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 86. Severe Asthma: Pathogenesis and Clinical Management, edited by S. J.
Szefler and D. Y. M. Leung
87. Mycobacterium avium-Complex Infection: Progress in Research and
Treatment, edited by J. A. Korvick and C. A. Benson
88. Alpha l-Antitrypsin Deficiency: Biology a Pathogenesis Clinical Mani-
festations a Therapy, edited by R. G. Crystal
89. Adhesion Molecules and the Lung, edited by P.A.Wardand J. C.
Fantone
90. Respiratory Sensation, edited by L. Adams andA. Guz
91. Pulmonary Rehabilitation, edited by A. P. Fishman
92. Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease,
edited by J.-P. Derenne, W. A. Whitelaw, and T. Similowski
93. Environmental Impact on the Airways: From Injury to Repair, edited by
J. Chretien and D. Dusser
94. Inhalation Aerosols: Physical and Biological Basis for Therapy, edited
by A. J. Hickey
95. Tissue Oxygen Deprivation: From Molecular to Integrated Function,
edited by G. G. Haddad and G. Lister
96. The Genetics of Asthma, edited by S. B. Liggett and D. A. Meyers
97. Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical Actions,
edited by R. P. Schleimer, W. W. Busse, and P. M. O'Byrne
98. Nitric Oxide and the Lung, edited by W. M. Zapol and K. D. Bloch
99. Primary Pulmonary Hypertension, edited by L. J. Rubin and S. Rich
100. Lung Growth and Development, edited by J. A. McDonald
101. Parasitic Lung Diseases, edited by A. A. F. Mahmoud
102. Lung Macrophages and Dendritic Cells in Health and Disease, edited by
M. F. Lipscomb and S. W. Russell
103. Pulmonary and Cardiac Imaging, edited by C. Chiles and C.E. Putman
104. Gene Therapy for Diseases of the Lung, edited by K. L. Brigham
105. Oxygen, Gene Expression, and Cellular Function, edited by L. Biadasz
Clerch and D.J. Massaro
106. Beta,-Agonists in Asthma Treatment, edited by R. Pauwels and P. M.
0 'Byrne
107. Inhalation Delivery of Therapeutic Peptides and Proteins, edited by A. L.
Adjei and P. K. Gupta
108. Asthma in the Elderly, edited by R. A. Barbee and J. W. Bloom
109. Treatment of the Hospitalized Cystic Fibrosis Patient, edited by D. M.
Orenstein and R. C. Stern
110. Asthma and Immunological Diseases in Pregnancy and Early Infancy,
edited by M. Schatz, R. S. Zeiger, and H. N. Claman
111. Dyspnea, edited by D. A. Mahler
112. Proinflammatory and Antiinflammatory Peptides, edited by S. l. Said
113. Self-Management of Asthma, edited by H. Kotses and A. Harver
114. Eicosanoids, Aspirin, and Asthma, edited by A. Szczeklik, R. J.
Gryglewski, and J. R. Vane
115. Fatal Asthma, edited by A. L. Sheffer
116. Pulmonary Edema, edited by M. A. Matthay and D. H. lngbar
117. Inflammatory Mechanisms in Asthma, edited by S. T, Holgate and W.
W. Busse
118. Physiological Basis of Ventilatory Support, edited by J. J. Marini and A.
S. Slutsky
119. Human Immunodeficiency Virus and the Lung, edited by M. J. Rosen
and J. M. Beck
120. Five-Lipoxygenase Products in Asthma, edited by J. M. Drazen, S.-€.
