Acute and Chronic Cough - 1st Edition

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Introduction

In 1833, the English essayist and poet Charles Lamb (1775–1834) wrote to
one of his friends:
My bed fellows are cough and cramp, we sleep 3 in a bed.
Lamb was undoubtedly not alone in his gloomy view of coughing,
especially if his cough happened to be a dry one. Indeed, another pessimis-
tic assessment of coughing is reflected in an English proverb: ‘‘A dry cough
is a trumpeter of death.’’ Although the originator of this prognostication is
unknown, it is unfortunately true that persistent dry cough is often caused
by an endobronchial tumor. Other pathologies can lead to the opposite and
arguably more welcome sort of cough—that is, the productive cough—
which functions as a mode of self-cleaning and, in effect, protects the lung.
As pointed out by the editors of Acute and Chronic Cough, Dr. Anthony
E. Redington and Prof. Alyn H. Morice, ‘‘the perception of cough as a symp-
tom is now changing.’’ Extensive research on the mechanisms of cough and
on the sites of stimulation has improved understanding—for instance, the
roles of receptors and neural pathways have been identified—and we can
expect that this work will lead to better ways to control some types of cough-
ing. On the other hand, it is recognized that drug-induced coughing can
occur, leaving no alternative but to shift to different classes of medications.

iii
iv Introduction

To add to the complexity, coughing may have circulatory consequences such

as posttussive syncope due to the very high intrapulmonary pressure that
coughing sometimes creates.
Acute or chronic, dry or productive, annoying to the patient or vir-
tually unnoticed—coughing is an important symptom that must not be
ignored. This new monograph presented by the series Lung Biology in
Health and Disease gives the readers a ‘‘timely, comprehensive, and author-
itative summary of current understanding.’’ The editors have called on
experts from many countries to contribute their knowledge and perspec-
tives. Coughing has surely been a bedfellow of man forever, but it is clear
that this is still a relatively young research field. It is hoped that this volume
will stimulate interest in exploring it further.
I want to thank the editors and contributors for the opportunity to
include this monograph in the series.

Claude Lenfant, MD
Gaithersburg, Maryland
Preface

Cough is one of the most frequent complaints for which patients seek med-
ical attention. Acute cough has massive health economic consequences and
yet available treatments are at best of limited efficacy. Chronic cough is a
common and debilitating symptom that in the past has frequently been
poorly managed. Our perception of cough as a symptom is now changing.
Progress has been made in defining the range of conditions responsible for
persistent cough and scientific advances in understanding the biology of the
cough reflex should in time lead to improved therapeutic strategies. In this
volume, we have drawn on the expertise of a body of international opinion
to present the current state of knowledge concerning the pathogenesis and
treatment of acute and chronic cough.
The opening chapters address the basic science of the cough reflex.
Dr. Hwang discusses the molecular biology of the putative cough receptor
TRPV1, activation of this receptor by endogenous ligands, and molecular
mechanisms that may operate to upregulate its function in the setting of
pathologic cough. Dr. Canning and Dr. Mazzone discuss the conflicting
work on afferent nerve pathways mediating cough and present evidence that
a distinct and previously unrecognized subtype of afferent neuron may play
a primary role in regulation of the cough reflex. Dr. Shannon and colleagues
review central neuronal networks involved in generating the motor pattern
of the cough reflex and present recent novel observations from their own

