Cough: Causes,
Mechanisms and
Therapy
Edited by
Kian Fan Chung
MD DSc FRCP
National Heart and Lung Institute
Imperial College and Royal Brompton & Harefield NHS Trust
London
UK
John G. Widdicombe
MA DPhil DM FRCP
University of London and
116 Pepys Road
London
UK
Homer A. Boushey
MD
Department of Medicine
University of California San Francisco
San Francisco
California
USA
Cough: Causes, Mechanisms and Therapy
Cough: Causes,
Mechanisms and
Therapy
Edited by
Kian Fan Chung
MD DSc FRCP
National Heart and Lung Institute
Imperial College and Royal Brompton & Harefield NHS Trust
London
UK
John G. Widdicombe
MA DPhil DM FRCP
University of London and
116 Pepys Road
London
UK
Homer A. Boushey
MD
Department of Medicine
University of California San Francisco
San Francisco
California
USA
© 2003 by Blackwell Publishing Ltd
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First published 2003
Library of Congress Cataloging-in-Publication Data
Cough : causes, mechanisms, and therapy / edited by Kian Fan Chung, John G. Widdicombe,
Homer A. Boushey.
p. ; cm.
Includes bibliographical references and index.
ISBN 1-4051-1634-X
1. Cough.
[DNLM: 1. Cough. WF 143 C854 2003] I. Chung, K. Fan, 1951– II. Widdicombe,
John G. III. Boushey, Homer A.
RC741.5.C68 2003
616.2 — dc21
ISBN 1-4051-1634-X
A catalogue record for this title is available from the British Library
Set in 9/111/2 pt Sabon by SNP Best-set Typesetter Ltd., Hong Kong
Printed and bound in Great Britain at CPI Bath, Bath
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Managing Editor: Rupal Malde
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2003011068
Contents
Contributors, vii
Preface, xi
Section 1: Introduction
1 The clinical and pathophysiological challenge of cough, 3
Kian Fan Chung
2 Epidemiology of cough, 11
Alyn H. Morice
3 A brief overview of the mechanisms of cough, 17
John G. Widdicombe
Section 2: Cough in the Clinic
4 Clinical assessment of cough, 27
Lorcan P.A. McGarvey
5 Measurement and assessment of cough, 39
Kian Fan Chung
6 Cough sensitivity: the use of provocation tests, 49
Rick W. Fuller
7 Causes, assessment and measurement of cough in children, 57
Anne B. Chang
8 The quality of life in coughers, 75
Richard S. Irwin, Cynthia L. French & Kenneth E. Fletcher
Section 3: Clinical Conditions with Cough
9 Cough in lower airway infections, 83
Wee-Yang Pek & Homer A. Boushey
10 Cough and gastro-oesophageal reflux, 97
Alvin J. Ing
11 Cough in postnasal drip, rhinitis and rhinosinusitis, 107
Bruno C. Palombini & Elisabeth Araujo
12 Cough and airway hyperresponsiveness, 115
Paul M. O’Byrne
13 Cough in chronic obstructive pulmonary disease, 125
Kian Fan Chung & Peter M.A. Calverley
14 Cough in suppurative airway diseases, 137
Robert Wilson
15 Cough in cancer patients, 147
Sam H. Ahmedzai & Nisar Ahmed
v
CONTENTS
Section 4: Pathophysiology
16 Sensory pathways for the cough reflex, 161
Stuart B. Mazzone, Brendan J. Canning & John G. Widdicombe
17 Neurogenesis of cough, 173
Donald C. Bolser, Paul W. Davenport, Francis J. Golder, David M. Baekey,
Kendall F. Morris, Bruce G. Lindsey & Roger Shannon
18 Plasticity of vagal afferent fibres mediating cough, 181
Marian Kollarik & Bradley J. Undem
19 Motor mechanisms and the mechanics of cough, 193
Giovanni A. Fontana
20 Mucus hypersecretion and mucus clearance in cough, 207
W. Michael Foster
21 Animal models of cough, 217
Maria G. Belvisi & David J. Hele
Section 5: Therapy
22 Mechanisms of actions of centrally acting antitussives — electrophysiological and
neurochemical analysis, 225
Kazuo Takahama
23 Pharmacology of peripherally acting antitussives, 237
Sandra M. Reynolds, Domenico Spina & Clive P. Page
24 Current and potential future antitussive therapies, 247
Peter V. Dicpinigaitis
25 Placebo effects of antitussive treatments on cough associated with acute upper
respiratory tract infection, 259
Ronald Eccles
26 Mucoactive agents for the treatment of cough, 269
Bruce K. Rubin
27 Management of cough, 283
Kian Fan Chung
Index, 299
vi
Contributors
Nisar Ahmed
Brendan J. Canning
Academic Palliative Medicine Unit, Division of
Clinical Sciences, Royal Hallamshire Hospital,
Glossop Road, Sheffield S10 2JF, UK
Johns Hopkins Asthma and Allergy Center, 5501
Hopkins Bayview Circle, Baltimore, MD 21224,
USA
Sam H. Ahmedzai
Anne B. Chang
Academic Palliative Medicine Unit, Division of
Clinical Sciences, Royal Hallamshire Hospital,
Glossop Road, Sheffield S10 2JF, UK
Paediatric Respiratory Consultant, Department of
Respiratory Medicine, Royal Children’s Hospital
Foundation, Herston, and Associate Professor of
Paediatrics, University of Queensland, Queensland
4029, Australia
Elisabeth Araujo
Otorhinolaryngology and Respiratory Diseases,
Universidade Federal do Rio Grande do Sul, 90020090 Porto Alegre, RS Brazil
David M. Baekey
Department of Physiology and Biophysics, College of
Medicine, University of South Florida, Tampa, FL
33612, USA
Maria G. Belvisi
Respiratory Pharmacology Group, Cardiothoracic
Surgery, National Heart & Lung Institute, Faculty of
Medicine, Imperial College of Science, Technology
and Medicine, London SW3 6LY, UK
Donald C. Bolser
Department of Physiological Sciences, College of
Veterinary Medicine, University of Florida, PO Box
100144, Gainesville, FL 32610-0144, USA
Homer A. Boushey
Professor of Medicine, Department of Medicine,
University of California San Francisco, 505 Parnassus
Avenue, San Francisco, CA 94143, USA
Peter M.A. Calverley
Department of Medicine, University of Liverpool, and
University Hospital Aintree, Liverpool, UK
Kian Fan Chung
National Heart & Lung Institute, Imperial College
and Royal Brompton & Harefield NHS Trust,
Dovehouse Street, London SW3 6LY, UK
Paul W. Davenport
Department of Physiological Sciences, College of
Veterinary Medicine, University of Florida,
Gainesville, FL 32610, USA
Peter V. Dicpinigaitis
Associate Professor of Clinical Medicine, Albert
Einstein College of Medicine, and Director, Intensive
Care Unit, Jack D. Weiler Hospital of the Albert
Einstein College of Medicine, Bronx, New York, NY
10461, USA
Ronald Eccles
Common Cold Centre, Cardiff School of Biosciences,
Cardiff University, Cardiff CF10 3US, UK
Kenneth E. Fletcher
Associate Professor of Psychiatry and the Graduate
School of Nursing, University of Massachusetts
Medical School, 55 Lake Avenue North, Worcester,
MA 01655, USA
vii
CONTRIBUTORS
Giovanni A. Fontana
Stuart B. Mazzone
Dipartimento di Area Critica Medico Chirurgica,
Unità Funzionale di Medicina Respiratoria, Università
degli Studi di Firenze, Firenze, Italy
Howard Florey Institute of Experimental Physiology
and Medicine, University of Melbourne, Melbourne,
Victoria 3010, Australia
W. Michael Foster
Lorcan P.A. McGarvey
Pulmonary and Critical Care Medicine, MSRB
Room #275, Research Drive, Duke University
Medical Center, Durham, NC 27710, USA
Cynthia T. French
University of Massachusetts Memorial Health Care,
55 Lake Avenue North, Worcester, MA 01655, USA
Rick W. Fuller
Director of Science Funding, The Wellcome Trust, 183
Euston Road, London NW1 2BE, UK
Francis J. Golder
Department of Physiological Sciences, College of
Veterinary Medicine, University of Florida,
Gainesville, FL 32610, USA
David J. Hele
Respiratory Pharmacology Group, Cardiothoracic
Surgery, National Heart & Lung Institute, Faculty of
Medicine, Imperial College of Science, Technology
and Medicine, London SW3 6LY, UK
Alvin J. Ing
Thoracic Physician, Clinical Senior Lecturer,
University of Sydney, Concord Hospital, Concord,
NSW 2139, Australia
Richard S. Irwin
Professor of Medicine, University of Massachusetts
Medical School, 55 Lake Avenue North, Worcester,
MA 01655-0330, USA
Marian Kollarik
Johns Hopkins Asthma and Allergy Center, 5501
Hopkins Bayview Circle, Baltimore, MD 21224, USA
Bruce G. Lindsey
Department of Physiology and Biophysics, College of
Medicine, University of South Florida, Tampa, FL
33612, USA
viii
Senior Lecturer/Consultant Physician, Department of
Medicine, The Queen’s University of Belfast, Belfast,
Northern Ireland
Alyn H. Morice
Head of Academic Department of Medicine, Castle
Hill Hospital, Castle Road, Cottingham, East
Yorkshire HU16 5JQ, UK
Kendall F. Morris
Department of Physiology and Biophysics, College of
Medicine, University of South Florida, Tampa, FL
33612, USA
Paul M. O’Byrne
Firestone Institute for Respiratory Health, St Joseph’s
Hospital, 50 Charlton Avenue East, Hamilton,
Ontario L8N 4A6, Canada
Clive P. Page
The Sackler Institute of Pulmonary Pharmacology, 5th
Floor Hodgkin Building, GKT School of Biomedical
Sciences, Guy’s Campus, King’s College London,
London SE1 1UL, UK
Bruno C. Palombini
Pavilhao Pereira Filho, Irmandade da Santa Casa de
Misericordia de Porto Alegre, Universidade Federal do
Rio Grande do Sul, Rua Prof. Annes Dias 285, 90020090 Porto Alegre, RS Brazil
Wee-Yang Pek
Visiting Postgraduate Fellow in Pulmonary and
Allergy/Immunology, Department of Medicine,
University of California San Francisco, 505 Parnassus
Avenue, San Francisco, CA, 94143, USA
CONTRIBUTORS
Sandra M. Reynolds
Kazuo Takahama
The Sackler Institute of Pulmonary Pharmacology, 5th
Floor Hodgkin Building, GKT School of Biomedical
Sciences, Guy’s Campus, King’s College London,
London SE1 1UL, UK
Department of Environmental and Molecular Health
Sciences, Graduate School of Pharmaceutical Sciences,
Kumamoto University, 5-1 Oe-honmachi, Kumamoto
862-0973, Japan
Bruce K. Rubin
Bradley J. Undem
Professor and Vice-Chair of Pediatrics, Professor of
Biomedical Engineering, Physiology and
Pharmacology, Department of Pediatrics, Wake Forest
University School of Medicine, Medical Center
Boulevard, Winston-Salem, NC 27157-1081, USA
Johns Hopkins Asthma and Allergy Center, 5501
Hopkins Bayview Circle, Baltimore, MD 21224, USA
John G. Widdicombe
University of London and 116 Pepys Road, London
SW20 8NY, UK
Roger Shannon
Department of Physiology and Biophysics, College of
Medicine, University of South Florida, Tampa, FL
33612, USA
Domenico Spina
Robert Wilson
Consultant Physician, Royal Brompton Hospital, and
Reader, National Heart & Lung Institute at Imperial
College of Science, Technology and Medicine, Sydney
Street, London SW3 6NP, UK
The Sackler Institute of Pulmonary Pharmacology, 5th
Floor Hodgkin Building, GKT School of Biomedical
Sciences, Guy’s Campus, King’s College London,
London SE1 1UL, UK
ix
Preface
Cough is the most common symptom of airway and
lung disease. More money is spent at the pharmacy on
‘coughs and colds’ than on any other symptom except
perhaps ‘aches and pains’. It can be a presenting symptom of more than 100 clinical conditions of the respiratory system. At international meetings of, for example,
the American Thoracic Society and the European Respiratory Society, cough is one of the most frequent
items listed in the Proceedings’ indices. Surprisingly, it
has seldom been comprehensively reviewed, although
most textbooks of respiratory medicine contain a short
chapter on the subject, as do texts on respiratory
pharmacology and therapeutics. Physiology textbooks
largely ignore it.
In 1970, Salem and Aviado published a three-volume
text on Antitussive Agents [1] which has become a classic that, while of limited scope, badly needs updating.
In 1974, Korpas and Tomori published Cough and
Other Respiratory Reflexes [2], a valuable text dealing
mainly with animal studies from distinguished research
centres in Eastern Europe. There is an excellent short
book (published in 2001 but in Italian!) La Tosse
Fisiopatologia e Clinica by Fontana, Lavorini, Pantaleo and Pistolesi [3]. There have been a number of published symposium proceedings dedicated to cough
[4–9]. All these publications are somewhat restricted in
their approach and most need to be brought up to date.
Two of the symposia [7,8], based on the 1st and 2nd
International Symposia on Cough held in London in
1996 and 2001, attracted much support and interest;
this response was in large part the stimulus to the
present book.
We therefore believe that this book is the first comprehensive review, by internationally distinguished authors, of a subject of great importance to respiratory
basic science and medicine, and to health care. We have
tried to make it inclusive, but are aware that there may
be gaps. We have particularly tried to review the significance of cough in the wider context of clinical medicine, a subject which has seen impressive advances in
understanding in recent years; and in the basic physiological mechanisms of cough. Understanding of the
latter has been transformed recently by studies of the
plasticity of cough mechanisms at peripheral and central nervous levels, research that has important relevance to what happens in acute, subacute and chronic
airways’ disease. Basic pharmacological studies are
also having a significant impact on the therapy of
cough, an influence which is likely to be dramatically
extended in the near future. With such an approach and
coverage, we hope that our book will be helpful to a
wide readership of clinicians (particularly general
practitioners), respiratory and paediatric physicians,
respiratory physiologists and scientists interested in
cough and lung reflexes, and pharmacologists in search
of better treatments for cough.
In compiling this volume, we have ourselves learnt a
lot more but have also realized that there are large gaps
both at the clinical and basic level of understanding and
treatment of this common symptom. We hope that the
readers will be similarly challenged.
We are grateful for the cooperation, diligence and
expertise of our many contributors; for the valuable
advice and support of our colleague Tim Higenbottam
at AstraZeneca UK; and for the skill and efficiency of
our publishers, Blackwell Publishing, in particular
Maria Khan, Rupal Malde and Nick Morgan.
Fan Chung
John Widdicombe
Homer Boushey
References
1 Salem H, Aviado DM, eds. Antitussive Agents. International Encyclopedia of Pharmacology and Therapeutics,
section 27, Volumes I–III. Oxford: Pergamon Press, 1970.
2 Korpas J, Tomori Z. Cough and other respiratory reflexes.
In: Progress in Respiratory Research, Vol. 12. Basel: Karger,
1978.
3 Fontana GA, Lavorini F, Pantaleo T et al., eds. La Tosse
Fisiopatologia e Clinica. Pisa: Primula, 2001.
4 Berglund E, Nilsson BS, Mossberg B et al. Cough and expectoration. Eur J Respir Dis 1980; 61 (Suppl. 110): 1–262.
5 Widdicombe JG, Korpas J, Salat D, eds. The cough reflex.
Bull Eur Physiopath Respir 1987; 23 (Suppl. 10): 11S–76S.
xi
PREFACE
6 Korpas J, Widdicombe JG, eds. Cough and related phenomena. Respir Med 1991; 85 (Suppl. A):1–68.
7 Widdicombe J, ed. Cough: methods and measurements.
Pulm Pharmacol 1996; 9: 261–392.
xii
8 Widdicombe J, Chung F, eds. Cough: pharmacology and
therapeutics. Pulm Pharmacol Ther 2002; 15: 185–338.
9 Korpas J, Widdicombe JG, eds. Cough: recent advances in
understanding. Eur Respir Rev 2002; 85: 221–82.
SECTION 1
Introduction
1
The clinical and pathophysiological
challenge of cough
Kian Fan Chung
Introduction
Cough is a symptom that has been experienced by every
human and is an essential protective and defensive act
whose action secures the removal of mucus, noxious
substances and infections from the larynx, trachea
and larger bronchi. Coughing is the most efficient
mechanism for clearing the upper airways, and can be
considered to be an innate inbuilt defence mechanism.
Impairment or absence of the coughing mechanism can
be harmful and even fatal in disease. On the other hand,
cough may be the first overt sign of disease of the airways or lungs, when it represents more than a defence
mechanism, and by its persistence becomes a helpful
pointer for both patient and physician of potential
disease. Nearly all conditions affecting the respiratory
system and some extrapulmonary conditions may
cause cough, but to the physician it is most important
to exclude the most serious conditions that need
prompt treatment. Cough may be persistent in incurable diseases such as in terminal lung cancer, when
other chronic symptoms are also present such as dyspnoea and pain. Cough may be the most prominent
symptom complained of by patients with chronic respiratory disease such as asthma [1]. Excessive persistent
cough may also be present in association with chronic
non-malignant disease with or without excessive
mucus production. The effect of persistent cough itself
may be harmful and deleterious to the patient by interfering with breathing, social activities and sleep, and by
causing deterioration in the quality of life and social
embarrassment, not to mention syncopal episodes, urinary incontinence, muscle ache, insomnia and fatigue.
Thus, cough is a symptom with many facets: a protec-
tive mechanism for the lungs, a warning sign of disease,
and a detrimental symptom when persistent.
With these several aspects of the problem of cough,
the challenge to understand and adequately treat cough
has been and remains daunting, from both the investigational and clinical angles. Our pathophysiological
understanding of the genesis of cough is incomplete,
particularly with reference to disease. This volume will
focus on all the clinical, pathogenetic and treatment
aspects of cough. To approach the challenge presented
by cough, this first chapter will discuss the following
themes: (i) the normal cough; (ii) the significance of
cough in the community; (iii) the spectrum of cough
presenting to the clinician; (iv) the mechanisms of
increased cough sensitivity; and (v) the treatment of
cough.
The normal cough
What is a normal cough pattern? How often do healthy
people cough? There are no clear data. Cough is not
necessarily an ‘abnormal’ symptom with clinical significance. But when does a normal pattern of cough becomes an abnormal one? One presumes that a cough is
necessary to clear the airways of the mucus and fluid
secretion from the airways (estimated to be 20–30 mL
over 24 h), and the amount of airway secretion may be
related to the amount of exposure to daily irritants.
City dwellers exposed to increasing pollution such as
particulate materials may cough more. The fact that
healthy people need to cough may be judged from the
occurrence of cough during large gatherings for a lecture or concert or during intervals of concerts, and a
3
CHAPTER 1
rate of 2.5 coughs/min has been quoted for a gathering
of 100 people in a lecture room [2]. In a small group of
healthy people in whom cough was monitored using a
portable cough counter, the frequency of cough over a
24-h period was found to be less than 16 coughs [3] and
11 bursts of cough per 24 h (range 1–34) in children [4],
or a range of 0–141 (median of 10) coughs per day if
children with respiratory infections are included [5].
We do not know whether the normal protective cough
reflex occurs during sleep, particularly during rapid eye
movement sleep; presumably it does, since there is no
other obvious protective mechanism that can be invoked. The smoker with a chronic morning cough usually considers his or her cough to be normal, necessary
to clear the airways of the excessive secretions induced
by cigarette smoke. However, to study the normality of
cough, it is important to exclude the possibility of an
enhanced cough reflex response which may be induced
by cigarette smoking or even perhaps daily exposure to
pollutants. A cough may be provoked by a tussive
stimulus, and the likelihood of this cough occurring is
increased by the presence of an enhanced cough reflex.
The definition of normality of cough experience needs
to be studied from the point of view of the event, the
type of cough and the cough sensitivity reflex, so that
the significance of cough prevalence studies can be
determined.
Prevalence of cough in the community
In several epidemiological surveys, persistent cough is
reported as a symptom that affects a large proportion
of the general population, being prevalent for example
in 18% of the US population, in up to 16% of a southeast English population and in 11% of the Swedish
population [6–8]. In these surveys, there has been no estimate of how many of these reported symptoms have
received medical attention, and whether the person
considers the cough to be a ‘normal’ symptom. In investigations of the Swedish part of the European Community Respiratory Health Survey (ECRHS) [9,10], a
higher prevalence of nocturnal and non-productive
cough was reported in females than in males. In a more
recent trans-European survey of ECRHS, about onethird of subjects reported that they had been woken up
by an attack of cough in the last 12 months, and about
20% reported a non-productive or productive cough
during the winter months [11]. There was again a pre4
ponderance of females with nocturnal and nonproductive cough, and nocturnal cough was related to
asthma, tobacco smoking, exposure to environmental
tobacco smoke and obesity. However, there has been
no detailed community survey of the potential diseases
underlying the cough reported.
Exposure to pollutants or environmental irritants
appears to be important, judging from the epidemiological information linking dry or productive cough
with outdoor air pollution, particularly in children. In
adults and schoolchildren, productive cough or chronic
nocturnal dry cough has been associated with levels of
the PM10 particulates [12,13]. Increases in levels of
PM10 are also related with reductions in peak expiratory flowsandwithincreasedreportingof cough,sputum
production and sore throat in children with or without
asthma [14]. Living close to heavy traffic may be associated with increased asthma symptoms and longstanding cough compared to not living close to heavy traffic
[15]. In the Italian Po Valley district, the increase in air
pollution has been associated with an increase in cough
incidence amongst females but not males [16]. Nocturnal cough in relation to indoor exposure to cat allergens
was observed not only in sensitized but also in nonsensitized subjects [17]. It is possible that population
surveys are picking up more cough in the community
from subjects being exposed to environmental pollutants and allergens, but we do not know whether these
factors induce or sensitize cough. It would seem most
important to determine the prevalence of sensitivity of
the cough reflex in the community and relate this to the
presence of cough, and thus determine levels of normal
vs. abnormal cough in the community. For example,
exposure of workers to capsaicin in a chilli processing
factory was associated with an increase in selfreporting of cough but no increase in capsaicin cough
responsiveness in these workers, indicating a ‘normal’
response to exposure to capsaicin [18].
When evaluating any community surveys, it is worth
remembering that up to 25–30% of the population are
usually cigarette smokers. In a survey in southeast England, up to 16% of 9077 responders had cough every
day or half of the days of the year, and up to 13.2% had
sputum every day or on half the days of the year; in this
cohort, 54% were current cigarette smokers [7]. The
chronic cough of cigarette smokers is a well-known feature, and is accompanied by hypersecretion of mucus
and possibly by slowing of mucociliary clearance.
Chronic bronchitis has been defined as the expectora-
THE CLINICAL AND PATHOPHYSIOLOGICAL CHALLENGE
tion of sputum on most days during at least three consecutive months per year over two successive years.
Apart from mucus stimulation of cough, chronic smoking may increase airway sensitivity to capsaicin [19],
and patients with chronic obstructive airways disease
caused by cigarette smoking show an increased tussive
response to capsaicin [20]. Cigarette smokers with
chronic cough do not usually seek medical help unless
the pattern of their cough changes.
More detailed analysis of the factors that may cause
cough, its severity and an assessment of the distribution
of cough responsiveness is needed in epidemiological
surveys. This indicates the need to have better methods
of recording the severity of cough, objective measurements and a rapid easy and safe method of measuring
the cough sensitivity reflex. There are no epidemiological data on the distribution of cough responsiveness in
the population, and this is important to know.
Cough presenting to the clinician
Cough is one of the most frequent reasons for seeking
a consultation with a doctor. In the US, a national
medical case survey reported that in 1991 cough was
the most common complaint for which patients
sought medical attention, and the second most common reason for a general medical consultation [21].
Much of this is likely to be due to cough occurring with
the common cold, which is a self-limiting disease. In the
US, for a chest specialist practice, patients with persistent chronic cough probably account for 10–38% of
outpatient practice [22,23]. In addition, treatment
of cough is a substantial proportion of health care expenditure. In the UK, about 3 million prescriptions for
cough preparations are given annually by general practitioners, representing a cost of £1.9 million [24]. This
is, however, an underestimate of the use of cough
preparations since cough mixtures can be obtained
over the counter.
Faced with a patient with a chronic cough, utilization
of an anatomical diagnostic protocol has been advocated [25], and application of such a protocol often
leads to a cause identified in 88–100% of cases, with
treatment success rates of between 84 and 98%
[22,23]. Such figures are perhaps overoptimistic, dependent on the referral practice of the clinic. Other
cough clinics report that in 12–31% of their patients
no underlying cause of the cough can be found
despite investigation and empirical treatment for
gastro-oesophageal reflux, postnasal drip and asthma
[26–28]. In patients referred with a chronic cough in
whom the diagnosis of cancer has been excluded, a proportion will respond to the institution of inhaled corticosteroid therapy, on the basis of which one could be
confident of the diagnosis of asthma, cough-variant
asthma or eosinophilic bronchitis as underlying the
cough [29]. Whether the eosinophil is the pathogenic
factor in the induction of the cough remains unclear.
Other prevalent diagnoses that are reported to ‘cause’
cough are chronic rhinosinusitis often with a postnasal
drip, gastro-oesophageal reflux, chronic bronchitis,
bronchiectasis or taking an angiotensin-converting
enzyme inhibitor medication [30]. There appears to
be little value in separating chronic dry cough from
chronic cough with excessive sputum production in
terms of the diagnostic yield since the frequency of the
causes of both symptoms appear to be similar [31].
Postnasal drip, asthma, gastro-oesophageal reflux and
bronchitis were the most frequent cause of a chronic
productive cough. When a ‘cause’ is established, one assumes that the specific treatment of that cause should
relieve the cough, and it sometimes does not. This
raises the issue as to whether the ‘cause’ is really involved in the genesis of cough, or whether the treatment
is really effective for the ‘cause’.
The role of postnasal drip in causing cough merits
some discussion [32]. Postnasal drip is defined as the
presence of secretions at the back of the throat associated with frequent throat-clearing. How could it trigger cough when there is no vagal afferent innervation of
the throat and there is no evidence for aspiration of secretions from the sinuses into the lungs in patients with
sinusitis [33]? Patients with gastro-oesophageal reflux
and cough may not respond to treatment with proton
pump inhibitors that suppress acid production, perhaps because other factors in the refluxate such as the
content of pepsin may be important in the pathogenesis
of cough. In spite of these uncertainties, there is a group
of chronic coughers in whom there appears to be no associated cause. There are other causes that remain
unidentified. For example, a condition of eosinophilic
bronchitis without bronchial hyperresponsiveness has
recently been established as a cause of chronic cough
[34]. Bordetella pertussis infection has been flagged as a
potential cause, when nasopharyngeal aspirates were
examined for the presence of Bordetella pertussis by
polymerase chain reaction [35].
