes, and aerosol exits via a one-way valve near the mouthpiece. Aerosol lost from the nebulizer on expiration is thus proportionally less than that from a conventional nebulizer. Nebulization times will be faster, and the drug dose received by the patient will be significantly greater than with conventional nebulizers. (From O’Callaghan C, Barry PW. The science of nebulized drug delivery. Thorax. 1997;52[Suppl 2]: 31–44; with permission.) Effective drug delivery to the airways of infants and toddlers depends on proper nebulization techniques and minimization of crying. A point of controversy is the effectiveness of aerosolized medications delivered by hood or “blow-by” from a mask or extension tubing held in front of the patient’s face (instead of delivery using a tightly fitting face mask, to which young patients often object). While some studies have suggested that the blow-by approach may provide acceptable drug delivery when a high-performance nebulizer system is used (72,73), others have concluded that blow-by generally provides only negligible pulmonary drug delivery (74); therefore, use of the blow-by method is generally discouraged (75). Aerosol therapy delivered to wheezing infants with a hood interface (76–78) may be a better alternative than blow-by for delivering inhaled medications via nebulizer to young children who cannot tolerate face mask treatment (75). The pacifier mask mentioned earlier in this chapter for use 1670
with MDI and face mask may also be utilized effectively in infants as a nebulizer interface and is being investigated as an interface with the Respimat SMI device (49). Drug delivery via valved holding chambers with mask is generally preferred to nebulizers in toddlers (79) because of shorter treatment times. Some toddlers and their caregivers object to the facial pressure needed to provide a tight seal for effective use of a valved holding chamber and instead prefer the lighter pressure of the nebulizer face mask. When instructed that incremental doses of up to 10 puffs of pMDI β-agonist rescue inhaler via spacer may be used for acute asthma episodes, older children and adults usually prefer this approach to nebulizer therapy for acute asthma (25). A home nebulizer may be the best option for some elderly patients with limited manual dexterity (25). Nebulizers are utilized for continuous delivery of β-agonists in hospitalized patients with life-threatening asthma. General age and medication-specific recommendations for choice of aerosol delivery devices are shown in Table 37.5. Most drugs used for nebulization currently are supplied in single-use ampoules, largely eliminating the need for preservative additives, some of which have been documented to have significant bronchoconstrictor effects. When multiple-use vials are used, the clinician should be aware of the additives present and any bronchoconstrictor potential that these may have with repetitive dosing (80). TABLE 37.5 USUAL RECOMMENDATIONS FOR USE OF AEROSOL DELIVERY DEVICES (UNITED STATES) SECOND CHOICE
AGE (y)
FIRST CHOICE(S)
0–3
MDI with spacer and face Nebulizer mask (pacifier mask preferred in infants)
3–6
MDI with spacer
6–12 (bronchodilators)
MDI with spacer
>12 (bronchodilators)
MDI with spacer
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Nebulizer
MDI alonea
>6 (low-dose ICS with or without LABA) DPI or MDI with spacer >6 (high-dose ICS with or without LABA) MDI with spacer
DPI
Acute bronchial obstruction (all ages)
MDI with spacer
Nebulizer
Continuous bronchodilator therapy prescribed in emergency department, intensive care unit (all ages)
Nebulizer
Soft Mist Inhaler is a first choice when available for a clinically indicated drug formulation. a
Only for those patients who demonstrate excellent technique with MDI alone.
DPI, dry powder inhaler; ICS, inhaled corticosteroids; LABA, long-acting β antagonist; MDI, metered-dose inhaler.
CONCLUSION Published evidence shows that, when used correctly, there is little difference in clinical efficacy between different inhaler types (81). Despite the development of several new and improved types of inhaler devices over the past 60 years described above, there has been no sustained improvement in patients’ ability to use their inhalers (27). In real-life studies, a large percentage of patients have shown serious deficiencies in their inhaler technique (82), and a majority of physician care providers are not able to provide sufficient instruction to their patients (83). Inadequate inhaler technique has clinical and economic consequences—in a cross-sectional study involving over 1,600 asthma outpatients, the finding of a single critical error in inhalation technique, irrespective of use of a pMDI or DPI, was associated with increased emergency department visits, hospitalizations, and oral medication utilization for asthma (84). As discussed earlier, outcomes are improved with avoidance of concurrent use of different types of inhalers in individual patients (67,85) and avoidance of switching of devices without personalized instruction (69). Provision of written materials does not substitute for direct observation, assessment, and instruction in technique appropriate for inhalers prescribed (86). At best, inhaler technique does not receive the prominence it deserves from patients, caregivers, care providers, and health insurance administrators; this situation clearly results in a major degree of modifiable morbidity and expense (27,87). All clinicians and 1672
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48. Gillies J. Overview of delivery system issues in pediatric asthma. Pediatr Pulmonol. 1997;15:55–58. 49. Amirav I, Newhouse MT, Luder A, et al. Feasibility of aerosol drug delivery to sleeping infants: a prospective observational study. BMJ Open. 2014;4:e004124. 50. Newman SP, Weisz AW, Talace N, et al. Improvement of drug delivery with a breath actuated pressurised aerosol for patients with poor inhaler technique. Thorax. 1991;46:712–716. 51. Hannaway PJ. Failure of a breath-actuated bronchodilator inhaler to deliver aerosol during a bout of near fatal asthma [letter]. J Allergy Clin Immunol. 1996;98:853. 52. Ollson B. Aerosol particle generation from dry powder inhalers: can they equal pressurized metered dose inhalers. J Aerosol Med. 1995;8(Suppl 3):13–18. 53. Prime D, Grant AC, Slater AL, et al. A critical comparison of the dose delivery characteristics of four alternative inhalation devices delivering salbutamol: pressurized metered dose inhaler, Diskus inhaler, Diskhaler inhaler, and Turbuhaler inhaler. Aerosol Med. 1999;12:75–84. 54. Selroos O. Dry-powder inhalers in acute asthma. Ther Deliv. 2014;5(1):69–81. 55. Pedersen S, Hansen OR, Fuglsang G. Influence of inspiratory flow rate upon the effect of a Turbuhaler. Arch Dis Child. 1990;65:308–310. 56. Chrystyn H, Niederlaender C. The Genuair inhaler: a novel, multidose dry powder inhaler. Int J Clin Pract. 2012;66:309–317. 57. Canonica GW, Arp J, Keegstra JR, et al. Spiromax, a new dry powder inhaler: dose consistency under simulated real-world conditions. J Aerosol Med Pulm Drug Deliv. 2015;28(5):309–319. 58. Chrystyn H. The Diskus: a review of its position among dry powder inhaler devices. Int J Clin Pract. 2007;61(6):1022–1036. 59. Grant AC, Walker R, Hamilton M, et al. The ELLIPTA dry powder inhaler: design, functionality, in vitro dosing performance and critical task compliance by patients and caregivers. J Aerosol Med Pulm Drug Deliv. 2015;28(6):474–485. 60. Newman S. Improving inhaler technique, adherence to therapy and the 1677
precision of dosing: major challenges for pulmonary drug delivery. Expert Opin Drug Deliv. 2014;11(3):365–378. 61. Chan AH, Stewart AW, Harrison J, et al. The effect of an electronic monitoring device with audiovisual reminder function on adherence to inhaled corticosteroids and school attendance in children with asthma: a randomised controlled trial. Lancet Respir Med. 2015;3(3):210–219. 62. Westerik JA, Carter V, Chrystyn H, et al. Characteristics of patients making serious inhaler errors with a dry powder inhaler and association with asthma-related events in a primary care setting. J Asthma. 2016;53(3):321–329. 63. Wieshammer S, Dreyhaupt J. Dry powder inhalers: which factors determine the frequency of handling errors? Respiration. 2008;75:18–25. 64. Hochrainer D, Holz H, Kreher C, et al. Comparison of the aerosol velocity and spray duration of Respimat Soft Mist Inhaler and pressurized metered dose inhalers. J Aerosol Med. 2005;18(3):273–282. 65. van der Palen J, Klein JJ, van Herwaarden CL. Multiple inhalers confuse asthma patients. Eur Respir J. 1999;14:1034–1037. 66. Alotaibi S, Hassan WH, Alhashimi H. Concurrent use of metered dose inhalers without spacer and dry powder inhalers by asthmatic children adversely affect proper inhalation technique. Internet J Pediatr Neonatol. 2011;13(1):29. 67. Price D, Chrystyn H, Kaplan A, et al. Effectiveness of same versus mixed asthma inhaler devices: a retrospective observational study in primary care. Allergy Asthma Immunol Res. 2012:4(4):184–191. 68. Global Initiative for Asthma (GINA), National Heart Lung and Blood Institute, National Institutes of Health. GINA report. Global strategy for asthma management and prevention. Bethesda, MD: National Institutes of Health; 2006. 69. Thomas M, Price D, Chrystyn H, et al. Inhaled corticosteroids for asthma: impact of practice level device switching on asthma control. BMC Pulm Med. 2009;9:1. 70. O’Callaghan C, Barry W. The science of nebulised drug delivery. Thorax. 1997;52(Suppl 2):31–44. 71. Smaldone GC, Cruz-Rivera M, Nikander K, et al. In vitro determination of 1678
inhaled mass and particle distribution for budesonide nebulizing suspension. J Aerosol Med. 1998;11:113–125. 72. Mansour MM, Smaldone GC. Blow-by as potential therapy for uncooperative children: an in-vitro study. Respir Care. 2012;57(12):2004– 2011. 73. Restrepo RD. Is it time to say good bye to blow-by? Respir Care. 2012;57(12):2127–2129. 74. El Taoum KK, Xi J, Kim JW, et al. In vitro evaluation of aerosols delivered via the nasal route. Respir Care. 2015;60(7):1015–1025. 75. DiBlasi RM. Clinical controversies in aerosol therapy for infants and children. Respir Care. 2015;60(6):894–916. 76. Amirav I, Balanov I, Gorenberg M, et al. Nebulizer hood compared to mask in wheezy infants: aerosol therapy without tears! Arch Dis Child. 2003;88(8):719–723. 77. Geller DE, Kesser B. Blow by vs. face mask for nebulized drugs in young children. J Allergy Clin Immunol. 2004;113(2):532. 78. Shakked T, Broday DM, Katoshevski D, et al. Administration of aerosolized drugs to infants by a hood: a three-dimensional numerical study. J Aerosol Med. 2006;19(4):533–542. 79. Cotterell EM, Gazarian M, Henry RL, et al. Child and parent satisfaction with the use of spacer devices in acute asthma. J Paediatr Child Health. 2002;38(6):604–606. 80. Asmus MJ, Sherman J, Hendeles L. Bronchoconstrictor additives in bronchodilator solutions. J Allergy Clin Immunol. 1999;104(2 Pt 2):S53– S60. 81. Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcome of aerosol therapy: evidence-based guidelines. Chest. 2005;127:335–371. 82. Lavorini F, Magnan A, Dubus JC, et al. Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD. Respir Med. 2008;102:593–604. 83. Press VG, Pincavage AT, Pappalardo AA. The Chicago Breathe Project: a regional approach to improving education on asthma inhalers for resident physicians and minority patients. J Natl Med Assoc. 2010;102:548–555.
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84. Melani AS, Bonavia M, Cilenti V, et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011;105:930–938. 85. Roth BJ. Back to the future: using inhalers correctly. Respir Care. 2008;53(3):314–315. 86. Lavorini F, Levy M, Corrigan C. The ADMIT series—issues in inhalation therapy. 6) Training tools for inhalation devices. Prim Care Respir J. 2010;19(4):335–341. 87. Papi A, Haughney J, Virchow JC, et al. Inhaler devices for asthma: a call for action in a neglected field. Eur Respir J. 2011;37:982–985.
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NOVEL IMMUNOLOGIC THERAPIES Afflicting up to 20% of the American population, allergic diseases are very prevalent; novel immunologic approaches to their abatement are avidly pursued. These approaches generally can be divided into four strategies. One approach is to administer monoclonal antibodies against molecules, usually proteins, that have been reported to be key in mediating allergic inflammation. Another is to administer other monoclonal proteins that will interfere with the allergic inflammatory process. A third approach is to target new enzymes or receptors with traditional low-molecular-weight (LMW) pharmacologic agents. A final strategy is to modify allergen immunotherapy using innovative techniques to reduce allergenicity and maintain and/or enhance immunogenicity; the latter is discussed in Chapter 13.
PHENOTYPES AND ENDOTYPES While some diseases that allergists treat are fairly homogeneous, many are not. Allergic rhinitis is an example of a fairly homogeneous disease that varies in severity but not in underlying mechanisms involved (1). Asthma, on the other hand, is a very heterogeneous disease. Several phenotypes (observable characteristics) have been described; they include severe nonatopic asthma with frequent exacerbations as well as early-onset mild allergic asthma. These different phenotypes are thought to have disparate underlying mechanisms and, therefore, are likely to respond to different novel therapies, depending upon the target of that therapy. This has led to the concept of endotype, that is, a group of individuals whose disease, in this case asthma, is caused by distinct pathophysiologic or biologic underlying mechanisms (1). For example, individuals whose asthma is primarily allergic would be more likely to respond to an anti-immunoglobulin E (IgE) therapy than to an anti-interleukin (IL)-17 therapy. If an individual with asthma is nonatopic and has high levels of IL-17
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and neutrophils in the sputum, then that individual might respond to anti-IL-17 therapy but would be less likely to respond to anti-IgE therapy. In short, these novel therapies are starting to assist in defining endotypes of allergic and related diseases. Table 38.1 lists target molecules, drugs, mechanisms, and diseases in which each novel therapy has been evaluated.
MONOCLONAL ANTIBODIES Monoclonal Anti-immunoglobulin E The elimination of IgE to provide an effective therapy for allergic diseases is based on the importance of IgE in both early- and late-phase reactions (2). Various strategies have been used to interfere with the binding of IgE to its receptors, thus abrogating allergic disease. Examples include inhibiting IgE production, use of IgE fragments to occupy the receptor, administration of soluble receptors to bind free IgE, and neutralizing antibodies against IgE. Polyclonal and monoclonal anti-IgE antibodies have been produced to study mechanisms of allergic disease (2). Omalizumab is a recombinant humanized monoclonal antibody that is reported to be effective for the treatment of patients with moderate-to-severe persistent asthma who have IgE-mediated disease not controlled by inhaled corticosteroids; it is also approved for use in chronic spontaneous urticaria, also called chronic idiopathic urticaria (3). Omalizumab has been approved for use by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). In addition to reducing free IgE, other mechanisms of action, including changes in eosinophil and T-cell function as well as reduction of FcεRI expression on dendritic cells, mast cells, and basophils, have been described. There is a newer high-affinity anti-IgE, ligelizumab that has been reported to inhibit allergen-induced early asthmatic response (4). Quilizumab targets the M1-prime segment of membrane-expressed IgE; there is a report of efficacy and safety in adults with inadequately controlled allergic asthma (5). TABLE 38.1 NOVEL IMMUNOLOGIC THERAPIES TARGET MOLECULE
DRUG
IgE
Omalizumab Anti-IgE
MECHANISMDISEASE Allergic asthma Urticaria
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DEVELOPMENT STAGE FDA and EMA approved
IL-4, IL-13
Ligelizumab
Anti-IgE
Allergic asthma
Phase II
Quilizumab
Anti-M1 prime Allergic asthma segment of membraneexpressed IgE
Phase II
Pascolizumab Anti-IL-4
Not effective in asthma
Pitrakinra
Not effective in asthma
Dupilumab
Anti-IL-4Rα
Eosinophilic asthma
Phase III
Atopic dermatitis AnrukinzumabAnti-IL-13
Asthma
Phase II
Ulcerative colitis
IL-5
IL-9
Lebrikizumab Anti-IL-13
Asthma with high Phase III periostin
Tralokinumab Anti-IL-13
Asthma with high periostin and DPP-4
Mepolizumab Anti-IL-5
Eosinophilic asthma
FDA and EMA approved
Reslizumab
Eosinophilic asthma
FDA and EMA approved
Benralizumab Anti-IL-5Rα
Eosinophilic asthma
Phase III
MEDI-528
Not effective in
Anti-IL-5
Anti-IL-9
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asthma Enokizumab
Anti-IL-9
Not effective in asthma
IL-12, IL-23
Ustekinumab Anti-p40
Atopic dermatitis Approved for psoriasis by FDA and EMA
IL-17
Secukinumab Anti-IL-17A
Not yet studied in Approved for neutrophilic psoriasis by FDA asthma and EMA
TSLP
AMG-157
Anti-TSLP
Asthma
TNF
Infliximab
Anti-TNP
Not effective in asthma
Interferon
Interferon γ1b Increase TH1
CGD
Chemokines
BMS-639623 Anti-CCR3
Not effective in asthma
GSK2239633 Anit-CCR4
Not effective in asthma
R343
Anti-Syk
Not effective in asthma
AUT-01
Anti-STAT1
Not effective in asthma
QAW039 (fevipiprant)
CRTH2 antagonist
Asthma
Phase II
AZD1981
CRTH2
Asthma
Phase II
Kinase transcription factors
CRTH2, PGD2
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Phase III
FDA approved for CGD
antagonist Muscarinic receptors
GlycopyrrolateUltra longacting muscarinic antagonist
COPD
Phase II
Darotropium Ultra longbromide acting muscarinic antagonist
COPD
Phase II
Selectins
Bimosiamose Pan-selectin antagonist
COPD
Phase II
Glucocorticoid receptors
AL-438 is an More Not effective in example of a transrepressionasthma SEGRAM with less transactivation
CCR3, CC chemokine receptor-3; COPD, chronic obstructive pulmonary disease; CRTH2, chemokine receptor T helper type 2 cells; EMA, European Medicines Agency; FDA, Food and Drug Administration; IgE, immunoglobulin E; IL-4, interleukin 4; PGD2, prostaglandin D2; SEGRAM, selective glucocorticoid receptor agonists and modulator; Syk, spleen tyrosine kinase; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoeitin.
In a ragweed rhinitis trial using omalizumab, some symptomatic improvement was described in patients who had markedly reduced free IgE levels and markedly increased bound IgE levels (6). Trials of omalizumab for atopic dermatitis have reported both positive and negative results (7,8). To date, there have been no reports of omalizumab inducing an antibody response in humans. Although the most common side effect has been the development of urticarial eruptions, patients have developed other adverse effects, including the rare possibility of anaphylaxis (9).
Anti-interleukin-4 and Anti-interleukin-13 The receptor for IL-4 and IL-13 shares the same IL-4Rα chain. The common γ chain is the other half of the IL-4 receptor, whereas the IL-13Rα1 chain is the
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other half of the IL-13 receptor. Both cytokines share signaling pathways and are involved in eosinophil activation and IgE synthesis (10). The anti-IL-4 monoclonal antibody, pascolizumab, was well tolerated but not efficacious (11). Pitrakinra, an anti-IL-4Rα/IL-13Rα, failed to demonstrate significant efficacy in asthma (12). There have been reports of safety and efficacy of dupilumab, an anti-IL-4Rα monoclonal antibody, in both persistent eosinophilic asthma and moderate-to-severe atopic dermatitis (13,14). Anrukinzumab is an anti-IL-13 being tested in asthma and ulcerative colitis (15). Another anti-IL-13, lebrikizumab, has been reported to be efficacious in asthma, particularly in those subjects with high levels of periostin (16). Tralokinumab also binds soluble IL-13 and has been reported to be efficacious in severe, uncontrolled asthma, only in those subjects with high levels of periostin and dipeptidyl peptidase-4 (17).
Anti-interleukin-5 IL-5 is a helper T-cell type 2 (TH2) cytokine that is reported to be essential for the recruitment and proliferation of eosinophils in the allergic inflammatory response. In animal models, anti-IL-5 blocking antibody has been reported to inhibit eosinophil recruitment and ablate the late-phase response (18). Two humanized anti-IL-5 blocking antibodies, mepolizumab and reslizumab, have been approved as add-on therapy for treatment of severe eosinophilic asthma by the FDA (19). An anti-IL-5Rα monoclonal antibody, benralizumab, has been reported to be safe and effective in severe eosinophilic asthma in phase III trials (20). Anti-IL-5 agents have been used off label for treatment of hypereosinophilic syndrome (HES). It should be noted that there are subgroups of HES, individuals with FIP1L1-PDGFRA fusion gene (F/P+ variant) or increased IL-5 production by a clonally expanded T-cell population (lymphocytic variant), most frequently characterized by a CD3−CD4+ phenotype. For F/P+ patients, imatinib, an LMW tyrosine kinase inhibitor, has become firstline therapy.
Anti-interleukin-9 Both activation of TH2 cells and differentiation of mast cells are roles played by IL-9. An anti-IL-9 monoclonal antibody, enokizumab (MEDI-528), was initially reported to have possible clinical efficacy. However, further trials failed to reach efficacy endpoints (21). There are no current trials of anti-IL-9 agents for asthma or related diseases. 1686
Anti-interleukin-12 and Anti-interleukin-23 IL-12 and IL-23 which are involved in T-cell effector function have a common subunit, p40. The receptors for IL-12 and IL-23 are found on dendritic cells and activated T cells that are thought to be important in mediating asthma, atopic dermatitis, and related diseases. Ustekinumab is a monoclonal antibody against p40 and has been approved by both EMA and FDA to treat psoriasis. There are reports of efficacy in atopic dermatitis but no randomized trials (22).