v
vi Preface

laboratory. In chapter 4, Dr. Advenier and colleagues consider the evidence

to support a role for tachykinins as important mediators of cough. They dis-
cuss the antitussive effects of tachykinin receptor antagonists in animal
models, including recent work from their own laboratory, and consider their
relevance to human disease. Angiotensin converting enzyme (ACE) inhibi-
tors represent an important cause of chronic cough. In chapter 5, Dr. Mor-
ishima and colleagues review animal studies that provide insights into the
mechanisms of ACE inhibitor-induced cough and also discuss the clinical
management of this condition.
There is a need for more effective antitussive medications and the next
chapters focus on recent developments in the pharmacology of cough.
Dr. Geppetti and colleagues concentrate on the pharmacology of TRPV1
and other putative cough receptors: selective TRPV1 antagonists are now
becoming available and it is likely these will play an important role in dis-
secting cough pathways in various settings. Dr. Chung appraises other
agents that are under investigation as potential novel therapies in cough.
The third section concerns experimental methodologies. Dr. Earis and
Dr. Smith describe their work on the acoustic properties of the cough sound
and the development of automated cough recognition algorithms, studies
that will be integral to the development of a robust, accurate, and clinically
useful cough recorder. The remaining chapters in this section deal with the
various sorts of inhalation cough challenge. The authors of these chapters
critically appraise the various approaches that have been taken, make spe-
cific recommendations about how factors such as reproducibility can be
improved, and consider the way forward in terms of increasing co-operation
and standardization between different centers.
The final section addresses the more clinical aspects of cough in both
the acute and chronic settings. The emphasis here is on helpful advice on
appropriate investigation, avoiding pitfalls in diagnosis, and providing prac-
tical strategies for successful management. Prof. Eccles reviews the
mechanisms of cough associated with acute upper respiratory tract infec-
tion and highlights the lack of evidence to support the various treatments
that are widely used in this condition. Dr. Everett and Prof. Morice review
the strategies that can be taken to investigate and manage patients with
chronic cough and consider the relative merits of the different approaches.
Chapters 14–19 are devoted to the major specific causes of chronic cough.
The first two of these chapters are devoted to cough associated with gastro-
esophageal reflux disease (GERD). Dr. Ing discusses the pathogenesis of
this condition in terms of a self-perpetuating cough-reflux cycle and also
includes important recent information about hereditary autonomic neuro-
pathies associated with cough. Dr. Allen concentrates on the effective man-
agement of GERD-related chronic cough, including assessment of nonacid
reflux and the role of laparoscopic fundoplication. In chapter 16, Dr.
Redington examines the epidemiology, pathophysiology, and pathology of
Preface vii

cough-variant asthma with emphasis on how this differs from more typical
asthma. Eosinophilic bronchitis has emerged as an important cause of
chronic cough in some populations and Dr. Brightling and colleagues
discuss the diagnosis, pathophysiology and management of this condition.
Dr. Bartter and colleagues discuss the definition, differential diagnosis,
and treatment of postnasal drip. Psychogenic cough is covered by
Dr. Greenberger who offers practical advice on the diagnosis and manage-
ment of this difficult condition. Prof. Morice discusses possible mechanisms
that may be responsible for hypersensitivity of the cough reflex in disease
states and speculates how this knowledge will allow rational drug design
to normalize cough. In chapter 21, Dr. Fujimura reviews the evidence that
chronic cough is more frequent in females and discusses possible mechan-
isms underlying this difference. Assessment of quality-of-life/health status
is increasingly becoming an important outcome measure in many clinical
studies. In chapter 22, Dr. Birring and Dr. Pavord describe the development
of a validated cough-specific quality-of-life instrument, the Leicester Cough
Questionnaire, and its use in clinical and research settings. Chronic cough in
children differs in many aspects from that in adults. In the final chapter,
Dr. Marchant and Dr. Chang describe the different approach that is
necessary to diagnose and manage cough in children.
Our intention in co-editing this volume has been to produce a timely,
comprehensive, and authoritative summary of current understanding, to
suggest likely future developments, and to identify areas where knowledge
is deficient and further research is required. We hope that this will be of
interest to investigators, clinicians, and students.

Anthony E. Redington
Alyn H. Morice
Contributors

Charles Advenier U.F.R. Biomédicale des Saints Pères, Laboratoire

de Pharmacologie, Paris, France
Christopher J. Allen Firestone Institute for Respiratory Health,
St. Joseph’s Healthcare—McMaster University, Hamilton, Ontario, Canada
David M. Baekey Department of Physiology and Biophysics, College of
Medicine, University of South Florida, Tampa, Florida, U.S.A.

Thaddeus Bartter Division of Pulmonary and Critical Care Medicine,

Robert Wood Johnson Medical School at Camden, Camden, New Jersey,
U.S.A.

Mike A. Berry Respiratory Medicine, University Hospitals of Leicester

NHS Trust, Glenfield Hospitals, Leicester, U.K.
Surinder S. Birring Respiratory Medicine, University Hospitals of Leice-
ster NHS Trust, Glenfield Hospitals, Leicester, U.K.

Ziad C. Boujaoude Division of Pulmonary and Critical Care Medicine,

Robert Wood Johnson Medical School at Camden, Camden, New Jersey,
U.S.A.

ix
x Contributors

Christopher E. Brightling Respiratory Medicine, University Hospitals of

Leicester NHS Trust, Glenfield Hospitals, Leicester, U.K.