Dahlen, and T. H. Lee
121. Complexity in Structure and Function of the Lung, edited by M. P.
Hlastala and H. T. Robertson
122. Biology of Lung Cancer, edited by M. A. Kane and P. A. Bunn, Jr.
123. Rhinitis: Mechanisms and Management, edited by R. M. Naclerio, S. R.
Durham, and N. Mygind
124. Lung Tumors: Fundamental Biology and Clinical Management, edited
by C. Brambilla and E. Brambilla
125. Interleukin-5: From Molecule to Drug Target for Asthma, edited by C. J.
Sanderson
126. Pediatric Asthma, edited by S. Murphy and H. W. Kelly
127. Viral Infections of the Respiratory Tract, edited by R. Dolin and P. F.
Wright
128. Air Pollutants and the Respiratory Tract, edited by D.L. Swift and W. M.
foster
129. Gastroesophageal Reflux Disease and Airway Disease, edited by M. R.
Stein
130. Exercise-Induced Asthma, edited by E. R. Mcfadden, Jr.
131. LAM and Other Diseases Characterized by Smooth Muscle Prolifera-
tion, edited by J. Moss
132. The Lung at Depth, edited by C. E. G. Lundgren and J. N. Miller
133. Regulation of Sleep and Circadian Rhythms, edited by F. W. Turek and
P. C. Zee
134. Anticholinergic Agents in the Upper and Lower Airways, edited by S. L.
Spector
135. Control of Breathing in Health and Disease, edited by M. D. Altose and
Y. Kawakami
136. Immunotherapy in Asthma, edited by J. Bousquet and H. Yssel
137. Chronic Lung Disease in Early Infancy, edited by R. D. Bland and J. J.
Coalson
138. Asthma's Impact on Society: The Social and Economic Burden, edited
by K. B. Weiss, A. S. Buist, and S. D. Sullivan
139. New and Exploratory Therapeutic Agents for Asthma, edited by M.
Yeadon and Z. Diamant
140. Multimodality Treatment of Lung Cancer, edited by A. T. Skarin
141. Cytokines in Pulmonary Disease: Infection and Inflammation, edited by
S. Nelson and T. R. Martin
142. Diagnostic Pulmonary Pathology, edited by P. T. Cagle
143. Particle-Lung Interactions, edited by P. Gehr and J. Heyder
144. Tuberculosis: A Comprehensive International Approach, Second Edi-
tion, Revised and Expanded, edited by L. B. Reichrnan and E. S.
Hershfield
145. Combination Therapy for Asthma and Chronic Obstructive PUhOnary
Disease, edited by R. J. Martin and M. Kraft
146. Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Di-
sease, edited by T. D. Bradley and J. S. Floras
147. Sleep and Breathing in Children: A Developmental Approach, edited by
G. M. Loughlin, J. L. Carroll, and C. L. Marcus
148. Pulmonary and Peripheral Gas Exchange in Health and Disease, edited
by J. Roca, R. Rodriguez-Roisen, and P. D. Wagner
149. Lung Surfactants: Basic Science and Clinical Applications, R. H. Notter
150. Nosocomial Pneumonia, edited by W. R. Jawis
151. Fetal Origins of Cardiovascular and Lung Disease, edited by David J. P.
Barker
152. Long-Term Mechanical Ventilation, edited by N. S. Hill
153. Environmental Asthma, edited by R. K. Bush
154. Asthma and Respiratory Infections, edited by D. P. Skoner