5
CHAPTER 1
The increased tussive response
Many patients with a chronic cough have a sensitized
cough reflex response, and patients whose cough disappears or is controlled with appropriate treatments normalize their cough reflex response [36,37]. A sensitized
cough reflex is also described in many other conditions
such as asthma, pulmonary fibrosis and chronic obstructive pulmonary disease (COPD) [20,38,39]. However, the prevalence of sensitized cough reflex in the
population and its association with different types of
cough are still to be determined. It is not necessary for
the cough to be ‘dry’ in order for the cough to be sensitized since patients with COPD with sputum production can demonstrate sensitization.
The sensitized cough reflex has various clinical connotations. Often, there is a history that the cough was
first triggered following an upper respiratory virus
infection or by a cold, and that the cough persisted,
despite the clearing of the infective period, which
indicates the notion of a central cough sensitization
process. Such patients usually present with a history of
persistent cough which may have lasted for many years.
The cough is described as an irritation in the throat or
upper chest, ranging from a feeling of wanting to cough
to severe episodes of violent coughing that cannot be
stopped. The severity of the cough may be variable over
periods of months with mild or asymptomatic periods
interspersed with periods of severe symptoms. Typically, the cough may be triggered by stimuli such as
changes in temperature of inhaled air, taking a deep
breath, talking over the telephone, laughing, eating
crumbly food, certain smells or perfumes and lying in a
supine posture. Often, any suspected associated cause
has been treated with no success in controlling the
cough.
Pathophysiology of cough
Understanding of the cough response and of how
cough may become persistent is of the utmost importance. The anatomy of the cough reflex has been dissected extensively, with the airway afferents and
receptors, a central pathway and efferent pathways defined. The cough reflex is subserved mainly by vagal
primary afferent nerves such as bronchopulmonary
rapidly adapting receptors (RARs) which can be
evoked by mechanical stimulation and deformation of
6
the airway epithelium such as particulate matter or
mucus, and by airway smooth muscle contraction induced by constrictor agents [40,41]. These are predominantly present in the larynx, trachea and carina.
Activation of bronchopulmonary C fibres by chemicals
such as bradykinin and capsaicin can evoke cough in
conscious animals and humans [42], although these
may also activate RARs. C fibres and RARs project to
different subnuclei in the nucleus tractus solitarius in
the brainstem, considered to be a cough centre, although these are not anatomically discrete, and the
concept of a cough centre is not universally accepted.
Various second-order neurones project to other nuclei
associated with the regulation of breathing. Integration
of the various inputs occur centrally. For example,
slow-adapting receptor afferent input may have a facilitatory effect on the genesis of cough [43].
This work has paved the way for an understanding of
the cough response, but there is more to be understood
regarding the cough reflex in the clinical situation. One
could take the cough associated with gastrooesophageal reflux as an example of how one could
work out how the refluxate could induce cough [44].
Protons within the refluxate or other components of
the refluxate could directly stimulate cough receptors
in the upper airways; alternatively, there could be a distal oesophageal–tracheobronchial reflex mechanism
which would be mediated through the usual pathway
of the cough receptor. The biochemical counterparts of
the cough reflex arc remain to be elucidated, and such
information may provide therapeutic targets.
One defining concept of the chronic cougher is that
of an enhanced cough reflex in patients with persistent
cough as being the fundamental abnormality. Through
understanding how this occurs, more targeted specific
suppressants of the cough response, irrespective of the
cause, can be devised. The process of cough ‘sensitization’ remains unclear, and this may invoke both ‘peripheral’ (i.e. in the airways) and/or ‘central’ (i.e. in the
brain) mechanisms, according to our current understanding of the cough reflex pathways. Central sensitization may occur by integration from various sensory
nerve subtypes in the central nervous system to initiate
exaggerated reflexes and sensation [45]. Substance P
may be involved as an important central mechanism for
sensitization of the cough reflex, and its persistence. In
a model of allergic inflammation, neuroplastic changes
in the response of vagal primary afferent neurones were
described, such that Ad mechanosensor RARs released
THE CLINICAL AND PATHOPHYSIOLOGICAL CHALLENGE
substance P, when under normal conditions, they do
not [46]. Substance P in the nucleus tractus solitarius
can increase bronchopulmonary C fibre reflex activity
[47]. Peripheral mechanisms that can heighten cough
reflex mechanisms have been mainly envisaged as an
effect of altered environment of the cough receptor
such as the release of inflammatory mediators such as
prostaglandins or bradykinin that could enhance the
response of the cough receptor [48,49]. Alternatively,
there may be direct interactions between inflammatory
cells and the cough receptor such that the threshold of
the cough receptor is altered.
It has not been possible to determine whether the
cough receptor itself is abnormal in terms of the
transduction of the stimulatory signals. Examination
of neural afferent profiles in the airways of persistent
coughers has been limited. A recent study of airway
biopsies reported an increase in total intraepithelial
nerve density together with augmented staining for the
neuropeptide calcitonin gene-related peptide (CGRP)
but not for substance P [27]. However, the significance
of the increase in intraepithelial nerves is unclear since
we do not know whether any of these profiles are indeed cough receptors. Detailed localization of cough fibres and their ultrastucture, particularly in an airway
that demonstrates augmented tussive response, is crucial to undertake.
Approach to the treatment of cough
The treatment of cough would be more efficacious if
one could understand the mechanisms of the phenomenon of cough sensitivity, since suppression of the
heightened responses would control the urge to cough.
The search for new antitussives has progressed along
several lines, from studies of airway afferent nerve activity in vitro (with the disadvantage that the activity
observed is not necessarily that of a ‘cough’ receptor) to
studies in whole organisms using tussive challenges,
and more rarely using patients with enhanced cough reflex or with chronic cough. The predictive value of antitussives tested in animals to their effectiveness in
humans is not known. Some investigators study rodents such as mice that cannot cough, while the best
model for studying cough is the guinea-pig which produces the explosive noise similar to the human cough.
The use of the capsaicin or citric acid challenge in normal subjects cannot be predictive of antitussive activity
since normal volunteers do not possess an enhanced
cough reflex. Even if we do not currently have an understanding of the enhanced cough reflex, it is imperative that novel antitussives be tested in patients with an
enhanced cough reflex. The aim would be to inhibit the
enhanced component of the cough reflex to maintain
the ‘normal’ cough reflex. This task would be easier if
the enhanced cough reflex was superimposed on the
normal reflex by entirely different mechanisms rather
than representing an amplification of ‘normal’
mechanisms.
Many targets can be defined if one considers treating
the ‘cause’ of the cough first. Treatment of the causes of
cough may include anti-inflammatory approaches such
as the cough associated with eosinophilic inflammation
in the airways as in asthma, cough-variant asthma or
eosinophil bronchitis [29]. Inhaled corticosteroids are
particularly effective here, although the eosinophil as a
causation of the cough is not entirely proven. Cough
and enhanced cough with a neutrophilic inflammation
[20] which do not respond to inhaled corticosteroids,
and approaches that suppress the neutrophilic response or neutrophil activation could be helpful. The
treatment of cough associated with gastro-oesophageal
reflux with acid suppressants such as histamine H2receptor antagonists or proton pump inhibitors, or
associated with rhinosinusitis with antihistamines or
with nasal steroid drops, is not always successful. This
may mean either that these conditions are not the cause
of the cough or that a central mechanism of cough sensitization has occurred.
Partly because there is no apparent cause associated
with a persistent cough in many patients, it is clear
that the development of effective antitussives (i.e. drugs
that specifically block cough whatever the cause) is
needed. Currently, the most commonly used antitussives are the centrally acting opiates such as codeine,
dihydrocodeine or pholcodeine. Sometimes for the
intractable cough in terminal disease, morphine or
diamorphine is used, with the advantage that these also
possess analgesic properties. However, at their effective
doses, these antitussives cause drowsiness, nausea and
vomiting, and constipation, and often cause physical
dependence. Development of new antitussives has occurred on a number of fronts. An improved understanding of the cough reflex pathways and of the
mechanisms by which the reflex is enhanced has led to
the identification of potential targets [50]. Finally, the
assessment of antitussives in clinical studies has also
7
CHAPTER 1
been improved with the use of cough reflex challenge
protocols such as capsaicin or citric acid, or of measuring the cough itself in ambulatory patients [51], but experience needs to be gathered.
It would be useful in clinical practice to divide the antitussive drugs into those that are acute relievers of
cough such as the opiates; and those that can prevent
cough (‘preventors’) when taken on a regular basis,
such as corticosteroid therapy for eosinophilassociated cough or proton pump inhibitors for gastrooesophageal reflux-associated cough (these preventors
would be specific to the cause of cough).
Conclusion
This chapter has provided an overview of the clinical
and pathophysiological challenges of cough, and highlighted areas of unmet needs and of future investigations. Because of the high prevalence of cough,
physicians commonly encounter patients presenting
with a cough problem for diagnosis and management.
The potentially wide diagnostic possibilities make it
necessary for a systematic protocol to be used to ensure
that diagnoses are not missed. New causes of chronic
persistent cough will certainly be discovered. The tools
to determine the severity of a chronic cough are being
developed, and these can be applied to the clinic as well
as to the evaluation of new antitussive therapies. In
cough pathophysiology, an understanding of the pathways that enhance the cough reflex is needed, and what
biochemical or structural abnormalities constitute a
hypertussive cough receptor should be determined. We
need to apply the knowledge obtained from studying
the cough reflex to clinical practice, which includes the
discovery of new treatments for suppressing cough.
4
5
6
7
8
9
10
11
12
13
References
1 Osman LM, McKenzie L, Cairns J, Friend JA, Godden DJ,
Legge JS et al. Patient weighting of importance of asthma
symptoms. Thorax 2001; 56: 138–42.
2 Loudon RG. Cough in health and disease. Current research in chronic obstructive lung disease. In: Proceedings
of the 10th Emphysema Conference. US Department of
Health, Education & Welfare, 1967: 41–53.
3 Hsu J-Y, Stone RA, Logan-Sinclair R, Worsdell M, Busst
C, Chung KF. Coughing frequency in patients with persis-
8
14
15
tent cough using a 24-hour ambulatory recorder. Eur
Respir J 1994; 7: 1246–53.
Munyard P, Bush A. How much coughing is normal? Arch
Dis Child 1996; 74: 531–4.
Chang AB, Phelan PD, Robertson CF, Newman RG,
Sawyer SM. Frequency and perception of cough severity. J
Paediatr Child Health 2001; 37: 142–5.
Barbee RA, Halonen M, Kaltenborn WT, Burrows B. A
longitudinal study of respiratory symptoms in a community population sample. Correlations with smoking, allergen skin-test reactivity, and serum IgE. Chest 1991; 99:
20–6.
Cullinan P. Persistent cough and sputum: prevalence and
clinical characteristics in south east England. Respir Med
1992; 86: 143–9.
Lundback B, Nystrom L, Rosenhall L, Stjernberg N. Obstructive lung disease in northern Sweden: respiratory
symptoms assessed in a postal survey. Eur Respir J 1991;
4: 257–66.
Bjornsson E, Plaschke P, Norrman E, Janson C, Lundback
B, Rosenhall A et al. Symptoms related to asthma and
chronic bronchitis in three areas of Sweden. Eur Respir J
1994; 7: 2146–53.
Ludviksdottir D, Bjornsson E, Janson C, Boman G.
Habitual coughing and its associations with asthma,
anxiety, and gastroesophageal reflux. Chest 1996; 109:
1262–8.
Janson C, Chinn S, Jarvis D, Burney P. Determinants of
cough in young adults participating in the European Community Respiratory Health Survey. Eur Respir J 2001; 18:
647–54.
Zemp E, Elsasser S, Schindler C, Kunzli N, Perruchoud AP,
Domenighetti G et al. Long-term ambient air pollution
and respiratory symptoms in adults (SAPALDIA study).
The SAPALDIA Team. Am J Respir Crit Care Med 1999;
159: 1257–66.
Braun-Fahrlander C, Wuthrich B, Gassner M, Grize L,
Sennhauser FH, Varonier HS et al. Validation of a rhinitis
symptom questionnaire (ISAAC core questions) in a
population of Swiss school children visiting the school
health services. SCARPOL team. Swiss study on childhood allergy and respiratory symptom with respect to air
pollution and climate. International study of asthma and
allergies in childhood. Pediatr Allergy Immunol 1997; 8:
75–82.
Vedal S, Petkau J, White R, Blair J. Acute effects of ambient inhalable particles in asthmatic and nonasthmatic children. Am J Respir Crit Care Med 1998; 157: 1034–43.
Montnemery P, Bengtsson P, Elliot A, Lindholm LH,
Nyberg P, Lofdahl CG. Prevalence of obstructive lung
diseases and respiratory symptoms in relation to living
environment and socio-economic group. Respir Med
2001; 95: 744–52.
THE CLINICAL AND PATHOPHYSIOLOGICAL CHALLENGE
16 Viegi G, Pedreschi M, Baldacci S, Chiaffi L, Pistelli F,
Modena P et al. Prevalence rates of respiratory symptoms
and diseases in general population samples of North and
Central Italy. Int J Tuberc Lung Dis 1999; 3: 1034–42.
17 Gehring U, Heinrich J, Jacob B, Richter K, Fahlbusch B,
Schlenvoigt G et al. Respiratory symptoms in relation to
indoor exposure to mite and cat allergens and endotoxins.
Indoor Factors and Genetics in Asthma (INGA) Study
Group. Eur Respir J 2001; 18: 555–63.
18 Blanc P, Liu D, Juarez C, Boushey HA. Cough in hot pepper workers. Chest 1991; 99: 27–32.
19 Bergren DR. Enhanced lung C-fiber responsiveness in sensitized adult guinea pigs exposed to chronic tobacco
smoke. J Appl Physiol 2001; 91: 1645–54.
20 Doherty MJ, Mister R, Pearson MG, Calverley PM.
Capsaicin responsiveness and cough in asthma and
chronic obstructive pulmonary disease. Thorax 2000; 55:
643–9.
21 Schappert SM. National ambulatory medical care
survey: 1991: Summary. In: Vital and Health Statistics,
Publication No. 230. US Department of Health and
Human Services, 1993: 1–20.
22 Irwin RS, Curley FJ, French CL. Chronic cough: the spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am
Rev Respir Dis 1990; 141: 640–7.
23 Irwin RS, Carrao WM, Pratter MR. Chronic persistent
cough in the adult: the spectrum and frequency of causes
and successful outcome of specific therapy. Am Rev Respir
Dis 1981; 123: 413–17.
24 British Thoracic Society. The Burden of Lung Disease.
London: BMJ Publishing, 2001.
25 Irwin RS, Madison JM. The diagnosis and treatment of
cough. N Engl J Med 2000; 343: 1715–21.
26 Poe RH, Harder RV, Israel RH, Kallay MC. Chronic
persistent cough. Experience in diagnosis and outcome
using an anatomic diagnostic protocol. Chest 1989; 95:
723–8.
27 O’Connell F, Springall DR, Moradoghli-Haftvani A,
Krausz T, Price D, Fuller RW et al. Abnormal intraepithelial airway nerves in persistent unexplained cough? Am J
Respir Crit Care Med 1995; 152: 2068–75.
28 McGarvey LP, Heaney LG, Lawson JT, Johnston BT,
Scally CM, Ennis M et al. Evaluation and outcome of
patients with chronic non-productive cough using a
comprehensive diagnostic protocol. Thorax 1998; 53:
738–43.
29 Chung KF. Assessment and measurement of cough: the
value of new tools. Pulm Pharmacol Ther 2002; 15:
267–72.
30 Chung KF, Lalloo UG. Diagnosis and management of
chronic persistent dry cough. Postgrad Med J 1996; 72:
594–8.
31 Smyrnios NA, Irwin RS, Curley FJ. Chronic cough with a
history of excessive sputum production. The spectrum and
frequency of causes, key components of the diagnostic
evaluation, and outcome of specific therapy. Chest 1995;
108: 991–7.
32 Campanella SG, Asher MI. Current controversies: sinus
disease and the lower airways. Pediatr Pulmonol 2001;
31: 165–72.
33 Bardin PG, Van Heerden BB, Joubert JR. Absence of
pulmonary aspiration of sinus contents in patients with
asthma and sinusitis. J Allergy Clin Immunol 1990; 86:
82–8.
34 Brightling CE, Pavord ID. Eosinophilic bronchitis: an important cause of prolonged cough. Ann Med 2000; 32:
446–51.
35 Birkebaek NH, Kristiansen M, Seefeldt T, Degn J, Moller
A, Heron I et al. Bordetella pertussis and chronic cough in
adults. Clin Infect Dis 1999; 29: 1239–42.
36 Choudry NB, Fuller RW. Sensitivity of the cough reflex
in patients with chronic cough. Eur Respir J 1992; 5:
296–300.
37 O’Connell F, Thomas VE, Pride NB, Fuller RW. Capsaicin
cough sensitivity decreases with successful treatment of
chronic cough. Am J Respir Crit Care Med 1994; 150:
374–80.
38 Lalloo UG, Lim S, DuBois R, Barnes PJ, Chung KF.
Increased sensitivity of the cough reflex in progressive
systemic sclerosis patients with interstitial lung disease.
Eur Respir J 1998; 11: 702–5.
39 Doherty MJ, Mister R, Pearson MG, Calverley PM.
Capsaicin induced cough in cryptogenic fibrosing alveolitis. Thorax 2000; 55: 1028–32.
40 Widdicombe JG. Neurophysiology of the cough reflex.
Eur Respir J 1995; 8: 1193–202.
41 Karlsson J-A, Sant’Ambrogio G, Widdicombe J. Afferent
neural pathways in cough and reflex bronchoconstriction.
J Appl Physiol 1988; 65: 1007–23.
42 Fox AJ. Modulation of cough and airway sensory fibres.
Pulm Pharmacol 1996; 9: 335–42.
43 Hanacek J, Davies A, Widdicombe JG. Influence of lung
stretch receptors on the cough reflex in rabbits. Respiration 1984; 45: 161–8.
44 Ing AJ, Ngu MC. Cough and gastro-oesophageal reflux.
Lancet 1999; 353: 944–6.
45 Canning BJ. Interactions between vagal afferent nerve
subtypes mediating cough. Pulm Pharmacol Ther 2002;
15: 187–92.
46 Myers AC, Kajekar R, Undem BJ. Allergic inflammationinduced neuropeptide production in rapidly adapting
afferent nerves in guinea pig airways. Am J Physiol Lung
Cell Mol Physiol 2002; 282: L775–L781.
47 Mutoh T, Bonham AC, Joad JP. Substance P in the nucleus
of the solitary tract augments bronchopulmonary C fiber
9
CHAPTER 1
reflex output. Am J Physiol Regul Integr Comp Physiol
2000; 279: R1215–R1223.
48 Nichol GM, Nix A, Barnes PJ, Chung KF. Enhancement
of capsaicin-induced cough by inhaled prostaglandin
F2a: modulation by beta-adrenergic agonist and anticholinergic agent. Thorax 1990.
49 Fox AJ, Lalloo UG, Bernareggi M, Belvisi MG, Chung KF,
10
Barnes PJ. Bradykinin and captopril-induced cough in
guinea-pigs. Nature Med 1996; 2: 814–7.
50 Chung KF. Cough: potential pharmacological developments. Expert Opin Investig Drugs 2002; 11:
955–63.
51 Chung KF. Methods of assessing cough and antitussives in
man. Pulm Pharmacol 1996; 9: 373–7.
2
Epidemiology of cough
Alyn H. Morice
Introduction
Cough is a universal experience common to us all. It
is also the commonest symptom for which medical
advice is sought [1]. For the purpose of classification
cough may be divided into defined, acute, self-limiting
episodes and chronic persistent cough. This distinction
is clinically useful since the aetiology of the two syndromes is very different. An arbitrary cut-off of 8 weeks
is taken to separate acute from chronic cough.
Acute cough
The majority of consultations with acute cough are due
to viral respiratory tract infections. The UK Morbidity
Statistics from General Practice survey [2] suggests an
average of two consultations per year for every adult
and six consultations for each child under 4. Of total
primary care workload Morrell [3] found cough to be
the presenting complaint in 527 per 1000 consultations
with new symptoms. Even this staggering statistic, that
over half of new consultations are due to cough, underestimates the true socioeconomic impact of of this
symptom. Many of us do not consult a physician for
viral cough, and if driven to treatment self-medicate
with over-the-counter products of dubious efficacy.
The market in cough and cold products in the US is estimated at over 2 billion dollars.
This enormous morbidity is caused by a wide array
of viral pathogens including influenza, parainfluenza,
rhinovirus, adenovirus, respiratory syncytial virus and
the respiratory corona virus [4]. All of these viruses
share a common short incubation period of between 1
and 4 days. Because of its ability to undergo antigenic
shift and genetic recombination influenza occurs in epidemics. Why these epidemics occur during the winter
months is unknown but may be related to cooling of the
airway epithelium decreasing host defence [5]. Parainfluenza viruses differ from influenza viruses in that they
are much more antigenically stable and of the four subtypes types one and three are particularly important,
causing serious lower respiratory tract infections,
croup and tracheobronchitis in infants and young children. In all, parainfluenza viruses are thought to be responsible for a fifth of all non-bacterial respiratory
tract disease in childhood. Since immunity to reinfection is only transient it is one of the commonest causes
of the typical infective cough which plagues families
with small children.
Respiratory syncytial virus (RSV) is the single most
important aetiological agent in cough in infancy [6].
RSV occurs in epidemics, usually between the autumn
and early spring. Each outbreak lasts between 2 and 3
months and can involve as many as half of all families
with children. There is also a second peak of infectivity
in the elderly. Unfortunately, immunity to RSV infection is transient so reinfection is common.
Of the over 100 serotypes of adenovirus eight are important in the production of a syndrome of severe acute
cough. Immunity following infection is good but since
so many serotypes are associated with cough the likelihood of repeated adenovirus-induced cough is high.
The common cold or rhinovirus again represents over
100 serotypes and is the major cause of mild upper respiratory tract infection and cough in both children and
adults. Unsurprisingly, rhinovirus immunity is very
poor. Coronaviruses are similar in clinical presentation
11
CHAPTER 2
to rhinoviruses and may be responsible for between 5
and 10% of human coughs and colds.
At the age of 15 a gender difference appears in
consultation rates reported in the morbidity statistics
in general practice. During the reproductive years
consultations are twice for women what they are for
men. After the age of 55 consultation rates in both men
and women become equal again. Whilst this could be
explicable by societal differences in that women may
consult more, there are intriguing clues to the fact
that women may have a heightened cough reflex compared with men. Women exposed to cough challenge
with protussive agents cough twice as much as men or,
conversely, cough the same amount at a lower dose
[7,8]. This could be an artefact of inhaling drug into
a smaller lung volume but women are also overrepresented in those patients who develop angiotensinconverting enzyme (ACE) inhibitor cough [9]. In the
majority of cough clinics women outnumber men and
when tested with cough challenge they exhibit a heightened cough response [10]. It is possible that women
have an intrinsically heightened cough reflex compared
with men.
Chronic cough
Several surveys have attempted to quantify the incidence of chronic cough within populations [11–14].
The objective of most of these surveys is to assess the
symptomatology associated with cigarette smoking
and so questions are directed towards discovering the
prevalence of chronic bronchitis. This leads to confusion in the data analysis between cough and chronic
sputum production. Despite these methodological
shortcomings it is clear that chronic cough is a common
problem with reported prevalence varying between 40
and 6%. In the UK four general practices undertook a
postal and telephone survey of over 11 000 patients.
Cough was reported every day or on over half of the
days of the year by 14% of males and 10% of females.
A worldwide study from 16 countries surveyed 18 277
subjects aged between 20 and 48. Nocturnal cough was
present in 30%, productive cough in 10%, and nonproductive cough in 10%. There was a clear doserelated effect of cigarette smoking on cough. The very
high prevalence of nocturnal cough arose because a
positive response to the question ‘Have you been
woken by an attack of coughing at any time in the last
12
12 months?’ was taken as indicating the symptom.
However, since acute cough could also lead to a positive
response, significant nocturnal cough was probably
overestimated in this study. Another problem is in the
choice of age group in which to study cough. Chronic
cough is present in older subjects as may be seen from
the average age of patients seen in cough clinics (Table
2.1). Whatever the failings of individual surveys
chronic cough is clearly a very common symptom
which although associated with considerable morbidity goes largely unheeded.
Those patients presenting to specialist cough clinics,
however, represent a subgroup of this population.
Most smokers assume that their morning cough reflects
their smoking habit and do not consult. Conditions
such as chronic bronchitis are therefore grossly underrepresented, even though they cause considerable morbidity within the population. Similarly, such tertiary
referral clinics are unlikely to represent the true prevalence of conditions such as asthma as a cause of chronic
cough, since at least in European practice, a therapeutic
trial of antiasthma medication is usually performed by
the primary physician. If such therapy is successful
the patient remains in primary care and the prevalence
of the condition is hidden from the tertiary referral
centre.
The three common causes of chronic cough
All of the reported series from tertiary referral centres
identify the same three common causes of cough. This
diagnostic triad underlies the vast majority of chronic
cough seen within the population. The problem of the
high morbidity from chronic cough is the failure of doctors, both generalists and specialists, to recognize that
cough as an isolated symptom may be generated from
any of three anatomical areas. The relative incidence of
asthma or asthma-like syndrome, gastro-oesophageal
reflux and rhinitis is illustrated in Table 2.1 which lists
the reported prevalence.
The individual reports from cough clinics illustrate a
wide variety in the prevalence of each syndrome. This
variation may represent different patient populations,
or the different prevalence of the underlying diseases
such as asthma in each individual population and different diagnostic methods. A further source of error is
the criteria for diagnosis. Some clinics only accept diagnosis when a therapeutic trial of appropriate treatment
has been successful [15]. Other clinics report a positive
EPIDEMIOLOGY OF COUGH
Table 2.1 Commonest causes of chronic cough in patients investigated in specialist clinics.