Brendan J. Canning Johns Hopkins Asthma and Allergy Center, Balti-

more, Maryland, U.S.A.

Anne B. Chang Royal Children’s Hospital, Herston Road, Herston,

Queensland, Australia

K. F. Chung National Heart & Lung Institute, Imperial College and

Royal Brompton & Harefield NHS Trust, London, U.K.

Peter V. Dicpinigaitis Albert Einstein College of Medicine and Montefiore

Medical Center, Bronx, New York, U.S.A.

John Earis Aintree Chest Centre, University Hospital Aintree, Liverpool,

U.K.

Ronald Eccles Common Cold Centre, Cardiff School of Biosciences,

Cardiff University, Cardiff, U.K.

Caroline F. Everett Postgraduate Medical Institute, University of Hull,

Castle Hill Hospital, Hull, U.K.

Giovanni A. Fontana Dipartimento di Area Critica Medico Chirurgica,

Università di Firenze, Firenze, Italy

Masaki Fujimura Kanazawa Graduate University School of Medicine,

Kanazawa, Japan

Pierangelo Geppetti Department of Critical Care Medicine and Surgery,

Clinical Pharmacology Unit, Medical School, University of Florence,
Florence, Italy

Paul A. Greenberger Department of Medicine, Northwestern University

Feinberg School of Medicine, Chicago, Illinois, U.S.A.

Selena Harrison Department of Critical Care Medicine and Surgery,

Clinical Pharmacology Unit, Medical School, University of Florence,
Florence, Italy

Sun Wook Hwang College of Medicine, Korea University, Seoul,

South Korea
Contributors xi

Alvin J. Ing University of Sydney, Concord Hospital, Concord,

New South Wales, Australia

Jack A. Kastelik Division of Academic Medicine, Postgraduate Medical

Institute, University of Hull, Castle Hill Hospital, East Yorkshire, U.K.

Vincent Lagente Faculté des Sciences Pharmaceutiques et Biologiques,

Université de Rennes, Rennes, France

Federico Lavorini Dipartimento di Area Critica Medico Chirurgica,

Università di Firenze, Firenze, Italy

Bruce G. Lindsey Department of Physiology and Biophysics, College

of Medicine, University of South Florida, Tampa, Florida, U.S.A.

Julie M. Marchant Royal Children’s Hospital, Herston Road, Herston,

Queensland, Australia

Stuart B. Mazzone Department of Neurobiology, Howard Florey

Institute, University of Melbourne, Melbourne, Victoria, Australia

Alyn H. Morice Division of Academic Medicine, University of Hull,

Hull, U.K.

Yuko Morishima Department of Pulmonary Medicine, Institute of

Clinical Medicine, University of Tsukuba, Tsukuba, Japan

Kendall F. Morris Department of Physiology and Biophysics, College

of Medicine, University of South Florida, Tampa, Florida, U.S.A.

Takashi Ohrui Department of Geriatric and Respiratory Medicine,

Tohoku University School of Medicine, Sendai, Japan

Ian D. Pavord Respiratory Medicine, University Hospitals of Leicester

NHS Trust, Glenfield Hospitals, Leicester, U.K.

Massimo Pistolesi Dipartimento di Area Critica Medico Chirurgica, Uni-

versità di Firenze, Firenze, Italy

Melvin R. Pratter Division of Pulmonary and Critical Care Medicine,

Robert Wood Johnson Medical School at Camden, Camden, New Jersey,
U.S.A.
xii Contributors

Anthony E. Redington Department of Respiratory Medicine, Hammer-

smith Hospital, London, U.K.

Hidetada Sasaki Department of Geriatric and Respiratory Medicine,

Tohoku University School of Medicine, Sendai, Japan

Kiyohisa Sekizawa Department of Pulmonary Medicine, Institute

of Clinical Medicine, University of Tsukuba, Tsukuba, Japan

Roger Shannon Department of Physiology and Biophysics, College

of Medicine, University of South Florida, Tampa, Florida, U.S.A.

Jaclyn Smith Manchester Royal Infirmary, Manchester, U.K.