ADDITIONAL VOLUMES IN PREPARATION

Airway Remodeling, edited by P. H.Howarth,J.W.Wilson, J. Bous-

quet, S. Rak, and R. Pauwels

Respiratory-Circulatory Interactions in Health and Disease, edited by S.

M. Scharf, M. R. Pinsky, and S. Magder

The Lung at High Altitudes, edited by T. F. Hornbein and R. B. Schoene

Genetic Models in Cardiorespiratory Biology, edited by G. G. Haddad

and T. Xu

The opinions expressed in these volumes do not necessarily represent

the views of the National Institutesof Health.
This Page Intentionally Left Blank
 ASTHMA AND
RESPIRATORY
INFECTIONS

Edited by

David P. Skoner
Children's Hospitalof Pittsburgh
University of Pittsburgh Schoolof Medicine
Pittsburgh, Pennsylvania

m
M A R C E L

MARCEL DEKKER,
INC. NEWYORK BASEL
__
D E K K E R
ISBN: 0-8247-7710-7

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INTRODUCTION

Asrl~rnaand Respircztory Infection is much more than the title of this volume; it
is an issue of major importance to the understandingof asthma, its pathogenesis,
as well as the reasons for its development. Indeed, rhinoviral infections, lower
respiratory tract infections, allergic rhinitis, and asthma are all pathologies that
are sometimes interconnected and sometimes unrelated.
Today, a large body of evidence links these pathologies in one way or
another, but seemingly contradictory questions persist. For example, do viral re-
spiratory infections actually trigger the developmentof asthma, or do they merely
exacerbate it‘? Conversely, are individuals with a history of asthma more likely
to become infected, especially with rhinovirus? Regardless of the sequence of
events that relate respiratory infection and asthma, much is to be learned about the
cellular, subcellular, and molecular mechanisms that may bind these pathologies.
The complexity of this relationship is heightened by the observation that
exposure to respiratory viral infections in very early life may protect a child from
developing asthma. This notion provokes a bit of knee-jerk skepticism . . . but
not so fast!Theso-called“hygienehypothesis”suggests thatareductionof
respiratory infectious disease, or increased use of antibiotics in early life, has
led to increased prevalence of allergic disease, including asthma. Although the

...
l11
biological mechanisms of this hypothesis are not yet fully understood, its epide-
miological basis is hard to challenge.
This volume, edited by David P. Skoncr, does not address the possibility
of asthma prevention by early respiratory infection, but it does open the window
o n the interplay between asthma and respiratory infection i n childhood and adult
lifc. The L L I I IBiology
~ i n Health and Disease scries of monographs has intro-
duced a large numberof volumes about asthma. each focusing o n a specific aspect
of this disease. And here and there, therole of respiratory infection has been
touched upon; however, this volume is the first to present a cotnprehensive dis-
cussion of how asthma and respiratory infections relate t o each other. Thus, it
is an itnportant addition to the series.
Dr. Skoner and theexpertcontributors he has assembled presenttothe
readership-basicresearcher and clinician as well-what we knowtoday and
what we do not know. It is clear that much additional work needs to be done to
illuminate further this very important area of lung disease. In Dr. Skoncr’s words
in his Preface, “ultimately the patients will be the beneficiaries.”
As the Executive Editor o f this series of monographs, 1 thank the editor
and the authors for this major contribution to our understanding of a complex
and elusive topic.

Claude Lenfant, M.D.