Author
Irwin et al. 1981 [18]
Poe et al. 1982 [20]
Poe et al. 1989 [21]
Irwin et al. 1990 [19]
Hoffstein 1994 [22]
O’Connell et al. 1994 [23]
Smyrnios et al. 1995 [24]
Mello et al. 1996 [17]
Marchesani et al. 1998 [25]
McGarvey et al. 1998 [15]
Palombini et al. 1999 [16]
Brightling et al. 1999 [26]
Mean age in years
(range)
50.3 (17–88)
? (15–89)
44.8 (19–79)
51 (6–83)
47
49 (19–83)
58 (18–86)
53.1 (15–83)
51
47.5 (18–77)
57 (15–81)
*
Diagnosis (% of total)
Asthma syndrome
GOR
Rhinitis
Most common other
causes (%)
25
36
35
24
25
6
24
14
14
23
59
31
10
0
5
21
24
10
15
40
5
19
41
8
29
8
26
41
26
13
40
38
56
21
58
24
Chronic bronchitis (12)
Postinfectious (27)
Idiopathic (12)
Chronic bronchitis (5)
Postinfectious (21)
Idiopathic (22)
Chronic bronchitis (11)
Bronchiectasis (4)
Chronic bronchitis (16)
Idiopathic (18)
Bronchiectasis (18)
Postviral (13)
GOR, gastro-oesophageal reflux.
* No figures given for the total sample but mean age of 12/91 patients with eosinophilic bronchitis given as 52 (28–76) years.
diagnosis as a positive result during investigation, leading to apparent multiple diagnoses [16].
There is no doubt that a positive result in terms of diagnosis and therapy can suggest multiple causes of
cough in individual patients. I believe, however, that
this illustrates the plasticity of the cough reflex. Lowgrade, subclinical, cough may be present in an individual but only become apparent when an additional
provoking feature occurs. A good example of this phenomenon is ACE inhibitor cough, where ACE inhibitors alter the cough reflex sensitivity as shown
by shift in the capsaicin dose–response curve [27] and
may reveal previous low-grade cough due to gastrooesophageal reflux or rhinitis [28].
Cough-predominant asthma
The term cough-predominant asthma has been introduced to illustrate that cough may be one facet of an
asthma syndrome which is variously represented in individual patients. In classic asthma where bronchoconstriction, and conversely bronchodilator response, can
be demonstrated cough may be an additional and
important feature. However, cough as an isolated
symptom without bronchoconstriction or breathlessness, but with the characteristic pathological features
of asthmatic airway inflammation, is the other end of
the spectrum [29,30]. This so-called cough variant
asthma is merely one end of a continuum. The term
cough-predominant asthma may be preferred since this
terminology includes patients in whom the major problem is cough but who also illustrate some or all of the
other features of classic asthma [31]. Why individuals
should vary so much in the expression of cough as a
symptom of asthma is at present unclear. An elegant series of papers by Brightling has explored the extreme
end of this spectrum, eosinophilic bronchitis. Here
airways inflammation is present but there are no features of classic asthma, including bronchial hyperresponsiveness. However there are subtle differences
in the cellular composition and location of the inflammation, particularly concerning mast cells and their
mediators [26,32].
Between a quarter and a third of patients presenting
to a tertiary referral centre with chronic cough will
be suffering from cough-predominant asthma (Table
2.1). This rate of detection probably does not reflect
the prevalence of cough-predominant asthma since
many patients, particularly those who have features of
classic asthma, are diagnosed and treated in the community. Indeed it is unusual for patients with chronic
cough to be seen in tertiary clinics who have not had an
unsuccessful trial of inhaled medication. The reasons
13
CHAPTER 2
for failure of therapy, even when the underlying diagnosis is of cough-predominant asthma, are all those
usually associated with poor asthma control: compliance, poor inhaler technique, inappropriate choice of
device, etc. In addition there are other features of
cough-predominant asthma, which unless recognized,
lead to failure of therapy. Clearly the usual diagnostic
measures of reversibility testing or home peak flow
monitoring are frequently unhelpful. Even methacholine challenge may not identify patients who respond adequately to corticosteroid therapy since those
with eosinophilic bronchitis are not hypersensitive
[33]. Whilst sputum examination in expert hands
clearly has a role the methodological difficulties
obviate its routine use. Ultimately, the diagnosis and
therefore prevalence of cough-predominant asthma
rests on the use of a therapeutic trial of antiasthma
medication. Here again the differences between coughpredominant asthma and classic asthma may lead to
confusion. Since bronchospasm may only be a minor
feature or even absent, add-on therapy with longacting b-agonists rarely proves successful and
leukotriene antagonists may be the preferred add-on
therapy [34]. The response to leukotriene antagonists
may illustrate the hypothesized role of lipoxygenase
products in the direct modulation of the putative VR1
cough receptor [35]. Ultimately, diagnosis of coughpredominant asthma may rely on the demonstration of
a response to parenteral steroids.
The oesophagus and cough
A considerable portion of patients presenting with
chronic cough have a disorder of the oesophagus. It
is clearly poorly recognized by many physicians, yet
cough as the sole presentation of gastro-oesophageal
reflux has been well described [36,37]. In addition to
reflux it is becoming increasingly clear that a number of
oesophageal disorders, broadly classified as dysmotility and including abnormal peristalsis and abnormal
lower oesophageal sphincter tone, may give rise to
cough [38]. That acid reflux alone is not the cause of
cough in oesophageal disease explains the partial response seen in many patients with even high doses of
proton pump inhibitors.
As with other causes of cough, diagnosis may be difficult because there can be few clues from the history.
However, whilst there is some disagreement [17], in individual patients there may be a strong association with
other symptoms, particularly heartburn. More unusual
14
characteristics such as an association with hoarseness,
choking sensation and postnasal symptoms are increasingly recognized as being part of a reflux phenomenon
by ENT specialists. Indeed, a striking reduction of
cough during sleep, which initially may be thought to
count against a diagnosis of oesophageal cough, may
indicate an oesophageal origin. Lower oesophageal
sphincter pressure increases physiologically in recumbency preventing reflux in the early stages of the disease
[39]. The clues to the diagnosis of cough of oesophageal
origin may be obtained by looking for associations between food, eating and cough.
Rhinitis and postnasal drip
There is marked geographical variation in the incidence
of rhinitis and postnasal drip in the reported series of
patients presenting to cough clinics. Patients in the
Americas present with symptoms of postnasal drip in
up to 50% of cases, whereas rhinitis is reported in
approximately 10% in most European experience.
The difference for this may be in part societal in that
patients from North America are far more likely to
describe upper respiratory tract symptoms as postnasal
drip [18,19]. In addition, the diagnosis of postnasal
drip or rhinitis is frequently accepted because of a
response to ‘specific therapy’ with broad-spectrum,
centrally acting antihistamines and systemic decongestants [40]. Of course, such treatment is anything but
specific. Such therapy may act in upper airway disease
and in asthma. Centrally acting antihistamines may
work either on the central pathways of the cough or
simply through a sedating mechanism unrelated to the
anatomical site of cough generation.
Until such problems in the definition of postnasal
drip and its subsequent specific diagnosis are resolved,
rhinitis or rhinosinusitis is probably the preferred term
describing this syndrome. One further problem is the
numerous observations from animal species, which
point to the absence of afferent cough sensory neurones
within the territory of the glossopharyngeal and
trigeminal nerves [41]. It is possible that the symptoms
of rhinitis and postnasal drip are epiphenomena associated with inflammation in the territory of the vagus.
Other rare causes of cough
Whilst the rarer causes of cough may not matter in the
overall epidemiology of cough, they are extremely important to the individual patient since prolonged suf-
EPIDEMIOLOGY OF COUGH
fering may result because of a lack of firm diagnosis.
The whole panoply of disorders within the territory of
the vagus nerve must be considered in patients with obscure cough. The ear (from the nerve of Arnold), the oesophagus, and even the heart may be the seat of the
generation of cough.
Some of the more important causes of chronic cough,
which lead to considerable diagnostic and social consequences are:
• Inhaled foreign body. Whilst this can occur in any
age group, typically it affects boys aged 3 [42]. There
may be little or no clue from the history or chest radiography. Foreign bodies can be radiolucent and those
with a lumen can produce wheezing without distal
atelectasis and may be frequently misdiagnosed as
asthma.
• Habit cough, a syndrome almost exclusively restricted to children and young people. The physical
characteristics of the cough are unlike those of an
‘organic’ cough and the sound produced has been
described as a ‘honk’. The cough characteristically disappears when the patient is asleep. Whilst most paediatricians treat habit cough with simple measures such as
reassurance and breathing exercises there remains a
hard core of patients who are resistant to therapy. In
these habit cough has many of the characteristics of
a tic and may on close observation be associated with
other mannerisms. Cough is a feature of Gilles de la
Tourette syndrome in approximately 10% of cases and
therapy with haloperidol or pimozide may be highly
effective.
• Postviral cough. Whilst most cough associated
with upper respiratory tract viral infection abates
within 1 week, in some patients coughing is prolonged
and may take several months to settle. Such patients
have a heightened cough reflex and may have some subclinical cause of cough which is exacerbated by virusinduced vagal hypersensitivity. There is no specific
therapy [43].
• ACE inhibitor cough. Similar to postviral cough,
ACE inhibitor cough causes a shift in the cough sensitivity to tussigenic agents [44]. This alteration in the
cough reflex may take several months to settle. Thus,
although patients usually improve within a week of cessation of ACE inhibitors, a number of individuals continue coughing weeks and months after the cessation of
treatment. As with postviral cough such individuals
frequently have a low-grade or subclinical cough
caused by other aetiologies.
References
1 Schappert KT. National Ambulatory Medical Care
Survey: 1991, Summary. Advance Data 93 A.D., Number
230. US Department of Health and Human Services,
National Center for Health Statistics, 1993.
2 Office of Population Censuses and Surveys. Morbidity
Statistics from General Practice: 4th National Study
1991–1992. London: HMSO, 1995: Series MB5, 3.
3 Morrell DC. Symptom interpretation in general practice. J
R Coll General Pract 1972; 22: 297–309.
4 Ison MG, Mills J, Openshaw P, Zambon M, Osterhaus
A, Hayden F. Current research on respiratory viral infections: Fourth International Symposium. Antiviral Res
2002; 55 (2): 227–78.
5 Eccles R. An explanation for the seasonality of acute upper
respiratory tract viral infections. Acta Otolaryngol 2002;
122 (2): 183–91.
6 Law BJ, Carbonell-Estrany X, Simoes EA. An update on
respiratory syncytial virus epidemiology: a developed
country perspective. Respir Med 2002; 96 (Suppl. B):
S1–S7.
7 Fujimura M, Kasahara K, Kamio Y, Naruse M,
Hashimoto T, Matsuda T. Female gender as a determinant
of cough threshold to inhaled capsaicin. Eur Respir J
1996; 9: 1624–6.
8 Dicpinigaitis PV, Allusson VRC, Baldanti A, Nalamati JR.
Ethnic and gender differences in cough reflex sensitivity.
Respiration 1901; 68 (5): 480–2.
9 Yeo WW, Maclean D, Richardson PJ, Ramsay LE. Cough
and enalapril: assessment by spontaneous reporting and
visual analogue scale under double-blind conditions. Br J
Clin Pharmacol 1991; 31 (3): 356–9.
10 Kastelik JA, Thompson RH, Aziz I, Ojoo JC, Redington
AE, Morice AH. Sex-related differences in cough reflex
sensitivity in patients with chronic cough. Am J Respir Crit
Care Med 2002; 166: 961–4.
11 Cullinan P. Persistent cough and sputum: prevalence and
clinical characteristics in south east England. Respir Med
1992; 86 (2): 143–9.
12 Janson C, Chinn S, Jarvis D, Burney P. Determinants
of cough in young adults participating in the European
Community Respiratory Health Survey. Eur Respir J
1991; 18 (4): 647–54.
13 Littlejohns P, Ebrahim S, Anderson R. Prevalence and diagnosis of chronic respiratory symptoms in adults. Br Med
J 1989; 298: 1556–60.
14 Boezen HM, Schouten JP, Postma DS, Rijcken B. Relation
between respiratory symptoms, pulmonary function
and peak flow variability in adults. Thorax 1995; 50:
121–6.
15 McGarvey LP, Heaney LG, Lawson JT, Johnston BT,
Scally CM, Ennis M, Shepherd DR, MacMahon J. Evalua-
15
CHAPTER 2
16
17
18
19
20
21
22
23
24
25
26
27
28
16
tion and outcome of patients with chronic non-productive
cough using a comprehensive diagnostic protocol. Thorax
1998; 53 (9): 738–43.
Palombini BC, Villanova CA, Araujo E, Gastal OL,
Alt DC, Stolz DP, Palombini CO. A pathogenic triad in
chronic cough: asthma, postnasal drip syndrome, and
gastroesophageal reflux disease. Chest 1999; 116 (2):
279–84.
Mello CJ, Irwin RS, Curley FJ. Predictive values of the
character, timing, and complications of chronic cough in
diagnosing its cause. Arch Intern Med 1996; 156 (9):
997–1003.
Irwin RS, Corrao WM, Pratter MR. Chronic persistent
cough in the adult: the spectrum and frequency of causes
and successful outcome of specific therapy. Am Rev Respir
Dis 1981; 123 (4 Part 1): 413–17.
Irwin RS, Curley FJ, French CL. Chronic cough. The
spectrum and frequency of causes, key components of the
diagnostic evaluation, and outcome of specific therapy.
Am Rev Respir Dis 1990; 141 (3): 640–7.
Poe RH, Israel RH, Utell MJ, Hall WJ. Chronic cough:
bronchoscopy or pulmonary function testing? Am Rev
Respir Dis 1982; 126 (1): 160–2.
Poe RH, Harder RV, Israel RH, Kallay MC. Chronic
persistent cough. Experience in diagnosis and outcome
using an anatomic diagnostic protocol. Chest 1989; 95
(4): 723–8.
Hoffstein V. Persistent cough in nonsmoker. Can Respir J
1994; 1: 40–7.
O’Connell F, Thomas VE, Pride NB, Fuller RW. Capsaicin
cough sensitivity decreases with successful treatment of
chronic cough. Am J Respir Crit Care Med 1994; 150:
374–80.
Smyrnios NA, Irwin RS, Curley FJ. Chronic cough with a
history of excessive sputum production. The spectrum and
frequency of causes, key components of the diagnostic
evaluation, and outcome of specific therapy. Chest 1995;
108 (4): 991–7.
Marchesani F, Cecarini L, Pela R, Sanguinetti CM. Causes
of chronic persistent cough in adult patients: the results of
a systematic management protocol. Monaldi Arch Chest
Dis 1998; 53 (5): 510–14.
Brightling CE, Ward R, Goh KL, Wardlaw AJ, Pavord ID.
Eosinophilic bronchitis is an important cause of chronic
cough. Am J Respir Crit Care Med 1999; 160 (2): 406–10.
Morice AH, Lowry R, Brown MJ, Higenbottam T. Angiotensin converting enzyme and the cough reflex. Lancet
1987; ii: 1116–18.
Ojoo JC, Kastelik JA, Morice AH. Duration of angiotensin converting enzyme inhibitor (ACEI) induced
cough. Thorax 1902; 56: 89.
29 Glauser FL. Variant asthma. Ann Allergy 1972; 30 (8):
457–9.
30 Corrao WM, Braman SS, Irwin RS. Chronic cough as the
sole presenting manifestation of bronchial asthma. N Engl
J Med 1979; 300 (12): 633–7.
31 Pratter MR, Bartter T, Akers S, Dubois J. An algorithmic
approach to chronic cough. Ann Intern Med 1993; 119
(10): 977–83.
32 Brightling CE, Ward R, Woltmann G, Bradding P, Sheller
JR, Dworski R, Pavord ID. Induced sputum inflammatory
mediator concentrations in eosinophilic bronchitis and
asthma. Am J Respir Crit Care Med 2000; 162 (3 Part 1):
878–82.
33 Gibson PG, Dolovich J, Denburg J, Ramsdale EH,
Hargreave FE. Chronic cough: eosinophilic bronchitis
without asthma. Lancet 1989; 1: 1346–8.
34 Dicpinigaitis PV, Dobkin JB. Effect of zafirlukast on cough
reflex sensitivity in asthmatics. J Asthma 1999; 36 (3):
265–70.
35 Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J,
Cho S, Min KH, Suh YG et al. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci USA
2000; 97 (11): 6155–60.
36 Irwin RS, Zawacki JK, Curley FJ, French CL, Hoffman PJ.
Chronic cough as the sole presenting manifestation of gastroesophageal reflux. Am Rev Respir Dis 1989; 140 (5):
1294–300.
37 Ing AJ, Ngu MC. Cough and gastro-oesophageal reflux.
Lancet 1999; 353: 944–6.
38 Kastelik JA, Aziz I, Thompson R et al. Gastroesophageal
dysmotility as a cause of chronic persistent cough. Thorax
2003 (in press).
39 Mittal RK, Balaban DH. The esophagogastric junction. N
Engl J Med 1997; 336 (13): 924–32.
40 Irwin RS, Madison JM. Anatomical diagnostic protocol
in evaluating chronic cough with specific reference to
gastroesophageal reflux disease. Am J Med 2000; 108
(Suppl. 4a): 126S–30S.
41 Widdicombe JG. Afferent receptors in the airways and
cough. Respir Physiol 1998; 114 (1): 5–15.
42 Hoeve LJ, Rombout J, Pot DJ. Foreign body aspiration in
children. The diagnostic value of signs, symptoms and preoperative examination. Clin Otolaryngol 1993; 18 (1):
55–7.
43 Ojoo JC, Kastelik JA, Morice AH. A boy with a disabling
cough. Lancet 2003; 361: 674.
44 Morice AH, Brown MJ, Higenbottam T. Cough associated with angiotensin converting enzyme inhibition. J
Cardiovasc Pharmacol 1989; 13 (Suppl. 3): S59–S62.
3
A brief overview of the mechanisms
of cough
John G. Widdicombe
Introduction
The aim of this chapter is to review briefly the pathophysiological mechanisms of cough so that the clinical
reader can see their relevance to the understanding of
the conditions being studied. It is an introduction to,
but not a substitute for, the detailed description of the
pathophysiology of cough given in Section 4 of this
book; the latter will provide the detailed basis of the
mechanisms of cough, and point to future developments in the understanding and treatment of cough.
Of all the specialized and forceful acts of breathing
(ignoring vocalization) — e.g. cough, sneeze, sigh/gasp,
yawn, hiccup — cough has special distinctive features: it
usually signals disease; it is not stereotyped but can take
many forms; it has a voiceprint that identifies the subject; it can be produced and mimicked voluntarily and
accurately; and it is used as a form of communication.
Possibly the last two features apply in part also to
yawns and sighs.
Definition and description
Cough has three defining features: an initial deep
breath, a brief powerful expiratory effort against a
closed glottis, and opening of the glottis with closure of
the nasopharynx and vigorous expiration through the
mouth. Within this definition there are several variants.
The act may be a single deep inspiration followed by a
single glottic closure interrupting an almost complete
expiration near to residual volume; the same but with
multiple glottic closures during the single expiration; or
a ‘bout’ of coughing with each expiratory effort either
completed or partial. Other acts, such as the ‘huff’ of
clearing the throat and the expiratory effort with glottic
closure due to touching the vocal folds or trachea (the
‘expiration reflex’), are by definition not cough but may
be fragments of a cough.
The problem is that we know virtually nothing about
the differences in activation of neural mechanisms that
determine the patterns of cough. Nor do we understand
the secondary mechanisms whereby a cough, once initiated, may itself strongly influence its own pattern by
feedback from the airway receptors stimulated by the
cough. Just as we do not understand the physiological
basis for different patterns of cough, the clinician can
seldom define the underlying causes of cough by observing and measuring it, apart from the broad distinction between ‘wet’ and ‘dry’ cough.
Cough is the most vigorous respiratory act to involve
the body. The commonest cause is probably cigarette
smoking, which has been very little studied because
subjects do not usually go to the physician. Acute cough
due to upper respiratory tract infection inflicts virtually
everyone in developed countries at least once a year, but
again has been little studied because patients prefer the
pharmacist to the physician. Chronic cough, the commonest symptom of respiratory disease, can have over
100 underlying causes, but the complexity of its mechanisms has baffled both the clinician and the basic
scientist.
Physiological mechanisms of cough
Cough is said to be exclusively mediated via the vagus
nerves [1]. If so, this may explain cough due to irritation
17
CHAPTER 3
of the external ear, which is innervated by a small
branch of the vagus. It should follow that pharyngeal
irritation due, for example, to postnasal drip cannot itself cause cough, since the pharynx has no vagal innervation; the mucus and its inflammatory mediators must
first reach the larynx. In experimental animals no-one
has shown that stimulation restricted to the pharynx
induces cough.
Cough can be initiated from the larynx, including its
supraglottal part, from the trachea and from the larger
bronchi. Irritation of the smaller bronchi, the bronchioles and the alveoli does not cause cough; cough initiated from such sites would not be very effective because
the luminal airflows and velocities would be too low to
have shear forces adequate to clear airway mucus and
debris [2,3].
Sensory mechanisms of cough
The airway zones that can initiate cough, from larynx
to bronchi, all contain rapidly adapting pulmonary
stretch receptors (RARs), and there is abundant
evidence that these mediate cough [4–6]. They have
small-diameter myelinated nerve fibres, the block of
which prevents cough, and all the mechanical, chemical
and pathological conditions that stimulate them also
induce cough. As their name implies, they adapt
rapidly to a maintained stimulus, which might limit a
continuous bout of coughing that could be harm-
ful; however, they do not accommodate to repeated
stimulation [7].
The morphology of RARs has not been clearly delineated [4,8–10]. However, they are almost certainly the
branching terminals of non-myelinated nerve fibres
under, and possibly in, the epithelium [10] (Fig. 3.1).
This gives them an ideal site for sensing inhaled irritants
and locally released inflammatory mediators. These
terminals link to vagal thin myelinated fibres, with cell
bodies mainly in the nodose ganglia.
The RARs are exquisitely mechanosensitive, and
also respond to acid and to non-isosmolar solutions
[7,11,12]. Their membranes have receptors and channels for these stimuli, all of which can cause cough.
However, in vitro the RARs are insensitive to a wide
range of chemicals and mediators that can produce
cough: histamine, bradykinin, prostaglandins, 5-hydroxytryptamine, capsaicin, tachykinins, etc. The explanation of this paradox is that RARs can be sensitized
or stimulated by mechanical events in the airway wall,
including smooth muscle contraction, vasodilatation
and oedema, mucus secretion and decrease in lung
compliance. All these changes occur in inflammatory
conditions such as asthma, either by the direct action of
inflammatory mediators released in the tissues, or by
the local actions of tachykinins released from C-fibre
receptors in the epithelium and mucosa (mediating the
local reflex effects known as neurogenic inflammation)
[13].
E
?R
r
g
L
BrV
SM
VA
L
?R
18
Fig. 3.1 Hypothetical location and
structure of a rapidly adapting pulmonary stretch receptor that causes
cough. It is proposed that the receptor
is localized in the extracellular space
in close proximity to bronchial
venules. An increase in interstitial
pressure in the venules, or vasoactive
substances such as histamine or substance P, will increase extravascular
fluid volume and stimulate the receptors. Irritant gases in the airways will
also stimulate the endings. VA, vagal
afferent fibre; BrV, bronchial venule;
L, lymphatic; g, gaps between endothelial cells; r, pharmacological receptors; SM, smooth muscle, E,
epithelial cells. From [9].
MECHANISMS OF COUGH
There has been some advocacy for the view that these
C-fibre receptors can directly cause cough [14], based
on the relative insensitivity of RARs in vitro to tussigenic chemical stimuli [15]. However, as explained
above, C-fibre receptors can release tachykinins with
mucosal responses that secondarily excite the RARs.
There is no convincing evidence that C-fibre receptors
can directly cause cough, and much evidence against
this belief [3,4,6]. The issue is an important one in view
of the current interest in peripherally acting antitussive
drugs; we need to know how they act on the RAR–Cfibre mediator–mucosal response complex, and this
complex must first be mapped out.
Other airway receptors are unlikely to play an important role in cough, although slowly adapting receptors (SARs), responsible for the Hering–Breuer reflex
and for controlling breathing pattern, can have a facilitatory effect on the cough reflex [4].
(See also Chapter 16.)
Central nervous mechanisms of cough
The old-fashioned concept of a ‘cough centre’ in the
brainstem has been discarded in the light of recent
understanding of the neuronal circuitry of cough and
its relation to the respiratory rhythm generator
[16–21]. The subject is complex and at least some conclusions are hypothetical. But since this is the site where
centrally acting antitussive agents act it is a topic with
important clinical implications.
The vagal fibres for cough enter the brainstem and
relay in the nucleus of the solitary tract with connections to second-order neurones [4,21]. Here their pathways overlap and interact with those from other airway
afferents — C-fibre receptors and SARs. The interaction
of multiple inputs is such that, for example, C-fibre activity will potentiate that of RARs, i.e. augment the
cough reflex. The neurotransmitters involved have
been studied and include glutamate and the tachykinins
substance P and neurokinin A [4,21].
If the activity of RARs increases sufficiently then
coughing is produced. This involves:
1 a gating process which determines whether the
‘cough input’ is adequate to cause cough; the gates are
in turn controlled by afferent inputs, for example from
SARs, and probably from higher centres;
2 a complex interaction with the respiratory rhythm
generator. Obviously we cannot cough and breathe at
the same time so, if cough is induced, breathing has to
be switched off, even although the same motor outputs
are involved in both activities; and
3 a coordination of motor activities to diaphragm,
abdominal and intercostal muscles, and the larynx
and upper airway muscles mainly via the nuclei
retroambigualis and ambiguus; here further integrative
processes take place and there are distinctive differences between motor controls for breathing and for
cough.
Recent studies on the brainstem cough generator circuit show several important features.
1 The gating systems for cough from the tracheobronchial tree and for that from the larynx are different
and with different control activities; at the same time
centrally acting antitussive agents can have different
actions on the cough from the two regions [18]. If
humans behave like experimental animals, at least
potentially physicians should give different cough
remedies for laryngeal compared with lower airway
inflammation.
2 Although cough and breathing have the same final
common integrative pathways, they can be dissociated both physiologically and pharmacologically
[18,19]; this explains why appropriate antitussive
agents can block cough without inhibiting breathing,
and why agents that depress breathing may not be
antitussive.
3 Antitussive drugs can inhibit some components
of the cough while leaving others intact [19,22]; for
example, codeine can block the frequency of cough
without affecting the pattern of the individual cough
cycle. This fits with experience of antitussive agents
on the pattern of cough in humans, where cough frequency is usually affected more than is cough
pattern [23].
Increasing knowledge of the neurotransmitters involved in the central cough complex has incriminated, as well as the tachykinins and glutamate,
5-hydroxytryptamine, g-aminobutyric acid, N-methylD-aspartate and dopamine; various types of opioid receptors have been described, and also nociceptin
receptors [8,21]. The scope for development of novel
centrally acting antitussive drugs is great.