Anti-interleukin-17 IL-17 may play a role in neutrophilic, steroid-resistant asthma (23). Secukinumab, a monoclonal antibody against IL-17A, has been approved for psoriasis and ankylosing spondylitis. Although there was no efficacy in an asthma trial of brodalumab, a human anti-IL-17 receptor monoclonal antibody, there may be a subgroup of asthma patients with high levels of IL-17 in whom anti-IL-17 therapy would be efficacious (24).
Thymic Stromal Lymphopoeitin Thymic stromal lymphopoeitin (TSLP) is a cytokine produced by epithelial cells; it initiates and promotes TH2 responses. The receptor for TSLP is known to be present on eosinophils, basophils, mast cells, and type 2 innate lymphoid cells (25). AMG-157 is a monoclonal antibody directed against TSLP and has demonstrated efficacy in reducing allergen-induced early- and late-phase bronchoconstriction (26). There are ongoing trials using AMG-157 as an adjunct to cat immunotherapy.
Anti–Tumor Necrosis Factor α It is well recognized that tumor necrosis factor α (TNF-α) is involved in the inflammation of certain TH1-associated diseases like psoriasis and rheumatoid arthritis. In those diseases, anti-TNF-α therapies have produced significant clinical improvement. In patients with severe, steroid-dependent asthma, TNF-α may be upregulated as well, resulting in the recruitment of neutrophils and eosinophils into the airways (27). While there was initial enthusiasm for antiTNF-α therapy, this has been dampened by concerns over safety. Moreover, the efficacy of anti-TNF-α therapy is likely to be confined to a small subgroup of patients with severe asthma that have high levels of TNF-α in sputum (28).
Interferons 1687
Recombinant interferon-γ (IFN-γ) is available as a therapy approved by the FDA for chronic granulomatous disease (29). IFN-γ is known to suppress IgE production and to downregulate the function and proliferation of CD4+ TH2 cells (24). The role of interferons in IgE-mediated diseases is essentially nonexistent because the risk for side effects, including fever, chills, headache, rash, depression, and even suicide, generally outweigh any possible benefit (30). Clinical improvement has been reported in patients with severe atopic dermatitis (31). As described earlier, there are safer novel agents to treat IgE-mediated disease, like allergic asthma.
Inhibitors of Chemokines Chemokines play important roles in migration of a variety of cells, including mast cells, basophils, eosinophils, and TH2 cells. CC chemokine receptor-3 (CCR3) is particularly important in eosinophil migration. The LMW anti-CCR3 agent, BMS-639623, and the CCR4 antagonist, GSK2239633, have been studied in clinical trials for asthma (32–34). There are no current trials of antichemokine biologics or LMW agents for asthma, atopic dermatitis, or related diseases.
LOW MOLECULAR WEIGHT PHARMACOLOGIC AGENTS Inhibitors of Kinases and Transcription Factors A variety of kinase pathways can activate downstream transcription factors in the airway, resulting in activation of many cell types and production of a number of inflammatory mediators (35). Spleen tyrosine kinase (Syk) controls an important pathway in airway mast cell activation and degranulation (36). LMW Syk inhibitors R112 and R343 have been reported to reduce symptoms in allergic rhinitis and asthma (37). Signal transduction activator of transcriptions (STAT) proteins are responsible for transmitting intracellular signals initiated by cytokines. TH2 cytokines IL-4 and IL-13 result in STAT6 activation (38); TH1 cytokines result in STAT1 activation. A STAT1 oligonucleotide AVT-01 has been reported to be in a phase II clinical trial for asthma (39). However, there are no ongoing trials of Syk inhibitors or STAT antagonists.
Prostaglandin D2 Receptor 2 A major receptor for prostaglandin D2 (PGD2) is the DP2 receptor, also known as the chemoattractant receptor-homologous molecule expressed on T helper 1688
type 2 cells (CRTH2). Through that receptor, PGD2 is able to induce TH2 recruitment and activation. It is thought that PGD2 is an important mediator of the inflammation that characterizes such diseases as allergic rhinitis and aspirinexacerbated respiratory disease. Two LMW CRTH2 antagonists, QAW039 (fevipiprant) and AZD1981, are being evaluated in allergic asthma (40,41).
Muscarinic Receptors There is increased parasympathetic activity in the setting of asthmatic inflammation; hence, antimuscarinic agents such as tiotropium, umeclidinium, and aclidinium are already approved for use in in chronic obstructive pulmonary disease (COPD). Airway smooth muscle cells express both M2 and M3 receptors; mucous production is caused primarily by M3 receptors (42). Newer antimuscarinic agents being studied for asthma and COPD are more M3 selective and very long lasting (43). They include glycopyrrolate and darotropium bromide (44,45).
Selectins There are three selectins which are cell-adhesion glycoproteins; E-selectin, Lselectin, and P-selectin are present on endothelium, leukocytes, and platelets, respectively (46). Selectins are capable of inducing cell activation and, therefore, are a target for suppressing allergic inflammation. A pan-selectin antagonist, bimosiamose, has been reported to reduce sputum eosinophils and late-phase reactions. Although there are no ongoing trials in asthma, bimosiamose has been reported to be a promising LMW therapeutic agent in the treatment of COPD (47).
Other Molecular Targets in Allergic Disease There is interest in the development of novel glucocorticoid compounds that would retain the transrepressing actions of the glucocorticoid receptor which are thought to be important for anti-inflammatory actions. These new glucocorticoids would have relatively little transactivating activity, assumed to be responsible for the undesirable side effects. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). SEGRAs and SEGRMs are collectively called selective glucocorticoid receptor agonists and modulators (SEGRAMs) (48). One such compound is AL-438 which caused less hyperglycemia and less inhibition of bone formation than prednisone in a rat 1689
model (49). No successful human SEGRAMs have yet been reported. Bitter taste receptors (TAS2Rs) have recently been found to be expressed on human airway smooth muscle. The activation of TAS2Rs results in marked smooth muscle relaxation (50). It has been suggested that compounds which would activate TAS2Rs could be a new class of bronchodilators in the treatment of obstructive lung diseases because they act differently than β-agonists or antimuscarinics. No such agents have yet been reported.
PROBIOTICS According to the World Health Organization Expert Consultation Report of 2001, probiotics are “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host” (51). Although there is a reasonable rationale for anticipating benefits from probiotics, there are currently no positive recommendations from any international medical society to use probiotics or prebiotics-nutrients that probiotics need for the treatment or prevention of food allergy (52). There are also no recommendations relative to preventing allergic rhinitis or asthma. There are conflicting recommendations for prevention of eczema in high-risk infants (52). Although there have been several studies reporting a benefit with probiotics in prevention of atopic disease such as eczema, other studies have failed to support this (53). None of the studies has shown any clear preventive effect on sensitization, nor any benefit in any allergic disease other than atopic dermatitis. The term probiotic is often used loosely to include bacterial strains with little documented immunomodulatory capacity or controlled studies to support the claims. It is not known whether effects in experimental systems have any clinical relevance. Finally, little is known about the large, complex gut ecosystem. Explanations for the varied results among studies include host factors such as genetic differences in microbial responses and allergic predisposition. The variable reported results may also be caused by environmental factors, including the preexisting microbial gut flora, individual organisms chosen to include in the probiotic, diet, and treatment of the host with antibiotics (54). Clinical studies continue to be performed and reported. Hopefully there will be a better understanding of which individuals will likely benefit from which probiotics, as studies, including careful characterization of subjects and probiotic composition, are conducted.
CONCLUSION 1690
Novel immunologic therapies offer the hope of true revolutions in treatment of asthma and allergic-immunologic disorders. Knowledge gained from basic research has led to potential therapies, but the clinical effectiveness remains to be established. When an antagonist or a biologic modifier becomes available, its administration helps to reinforce or minimize the contribution of the agonist or biologic reactant to disease processes. For example, platelet-activating factor (PAF) is known to be a bronchoconstrictor agent and is a potent chemotactic factor for eosinophils. To date, PAF antagonists have had modest effects on inhibiting allergen-induced as opposed to PAF-induced bronchial responses. Thus, the contribution of PAF to allergen-induced bronchial responses seems less than initially anticipated based on the potency of PAF as a bronchoconstrictor agonist. Novel therapies need to be safe if widespread use is planned. Physicians will need to be aware of possible unexpected positive or negative effects when new therapies are used. For example, administration of novel immunologic therapy for patients with asthma and allergic rhinitis might concurrently exacerbate the patient’s rheumatoid arthritis or vice versa. There will be opportunities to revolutionize therapy, and learning how best to use the novel agents will involve pharmacologic studies, clinical trials, effectiveness studies, and post licensing surveillance. REFERENCES 1. Corren J. Asthma phenotypes and endotypes: an evolving paradigm for classification. Discov Med. 2013;83:243–249. 2. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med. 2012;18:693–704. 3. Lowe PJ, Tannenbaum S, Gautier A, et al. Relationship between omalizumab pharmacokinetics, IgE pharmacodynamics and symptoms in patiens with severe persistent allergic (IgE-mediated) asthma. Br J Clin Pharmacol. 2009:68:61–76. 4. Gauvreau GM, Arm JP, Boulet LP, et al. Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses. J Allergy Clin Immunol. 2016;138:1051–1059. 5. Harris JM, Maciuca R, Bradley MS, et al. A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma. Respir Res. 2016;17:29–39. 1691
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18. Wechsler ME, Fulkerson PC, Bochner BB, et al. Novel targeted therapies for eosinophilic disorders. J Allergy Clin Immunol. 2012;130:563–571. 19. Hern-Tze TT, Sugita K, Akdis CA. Novel biologicals for the treatment of allergic diseases and asthma. Curr Allergy Asthma Rep. 2016;16:70–83. 20. Fitzgerald JM, Bleker ER, Nair P, et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody as add on treatment for patients with severe uncontrolled eosinophilic asthma (CALIMA): a randomized doubleblind placebo controlled phase 3 trial. Lancet. 2016;388:2128–2141. 21. Oh CK, Leigh R, McLaurin KK, et al. A randomized controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma. Respir Res. 2013;14:93–98. 22. Fernandez-Anton Martinez MC, Alfageme RF, Ciudad BC, et al. Ustekinumab in the treatment of severe atopic dermatitis: a preliminary report of our experience with 4 patients. Actas Dermosifiliogr. 2014;105:312–313. 23. Zijlstra GJ, Ten Hacken NH, Hoffman RF, et al. Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells. Eur Respir J. 2012;39:439–445. 24. Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188:1294–1302. 25. Kabata H, Moro K, Koyasu S, et al. Mechanisms to suppress ILC2-induced airway inflammation. Ann Thorac Soc. 2016;(Suppl 1):S95. 26. Gauvreau GM, O’Byrne PM, Boulet LP, et al. Effects of an anti-TSLP antibody on allegen-induced asthmatic responses. N Engl J Med. 2014;370:2102–2110. 27. Brightling C, Berry M, Amrani Y. Targeting TNF-alpha: a novel therapeutic approach for asthma. J Allergy Clin Immunol. 2008;121(1):5– 10. 28. Jacobi A, Antoni C, Manger B, et al. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol. 2005;52:522– 526. 29. Leiding JW, Holland SM. Chronic granulomatous disease. In: Pagon RA, 1693
Adam MP, Ardinger HH, et al, eds. GeneReviews. Seattle, WA: University of Washington, 2012:1993–2016. 30. Pung YH, Vetro SW, Bellanti JA. Use of interferons in atopic (IgEmediated) diseases. Ann Allergy. 1993;71:234–238. 31. Jang IG, Yang JK, Lee HJ, et al. Clinical improvement and immunohistochemical findings in severe atopic dermatitis treated with interferon gamma. J Am Acad Dermatol. 2000;42(6):1033–1040. 32. Pruitt JR, Batt DA, Wacker LL, et al. CC chemokine receptor-3 (CCR3) antagonists: improving the selectivivty of DPC168 by reducing central ring lipophilicity. Bioorg Med Chem Lett. 2007;17:2992–2997. 33. Santella JB III, Gardner DS, Yao W, et al. From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part 1: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis. Bioorg Med Chem Lett. 2008;18:576–585. 34. Cahn A, Hodgson S, Wilson R, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. BMC Pharmacol Toxicol. 2013;14:14–22. 35. Adcock IM, Chung KF, Caramori K, et al. Kinase inhibitors and airway inflammation. Eur J Pharmacol. 2006;533(1–3):118–132. 36. Ramis R, Otal C, Carreno A, et al. A novel inhaled Syk inhibitor blocks mast cell degranulation and early asthmatic response. Pharmacol Res. 2015;99:116–124. 37. Meltzer EO, Berkowitz RB, Grossbard EB. An intranasal Syk-kinase inhibitor (R112) improves the symptoms of allergic rhinitis in a park environment. J Allergy Clin Immunol. 2005;115:791–796. 38. Kuperman D, Schofield B, Wills-Karp M, et al. Signal transducer and activator of transcription factor 6 (Stat6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production. J Exp Med. 1998;187:939–948. 39. Caramori G, Groneberg K, Ito K, et al. New drugs targeting Th2 lymphocytes in asthma. J Occup Med Toxicol. 2008;3(Suppl 1):S6. 40. Erpenbeck VJ, Popov TA, Miller D, et al. Data on the oral CRTh2 1694
antagonist QAW039 (fevipiprant) in patients with uncontrolled allergic asthma. Data Brief. 2016;9:199–205. 41. Kuna P, Bjermer L, Tomling G. Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma. Drug Des Devel Ther. 2016;10:2759–2770. 42. Ramrarine SI, Haddad EB, Khawaja AM, et al. On muscarinic control of neurogenic mucus secretion in ferret trachea. J Physiol. 1996;494:577– 586. 43. Gavalda A, Garcia-Gil E. Aclidinium bromide, a novel long-acting muscarinic antagonist (LAMA). Prog Respir Res. 2010;39:33–38. 44. Busse WW, Dahl R, Jenkins C, et al. Long-acting muscarinic antagonists: a potential add-on therapy in the treatment of asthma? Eur Respir Rev. 2016;139:54–64. 45. Cazzola M, Matera MG. Emerging inhaled bronchodilators: an update. Eur Respir J. 2009;34:757–769. 46. Ley K. Functions of selectins. Results Probl Cell Differ. 2001;33:177–200. 47. Gross NJ. The COPD pipeline XXII. COPD. 2013;10:390–392. 48. Sundahl N, Bridelance J, Libert C. Selective glucocorticoid receptor modulation: new directions with non-steroidal scaffolds. Pharmacol Ther. 2015;152:28–41. 49. Doggrell S. Is AL-438 likely to have fewer side effects than the glucocorticoids? Expert Opin Investig Drugs. 2003;12:1227–1229. 50. Robinett KS, Koziol-White CJ, Akoluk A, et al. Bitter taste receptor function in asthmatic and non-asthmatic human airway smooth muscle cells. Am J Respir Cell Mol Biol. 2014;50:678–683. 51. FAO/WHO. Health and Nutritional Properties of Probiotics in Food. Report of a Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food. 2001. 52. Koletzko S. Probiotics and prebiotics for prevention of food allergy: indications and recommendations by societies and institutions. J Pediatr Gastroenterol Nutr. 2016;63:S9–S10. 53. Prescott SL, Bjorksten B. Probiotics for the prevention or treatment of allergic diseases. J Allergy Clin Immunol. 2007;120:255–262.
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INTRODUCTION The major conditions that the allergist-immunologist diagnoses and treats can occur in the context of gestation or in anticipation of pregnancy. Examples include asthma, allergic and nonallergic rhinitis, acute or chronic rhinosinusitis, nasal polyposis, urticaria, angioedema, anaphylaxis, and immunodeficiency. Goals of managing gravidas should include effective control of the underlying allergic-immunologic conditions; avoidance measures; guidance on medications, diets, and supplements; action plans or preparedness for emergencies such as acute severe asthma or anaphylaxis; and communication between the physician managing the allergic-immunologic conditions and the physician managing the pregnancy.
ASTHMA Asthma occurs in 3.7% to 8.4% of pregnancies in the United States (1–3) and in up to 12.4% of pregnancies in Australia (4) and 12.3% in Canada (5). Asthma may have its onset during gestation and present as acute severe asthma, requiring hospitalization. Wheezing dyspnea may result in interrupted sleep, persistent coughing, hypoxemia, and even rib fractures during gestation. The sequelae of 1697
ineffectively controlled asthma on the gravida can be devastating in that maternal deaths may occur in the most extreme cases (6,7). Other untoward outcomes of asthma during gestation include fetal loss (abortions or stillbirths), increased rate of preterm deliveries (20 ng/mL in a patient without acute symptoms of anaphylaxis, indolent systemic mastocytosis should be suspected and further evaluation sought. Histamine elevation is short-lived after an anaphylactic episode; however, metabolites, such as N-methyl histamine and prostaglandins, can be measured in the urine for 24 hours after an anaphylactic event and may be useful for diagnosis. Other potentially useful biomarkers are being studied, including platelet-activating factor, bradykinin, chymase, and others (38).
Nasal Provocation Nasal provocation is primarily a research test in North America; however, in some countries this test is used clinically. Nasal reactivity is thought to be predictive of bronchial reactivity to allergens (39). This test may be useful if the history of allergic rhinitis is highly convincing, but SPT, intradermal, and sIgE tests are negative. This test is also useful for the evaluation of occupational allergens or to demonstrate nonallergic irritant rhinitis. Nasal provocation is performed using dilute allergen extracts. The nose is examined for structural pathology, including polyps, septal deviation, or acute infection. A diluent solution (negative control) is then sprayed into one or both nostrils using a metered-dose delivery device to assess for nonspecific responses. Sneezes are counted over the next 15 minutes, and nasal discharge is collected. Pruritus, rhinorrhea, nasal stuffiness, and ocular symptoms are scored using a severity scale. If there are no symptoms, the provocation is performed every 15 minutes with increasing concentrations of serially diluted allergen. The downsides of nasal provocation include the multiple different techniques used for this test as well as the absence of standardized methods and reagents. Standardization may increase the utility of nasal provocation test for clinical practice (40).
TESTS FOR DISEASES
PRIMARY
IMMUNODEFICIENCY
Patients with primary immunodeficiencies present with recurrent or severe infections, autoimmunity, or both. In infants and young children, failure to thrive is a common presenting sign. Appropriate diagnostic testing is essential for early diagnosis. Immunologic testing is guided by the clinical presentation of the patient, including age, sex, type of infections, autoimmunity, and family history. 1846
General testing includes a complete blood count (CBC) and differential to assess for abnormalities, including lymphopenia or neutropenia. Chemistry studies, including electrolytes, blood urea nitrogen and creatinine, glucose, and a urinalysis, may be helpful to exclude systemic disease causing a secondary immune deficiency. A low albumin suggests protein loss or malnutrition. Erythrocyte sedimentation rate or C-reactive protein may be elevated in infections and inflammatory disorders. Additional laboratory tests have been developed to assess the major components of the humoral and cellular arms of the immune system (41,42). A practice parameter outlining the approach to primary immunodeficiency, including diagnostic testing, was published in 2015 (43,44).