Bethesda, Maryland
PREFACE

Healthy individuals experience many upper respiratory tract infections per year,
commonly referred to as “colds.” Asthma has also become an increasingly prev-
alent and costly disorder in our society. A link between these two disorders has
been postulated for the last few decades, but has now been soliditied based on
recent information.
Patients who experience acute asthma attacks often report the presence of
a cold in the days preceding the attack. Since approximately 1957, respiratory
viruses have been implicated as the cause of such colds in asthmatic patients.
However, the magnitude of the virus-asthma link and the cellular and biochemi-
cal mechanisms by which viruses could trigger asthma have only recently be-
come the subject of intense investigation in a number of laboratories across the
world. This accumulating baseof evidence collected through modern technology
prompted the publication of this volumein the prestigious Lung Biologyin Health
and Disease series.
The discovery and isolation of viruses were pivotal to investigating the
virus-asthma relationship. Influenza viruses were first isolated in 1933 and the
discovery of other respiratory viruses, such as parainfluenza virus and respiratory
syncytial virus, followed in the 1940s and 1950s. It was not until I960 that David
Tyrrell and colleagues at the Common Cold Research Unit of Salisbury, England,
1’
discovered rhinoviruses, which are now recognized as the most common precipi-
tants of acute asthma attacks. Rhinoviruses have also been associated with exacer-
bations of chronic bronchitis and acute otitis media; however, this book focuses
exclusively upon their role in asthma.
The list of contributors to this volumeis impressive. It includes both clinical
and basic scientists, which fosters a bench-to-bedside approach, an approach that
is warranted more than ever due to the rapid and unprecedented development of
new vaccines and antiviral agents with the potential to modify the development
and/or expression of asthma, and the publication of national and international
guidelines on the diagnosis and management of adult and pediatric asthma.
This comprehensive andtimely review of the relationship between respira-
tory viruses and asthma is unique and should be of great interest to basic scien-
tists, virologists. clinicians and clinical investigators with an interest in asthma
(e.g., allergists/immunologists, pulmonologists, pediatricians, internists,and gen-
eral practitioners), as well as individuals in the pharmaceutical industry. In addi-
tion to incorporating a wide body of recent research, this state-of-the-art volume
should illuminate future pathways of research in this important field, with the
goal of ultimately benefiting affected patients.
I would liketo acknowledge the assistance and support of a number of
individuals, including Mary Beth Wesesky; Betty Angelini, R.N., B.S.N.; Wil-
liam J. Doyle, Ph.D.; and Mark Sperling, M.D. To my parents, Peter and Helen,
my wife, Janet, my children, Jessica, Alison, Jonathan, Amanda, and Julianne.
siblings Barbara, Peter, and John, and special friends Joseph Kenneth Skoner and
Rev. John T. Boyle, I express my sincere gratitude. Finally, 1 acknowledge the
contribution ofthe eminent editorof this series, Dr. Claude Lenfant, whose enthu-
siasm, support, and gentle,but firm, direction made the completionof this volume
possible.
CONTRIBUTORS

Robert L. Atmar, M.D. Associate Professor of Medicine, Microbiology and

Immunology, and Molecular Virology, Department of Medicine, Baylor College
of Medicine, Houston, Texas

Richard Beasley, M.B.Ch.B., D.M., F.R.A.C.P. Professor of Medicine, De-

partment of Medicine, Wellington School of Medicine, Wellington, New Zea-
land

William W. Busse, M.D. Professor,Department of Medicine,University of

Wisconsin Medical School, Madison, Wisconsin

A. J. Chauhan University of Southampton, Southampton, England

Sheldon Cohen, Ph.D. Professor, Department of Psychology, Carnegie Mellon

University, Pittsburgh, Pennsylvania

Jonathan M. Corne, M.A., M.R.C.P. UniversityMedicine,University of

Southampton, Southampton, England
vii
 ...
1’1l l Cor~trihutors

Floyd W. Denny, Jr., M.D. EmeritusProfessor of Pediatrics.University of

North Carolina School of Medicine, Chapel Hill, North Carolina

Elliott F. Ellis, M.D. FormerMedicalDirector,MUROPharmaceutical,

Tewksbury, Massachusetts

Gert Folkerts, Ph.D. AssociateProfessor.Department of Pharmacologyand

Pathophysiology. Faculty of Pharmacy, Utrecht University, Utrecht, The Nether-
lands

Deborah A. Gentile, M.D. Assistant Professor, Department of Pediatrics, Chil-

dren’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania

James E. Gern, M.D. Associate Professor, Department of Pediatrics, Univer-

sity of Wisconsin Medical School, Madison, Wisconsin

Jack M. Gwaltney, Jr., M.D. Head, Division of Epidemiology and Virology,

and Professor, Department of Internal Medicine, University of Virginia Health
Sciences Center, Charlottesville, Virginia

Richard G. Hegele, M.D., F.R.C.P.(C), Ph.D. AssociateProfessor,Depart-

ment of Pathology and Laboratory Medicine, University of British Columbia,
Vancouver, British Columbia. Canada

James C. Hogg, M.D., Ph.D., F.R.C.P.(C) Professor of Pathology, Pulmonary

Research Laboratory, Universityof British Columbia, Vancouver, British Colum-
bia, Canada

Sebastian L. Johnston, M.B., B.S., M.R.C.P., Ph.D. Senior Lecturer, Univer-

sity Medicine, University of Southampton, Southampton, England

Michael Kabesch, M.D. UniversityChildren’sHospital,Munich,Germany

Robert F. Lemanske, Jr., M.D. Professor,Departments of Pediatricsand

Medicine, University of Wisconsin Medical School, Madison, Wisconsin

Frans P. Nijkamp, Ph.D. Professor of PharmacologyandPathophysiology.