Recently the role of the cerebral cortex in influencing
cough has been studied [24,25]. Of course we can voluntarily produce cough, but voluntary inhibition of
cough due to upper respiratory tract infection (URTI)
has now been measured. Of course there are limits; it
would be impossible to inhibit cough due to touching
19
CHAPTER 3
the vocal folds. These studies should be compared with
recent evidence that the standard dose of over-thecounter dextromethorphan is little more effective than
placebo [25] (although this view is disputed [23,26]). It
is proposed that both a small dose of the antitussive and
the placebo act on cortical or subcortical pathways; this
opens another avenue for antitussive research. Figure
3.2 illustrates a possible neuronal system that includes
the cerebral cortex [24].
This view of the importance of higher centres in
cough is supported by the observation that some patients with stroke exhibit a weak or absent cough reflex
[27], which may increase the likelihood of aspiration
pneumonias. A similar condition is seen in Parkinson’s
disease, where the cough reflex may be inhibited and its
pattern altered [22].
(See also Chapters 17, 22 and 25.)
Motor actions of cough
Typical cough consists of four phases [1] (Fig. 3.3).
1 Inspiratory, when a near-maximal deep inspiration is
taken.
2 Compressive, when the glottis closes and forced expiration takes place. The closure is for about 200 ms,
and intrapleural and intra-alveolar pressures as high as
300 mmHg can be achieved.
3 Expulsive, when the glottis opens and forced expiration takes place. Velocities as great as 28 000 cm/s
(85% of the speed of sound) have been reported, but it
is impossible to determine the gas velocity at points of
airway constriction, where the greatest shearing forces
will be developed. During this phase there is dynamic
collapse in the bronchial tree, with large pressure gradients across the collapsed segment. Maximum expirato-
Cerebral cortex
Voluntary
control
of cough
Placebo effect
Sensation
of
irritation
Cough control
centre
+ve
Endogenous
opioids
–ve
Exogenous
opioids
Respiratory area of brainstem
Vagus
nerve
Airway irritation
Respiratory
muscles
COUGH
20
Fig. 3.2 Cough model to illustrate reflex and voluntary control mechanisms. Irritation of airway receptors
may cause reflex cough via a brainstem
control area. A sensation of irritation
may cause cough via higher centres
such as the cerebral cortex. Cough can
be voluntarily initiated and inhibited
via the cerebral cortex that influences
cough by two pathways: via the brainstem and via a descending pathway to
the spinal cord. Cough can also be inhibited by endogenous or exogenous
opioids. Cough associated with common cold may be a mixture of both
voluntary and reflex cough. From [24].
MECHANISMS OF COUGH
Sound
L/s
5.0
Air
volume
50
4.0
3.0
Flow
rates
Subglottic
pressure
2.0
1.0
40
30
cm H2O
6.0
20
10
0.1 s
0
0.0
1
2
3
Negative Min flow
flow phase phase
Positive
flow phase
Inspiratory Glottis
phase
closure
Expiratory
phase
(explosive)
Fig. 3.3 Diagrammatic representation of the changes of the
following variables during a representative cough: flow rate,
volume, subglottic pressure and sound level. During inspiration, the flow rate is negative; at the glottic closure, the flow is
zero; and during the expiratory phase the flow is positive. The
last phase can be divided into three parts: growing, constant
and decreasing. From [30].
cough from this bronchial site effective. It is disputed
whether closure of the glottis is essential for an effective
cough [28]; a forced expiratory effort with an open
glottis can be effective, and tracheostomized patients
can ‘cough’ quite efficiently.
The action of skeletal muscles in cough, including
those in the larynx, have been frequently studied and
described [29,30]. Other motor outputs associated
with cough include bronchoconstriction, mucus secretion and submucosal vasodilatation [6]. The bronchoconstriction may be masked by the dramatic
changes in airway calibre induced mechanically by the
cough. Since these changes can sensitize or stimulate
RARs there is the possibility of an enhanced cough reflex, which could be a factor in cough hyperreactivity in
conditions such as asthma (see Chapter 19).
The importance of secreted mucus in coughing is that
it will be a stimulus to cough, it will remove inhaled particles, irritants and inflammatory mediators, and it
could act as a physicochemical barrier between lumen
and mucosa [31] (see also Chapter 21). However, these
concepts are largely speculative; the increase in mucus
secretion in conditions associated with cough has never
been measured accurately, perhaps because of the lack
of appropriate methods. ‘Wet’ and ‘dry’ cough are
terms based almost entirely on subjective evaluation,
by the patient or by his or her attendant.
Plasticity of the cough reflex
ry flow is effort independent, because it is limited by this
dynamic compression. The dynamic compression increases velocity, kinetic energy of the gas, and turbulence of the air passing through the compression point;
these features will improve the clearing capacity of the
cough.
4 Relaxation, when functional residual capacity is
resumed, possibly before another cough effort.
As already stated, the exact pattern of coughing can
vary greatly, and little is known about the mechanisms
of this variation. Certainly ‘cough’ from the larynx and
trachea can be either a single expiration (the expiration
reflex) or a full cough, while that from the bronchi
seems always to be a full cough. This may be related to
the undesirability of cough from the larynx or trachea
starting with an inspiration, which might draw foreign
material into the lungs; this would be a lesser problem if
the foreign material is already deep in the lungs, when a
large alveolar volume would be desirable to make the
One of the most important recent advances in our
understanding of the cough reflex has been the demonstration of plasticity, at receptor, ganglionic and central
nervous levels [7,32,33]. This phenomenon as so far
studied always leads to an enhancement of the activity
of cough pathways, and may cause or contribute to the
hypersensitive cough reflex seen in airways diseases.
Whether similar mechanisms in other conditions could
lead to desensitization of cough pathways does not
seem to have been studied.
At the level of the airway mucosa, the mechanical
sensitivity of cough-mediating RARs can be increased
by administration of histamine, ozone or allergen
challenge in sensitized animals [7,8,32,33]. At the
ganglionic level both respiratory tract viral infection
and allergen challenge in sensitized animals can promote the appearance of tachykinins in RAR cell bodies
in the nodose ganglion, presumably with changes in
21
CHAPTER 3
sensitivity and function [7,8,32,33]. At the central
nervous level, the expression of tachykinins in fibres
from RARs could ‘tune’ the cough and bronchomotor
pathways, presumably by facilitating them [18].
To date studies on plasticity have usually been with in
vitro models, and any deductions with regard to an effect on cough in vivo have been inferential. However it
seems certain that in time the mechanisms of enhanced
cough reflexes in a wide range of airways diseases will
be clarified.
Conclusions
The old concept that cough was a rather stereotyped activity with a separate coordinating ‘cough centre’ has
been discarded. In its peripheral sensory mechanisms,
in its neuronal circuitry in the brainstem and interactions with the respiratory rhythm generator, and in its
motor outputs with possibilities for feedback activity,
cough emerges as a highly complex and variable
process. Acute studies in healthy animals may bear little
quantitative relationship to what happens in human
disease, when the plasticity of the reflex may become
paramount.
References
1 Irwin RS, Widdicombe J. Cough. In: Murray, JF, Nadel,
JA, eds. Textbook of Respiratory Medicine, 3rd edn.
Philadelphia: W. B. Saunders, 2000: 553–66.
2 Widdicombe JG. Afferent receptors in the airways and
cough. Respir Physiol 1998; 114: 5–15.
3 Widdicombe JG. Airway receptors. Respir Physiol 2001;
125: 3–15.
4 Widdicombe JG. Functional morphology and physiology
of rapidly adapting receptors (RARs). Anat Rec 2003;
270A: 2–10.
5 Sant’Ambrogio G, Widdicombe JG. Reflexes from airway
rapidly adapting receptors. Respir Physiol 2001; 125:
33–45.
6 Karlsson J-A, Sant’Ambrogio G, Widdicombe JG. Afferent neural pathways in cough and reflex bronchoconstriction. J Appl Physiol 1988; 65: 1007–23.
7 Undem BJ, Carr MJ, Kollarik M. Physiology and plasticity of putative cough fibres in the guinea pig. Pulm Pharmacol Ther 2002; 15: 193–8.
8 Widdicombe JG. Neuroregulation of cough: implications
for drug therapy. Curr Opin Pharmacol 2002; 2: 256–63.
22
9 Ravi K, Kappagoda CT. Reflex effects of pulmonary venous congestion: role of vagal afferents. News Physiol Sci
1990; 5: 95–9.
10 Baluk P, Nadel JA, McDonald DM. Substance P immunoreactive sensory axons in the rat respiratory tract:
a quantitative study of their distribution and role in
neurogenic inflammation. J Comp Neurol 1992; 319:
586–98.
11 Carr MJ, Undem BJ. Ion channels in airway afferent neurons. Respir Physiol 2001; 125: 83–97.
12 Undem BJ, Carr MJ. Pharmacology of afferent nerve activity. Respir Res 2001; 2: 234–44.
13 Barnes PJ. Neurogenic inflammation in the airways.
Respir Physiol 2001; 125: 145–54.
14 Karlsson J-A, Fuller RW. Pharmacological regulation
of the cough reflex. Pulm Pharmacol Ther 1999; 12:
215–28.
15 Fox AJ. Modulation of cough and airway sensory fibres.
Pulm Pharmacol Ther 1996; 9: 335–42.
16 Shannon R, Baekey DM, Morris KF, Lindsey BJ. Ventrolateral medullary respiratory network and a model of
cough motor pattern generation. J Appl Physiol 1998; 84:
2020–35.
17 Shannon R, Baekey DM, Morris KF, Lindsey BJ. Functional connectivity among ventrolateral medullary neurons and responses during fictive cough in the cat. J
Physiol (Lond) 2000; 525: 207–24.
18 Bolser DC, Davenport PW. Functional organization of the
central cough generation mechanism. Pulm Pharmacol
Ther 2002; 15: 221–5.
19 Bolser DC, Hey JA, Chapman RW. Influence of central antitussive drugs on the cough motor pattern. J Appl Physiol
1999; 86: 1017–24.
20 Pantaleo T, Bongianni F, Mutolo D. Central nervous
mechanisms of cough. Pulm Pharmacol Ther 2002; 15:
227–33.
21 Mazzone SB, Canning BJ. Central nervous system control
of the airways: pharmacological implications. Curr Opin
Pharmacol 2002; 2: 220–8.
22 Fontana GA, Lavorini F, Pistolesi M. Water aerosols and
cough. Pulm Pharmacol Ther 2002; 15: 205–11.
23 Pavesi L, Subburaj S, Porter-Shaw K. Application and validation of a computerised cough acquisition system for
objective monitoring of acute cough: a meta-analysis.
Chest 2001; 120: 1121–8.
24 Lee PCL, Cotterill-Jones C, Eccles R. Voluntary control of
cough. Pulm Pharmacol Ther 2002; 15: 317–20.
25 Eccles R. The powerful placebo. Do we need antitussives?
Pulm Pharmacol Ther 2002; 15: 303–8.
26 Morice AH, Widdicombe J, Dicpinigaitis P, Groenke L.
Understanding cough. Eur Respir J 2002; 19: 6–7.
27 Stephens RE, Addington WR, Widdicombe JG. The effect
of acute unilateral MCA infarcts on voluntary cough and
MECHANISMS OF COUGH
the laryngeal cough reflex. Am J Phys Med Rehabil 2003
(in press).
28 Young S, Abdul-Sattar N, Caric D. Glottic closure and
high flows are not essential for productive cough. Clin
Respir Physiol 1987; 23 (Suppl. 10): 11S–17S.
29 Leigh DE, Butler JP, Sneddon SL, Brain JD. Cough. In:
Cherniack, NS, Widdicombe, JG, eds. Handbook of
Physiology, Section 3: Respiration, Vol. 3: Mechanics
of Breathing (Part I). Baltimore: American Physiological
Society, 1986: 315–36.
30 Bianco S, Robuschi M. Mechanics of cough. In: Braga, PC,
Allegra, L, eds. Cough. New York: Academic Press, 1987:
95–108.
31 Rogers D. Motor control of airway goblet cells and glands.
Respir Physiol 2001; 125: 129–44.
32 Carr MJ, Hunter DD, Jacoby DB, Undem BJ. Expression
of tachykinins in nonnociceptive vagal afferent neurons
during respiratory viral infection in the guinea pig. Am J
Respir Crit Care Med 2002, 1071–5.
33 Carr MJ, Undem BJ. Inflammation induced plasticity of
the afferent innervation of the airways. Environ Health
Perspect 2001: 109 (Suppl. 4): 567–71.
23
SECTION 2
Cough in the Clinic
4
Clinical assessment of cough
Lorcan P.A. McGarvey
Introduction
Cough frequently accompanies the common cold and is
usually self-limiting, causing little more than a nuisance [1]. In this circumstance, many individuals selfmedicate, as is implied by the considerable annual
expenditure on ‘over-the-counter’ antitussive preparations [2,3]. Although there is a close association between smoking and cough, smokers may become so
accustomed to their cough that it becomes less apparent
to them on a daily basis [4].
Despite these two well-recognized scenarios, cough
remains one of the most common symptoms for which
patients seek medical attention [5]. Patients requesting
medical help for a chronic cough are often concerned
that ‘something is wrong’, a number report exhaustion
from sleep deprivation and many become socially selfconscious [6]. Coughing can be so severe as to induce
vomiting, incontinence and syncope, and is known to
significantly impair quality of life [7].
In the last 30 years there has been expanding clinical
and research interest in the whole area of cough. Recommendations on the management of cough have been
published, but the cost-effectiveness of the suggested
strategies needs to be evaluated [8]. Acceptable guidelines must consider the availability of laboratory tests
to the general and specialist physician in both hospital
and general practice and address the role of empirical
therapy.
To date, no completely satisfactory agreement on the
clinical assessment and treatment of cough exists. The
aim of this chapter is to review the current diagnostic
approach to the adult presenting with a cough, provide
some additional suggestions for effective clinical as-
sessment and consider the areas of contention that
remain to be resolved.
An overview of current
diagnostic protocols
An effective cough involves a complex reflex arc initiated by stimulation of afferent structures, innervated
by the vagus nerve and its branches [9] (see Fig. 4.1).
The neurophysiological mechanisms underlying cough
have already been extensively covered elsewhere in this
book. In 1981, a protocol to evaluate patients with
chronic cough was devised [10]. This approach was
based on the systematic evaluation, using history,
examination and laboratory investigations directed
at the anatomical sites of cough receptors which comprise the afferent limb of the cough reflex. Suspected
aetiologies were confirmed if the cough resolved or significantly improved after a trial of diagnosis-specific
therapy. It was termed the ‘anatomic diagnostic protocol’ and encouraged physicians to consider both pulmonary and extrapulmonary conditions as potential
causes for cough. The findings have contributed significantly to what are now accepted as the main disease
processes which underpin chronic cough. The main
observations have been supported by a repeat study almost 10 years later [11] and by a number of prospective
studies in both community and hospital settings, using
modifications of the protocol [12–16]. The consistent
findings from all these studies are summarized as
follows.
1 A cause for chronic cough could be determined in
most cases (82–100%).
27
CHAPTER 4
N
VN
VN
VN
VN
VN
VN
Fig. 4.1 The anatomy of the afferent limb of the cough reflex.
Solid dots represent receptors, circled dot represents the
cough centre. N, cortical input; VN, vagus nerve. (Reprinted
from Gibson et al. (2003), Respiratory Medicine, 3rd Edn. ©
(2003), with permission from Elsevier.)
2 In nearly every case, postnasal drip syndrome
(PNDS), asthma, and gastro-oesophageal reflux
disease (GORD) either alone or in combination
accounted for the cough.
3 Multiple causes for cough were frequently identified
(approximately one-quarter of cases).
4 Despite extensive investigation and treatment a subgroup of patients with idiopathic or unexplained cough
remained (up to 30%).
Despite the consistencies between studies, a wide
variation in the frequencies of the three most common
causes of cough exists. This is most likely attributable
to differences in how diagnoses are established and
some variation in the study populations. In one
prospective study, patients were treated empirically for
PNDS as first line with cough improvement in 87% of
cases [17]. This extremely high prevalence of upper airway disease contrasts with other studies reporting fre28
quencies of between 13% and 21% [13,15]. The failure
to use optimal diagnostic methods may also explain differences in diagnostic frequencies reported. One group
suggested that their use of barium swallow rather than
a more sensitive and specific test, namely ambulatory
oesophageal pH monitoring, contributed to a lower
frequency of GORD-associated cough [13]. Cough
symptom duration may differ between study populations and consequently modify the diagnostic outcomes. One study group with relatively short average
cough duration reported postviral cough in 27% of patients evaluated [12]. It is widely appreciated that
asthma, gastro-oesophageal reflux (GOR) and post
nasal drip coexist and may simultaneously contribute
to the cough, and failure to appreciate this leads to
treatment failure. However, a complex protocol, which
serially investigated these aetiologies in all patients, reported all three causes concurrently causing cough in
15% of patients [16].
Alternative management strategies include trials of
empirical therapy alone or in combination with laboratory investigations. There is some evidence that empirical treatment of GORD is more cost-effective than
investigation followed by treatment in chronic cough
[18]. There is at least general agreement as to the importance of a protocol, which considers the most common causes of cough. In general clinics and hospitals
where no such approach exists, extrapulmonary causes
are often overlooked and consequently treatment success is poor [19,20].
What follows is a commentary on the current approach to clinical assessment of patients with cough
including a suggested management pathway incorporating courses of empirical therapy.
The clinical assessment of
an adult with cough
History
It is unlikely for the history alone to provide sufficient
information to support a diagnosis for the cough.
Nonetheless, a careful history should include questioning of the duration, characteristics, associated symptoms and timing of the cough.
Cough duration
Classification of cough based on symptom duration is
somewhat arbitrary. A cough lasting less than 3 weeks
CLINICAL ASSESSMENT OF COUGH
is termed acute and one lasting longer defined as
chronic. Acute cough is usually a result of a viral upper
respiratory tract infection as almost all such coughs resolve within this time period [1]. A postinfective cough
may, however, persist for considerable periods of time
It may be more satisfactory to define chronic cough as
one lasting greater than 8 weeks and to recognize an
overlap period of between 3 and 8 weeks.
Sputum production
Attempts to accurately measure sputum volume may be
difficult, as the amount swallowed is variable. The
cough may be dry or productive of only scanty amounts
of phlegm. A productive cough has been defined as
one productive of more than 30 mL of sputum per day
[14]. In practical terms what is more relevant is the finding of expectoration of large volumes of purulent
phlegm on a daily basis or the presence of haemoptysis.
Furthermore, the diagnostic approach and outcome is
almost identical, whether the cough is productive or
not [14].
Cough characteristics
Experience from specialist cough clinics suggests that
the character and timing of a cough are not diagnostically helpful [21]. The history may establish that the
cough is associated with frequent throat clearing or the
sensation of postnasal drip, occurs mainly at night or
after meals, or is made worse with exercise or cold air.
Reliance solely on the characteristics may be misleading: the symptoms of postnasal drip in a patient may
reflect only coexistent rhinitis and the absence of dyspepsia does not rule out reflux as the cause of cough. In
one study, the predictive values for cough characteristics and associated symptoms were calculated and the
findings have been outlined in Table 4.1 [15].
A cough with a ‘honking’ or ‘barking’ quality and
which disappears with sleep has been suggested as typical of a psychogenic or habit cough. Such characteristics have been frequently reported in the paediatric
literature. Such features obtained at history in adults
with cough are not helpful [21]. Furthermore, sleep is
known to suppress the cough reflex. In a series of patients with lung disease and nocturnal cough, spontaneous cough was almost abolished during stage 3 and 4
sleep [22].
Smoking history
There is a threefold greater prevalence of cough among
smokers compared to never smokers. The causes of
cough identified in current or ex-smokers are quite different from never smokers and usually due to chronic
bronchitis. A cough which is productive of phlegm on
most days for 3 months for 2 consecutive years, satisfies
the diagnosis of chronic bronchitis [23]. However,
smokers account for only about 5% of those seeking
specialist help for their cough [11]. Over time, presumably they attribute their symptom to the direct effects of
tobacco exposure. In one study, half of the smokers
with an initial cough complaint denied it as a problem 8
years later [4]. In a smoker, the onset of a new cough, a
change in cough character, or presence of haemoptysis
should raise the suspicion of a bronchogenic carcinoma. Smoking cessation is associated with resolution or improvement of the cough in over 90% of
individuals, with over 50% reporting disappearance
of cough within 1 month [24].
Occupational history
A thorough occupational history may identify a possible aetiological factor. Cough has been reported as
consequence of working with tussive irritants [25,26].
Table 4.1 Predictive value of symptom characteristics obtained from history. Reproduced from [15] with permission.
Asthma (nocturnal cough, precipitated by cold air,
exercise, aerosols)
PNDS (throat clearing, sensation of postnasal drip,
nasal discharge, previous sinusitis)
GORD (dyspepsia, cough worse after meals)
Number with positive
history
Number correctly
identified
Positive predictive
value (%)
27
15
56
27
14
52
20
8
40
PNDS, postnasal drip syndrome; GORD, gastro-oesophageal reflux disease.
29
CHAPTER 4
Sensitization to a growing list of agents in the work
place may explain the increasing prevalence of occupational asthma and asthma-like symptoms including
cough [27].
Drug history
Angiotensin-converting enzyme (ACE) inhibitors are
increasingly used in the treatment of hypertension and
heart failure and although usually well tolerated, a persistent cough has been reported as the most common
side-effect, occurring in around 10% patients treated
[28]. Typically the cough is dry and tickly and more
common among women. It can develop within a week
or not for some months after starting therapy. The drug
should be withdrawn or substituted with another
family of antihypertensive or heart failure medication.
When this is necessary, the cough usually subsides
within a few days but may take a few months in some
cases. Any drug that induces parenchymal lung damage
may be associated with cough.
Physical examination
The physical examination of the patient with cough
may demonstrate clinical signs of obstructive lung disease, lung cancer, bronchiectasis, pulmonary fibrosis or
cardiac failure. More often though, the examination reveals less specific findings.
Acute cough
At the outset of the common cold there may be clinical
evidence of a rhinitis and pharyngitis with inflamed
nasal mucosa and posterior pharynx with adherent or
draining secretions. Inspection of the ears may reveal a
serous otitis. A computed tomographic (CT) study of
the nasal passages and sinuses in the common cold has
demonstrated that a widespread rhinosinusitis, which
clears on resolution of the infection, is most typical
[29]. The findings on high-resolution CT of the lung
have been reported in a group of 76 young adults
with the common cold [30]. No important pulmonary
changes were reported which is consistent with the normal findings usually reported on examination of the
lower respiratory tract.
Acute cough is common in any patient who has a
pneumonia. Physical findings on examination of the
chest are often very helpful and include dullness on
percussion, bronchial breathing and crackles on
auscultation.
30
Rarely, on examination of a patient with an acute
cough there may be distinguishing features suggesting
specific infective aetiologies. These include bullous
myringitis in patients with a Mycoplasma pneumoniae
infection and subconjunctival haemorrhages described
in acute pertussis infection.
Chronic cough
Physical examination should concentrate on the afferent sites identified as most commonly associated with
chronic cough.
An ear, nose and throat (ENT) examination may
reveal evidence of nasal obstruction due to inflamed
turbinates or the presence of polyps. The appearance
of secretions draining in the posterior pharynx may
be apparent. A ‘cobblestone’ appearance of the
oropharyngeal mucosa has been suggested but is an
uncommon finding in the routine examination of
patients with chronic cough [15]. A more comprehensive discussion on the physical findings in rhinitis,
sinusitis and postnasal drip can be found elsewhere
in the text. Evidence of irritation of the larynx and
pharynx on indirect laryngoscopy could suggest
proximal GOR [31].
Examination of the chest is not useful in differentiating reversible airflow obstruction from fixed or partially reversible airflow limitation. Likewise, there
are no features that easily distinguish cough-variant
asthma. Asking the patient to inhale may trigger paroxysms of coughing. Chest auscultation may reveal
rhonchi and a prolonged expiratory phase on auscultation. Coarse crackles may be a prominent finding on
examination of a patient with bronchiectasis while
widespread fine late inspiratory crackles are typical of
diffuse parenchymal lung disease.
The presence of finger clubbing in a smoker together
with evidence of a pleural effusion or lobar collapse on
examination almost certainly points to a diagnosis of
bronchogenic carcinoma.
Assessing frequency and severity of cough
Clinical assessment involves an appreciation of the
severity of cough in terms of its frequency and intensity
and any impact on psychological well-being. A coughspecific quality of life questionnaire has recently been
validated and may prove a useful tool in routine clinical
assessment of both acute and chronic cough [32]. Subjective assessment including cough diaries and symp-
CLINICAL ASSESSMENT OF COUGH
tom scores have been used but are often inaccurate. In
relation to nocturnal cough, for example, scoring of
cough severity by children and their parents correlated
poorly with objective monitoring [33]. Ambulatory
cough monitoring is more objective but not widely
available and limited by cost and size of the device together with insufficient computer memory. Current advances in technology should resolve these problems
and widen the opportunity to accurately record cough
frequency.
A wide range of tussigenic agents may be delivered by
inhalation challenge to assess cough severity and treatment efficacy [34]. A full discussion of these is outside
the scope of this chapter and has been covered elsewhere within the book.
Clinical investigations
The routine clinical assessment of cough should include
a number of baseline investigations. These, together
with any additional tests, should reflect the pulmonary
and extrapulmonary diseases known to commonly
cause chronic cough. Investigations should be requested until a cause is identified but given that cough
may have a multiplicity of aetiologies, the diagnostic
strategy may become unwieldy and expensive.
The sequence in which investigations are ordered
and the degree to which they are pursued will depend
on the clinician’s impression of each case. However, the
dominant factor in many scenarios will be what tests
are available to the physician either in hospital or in
general practice. The investigations relevant to the
most common causes of chronic cough, namely
asthma, PNDS and GOR, will be dealt with in detail in
the pertinent chapters of this book.
However, the following section aims to provide an
overview of the diagnostic tests that may be available to
the physician. An outline of the most common investigations is provided in Table 4.2.
Chest radiograph
A chest radiograph is mandatory at an early stage as a
significant abnormality will alter the diagnostic algorithm and avoid unnecessary investigation. In the selected population assessed at specialist clinics, the chest
radiograph is almost always normal. In a series of studies the chest radiograph was abnormal less than 10% of
the time [10,11]. The frequency of abnormal chest radiographs among unselected cases presenting with
chronic cough to a general respiratory clinics has been
reported to be 30% [19].
Spirometry and peak expiratory flow measurements
When available, spirometry both before and after an inhaled bronchodilator should be performed at an
early stage in the routine diagnostic testing of all patients with cough. Testing may demonstrate significant
reversibility, establishing the diagnosis of asthma.