Humoral Immunodeficiency Testing Patients who present with recurrent bacterial infections of the sinopulmonary tract should be tested for humoral immunodeficiencies. This includes measuring quantitative serum immunoglobulins (IgG, IgA, IgM, and IgE) and comparing them to age-matched normal ranges to detect a deficiency or excess in any of these. Most clinical laboratories use nephelometry to measure immunoglobulin levels quantitatively. Nephelometry measures scatter of light from a light source projected through the liquid sample in a transparent container. The scatter of light is proportional to the concentration of the immunoglobulin in the solution (6). As a general rule, a total serum IgG concentration of 200 kU/L and eosinophil cationic protein >15 µg/L, PC20 methacholine 10% in 16% and from 5% to 10% in 17% of children (8). Otherwise, improvements in FEV1 were smaller. Some patients have improved 1894
with montelukast administration in terms of fewer symptoms and greater numbers of asthma control days. Similarly, in adults with either mild or moderate persistent asthma, the responders to montelukast 10 mg daily had mean urinary LTE4 >225 pg/mg creatinine compared with 175 pg/mg creatinine for nonresponders (15). The definition of responder required meeting three conditions: (1) >20% reduction of symptom scores, (2) >20% reduction in β2adrenergic agonist doses, and (3) an increase >10% in FEV1 (15). At the end of 4 weeks, there were 25 of 48 (52%) of patients who were the responders (15). In particular, the change in FEV1 in responders was from 77% to 89% predicted, whereas in nonresponders, the FEV1 decreased from 79% at baseline to 76% in 4 weeks (15). In an investigation from two clinical trials with montelukast, where 10% to 13% of patients had increases in FEV1 from 18% to 25% compared with 8% to 10% in the rest of the patients, there were good responder SNPs (rs91227 and rs912278) identified in the cysteinyl leukotriene receptor 2 gene and SNPs (rs4987105 and rs4986832) in the 5-lipoxygenase (LO)-activating protein (ALOX5) gene (16). The 5-LO synthesis inhibitor, zileuton, inhibits from 26% to 83% of leukotriene production (17) and leads to bronchodilation in the first 60 minutes of 14.6% compared to 0% with placebo (18). In a separate study where treatment was continued for 12 weeks, zileuton, 1,200 mg twice daily, caused the FEV1 to increase by 20.8% compared with 12.7% in placebo-treated subjects (19). Depending on the contributions of leukotrienes to the pathobiology of asthma, there will be variations in response to zileuton or CysLTR1 antagonists that can be identified empirically. Short-acting β2-adrenergic agonists (SABAs), such as albuterol, have a very wide range of responses (increases in FEV1 and reduction of or prevention of symptoms), and adverse effects (tremulousness and palpitations) (20). In a dose– response study beginning with albuterol, 100 µg, the maximum extent of bronchodilation varies among patients (20). The wild-type genotype at the β2adrenergic receptor is designated as B16 Gly-Gly. Polymorphisms at position 16 (Gly16Arg) have been associated with reduced protection from bronchoconstrictor stimuli and smaller degrees of control of asthma in patients using SABAs and long-acting β agonists (LABAs) (21–24). However, in patients using ICS, this finding hasn’t always been confirmed (22,25). The rationale is that being homozygous for the SNP of the 16th amino acid in the β2-adrenergic receptor (B16 Arg/Arg) instead of wild type (B16 Gly-Gly) would predispose to 1895
less bronchodilation and more exacerbations (24). There has been a concern that the reduced bronchodilation and loss of control of asthma are more likely to occur in African Americans, of whom about 20% have the B16 Arg/Arg mutation (22). However, when an LABA is added to baseline ICS therapy, irrespective of genotypes, there have not been large clinical differences between responses of Caucasians and African Americans (25). Omalizumab has been approved in the United States since 2003 for persistent severe asthma and has multiple biologic effects (26). Clinical improvement can be established after 16 weeks of treatment (27). For example, in a large realworld study in the United Kingdom, the ACT score increased from 10 at baseline to 16 by 16 weeks (27). No further improvement in the ACT score occurred with continued treatment through 8 and 12 months (27). Some characteristics of good responders include (1) experiencing an exacerbation in the run-in period of a clinical trial for patients in steps 2 to 5 persistent asthma, (2) exhibiting type 2 asthma biomarkers, including FeNO >24 ppb, peripheral blood eosinophils >260/µL, and periostin >50 ng/mL, and (3) having more robust ex vivo production of interferon (IFN)-α by peripheral blood mononuclear cells (PBMCs) when stimulated with rhinovirus in the presence of omalizumab (the production of IFN-α from PBMCs experimentally is reduced in the presence of IgE cross-linking, but omalizumab interferes with this process) (26,28). Mepolizumab, the anti-IL-5 monoclonal antibody, was approved in the United States in 2015 for patients aged 12 years and older with severe asthma and an eosinophilic phenotype meaning absolute peripheral blood eosinophils ≥150/µL (currently in the past 4 to 6 weeks) or ≥300/µL in the past year (29,30). There are fewer exacerbations, reduced oral corticosteroids, and increased FEV1 in responders (29). The reduction in symptoms as measured by the asthma control questionnaire-5 was present as early as 2 weeks (29). Subsequent cluster analysis identified better responders as patients with peripheral blood eosinophils >150/µL combined with a bronchodilator response >16.2% (30). Indeed, when body mass index >30 was incorporated with the first two biomarkers, the response rate was even higher (30).
Endotypes and Phenotypes Phenotypes are observable characteristics, such as bronchodilator responsiveness, obesity, good/poor adherence, allergic inflammation rich (type 2 asthma), neutrophilic, TH17-rich inflammation in asthma, poor perceiver, and hypervigilant observer. Alternatively, an endotype is a distinctive subtype of a 1896
disease with its own pathobiology and particular responses to treatment (31). Some proposed examples include aspirin-exacerbated respiratory diseases (formerly Samter syndrome), allergic bronchopulmonary aspergillosis, persistent severe neutrophilic asthma in adults, and asthma predictive index positive children with asthma (31). Identifying such endotypes of asthma could lead to greater predictive enrichment in clinical research trials so as to determine the good or superior responders to a treatment. Alternatively, if the trial of a new therapy for an endotype fails to result in efficacy, then the hypothesis, even if very attractive based on previous investigations, may well be incorrect. Such is the process of scientific investigation. Nevertheless, the path to demonstration of a new treatment’s efficacy or lack thereof will have be carried out in a population of research subjects who were more likely to respond. It should be noted that phenotypes can be present in many endotypes (e.g., bronchodilator responsiveness), but an endotype is distinctive as a subtype of the disease (31). TABLE 46.2 EXAMPLES OF HIGHLY EFFECTIVE INTERVENTIONS AND PERSONALIZED TREATMENTS FOR SELECTED PATIENTS WITH ASTHMA Avoidance measures for patients with asthma or allergic rhinitis (e.g., animal danders, molds, dust mites) Establishing shared therapeutic goals with patients so that an action plan can be started by the patient for early treatment of and improved control of exacerbations of asthma Attempting a step-down approach to medications after 3 mo of effective control of asthma Recognizing when patients are nonadherent or for other reasons wouldn’t meet inclusion criteria for clinical trials, implying that evidence-based approaches may be unsuccessful and that individualized and successful treatment recommendations will not be evidenced based Utilizing allergen immunotherapy (subcutaneous or sublingual) for patients with asthma and allergic rhinitis Employing ICS or leukotriene D4 receptor antagonists in good responder patients
Recognizing limitations of ICS, LABAs, ICS/LABA combinations, long-acting
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muscarinic antagonists, leukotriene D4 antagonists, 5-lipoxygenase biosynthesis inhibitors, theophylline, and macrolides Identifying good responders to immunobiologics Suspecting cough equivalent asthma in patients and clearing the cough with a short course of prednisone and continued therapy with an ICS Determining how important the unified (integrated) airway is for each patient to optimize management
ICS, inhaled corticosteroids; LABA, long-acting β agonists.
EXAMPLES OF EFFECTIVE AND PERSONALIZED INTERVENTIONS Asthma is a complex disease, and many patients are not achieving control even with high-dose ICS/LABA (32), immunobiologics, and oral corticosteroids. Many patients with persistent asthma have allergic rhinitis and gastroesophageal reflux, whether symptomatic or not. Perception of dyspnea may be impaired or in other patients, there is hypervigilance regarding symptoms with no physiologic evidence of airways obstruction or a truncated inspiratory flow loop. Or, vocal cord dysfunction or hyperirritable larynx coexists with persistent or intermittent asthma, thus requiring a high level of clinical acumen. In attempting to institute personalized approaches, it is advisable for the physician or health care professional to reassess their own decision-making focusing on the patient’s level of control of asthma in perspective to medications and other interventions and comorbidities. Some examples of what can be very highly effective personalized/individualized treatments for certain patients are presented in Table 46.2. REFERENCES
1. US Department of Health and Human Services, US Food and Drug Administration. Paving the way for personalized medicine: FDA’s role in a new era of medical product development. Federal Drug Administration (FDA); 2013. Accessed February 12, 2017. www.fda.gov/downloads/scienceresearch/specialtopics/precisionmedicine/ucm372421.p 2. Mancinelli L, Cronin M, Sadée W. Pharmacogenomics: the promise of 1898
personalized medicine. AAPS PharmSci. 2000;2:29–41. 3. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372:793–795. 4. Dzau VJ, Ginsburg GS, Chopra A, et al. Realizing the Full Potential of Precision Medicine in Health and Health Care. Vital Directions for Health and Health Care Series. Discussion paper. Washington, DC: National Academy of Medicine, 2016. https://nam.edu/wpcontent/uploads/2016/09/realizing-the-full-potential-of-precisionmedicine-in-health-and-health-care.pdf. 5. Jameson JL, Longo DL. Precision medicine—personalized, problematic, and promising. N Engl J Med. 2015;372:2229–2234. 6. Spear BB, Heath-Chiozzi M, Huff J. Clinical pharmacogenetics. Trends Mol Med. 2001;7:201–204.
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outcome of asthma: no clinical application for long-term steroid effects by CRHR1 polymorphisms. J Allergy Clin Immunol. 2008;121:1510–1513. 14. Mosteller M, Hosking L, Murphy K, et al. No evidence of large genetic effects on steroid response in asthma patients. J Allergy Clin Immunol. 2017;139(3):797.e7–803.e7. doi:10.1016/j.jaci.2016.05.032. 15. Cai C, Yang J, Hu S, et al. Relationship between urinary cysteinyl leukotriene E4 levels and clinical response to antileukotriene treatment in patients with asthma. Lung. 2007;185:105–112. 16. Klotsman M, York TP, Pillai SG, et al. Pharmacogenetics of the 5lipoxygenase biosynthetic pathway and variable clinical response to montelukast. Pharmacogenet Genomics. 2007;17:189–196. 17. Peters-Golden M, Henderson WR Jr. Leukotrienes. N Engl J Med. 2007;357:1841–1854. 18. Israel E, Rubin P, Kemp JP, et al. The effect of inhibition of 5lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med. 1993;119:1059–1066. 19. Nelson H, Kemp J, Berger W, et al. Efficacy of zileuton controlled-release tablets administered twice daily in the treatment of moderate persistent asthma: a 3-month randomized controlled study. Ann Allergy Asthma Immunol. 2007;99:178–184. 20. Lipworth BJ, Clark RA, Dhillon DP, et al. Beta-adrenoceptor responses to high doses of inhaled salbutamol in patients with bronchial asthma. Br J Clin Pharmacol. 1988;26:527–533. 21. Lee DK, Currie GP, Hall IP, et al. The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br J Clin Pharmacol. 2004;57:68– 75. 22. Wechsler ME, Kunselman SJ, Chinchilli VM, et al. Effect of beta2adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebocontrolled, crossover trial. Lancet. 2009;374:1754–1764. 23. Palmer CN, Lipworth BJ, Lee S, et al. Arginine-16 beta2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax. 2006;61:940–944.
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25. Jabbal S, Manoharan A, Lipworth J, et al. Is Gly16Arg β2 receptor polymorphism related to impulse oscillometry in a real-life asthma clinic setting? Lung. 2016;194:267–271. 26. Teach SJ, Gill MA, Togias A, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol. 2015;136:1476–1485. 27. Niven RM, Saralaya D, Chaudhuri R, et al. Impact of omalizumab on treatment of severe allergic asthma in UK clinical practice: a UK multicentre observational study (the APEX II study). BMJ Open. 2016;6(8):e011857. doi:10.1136/bmjopen-2016-011857. 28. Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187:804–811. 29. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189– 1197. 30. Ortega H, Li H, Suruki R, et al. Cluster analysis and characterization of response to mepolizumab. A step closer to personalized medicine for patients with severe asthma. Ann Am Thorac Soc. 2014;11:1011–1017. 31. Lötvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127:355–360. 32. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The gaining optimal asthma control study. Am J Respir Crit Care Med. 2004;170:836–844.
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Index Page numbers followed by f and t indicated figures and tables respectively. A Accelerated reactions, 358 Accessory sinus ostia, 229 Acetaminophen, 374 Acetylcholine, 436 Acetylhydrazine, 336 Acidosis, 510 Acoustic reflectometry 658 Acrivastine, 724t, 726t Acupressure, 615 Acupuncture, 615, 880 Adenoid cystic carcinoma, 213 Adenosine, 35 Adenosine deaminase deficiency gene defects in, 50t gene therapy for, 55 skeletal abnormalities associated with, 46, 47t Adrenocorticotropic hormone, 746 Aeroallergens. See also Allergen(s) allergenicity of, 94–95 in atopic dermatitis, 670 dander, 86, 119, 157, 588
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definition of, 86 eosinophilic esophagitis caused by, 821 fungal culture of, 90–91 immunologic methods for identifying, 91–92 nomenclature for, 86–87 particle size of, 95–96 sampling methods for, 87–92 sensitivity to, 495 skin tests, 160, 161t symptoms produced by, 157t Agger nasi cells, 186 Agranulocytosis, 335 AIDS, 367–368 Ailanthus trees, 100 Air cells, ethmoid, 188 Air pollutants asthma risks secondary to, 496 description of, 124–125 Airborne pollen. See also Pollen/pollen grains in Alaska, 150t asthma and, 95 in California, 149t description of, 132 in Great Plains of United States, 143–146t in Hawaii, 150t in Midwest United States, 141–143t in Northeast United States, 134–137t in Northwest of United States, 148t 1903
particle size of, 95–96 in Southeast United States, 137–140t in Southwest United States, 146–147t Airway inflammation of, 524 obstruction of, in asthma, 171, 507–508 Airway hyperresponsiveness, 408, 524 Airway tone, 436–438 AL-438, 795 Alaska, 150t Albuterol, 735t asthma treated with, 459, 460t acute severe, 502t, 511f, 511–512, 511t during pregnancy, 804 bronchodilation caused by, 737 metered-dose inhaler delivery of, 515 (R)-, 737 racemic, 511 (S)-, 737 Albuterol/ipratropium bromide, 460t All-or-nothing thinking distortion, 862t α1-Antitrypsin deficiency, 442 Allergen(s) aeroallergens. See Aeroallergens allergenicity assessments. See Allergenicity animal, 119–121, 157, 446, 469 in atopic diseases, 85 cat, 120, 446, 470 challenge, 86, 525f 1904
characterization of, 93–96 chemical avoidance of, 882–883 chemical properties of, 95 cockroach, 86, 121, 123–124t, 158, 239, 496, 595 criteria for classification as, 86 cross-reactive, 599 dander, 86, 120, 158, 239, 588 definition of, 85 dog, 120 dust mite. See Dust mites eosinophilic esophagitis, 819–822 epithelial, 119–121 exposure risk, 239 extracts, 92–93, 161 fungal. See Fungi furry animal, 240 grass pollen, 107, 108t hypersensitivity pneumonitis, 543–546 IgE-specific tests, 412 immunotherapy. See Immunotherapy, allergens indoor, 158, 426 insect, 121–124 isoallergens, 86 major, 86, 94 minor, 86 moth, 121–122 nomenclature for, 86–87 occupational, 587t 1905
pollen. See Pollen/pollen grains protein-nitrogen unit system for, 93 quantification of, 93 radioallergosorbent testing of, 93 rodent, 240 sensitivity testing for, 85 sensitization to, 239 tree pollen, 107–110 types of, 85 weed pollen, 106 Allergen-specific IgE, 866–867 Allergenic plants anatomy of, 97 grasses. See Grass(es) taxonomy, 97–106 trees, 98–101 weeds, 103–106 Allergenicity assessment of, 94 theories of, 94 Allergic conjunctivitis, acute, 642–645, 644t, 653t Allergic fungal rhinosinusitis (AFS), 608 Allergic rhinitis asthma and, 596, 607 burden of disease, 596–597 in children, 601–602 chronic rhinosinusitis and, 229–231 classification of, 595 1906
clinical features of, 599–602 complications of, 609 course of, 609 definition of, 595 diagnosis of, 604 differential diagnosis, 604–608, 605t drug-induced, 604 in EGPA, 74 eosinophils in, 603 epidemiology of, 596–597 etiology of, 599 food allergens and, 599 genetics of, 597–599 genomic searches conducted in, 598t grass pollen as cause of, 595 health care costs for, 596 incidence of, 596 laboratory findings, 603–604 local, 609 mast cells in, 603 mold spores as cause of, 599 nasal provocation test for, 605–606 ocular symptoms of, 596 otitis media with effusion and, 659 pathophysiology of, 602–603 perennial, 595 periodicity of, 601 physical examination for, 155–156, 601–602 1907
prevalence of, 596 radioallergosorbent test of, 604 ragweed as cause of, 599 rhinorrhea caused by, 600, 606 sneezing caused by, 599 symptoms of, 599–602 treatment of anticholinergics, 614 antihistamines, 613 avoidance therapy, 609 capsaicin nasal spray, 615 complementary and alternative therapies, 615–616 intranasal corticosteroids, 610–612, 756–757 intranasal cromolyn, 614–615 leukotriene-receptor antagonists, 614 pharmacologic treatment, overview of, 610 sympathomimetic agents, 613–614 Allergy(ies) anxiety disorders and, 856 controversial theories about, 875–876 drug. See Drug allergy evaluation and history, 153–155 food. See Food allergies in infants, 496–497 latex, 267–268, 321, 393, 683 mood disorders, 855 in otitis media with effusion, 654–657 photoallergy, 679 1908