Utrecht University, Utrecht, The Netherlands

Mario Rodriguez Assistant Professor, Department of Medicine, Medical Col-

lege of Pennsylvania, Hahnemann University, Philadelphia, Pennsylvania
Contributors i.u

David P. Skoner, M.D. Chief,AllergyandImmunologySection,Children’s

Hospital of Pittsburgh, and Associate Professorof Pediatrics and Otolaryngology.
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Ronald B. Turner, M.D. Professor of Pediatrics,Department of Pediatrics,

Medical University of South Carolina, Charleston, South Carolina

David Tyrrell, M.D., F.R.C.P., F.R.C.Path, F.R.S. FormerDirector,Com-

mon Cold Unit, Salisbury, Wiltshire, England

Henk J. Van der Linde Utrecht University, Utrecht, The Netherlands

Erika von Mutius, M.D. Head, Allergy and Outpatient Clinic, University Chil-
dren’s Hospital, Munich, Germany

Theodore J. Witek, Jr. BoehringerIngelheimPharmaceuticals,Ridgefield,

Connecticut
This Page Intentionally Left Blank
CONTENTS

...
Series Itltrocluction (Clrr~tde Let6ltlt) 111
PrefilcL. 1'
Cotltrihtors 11;;

Part
One EPIDEMIOLOGY
1. The Impact of Respiratory Virus Infections on the
World's Children 1
Floyd W. Denny, Jr.
1. Introduction 1
11. Classification of AcuteRespiratoryInfections 2
111. Etiology of AcuteRespiratoryTractInfections 3
IV. Role of RespiratoryVirusesandBacteriaasCauses
of Acute Respiratory Infections 7
V. Role of Various Risk Factors in the Occurrence of
Acute Respiratory Infections 13
VI.Role of AcuteRespiratoryInfections in Developing
Countries 15
VII. SummaryandConclusions 19
References 20
Xi
.\-ii

2. RespiratoryViruses and Asthma: Epidemiological

Considerations in Evaluating Their Association 23
T l ~ r o c l o r.I.~ Wit& Jr.

I. Introduction 23
11. RespiratoryVirusesAssociatedwithAsthma 24
111. BasicObservations 27
IV. Host andEnvironmentalFactors 37
V. Summary 39
References 40

45

1. Early Case Reports 45

11. Indirect Evidence-Time-Series Studies 46
111. Studies i n Adults 48
IV. Cross-Sectional Studies i n Children 48
V. Hospital-Based Incidental Studies in Children 51
VI. Hospital-Based Incidental Studies i n Adults 52
vu. Cohort Studies i n Children 52
VIII. Cohort Studies in Adults 55
IX. Studies Utilizing PCR-Children 56
X. Studies Utilizing PCR-Adults 58
XI. Summary of Studies 58
XII. Future Studies 59
XIII. Conclusions 60
References 60

4. Risk Factors for Wheezing withViralUpperRespiratory

Tract Infections in Children 63
Michcrc~lK t h ~ s c / 1rrrd Eriktr 11011 MLrtir1.s

I . Introduction 63
11. Wheezing i n Infancy andChildhood 64
111. IncidenceandType of ViralInfections in Wheezing
Lower Respiratory Tract Illnesses 66
IV.RiskFactors for Wheeze withViralRespiratoryTract
Infections 67
V. Summary 78
References 79