Spirometry is not readily available in primary care and
it has been advocated that peak flow meters should be
used as an alternative [35]. It is unclear if daily peak expiratory flow (PEF) monitoring at home or the use of a
Table 4.2 Investigations used in the evaluation of patients with chronic cough.
Investigation
Comment
Chest radiograph
Spirometry and reversibility testing
Peak flow recording
Bronchial challenge
Essential investigation in all patients
A baseline investigation; not readily available in primary care
May reliably demonstrate diurnal variability
A negative study effectively rules out asthma but not steroid responsive
cough
If available; helpful in patients with no reflux symptoms to assess duration
and frequency of reflux episodes and any temporal association with
cough
May reveal sinus opacity, mucosal thickening and air–fluid levels
Diagnostic utility is low if chest radiograph is normal
Induced sputum useful in identifying an eosinophilic bronchitis; best
reserved for patients with negative bronchoprovocation test
24-h ambulatory pH monitoring
Paranasal sinus radiograph (or CT scan)
Fibreoptic bronchoscopy
Non-invasive assessment of airway inflammation
31
CHAPTER 4
peak flow meter to assess bronchodilator reversibility
are diagnostically reliable for patients with persistent
cough. An analysis of the value of measuring diurnal
peak flow variability in patients with cough concluded
that this method provided accurate diagnostic information [36]. However, peak expiratory flow
measurements are not reliable for use in assessing
bronchodilator response in primary care patients with
persistent cough [37].
Bronchoprovocation testing
If doubt remains about the diagnosis of asthma, bronchoprovocation testing should be considered. As bronchial hyperresponsiveness is invariably present in
symptomatic asthma, a positive test is persuasive evidence to begin treatment with inhaled steroids and a
favourable response confirms the diagnosis of asthma.
A negative test reliably rules out asthma [15] but
does not exclude a steroid-responsive cough [38].
Eosinophilic bronchitis has none of the airway dysfunction typically associated with asthma. Critically,
the diagnosis relies in part on the demonstration of normal airway hyperresponsiveness (provocative concentration of methacholine producing a 20% decrease in
FEV1 (PC20) > 16 mg/mL) [38]. Therefore, a negative
bronchial challenge may trigger additional tests aimed
at assessing the cellular characteristics of the airway.
The nature of such investigations will be discussed
below.
Upper airway provocation studies
It has been suggested that asthma-like symptoms in
particular cough are associated with extrathoracic airway dysfunction. Using flow–volume loops, variable
extrathoracic upper airway obstruction has been observed in a series of patients with cough due to PNDS,
which improved with treatment [39]. Extrathoracic
airway responsiveness can be assessed by recording the
maximal inspiratory flow/volume curve during conventional bronchial challenge testing [40]. Extrathoracic airway hyperresponsiveness in the absence of
bronchial hyperresponsiveness may be an indicator of
upper airway disease as a cause for cough [41].
Sinus imaging
Empirical trials of therapy for postnasal drip have been
advocated but the place of sinus imaging in cough
evaluation has yet to be established [17]. A plain radiograph of the sinuses may reveal evidence of opacity,
32
mucosal thickening and air–fluid levels in individuals
with sinusitis but is rather less helpful when rhinitis is
the prominent element. Plain sinus radiography alone
has low specificity but improves when combined with
history and findings at ENT inspection [42]. When the
cough is productive, sinusitis accounts for postnasal
drip in 60% of cases [14] and in this circumstance ordering sinus radiograph has been recommended [8].
CT imaging of the sinuses and nasal passages has superior specificity to plain radiography [43]. Screening
coronal CT studies have reduced both cost and radiation exposure without compromising accuracy [44]. In
a prospective evaluation of a diagnostic protocol for
cough which included routine CT sinus imaging, the
predictive value of the scan was no better than ENT examination in accurately identifying upper airway disease [15]. Sinus CT scanning should be reserved for
refractory cases, which may require surgical referral.
Gastrointestinal investigations
If symptoms of GOR seem prominent from the history
then an empirical trial of an antireflux regimen should
precede investigation of the upper gastrointestinal
tract. In a double blind randomized study of patients
with chronic cough, empirical treatment with a highdose proton pump inhibitor proved cost-effective when
compared with routine gastrointestinal investigation
[18]. However, typical symptoms of GOR are frequently absent and investigations may be necessary.
Barium swallow has been extensively used in the diagnosis of GOR. However, free reflux of barium is not
uncommonly observed in healthy individuals and often
not at all in those with known GOR [45]. The low sensitivity and specificity exclude barium swallow as a routine diagnostic tool for cough. Endoscopy accurately
identifies oesophagitis but does not establish that the
cough is due to oesophageal reflux. Twenty-four-hour
oesophageal pH monitoring is regarded as the most
sensitive and specific test for diagnosing GOR. Hypothetically it has the additional advantage of identifying
any temporal association between an acid reflux event
and a cough episode. A series of prospective studies of
diagnostic cough protocols have reported positive predictive values for the investigation in the range of
68–100% [11,15,16]. All studies agreed, however, that
a negative test effectively excluded GOR as the cause
for the cough. Nevertheless, as the oesophageal pH
profile may not predict response to antireflux therapy,
and factors other than acid may be contributing to
CLINICAL ASSESSMENT OF COUGH
oesophageal cough, caution is needed in particular
when interpreting a negative study [46]. The role of
ambulatory 24-h oesophageal pH monitoring in the
evaluation of chronic cough needs further scrutiny.
Fibreoptic bronchoscopy
Fibreoptic bronchoscopy together with a chest radiograph are the first tests to consider in evaluating a
smoker with cough. However, the diagnostic yield from
bronchoscopy in the routine evaluation of chronic
cough is low, about 5% [8]. This reflects the low frequency of smokers and radiograph abnormalities
among patients seeking medical attention for their
cough. In spite of this, bronchoscopy has significant diagnostic potential in selected patients where the more
common causes have been rigorously excluded [47]. In
this study diagnoses were found in 7 of 25 patients undergoing bronchoscopy for unexplained cough. They
included broncholithiasis, tracheobronchopathia and
laryngeal dyskinesia. Aspirated foreign bodies may go
unrecognized for prolonged periods of time although
bronchoscopy is probably only indicated when there is
a clue in the medical history.
Fibreoptic bronchoscopy provides the opportunity
for airway sampling by either mucosal biopsy or
bronchial lavage. There has been expanding interest in
the role of non-invasive methods to assess airway inflammation and this will be discussed below.
Thoracic CT scanning
Diagnoses including diffuse parenchymal lung disease
or bronchiectasis not appreciated on history or chest
radiograph may be identified on high-resolution CT
scanning of the thorax. Only one study has employed
thoracic CT scanning routinely in the evaluation of patients referred to a specialist cough clinic [16]. In this
report, an abnormality was identified in over a quarter
of tests performed with a positive predictive value of
83%. The diagnosis in each case was bronchiectasis but
it was not clear if this could have been made on history,
examination and/or chest radiograph alone. The addition of thoracic CT scanning to baseline investigations
is unlikely to be cost-effective.
Assessing airway inflammation
Eosinophilic bronchitis has now been added to the
spectrum of diseases that commonly cause chronic
cough [48]. It may account for between 10 and 15% of
cases referred for specialist attention [38,41]. It has
therefore been suggested that the assessment of airway
inflammation should be an important addition to the
clinical evaluation of cough [38]. The development of
non-invasive techniques such as induced sputum provides a means by which this may be achieved. The
methodology involved has been well documented [49]
but is not widely employed outside of specialist cough
clinics. A greater than 3% sputum eosinophil count has
been taken as indicative of eosinophilic bronchitis and
warranting a trial of corticosteroid therapy [38].
Exhaled nitric oxide (NO) represents an alternative
non-invasive technique for assessing airway inflammation. Exhaled NO levels appear to be lower in nonasthmatic coughers allowing some differentiation from
asthmatic cough [50]. Conversely, elevated levels of exhaled NO have been reported in eosinophilic bronchitis
[51]. The technique and interpretation of measurements has yet to be fully evaluated. For the near future,
in the evaluation of cough at least, the role of exhaled
NO outside of a research capacity is likely to remain
limited.
Psychological assessment
A psychogenic or ‘habit’ cough has been most frequently reported in children and adolescents [52]. In a
very few case reports detailing adults with refractory
cough, psychotherapy was the only successful intervention [53,54]. Criteria to help identify patients with
unexplained cough, or even those in whom a cause has
been established, who may benefit from psychological
intervention, have not been established.
Suggestions for the effective clinical
assessment of cough
A revised protocol for evaluating patients with chronic
cough should continue to appreciate the three most
common aetiologies, which may operate singly or simultaneously. It should ensure both correct interpretation of diagnostic tests and the timely inclusion of
empirical therapeutic trials which must be of adequate
dose and duration. One such protocol has been outlined in Fig. 4.2.
The objective of the history, physical examination
and baseline investigations (which at a minimum
should include chest radiograph and spirometry) is to
identify any primary pulmonary pathology. ACE inhibitor therapy should be stopped or replaced with an
33
CHAPTER 4
History and physical examination
Stop ACE-I and
consider alternative
to ACE-I
Review in 3 months
YES
Is patient taking an ACE-I?
NO
Chest radiograph
Spirometry + reversibility testing (hospital setting)
Home PEF recording (general practice or spirometry unavailable)
Any obvious primary pulmonary pathology?
YES
Manage according to
treatment guidelines
NO
Is patient currently taking any therapy for cough?
YES
Stop therapy
Cough
worse
Cough still
present
NO
Cough
persists
Cough
resolved
Diagnostic testing/Empirical therapy
Does patient have a symptom
complex suggestive of
PNDS or GORD?
Reintroduce
therapy, ensure
compliance,
maximize dose and
consider additional
diagnosis
YES
Empirical trial of therapy
NO
Review
Diagnostic testing in the following order:
1) PNDS
2) Asthma–induced sputum if bronchoprovocation
challenge negative
3) GORD
Consider an
additional
diagnosis acting
simultaneously
Cough still
present
Cough
resolved
Review
No resolution
Partial resolution
Complete
resolution
Additional investigations: Fibre-optic
bronchoscopy, high-resolution CT thorax,
cardiac studies, psychiatric appraisal
Fig. 4.2 Protocol for the evaluation of chronic cough in an adult. Adapted with permission from [8]. ACE-I, angiotensinconverting enzyme inhibitor; PEF, peak expiratory flow; PNDS, postnasal drip syndrome; GORD, gastro-oesophageal reflux
disease; CT, computed tomography.
34
CLINICAL ASSESSMENT OF COUGH
alternative. As patients attending specialist cough clinics are rarely treatment naïve, stopping any existing
cough treatment can be a useful next step. If as a consequence, symptoms worsen, treatment should be reintroduced, compliance checked, dose maximized and if
necessary a coexistent aetiology sought.
The next stage involves a combination of diagnostic
testing and trials of empirical therapy. Patients reporting symptoms suggestive of GORD or PNDS should be
first offered a trial of empirical therapy. In a placebocontrolled trial in patients with GORD-associated
cough, omeprazole 40 mg o.d. for 8 weeks produced an
effective and sustained resolution of symptoms [55].
Older (first-generation) antihistamines in combination
with decongestants have been recommended as empirical therapy for PNDS [8,17].
In the absence of symptoms, diagnostic testing
should be arranged systematically in an order which reflects the three most likely possibilities, i.e. PNDS, asthma and GORD. A further advance in current protocols
is the place of induced sputum in the diagnosis of
eosinophilic bronchitis. Where available, induced sputum should be reserved for patients with a negative
bronchoprovocation test.
In the event of any positive investigation, an appropriate trial of therapy should be commenced, ensuring
that both patient compliance and effective doses are
prescribed. If the outcome of treatment effects only a
partial response, then another cause acting simultaneously should be considered. Each case should be
considered on its own merits but testing should be continued until a cause is determined. In general, once the
most common causes for cough have been reliably excluded, additional tests may prove valuable. These may
comprise fibreoptic bronchoscopy, high-resolution
thoracic CT scanning and psychiatric appraisal.
Cost-effectiveness of clinical
assessment of cough
Current management strategies for cough have undergone cost-effectiveness analysis [56]. The approach to
‘test all then treat’ similar to that advocated by Palombini and colleagues [16] was the most expensive approach but had the shortest treatment duration. In
contrast, treating sequentially starting with PNDS as
recommended by Pratter and coworkers [17], was the
cheapest option but had the longest treatment dura-
tion. The challenge therefore appears to be balance of
cost against time to treatment success.
Conclusions
Although the clinical approach to cough has been well
defined it needs to be continually refined. Based on current experience, a large proportion of patients with
cough can be successfully managed using existing
strategies. However, important questions remain as to
the complexity and cost-effectiveness of cough algorithms. Identifying more precise and reliable diagnostic
tests, determining the specific role of empirical therapeutic trials and understanding more completely pathogenic mechanisms of cough remain the challenges for
future research.
References
1 Curley FJ, Irwin RS, Pratter MR. Cough and the common
cold. Am Rev Respir Dis 1988; 138: 305–11.
2 Couch RB. The common cold: control? J Infect Dis 1984;
150: 167–73.
3 Higgenbottom T. Cough induced by changes of ionic composition of airway surface liquid. Bull Eur Physiopathol
Respir 1984; 20: 553–62.
4 Barbee RA, Halonen M, Kaltenborn WT, Burrows B. A
longitudinal study of respiratory symptoms in a community population sample. Correlations with smoking
allergen skin-test reactivity and serum IgE. Chest 1991;
99: 20–6.
5 Schappert SM. National ambulatory medical care survey
1991; Summary. In: Adv Data Stat No. 230. US Department of Health and Human Services. March 29, 1993:
1–20.
6 Irwin RS, Curley FJ. The treatment of cough: a comprehensive review. Chest 1991; 99: 1477–84.
7 French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of
chronic cough on quality of life. Arch Intern Med 1998;
158: 1657–61.
8 Irwin RS, Boulet LP, Cloutier MM et al. Managing cough
as a defence mechanism and as a symptom. A consensus
panel report of the American College of Chest Physicians.
Chest 1998; 114: 133S–181S.
9 Korpas J, Tomori Z. Cough and Other Respiratory Reflexes, 12th edn. Basel: S. Karger, 1979.
10 Irwin RS, Corrao WM, Pratter MR. Chronic persistent
cough in the adult: the spectrum and frequency of cases
and successful outcome of specific therapy. Am Rev Respir
Dis 1981; 123: 414–7.
35
CHAPTER 4
11 Irwin RS, Curley FJ, French CL. Chronic cough: the
spectrum and frequency of causes, key components of
the diagnostic evaluation and outcome of specific therapy.
Am Rev Resp Dis 1990; 141: 640–7.
12 Poe HR, Harder RV, Israel RH. Chronic persistent cough:
experience in diagnosis and outcome using an anatomic
diagnostic protocol. Chest 1989; 95: 723–7.
13 O’Connell F, Thomas VE, Fuller RW et al. Cough sensitivity to inhaled capsaicin decreases with successful treatment of chronic cough. Am J Respir Crit Care Med 1993;
150: 374–80.
14 Smyrnios NA, Irwin RS, Curley FJ. Chronic cough with a
history of excessive sputum production: The spectrum and
frequency of causes, key components of the diagnostic
evaluation, and outcome of specific therapy. Chest 1995;
108: 991–7.
15 McGarvey LPA, Heaney LG, Lawson JT et al. Evaluation
and outcome of patients with chronic non-productive
cough using a comprehensive diagnostic protocol. Thorax
1998; 53: 738–43.
16 Palombini BC, Villanova CA, Araujo E et al. A pathogenic
triad in chronic cough: asthma, postnasal drip syndrome
and gastrooesophageal reflux disease. Chest 1999; 116:
279–84.
17 Pratter MR, Bartter T, Akers S, Dubois J. An algorithmic
approach to chronic cough. Ann Intern Med 1993; 119:
977–83.
18 Ours TM, Kavuru MS, Schilz RJ, Richter JE. A prospective evaluation of esophageal testing and a double blind,
randomized study of omeprazole in a diagnostic and
therapeutic algorithm for chronic cough. Am J Gastroenterol 1999; 94: 3131–8.
19 McGarvey LPA, Heaney LG, MacMahon J. A retrospective survey of diagnosis and management of patients presenting with chronic cough to a general chest clinic. Int J
Clin Pract 1997; 52: 158–61.
20 Al-Mobeireek AF, Al-Sarhani A, Al-Amri S, Bamgboye E,
Ahmed S. Chronic cough at a non-teaching hospital: Are
extrapulmonary causes overlooked? Respirology 2002; 7:
141–6.
21 Mello CJ, Irwin RS, Curley FJ. The predictive values of
the character, timing and complications of chronic cough
in diagnosing its cause. Arch Intern Med 1993; 119:
997–1003.
22 Power JT, Stewart IC, Connaughton JJ et al. Nocturnal
cough in patients with chronic bronchitis and emphysema.
Am Rev Respir Dis 1984; 130: 999–1001.
23 Medical Research Council. Committee report on the aetiology of chronic bronchitis: Definition and classification
of chronic bronchitis for clinical and epidemiological purposes. Lancet 1965: 775–8.
24 Wynder EL, Kaufman PL, Lesser RL. A short term follow
up study on ex-cigarette smokers: With special emphasis
36
25
26
27
28
29
30
31
32
33
34
35
36
37
38
on persistent cough and weight gain. Am Rev Respir Dis
1967; 96: 645–55.
Blanc P, Liu D, Juarez C, Boushey HA. Cough in hot pepper workers. Chest 1991; 99: 27–32.
Gordon SB, Curran AD, Turley A, Wong C, Rahman S,
Wiley K, Morice AH. Glass bottle workers exposed to low
dose irritant fumes cough but do not wheeze. Am J Respir
Crit Care Med 1997; 156: 206–10.
Chan-Yeung M, Malo J. Aetiological agents in occupational asthma. Eur Respir J 1994; 7: 346–71.
Israili ZH, Hall WD. Cough and angioneurotic oedema
associated with angiotensin-converting enzyme inhibitor
therapy: a review of the literature and pathophysiology.
Ann Intern Med 1992; 117: 234–42.
Gwaltney JM Jr, Phillips CD, Miller RD, Riker DK. Computed tomographic study of the common cold. N Engl J
Med 1994; 330: 25–30.
Puhakka T, Lavonius M, Varpula M et al. Pulmonary imaging and function in the common cold. Scand J Infect Dis
2001; 33: 211–4.
Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH
monitoring and an experimental investigation of the role
of acid and pepsin in the development of laryngeal injury.
Laryngoscope 1991; 101: 1–78.
French CT, Irwin RS, Fletcher KE, Adams TM. Evaluation
of a cough specific quality of life questionnaire. Chest
2002; 121: 1123–31.
Chang AB, Newman RG, Carlin JB, Phelan PD,
Robertson CF. Subjective scoring of cough in children:
parent-completed vs child-completed cards vs an objective
method. Eur Respir J 1998; 11: 462–6.
Morice AH, Kastelik JA, Thompson R. Cough challenge
in the assessment of cough reflex. Br J Clin Pharmacol
2001; 52: 365–75.
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, Publ. 95-3659.
Washington, DC: National Heart, Lung and Blood Institute, National Institutes of Health, 1995: 1–176.
Thiadens HA, De Bock GH, Dekker FW et al. Value of
measuring diurnal peak flow variability in the recognition
of asthma: a study in general practice. Eur Respir J 1998;
12: 842–7.
Thiadens HA, De Bock GH, Van Houwelingen JC
et al. Can peak expiratory flow measurements reliably
identify the presence of obstruction and bronchodilator
response as assessed by FEV(1) in primary care patients
presenting with a persistent cough? Thorax 1999; 54:
1055–60.
Brightling C, Ward R, Goh KL, Wardlaw AJ, Pavord ID.
Eosinophilic bronchitis is an important cause of chronic
cough. Am J Respir Crit Care Med 1999; 160: 406–10.
CLINICAL ASSESSMENT OF COUGH
39 Irwin RS, Pratter MR, Holland PS, Corwin RW, Hughes
JP. Postnasal drip causes cough and is associated with reversible upper airway obstruction. Chest 1984; 85:
346–52.
40 Bucca C, Rolla G, Brussino L, De Rose V, Bugiani M. Are
asthma-like symptoms due to bronchial or extrathoracic
airway dysfunction? Lancet 1995; 346: 791–5.
41 Carney IK, Gibson PG, Murree-Allen K, Saltos N, Olson
LG, Hensley MJ. A systematic evaluation of mechanisms
in chronic cough. Am J Respir Crit Care Med 1997; 156:
211–6.
42 Pratter M, Bartter T, Lotano R. The role of sinus imaging
in the treatment of chronic cough in adults. Chest 1999;
116: 1287–91.
43 Davidson TM, Brahme FJ, Gallagher ME. Radiographic
evaluation for nasal dysfunction: computed tomography
versus plain films. Head Neck 1989; 11: 405–9.
44 Goodman GM, Martin DS, Klein J, Awwad E, Druce HM,
Sharafuddin M. Comparison of a screening coronal CT
versus contiguous coronal CT for the evaluation of patients with presumptive sinusitis. Ann Allergy Asthma Immunol 1995; 74: 178–82.
45 Richter J, Castell DO. Gastroesophageal reflux. Pathogenesis, diagnosis and therapy. Ann Intern Med 1982; 97:
93–103.
46 Irwin RS, Zawacki JK, Wilson MM, French CT, Callery
MP. Chronic cough due to gastroesophageal reflux disease: failure to resolve despite total/near-total elimination
of esophageal acid. Chest 2002; 121: 1132–40.
47 Sen RP, Walsh TE. Fibreoptic bronchoscopy for refractory
cough. Chest 1991; 99: 33–5.
48 Gibson PG, Dolovich J, Denberg JA, Ramsdale EH, Hargreave FE. Chronic cough: eosinophilic bronchitis without
asthma. Lancet 1989, 1346–8.
49 Pavord I, Pizzichini MM, Pizzichini E, Hargreave FE. The
use of induced sputum to investigate airway inflammation. Thorax 1997; 52: 498–501.
50 Chatkin JM, Ansarin K, Silkoff PE et al. Exhaled nitric
oxide as a noninvasive assessment of chronic cough. Am J
Respir Crit Care Med 1999; 159: 1810–3.
51 Berlyne GS, Parmeswaran K, Kamada D, Efthimiadis A,
Hargreave FE. A comparison of exhaled nitric oxide and
induced sputum as markers of airway inflammation. J
Allergy Clin Immunol 2000; 106: 638–44.
52 Lokshin B, Lindgren S, Weinberger M, Koviach J. Outcome of habit cough in children with a brief session of suggestion therapy. Ann Allergy 1991; 67: 579–82.
53 Riegal B, Warmoth JE, Middaugh SJ et al. Psychogenic
cough treated with biofeedback and psychotherapy. A review and case report. Am J Phys Med Rehabil 1995; 74:
155–8.
54 Mastrovich JD, Greenberger PA. Psychogenic cough in
adults: a report of two cases and review of the literature.
Allergy Asthma Proc 2002; 23: 27–33.
55 Kiljander T, Salomaa ERM, Hietanen EK, Terho EO.
Chronic cough and gastro-oesophageal reflux: a doubleblind placebo-controlled study with omeprazole. Eur
Respir J 2000; 16: 633–8.
56 Lin L, Poh KL, Lim TK. Empirical treatment of chronic
cough: A cost-effective analysis. Proc AMIA Symp 2001,
383–7.
37
5
Measurement and assessment
of cough
Kian Fan Chung
Introduction
The assessment of cough by the clinician should include
both tools that measure the amount and severity of the
cough, and also investigations that may lead to unravelling the cause of the cough, in terms of both disease
and disease processes. An anatomical approach to the
investigation of the patient with chronic cough has
been successfully advocated [1], and many investigations that are part of the work-up of the patient with
persistent cough (Table 5.1) contribute to this approach. However, not only anatomical evaluation but
assessing disease processes must be part of the investigation. In this chapter, I will focus on the measurement
of the cough itself, and on the assessment of airway inflammation in chronic cough. Other aspects of measurement and assessment of patients with cough are
covered elsewhere.
Measuring cough
The measurement of cough is important in order to determine its severity, following which an approach to
treating the cough can be planned. A reliable measure is
needed so that the evolution of a persistent cough in a
particular patient can be measured and the effectiveness of treatments can be determined.
Cough severity can be measured in several ways
(Table 5.2) but the clinician can simply ask the patient
how the cough affects his or her daily living and activities, the frequency and intensity of episodes of cough,
and his or her own appreciation of the overall severity,
and thus obtain a subjective evaluation of the patient’s
perception of this symptom. Perception of severity on
a linear cough symptom score scale ranging from
mild to severe has been widely used, but there has been
few comparative studies performed with other measures of cough. The notation of the patient, scaling of
cough intensity and frequency, and patients’ diaries
have been used to assess severity [2–4]. Table 5.3 shows
a scale that rests on the frequency and intensity of the
cough, although the intensity component is not included at the lower scores. The table also uses a scoring
system for the daytime as well as the night-time although the reliability of such a measure at night-time is
not known.
Although this is the most convenient tool that the clinician has to assess severity of cough, it remains a relatively unvalidated measure. For example, one does not
know whether this scale is linear and whether this represents the physical or mental effects of the persistent
cough. The sensitivity of the scale is not known and the
basis for any changes reported on the score is unclear
(for example, psychological factors or the intensity or
the frequency of the cough itself).
The impact of cough on patients has been evaluated
using a cough-specific health-related quality of life
questionnaire [5]. Such a tool provides a more quantitative reflection, but what do changes in the score reflect? In a study of chronic persistent coughers of
unknown cause, we found that according to a general
health questionnare (the SF-36) the mental but not the
physical scores were impaired (R.G. Stirling & K.F.
Chung, unpublished data), which is not surprising
since chronic coughing itself is unlikely to be associated
with any physical impairment, except in the very severe
cougher. It also indicated the potential mental effects of
39
CHAPTER 5
Table 5.1 Tests used to investigate cough.
Chest radiograph
Lung function tests
Bronchodilator reversibility
Methacholine or histamine bronchial responsiveness
Exercise-induced bronchoconstriction
Exhaled nitric oxide
Induced sputum eosinophilia
Fibreoptic bronchoscopy
High-resolution computed tomography of thorax
High-resolution computed tomography of the nose and
sinuses
Barium swallow studies
Gastro-oesophagoscopy
24-h monitoring of acid in oesophagus
Oesophageal manometry
Total serum immunoglobulin E
Skin prick tests to common allergens
Table 5.2 Analysis of cough severity.
1
2
3
4
5
6
7
Clinical history
Cough symptom score
Cough-specific quality of life
Ambulatory cough counts
Ambulatory cough intensity
Spectral analysis of cough sound
Cough sensitivity (to capsaicin or citric acid)
Table 5.3 Cough symptom score.