Marcello Trevisani Department of Critical Care Medicine and Surgery,

Clinical Pharmacology Unit, Medical School, University of Florence,
Florence, Italy
Contents

Introduction Claude Lenfant . . . . iii

Preface . . . . v
Contributors . . . . ix
1. Molecular Biology of TRPV1 and Related Receptors . . . . . . 1
Sun Wook Hwang
Introduction . . . . 1
The TRP Channel Superfamily . . . . 2
Molecular Characterization of TRPV1 . . . . 6
Studies in TRPV1-Deficient Mice . . . . 11
Expression of TRPV1 . . . . 12
Functions of TRPV1 in the Airway . . . . 13
TRPs in Nonneuronal Cells of the Airway . . . . 14
Conclusion . . . . 15
References . . . . 15
2. Afferent Pathways Regulating the Cough Reflex . . . . . . . . 25
Brendan J. Canning and Stuart B. Mazzone
Introduction . . . . 25
Classification of Airway Afferent Nerve Subtypes . . . . 26

xiii
xiv Contents
Properties of Airway Afferent Nerve Subtypes
and Their Potential Role in Regulating Cough . . . . 27
Other Airway Afferent Nerve Subtypes . . . . 34
Interactions Between Afferent Nerve Subtypes
Evoking Cough . . . . 37
Concluding Remarks . . . . 41
References . . . . 41

3. Central Cough Mechanisms: Neuroanatomy and

Neurophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Roger Shannon, David M. Baekey, Kendall F. Morris, and
Bruce G. Lindsey
Introduction . . . . 49
Bötzinger, Pre-Bötzinger, Ventral Respiratory Group . . . . 51
Dorsal Respiratory Group . . . . 51
Pontine Respiratory Group . . . . 53
Medullary Raphe Nuclei . . . . 53
Nucleus Tractus Solitarii . . . . 54
Cerebellum . . . . 55
Lateral Tegmental Field . . . . 57
Cough Gating Mechanism/Process . . . . 57
Laryngeal Expiration Reflex . . . . 58
Summary . . . . 61
References . . . . 61

4. Role of Tachykinins in Cough . . . . . . . . . . . . . . . . . . . . . 65

Charles Advenier, Brendan J. Canning, and Vincent Lagente
Introduction . . . . 65
Tachykinins and Tachykinin Receptors
in the Airways . . . . 65
Involvement of Tachykinins in Cough . . . . 68
Tachykinin Receptor Antagonists and Cough . . . . 71
Conclusion . . . . 74
References . . . . 75

5. ACE Inhibitor-Induced Cough: Lessons from Animal

Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Yuko Morishima, Kiyohisa Sekizawa, Takashi Ohrui, and
Hidetada Sasaki
Introduction . . . . 81
Clinical Aspects of ACE Inhibitor-Induced Cough . . . . 82
Contents xv
Enzymatic Modulation of ACE and ACE Inhibitors . . . . 83
Pathogenesis of ACE Inhibitor-Induced Cough . . . . 84
Clinical Management of ACE
Inhibitor-Induced Cough . . . . 91
Summary . . . . 92
References . . . . 93

6. Pharmacology of Putative Cough Receptors . . . . . . . . . . 105

Pierangelo Geppetti, Marcello Trevisani, and Selena Harrison
Introduction . . . . 105
Molecular Mechanisms Underlying the Cough Response
in Primary Sensory Neurons . . . . 106
Modes of Activation and/or
Sensitization of TRPV1 . . . . 109
Pharmacological Intervention in
TRPV1-Mediated Cough . . . . 112
Conclusions . . . . 116
References . . . . 117

7. Pharmacological Modulation of the Cough Reflex and

Development of New Antitussives . . . . . . . . . . . . . . . . . 125
K. F. Chung
The Normal and Abnormal Cough Reflex . . . . 125
The Enhanced Cough Reflex . . . . 126
Current Cough Treatments . . . . 128
Potential Novel Classes of Antitussives . . . . 128
Conclusion . . . . 135
References . . . . 136

8. Analysis of the Cough Sound . . . . . . . . . . . . . . . . . . . . 143

John Earis and Jaclyn Smith
Introduction . . . . 143
Cough Production Mechanism . . . . 144
Recording and Analysis of the Cough Sound . . . . 145
Conclusions . . . . 157
References . . . . 158

9. Capsaicin Inhalation Cough Challenge . . . . . . . . . . . . . . 161

Peter V. Dicpinigaitis
Capsaicin . . . . 161
Cough Inhalation Challenge . . . . 161