physical examination, 155–157 remote practice of, 884 shellfish, 254, 266 sinusitis and, 203 testing-directed elimination diet, 827 treatment methods, unconventional, 879–883 unconventional diagnostic methods, 876–879 unproven methods for prevention, 883–884 in vivo and in vitro testing in allergen-specific IgE, 866–867 basophil activation test (BAT), 868 complementary and alternative testing, 868 component-resolved diagnostics, 867 intradermal skin test, 866 nasal provocation, 869 patch tests, 868 precipitating IgG antibodies, 868 serum tryptase and other tests for anaphylaxis, 868–869 skin-prick testing, 865–866 total serum IgE, 867 Allergy-immunology, personalized medicine in effective and personalized interventions, 893, 893t introduction and terminology, 889 heterogeneity of responses, 889–891 treatment for asthma, 891–892 endotypes and phenotypes, 892–893 Alstromeria, 685 Alt a 1, 115 1909
Alt a 13, 115 Alt a 6, 115 Alternaria alternata, 112f Alternaria spp., 96 Alveolar macrophages, 554 Alveolar noncaseating granulomas, 551 Amaranths, 105 Amb a 1, 106 Amb a 2, 106 Amb a 3, 106 Amb a 5, 106 Amb a 6, 106 Amb a 7, 106 Ambrosieae, 103 Aminoglycosides, 369 Aminophylline, 479, 512 5-aminosalicylic acid, 367 Amiodarone, 333 Amphotericin, 370–371 Anaphylactoid reactions, drug-induced, 319, 370 Anaphylaxis antihistamines for, 277, 728 basophils in, 257–258 biologic agents that cause, 395–397 biphasic, 255, 414 blood transfusion-induced, 270 carcinoid syndrome vs., 261 causes of, 252–253, 252t, 263–271 1910
chemotherapeutic causes of, 264, 320, 380 clinical manifestations of, 255–256 comorbidities associated with, 253 death caused by, 251 definition of, 251 diagnosis of, 260–262, 260t, 289 differential diagnosis, 260–262, 274t discharge instructions for patients, 277 drug-induced, 254, 264, 268, 319–320 epidemiology of, 253–255 epinephrine for, 274–277, 275t exercise-induced, 271, 409 factors that affect the severity of, 262–263, 263t food dependent exercise-induced, 271, 409 food-induced, 254, 266–267, 408–409, 447 historical descriptions of, 15, 251 idiopathic, 272–274, 273t, 759 in IgA deficiency, 59 in-hospital, 254 incidence of, 253 insect stings as cause of, 255, 266, 289 laboratory studies, 258–259 latex, 267–268, 321, 393, 683 mast cells in, 256–260 mastocytosis vs., 258–259 mechanism of action, 251–253 microscopic examination findings, 256–257 Munchausen stridor vs., 261 1911
nitric oxide production during, 258 nonsteroidal anti-inflammatory drugs as cause of, 264, 372 omalizumab-induced, 273 onset of, 255 pathophysiology of, 256–262 pediatric, 273 penicillin-induced, 264 peri-anesthetic, 268 perioperative, 268–270 persistent, 256 physical examination findings, 156–157 prednisone for, 272–273 during pregnancy, 809–810 radiocontrast material-induced, 253 risk factors, 253 seminal fluid-induced, 270–271 serum tryptase and other tests for, 868–869 severity of, 262, 263t shock associated with, 255, 260, 393 signs and symptoms of, 255–256 treatment of, 274–277, 413–414 tryptase, 256–257, 261–262 undifferentiated somatoform idiopathic, 272 vascular permeability increases during, 263 Anderson sampler, 90 Anesthetic allergy, 377–378, 378t Angioedema ACE inhibitors as cause of, 699 1912
acquired, 694t angiotensin-converting enzyme inhibitors as cause of, 325, 379 autoimmune, 694t biopsy, 693, 693t drug-induced, 325, 379 hereditary description of, 692, 694t historical descriptions of, 689 inherited, 696–698 mast cell activation in, 692t physical examination findings, 156 in pregnancy, 809–810 urticaria and, 689 vibratory, 694t, 698 Angiofibroma, 607 juvenile nasopharyngeal, 207 Angiosperms, 98 Angiotensin-converting enzyme inhibitors, 155 allergy to, 379 anaphylaxis and, 263 angioedema caused by, 325, 379, 699 bronchospasm induced by, 331 cough caused by, 331, 469, 837 rhinorrhea caused by, 631 substrates of, 379 Angiotensin I, 379 Angiotensin II receptor antagonists allergy, 379 Animal allergens, 119–121, 158, 446, 469. See also Cat allergens; Dog allergens Animal dander, 86, 119, 158, 588 1913
Anisakis, 95 Anrukinzumab, 793 Anti-interleukin-12, 793–794 Anti-interleukin-13, 793 Anti-interleukin-17, 94 Anti-interleukin-23, 793–794 Anti-interleukin-4, 793 Anti-interleukin-5, 793 Anti-interleukin-9, 793 Anti-neutrophil cytoplasmic antibody, 74, 324 Anti-tumor necrosis factor α, 794 Anti-tumor necrosis factors, 395 Antibiotics during pregnancy, 808–809 resistance, 629 Antibody deficiency syndromes infection responses, 59 management of, 57–60 Anticholinergics allergic rhinitis treated with, 614 asthma treated with, 464, 501 drug interactions, 769 efficacy of, 769 mechanism of action, 769 pharmacology of, 769 Anticonvulsant hypersensitivity syndrome, 380 Antidepressants, 469, 860–861 Antifungal agents 1914
allergic bronchopulmonary aspergillosis treated with, 577–578 description of, 370–371 Antifungal medications, 883 Antigen(s) adaptive immunity, 5 aqueous, 247 hypersensitivity pneumonitis, 543–546, 544–545t leukocyte cellular antibody test, 877 purified, 247 Antihistamines acute allergic conjunctivitis treated with, 644t, 645 adverse effects of, 729–730 allergic rhinitis treated with, 613, 808 anaphylaxis management using, 277, 728 clinical use of, 728–729 description of, 38 dual-action, 727 histamine1 receptorantagonists. See Histamine1 receptor antagonists histamine2 antagonists, 731 histamine2 receptor antagonists, 382 histamine3 antagonists, 731 histamine4 antagonists, 732 metabolism of, 312 nonallergic disorders treated with, 729 prophylactic administration of, 345 pruritus treated with, 713 side effects of, 311 skin testing affected by, 162 1915
tolerance to, 730 urticaria management using, 322, 702–704 Antileukotrienes, 767–768 Antimicrobial agents aminoglycosides, 369 chloramphenicol, 370 clindamycin, 370 fluoroquinolones, 370 Jarisch-Herxheimer phenomenon associated with, 311 macrolides, 370 metronidazole, 370 tetracyclines, 370 vancomycin, 369–370 Antinuclear antibodies, 322 Antiplatelet therapies, 382 Antithymocyte globulin, 391 Antituberculous agents, 371 Antiviral agents, 371 Antro-choanal polyp, 197, 199f Anxiety disorders, 856–857 Applied kinesiology, 877–878 Aqueous antigens, 247 Arachidonic acid, 33 Artemisia spp., 104–105 Arterial blood gases, 510 Arylamine N-acetyltransferase 2, 367 Ash trees, 101, 101f Asp f 1, 115, 569 1916
Asp f 13, 115 Asp f 18, 115 Asp f 22, 115 Asp f 5, 115 Asp f 6, 115 Aspergillus spp. A. flavus, 561–563 A. fumigatus, 114, 114f, 115, 561–563, 568–572, 569t, 579 A. terreus, 562 environmental exposure to, 579 Aspiration, 837 Aspirin, 647 allergy to, 372–374 asthma induced by, 448–449, 471–472, 606 conversion rates for, 472 exacerbated respiratory disease, 372, 448–449, 472 intolerance, 624 triad, 624 Astemizole, 725 Asthma acute auscultatory findings of, 156 exacerbations, corticosteroids for, 755–756 inspiratory increases during, 435 lung volumes in, 435 pneumomediastinum in, 442 respiratory failure caused by, 480 severity assessments, 477, 478t 1917
signs and symptoms of, 156 sputum production during, 438 status asthmaticus, 434, 434f, 477–480, 496 treatment of, 473 acute severe airflow obstruction in, 507–508 albuterol, 511–512, 511t aminophylline for, 512 antibiotics for, 511t, 513 arterial blood gases in, 510 β adrenergic agonists, 511–512 chest auscultation, 509 chest radiographs of, 510 corticosteroids for, 512 differential diagnosis, 509 emergency management of, 510 heliox for, 513, 516 incidence of, 507 ipratropium bromide for, 512 leukotriene modifiers for, 513 magnesium sulfate, 512–513 mechanical ventilation for, 513–516 onset of, 507 oxygen supplementation for, 510–511 physical examination for, 509 theophylline for, 512 airway obstruction in, 171 airway tone, 436–438 1918
allergic, 446–447, 469–470 allergic rhinitis and, 596, 607 anatomy of, 430–432 aspirin-induced, 448–449, 606 atopy and, 426 autopsy studies, 433, 434f Baker’s, 408 behavioral patterns associated with, 444 β-adrenergic agonists and, 442–443 β-adrenergic inhaled agonists for, 735t biological modifiers, 465–468 bronchial biopsy evaluations, 427 bronchial challenge of, 432 bronchial hyper responsiveness in, 433, 434t bronchial thermoplasty, 470–471 bronchoprovocation testing, 174 cardiac, 509 characteristics of, 171, 423 chest radiographs, 165 in children, 445 cholinergic mechanisms in, 768 chromones, 467–468 chronic obstructive pulmonary disease and, 424, 452 chronic rhinosinusitis and, 237, 453 classification of, 444–452, 444t clinical features of, 423 clinical trials airway hyper responsiveness testing, 524 1919
description of, 520 early airway responses, 525 inflammation measures, 524 information sources in, 529t late airway responses, 525 list of, 530–536t outcomes, 523t, 524–528 phase I, 521 phase II, 521 phase III, 522 phase IV, 522 quality of life measurements, 527 remodeling, 524 complete blood count evaluation, 440 complexity of, 427–428 complications of, 442–443, 481–482 computed tomography findings, 219–220t congestive heart failure and, 453 corticosteroids in, 891t costs of, 430 coughing caused by, 438, 835–836 croup and, 426 deaths from, 429–430, 442, 482 definition of, 423 depression and, 475 diffusing capacity for carbon monoxide in, 175, 440 drug-induced, 331 drugs contraindicated in, 469 1920
dyspnea in, 436t, 438 electrolyte abnormalities in, 441 emergency treatment for, 429–430 empty airways, 433 environmental factors, 425–427 eosinophils in, 427, 430, 441 epidemiology of, 494 epithelial cell shedding, 431 exacerbations of, 96, 524 exercise-induced, 450–451 factitious, 444, 451 FEV1 loss in, 482 FEV1/FVC ratio in, 176 food allergies in, 402t, 408 forced spirometry, 171–173 forced vital capacity in, 438 fractional exhaled nitric oxide, 164, 174–175 future considerations for, 482–483 gastroesophageal reflux disease as trigger for, 452, 495 genes associated with, 425t genetic factors, 425–427 glucocorticoid-resistant, 477 good/poor responders to treatment for, 891–892 heritability of, 424 heterogeneous presentation of, 427–428 in high-risk patients, 482 IgE-mediated bronchoconstriction in, 424 immunotherapy, 470 1921
indoor allergens and, 426 in infants and toddlers allergy, 496–497 anticholinergics for, 501 β-agonists for, 501 corticosteroids, 502–503 cromolyn sodium, 502t epidemiology of, 494 immunotherapy for, 503 leukotriene antagonists, 501–502 natural history of, 494–495 passive smoke inhalation, 495–496 prednisone, 502t treatment of, 501–503, 502t triggers, 495 viral infections, 496 intractable, 475–477 during labor and delivery, 807 laboratory tests, 440–441 linear growth retardation caused by, 443 long-acting β-adrenergic agonist, 503 lung volumes, 176 maintenance drugs for, 764t malignant, potentially fatal, 443 management principles for, 483 manifestations of, 438–439 mortality from, 443, 482 mucus hypersecretion in, 432–433 1922
Mycoplasma pneumoniae infections and, 471 myocardial contraction band necrosis in, 435 National Asthma Education and Prevention Program, 171, 428, 445t neuroimmunologic abnormalities in, 428 nitric oxide in, 428 nonallergic, 447–448, 471 nonantigenic precipitating stimuli, 452–453 obstructive sleep apnea effects on, 850–851 obstructive ventilatory defects in, 171 occupational, 408, 429, 449–450 onset of, 429 pathologic findings, 425–426 pathophysiology of, 432–435 peak expiratory flow rate in, 440 persistent, 473–475, 806–807 physical examination findings, 156, 438–439 physiologic characteristics of, 427–428 pollen exposure and, 95 postmarketing trials, 523–524 potentially (near) fatal, 443, 448, 472–473 predisposing factors, 426 in pregnancy, 799–800 allergen immunotherapy for, 804–805 avoidance measures for, 802 choice of therapy, 802–805 classification of, 806t corticosteroids for, 803 medications for, 802–804 1923
persistent, 806–807 prednisone for, 803 treatment of, 802t prevalence of, 428–430 psychological factors, 443–444 pulmonary function tests for, 440 pulmonary parenchyma findings, 435f quality of life measurements, 527 radiographic imaging of, 439–442, 439f ragweed, 96 refractory, 475–477 signs and symptoms of, 438–439 single nucleotide polymorphisms associated with, 425 smoking cessation, 473 sputum, 438, 441 steroid-resistant, steroid-dependent, 756 sudden asphyxic, 433 surgery in patients with, 480–481 therapy, practical considerations, 468 thunderstorm, 96 treatment of albuterol, 459, 460t, 502t, 511–512 anticholinergic agents, 464 β-agonists, 738–739 b2-adrenergic receptor agonists, 459–464 b2-adrenergic receptor antagonists, 459–464, 460t, 461f, 481 biosynthesis inhibitors, 465 complications of, 481–482 1924
corticosteroids, 455–459, 471, 474–475, 474t, 479, 502–503, 511t, 752–753 cromolyn, 468, 474–475, 804 dry-powder inhaler, 463 ephedrine, 462 epinephrine, 462 formoterol, 460t, 462–463 goals for, 454t leukotriene antagonists, 465 levalbuterol, 460t, 461, 738 nedocromil, 468 omalizumab, 476 prednisone, 456 principles of, 455 salmeterol, 460t, 462 theophylline, 467 tips for, 456t triamcinolone, 475 triggers for, 424, 452, 495 variant, 451 vocal cord dysfunction and, 451–452, 509 Asthma Predictive Index, 494, 495t Ataxia telangiectasia, 47t Atelectasis, 439, 481 Atomizer, 785 Atopic condition description of, 21 IgE’s role in, 21–22 Atopic dermatitis 1925
aeroallergens, role of, 670 calcineurin inhibitors for, 671 cataract formation in, 647 conjunctivitis associated with, 646 corticosteroids for, 670t, 671–672, 758–759 definition of, 665 diagnosis of, 666, 667t differential diagnosis, 667t dupilumab, 671 eczema coxsackium, 671 eczema herpeticum in, 671 eczema vaccinatum in, 671 epidemiology of, 665–666 food allergies in, 402t, 669–670 IgE concentrations in, 22, 162 immunosuppressants for, 672 infections in, 670–671 itching caused by, 668–669 natural history of, 665–666 ocular involvement, 640, 642 ocular manifestations of, 640–642, 647–648 onset of, 676 pathogenesis of, 666 phosphodiesterase 4 inhibitor, 671 phototherapy for, 672 physical examination findings, 156 severity, evaluation of, 667 skin care for, 668 1926
sleep management in, 668–669 systemic treatments for, 671–672 therapy on horizon, 671 topical corticosteroids for, 668 topical therapies calcineurin inhibitors, 671 corticosteroid, 668, 670t dupilumab, 671 phosphodiesterase 4 inhibitor, 671 systemic treatments for, 671–672 therapy on horizon, 671 wet-wrap therapy, 671 treatment of, 667 wet-wrap therapy, 671 Atopic keratoconjunctivitis, 648 Atopic reactions, 85 Atopic sensitization, 496–497 Atopy, 253, 317, 426 Atopy patch test, 412, 868 Atracurium, 515 Atrophic rhinitis, 608, 631 treatment for, 633 Atropine, 769 Auto positive end-expiratory pressure, 508 Autoimmune diseases, drug-induced, 323 Autoimmune lymphoproliferative syndrome, 53 Autoimmunity, drug-induced, 322–324 Autologous serum skin test, 692 1927
Azelastine, 613, 632, 644t Azithromycin, 370 Aztreonam, 360 B B cells antigen recognition, adaptive immunity, 8–10 IgE production from, 18, 602 subsets, adaptive immunity, 10 Babesia spp., 68 Bacille-Calmette-Guérin vaccine, 56 Bacitracin, 682 Bacterial conjunctivitis, acute, 650, 653t Baker’s asthma, 408 BALF T cells, 555 Balsam of Peru, 680 Barbiturates, 269 Basal lamella, 180 Basophil activation test (BAT), 868 Basophils activation of, 28–30 in anaphylaxis, 257–258 characteristics of, 26 cytokine response by, 28 FcepsilonR1 receptors, 28 ILC2, role in, 30 kallikrein activation, 257 Bayberry trees, 100 Beclomethasone, 758t 1928
Beclomethasone dipropionate, 773, 806 Bee stings, 266, 287. See also Insect stings Beech trees, 99 Behavioral psychotherapy, 861 Benzocaine, 681 Benzodiazepines, 860 Benzophenones, 682 Benzylpenicillin, 360 Bermuda grass, 102 Bet v 1, 109 Bet v 2, 107 Bet v 3, 109 Bet v 4, 107, 109 β-adrenergic agonists adverse effects of, 861 asthma treated with, 459–464, 460t, 461f, 481, 805 epinephrine and, 262 mortality risks, 482 β-agonists adverse effects of, 739 asthma treated with, 738–739 bronchospasm caused by, 739 description of, 501 historical perception of, 735 inhaled corticosteroids and, 738 long-acting, 738 mechanism of action, 736–737 pharmacology of, 736–737 1929
and safety, 739–741 short-acting, 737–738 single inhaler therapy, 741 summary of, 741 β-imidazolylethylamine. See Histamine β-lactam antibiotics allergy to background on, 356–360 diagnostic testing for, 360–363 evaluation of, 357t management of, 363–366 prevalence of, 358 skin testing, 360–363, 362t specific reactions, 359 test dosing for, 363t anaphylaxis caused by, 321 cross-reactivity among, 360 desensitization to, 346, 363–364, 365–366t reaction with proteins, 313 serum sickness caused by, 321 β2 adrenergic agonists description of, 511–512 β2-adrenergic receptor, 736f β2-agonists, inhaled corticosteroids and, 753 β2-microglobulin, 6 Betaxolol, 469 Biologic agents, 395–397 Biophysical information therapy, 882 1930
Bioresonance, 882 Biphasic anaphylaxis, 414 Bipolar disorder, 855 Birch trees, 99, 99f Bitter taste receptors (TAS2Rs), 795 Black dermatographism, 683 Black rubber PPD, 684 Blepharoconjunctivitis, 648–649, 653t Blood products allergy, 321, 393–394 Blood transfusion anaphylaxis, 270 Bluegrass, 101f Bone marrow aplasia, 370 eosinophil production in, 64 Bradykinin, 379, 437t, 692–693 Breastfeeding, allergy and, 884 Breath-actuated metered-dose inhalers, 780–781 Broadband or narrowband ultraviolet light B (UVB) therapy, 713–714 Bronchi, 427–428 Bronchial thermoplasty, 470, 477 Bronchial wall, 431 Bronchiectasis, 575, 836–837 Bronchoalveolar lavage fluid analysis description of, 170 in eosinophilic pneumonia, 177 in hypersensitivity pneumonitis, 177, 550–551 T cells, 554 Bronchocentric granulomatosis, 220t, 221 1931
Bronchoconstriction exercise-induced, 450 IgE-mediated, 424 Bronchodilators, 515 Bronchoprovocation testing, 174, 450 Bronchopulmonary aspergillosis, allergic age of onset, 575 antifungal agents for, 578 Aspergillus spp., 113, 561–563 B cell analysis in, 571 bronchiectasis in, 572, 575 bronchoalveolar lavage analysis in, 574 bronchocentric granulomatosis associated with, 221 bronchogram of, 566f characteristics of, 561 clinical features of, 563–564 computed tomography of, 219–220t, 221, 567–568, 567f, 572f corticosteroids for, 576–577, 577t in cystic fibrosis patients, 579 diagnosis of, criteria for, 563–564, 577t differential diagnosis, 575 epidemiology of, 561 IgA-A. fumigatus antibodies in, 575 IgE concentrations in, 22, 570–571 imaging of, 565–568, 565–568f immune complexes in, 571 itraconazole for, 577–578 laboratory tests, 568–572 1932
lung biopsy in, 572 natural history of, 575–576 pathogenesis of, 573–575, 573f peripheral blood eosinophilia in, 574 physical examination for, 564–565 prednisone for, 564, 576–577, 577t prognosis for, 575–576 radiographs of, 565–568, 565f seasonal onset of, 575 staging of, 568 T cell analysis in, 571 treatment of, 576–579 Bronchospasm β-agonists, 739 drug-induced, 331 paradoxic, 739 Bruton agammaglobulinemia, 49t Bryan test, 876–877 Buckwheat, 105 Budesonide, 456, 463, 468, 502t, 758t, 824 Budesonide-formoterol, 460t, 741, 806 Budesonide suspension, 824 Bumblebee stings, 287 Burweed marsh elder, 104, 104f C C-type lectin receptors, 3 C-X-C chemokines, 36 C1-INH, 696–697 1933