Daytime
0 No cough
1 Cough for one short period
2 Cough for more than two short periods
3 Frequent cough not interfering with usual activities
4 Frequent cough interfering with usual activities
5 Distressing cough most of the day
Night-time
0 No cough
1 Cough on waking only/cough on going to sleep only
2 Awoken once or woken early due to coughing
3 Frequent waking due to coughing
4 Frequent coughs most of the night
5 Distressing cough
40
chronic cough. For this reason, it is important to examine objective measures of cough so as to determine what
components of the cough response contribute to the ‘integrated’ severity profiles measured either from the
cough symptom score or from a cough-specific quality
of life assessment. One has to hypothesize that the
severity of the cough symptom may depend on its frequency of occurrence and on its intensity. The cough reflex measurement may be considered as similar to the
relationship of methacholine or histamine bronchial
hyperresponsiveness to asthma severity but there is
much less investigation of the cough reflex. Other potential contributions to the severity of cough may include bronchial hyperresponsiveness and submucosal
inflammatory changes.
Monitoring cough counts
The quantitative recording of cough over a representative period of time is necessary for the objective evaluation of cough associated with different diseases and for
the assessment of the efficacy of different treatments for
chronic cough. Early methods recorded cough in nonambulatory patients, usually limited to short periods of
time [6–11]. Pneumographic recording of thoracic
pressure change during cough and measurement of airflow have been used to count cough numbers and the
use of the cassette recorder using a free-air microphone
was described in the 1960s [12,13]. A variety of methods have been developed initially recording cough in
the non-ambulatory subject while sitting in a room and
usually limited to short periods of time by having an observer count cough sounds as they occur. Such recordings are limited because the patients are not exposed to
the presumed tussive stimuli that they encounter in
their daily activities. Monitoring of patients with a cold
while sitting in a room shows that cough counts fall significantly over the first 60 min [14].
The intensity and duration of cough have been examined by recording of the pneumogram on a kymograph
[15], but the most common method has been to record
the coughs onto a tape recorder either fixed on the wall
of the patient’s room or placed in close contact to the
patient’s throat [16,17]. Cough sounds have also been
recorded with a dynamic microphone placed in the
acoustic focus of a paraboloid mirror [18]. Cough intensity has also been measured using an integrated surface abdominal electromyogram [19].
MEASUREMENT AND ASSESSMENT
3500
subsequent computerized analysis is likely to be the
way forward. Cough frequency, in addition to other parameters from the cough sound such as the range of frequencies of the cough, spectral bursts and duration of
cough, can be measured [23].
Analysis of cough counts and intensity
Most of the coughs of patients with chronic persistent
cough occurred during the awake hours, with reduced
or little activity during the sleeping hours [20]. This is in
agreement with studies showing a depression of the
cough reflex during rapid eye movement sleep [24]. In
chronic coughers, there was a good correlation between daytime coughs and the self-assessment cough
scores (Fig. 5.1). In both adults and children, a correlation has been demonstrated between a cough scoring
system and the cough counts, particularly during the
day [20,25]. However, the correlation is not perfect, indicating that the cough scoring system may also reflect
other parameters than just the cough numbers, such as
the intensity of the cough or the physical effects of
cough.
Pharmacological assessment
In children with recurrent cough, the effects of salbutamol or beclomethasone (beclometasone) were examined on the cough counts. Overall, these drugs did not
inhibit cough. However, a 70% reduction in cough
counts was taken as representing success of treatment
and, on individual assessment, 4 out of 21 and 12 out of
P < 0.01
3000
2500
2000
1500
1000
500
0
0 1 2 3 4 5
Daytime cough symptom score
Number of coughs (23:00–05:00)
Fig. 5.1 Relationship of cough counts
with cough symptom scores during the
day or night. From [20].
Number of coughs (05:00–23:00)
Recent developments have given rise to ambulatory
methods of monitoring cough over a period of days
[20,21]. A 24-h ambulatory system using a solid-state,
multiple channel recorder to measure the number of
coughs has been devised. Coughs were measured as the
simultaneous occurrence of the digitized cough sound
recorded by a microphone and the electromyographic
signals from the lower respiratory muscles. The signals
were analysed visually, and it was possible in this way
to distinguish a cough from sneezing, Valsalva manoeuvre, laughing and speaking loudly. What probably remains most difficult to distinguish from cough is
throat-clearing but the intensity of the noise induced by
throat-clearing is less. The data could be analysed either as single cough events or as episodes of successive
burst of coughs, termed epochs, and there was an excellent correlation between the cough epochs and the total
number of coughs.
Another system that has been described is the acquisition of only the cough sound from a computerized audiotimed portable recorder connected to a transmitter
using telemetry to send the collected sound signals to a
computer in the home that digitizes and stores the signals [22]. The volunteer is free to move within 100 m of
the computer. The parameters that were measured included the cough count, the cough latency (periods between coughs), the cough effort (integral of the cough
acoustic power spectrum), cough intensity (cough effort divided by cough count) and the ‘wetness’ of the
cough. It is interesting that there is no system commercially available for ambulatory cough monitoring for
clinical use. The automatic computerized analysis of
cough events is still an issue. The ability to record highfidelity cough sounds acquired on a sound card with
350
P = 0.842
300
250
200
150
100
50
0
0 1 2 3 4 5
Night-time cough symptom score
41
Change in frequency of coughs/24 h (%)
CHAPTER 5
200
100
0
Failure
–70
Success
–100
–200
AHR –
AHR +
AHR +
AHR –
salbutamol placebo salbutamol placebo
Success = 0 Success = 1 Success = 4 Success = 4
Failure = 6 Failure = 7 Failure = 11 Failure = 10
22 children had a therapeutic response following salbutamol and beclomethasone, respectively [26] (Fig. 5.2).
The telemetric method of acquisition of cough sounds
has been used mainly to test the effects of antitussives
during acute cough associated with an upper respiratory tract virus infection. The effects of a reliever antitussive, dextromethorphan, were examined by comparing recordings over a 1-h baseline period with a 3-h
postdose period. In a meta-analysis of six studies involving 710 subjects, dextromethorphan was significantly effective in reducing cough counts (by 13%),
cough intensity (by 6%) and cough effort (by 17%),
and increasing cough latency period (by 17%) [27]. In a
similar study of 43 subjects who were observed in a
non-ambulatory study, dextromethorphan had no significant effect on the cough counts [28]. The study with
the ambulatory monitoring indicates that large cohorts
are needed to show an effect of dextromethorphan. The
remaining question is how significant are the changes in
the objective measurements observed?
The use of ambulatory monitoring of chronic persistent cough is still surprisingly limited. What are the issues raised and the potential advantages that the 24-h
ambulatory cough monitoring system will provide?
First, it is necessary to determine the variability of the
cough count and intensity: patients with chronic cough
often mention a variable course of chronic cough. This
could be related to various environmental factors, and
triggers may be identified. Secondly, it would be possible to relate temporally specific triggers with the
42
Fig. 5.2 Effect of salbutamol treatment
on cough counts in children with a
chronic cough. AHR, airway hyperresponsive. From [26].
cough event, such as an episode of gastro-oesophageal
reflux, timed with a decrease in oesophageal pH. In one
study where cough was noted by the patient as it occurred, about 46% of coughs were temporally associated with acid reflux as measured by oesophageal pH
monitoring [29]. Thirdly, it would be possible to relate
the measures of count and intensity to the cough responsiveness to capsaicin, to the cough symptom score
and to cough-associated quality of life score. Finally,
we may obtain useful ways of determining the effects of
therapy in particular patients and also for trials of drug
or other therapies as illustrated above.
Can quantitative analysis of the cough
sound help in the diagnosis?
An interest in quantitative analysis of the cough sound
has been generated with the hope that such analysis
may be used for diagnostic purposes, as well as for assessing the severity of the disease process [30]. Analysis
of the cough sound (the tussiphonogram) can often discern two components, with the first sound originating
at the level of the tracheal bifurcation or below, while
the second sound probably from the vocal cords. The
second cough sound is often absent in voluntary coughing, in patients following laryngectomy or chordectomy, during laryngeal paralysis and in patients with a
cough due to psychological reasons [31]. Abnormalities of the first cough sound such as a prolongation is
MEASUREMENT AND ASSESSMENT
due to tracheobronchial collapse. The presence of
mucus in the airways could lead to doubling or tripling
of the first cough sound. Changes in airway calibre
resulting from pharmacological drugs do not appear
to change the quality of the cough sound. Various characteristics have been described in terms of the cough
sounds associated with tracheitis, bronchitis and
laryngitis, but these have not been put to test in clinical
practice. A barking cough is typical of subglottic stenosis with the deep hollow cough sounds also coming
from the trachea. Whoops are typical of pertussis infections. A brassy sound is characteristic of bronchial
compression.
The intensity of the sound at a wide range of frequency levels can be analysed using a fast Fourier transformation (spectral analysis). Using this analysis, the
spontaneous cough of an asthmatic has been characterized by relatively long duration with a prolonged
wheezing sound and by a lower frequency than those
patients with chronic bronchitis or with tracheobronchial collapse [32,33]. Differences in the cough
spectrogram have also been reported between asthmatic and non-asthmatic children [34] and exercise
changed cough sound of the asthmatic child but not
that of the non-asthmatic child [35]. Spectrographic
differences in children with cystic fibrosis, acute bronchiolitis and whooping cough have been described. Different patterns of cough spectra may provide possible
discrimination between normal and abnormal cough
sounds [36]. Higher frequencies of voluntary cough
spectrograms were reported in patients with asthma,
chronic bronchitis, bronchial carcinoma and laryngeal
nerve paralysis compared with healthy volunteers [37].
However, there are inherent difficulties in the use of this
analysis in diagnostic work, and these have limited the
usefulness of such an approach. The frequency distribution of the cough sound is variable between subjects
and also within the same subject under different conditions. One disappointing feature of spectral analysis of
cough is that it does not appear to be different within
the same subject when challenged with different tussive
stimuli such as with capsaicin or prostaglandin F2a or
chloride-deficient solutions.
Assessment of airway inflammation in
chronic cough
Many of the tests in the assessment of airway inflam-
mation relate to the diagnosis of asthma or coughvariant asthma, because these conditions are associated
typically with airway eosinophilia. Sputum can be induced by inhalation of hypertonic solutions of salt, and
the resulting expectorate can be examined for inflammatory cells such as eosinophils [38]. The value of performing fibreoptic bronchoscopy in patients with
persistent cough of indeterminate cause remains unclear [39], mainly because the significance of inflammatory cells in the submucosa apart from eosinophils
remains uncertain. Other non-invasive measures that
may help in the diagnostic process of confirming asthma or asthma-associated cough include exhaled nitric
oxide.
Assessment of airway inflammation
by induced sputum
In asthma, one expects to see high levels of eosinophil
counts, often related to the severity of the disease
[40]; in addition, raised levels of neutrophils can also
be seen in patients with more severe asthma needing
oral corticosteroid therapy [41]. There are three conditions of persistent cough associated with eosinophilic inflammation as assessed by induced sputum
(Table 5.4).
Cough-variant asthma, first described in six patients
with chronic persistent cough without wheezing or
dyspnoea or airflow obstruction, but with bronchial
hyperresponsiveness [42], responds well to bronchodilator therapy and inhaled corticosteroids. In a
comparative study, serum eosinophil cationic protein
levels and the percentage of eosinophils in bronchoalveolar lavage fluid and in bronchial biopsy specimens were elevated in patients with cough-variant
asthma and comparable to those levels found in patients with classic asthma associated with wheeze [43].
Increased thickness of the bronchial basement membrane has also been described in patients with coughvariant asthma, indicating that a similar process of
‘airway remodelling’ as observed in asthma may be
present in cough-variant asthma [44]. The relationship
of bronchial hyperrresponsiveness to the cough reflex
to capsaicin in this group of patients is interesting.
These patients have been divided into those hyperresponsive to methacholine whose coughs were responsive to bronchodilators, and into those who were
normoresponsive and whose cough did not respond to
43
CHAPTER 5
Table 5.4 Common causes of cough with eosinophilia.
Asthma
Cough-variant asthma
Eosinophilic bronchitis
Peak flow variability
BHR
Sputum
Sputum eosinophils
Steroid responsiveness
+
±
-
+
+
-
±
+
+
+
+
+
+
+
Eosinophil-associated cough: +, present; ±, variable; -, absent.
BHR, bronchial hyperresponsiveness.
7
(a)
200
3
2
150
TNFa (pg/mL)
IL-8 (ng/mL)
4
100
50
1
0
0
bronchodilators [45]. The former group had a normal
capsaicin cough threshold, while the latter had a hypertussive response to capsaicin, which reverted to normal
when treated with steroids or anti-H1 histamine drugs.
In this group, eosinophilia was not present in bronchoalveolar lavage fluid, but there was a small number
of eosinophils in the subepithelium of the trachea and
bronchi [46].
Eosinophilic bronchitis is a condition presenting
with chronic cough, and characterized by sputum
eosinophilia but without any evidence of variable
airflow obstruction or airway hyperresponsiveness
[47,48]. It is found in 10–20% of patients presenting
with a persistent cough to a hospital cough clinic [49].
Sputum eosinophilia ranging between 3 and 95% has
been reported with normal bronchial responsiveness to
histamine but with a hypertussive response to capsaicin. With inhaled corticosteroid treatment, the
cough improves with a reduction in capsaicin tussive
response and with a significant reduction (not suppression) of the sputum eosinophilia [50].
In patients with eosinophilic bronchitis, similar to
44
P < 0.01
P < 0.05
6
5
(b)
Fig. 5.3 Levels of interleukin-8 (IL-8)
and tumour necrosis factor-a (TNFa)
in supernatants of induced sputum
from non-asthmatic chronic coughers
(closed symbols) and from control noncoughing volunteers (open symbols).
From [52].
asthmatics, gene expression of the cytokines interleukin-5 (IL-5) and granulocyte–macrophage colonystimulating factor (GM-CSF), measured by in situ
hybridization were expressed in bronchoalveolar
lavage cells from most of these patients [51]. By contrast, in cells obtained from patients whose cough did
not respond to inhaled corticosteroids, these cytokines
were not expressed. Similar to patients with asthma,
patients with steroid-responsive cough demonstrate
expression of IL-5 and GM-CSF. On the other hand, in
a study of patients with chronic cough without asthma
or asthma-related conditions, examination of sputum
revealed no eosinophils but an excess of neutrophils
[52]. These included patients with ‘idiopathic’ cough or
cough associated with postnasal drip or gastrooesophageal reflux. There were also increased levels of
interleukin-8 and tumour necrosis factor-a which are
neutrophil-associated cytokines (Fig. 5.3). Interestingly, patients with chronic obstructive pulmonary
disease of moderate severity, a condition associated
with neutrophilic inflammation, have an enhanced capsaicin tussive response [53].
MEASUREMENT AND ASSESSMENT
Wark et al. have looked at the measurement of
induced eosinophil count in the assessment of asthma
and chronic cough, and concluded that this may be a
useful guide to therapy, especially in the assessment of
persistent symptoms in asthmatics on corticosteroids,
and in the assessment of non-asthmatic subjects with
cough [54]. Of interest, in cough patients without sputum eosinophilia, inhaled corticosteroids had no effect
on the cough [55].
Overall, one could define a group of chronic
cough associated with eosinophilic inflammation
(‘eosinophilic cough’), an enhanced cough reflex to
capsaicin, and a suppression of the cough to inhaled
corticosteroids. These patients reflect the spectrum of
conditions ranging from asthma to eosinophilic bronchitis. Clinically, these conditions can be grouped together because of their good therapeutic response
to inhaled steroids. We do not know whether cough
due to gastro-oesophageal reflux is an eosinophilassociated condition: in a small study that included two
patients with gastro-oesophageal reflux and in another
larger study there was no sputum eosinophilia [52,56]
but, in a bronchoalveolar lavage study, eosinophilia
was reported [57].
Exhaled nitric oxide
Nitric oxide is an intracellular messenger with actions
as an inflammatory mediator, vasodilator and a
non-adrenergic non-cholinergic neurotransmitter. Increased levels of exhaled nitric oxide are observed in
patients with asthma, after upper airway viral infections and in bronchiectasis [58]. Raised levels of exhaled nitric oxide have been used as a non-invasive
marker of airway inflammation. Exhaled nitric oxide
levels are raised in patients presenting with chronic
cough in whom asthma has been documented with
an increased methacholine hyperresponsiveness [59],
while in chronic cough not attributable to asthma,
levels are within normal. The sensitivity and specificity
of exhaled nitric oxide for detecting asthma in patients
with chronic cough were 75% and 87%, respectively.
Exhaled nitric oxide is not elevated in patients with
cough associated with gastro-oesophageal reflux [56],
nor in non-asthmatic coughing children [60,61].
Therefore, a normal level of exhaled nitric oxide may
confidently exclude the diagnosis of asthma-associated
cough, although these measurements should be made
with patients not taking inhaled corticosteroids since
this inhibits exhaled nitric oxide levels [62]. The levels
of exhaled nitric oxide in eosinophilic bronchitis are
not known. The relationship between exhaled nitric
oxide levels and induced sputum eosinophils or submucosal eosinophils in chronic asthmatic coughers is not
known. In mild asthma, exhaled nitric oxide correlates
with bronchial hyperresponsiveness but not with sputum eosinophilia [63,64].
Bronchial mucosal biopsies
There are limited data regarding the inflammation
observed in bronchial biopsies from patients with
chronic cough, and therefore the interpretation of the
presence of inflammatory cells in these biopsies remains unclear. In addition, it is possible that coughing
itself could perpetuate a chronic inflammatory airway
response. This issue remains unresolved. Bronchial
biopsies from 25 patients with a chronic dry cough as
an isolated symptom over a 3-week period revealed in
21 patients an infiltrate with eosinophils, of whom five
were hyperresponsive to methacholine; in the other
four, a lymphocytic infiltrate was found [65]. The significance of airway lymphocytic inflammation in
chronic cough is not known but this has also been
observed by other groups [66]. In a group of nonasthmatic patients with chronic cough associated
with postnasal discharge, chronic sinusitis, gastrooesophageal reflux, or without any associated cause,
endobronchial biopsies showed increased epithelial
desquamation and the presence of inflammatory cells,
particularly mononuclear cells [66]. In addition, submucosal fibrosis, squamous cell metaplasia and loss of
cilia are also described. The significance of these
changes are unclear and more detailed analysis is
necessary.
Conclusion
This chapter has reviewed the measurement and assessment of airway inflammation in chronic persistent
cough. Measurement of cough severity needs more
validated tools, which are also required for the
proper evaluation of antitussive drugs. Assessment of
airway inflammation by invasive and non-invasive
techniques is required for investigating the cause of
45
CHAPTER 5
cough, but may also provide clues to the pathogenesis
of cough.
References
1 Irwin RS, Curley FJ, French CL. Chronic cough: the spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am
Rev Respir Dis 1990; 141: 640–7.
2 Aylward M, Maddock J, Davies DE, Protheroe DA, Leideman T. Dextromethorphan and codeine: comparison of
plasma kinetics and antitussive effects. Eur J Respir Dis
1984; 65: 283–91.
3 Gulsvik A, Refvem OK. A scoring system on respiratory
symptoms. Eur Respir J 1988; 1: 428–32.
4 Ellul-Micallef R. Effect of terbutaline sulphate in
chronic ‘allergic’ cough. Br Med (Clin Res Ed) 1983; 287:
940–3.
5 French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of
chronic cough on quality of life. Arch Intern Med 1998;
158: 1657–61.
6 Barach AL, Bickerman HA, Beck GJ. Clinical and physiological studies on the use of metacortandracin in respiratory disease. 1. Bronchial asthma. DC 1955; 27: 515–22.
7 Bickerman HA, Borach AL. The experimental production
of cough in human subjects induced by citric acid aerosols.
Preliminary studies on the evaluation of antitussive
agents. Am J Med Sci 1954; 228: 156–63.
8 Morris DJ, Shane SJ. Human bioassay of a new antitussive
agent. Can Med Assoc J 1960; 83: 1093–5.
9 Prime FJ. The assessment of antitussive drugs in man. Br
Med J 1961; 1: 1149–51.
10 Calesnik B, Christensen JA, Munch JC. Antitussive action
of 1-propoxyphene in citric acid-induced cough response.
Am J Med Sci 1961; 242: 560–4.
11 Chernish SM, Lewis G, Kraft B, Howe J. Clinical evaluation of a new antitussive preparation. Ann Allergy 1963;
21: 677–82.
12 Loudon RG, Brown LC. Cough frequency in patients
with respiratory disease. Am Rev Respir Dis 1967; 96:
1137–43.
13 Reece CA, Cherry AC, Reece AT, Hatcher AT, Diehl AM.
Tape recorder for evaluation of cough in children. Am J
Dis Child 1966; 112: 124–8.
14 Eccles R, Morris S, Jawad M. Lack of effect of codeine in
the treatment of cough associated with acute upper respiratory tract infection. J Clin Pharm Ther 1992; 17:
175–80.
15 Gravenstein JS, Devloo RA, Beecher HK. Effect of antitussive agents on experimental and pathological cough in
man. J Appl Physiol 1954; 7: 119–39.
46
16 Woolf CR, Rosenberg A. The cough suppressant effect of
heroin and codeine: a controlled clinical study. Can Med
Assoc J 1962; 87: 810–4.
17 Sevelius H, Colmore JP. Objective assessment of antitussive agents in patients with chronic cough. J New Drugs
1966; 6: 216–33.
18 Salmi T, Sovijarvi ARA, Brander P, Piirila P. Long-term
recording and automatic analysis of cough using filtered
acoustic sign movements on static charge sensitive bed.
Chest 1988; 94: 970–5.
19 Cox ID, Wallis PJW, Apps MCP, Hughes DTD, Empey
DW, Osman RCA et al. An electromyographic method
of objectively assessing cough intensity and use of the
method to assess effects of codeine on the dose–
response curve to citric acid. Br J Clin Pharmacol 1984;
18: 377–82.
20 Hsu J-Y, Stone RA, Logan-Sinclair R, Worsdell M, Busst
C, Chung KF. Coughing frequency in patients with persistent cough using a 24-hour ambulatory recorder. Eur Resp
J 1994; 7: 1246–53.
21 Chang AB, Phelan PD, Robertson CF, Newman RG,
Sawyer SM. Frequency and perception of cough severity. J
Paediatr Child Health 2001; 37: 142–5.
22 Subburaj S, Parvez L, Rajagopalan TG. Methods of
recording and analysing cough sounds. Pulm Pharmacol
1996; 9: 269–79.
23 Dalmasso F, Isnardi E, Sudaro L, Bellantoni R. Bioacoustics of cough during bronchial inhalation challenge
(BIC) with methacholine. Eur Resp J 2001; 18 (33):
135s.
24 Power JT, Stewart IC, Connaughton JJ, Brash HM,
Shapiro CM, Flenley DC et al. Nocturnal cough in patients
with chronic bronchitis and emphysema. Am Rev Respir
Dis 1984; 130: 999–1001.
25 Chang AB, Newman RG, Carlin JB, Phelan PD,
Robertson CF. Subjective scoring of cough in children:
parent-completed vs child-completed diary cards vs an
objective method. Eur Respir J 1998; 11: 462–6.
26 Chang AB, Phelan PD, Carlin JB, Sawyer SM, Robertson
CF. A randomised, placebo controlled trial of inhaled
salbutamol and beclomethasone for recurrent cough.
Arch Dis Child 1998; 79: 6–11.
27 Pavesi L, Subburaj S, Porter-Shaw K. Application and validation of a computerized cough acquisition system for
objective monitoring of acute cough: a meta-analysis.
Chest 2001; 120: 1121–8.
28 Lee PCL, Jawad MS, Eccles R. Antitussive efficacy of dextromethorphan in cough associated with acute upper respiratory tract infection. J Pharm Pharmacol 2000; 52:
1137–42.
29 Avidan B, Sonnenberg A, Schnell TG, Sontag SJ. Temporal
associations between coughing or wheezing and acid reflux in asthmatics. Gut 2001; 49: 767–72.
MEASUREMENT AND ASSESSMENT
30 Korpas J, Sadlonova J, Vrabec M. Analysis of the cough
sound: an overview. Pulm Pharmacol 1996; 9: 261–8.
31 Korpas J, Sadlonova J, Salat D, Masarova E. The origin of
cough sounds. Bull Eur Physiopathol Respir 1987; 23
(Suppl. 10): 47s–50s.
32 Piirila P, Sovijarvi AR. Differences in acoustic and dynamic characteristics of spontaneous cough in pulmonary
diseases. Chest 1989; 96: 46–53.
33 Salat D, Korpas J, Salatova V, Korpasova Sadlonova J,
Palecek D. The tussiphonogram during asthmatic attack.
Acta Physiol Hung 1987; 70: 223–5.
34 Thorpe CW, Toop LJ, Dawson KP. Towards a quantitative
description of asthmatic cough sounds. Eur Respir J 1992;
5: 685–92.
35 Toop LJ, Dawson KP, Thorpe CW. A portable system for
the spectral analysis of cough sounds in asthma. J Asthma
1990; 27: 393–7.
36 Debreczeni LA, Korpas J, Salat D. Spectral analysis of
cough sounds recorded with and without a nose clip.
Bull Eur Physiopathol Respir 1987; 23 (Suppl. 10):
57s–61s.
37 Debreczeni LA, Korpas J, Salat D, Sadlonova Korpasova
J, Vertes C, Masarova E et al. Spectra of the voluntary first
cough sounds. Acta Physiol Hung 1990; 75: 117–31.
38 Jayaram L, Parameswaran K, Sears MR, Hargreave FE.
Induced sputum cell counts: their usefulness in clinical
practice. Eur Respir J 2000; 16: 150–8.
39 Markovitz DH, Irwin RS. Is bronchoscopy overused in the
evaluation of chronic cough? Bronchoscopy is overused. J
Bronchol 1997; 4: 332–6.
40 Peleman RA, Rytila PH, Kips JC, Joos GF, Pauwels RA.
The cellular composition of induced sputum in chronic
obstructive pulmonary disease. Eur Respir J 1999; 13:
839–43.
41 Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF,
Barnes PJ. Neutrophilic inflammation in severe persistent
asthma. Am J Respir Crit Care Med 1999; 160: 1532–9.
42 Carrao WM, Braman SS, Irwin RS. Chronic cough as the
sole presenting manifestation of bronchial asthma. N Engl
J Med 1979; 300: 633–7.
43 Niimi A, Amitani R, Suzuki K, Tanaka E, Murayama T,
Kuze F. Eosinophilic inflammation in cough variant
asthma. Eur Respir J 1998; 11: 1064–9.