Caine mix, 681 Calcineurin inhibitors, 671 Calcitonin gene-related peptide, 29 Caldwell-Luc procedure, 180 California, 149t Candida albicans, 112, 875 Candida hypersensitivity syndrome, 875–876, 883 Capsaicin nasal spray, 615 Carbacephems, 360 Carbapenems, 360 Carbohydrate determinants, 94 Carbon dioxide (CO2), intranasal, 616 Carboplatin, 320, 380 Carcinoid syndrome, 261 Cardiac asthma, 509 Cartilage-hair hypoplasia, 47t Cat allergens, 120, 446, 470 Cataracts, 648 Catastrophizing distortion, 862t Catechol O-methyltransferase, 736 Cavernous sinus thrombosis, 628–629 CD 23, 17 CD 3, 395 CD 40, 395 CD 69, 54 CD4+ cells, 19 CD40L, 53, 395 CD8 T cells, 7 1934
CD8+ T cells, 554, 625 Cedar trees, 97–98 Ceftazidime, 360 Celiac disease, 410 Cell-mediated immunity, 48 Cellular immunodeficiency testing, 870–871 Centrilobular nodules, 221 Cephalosporins allergy to, 359 penicillins and, 360 tolerance to, 360 Cephalothin, 335 Cerebrospinal fluid (CSF) fistula, 188 leakage of, 188 rhinorrhea, 606, 632 Cetirizine, 724t, 725, 726t CH50, 53 Charcot-Leydon crystals, 441 Chartarum. See Stachybotrys atra Chédiak-Higashi syndrome, 47t Chemoattractant cytokine receptor 3, 65 Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2). See Prostaglandin D2 receptor Chemokines, 36 inhibitors of, 794 innate immunity, 2 Chemotactic mediators, 36
1935
Chemotaxis, 54 Chemotherapy agents anaphylaxis to, 264, 320, 380 pulmonary reactions caused by, 332 Chenopodiaceae, 105 Chest pain, 480 Chest radiographs asthma, 439, 439f, 510 description of, 165 hypersensitivity pneumonitis, 549 Children allergic rhinitis in, 601–602 asthma in, 445 allergy, 496–497 anticholinergics for, 501 β-agonists for, 501 corticosteroids, 502–503 cromolyn sodium, 502t epidemiology of, 494 immunotherapy for, 503 leukotriene antagonists, 501–502 natural history of, 494–495 passive smoke inhalation, 495–496 prednisone, 502t treatment of, 501–503, 502t triggers, 495 viral infections, 496 cough in, 838–842 1936
cow’s milk allergy in, 404, 415, 599 drug allergies in, 315 metered-dose inhalers in, 780 Chlamydial (inclusion) conjunctivitis, 650 Chloramphenicol, 370 Chlorpheniramine, 724t Cholestasis, drug-induced, 336 Cholestatic pruritus, 714, 715t Cholestyramine, 713 Cholinergic urticaria, 695–696 Chondroitin sulfates, 37 Chromium, 683 Chromones, asthma and, 467–468 Chronic obstructive pulmonary disease (COPD), 424, 452 Chronic rhinosinusitis abnormalities associated with, 196–203 allergic fungal sinusitis and, 231 allergic rhinitis and, 229–231 anatomic influences, 228–229 asthma and, 237, 453 classification of, 232 computed tomography of, 195–196, 234 definition of, 228 diagnosis of, 232–234, 232t environmental factors, 228 functional endoscopic sinus surgery for, 234–237, 630 imaging findings, 195–196 immune deficiencies and, 231 1937
incidence of, 226 infection and, 229 innate immunity and, 232 magnetic resonance imaging of, 195, 234 mucocele associated with, 197–201, 200f mucus retention cysts associated with, 196–197, 199f nasal polyps and, 231, 234 odontogenic rhinosinusitis, 202 pathophysiology of, 228–232 radiologic diagnosis of, 234 rhinoscopic diagnosis of, 229f, 233–234 silent sinus syndrome associated with, 201–202, 201f sinonasal polyps associated with, 196–197 summary of, 237 superantigens, 232 treatment of, 629–630 Churg-Strauss syndrome, antileukotrienes and, 768 Chymase, 37, 257 Ciclesonide, 611 Ciliary disorders, 607 Cimetidine, 723f, 731 Circadian rhythms, 846 Cis-repression, 748 Cisplatin, 320, 380 Cladosporium spp., 112, 112f Clara cells, 430 Clarithromycin, 370 Class switch recombination, 19 1938
Clindamycin, 370 Clinical ecology practitioners, 875 Clinoid pneumatization, 188 Clopidogrel, 382 Clostridium difficile, 311 Clothing-related dermatitis, 684 Clusters of differentiation, 879 Coagulation cascade, 28 Cobalt, 683 Cobblestoning, 156 Cocaine, 70 Cocamidopropyl betaine, 682 Coccidioidomycosis, 69 Cocklebur, 103, 104 Cockroach allergens, 86, 121, 123–124t, 158, 240, 496, 595 Codeine allergy, 380 Cognitive and behavioral theories and therapies, 861–862 Cognitive psychotherapy, 861–862 Coincidental reaction, 310 Cold urticaria, 694t, 696 Colophony, 682 Combinedimmunodeficiency testing, 870–871 Complement deficiency testing, 871 Complementary and alternative medicine, 874 Complementary and alternative testing, 868, 868t Complete blood count with differential, 51 Component-resolved diagnostics, 867 Compositae, 684–685 1939
Computed tomography acute eosinophilic pneumonia, 220t allergic bronchopulmonary aspergillosis, 221, 567–568, 567f, 572f asthma, 219–220t bronchocentric granulomatosis, 220t chronic eosinophilic pneumonia, 219–220t chronic rhinosinusitis, 234 cisternogram, 190 contrast-enhanced, 217 eosinophilic pneumonia, 219–220t granulomatosis with polyangiitis, 219–220t Haller cell, 186f helical, 193 high resolution allergic bronchopulmonary aspergillosis imaging using, 567, 567f description of, 217 hypereosinophilic syndrome, 220t hypersensitivity pneumonitis, 219t, 549 IgG4-Related Disease, 224 lung anatomy, 218 magnetic resonance imaging vs., 194 mucocele findings, 198 multi-detector, 217 nasal cavity imaged using, 182f nasoseptal deviation, 185f rhinosinusitis, 194f, 628, 628f sinonasal polyposis, 203 sinus imaging using, 181f, 194 1940
Wegener granulomatosis, 219–220t Concha bullosa, 185, 185f Conjunctivitis acute allergic, 642–645, 644t, 653t acute bacterial, 650, 653t allergic, 642–645, 644t blepharoconjunctivitis, 648–649, 653t chlamydial, 650 conjunctivitis, 651 description of, 155 giant papillary, 647, 650–651 infectious, 649–650 keratoconjunctivitis sicca, 650 perennial, 651 vasomotor, 651 vernal, 645–647, 653t viral, 649, 653t Connective tissue-type mast cells, 26, 28t Consolidation, 218 Contact dermatitis allergic, 325–326, 677–678, 684, 758–759 causes of allergens, 676–677, 679t clothing, 684 cosmetics, 680–682 food allergy, 407 identifying of, 676–685 irritants, 676 1941
medications, 682–684 photoallergy, 679 photoreactions, 685 plants, 684–685 plastics, 684 poison ivy, 677 skin care products, 680–682 clinical features of, 675–676 complications of, 685 corticosteroid for, 686 differential diagnosis, 676 eczematous lesions, 674 eyelid, 638–640 histopathology of, 675 history, 675 management of, 685, 686t patch testing, 677–680 photopatch testing, 679 physical examination for, 675–676 prophylaxis, 686 sensitization, 674–675 stages of, 675 symptomatic treatment of, 685–686 systemic, 674 Contact urticaria (CU), 676 Continuous positive airway pressure (CPAP), 850, 850t Contrast agents allergy to, 376–377 1942
anaphylaxis caused by, 253 computed tomography enhanced with, 217 Controversial methods, definition of, 874 Coombs test, 335 Corticosteroids, 610. See also Glucocorticoid(s); specific drug allergic bronchopulmonary aspergillosis treated with, 577–578, 577t allergic contact dermatitis caused by, 325–326, 758–759 allergic reactions to, 752 allergic rhinitis treated with, 610–612 anti-inflammatory effects of, 474t asthma treated with, 455–459, 471, 474–475, 474t, 479, 891t acute exacerbations, 755–756 acute severe, 502–503, 511t, 512 during pregnancy, 803 atopic dermatitis treated with, 668, 670t, 671–672, 758–759 b2-adrenergic agonist with, 459 bone mineral metabolism affected by, 458 contact dermatitis treated with, 686, 759 description of, 38 discovery of, 745 eosinophilic esophagitis treated with, 823–825 fractional exhaled nitric oxide affected by, 164, 174 growth retardation caused by, 443 history of, 745 hypereosinophilic syndromes treated with, 72–73, 556 hypersensitivity myocarditis treated with, 338 hypothalamic-pituitary-adrenal suppression by, 443 inhaled 1943
asthma treated with, 512, 526, 752–753 β-agonists and, 738 b2-agonists and, 753 clinical use of, 753–754 delivery devices for, 754, 755t description of, 456 dose-response for, 754–755 history of, 745 metered-dose inhaler delivery of, 780 preparations, 753 intranasal, 610–612, 625 intravenous, 458 mechanism of action, 455 nasal polypsis treated with, 625, 757–758 neuropsychiatric side effects of, 861 ocular allergies treated with, 759 oral, 458 otitis media with effusion treated with, 659 parenteral, 455–456 pharmacologic variables and, 746t physiology and pharmacology of, 745–748 side effects of, 458–459 skin testing affected by, 162 sparing drugs, 756 Stevens-Johnson syndrome treated with, 328, 343 systemic, 612–615, 825 topical, 668, 670t, 682, 713, 823–825 urticaria treated with, 703 1944
withdrawal model, 526 Corticotropin-releasing factor, 746 Corticotropin-releasing hormone receptor 1 gene (CRHR1), 891 Cortisol, 746 Cosmetics, 680–682 Costochondritis, 481 Cough angiotensin-converting enzyme inhibitor-induced, 331, 469, 837 aspiration and, 837 asthma-related, 438, 835–836 -associated cyanosis, 443 bronchiectasis and, 836–837 characterization of, 838–840 in children, 838–842 description of, 834 differential diagnosis, 453–454, 835t dry, 841–842 gastroesophageal reflux, 836 infection and, 837 interstitial lung disease and, 837 lung tumors and, 837 management of, 838, 839f nonasthmatic eosinophilic bronchitis and, 836 nonspecific, 841 pediatric, 838–842 primary pulmonary disease and, 836 psychogenic, 837–838 treatment of, 842 1945
upper airway cough syndrome, 834–835 use of algorithms in evaluation of, 841 wet, 841 Coumarin, 330 Cow’s milk allergy, 404, 415, 599 Coxsackie virus, 671 Cribriform plate, 180, 188, 227 Crisaborole, 671 Cromolyn asthma treated with, 468, 474–475, 502t, 804 challenge studies for, 764 characteristics of, 765t dosing of, 767 efficacy of, 767 eosinophilic esophagitis treated with, 825 exercise-induced bronchoconstriction treated with, 451 intranasal, 614–615 mechanism of action, 764–767 pharmacology of, 764 vernal conjunctivitis treated with, 645 Cross-sensitization, 317 Croup, 426 Cryoprecipitate, 270 Cryptogenic organizing pneumonia, 218 Cryptomeria japonica, 109 Culturing, of allergens, 90–91 Cutaneous mastocytosis, 695 Cyclic adenosine monophosphate (cAMP), 736 1946
Cyclooxygenase-1, 372, 374t Cyclooxygenase, 33 Cypress trees, 97–98 Cyproheptadine, 696 Cysteine proteases, 95 Cysteinyl leukotrienes, 34 Cystitis, eosinophilic, 77 CystLTR, 34 Cystoscope, 226 Cytokines basophil response to, 28 circadian cycling of, 847, 847t eosinophil release of, 65 in hypersensitivity pneumonitis, 554 innate immunity, 2 mast cell production of, 38 production of, 29 Cytotoxic cells, 7 Cytotoxic test, 876–877 D D-penicillamine, 323 Dander, 86, 119, 158, 239, 588 Darier sign, 699 Degranulation, 4 Delayed reactions, 358 Delayed-type hypersensitivity description of, 23 Dendritic cells, 722, 791, 794 1947
Depression, 475, 854–856, 854t distortion, 862t Der p 1, 95 Dermatitis allergic contact. See Contact dermatitis, allergic atopic. See Atopic dermatitis clothing-related, 684 contact. See Contact dermatitis exfoliative, 328 herpetiformis, 410 psoriatic, 676 Dermatoconjunctivitis, 638–640 Dermatographism, 163 black, 683 Dermatophagoides spp., 115, 158 Dermographism, 694–695, 694t Desensitization administration routes for, 364, 365–366t β-lactam antibiotics, 346, 363–364, 365–366t description of, 341, 345–346, 355 enzyme-potentiated, 881 immune sera, 394–395 insulin, 391–393, 392t intravenous, 365t oral, 366t penicillin, 363–364, 365–366t trimethoprim-sulfamethoxazole, 367 Desloratadine, 724t, 725, 726t 1948
Determinant, epsilon, 15 Detoxification, 881 Deuteromycetes, 110, 112 Dexamethasone, 502t, 746t Diacylglycerol lipase, 33 Dicotyledons, 97 Diesel exhaust particles, 125 Diet diaries, 411 Diets, 882 Diffusing capacity, for carbon monoxide in asthma, 440 description of, 175, 333 DiGeorge syndrome dentofacial abnormalities in, 47t gene defects in, 50t physical findings associated with, 46, 47t, 51 Digoxin, 396 Diphenhydramine, 723f, 724t, 726t Dishpan hands, 676 Diskus, 782f Disulfiram, 684 DNA sequencing, 56 Dog allergens, 120 Double-blind placebo-controlled food challenge, 412–413 Doxepin, 724t DPI inhalers, concurrent use of, 784–785 Drug(s) administration of, 344 1949
adverse reactions. See Adverse drug reactions anaphylaxis caused by, 253–255, 264, 268, 319–320 animal testing of, 521 chronic liver disease caused by, 337 contact dermatitis caused by, 682–684 cross-sensitization, 317 desensitization to, 341, 345–346, 355 development of, 520–523, 521f eosinophilia caused by, 69–70 eruptions, 324, 326 fever, 322 as immunogens, 313–314 immunologic response to, 314 indirect effects of, 311 lung disease caused by, 223–224 overdosage of, 310 pharmacodynamics testing, 521 provocation tests, 355–356 pruritus caused by, 710t rash with eosinophilia and systemic symptoms, 325, 338, 380–381 reintroduction of, to drug allergy patients, 344–346 rhinitis caused by, 605–606, 631, 632t secondary effects of, 311 side effects of, 311 Stevens-Johnson syndrome caused by, 300–305 systemic lupus erythematosus induced by, 322–323 test dosing of, 346, 355 tolerance, 355–356 1950
urticaria caused by, 325, 701 withdrawal of, 342 Drug allergy. See also Adverse drug reactions; specific reaction acetaminophen, 374 administration methods and, 344 age of patient and, 315 agranulocytosis, 335 angiotensin-converting enzyme inhibitors, 379 angiotensin II receptor antagonists, 379 anticonvulsants, 380–381 antifungal agents, 370–371 antiplatelet therapies, 382 antituberculous agents, 371 antiviral agents, 371 aspirin, 372–374 biologic agents, 395–397 blood products, 393–394 bronchial asthma caused by, 331 cardiac manifestations of, 338 chemotherapeutic agents, 264, 320, 380 in children, 315 classification of, 319–338, 319t concurrent medical illness and, 317–319 cutaneous manifestations of, 324–331 dermatologic manifestations of acute generalized exanthematous pustulosis, 327 allergic contact dermatitis, 325–326 angioedema, 325 1951
erythema multiforme-like eruptions, 327–328 erythema nodosum, 330–331 exanthematous/morbilliform eruptions, 324–325 fixed drug eruptions, 326–327 generalized exfoliative dermatitis, 328 photosensitivity, 328–329, 329t purpuric eruptions, 329–330 toxic epidermal necrolysis, 330 urticaria, 325 drug fever, 322 eosinophilia, 69, 332 epidemiology of, 308–310 evaluative approach to history-taking, 338–340 IgE antibody testing, 341–342 patch tests, 340 provocative testing, 340–341 radioallergosorbent test, 341 in vitro testing, 341–342 in vivo testing, 340–341 wheal-and-flare skin tests, 340, 344 familial, 317 fibrotic reactions, 332–333 genetic factors, 315–317 hematologic manifestations of, 333–335 hemolytic anemia, 334–335 hepatic manifestations of, 335–337 histamine2 receptor antagonists, 382 1952
human recombinant proteins, 391, 396–397 hypersensitivity vasculitis caused by, 323–324 immune sera therapy, 394–395 immunochemical basis of, 313–314 immunopathology of, 314, 315t incidence of, 309 influenza vaccine, 398 insulin, 391–393, 392t latex, 267–268, 321, 393 local anesthetics, 377–378, 378t lymphoid system manifestations of, 337–338 measles, mumps, rubella vaccine, 398 monoclonal antibodies, 396 multiple antibiotic sensitivity syndrome, 372 multisystem involvement, 319–322 muscle relaxants, 381–382 neurologic manifestations of, 338 noncardiogenic pulmonary edema caused by, 333 opiates, 379–380 patient-related factors associated with, 315–319 pertussis and rubella vaccine, 398 pneumonitis caused by, 332–333 prior history of, 317 proton pump inhibitors, 382 pulmonary infiltrates with eosinophilia caused by, 332 pulmonary manifestations of, 331–333 radiographic contrast media, 376–377 reintroduction of drugs to patients after, 344–346 1953
renal manifestations of, 337 risk factors for, 315–319, 316t serum sickness reactions, 321–322 streptokinase, 393 tetanus toxoid vaccine, 397–398 thrombocytopenia, 334 thrombolytics, 393 vaccines, 397–399 withdrawal of drug, 342 yellow fever vaccine, 398 Drug-drug interactions, 311 Drug hypersensitivity evaluations history-taking, 338–340 IgE antibody testing, 341 patch tests, 340 provocative testing, 340–341 radioallergosorbent test, 341 in vitro testing, 341–342 in vivo testing, 340–341 wheal-and-flare skin tests, 340, 344 Drug reactions, adverse allergic drug reactions, 309, 312, 313t classification of, 310–313, 310t definition of, 308 discovery of, 309 drug-drug interactions, 311 idiosyncratic, 312 incidence of, 308 1954
indirect effects, 311 information resources, 309 intolerance, 312 overdosage, 310 predictable, 310, 310t pseudoallergic reactions, 312–313 reporting of, 309t secondary effects, 311 side effects, 311 unpredictable, 310, 310t Drug reactions, allergic classification of, 319–338 description of, 309, 312, 313t, 315 drugs that frequently cause, 339t follow-up after, 344 patient considerations, 343 prevention of, 343–344 screening tests for, 343–344 treatment of, 342–343 Dry cough, 841–842 Dry-powder inhalers, 463, 781–783 Dupilumab, 671 Dust mites allergen testing, 243 avoidance of, 503 description of, 115–119, 239–240, 240t Dyskinetic cilia syndrome, 607 Dyspnea 1955
in asthma, 436t, 438 differential diagnosis, 453–454 in pregnancy, 806 wheezing, 424 E Ear eustachian tube of, 654–656 otitis media with effusion. See Otitis media, with effusion Ebastine, 726t Eczema coxsackium, 671 Eczema herpeticum, 671 Eczema vaccinatum, 671 Egg allergies, 404, 414 EGPA, characteristics of, 74–75 Eicosanoids, 258 Electrodermal diagnosis, 877 Elemental diet, 827 Elm trees, 99 Emedastine, 644t Emotional reasoning distortion, 862t Emphysema, 481 Empiric elimination diet, 827–828 Empty airways asthma, 433 Empty nose syndrome, 192, 193f Encephalocele, 191f, 607 Endocrine pruritus, 716 Endotypes, 791, 792–793t, 892–893 Enteroviral meningoencephalitis, 48 1956
Entomophilous plants, 96 Environmental chemical avoidance, 882–883 Enzyme-linked immunosorbent assay, 85 Enzyme-potentiated desensitization, 881 Eosinophil(s) activation of, 66 in allergic rhinitis, 603 in asthma, 427, 430 in blood, 64 chemoattractants, 65 chemotactic factors, 36 cytokines released by, 65 development of, 64–66 discovery of, 64 half-life of, 64 immune response modulation by, 66 mediators released by, 66 morphology of, 64–66 progenitor cells of, 65 staining of, 64 in tissues, 64 Eosinophil cationic protein, 66, 428 Eosinophil chemotactic factor, 437t Eosinophil count, 64 Eosinophil peroxidase, 66 Eosinophilia in asthma, 441 definition of, 64 1957
diagnostic algorithm for, 78f differential diagnosis, 66–79, 67–68t drug-induced, 70, 334 drug rash with eosinophilia and systemic symptoms, 325, 338, 380–381 EGPA as cause of, 74 evaluation of, 77–79 helminthic diseases, 67t, 68 hypereosinophilic syndrome, 64, 70–74 IgG4 related diseases, 77 laboratory tests, 79 Löffler syndrome, 76 pathogenesis of, 66–68 primary causes of, 66 pulmonary infiltrates with, 332 secondary causes of, 66 simple pulmonary, 221, 222f sputum, 526 tropical pulmonary, 76 Eosinophilia-myalgia syndrome, 70 Eosinophilic bronchitis, nonasthmatic, 836 Eosinophilic cystitis, 77 Eosinophilic esophagitis aeroallergens and, 821 allergens associated with, 819–822 clinical features of, 816–818 demographics of, 815 diagnosis of, 817 endoscopic findings, 816, 817f 1958
epidemiology of, 815 esophageal dilation for, 828–829, 828f food allergies that cause, 820 functional luminal impedance planimetry, 818 gender predilection of, 815 histologic features of, 816, 818f intraesophageal pH testing for, 818 manometry evaluations, 818 pathogenesis of, 818–822 proton pump inhibitor-responsive esophageal eosinophilia, 817–818 radiographic studies of, 818 summary of, 829–830 treatment of algorithm for, 829, 829f biologic therapy, 826–827 corticosteroids, 823–825 cromolyn sodium, 825 dietary, 827–828 immunomodulators, 825–826 infliximab, 826 mepolizumab, 826 montelukast, 825 omalizumab, 826 overview of, 822 proton pump inhibitors, 823 summary of, 829–830 systemic corticosteroids, 825 Eosinophilic gastroenteritis, allergic, 407 1959
Eosinophilic gastroenteropathies, allergic, 407 Eosinophilic granulomatosis, with polyangiitis, 74–75 Eosinophilic leukemia, 71 Eosinophilic pneumonia acute, 221–222, 222f computed tomography findings, 220t description of, 76, 176–177, 221–223 idiopathic, 176–177 bronchoalveolar lavage fluid analysis in, 177 characteristics of, 75–77 chronic, 221–222, 223f computed tomography findings, 219–220t description of, 76, 176–177, 221–223, 223f idiopathic, 176–177 computed tomography findings, 219–220t drug-induced, 220t idiopathic acute, 176–177 idiopathic chronic, 176–177 microscopic appearance of, 573f pulmonary function testing in, 176–177 Eotaxins, 65 Ephedrine, 462, 735 Epicoccum nigrum, 113f Epicutaneous test, 159 Epidemic keratoconjunctivitis, 649 Epinastine, 644t Epinephrine anaphylaxis treated with, 274–277, 275t 1960
asthma treated with, 462, 511t side effects of, 462 Epithelial allergens, 119–121 Epithelial cells and, innate immunity, 3 Epsilon determinants, 15 Erythema multiforme, 300–305, 301f, 327–328 minor, 327–328 Erythema nodosum, 330–331 Esophageal dilation, 828–829, 828f Esophageal manometry, 818 Esthesioneuroblastoma, 208 Ethmoid air cells anatomy of, 180, 181f, 184, 188 anterior, 227 Ethmoid sinus embryologic development of, 226 posterior, 227 Ethmoidal artery, anterior, 188 Ethmoiditis, acute, 628 Ethylenediamines, 326, 682 Ethylenediaminetetraacetate, 639 Eustachian tube, 654–656 Exanthematous eruption, 324–325 Exanthematous pustulosis, acute generalized, 327 Exfoliative dermatitis, 328 Exfoliative dermatitis, generalized, 328 Experimental procedures, definition of, 874 Extrathoracic obstruction, variable, 172 1961
Eye diseases anatomy, 638f approach to, 651–652 blepharoconjunctivitis, 648–649, 653t conjunctivitis. See Conjunctivitis contact dermatitis, 638–640 corticosteroids for, 759 dermatoconjunctivitis, 638–640 description of, 638 evaluative approach to, 653t herpes zoster, 650 rosacea, 649 topical agents for, 644t Eyelids atopic dermatitis of, 640, 642 contact dermatitis of, 638–640 dermatoconjunctivitis of, 638–640 seborrheic dermatitis of, 649 staphylococcal blepharoconjunctivitis, 648–649 F Factitious asthma, 444, 451 Factor VIII concentrate, 270 Familial drug allergy, 317 Famotidine, 731 FceR1 receptors basophils, 28 composition of, 29 description of, 17 1962
Fcτ-Fcε protein, 29, 257 Fel d 1, 119 Fel d 2, 97 Fel d 3, 119 Fel d 4, 119 Fenoterol, 460t, 735, 740 Fescue, 102 Fetus oxygenation for, 801 in utero exposure to smoking, 495 Fexofenadine, 724t, 726t Fibrosis, 218, 332–333 Fibrosis transmembrane regulator, cystic, 570 FIP1-like 1 gene, 70 Fir trees, 97 Fire ant stings, 287–288, 289f First-generation agents pharmacodynamics, 723, 725 pharmacokinetics, 723 pharmacy, 725, 728t structure, 722 Fish allergies, 405 Fixed drug eruptions, 326–327 FLAP (5-5-lipoxygenase-activing protein), 34 Flexhaler (AstraZeneca), 782 Floppy eye syndrome, 651 Flow cytometry, 52 Flow-volume curve, 172, 173f 1963
Flower, 97 Flunisolide, 758t, 779f Fluorescence in situ hybridization, 56 Fluoroenzyme-immunoassay, 163 Fluoroquinolones, 370 Fluticasone, 758t, 823, 824 Fluticasone/salmeterol, 460t, 502t, 806 Folic acid, supplemental, 884 Food allergies airway hyperresponsiveness induced by, 408 allergens allergic rhinitis caused by, 599 description of, 403–406 anaphylaxis secondary to, 254, 262, 266–267, 408–409, 447 asthma and, 402t, 408 atopic dermatitis caused by, 669–670 cow’s milk, 404, 415, 599 cutaneous manifestations of, 407 diagnosis of, 410–413 differential diagnosis, 401t eggs, 404, 414 elimination diets for diagnosing, 411 eosinophilic esophagitis caused by, 818–822 epidemiology of, 401–402 fish, 405 gastrointestinal manifestations of, 407 hen’s egg, 404, 414 IgE-mediated food reactions, 407–409 1964
IgE testing, 163 natural history of, 415 non-IgE-mediated food reactions, 409–410 oral tolerance induction, 403 pathogenesis-related proteins, 406, 406t pathophysiology of, 402–403 patient education about, 413–414 peanuts, 266–267, 404, 415, 881 pollen-food syndrome, 409 prevention of, 414–415 respiratory manifestations of, 407–408 shellfish, 254, 266, 406 skin tests, 160–161 soybean, 405 treatment of, 413–414 tree nut, 405 urticaria caused by, 407, 700–701, 700t wheat, 405 Food and Drug Administration (FDA), 889 Food dependent exercise-induced anaphylaxis, 271, 409 Food extracts, injection of, 881 Food immune complex assay, 879 Food-induced anaphylaxis, 254, 262, 266–267, 408–409 Food protein-induced enterocolitis syndrome, 409–410 Food protein-induced proctocolitis, 410 Forced expiratory flow between 25% and 75% of the FVC, 170 Forced expiratory volume in 1 second, 170, 173, 432, 495 Forced expiratory volume in 6 second, 170 1965
Forced spirometry in asthma, 171–173 components of, 170–171 Forced vital capacity, 170, 172f, 438 Foreign body airway obstruction caused by, 509 rhinitis vs., 606 Formaldehyde, 125, 589 -releasing preservatives, 680 resin, 681–682 Formication, 710 Formoterol, 460t, 462–463, 511, 735t, 737, 806 Fortune-telling error distortion, 862t Fractional exhaled nitric oxide, 164, 174 Fragrance, 680 Fraud, definition of, 874 Frontal sinus anatomy of, 180, 181f embryologic development of, 226 outflow tract of, 184 Frontal sinusitis, 628 Frontoethmoidal recess, 181f, 184 Functional endoscopic sinus surgery (FESS) in aspirin triad patients, 626 cerebrospinal fluid leak caused by, 188 chronic rhinosinusitis treated with, 234–237, 630 complications of, 187–192, 236–237 coronal and axial imaging before, 193 1966
definition of, 226 hemorrhage after, 236 indications for, 180, 234–235 intraoperative procedure, 235, 237f orbital penetration during, 237 postoperative management, 236 preoperative imaging for, 235 principle of, 237f prognosis after, 237 wound healing after, 236 Functional luminal impedance planimetry, 818 Functional residual capacity, 175, 175f, 435 Fungal culture, 90–91 Fungal sinusitis allergic, 199–200f characteristics of, 199–200f, 204–205 chronic rhinosinusitis and, 231 description of, 627 rhinoscopic findings, 231 invasive, 203–204 Fungi allergens, 110, 116–118t characteristics of, 158 deuteromycetes, 110–112 Phylum Ascomycetes, 111–115 Phylum Basidiomycota, 115 Phylum Zygomycetes, 111 taxonomy, 110–115 1967
Furry animal allergens, 240 Fusarium vasinfectum, 114f G G-protein coupled receptors, 29 Gabapentin, 713 Gad c 1, 405 Gadolinium, 190 Galvanometer, 877 Gastric carcinoids, 714 Gastroesophageal reflux disease, 816 asthma and, 453, 495 coughing caused by, 836 rhinitis and, 608 treatment of, 836 Gene therapy, 55 Generalized anxiety disorder (GAD), 856 Generalized heat urticaria. See Cholinergic urticaria Giant papillary conjunctivitis, 647, 650–651 Giardia lamblia, 46 Gleich syndrome, 71 Glomerulitis, 337 Glomerulonephritis, chronic, 337 Glomerulonephritis, chronic, 337 Glucocorticoid(s). See also Corticosteroids anti-inflammatory mechanisms of, 748–749 asthma treated with, 752–753 chemical structure of, 745 intranasal, 756–757 1968
nasal polyps treated with, 625 pharmacologic variables and, 746t receptor, 746 -resistant asthma, 477 Glucose-6-phosphatase deficiency, 49t Glucose-6-phosphate dehydrogenase deficiency, 312 Glyceryl thioglycolate, 681 Gold, 683 Gold-induced pneumonitis, 333 Goldenrod, 102f Goodpasture syndrome, 337 Goosefoot, 105 Graded challenge description of, 340 penicillin allergy, 360 Granulocyte-macrophage colony stimulating factors in eosinophil production, 65 physiologic actions of, 437t recombinant human, 396 Granulomatosis with polyangiitis computed tomography of, 219–220t radiologic findings, 219–220t Granulomatous diseases, 203, 204f chronic gene defects in, 49t recombinant interferon-α for, 397 Grass(es) in California, 149t 1969
in Great Plains of United States, 144–146t in Midwest United States, 141–143t in Northwest of United States, 135–137t, 148t pollen grains of, 101–103, 101–102f, 107 in Southeast United States, 138–140t, 147t Grass pollen allergens caused by, 107 allergic rhinitis caused by, 595 asthma exacerbations caused by, 96 Ground-glass attenuation, 218 Gulf War syndrome, 875 Gustatory rhinitis, 630–631 Gut-associated immune system, 402 Gymnosperms, 97 H H1 antihistamines adverse effects of, 861 in pregnancy, 810 Hackberry trees, 99 Haller cell, 186, 186f Halotherapy, 882 Hamman sign, 481 Hapten, 263, 313, 335, 674 Hawaii, 150t Hawthorne effect, 476 Hazard Communication Standard, 585 Heart failure, congestive, 453, 509 Helical computed tomography, 193 1970
Helicobacter pylori infection, eradication of, 883 Heliox, 513, 516 Helminthic diseases eosinophilia caused by, 67t, 68 IgE levels associated with, 95 Helminthosporium spp., 113, 113f Helper T cells, 7, 19, 675 Hematological pruritus, 716 Hematopoietic stem cell transplantation, 55 Hemlock trees, 97 Hemolytic anemia, 334–335 Hen’s egg allergy, 404, 414 HEPA filters, 447 Heparin, 36–37 -induced thrombocytopenia, 334 Hepatocellular injury, drug-induced, 336 Herbal therapy, 880 Hereditary angioedema description of, 692–693, 694t, 696–698 in pregnancy, 809 Hering-Breuer inflation reflex, 432 Heroin, 70 Herpes simplex keratitis, 650 Herpes zoster, 650 Hertoghe sign, 640 High-molecular-weight (HMW), 584 Hirst spore trap, 87 Hirudin, 397 1971
Histamine in allergic inflammation, 722 antagonists, 277 chemical structure of, 723f definition of, 719 discovery of, 720–722 mast cell storage of, 722 physiologic effects of, 32, 257, 437t properties of, 31 T cells affected by, 722 in urticaria, 690 Histamine receptors, 32, 257, 720t, 721f antagonists, eosinophilic esophagitis treated with, 825 Histamine-releasing factors, 689 Histamine1 receptor antagonists adverse effects of, 729–730 clinical use of, 728–729 first-generation, 723, 724t, 725, 731 second-generation, 724t, 725–727, 726t, 731 Histamine2 antagonists, 731 Histamine2 receptor antagonists, 382 Histamine3 receptor antagonists, 731 Histamine4 receptor antagonists, 732 History-taking and evaluation allergy, 153–155 drug allergy, 338–340 HIV, 367–368
1972
pruritus, 715t, 716 Home sleep apnea testing (HSAT), 848 Homeopathic remedies, 880 Homeostasis, 846 Honeybee stings, 287 Horse allergens, 121 “Hot tub lung,” 552 House dust mites, 95, 115–119, 239–240, 240t 5-HPETE, 34 Human leukocyte antigens, 316, 410, 571 Human recombinant proteins, 391, 396–397 Humoral immunity panel, 53 Humoral immunodeficiency testing, 869–870 Hydralazine-induced lupus, 323 Hydrocortisone, 481, 756 Hydrofluoroalkane (HFA), 775 5-hydroxyeicosanoid dehydrogenase, 35 Hydroxyurea, for hypereosinophilic syndromes, 73 Hydroxyzine, 703, 724t, 726t Hygiene hypothesis, 883 Hymenoptera stings, 253, 266, 287. See also Insect stings Hymenoptera venoms, 701 components, 290t Hyper-IgE syndrome, 47t Hypercapnia, 515 Hypereosinophilic syndromes cardiac manifestations of, 72 classification of, 71f 1973
clinical manifestations of, 70 computed tomography findings, 220t corticosteroids for, 72–73 cutaneous manifestations of, 72 diagnostic criteria for, 70 diarrhea associated with, 72 eosinophilia caused by, 64, 70–74 epidemiology of, 70 familial, 71 hydroxyurea for, 73 idiopathic, 223 imatinib for, 73–74 interferon-τ for, 73 laboratory findings, 70 lymphocytic variant, 71 mepolizumab for, 826 myeloproliferative, 70–71, 72 neurologic findings, 72 respiratory findings, 72 treatment of, 72–74 types of, 70 Hypersensitivity classification of, 23–24, 674 immediate. See Immediate hypersensitivity myocarditis, 338 type I, 23, 315t type II, 23, 315t type III, 23, 315t 1974
type IV, 23, 315t Hypersensitivity pneumonitis acute, 552 algorithm for evaluating, 547f allergens, 543–546 antigens of, 543–546, 544–545t avoidance, 555–556 in bird handlers, 546 bronchoalveolar lavage for, 177, 550–551 chest radiographs of, 549 chronic, 221, 222f, 552, 553t clinical features of, 546–548, 552t computed tomography of, 219, 221, 549 corticosteroids for, 556 cytokine production, 555 definition of, 543 diagnostic criteria, 546–548 differential diagnosis, 551–552 discovery of, 543 epidemiology of, 546 incidence of, 546 inhalation challenge for, 551 laboratory tests, 549–550 management of, 555–556 Mycobacterium avium complex associated, 177 neutrophils in, 177 occupational, 546, 589, 590t pathogenesis of, 552–555, 554f, 565f 1975
pathologic features of, 551 pharmacologic treatment of, 556 physical examination for, 548 prevention of, 556–557 prognosis for, 557 pulmonary function tests for, 176, 548–549 screening for, 556–557 skin testing for, 550 specific inhalation challenge for, 551 subacute, 222f Hypersensitivity syndrome, 325 Hypersensitivity vasculitis, 323–324 Hypnotic induction agents, 269 Hypochondriasis, 857–858 Hypogammaglobulinemia chest radiograph evaluations, 51 thymic abnormalities associated with, 47t Hypothalamic-pituitary-adrenal (HPA) axis, 746 Hypothalamic-pituitary-adrenal suppression, 443 Hypothyroidism, 607 Hypoxemia, 480–481 I ID50 EAL method, 243 Idiopathic environmental intolerances (IEI), 875 Idiosyncratic reactions, 312 IgA antihuman antibodies, 270 characteristics of, 16t 1976
deficiency anaphylaxis in, 59 blood products for, 393–394 intravenous immunoglobulin therapy for, 58 mucosal infections and, 48 IgD, 16t IgE in allergenicity determinations, 94 in allergic bronchopulmonary aspergillosis, 571 anti-IgE antibodies, 414 antigen-activated prostaglandin D2 (PGD2)production, 34 in atopic dermatitis, 22, 162 B cell production of, 18 bronchoconstriction mediated by, 424 characteristics of, 16t desensitization methods, 345–346 discovery of, 15 disease role of, 21–23 food reactions mediated by, 407–409 health role of, 20–21 hypersensitivity mediated by, 15 measurement of, 22–23 metabolic properties of, 18 molecular control of, 19f monoclonal anti-immunoglobulin E, 791, 793 penicillin allergy, 356 physiology of, 15–20 production sites for, 18–19 1977
properties of, 15, 16t radioallergosorbent test of, 22, 163 receptors, 15–18 role of, 19f specific, 22–23, 163 structure of, 15–18, 16t synthesis of, 19–20 testing for, 341 tissue localization of, 18–19 total, 22, 163 turnover of, 18–19 in vitro allergen-specific tests, 412 IgG characteristics of, 16t half-life of, 58 replacement therapy, 57–58, 57t screening tests for, 52 serum immunoglobulin antibodies, 878 subcutaneous administration of, 59 supplementation, 57, 57t in type II hypersensitivity, 23 IgG4-related disease, 224 IgM characteristics of, 16t in type II and III hypersensitivity, 23 Imatinib, 73–74 Immediate generalized reactions, 320, 320t, 359 Immediate hypersensitivity 1978
allergens that cause, 157–159. See also Allergen(s) causes of, 674 characteristics of, 23 chest radiographs, 165 conjunctivitis caused by, 155 historical studies of, 15 nonimmunologic factors, 159 physical examination, 155–157 respiratory function evaluations, 164 Immune complex disease, 23 Immune deficiencies chronic rhinosinusitis secondary to, 231 hereditary, 48, 49–50t laboratory screening tests for assessing, 51 newborn screening for, 55 physical findings associated with, 47t, 51 prevalence of, 44 primary, 46 summary of, 60 warning signs of, 45, 45f workup for, 44–48 Immune deficiency primary, 46 severe combined immunization concerns, 56 management of, 56 neonatal screening for, 55 physical examination findings, 44t 1979
physical findings associated with, 46 Immune responses, 10–13 complement system, 10–11 eosinophil modulation of, 66 immune-mediated diseases, 13 proactive immunity, 11–12 tolerance, 12–13 Immune sera therapy, 394–395 Immune serum globulin, 394 Immune system adaptive. See Adaptive immunity laboratory evaluation of, 53–55 pollen extract effects on, 95 sleep and, 846–848 Immunity, adaptive, 5–10 antigens, 5 B cell antigen recognition, 8–10 B cell subsets, 10 T cell antigen recognition, 5–7 T cell subsets, 7–8 ImmunoCAP Solid-phase Allergen Chip, 867 Immunodeficiency diseases in vivo and in vitro testing in cellular and combined, 870–871 complement deficiency testing, 871 humoral, 869–870 next-generation sequencing, 871 other, 871 1980
phagocytic defects, tests for, 871 Immunodeficiency disorder, common variable age at onset, 50 IgG replacement therapy for, 58 physical examination findings, 51 summary of, 60 Immunogens, 5 Immunoglobulin(s). See also specific immunoglobulin class switch recombination, 18 heavy chain deletion, 49t isotypes of, 16t Immunologic contact urticaria (ICU), 676 Immunologic manipulation, 883 Immunologic screening tests, 51–53 Immunomodulators, 825–826 Immunoreceptor tyrosine-based activation motifs, 29 Immunotherapy administration of, 244, 245t, 247 allergens acute allergic conjunctivitis treated with, 645 administration of, 244, 245t allergic rhinitis treated with, 809 asthma during pregnancy treated with, 804–805 dosage schedules, 242 extract potency, 242–243, 243t in infants and toddlers, 503 modified, 247 SCIT dose schedule, 244 1981
selection of, 242 SLIT dose schedule, 243–244 Aspergillus, 579 cluster, 244 definition of, 241 failure of, 247 food allergies treated with, 414 guidelines for, 133 historical studies of, 241 immunologic changes with, 241t indications for, 242t injections, 244–245 insect stings, 292–296, 294t medication use during, 247 nasal, 247 occupational immunologic lung disease treated with, 591 oral, 247 otitis media with effusion treated with, 660 during pregnancy, 246–247 reactions to, 245–246, 246t rush, 244 safety of, 246 skin testing affected by, 162 venom, 290, 810 Impaction samplers, 87, 92f In vivo and in vitro testing for allergic diseases, 865–869 for immunology diseases, 869–871 1982
Incremental test dosing, 340–341 Indirect effects of drugs, 311 Indoor allergens, 158 Inducible nitric oxide synthase, 258, 527 Infants aeroallergen sensitivity, 495 allergies in, 496–497 asthma allergy, 496–497 anticholinergics for, 501 β-agonists for, 501 corticosteroids, 502–503 cromolyn sodium, 502t epidemiology of, 494 immunotherapy for, 503 leukotriene antagonists, 501–502 natural history of, 494–495 obesity, monitoring of, 503 passive smoke inhalation, 495–496 prednisone, 502t treatment of, 501–503, 502t triggers, 495 viral infections, 496 eustachian tube of, 654–656 IgG supplementation in, 57 metered-dose inhalers in, 780 otitis media with effusion in. See Otitis media, with effusion wheezing in, 494, 496, 498–500t 1983