44 Niimi A, Matsumoto H, Minakuchi M, Kitaichi M, Amitani R. Airway remodelling in cough-variant asthma.
Lancet 2000; 356: 564–5.
45 Fujimura M, Kamio Y, Hashimoto T, Matsuda T. Cough
receptor sensitivity and bronchial responsiveness in patients with only chronic non-productive cough: in view of
effect of bronchodilator therapy. J Asthma 1994; 31:
463–72.
46 Fujimura M, Ogawa H, Yasui M, Matsuda T. Eosinophilic
tracheobronchitis and airway cough hypersensitivity in
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
chronic non-productive cough. Clin Exp Allergy 2000;
30: 41–7.
Gibson PG, Dolovich J, Denburgh J, Ramsdale EH,
Hargreave FE. Chronic cough: Eosinophilic bronchitis
without asthma. Lancet 1989; 1: 1246–7.
Brightling CE, Pavord ID. Eosinophilic bronchitis: an important cause of prolonged cough. Ann Med 2000; 32:
446–51.
Brightling CE, Ward R, Goh KL, Wardlaw AJ, Pavord ID.
Eosinophilic bronchitis is an important cause of chronic
cough. Am J Respir Crit Care Med 1999; 160: 406–10.
Brightling CE, Ward R, Wardlaw AJ, Pavord ID. Airway
inflammation, airway responsiveness and cough before
and after inhaled budesonide in patients with eosinophilic
bronchitis. Eur Respir J 2000; 15: 682–6.
Gibson PG, Zlatic K, Scott J, Sewell W, Woolley K, Saltos
N. Chronic cough resembles asthma with IL-5 and
granulocyte-macrophage colony-stimulating factor gene
expression in bronchoalveolar cells. J Allergy Clin
Immunol 1998; 101: 320–6.
Jatakanon A, Lalloo UG, Lim S, Chung KF, Barnes PJ. Increased neutrophils and cytokines, TNF-alpha and IL-8,
in induced sputum of non-asthmatic patients with chronic
dry cough. Thorax 1999; 54: 234–7.
Doherty MJ, Mister R, Pearson MG, Calverley PM. Capsaicin responsiveness and cough in asthma and chronic
obstructive pulmonary disease. Thorax 2000; 55: 643–9.
Wark PA, Gibson PG, Fakes K. Induced sputum
eosinophils in the assessment of asthma and chronic
cough. Respirology 2000; 5: 51–7.
Pizzichini MM, Pizzichini E, Parameswaran K, Clelland L,
Efthimiadis A, Dolovich J et al. Nonasthmatic chronic
cough: no effect of treatment with an inhaled corticosteroid in patients without sputum eosinophilia. Can
Respir J 1999; 6: 323–30.
Parameswaran K, Allen CJ, Kamada D, Efthimiadis A,
Anvari M, Hargreave FE. Sputum cell counts and exhaled
nitric oxide in patients with gastroesophageal reflux, and
cough or asthma. Can Respir J 2001; 8: 239–44.
McGarvey LP, Forsythe P, Heaney LG, MacMahon J,
Ennis M. Bronchoalveolar lavage findings in patients with
chronic nonproductive cough. Eur Respir J 1999; 13:
59–65.
Kharitonov SA, Barnes PJ. Clinical aspects of exhaled nitric oxide. Eur Respir J 2000; 16: 781–92.
Chatkin JM, Ansarin K, Silkoff PE, McClean P, Gutierrez
C, Zamel N et al. Exhaled nitric oxide as a noninvasive assessment of chronic cough. Am J Respir Crit Care Med
1999; 159: 1810–3.
Avital A, Uwyyed K, Berkman N, Godfrey S, Bar-Yishay E,
Springer C. Exhaled nitric oxide and asthma in young children. Pediatr Pulmonol 2001; 32: 308–13.
Formanek W, Inci D, Lauener RP, Wildhaber JH, Frey U,
47
CHAPTER 5
Hall GL. Elevated nitrite in breath condensates of children
with respiratory disease. Eur Respir J 2002; 19: 487–91.
62 Kharitonov SA, Yates DH, Barnes PJ. Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1996; 153: 454–7.
63 Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ.
Correlation between exhaled nitric oxide, sputum
eosinophils, and methacholine responsiveness in patients
with mild asthma. Thorax 1998; 53: 91–5.
64 Dupont LJ, Rochette F, Demedts MG, Verleden GM. Ex-
48
haled nitric oxide correlates with airway hyperresponsiveness in steroid-naive patients with mild asthma. Am J
Respir Crit Care Med 1998; 157: 894–8.
65 Lee SY, Cho JY, Shim JJ, Kim HK, Kang KH, Yoo SH et al.
Airway inflammation as an assessment of chronic nonproductive cough. Chest 2001; 120: 1114–20.
66 Boulet LP, Milot J, Boutet M, St Georges F, Laviolette M.
Airway inflammation in non-asthmatic subjects with
chronic cough. Am J Respir Crit Care Med 1994; 149:
482–9.
6
Cough sensitivity: the use of
provocation tests
Rick W. Fuller
Introduction
Cough has been identified as a significant symptom in
the population. Everybody will experience cough at
some time, either during a respiratory infection or as
one of a significant number of people who will have
chronic cough from other causes [1]. Almost any
disease of the respiratory tract, as well as some nonrespiratory conditions, such as gastro-oesophageal
reflux, can cause cough. Traditionally the study of
cough has relied on patient reports via questionnaires
or by mechanical recording of cough events. Provocation tests provide another mechanism to study cough
[2]. Despite the demonstration in 1957 [3] that cough
provocation could be safely and reliably performed,
such methodology has not been as well developed as
those for provoking bronchoconstriction. Nevertheless, there are data on cough provocation studies in
three areas, which I will discuss in this chapter. They are
the epidemiology of cough, the clinical management of
cough and the clinical research of cough.
Epidemiology
Cough is a symptom which is found commonly in all
communities with an incidence varying from 5 to 40%
[1]. Environmental and lifestyle factors, e.g. smoking,
appear to have the greatest influence on the frequency
with which cough is reported. A recent study in Europe
[4] has shown that three distinct types of cough can be
identified in the population: productive cough, nonproductive cough and nocturnal cough. These different
cough types have different associations with the data
gained in the survey, i.e. increased body mass and cigarette exposure contributed to all three whereas rhinitis
and gender did not. The question is whether cough
provocation testing, as an index of the sensitivity of the
cough reflex in those populations, would have enriched
the information. Unfortunately no true epidemiology
study has used cough reflex testing as a variable; there
are, however, data from small studies, which point to its
possible value.
Data in patient groups have been gathered using
challenges such as low Cl- solutions [5], which is a
timed tidal breathing challenge, and single breath challenges with citric acid [6] and capsaicin [7], although
the methods used tend to vary from group to group.
Broadly speaking, the studies show that in the noncoughing population there is little variability in the
cough reflex sensitivity, i.e. very few people do not
cough or have very sensitive reflexes (Fig. 6.1). There is
some evidence that children are more sensitive than
adults [8], which may well be an artifact of dosing due
to their smaller airways. In addition, a clear difference
can be defined between males and females (the females
being more sensitive) with low Cl- challenge [9] and in
some studies with the single breath challenges [10] but
not others [7]. The explanation is likely to be anatomical differences in airway size and therefore a dose issue
until proven otherwise.
The cough reflex has been studied in a number of different patient groups with respiratory diseases with
and without cough. Patients with stable disease without cough, chiefly asthma, have a normal reflex (Table
6.1); however, if the disease is associated with dry
cough then an increased sensitivity of the reflex has
been observed [7] (Table 6.1). The exception in the
49
CHAPTER 6
study in Table 6.1 was a patient group with postnasal
drip who complained of a dry cough but had on average
a normal reflex; however, the variability was large and
the sample small so the conclusion may not stand the
test of time. On the other hand the patients who had
productive cough were likely to have a normal cough
Log C2 and C5
2
1.5
*
1
*
0.5
0
No cough Dry cough Productive cough
Fig. 6.1 The log concentration (μmol/L) of capsaicin that
caused at least 2 (C2, 䊉) or at least 5 (C5, 䊏) coughs. In patients with no cough, dry cough and productive cough, the
data are significantly (*P < 0.05) different in the no cough
compared to the other patients. Data from [7].
reflex (Fig. 6.1). In this series (Table 6.1) the exception
was a group of patients with bronchiectasis with active
infection who as a group had an increased reflex sensitivity likely to be due to the acute inflammation associated with the infection. There is some variability in
the data on chronic obstructive pulmonary disease
(COPD) who as a group were normal in our study
whereas others [11] have seen increases in the sensitivity of the reflex. Our group was stable and screened
to rule out acute disease while in the other series the
disease activity status was less clear and any active inflammation would change the picture.
In summary, an abnormal reflex is observed in some
patient groups with cough and it does relate to the presence of non-productive cough. I would submit that
this is sufficiently similar to the early information on
bronchial hyperreactivity in asthma to support the use
of cough reflex testing to enhance the data of epidemiology studies in respiratory diseases.
Table 6.1 The various disease groups in the population covered in Fig. 6.1.
Patient group
n
C2 ± 95% CI
C5 ± 95% CI
(a) No cough
Normal
ACE-I
Hypertension
Asthma
90
35
15
18
1.04 ± 0.02
0.94 ± 0.18
0.91 ± 0.27
0.87 ± 0.22
1.81 ± 0.14
1.8 ± 0.1
1.77 ± 0.36
1.49 ± 0.37
(b) Dry cough
Idiopathic
Postnasal drip
Post viral
Asthma
GOR
65
13
5
23
14
0.6 ± 0.12
1.3 ± 0.49
0.59 ± 0.35
0.65 ± 0.25
0.54 ± 0.07
1.08 ± 0.37
1.93 ± 0.39
1.14 ± 0.62
1.06 ± 0.41
0.8 ± 0.12
(c) Productive cough
Bronchiectasis
Bronchiectasis with infection
COPD
Inflammatory lung disease
12
7
11
12
1.25 ± 0.41
0.5 ± 0.22
0.92 ± 0.43
1.29 ± 0.53
1.94 ± 0.38
1.11 ± 0.58
1.44 ± 0.52
1.5 ± 0.51
C2 = log concentration (μmol/L) of capsaicin causing 2 or more coughs.
C5 = log concentration (μmol/L) of capsaicin causing 5 or more coughs.
ACE-I, angiotensin-converting enzyme inhibitor; COPD, chronic obstructive
pulmonary disease; GOR, gastro-oesophageal reflux.
Data from [7].
50
COUGH SENSITIVITY
Clinical management
The symptom of cough as noted in the previous section
can have several attributes attached to it, i.e. dry (no
sputum), productive (sputum), temporal (night, etc.) or
provoking (cold air, etc.) events. Unfortunately, none of
these attributes narrow down the cause of the cough.
Standard history-taking and routine investigations
may help identify the cause, which can then be investigated by more specific tests and eventually therapeutic
trials. A cough-specific test, which could pinpoint the
diagnosis, would therefore be of great clinical value.
Does cough provocation testing meet this need? Unfortunately, as the data in Table 6.1 and Fig. 6.1 show,
provocation testing can differentiate between productive and dry coughing but not for various causes within
those subsets. It can therefore be used only to confirm
that aspect of the history which may have some limited
value. In addition, it can be used to rule out psychogenic
or fictitious cough if the test is performed blind to
the subject and yet is still abnormal. These findings appear to be true of all the provocation tests studied sufficiently to date. It is unlikely that provocation testing
will be used as a routine in clinical diagnosis but will be
reserved as a research tool.
Prognosis
Like diagnosis, the prognosis of a patient with cough
once chronic cannot be easily judged until the success
or failure of a therapeutic trial is known. This is not
to say that it is not a safe bet to reassure the sufferer of
an acute cough during a respiratory infection that their
suffering will be relatively short-lived! Theoretically
the relative abnormality of a cough provocation test
could inform on prognosis. However, there is insufficient information in the studies such as those in Fig. 6.2
to know whether this is a possibility. This question is
clearly an area that would benefit from systematic
evaluation.
C2 and C5 (mmol/L)
Diagnosis
2
*
1.5
1
*
0.5
0
Pre
IIIness
Recovery
Fig. 6.2 The log concentration (μmol/L) of capsaicin that
caused at least 2 (C2, 䊉) or at least 5 (C5, 䊏) coughs. In 31 patients before (Pre), during (Illness) and after (Recovery) upper
respiratory infection, the data are significantly different
(*P < 0.05) in the illness compared to the ‘Pre’ and ‘Recovery’
data. Data from [15].
C2 and C5 (mmol/L)
Cough provocation testing has a potential role in three
areas of clinical management: first, as an aid in diagnosis; second, as a guide to prognosis; and finally, as a tool
for monitoring the course of treatment.
2.5
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
*
*
Success
pre
Success
post
Failure
pre
Failure
post
Fig. 6.3 The log concentration (μmol/L) of capsaicin that
caused at least 2 (C2, 䊉) or at least 5 (C5, 䊏) coughs. In patients before (pre) and after (post) successful (success n = 48)
or unsuccessful (failure n = 39) treatment of the underlying
cause for their cough, the data for the successfully treated patients are significantly (*P < 0.05) different from the ‘pre’
data. Data from [42].
Monitoring
The monitoring of the clinical course of cough and the
response to therapy is a more fruitful area than cough
provocation tests. The data exemplified in Figs 6.2 and
6.3 show that an abnormal cough provocation test, if
identified, will be present while the disease is active and
resolve with the disease. The use of provocation testing
can clearly help in this aspect of management especially
51
CHAPTER 6
in a patient with no clear diagnosis that may require a
number of therapeutic interventions before the diagnosis is finally made.
A clear case for use of cough provocation comes in
the management of neurological diseases where respiratory infection is a common sequela [12]. The loss of a
functioning cough reflex is thought to be behind the
mechanism for these respiratory infections in patients
with a loss of neurological functions.
Efferent testing of cough reflex by asking the patient
to cough will usually inform on the capacity of that
limb of the reflex. However, it does not inform on the
function of the sensory input. Cough provocation will
so inform, as a negative provocation test in a patient
who can cough voluntarily identifies the perturbation
of the sensory limb of the reflex. Data to support such
an abnormality are limited to date [13]; however, what
data there are support the hypothesis and in view of its
importance to the mobility of the patient it does require
comprehensive assessment.
Cough provocation in clinical research
Pathophysiology
Cough provocation is able to provide an objective
measure of the sensitivity of the cough reflex so that its
function can be assessed in respiratory disease. It is
therefore possible to use it to understand the pathophysiology of cough. Cough is a response either to the
need to clear the airway of unwanted material or to an
alteration in the sensitivity of the cough reflex as in dry
cough. It is therefore of value to understand what may
change the sensitivity of the reflex. Cross-sectional
studies have shown that in some diseases the reflex can
be normal or abnormal, with a suggestion that this is
related to the level of activity of the diseased state.
Prospective studies have confirmed that in angiotensinconverting enzyme inhibitor-associated cough [14] and
common cold-associated cough [15], patients with
cough start with a normal reflex which becomes exaggerated with the cough and returns to normal with the
resolution of the condition.
What causes this change in the response of the reflex
is not fully elucidated. Airway biopsy in a small series of
dry cough patients [16] with an abnormal reflex has
shown an increase in airway nerve and neuropeptide
associated with those nerves. However, prospective
52
studies have yet to be performed. Additional data
has been obtained that inhaled PGE2 [17] but not
bradykinin or substance P can invoke a temporary
change in the sensitivity of the reflex. This would suggest that hyperalgesic mediators could increase the sensory limb of the reflex, probably not by altering the
number of fibres in view of the rapidity of the response.
The unravelling of the mechanisms behind the change
in sensitivity of the cough reflex would give a new basket of targets for developing antitussive drugs.
Pharmacology
Most of the investigations of the pharmacology of the
cough reflex have been made using cough provocation
either by citric acid, low Cl- solution or capsaicin in
normal volunteers. In addition there has been some limited investigation of the pharmacology of the exaggerated reflex in patients with dry cough.
Table 6.2 summarizes the results of studies using
cough challenge in normal volunteers. This list may
well not contain all data, as it is likely that a number of
negative investigations are not in the public domain.
There is consistent and predictable evidence that local
anaesthesia [18] and centrally acting opiates [19] reduce the sensitivity of the reflex, however tested. Other
results are either conflicting, e.g. bronchodilatation
and inhaled diuretics which have shown positive results
in some, but by no means all studies, or are based on the
unconfirmed results of one study. If the results are confirmed, then humans [20] like cats [21] may have a 5HT-dependent cough-suppressing mechanism, which
could be exploited for antitussive therapies. Other than
that there is little of encouragement from the extensive
studies to date.
Equally disappointing is the data in patients with
dry cough. A 4-week study with nedocromil sodium
was negative [22] and despite anecdotal evidence of
non-steroidal anti-inflammatory drugs working in
angiotensin-converting enzyme inhibitor cough, controlled trials failed to show an effect on dry cough [23]
overall.
Conclusion
Cough challenge is a safe and easy method for assessing
the sensitivity of the cough reflex. However, there are
not yet any standards agreed for the methodology,
COUGH SENSITIVITY
Table 6.2 Results of pharmacological studies on cough provocation tests.
Pharmacological tool (Reference)
Capsaicin
Local anaesthesia [18,24]
Opiates [19,25]
b2-Agonists [5,6,26,27]
Antimuscarinics [6,26,41]
Antihistamines [28]
5-HT3 antagonists [29]
5-HT1 agonists [20]
NSAID [30,31]
Sodium cromoglycate [32]
Nedocromil sodium [33]
Baclofen [34]
a2-Agonists [35]
Diuretics [36]
MAO-I [37]
Demulcents [38,39]
Antileukotriene [40]
Ø
Ø
0
0
0
0
0
0
0
0
Ø
0
0
0
Ø
0
Low Cl-
Ø
Ø
Citric acid
Other
Ø
Ø
±
Ø
Ø
Ø
Ø
MAO-I, monoamine oxidase inhibitor; NSAID, non-steroidal anti-inflammatory
drug.
Ø, Reduced; ±, equivocal or conflicting data; 0, no effect.
which tend to be laboratory specific making comparisons between studies difficult. As well as data compatibility issues, the different methodologies occasionally
lead to results that need explaining, such as differences
between males and females, adults and children and in
COPD. These differences could be true physiological
variability or artefacts of methodology and this needs
to be resolved through a consensus on methodology.
Despite the methodological issues there is sufficient
evidence that the provocation tests can detect differences in the sensitivity of the reflex in disease. These differences make the cough challenge of likely value in
epidemiology studies, some aspects of clinical management and in particular in hypothesis testing. In hypothesis testing it is difficult to imagine a strategy to unravel
the pathophysiology and pharmacology of the reflex
without using cough challenge even if the results require validation in large studies using more clinical
end-points.
References
1 Fuller RW, Jackson DM. Physiology and treatment of
cough. Thorax 1990; 45: 425–30.
2 Prime FJ. The assessment of antitussive drugs in man. Br
Med J 1961; April 22: 1149–51.
3 Tiffeneau R. The acetylcholine cough test. Dis Chest
1957; 31: 404–22.
4 Janson C, Chinn S, Jarvis D, Burney P. Determinants of
cough in young adults participating in the European Community Respiratory Health Survey. Eur Respir J 2001; 18:
647–54.
5 Lowry R, Wood A, Johnson T, Higenbottam T. Antitussive
properties of inhaled bronchodilators on induced cough.
Chest 1988; 93/6: 1186–9.
6 Pounsford JC, Birch MJ, Saunders KB. Effect of bronchodilators on the cough response to inhaled citric acid
in normal and asthmatic subjects. Thorax 1985; 40:
662–7.
7 Choudry NB, Fuller RW. Sensitivity of the cough reflex in
patients with chronic cough. Eur Respir J 1992; 5:
296–300.
8 Chang AB, Phelan PD, Roberts RGD, Robertson CF. Capsaicin cough receptor sensitivity test in children. Eur
Respir J 1996; 9: 2220–3.
9 Stone RA. Investigations into the neural control of the
cough reflex. PhD thesis, Department of Thoracic Medicine, Royal Brompton National Heart and Lung Institute,
University of London, December 1992.
10 Dicpinigaitis PV, Rauf K. The influence of gender on cough
reflex sensitivity. Chest 1998; 113: 1319–21.
53
CHAPTER 6
11 Doherty MJ, Mister R, Pearson MG, Calverley PMA.
Capsaicin responsiveness and cough in asthma and
chronic obstructive pulmonary disease. Thorax 2000; 55:
643–9.
12 Smith Hammond CA, Goldstein LB, Zajac DJ, Gray L,
Davenport PW, Bolser DC. Assessment of aspiration risk
in stroke patients with quantification of voluntary cough.
Neurology 2001; 56: 502–6.
13 Addington WR, Stephens RE, Gilliland KA. Assessing the
laryngeal cough reflex and the risk of developing pneumonia after stroke — an interhospital comparison. Stroke
1999; 30: 1203–7.
14 McEwan JR, Choudry N, Street R, Fuller RW. Change in
cough reflex after treatment with enalapril and ramipril.
Br Med J 1989; 299: 13–6.
15 O’Connell F, Thomas VE, Studham JM, Pride NB,
Fuller RW. Capsaicin cough sensitivity increases during
upper respiratory infection. Respir Med 1996; 90: 279–
86.
16 O’Connell F, Springall DR, Moradoghli-Haftvani A,
Krausz T, Price D, Fuller RW, Polak JM, Pride NB. Abnormal intraephithelial airway nerves in persistent unexplained cough? Am J Respir Crit Care Med 1995; 152:
2068–75.
17 Choudry NB, Fuller RW, Pride NB. Sensitivity of the
human cough reflex: effect of inflammatory mediators
prostaglandin E2, bradykinin and histamine. Am Rev Rep
Dis 1989; 140: 137–41.
18 Choudry NB, Fuller RW, Anderson N, Karlsson J-A. Separation of cough and reflex bronchoconstriction by inhaled
local anaesthetics. Eur Respir J 1990; 3: 579–83.
19 Fuller RW, Karlsson J-A, Choudry NB, Pride NB. Effect
of inhaled and systemic opiates on responses to inhaled
capsaicin in humans. Am Physiol Soc 1988; 88: 1125–30.
20 Stone RA, Worsdell YM, Fuller RW, Barnes PJ. Effect of 5hydroxytryptamine and 5-hydroxytryptophan on sensitivity of the human cough reflex. J Appl Physiol 1993; 74:
396–401.
21 Karlsson J-A, Fuller RW. Pharmacological regulation of
the cough reflex — from experimental models to antitussive effects in man. Pulm Pharmacol Ther 1999; 12:
215–28.
22 Choudry NB. Investigation of the sensitivity of the cough
reflex in humans. MD thesis, Faculty of Medicine, University of London, December 1990.
23 McEwan JR, Choudry NB, Fuller RW. The effect of sulindac on the abnormal cough reflex associated with dry
cough. J Pharmacol Exp Ther 1990; 255: 161–4.
24 Addington WR, Stephens RE, Goulding RE. Anesthesia of
the superior laryngeal nerves and tartaric acid-induced
cough. Arch Phys Med Rehabil 1999; 80: 1584–6.
25 Empey DW, Laitinen LA, Young GA, Bye CE, Hughes
DTD. Comparison of the antitussive effects of codeine
54
26
27
28
29
30
31
32
33
34
35
36
37
38
39
phosphate 20 mg, dextromethorphan 30 mg and noscapine 30 mg using citric acid-induced cough in normal subjects. Eur J Clin Pharmacol 1979; 16: 393–7.
Choudry NB, Fuller RW. Effect of airway calibre on the
sensitivity of the human cough reflex. Thorax 1990; 45:
311P–12P.
Katsumata U, Sekizawa K, Inoue H, Sasaki H, Takishima
T. Inhibitory actions of procaterol, a beta-2 stimulant, on
substance P-induced cough in normal subjects during
upper respiratory tract infection. Tohoku J Exp Med
1989; 158: 105–6.
Studham J, Fuller RW. The effect of oral terfenadine on the
sensitivity of the cough reflex in normal volunteers. Pulm
Pharmacol, 1992; 5 (1): 51–2.
Choudry NB, McEwan JR, Lavender EA, Williams AJ,
Fuller RW. Human responses to inhaled capsaicin are not
inhibited by granisetron. Br J Clin Pharmacol 1991; 31
(3): 337–9.
Stone RA, Barnes PJ, Fuller RW. The low-chloride cough
response is not inhibited by a single, high dose of aspirin.
Br J Clin Pharmacol 1992; 34: 370–2.
Dicpinigaitis PV. Effect of the cyclooxygenase-2 inhibitor
celecoxib on bronchial responsiveness and cough reflex
sensitivity in asthmatics. Pulm Pharmacol Ther 2001; 14:
93–7.
Collier JG, Fuller RW. The effect of inhaled capsaicin in
man and the action of SCG on this response. Br J Pharmacol 1984; 81: 113–7.
Hansson L, Choudry NB, Fuller RW, Pride NB. Effect of
nedocromil sodium on the airway response to inhaled capsaicin in normal subjects. Thorax 1988; 43: 935–6.
Dicpinigaitis PV, Dobkin JB. Antitussive effect of the
GABA-agonist baclofen. Chest 1997; 111: 996–9.
O’Connell F, Thomas VE, Fuller RW, Pride NB, Karlsson
J-A. Effect of clonidine on induced cough and bronchoconstriction in guinea pigs and humans. J Appl Physiol
1994; 76: 1082–7.
Karlsson JA, Choudry NB, Zackrisson C, Fuller RW. A
comparison of the effect of inhaled diuretics on airway
reflexes in humans and guinea pigs. J Appl Physiol 1992;
1: 72 (2), 434–8.
Choudry NB, Studham J, Harland D, Fuller RW. Modulation of capsaicin induced airway reflexes in humans: effect
of monoamine oxidase inhibition. Br J Clin Pharmacol
1993; 35: 184–7.
Packman EW, London SJ. The utility of artificially induced
cough as a clinical model for evaluating the antitussive
effects of aromatics delivered by inunction. Eur J Respir
Dis 1980; 110 (Suppl.): 101–9.
Fuller RW, Haase G, Choudry NB. The effect of dextromethophan cough syrup on capsaicin-induced cough
in normal volunteers. Am Rev Respir Dis 1989; 139:
A11.
COUGH SENSITIVITY
40 Dicpinigaitis PV, Dobkin JB. Effect of zafirlukast on cough
reflex sensitivity in asthmatics. J Asthma 1999; 36 (3):
265–70.
41 Fuller RW. Pharmacology of inhaled capsaicin in humans.
Respir Med 1991; 85 (Suppl. A): 31–4.
42 O’Connell F, Thomas VE, Pride NB, Fuller RW. Capsaicin
cough sensitivity decreases with successful treatment of
chronic cough. Am J Respir Crit Care Med 1994; 150:
374–80.