Infection age at onset of, 50 in antibody-deficient patients, 58 antibody-replacement therapy to prevent, 59 atopic dermatitis, 670–671 chronic rhinosinusitis caused by, 229 cough caused by, 837 documenting the history of, 48–50 frequency of, 46 otitis media with effusion caused by, 656 urticaria caused by, 701 Infectious conjunctivitis, 649–650 Inferior turbinates, 180, 182f Infliximab, 826 Influenza vaccine allergy, 398 Infundibulum, 186 Inhalation therapy aerosol particles, 773–775, 774t, 774f device recommendations, 787t dry powder inhalers, 781–783 history of, 773 metered-dose inhalers. See Metered-dose inhalers nebulizers, 785–787, 785–786f summary of, 787 Inhaled corticosteroids asthma treated with, 512, 526, 752–753 β-agonists and, 738, 753 clinical use of, 753–754 1984
delivery devices for, 754, 755t description of, 456 dose-response for, 754–755 history of, 745 metered-dose inhaler delivery of, 780 preparations, 753 Inhalers dry-powder, 463, 781–783 metered-dose. See Metered-dose inhalers Innate immunity, 1–4 chemokines, 2 in chronic rhinosinusitis development, 232 cytokines, 2 epithelial cells and, 3 innate lymphoid cells, 3–4 myeloid cells and, 4 pattern recognition receptors, 2–3 Innate lymphoid cells, innate immunity, 3–4 Insect allergens, 121–124 Insect stings anaphylaxis caused by, 255, 266, 289 avoidance of, 292 fire ants, 287–288, 289f immunotherapy, 292–296 insects, 287–288 reactions to, 288–290 risks, 292–293t testing for specific IgE, 290–291 1985
therapeutic approach, 291–292 treatment of, 291–292 urticaria caused by, 701 venom immunotherapy for, 290 Insomnia, 851, 851t Insulin allergy, 391–393, 392t Integrative medicine, 874 Intercellular adhesion molecule 1, 328 Interferons, 794 Interferon-τ description of, 19 hypereosinophilic syndromes treated with, 73 Interleukin-1, 437t, 846 Interleukin-2, 437t Interleukin-3 characteristics of, 437t in eosinophil production, 65 Interleukin-4, 17, 437t Interleukin-5 characteristics of, 437t in eosinophil production, 65 in eosinophilic esophagitis treatment, 819 Interleukin-9, characteristics of, 437t Interleukin-10, 21 Interleukin-13, 17 Interleukin-25, characteristics of, 437t Interleukin-33, characteristics of, 437t Intermittent rhinitis, 596 1986
Interstitial fibrosis, 551 Interstitial lung disease, 837 Intolerance, 312 Intractable asthma, 475–477 Intradermal skin test, 159, 162, 411, 866 Intranasal carbon dioxide (CO2), 616 Intranasal corticosteroids, 610–612 injection, 612 Intravenous corticosteroids, 458 Intravenous immunoglobulin indications for, 58 Stevens-Johnson syndrome treated with, 301 toxic epidermal necrolysis treated with, 301, 330 Intubation, for mechanical ventilation, 513 Invasive fungal sinusitis, 203–204 Inverted papilloma, 206–207, 607 Investigational new drug, 521 Iodopropynylbutylcarbamate, 681 Ipratropium bromide, 614 acute severe asthma treated with, 512 asthma treated with, 464, 473, 501 characteristics of, 765–766t pharmacology of, 769 Isoallergens, 86 Isocyanates, 588–589 Isohemagglutinins, 870 Isoniazid, 371 Isoproterenol, 735 1987
Itch. See Pruritus Itraconazole, 371, 577–578 J Januse kinase 3 deficiency findings suggestive of, 55 gene defects in, 50t Japanese encephalitis vaccine, 398 Jarisch-Herxheimer phenomenon, 311 JNJ7777120, 723f, 731 June grass, 101f Juniper trees, 97–98 Juvenile nasopharyngeal angiofibroma, 207 K Kallikrein-kinin system, 28 Kathon CG, 681 Keratoconjunctivitis sicca, 650 Keratoconus, 648 Ketamine, 515 Ketoconazole, 371 Ketorolac, 644t Ketorolac tromethamine, 645 Ketotifen, 644t, 703 Kidneys drug allergy manifestations in, 337 pruritus, 714, 715t Kinases, inhibitors of, 794 L L-Asparaginase, 320 1988
Labeling distortion, 862t Lactic acidosis, 510 Lambs quarter’s grass, 102f Lamina papyracea anatomy of, 180 functional endoscopic sinus surgery complications of, 188 Langerhans cells, 675 Lanolin, 681 Laryngeal dyskinesia, 451 Laryngopharyngeal reflux, 453 Late phase response, 161 Latex allergy/anaphylaxis, 267–268, 321, 393, 683–684 Leukocyte adherence protein deficiency cutaneous abnormalities associated with, 47t physical findings associated with, 47 Leukocyte adhesion deficiency testing, 871 Leukocytotoxic test, 876–877 Leukotriene antagonists, 465, 501–502 Leukotriene modifiers, 513 Leukotriene-receptor antagonists, 614 Leukotrienes, 34–35, 372, 437t, 449, 471, 767 Levalbuterol, 460t, 461, 502t, 735, 735t, 738 Levocabastine, 644t, 645 Levocetirizine, 724t, 725 Lichenification, 156 Linden trees, 100 Lipoxygenase, 34–35, 424 Liver 1989
drug allergy manifestations in, 335–337 halothane-induced injury to, 336 Liver disease, drug-induced, chronic, 337 Local allergic rhinitis (LAR), 609 Local anesthetic allergy, 377–378, 378t Local heat urticaria, 694t, 696 Lodoxadine, 644t Loffler syndrome, 76 Lol p 1, 107 Lol p 5, 107 Long-acting β-Agonists, 738 Long-chain ω-3 polyunsaturated fatty acids, 884 Loratadine, 723f, 724t, 725, 726t 5-LO synthesis inhibitor, 892 Low-molecular-weight drugs description of, 313 pharmacologic interactive model of, 314 LTB4, 258 LTC4, 34 LTRII, 34 Lung(s) anatomy of, 430–432 biopsy, in allergic bronchopulmonary aspergillosis, 572 bronchial wall, 431 computed tomography anatomy of, 218 drug-induced reactions, 331–333 function of, 430 innervation of, 432 1990
tumors of, 837 volumes, 175–176, 175f, 800 Lymphadenopathy, 337 Lymphocyte(s) B. See B cells flow cytometry quantitation of, 52 subset enumeration, 879 T. See B cells Lymphocyte blastogenesis, 342 Lymphocyte mitogen proliferation assays, 54 Lymphocytic alveolitis, 177 Lymphocytic hypereosinophilic syndromes, 71 Lymphocytosis, 177 Lymphonodular hyperplasia, 46 M Macrolides, 370 Macrophages, 431, 554–555 Madarosis, 640 Magnesium sulfate, 512–513 Magnetic resonance imaging allergic fungal sinusitis, 205 chronic rhinosinusitis, 234 computed tomography vs., 194 inverted papilloma, 206 mucocele findings, 198 mucus retention cysts, 196 sinonasal polyposis, 203 Magnification distortion, 862t 1991
Major basic protein, 66 Major depressive disorder, 854–856, 854t Malignant, potentially fatal asthma, 443 Mania, 855, 855t Maple trees, 100 Marginal blepharitis. See Blepharoconjunctivitis Marsh elder, 103 Mass mean aerodynamic diameter (MMAD), 774, 775t Mast cells activation of, 28–30, 38, 436, 692t in allergic rhinitis, 603 in anaphylaxis, 256–260 in angioedema, 692t antigen activation of, 38 characteristics of, 26 connective tissue, 26, 28t cytokine production, 38 degranulation of, 764 eicosanoids produced by, 258 FcepsilonR1 receptors, 17, 28 histamine storage in, 722 homeostatic role of, 39 IgE-dependent activation of, 38 ILC2, role in, 30 immodulation of, 30–31 kininogenase, 257 in lung, 431 mediators of. See Mediators 1992
mucosal, 26, 28t, 431 role of, 38 stem cell factor effects on, 26 subtypes, 27t, 28t in urticaria, 692t Mastocytosis, 296 anaphylaxis vs., 258–259 Maternal diet, 810–811 Maxillary sinus anatomy of, 180, 181f mucociliary clearance, 228 sinusitis of, 201–202 Maxillary sinusitis, 627 Measles, mumps, rubella vaccine, 398 Mechanical ventilation acute severe asthma treated with, 513–516 auto positive end-expiratory pressure, 508 bronchodilator administration during, 515 extubation, 516 intubation for, 513 lung inflation assessments, 514 noninvasive positive pressure ventilation, 513 paralysis during, 515 positive end-expiratory pressure, 508 sedation during, 515 synchronized intermittent mandatory ventilation, 514 ventilator settings and adjustments, 514 Mediators 1993
adenosine, 35 characteristics of, 437t chemotactic, 36 definition of, 31 with enzymatic properties, 36–37 generating cells description of, 26 mast cells. See Mast cells interactions among, 37–38 lipoxygenase products, 34–35 mast cell, 31, 31t osteopontin, 36 phospholipases, 35 platelet-activating factor, 32–33 proteoglycans, 37 spasmogenic, 31–32, 31t tryptase, 36–37 vasoactive, 31t MedWatch, 309, 309t Melanotic tumors, 213 Mental health, 857 Mepolizumab, 793, 826, 892 Mercurials, 683 Metabisulfites, 331 Metaherpetic keratitis, 650 Metals, 683 Metapneumovirus, 496 Metaproterenol, 460t 1994
Metered-dose inhalers, 775–779 albuterol delivery using, 515 β-adrenergic agonist delivery using, 511 breath-actuated, 780–781 in children, 780 corticosteroid delivery using, 752 errors in using, 779t in infants, 780 inhaled corticosteroid delivery using, 780 spacer devices, 778–779f, 779–780 summary of, 787 technique of use, 776f Methacholine challenge test, 164, 174 Methacholine inhalation challenge (MIC), 835 Methotrexate, 332, 476 Methyldibromoglutaronitrile, 681 Methyldopa, 335 Methylprednisolone, 476, 746t, 806, 825 Methylprednisolone acetate, 502t, 756 Metronidazole, 370 Middle ear effusion, 655f, 656 Middle turbinates, 182f, 185, 185f Midwest United States, 141–143t Mind-reading distortion, 862t Mineral supplementation, 882 Mineralocorticoids, 745 Minimization distortion, 862t Minor determinant mixture, 361 1995
Mirtazapine, 713 Mislabeling distortion, 862t Mitogens, 54 Mixed pattern disease, 336 Mizolastine, 724t Mold spores, 158, 240, 599, 876 Molecular genetic diagnosis, 55–56 Mometasone, 758t Monoamine oxidase inhibitors, 247, 860–861 Monoclonal anti-immunoglobulin E, 791, 793 Monoclonal antibodies, 396, 791–794 Monocotyledons, 97 Mononeuritis multiplex, 72, 75 Montelukast, 465, 502, 502t, 765t, 825 Mood disorders, 854–856 μ-Opioid receptor antagonists, 713 Morbilliform eruption, 324–325 Morphine, 380, 469 Moth allergy, 121–122 Mouse allergens, 121 Moxibustion, 880 Mucocele, 197–201, 199f Mucociliary dysfunction, 656 Mucoperiosteal congestion, 194 Mucopyocele, 201 Mucosal-type mast cells, 26, 28t Mucus retention cysts, 196–197, 198f Mulberry trees, 100 1996
Multiple antibiotic sensitivity syndrome, 372 Multiple chemical sensitivities, 875 Munchausen stridor, 261 Muscarinic receptors, 795 Muscle relaxants, 381–382 Mycetoma, 196f, 205 Mycoplasma pneumoniae infections, 471 Myeloid cells, innate immunity and, 4 Myeloproliferative hypereosinophilic syndromes, 70–71 Myocardial contraction band necrosis, 435 Myocarditis, hypersensitivity, 338 Myofibroblast, 427 N Naltrexone, 713 Nasal cavity anatomy of, 180, 182f malignancies of, 208 variants in, 184–187 Nasal choanae, 180, 182f Nasal cycle, 195f Nasal immunotherapy, 247 Nasal mucosa, 602 Nasal obstruction, 655–656 Nasal polyps in chronic rhinosinusitis, 231, 235 clinical presentation of, 624 corticosteroids for, 625, 757–758 description of, 156 1997
discovery of, 624 disorders associated with, 231 etiology of, 624–625 glucocorticoids for, 625 illustration of, 229f microbial pathogens in, 625 prevalence of, 624 removal of, 235 surgical removal of, 475 surgical treatment for, 625 treatment of, 625–626 Nasal provocation, 869 Nasal septum anatomy of, 180 deviation of, 185, 185f, 630 perforation of, 203 Nasolacrimal duct, 227 National Asthma Education and Prevention Program, 171, 428, 445t National Institute of Occupational Health and Safety, 585 Natural killerlike T cells, 555 Nebulizers, 785–787, 785–786f Nedocromil challenge studies for, 764 characteristics of, 765t description of, 468, 644t dosing of, 767 efficacy of, 767 mechanism of action, 764–767 1998
pharmacology of, 764 Neomycin, 325–326, 682 Neoplasm, urticaria caused by, 701 Nephritis, interstitial, acute, 337 Nephrotic syndrome, 337 Neutralization, 879–880 Neutropenia, 51, 335 Neutrophil(s). See also Phagocytic defects chemotactic factor, 437t in hypersensitivity pneumonitis, 177 Next-generation sequencing techniques, 871 Niacin, high-dose, 881 Nickel, 683 Nitric oxide anaphylaxis-related production of, 258 in asthma, 428 exhaled, 527 description of, 33 exhaled, 527 fractional exhaled, 164, 174–175 synthase, 258 Nitrofurantoin, 332 Nizatidine, 731 NOD-like receptors, 3 Nonadherence, 859t problem, 859–860 Nonallergic asthma, 447–448, 471 Nonallergic rhinitis 1999
classification of, 630, 631t definition of, 630 with eosinophilia syndrome, 603, 607–608, 630 perennial, 607–608 subtypes of, 631t treatment of, 632–633 Nonasthmatic eosinophilic bronchitis, 836 Noncardiogenic pulmonary edema, 333 Nonimmunologic contact urticaria (NCU), 676 Noninvasive positive pressure ventilation, 513 Nonsteroidal anti-inflammatory drugs acute interstitial nephritis caused by, 337 allergy to, 372–374 anaphylaxis caused by, 264, 372 conversion rates for, 472 description of, 70 wheezing dyspnea caused by, 424 Nonthrombocytopenic purpura, 330 Norepinephrine, 436 Northeast United States, 134–137t Novel therapies, 248 NREM sleep, 845, 847t Nuclear factor-κB essential modulator deficiency dentofacial abnormalities in, 47t gene defects in, 50t physical findings associated with, 46 Nut allergies, 405 Nutrient supplementation, 882 2000
O Oak trees, 99 Obesity, infants, monitoring of, 503 Obstructive sleep apnea (OSA), 850–851 symptoms and physical findings of, 849t Obstructive ventilatory defects, 171 Occupational asthma allergens, 587t animal-related causes of, 587–588 chemicals, 588–589 definition, 584 description of, 408, 449–450 etiology of, 586–589, 587t pathophysiology of, 586 reaction patterns, 586 trimellitic anhydride, 584t, 589 vegetable origin, 588 Occupational immunologic lung disease asthma. See Occupational asthma bronchial challenge, 589 bronchoprovocation testing, 589 description of, 584 diagnosis of, 589–590 epidemiology of, 584–585 hypersensitivity pneumonitis, 589, 590t immunotherapy for, 591 medicolegal aspects of, 585–586 prevention of, 591 2001
prognosis for, 590 treatment of, 590–591 Odontogenic rhinosinusitis, 202 Olopatadine, 644t, 727 Olopatadine hydrochloride, 632 Omalizumab, 18, 273, 466, 476, 483, 522, 826, 892 Omenn’s syndrome, 56 Onodi cells, 187, 188f Open vent nebulizers, 785, 786f Opiate allergy, 379–380 Oral allergy syndrome, 409 Oral tolerance, 403 Orbital hemorrhage, 189 Orchard grass, 102f Organic dust toxic syndrome, 551 Oseltamivir, 371 Osteoma, 206 Osteomeatal complex anatomy of, 181f, 226 opacified, 183f Osteomyelitis, 48 Osteopenia, 458 Osteopontin, 36 Osteosarcoma, 213 Ostiomeatal complex, anatomy of, 180 Ostiomeatal complex, posterior, 184 Otitis media acute, 652, 656 2002
definition of, 652 with effusion allergic rhinitis and, 659 allergy and, 654–657 corticosteroids for, 659 definition of, 652 description of, 597 diagnosis of, 657–658 environmental control for, 659 heptavalent pneumococcal conjugate vaccine for prevention of, 659–660 immunotherapy for, 660 infection as cause of, 656 management of, 658–660 mucociliary dysfunction, 656 pathogenesis of, 654–657 pharmacotherapy for, 658–659 physical examination for, 658 prognosis for, 660 risk factors for, 654t surgical treatment of, 660 tympanometry of, 657–658 tympanostomy tubes for, 660 vaccination, 659–660 recurrent, 658 Otorrhea, 657 Ouchterlony double-gel immunodiffusion technique, 550f Ovalbumin, 404 Overdosage, 310 2003
Overgeneralization distortion, 862t Overlap syndrome, 330 Ovomucoid, 404 5-oxo-ETE, 35, 36 Oxygen therapy acute severe asthma treated with, 510–511 anaphylaxis managed using, 276 status asthmaticus managed using, 479 Ozone, 124 P P-selectin glycoprotein ligand 1, 65 PABA, 682 Pancuronium, 382 Panic attack, 856 Panic disorder, 856 Papain, 587 Papilloma, inverted, 206, 607 Papular urticaria, 698 Para-aminobenzoic acid, 326 Parabens, 326, 680 Paralysis, during mechanical ventilation, 515 Paranasal sinuses. See Sinuses Paraphenylenediamine, 678, 681 Parasitic infections, 67t, 69 Paroxetine, 713 Passive smoke inhalation, 495–496 Patch tests/testing, 868 contact dermatitis, 677–680 2004
description of, 340 eosinophilic esophagitis, 821 ocular, 640, 641t precautions in, 685 reading and interpretation, 531 techniques for, 678–679 Pathogen-associated molecular patterns, 2 Pathogenesis-related proteins, 406, 406t Pattern recognition receptors, innate immunity, 2–3 Peak expiratory flow rate in asthma, 440 description of, 170, 173–174 Peak flow meter, 475 Peanut allergy, 266–267, 404, 414, 881 Pecan trees, 100 Pemirolast, 644t Penetrants, urticaria caused by, 701 Penicillin allergy anaphylaxis caused by, 264 background on, 356–360 cross-reactivity, 360 description of, 314 desensitization protocols for, 363–364, 365–366t diagnostic testing for, 360–363 evaluation of, 357t graded challenge for, 360 IgE antibody, 356 immediate reactions, 359 2005
management of, 363–366 prevalence of, 358 prior history of, 358 skin testing for, 360–363 Penicillium chrysogenum, 114, 114f Penicilloylpolylysine, 361 Pentamidine, 368 Perforin, 304 Perioperative anaphylaxis, 268–270 Peripheral eosinophilia syndrome, 332, 575 Peripheral Tregs, 12 Peroxidase, 437t Persistent asthma, 473–475, 806–807 Personality disorders, 858–859 Personalization distortion, 862t Pertussis and rubella vaccine, 398 Peruvian lily. See Toxicodendron dermatitis Petals, 97 Petri dishes, 90 Phagocytes, complete blood count of, 53 Phagocytic defects, tests for, 871 Pharmacogenetics, 312 Pharmacologic agents, low molecular weight, 794–795 Phenothiazines, 685 Phenotypes, 791, 792–793t, 892–893 Phl p 1, 107 Phosphodiesterase 4 inhibitor, 671 Phospholipase C, 35 2006
Phospholipases, 35 Photoallergic contact reactions, 685 Photoallergy, 679 Photopatch testing, 679 Photosensitivity, 328–329, 329t Phototherapy, for atopic dermatitis, 672 Phylum Ascomycetes, 111–115 Phylum Basidiomycota, 115 Phylum Zygomycetes, 111 Physiologic testing bronchoprovocation testing, 174 pulmonary function tests. See Pulmonary function tests Phytophotodermatitis, 685 Pigweed, 105, 105f Pine trees, 97, 98f Pirbuterol, 460t, 735t Piriform aperture, 180, 182f Pistils, 97 Plantaginaceae, 106 Plantain, 102f Plasma cells, IgE-forming, 18 Plasmodium falciparum infection, 68 Plastics-related dermatitis, 684 Platelets, 27 activating factor, 32–33, 437t, 796 Pleural effusions, 222, 223 PMDI inhalers, concurrent use of, 784–785 Pneumatization of sinuses, 188 2007
Pneumocystic carinii pneumonia, 56 Pneumomediastinum, 443, 481 Pneumonia eosinophilic. See Eosinophilic pneumonia Pneumoniam, Pneumocystic carinii, 56 Pneumonitis drug-induced, 332–333 hypersensitivity. See Hypersensitivity pneumonitis ventilation, 545 Pneumothorax, 443, 481 Poison ivy, 677 Pollen-food syndrome, 409 Pollen/pollen grains airborne. See Airborne pollen in Alaska, 150t allergenicity of, 95 angiosperms, 98–99f asthma and, 95 in California, 149t characteristics of, 157–159 definition of, 96 description of, 132 dispersal of, 157 grasses. See Grass pollen in Great Plains of United States, 143–146t gymnosperms, 97, 98f in Hawaii, 150t insect dispersal of, 157 in Midwest United States, 141–143t 2008
in Northeast of United States, 134–137t in Northwest of United States, 148t particle size of, 95 properties of, 95 radioallergosorbent testing of, 93 ragweed, 96, 102–103f, 103 scanning electron microscopy of, 98f in Southeast United States, 137–140t in Southwest United States, 146–147t structure of, 96 walnut, 100, 100f Pollinosis, 96 Polycythemia vera, 715t Polygonaceae, 105 Polymorphic eruption of pregnancy (PUPPP) syndrome, 810 Polyps antro-choanal, 197, 199f nasal. See Nasal polyps sinonasal, 196, 198f Poplar trees, 98–99 Positive end-expiratory pressure, 508 Potentially (near) fatal asthma, 443, 448, 472–473 Pott’s puffy tumor, 628 Practice guidelines or parameters, definition of, 874 Prausnitz-Küstner test, 15 Precipitating IgG antibodies, 868 Precipitins. See Precipitating IgG antibodies Predictive enrichment, 889 2009
Prednisolone, 746t Prednisone, 746t allergic bronchopulmonary aspergillosis treated with, 564, 577t, 578 anaphylaxis treated with, 272–273 asthma treated with, 456, 476, 502t acute severe, 512 in pregnancy, 804 urticaria treated with, 703 Pregnancy adolescent, 802 anaphylaxis during, 809–810 antibiotics during, 808–809 antihistamine use during, 808 asthma during, 799–800 allergen immunotherapy for, 804–805 avoidance measures for, 802 choice of therapy, 802–805 classification of, 806t medications for, 802–804 persistent, 806–807 prednisone for, 804 treatment of, 802t cardiac output changes during, 800–801 dyspnea in, 806 fetal oxygenation during, 801 H1 antihistamine use during, 810 immunotherapy during, 246–247 lung volumes in, 800 2010
maternal diet, 810–811 physiologic changes during, 800–801 rhinitis of, 606, 633, 807–809 smoking during, 495 total lung capacity in, 800 urticaria in, 809–810 venom immunotherapy during, 810 wheezing in, 807 Prick test description of, 159, 360 drug allergy diagnosis using, 398 food allergy diagnosis, 411–412 Proactive immunity, immune responses, 11–12 Probiotics, 795–796, 883–884 Proctocolitis, food protein-induced, 410 Profilin, 406 Properdin deficiency, 49t Propofol, 269 Propylene glycol, 681 Prostaglandin D2, 33, 257, 449 receptor, 794–795 Protein contact dermatitis (PCD), 676 Protein-nitrogen unit, 93, 243 Proteoglycans, 37 Proton pump inhibitors, 382, 823 responsive esophageal eosinophilia, 817–818 Protracted bacterial bronchitis (PBB), 840 Provocation-neutralization testing, 877 2011
Provocation tests description of, 164, 174 desensitization vs., 341 drug hypersensitivity testing using, 340 Provocative concentration, 174 Pruritus antihistamines for, 713 causes of, 710t cholestatic, 714, 715t classification of, 709 common systemic causes of generalized, 711t differential diagnosis, 712 endocrine, 716 etiology of, 709 hematological, 716 history, 709–710, 710t imaging studies for, 712 laboratory findings, 712, 712t malignancy-associated, 714–716, 715t pathophysiology of, 709 physical examination for, 710–711 renal, 714, 715t without skin signs related to infectious disease, 716 treatment of, 712–714 uremic, 714, 715t Pseudoallergy, 312–313 Pseudoeosinophilia, 64 Pseudomonas aeruginosa, 49 2012
Pseudostratified ciliated columnar epithelium, 430 Pseudostratified columnar ciliated epithelium, 180, 228 Psoriatic dermatitis, 676 Psychogenic cough, 837–838 Psychologically complicated patients anxiety disorders, 856–857 cognitive and behavioral theories and therapies for, 861–862 mood disorders, 854–856 nonadherence, 859–860, 859t overview of, 854 personality disorders, 858–859 pharmacologic interventions for, 860–861 somatization and hypochondriasis, 857–858 substance use disorder, 858 Psychophysiologic reactions, 310 Psychotherapy, 855–856, 861 Psyllium seed, 321 Pulmonary disease, primary, 836 Pulmonary edema, noncardiogenic, 333 Pulmonary fibrosis, 218, 332–333 Pulmonary function tests in asthma, 440 diffusing capacity, 176 in eosinophilic pneumonia, 176–177 hypersensitivity pneumonitis evaluations, 176, 548–549 in infants and toddlers, 501 lung volumes, 175–176, 175f types of, 176–177 2013
Pulmonary infiltrates with eosinophilia, 332 Pulmonary lobule, 218 Pulse test, 878 Pulsus paradoxus, 443, 508 Puncture test, 159 Purine nucleoside phosphorylase deficiency gene defects in, 50t physical findings associated with, 47, 47t Purpuric eruptions, 329–330 Putulosis, exanthematous, 327 Pyrethrum, 104 Q Quackery, definition of, 874 Quality of life allergic rhinitis effects on, 597 asthma effects on, 527 Quinolones, 682–683 R Racemic albuterol, 511 Radioallergosorbent test (RAST), 866 allergen testing using, 93 allergic rhinitis, 604 description of, 22, 85, 163 inhibition assay, 93–94 penicillin allergy testing, 341 pollen grains, 93 ragweed testing, 92 Radiographic contrast media allergy, 376–377 2014
Radiographs allergic bronchopulmonary aspergillosis imaging, 565–568, 565f asthma imaging, 439, 439f sinus imaging using, 192–194 Ragweed allergic rhinitis caused by, 599 asthma exacerbations caused by, 96 dermatitis caused by, 684 giant, 103f illustration of, 103f pollen grains of, 96, 102–103f, 103 radioallergosorbent testing of, 92 short, 103f species of, 104–105 (R)-albuterol, 737 Ranitidine, 723f, 731 RANTES, 66 Rat allergens, 121 Reactive airways dysfunction syndrome, 584, 585t Reactive metabolites, 313–314 Recombinant human granulocyte macrophage-colony stimulating factor, 396 Recombinant interferon-α, 397 Recombinant interferon-γ (IFN-γ), 794 Red-man syndrome, 369 Refractory asthma, 475–477 Regulator of G-protein signaling, 29 Regulatory T cells, 12 REM sleep, 845 2015
Remote practice of allergy, 884 Renal pruritus, 714, 715t Replacement immunoglobulin, in pregnancy, 809 Residual volume, 175, 175f, 438 Reslizumab, 793 Respimat Soft Mist Inhaler (SMI), 783–784, 784f Respiratory alkalosis, 510 Respiratory failure, 480 Respiratory function testing, 164 Respiratory muscles, 432 Respiratory syncytial virus, 496 Respiratory system food allergy manifestations, 407–408 hypereosinophilic syndrome findings, 72 Reversibility testing, 170 Rhinitis, 850–851 allergic. See Allergic rhinitis atrophic, 608 ciliary disorders that cause, 607 drug-induced, 605–606, 631, 632t gastroesophageal reflux and, 608 gustatory, 630–631 hypothyroidism, 607 medicamentosa, 604–605, 631 nonallergic classification of, 630, 631t definition of, 630 with eosinophilia syndrome, 603, 607–608, 630 2016
subtypes of, 631t treatment of, 632–633 occupational asthma and, 586–589 physical obstruction, 606 of pregnancy, 606, 633, 807–809 syphilis, 607 vasomotor, 607, 630, 631 Rhinophototherapy, 615–616 Rhinorrhea, 600, 606 Rhinoscopy, 233f allergic fungal sinusitis findings, 231 chronic rhinosinusitis diagnosis, 229f, 233–234 description of, 226 Rhinosinusitis. See also Sinusitis air-fluid level in, 195 allergic fungal, 199–200f, 608 allergy and, 203 causative microorganisms for, 626–627 chronic. See Chronic rhinosinusitis classification of, 196 clinical presentation of, 627–628 complications of, 628–629 computed tomography of, 194f, 628, 628f definition of, 194, 228, 626 diagnosis of, 628 fungal. See Fungal sinusitis imaging of, 194–195, 195f intracranial complications of, 202–203 2017
mucoperiosteal thickening in, 195 Rhus dermatitis, 684 Rifampin, 371 RIG-I–like receptors, 3 Rituximab, 396 Rodent allergens, 240 Rosacea, of eyelids, 649 Rosin. See Colophony Rubber-related compounds, 683–684 Ryegrass, 107 S (S)-albuterol, 737 S-IgA, 402 Salmeterol, 460t, 462, 735t, 737 Salute, allergic, 602 Sampling aeroallergen, 86–87 impaction samplers, 87, 92f suction samplers, 87–90 Sarcoidosis, 203, 204f Savin trees, 97–98 Screening tests immunologic, 51–53 laboratory, 51 Seborrheic dermatitis, of eyelids, 649 Second-generation agents pharmacodynamics, 727 pharmacokinetics, 725–727 2018
pharmacy, 727, 728t structure, 725 Secondary effects of drugs, 311 Secukinumab, 794 Segmental allergen challenge, 526 Selectins, 795 Selective glucocorticoid receptor modulators (SEGRMs), 795 Selective serotonin reuptake inhibitors, 713, 860 Seminal fluid-induced anaphylaxis, 270–271 Sepals, 97 Septoplasty, 235, 633 Serotonin-norepinephrine reuptake inhibitors (SNRIs), 860 Serum immunoglobulin G antibodies, 878 Serum sickness, 290, 321–322, 337, 343, 701–702 Serum tryptase and other tests for anaphylaxis, 868–869 Shellfish allergy, 254, 266, 406 Shiners, allergic, 602, 640 Shock, in anaphylaxis, 255, 260, 393 Short-acting β-agonists, 737–738 Short-acting b2-adrenergic agonists (SABAs), 892 Should statements distortion, 862t Sick building syndrome, 125 Side effects, 311 Signal transduction activator of transcriptions (STAT) proteins, 794 Silent sinus syndrome, 201–202, 201f Simple pulmonary eosinophilia, 221, 222f Single inhaler therapy (SiT), 741 Single nucleotide polymorphisms, 425, 891 2019
Sinonasal masses, 206–213 Sinonasal polyposis, 196, 198f Sinonasal polyps, 196, 198f Sinonasal tract, 226–228 Sinonasal undifferentiated carcinoma, 208 Sinuses anatomy of, 180, 181f embryologic development of, 226 frontal anatomy of, 180, 181f embryologic development of, 226 outflow tract of, 184 granulomatous disease involvement in, 203 imaging of, 192–194 malignancies of, 208, 229f maxillary, 180, 181f mucociliary flow from, 228 pneumatization of, 188 pseudostratified columnar ciliated epithelium of, 180, 228 Sinusitis. See also Rhinosinusitis acute, 629 maxillary, 627 Sinusitis, acute, treatment for, 629 Skin atopic dermatitis care, 668 biopsy, 702 care products, 680–682 drug allergy manifestations, 324–331 2020
food allergy manifestations, 407 Skin-prick testing (SPT), 865–866 Skin testing, 159–163 adverse reactions from, 161–162 β-lactam antibiotics, 360–363, 362t chemotherapeutic agents, 320 description of, 242 food allergies, 266 grading of, 159–160, 160t hypersensitivity pneumonitis, 550 interpretation of, 160–161, 161t intradermal test, 159, 162 medication considerations, 162 nonallergic asthma, 447 penicillin allergy, 360–363 prick description of, 159, 360 drug allergy diagnosis using, 398 food allergy diagnosis, 411–412 site of, 160 techniques for, 159 urticaria, 700–701 variables that affect, 162–163 wheal-and-flare, 340, 344 Sleep apnea, 848–850 architecture of, 845–846, 845f circadian rhythms, 846 2021
continuous positive airway pressure for, 850 deprivation, immunologic impacts of, 847–848 -disordered breathing, 850–851 disorders, in allergy patients, 848–850 as homeostatic process, 846 immune system and, 846–848 loss, 847 NREM, 845, 847t regulation of, 846 REM, 845 study, 849t Smoking acute eosinophilic pneumonia caused by, 76 asthma and chronic obstructive pulmonary disease caused by, 452 fetal exposure, 495 infant and toddler exposure to, 495–496 passive smoke inhalation, 495–496 Snoring, 848 Solar urticaria, 694t, 695 Somatic hypermutation, 10 Somatization disorder, 857–858 Sorbic acid, 681 Southeast United States, 137–140t Southwest United States, 146–147t Soybean allergy, 405 Spacer devices, 779–780, 779f Spasmogenic mediators, 31–32, 31t Specific bronchial challenge, 551 2022
Specific polysaccharide antibody deficiency, 54 Speleotherapy, 882 Sphenoethmoidal recess, 180, 181f, 182f, 184, 227 Sphenoid sinus anatomy of, 180, 181f embryologic development of, 226 pneumatization of, 188 Sphenoid sinusitis, acute, 629 Spiramycin, 331 Spirometry. See Forced spirometry Spleen tyrosine kinase (Syk), 794 Spontaneous chronic urticarial. See Urticaria, idiopathic chronic Spruce trees, 97 Sputum eosinophilia, 526 Squamous cell carcinoma, 206 Stachybotrys atra, 876 Stamen, 97 Standard of care, definition of, 875 Standard practice, definition of, 874 Staphylococcal blepharoconjunctivitis, 648–649 Staphylococcal enterotoxins, 54 Staphylococcal scalded-skin syndrome, 330 Staphylococcus aureus, 54, 229, 656, 665 Status asthmaticus, 434, 434f, 477–480, 496 Stem cell factor, 26 Stemphylium spp., 113f Stevens-Johnson syndrome, 300–305, 328, 343, 382 Stimulation index, 54 2023
Stings. See Insect stings Streptococcus pyogenes, 656 Streptokinase, 393 Strongyloides spp., 69 Subacute hypersensitivity pneumonitis, 222f Substance P, 29, 379, 432 Substance use disorders, 858 Succinylcholine, 269, 381–382 Suction samplers, 87–90 Sudden asphyxic asthma, 433 Sulfasalazine, 368–369 Sulfites, 331 Sulfonamide allergy, 316, 367, 685 Sulfur dioxide, 125 Sunscreen, ingredients for, 682 Superantigens, 232 Superior meatus, 184 Superior turbinates, 180, 182f Supraesophageal reflux disease, 453 Surfactant, 555 Sycamore trees, 100 Sympathomimetic agents, 613–614, 703 Sympathomimetics, 731 Synchronized intermittent mandatory ventilation, 514 Synechiae, 236 Syphilis, 607 Systemic contact dermatitis, 674 Systemic corticosteroids, 612–615 2024
anticholinergics, 614 antihistamines, 613 intranasal cromolyn, 614–615 leukotriene-receptor antagonists, 614 sympathomimetic agents, 613–614 Systemic lupus erythematosus, drug-induced, 322–323 Systemic vascular resistance, 800 T T cell antigen recognition adaptive immunity, 5–7 T-cell defects, 870 T-cell effector, 793–794 T-cell receptor excision circles (TRECs), 870–871 T-cell receptor, generation, 6f T cell subsets, adaptive immunity, 7–8 T cells bronchoalveolar lavage fluid, 554 CD4+, 19 CD8+, 554 helper, 21, 675, 846 histamine effects on, 722 natural killerlike, 555 T-helper cells, 846 Tachyphylaxis, 740 Tacrolimus, 671 Tartrazine, 472 Tattoos, 683 Teratogenic agents, 803 2025
Terbutaline, 460t Terfenadine, 725 Test dosing β-lactam antibiotics, 363t description of, 346, 355 sulfasalazine, 369t Tetanus toxoid vaccine, 398–399 Tetracyclines, 370, 809 Thalidomide, 713 Theophylline, 467, 512, 766t, 770–771 efficacy, 770 mechanism of action, 770 pharmacology, 770 preparations and dosing, 771 safety and drug interactions, 770–771 Thermoplasty, bronchial, 477 Thimerosal, 326, 681 Thioperamide, 723f, 731 Thrombocytopenia, 334 Thrombolytics, 393 Thunderstorm asthma, 96 Thymic stromal lymphopoeitin (TSLP), 794 Thymus activation-related chemokine, 71 Ticlopidine, 382 Timothy grass, 101–102f, 102, 107 Tiotropium, 766t, 770 Tiotropium bromide, 464 Tissue plasminogen activator, 397 2026
Tolerance, to antihistamines, 730 Toll-like receptors, 2, 426 Toluene diisocyanate, 590t Toluene sulfonamide, 681–682 Topical decongestants, 155 Torsades de pointes, 309 Total lung capacity, 175, 175f Total serum IGE, 867 Total serum immunoglobulin concentrates, 878–879 Toxemia, allergic, 875 Toxic epidermal necrolysis, 300–305, 330, 343 Toxicodendron dermatitis, 684 Toynbee phenomenon, 655 Trachea, 430 Transcription factors, inhibitors of, 794 Transrepression, 748 Tree nut allergy, 405 Trees angiosperms, 98 in California, 149t in Great Plains of United States, 144–146t gymnosperms, 97, 98f in Midwest United States, 141–143t in Northeast United States, 134–137t in Northwest of United States, 148t pollen allergens, 97, 107–110 in Southeast United States, 137–140t in Southwest United States, 146–147t 2027
Triamcinolone, 475, 758t Tricyclic antidepressants (TCA), 667–668 Trimellitic anhydride, 584t, 589 Trimethoprim-sulfamethoxazole allergy, 318, 366–367 Troleandomycin, 476 Tropical pulmonary eosinophilia, 76 Tropomyosin, 406 TRUE Test, 678, 680 Tryptase description of, 36–37, 257, 262, 296 mast cell-derived, 431 physiologic actions of, 437t testing for, 342 TSLP, characteristics of, 437t Tuberculosis (TB), 837 Tumor necrosis factor, 395, 846 Tumor necrosis factor-α, 437t, 476, 695 Turbinates function of, 192 inferior, 180, 182f middle, 180, 182f, 185, 185f superior, 180, 182f Turbuhaler, 781, 781f Two-process model, of sleep regulation, 846 Tympanometry, 657–658 Tympanostomy tubes, 660 Type I hypersensitivity, 23 Type II hypersensitivity, 23 2028
Type III hypersensitivity, 23 Type IV hypersensitivity, 23 U Uncinate process, 185, 227 Unconventional diagnostic methods, undifferentiated somatoform idiopathic anaphylaxis, 272 Unexplained chronic cough, 838 Unproved methods. See Controversial methods Upper airway cough syndrome (UACS), 834–835 Upper airways computed tomography of, 165 obstruction of, 509 Uremic pruritus, 714, 715t Uric acid, 51 Urine injections, 881 Urticaceae, 106 Urticaria acute, 689 adrenergic, 696 aggravating factors, 693 angioedema and, 689 antihistamines for, 322, 703–704 aspirin and, 372 biopsy, 693, 693t cholinergic, 695–696 chronic, 689 chronic idiopathic, 693, 694t, 702t classification of, 693–704 2029
clinical approach diagnostic studies, 700 drugs, 701 foods, 700–701 history, 699–700 infections, 701 insect stings, 701 neoplasm, 701 penetrants, 701 physical examination, 700 serum sickness, 701–702 vasculitis, 701 cold, 694t, 696 contact, 676 corticosteroids for, 703 delayed pressure, 694, 694t drug-induced, 325, 701 food-induced, 407 allergy, 700t, 700–701 histamine’s role in, 690 historical descriptions of, 689 idiopathic chronic, 702–704 incidence of, 689 infectious causes of, 701 insect stings, 701 latex-induced, 393 local heat, 694t, 696 mast cell activation in, 692t 2030
nonimmunologic, 693–696, 694t nonsteroidal anti-inflammatory drugs and, 372 papular, 698 pathogenesis of, 690–693 physical, 693–696 physical examination findings, 156 prednisone for, 703 in pregnancy, 809–810 radiographic contrast material-induced, 376 serum sickness and, 701–702 solar, 694t, 695 treatment of, 702–704, 759 vasculitis, 701 Urticaria pigmentosa, 699 V Vaccines, 243, 398–399 Vancomycin, 369–370 Variant asthma, 451 Vascular cell adhesion molecule-1, 66 Vasculitis hypersensitivity, 323–324 urticaria, 701 Vasoactive intestinal polypeptide, 428 Vasoactive mediators, 31t Vasoconstrictors, 644–645 Vasomotor conjunctivitis, 651 Vasomotor rhinitis, 607, 630 Vecuronium, 382 2031
Vei, 514 Venom, immunotherapy, 290, 810 Ventilation. See Mechanical ventilation Ventilation pneumonitis, 545 Ventilation/perfusion scans, 440 Vernal conjunctivitis, 645–647, 653t Vibratory angioedema, 694t, 699 Vilanterol, 735t Viral conjunctivitis, 649, 653t Vital capacity, 175 Vitamin supplementation, 882 Vocal cord dysfunction, 451–452, 509 W Walnut trees, 100, 100f Weeds in California, 149t definition of, 103 in Great Plains of United States, 144–146t in Midwest United States, 141–143t in Northwest of United States, 135–137t, 148t pollen allergens, 106 in Southeast United States, 138–140t, 147t types of, 103–106 Wegener granulomatosis definition of, 218 description of, 203 Wet cough, 841 Wet-wrap therapy (WWT), 671 2032
Wheal-and-flare skin tests allergic bronchopulmonary aspergillosis, 568 β-lactam antibiotic allergy testing, 362 Aspergillus fumigatus, 568 description of, 340, 344 Wheat allergy, 405 Wheezing description of, 407 differential diagnosis, 453–454, 496, 499–500t evaluation of, 497–500 in infants and toddlers, 494, 497–500, 498–500t in pregnancy, 807 in pulmonary embolism, 509 Whey, 404 Willow trees, 98–99 Wiskott-Aldrich syndrome cutaneous abnormalities associated with, 47t description of, 44 gene defects in, 49t physical examination findings, 47t X X-linked agammaglobulinemia gene defects in, 49t immunoglobulin replacement for, 57, 57t X-linked hyper-IgM syndrome gene defects in, 49t physical examination findings, 51 Y 2033
Yeasts, 112 Yellow fever vaccine allergy, 398 Yellow jacket stings, 287 Z Zafirlukast, 465, 765t, 767–768 Zanamivir, 371 Zap 70, 55 Zeta chain associated protein deficiency, 50t Zileuton, 465, 765t, 767
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