55
7
Causes, assessment and
measurement of cough in children
Anne B. Chang
Introduction
The prevalence of childhood cough without wheeze
is high, 12.8–15.5% [1] in community studies based
on parent-completed questionnaires, and that of
nocturnal cough varies from 4.9 to 28.1% [2,3]. This
high prevalence raises the question as to when childhood cough should be considered ‘normal’ or pathological. In childhood, cough may be ‘normal’ [4] or a
symptom of any respiratory illness and rarely of a nonrespiratory illness. The management of childhood
cough [4,5] differs from that of adults [6]; and paediatricians worldwide have long been passionate
about managing childhood illness differently from
that of adults, and about the dangers of extrapolating
adult data to young children. The pattern of respiratory illness in children can be clearly different from
that in adults. For example, viruses associated with
the common cold in adults can cause life-threatening
illness in children, such as bronchiolitis and croup; the
natural history of asthma in children is dominated
by decreasing severity with age and, in some, complete
resolution [7] whereas asthma acquired in adulthood
usually persists. The aetiology and management of
childhood cough should also be clearly distinguished
from adult cough. Extrapolation of adult cough
literature to children can be harmful, for example the
suggestion of fundoplication for gastro-oesophageal
reflux as the sole symptom of cough without evidence
of secondary aspiration [8] is inappropriate for children. Indeed current evidence suggests that it is erroneous to extrapolate the three commonest causes of
cough in adults (cough-variant asthma, postnasal drip,
gastro-oesophageal reflux) to children [9,10]. This
chapter discusses the issues of cough unique to
children.
Causes of cough in children
The aetiology of cough can be broadly divided into
groups of primary pathophysiology, although there is
undoubtedly an overlap in the pathophysiology of
some diseases (Table 7.1). The first clinical challenge
that faces the physician is deciphering whether the
cough is ‘normal’ or ‘expected’, non-specific or specific.
Non-specific overlaps with both ‘normal/expected’ and
specific cough, but ‘expected’ cough is distinctly separate from specific cough (Fig. 7.1). The relative frequency of each category will depend on the setting, and
general practitioners would more likely encounter ‘expected/normal’ cough whereas in a tertiary setting specific cough would dominate. These descriptions and the
common and/or controversial aetiologies of childhood
cough are briefly discussed below. A complete clinical
review of each specific aetiology is beyond the scope of
this chapter and can be found in standard paediatric
respiratory textbooks.
Cough categories
‘Normal’ or ‘expected’ cough
Diagnosing this category of cough requires the most
skill and experience [4]. All cough is arguably representative of some process. However, as the cough reflex
is subjected to cortical modulation [9] and can be
57
CHAPTER 7
Table 7.1 Causes of cough in children.
Infectious
Acute, subacute
Viral infections, mycoplasma, chlamydia, pneumocystis, etc.
Chronic
Tuberculosis, non-TB mycobacteria, fungal
Suppurative lung disease
Cystic fibrosis, ciliary dyskinesia, postpneumonia, immunodeficiency (primary or
secondary)
Allergy/inflammatory
Asthma
Postviral
Nasal space disease (see text)
? Eosinophilic bronchitis
Airway clearance
1 Aspiration
(a) Primary: bulbar lesions, laryngopalatal discoordination, cerebral palsy,
Moebius syndrome, vocal cord palsy
(b) Secondary: gastro-oesophageal reflux
(c) Anatomical: laryngeal cleft, tracheo-oesophageal fistula, tonsil–adenoid
hypertrophy
2 Airway lesions
(a) Primary: laryngomalacia, bronchomalacia, tracheomalacia
(b) Secondary: external compression (vascular slings, tumours, etc.), intraluminal
lesions, foreign body
Pulmonary toxicants
Tobacco
Particulate matter
Gaseous
Biomass combustion
Primary lung disease
Interstitial lung disease
Pulmonary hypertension
Congenital bronchiolitis of infancy
Tumours
Follicular bronchiolitis
Bronchiolitis obliterans
Pulmonary vascular congestion
Non-pulmonary disease
Drugs
Angiotensin-converting enzyme inhibitors
Cardiac disease
Arrhythmias
Psychological
Psychogenic cough
Habit, tic
Gastro-oesophageal reflux without aspiration
58
COUGH IN CHILDREN
Table 7.2 Specific cough pointers.
‘Normal’ or
‘expected’ cough
Nonspecific
cough
Specific
cough
Fig. 7.1 Broad categories of childhood cough. The diagram
depicts the overlap between the categories of childhood
cough. Non-specific cough overlaps with both specific cough
and ‘normal or expected cough’, whereas specific cough is
distinct from ‘normal or expected cough’.
voluntarily initiated, it is not surprising that cough
(1–34 per 24 h) can be found in ‘normal’ children free of
a respiratory infection in the previous 4 weeks [11]. In
another study, age-, sex- and season-matched ‘normal
controls’ have 0–141 coughs per day (median 10) [12].
In this study, children with recent viral infections were
not excluded but were considered well by their parents.
Children can have 6–8 viral acute respiratory infections
(ARIs) per year, especially when they are in daycare
centres, and arguably childhood cough within this
spectrum can be considered ‘normal’ or ‘expected’.
Children with recurrent cough who present to a tertiary
centre do have a higher cough frequency than controls,
and have a higher cough frequency during the day than
the night [12].
Specific cough
Specific refers to cough to which a definable cause
(or causes) can be attributed. In specific cough, pointers
of respiratory impairment are usually present. The aetiology and necessity of further investigations is usually
evident from the presence of these pointers (Table 7.2).
Non-specific cough
In non-specific cough, the cough is dry and pointers of
Presence of:
Haemoptysis
Recurrent pneumonia
Exertional dyspnoea
Chronic sputum production
Wheeze
Stridor
Immune deficiency
Cardiac abnormality
Swallowing difficulties
Dyspnoea
Chest deformity
Clubbing
Ausculatory abnormality
Poor growth
respiratory impairment are absent. The aetiology
may be ill-defined and we suspect that the majority is
related to postviral cough and/or increased cough receptor sensitivity [13,14]. In non-specific cough, there
is no serious underlying condition and the child is
otherwise well.
Brief overview of common causes
and controversies
Cough and respiratory infections
The spectrum of respiratory infections causing
cough varies from benign (e.g. common cold) to lifethreatening infections (e.g. lung abscess, pneumocystis
pnuemonia). The manifestation of the infection depends on various pathogens, ‘host or patient’ factors
(asthma, immunodeficiency, established cardiopulmonary impairment, malnutrition, genetics, etc.) and
environmental factors (smoke, biomass combustion
exposure).
ARIs and post-ARI-associated cough are the most
common causes of childhood cough. In Australia, the
reported use of medications for coughs and colds in the
2 weeks before assessment was 167 and 87 per 1000 for
children under 5 years and children between 5 and 14
years, respectively, corresponding to the most frequently and third most frequently used medications in
their respective age groups [15]. Approximately US $2
billion per year is spent on cough and cold remedies in
59
CHAPTER 7
the US [16]. A national US survey reported that approximately 35% of 8145 preschool-aged children had
used ‘over the counter’ medications for cough in the
past 30 days [16].
It is sometimes argued that ‘the common cold’, an
upper respiratory infection, should not cause cough,
and the presence of cough reflects the presence of a
lower respiratory tract infection. However, lower airway inflammation has been demonstrated in children
with colds, not only in the active phase but also in those
who were asymptomatic 1–14 days before a bronchoalveolar lavage was taken [17]. Also, clinically unapparent alterations in lower airway function occur
during upper ARI in infants, children and adults [18].
There are few prospective epidemiological data on
the length of cough associated with a common cold in
children. In one study, 80% of adults were cough free
by 2 weeks [19] and cough sensitivity has been shown
to be increased during upper ARIs [20]. Transient enhanced cough sensitivity has also been shown in children with influenza infection [21]. Like the clinical
manifestation of ARIs, the length of cough most likely
depends on patient and environmental factors.
Cough and asthma in children
There is little doubt that children with asthma may
present with cough and that wheeze may be absent
during physical examination. Isolated cough has been
postulated as a marker of asthma, and improper
interpretation of cough as a symptom was previously
thought to be a key factor in the underdiagnosis of
asthma. However, more recently increasing numbers of
children are misdiagnosed as having asthma on the
basis of cough alone [22–24], although there is also ongoing concern that children with significant asthma
symptoms are still being missed and consequently
undertreated [25]. The importance of cough in the
diagnosis of asthma and the frequency of coughvariant asthma is debatable [23]. Current epidemiological, inflammatory and cohort studies suggest that most
cough in children is not asthma [23,26,27] and most
cough in children spontaneously resolves [26,28]. A
review on this is available elsewhere [9].
Recent work on airway inflammatory markers in
community children with isolated persistent cough
show that, unlike in the adult, most children with persistent isolated cough do not have asthma, since their
airway inflammatory markers are significantly differ60
ent from those in children with asthma [27,29]. How
many children in the community with persistent cough
do indeed have asthma is unknown. There are only two
randomized controlled trials on the use of current
asthma medications in children with isolated cough
[30,31]. Both studies objectively measured cough,
which is crucial, since cough as an outcome measure is
subjective and unreliable [32]. Neither recommended
prolonged or high doses of asthma-type therapy when
managing these children [30,31].
Indeed, the misdiagnosis of isolated cough as asthma
is not uncommon [23,24,33]. We recently showed that
the overdiagnosis of asthma and the overuse of asthma
treatments with significant side-effects, in children with
persistent cough referred to a respiratory clinic, is common [24]. While a trial of asthma-type medications
may be considered, the child must be reviewed and, if
the cough does not respond to the asthma therapy, the
diagnosis must be withdrawn and the medications
stopped [4,5]. Failure to do so will lead to escalating
doses being used with significant side-effects [24].
There is however, difficulty in defining what constitutes
a response to treatment, particularly when the natural
resolution of the underlying condition such as viral respiratory infection may mimic a response to treatment.
Recurrence of cough on cessation and elimination of
cough upon commencement of inhaled corticosteroids
is sometimes necessary for confident diagnosis [4]. The
original studies describing cough as a manifestation of
asthma showed that the cough responded within a
week to medications used for asthma during that era
(theophylline and hypnotics) [34,35]. It could be
argued that the currently available more potent antiinflammatory medications for asthma would reduce
the symptoms as efficaciously, if not more so. However,
following an acute exacerbation of asthma, cough was
present in 23% of children [36]. In this group of children whether the cough is related to concurrent viral
respiratory infections, the cause of asthma exacerbations in 80% of children [37], or a marker of nonresolution of asthma is unknown. Markers of cough
severity are known to correlate poorly with clinical, inflammatory and spirometry markers of asthma severity
[38]. The relationship between cough and asthma is
complex [39,40] and beyond the scope of this chapter.
The existence of cough-dominant asthma, where
cough is a dominant feature of asthma exacerbations in
patients with classical asthma, is recognized in both the
paediatric [41] and the adult literature [42]. However,
COUGH IN CHILDREN
whether cough-dominant asthma represents a truly different phenotype is not yet confirmed at the cellular or
genetic level. Increasingly asthma phenotypes are recognized and ‘treatment response genes’ to b2-receptor
agonists have recently been described. However, for clinicians, the aetiology of isolated cough in children with
asthma can be difficult to determine, when objective
markers such as spirometry are unavailable. Cough is
included in asthma severity scales [43], and in children
without wheeze the presence of this isolated symptom
can categorize children into the moderately severe
group. Isolated cough in children with asthma can be
associated with any other respiratory illness, or with
environmental exposure. Several studies on air pollution (environmental tobacco smoke, bioaerosols) have
shown that air pollution is more likely to affect children
with asthma than those without, and cough is the
major symptom manifestation [44]. Many studies have
shown a poor relationship between cough and other
markers of asthma (day and night oxygen saturations
(SpO 2), lung volumes, airway resistance (Raw), peak expiratory flow (PEF) and variability, spirometry) in children with asthma during a non-acute phase as well in
the recovery phase of an acute exacerbation, as recently summarized [40].
Does ‘allergic or atopic cough’ exist in children?
This poorly defined condition is probably an overlap
with asthma and eosinophilic bronchitis, a condition
well recognized in adults but not well defined in
children. The association between atopy and respiratory symptoms has been the subject of many epidemiological studies [45,46]. Some have described
greater respiratory symptom chronicity [1] but others
have not [45,46]. In the seminal prospective study of infants followed up to 11 years old, the Tuscon group
showed that recurrent cough present early in life resolved in the majority of children [26]. These children
with recurrent cough and without wheeze did not have
airway hyperresponsiveness (AHR) or atopy and significantly differed from those with classical asthma
with or without cough [26]. These important differences were: maternal allergy, wheezing, airway respiratory infection, high IgE, atopy, reduced maximal flow
·
(Vmax) at functional residual capacity (FRC) (significant for asthma) and exposure to tobacco smoke (significant for recurrent cough). In laboratory and clinical
studies, others have studied the association between
atopy, AHR, asthma and cough [14,30,47]. In these
studies, AHR is an important confounder associated
with atopy and is independent of other respiratory
symptoms [48,49]. Studies where confounding variables were not controlled, and where standard criteria
for AHR were not observed, can be misleading in their
conclusions [47].
Cough and gastro-oesophageal reflux
(GOR) in children
Aspiration lung disease can result from laryngopalatal
discoordination or discoordinated swallowing (primary aspiration), or severe GOR (secondary aspiration). Children with primary aspiration may present
with chronic cough but usually in the context of severe
developmental or neurological disturbance. The investigatory evidence for aspiration lung disease can be difficult but it is important to exclude this diagnosis in the
correct setting as recurrent aspiration may lead to
chronic respiratory illnesses such as bronchiectasis and
bronchiolitis obliterans. Oesophageal disorders can
undoubtedly trigger cough in children which may cause
cough by at least three mechanisms: aspiration of gastric contents, acid reflux and volume reflux. However,
while GOR can cause cough, cough can also cause
GOR and causative links are hard to identify [50]. The
relationship between the two is probably complex. The
view that GOR is a frequent cause of cough in adults
has been challenged [51,52]. Like the difference between the paediatric and adult literature for asthma
and cough, there is indeed little evidence that GOR
without aspiration is a specific or frequent cause of
cough in children. As cough is very common in children
and respiratory symptoms may exacerbate GOR, it is
difficult to delineate cause and effect. Infants regularly
regurgitate [53], yet few, if any, well infants cough with
these episodes.
Cough and nasal space disease
In adults, sinusitis/postnasal drip is a common cause
of cough. In children, there is little supportive evidence
for this condition [10]. There are no cough receptors in
the pharynx or postnasal space [42]. Although sinusitis
is common in childhood, it is not associated with
asthma or cough once allergic rhinitis, a common association, is treated [54]. The relationship between nasal
secretions and cough is more likely linked by common
61
CHAPTER 7
aetiology (infection and/or inflammation causing both)
or due to throat clearing of secretions reaching the
larynx. In a prospective study, 50% of 137 children
aged under 13 years had CT sinus scans consistent with
sinusitis but all were asymptomatic [55]. Abnormal
sinus radiographs may be found in 18–82% of asymptomatic children [56]. Using a continuous infusion of
2.5 mL/min of distilled water into the pharynx of
asymptomatic adults, Nishino et al. demonstrated that
laryngeal irritation and cough only occurred in the presence of hypercapnia (45–55 mmHg) [57], suggesting
that pharyngeal secretion itself does not cause cough.
Cough and chronic suppurative lung disease
This is an essential diagnosis that should never be
missed. Children with bronchiectasis have a chronic
moist or productive cough and are typically but not always finger-clubbed. The cough is characteristically
worse in the mornings. Physical findings are nonspecific; clubbing, pectus carinatum, and coarse
crepitations and localized wheeze may or may not be
present. Plain chest radiography will suggest features in
severe disease (dilated and thickened bronchi may
appear as ‘tramtracks’) but is insensitive in mild disease. Confirmation is by high-resolution computed tomography (CT) scan of the chest (routine CT scan
provides insufficient detail). A child with suspected
bronchiectasis should be referred for investigation of
a specific cause and specific treatment instituted when
indicated (e.g. cystic fibrosis, primary ciliary dyskinesia, immunodeficiency).
Cough and airway lesions in children
Cough can be due to intrinsic (tracheomalacia and
bronchomalacia) [58,59] and extrinsic (foreign bodies
and other endobronchial obstruction) airway lesions.
An inhaled foreign body usually presents in the acute
stage, with a history of acute cough following a choking
event, but may be found many years later [24]. When
the foreign body causes a ball-valve effect, air trapping
seen in an expiratory film when compared with an inspiratory chest radiograph (CXR) may be useful. When
suspected, bronchoscopy allows for the definitive
diagnostic and concomitant therapeutic procedure.
Airway malacia disorders (tracheomalacia, bronchomalacia) are well recognized causes of persistent
and/or recurrent cough in children [24,58,59], but not
62
in adults [60]. In one study, 75% of children with tracheomalacia secondary to congenital vascular anomaly
had persistent cough at presentation [58], whereas of
24 adults with tracheomalacia secondary to vascular
rings 16 were symptomatic and none complained of
cough [60]. The pathophysiology of cough in the presence of airway lesions is poorly understood but is possibly related to a localized bronchitic process.
Environmental causes
In utero tobacco smoke exposure alters pulmonary development and physiology [61]. How this influences
the developmental aspects of the central and peripheral
cough pathways as well as the plasticity of the cough
pathway is unknown. Exposure to environmental
smoke and other ambient pollutants (particulate matter [62], nitrogen dioxide, etc.) is associated with increased cough in children, especially in the presence of
other respiratory illness such as asthma [62]. Irrespective of the primary aetiology of cough, exposure to environmental smoke can exacerbate the frequency and
severity of cough.
Other causes of cough
Other than habitual cough, non-respiratory causes of
cough are rare, but should be considered when appropriate clinical features are present.
Habitual and psychogenic cough
Habitual cough or cough as a ‘vocal tic’ may be transient or chronic. While psychogenic cough is more common in adolescents, the habitual cough occurs in
younger children. The mean age of diagnosis for habitual cough ranges from 4 to 15 years [63]. The typical
psychogenic cough (honking cough) is recognizable
and can often be heard even before the child is seen.
Irrespective of the cause of cough, psychological influences on severity of cough have been documented in
both children [64] and adults.
Assessment in children
Cough is a very common symptom of respiratory disease. As cough is audible and can interfere with sleep
and may represent serious underlying disorders such as
COUGH IN CHILDREN
cystic fibrosis, it is not surprising that parents are often
anxious about their children’s cough and often seek
medical advice and remedy. Parental concerns may differ significantly from physicians’ concerns. Physicians
are usually concerned about the aetiology of cough and
getting the correct diagnosis. Parental concerns, however, often relate to their perceived effects of cough on
their child (sleep, choking, permanent chest damage)
[65].
Clinical assessment
When presented with a child with a cough, the key
questions are aimed at clearly defining the nature and
impact of the cough on the child and family:
1 Is it a symptom of an underlying problem?
2 Are there possible modifiers of exacerbation and/or
contributing factors?
3 How does the cough affect the child and parents?
4 Is it necessary to investigate?
5 Are any treatment modalities available or
necessary?
The clinical assessment of cough can be approached
from many ways, e.g. dry vs. moist, age of the child and
length of cough. Each obviously influences the others
and none can be considered in isolation. A suggested
pathway primarily based on the length of cough is presented (Fig. 7.2) [5]. The aetiology of cough that backdates to infancy is clearly different to that of recent
onset. A history of chronicity or exertional dyspnoea
may not be offered unless specifically asked for. Cough
associated with pointers of respiratory impairment
(Table 7.2) are immediately differentiated (pathway III
in Fig. 7.2c) irrespective of the historical length of
cough. These pathways are only a guide and based on
clinical experience and available scientific literature. In
paediatrics there are indeed insufficient data to provide
a comprehensive evidence-based approach.
In a child with persistent cough, the initial clinical
challenge is deciphering whether the persistent cough is
specific or non-specific. The definition of persistent or
chronic cough varies (> 3–6 weeks) and the aetiological
factors in children vary from the benign to lifethreatening causes. Specific pointers should be sought
from a thorough history and examination (Table 7.2).
In specific cough, the aetiology and necessity of further
investigations is usually evident from the presence of
coexisting symptoms and signs. The presence of any of
these pointers suggests that the cough is likely to repre-
sent an underlying disorder and that further complex
investigations are probably indicated, other than symmetrical polyphonic wheeze representative of asthma.
The type of investigations depends on the clinical findings. Diagnoses that need to be considered include
bronchiectasis, retained foreign body, aspiration lung
disease, atypical respiratory infections, cardiac anomalies and interstitial lung disease, amongst other
diseases. The diagnosis and management of cough
associated with an underlying disorder is most appropriately undertaken by paediatric respiratory physicians and will not be discussed further in this
chapter.
In deciding the aetiology of the child’s cough, Bush
[4] suggests that the child’s cough can be placed in one
of the five categories:
1 Normal.
2 A serious illness such as cystic fibrosis (rare but
essential to get right).
3 An unserious but treatable cause (e.g. GOR).
4 A child with an asthma syndrome.
5 Overestimation of symptoms for psychological or
other reasons by either or both child or family.
An additional category to the above would be:
6 A non-respiratory cause such as habitual cough,
medications (ACE inhibitors), etc.
Exposure to tobacco smoke is the most important
modifier of childhood cough and is known to increase
susceptibility to respiratory infections [66], cause adverse respiratory health outcomes and increase coughing illnesses [67]. When appropriate, a non-judgmental
discussion of how tobacco smoke affects children
forms part of any clinical management of a child with a
cough.
Effect on parents and child
In childhood illnesses, parental expectations often
drive presentations to medical personnel [68]. In adults
with asthma, asthma severity determined emergency
presentations whereas in paediatrics, parental anxiety
was found to be the most important factor [69]. In a
study on upper respiratory tract infection, the main
reason for repeated consultations for the same episode occurred when parental expectations about the
natural history of the illness were not fulfilled [68].
When adopting a ‘wait and see’ approach in a child
with non-specific cough, discussing parental expectations, concerns and anxiety often proves useful, diagnostically and therapeutically.
63
CHAPTER 7
64
(a)
Pathway I: Coughing child and length of cough
Acute
(<2 weeks)
Subacute
2–4 weeks
Chronic or persistent
(>4 weeks)
Is it the first presentation of a chronic illness?
See pathway II
See pathway III
Presence of 'respiratory pointers'
Poor growth, chest deformity, clubbing, haemoptysis,
recurrent pneumonia, dyspnoea, sputum production,
exertional dyspnoea, ausculatory abnormality, cardiac
abnormality, immune deficiency, swallowing difficulties
No
Yes
Is the cough characteristic?
Yes
•
•
•
•
No
Classical recognizable cough
Psychogenic—honking cough [94]
LTB—barking cough (watch for other causes, e.g. tracheomalacia)
Staccato—Chlamydia (in infants)
Paroxysmal—pertussis and para pertussis
Look for symptoms of
Fever, rhinorhoea, coryza,
sneezing, generalized aches,
pains, sore throat, tachypnoea
Acute upper and/or
lower respiratory tract
infection entities (ARI)
History of aspiration followed
by immediate choking,
coughing, +/– wheeze,
stridor, tachypnoea, cyanosis
Aspiration of
foreign object
Wheeze, dyspnoea,
exertional symptoms,
hyperinflation, previous
response to beta-2
agonist +/– atopy
Acute exposure,
e.g. smoke,
volatile
compounds
Inhalation injury
Asthma
Hypoxia, chest
pain, risk
factors present
Embolism
haemorrhage
(rare)
(b)
Pathway II: Subacute cough not associated with other symptoms
CXR
Spirometry (if >6 years old)
Both normal
Either abnormal
Wait and see
usually
• post viral cough
• acute bronchitis
See pathway III
Evaluate
• smoke/other pollutants
• child's activity
• parental expectations
• functional disorders
Review in a week
Resolving
Further symptoms develop
or increased severity
Resolved
Discharge
to factor the various possible combinations in these pathways. Note: ARI
could coexist with another diagnosis. ARI, acute respiratory infection;
CRS, cough receptor sensitivity; CXR, chest X-ray; FTT, failure to
thrive; GOR, gastro-oesophageal reflux; HRCT, high-resolution computed
tomography of the chest; LTB, laryngotracheobronchitis; TOF, tracheooesophageal fistula; TB, tuberculosis; UA, upper airway. Adapted with permission from [5]. (Continued on p. 66.)
65
COUGH IN CHILDREN
Fig. 7.2 An approach to cough based on length of cough. These pathways are a
guide to the approach to a child with a cough. However, most childhood coughs
are benign and do not require drug therapy or investigations. The suggested approach depends on the length of cough (pathway I) and whether any symptoms
and/or signs are present (‘pointers’ listed in pathway I). Symptoms and signs can
be age dependent and thus the child’s age and severity of illness must also be
considered when approaching a child with cough. It would not be possible
CHAPTER 7
66
(c)
Pathway III: Chronic/persistent cough (>4 weeks) or acute/subacute cough associated with other symptoms
CXR
Spirometry (if >6 years old)
Both normal
Either abnormal
Consider early consultation with paediatric
pulmonologist for assessment
Reversible airway obstruction?
Absence of 'pointers', wheeze and
productive/wet cough?
Yes
Non-specific cough
No
If cough does not
settle consider
No
Assess risk factors for
'Pointers'
present?
Bronchiectasis
or recurrent
pneumonia
Consider:
• post viral [20]
• increased CRS [13] No
Yes
• asthma [40]
• GOR
• UA problems
• functional
Purulent productive or
disorders (habit moist/wet cough and
cough, tics,
without wheeze
psychogenic)
Yes
No
Subacute
bronchitis:
needs follow-up;
if recurrent or
persistent, needs
investigation
Asthma
but review
for other
causes of
wheezing
Review and if 'pointers' present
Fig. 7.2 Continued.
Yes
Asthma
• cystic fibrosis
• ciliary dyskinesia
• previous severe
pneumonia
• immunodeficiency
• structural airway
lesions
• congenital lung
lesions
• missed foreign
body
• TOF/H fistula
Sweat test
Bronchoscopy
Cilia biopsy
Immune work-up
HRCT chest
Ba swallow
Aspiration
• primary and
secondary
• neurologically
abnormal
• altered swallow
• weak cough
reflex
• neuromuscular
disease
• laryngeal
abnormalities
• tonsil adenoid
hypertrophy
• TOF/H fistula
• severe GOR
Chronic or
less common
infections
• TB
• non-tuberculous
mycobacteria
• mycoses
Mantoux
Bronchoscopy
and lavage
HRCT chest
Ba swallow
Bronchoscopy and lavage
Video fluoroscopy
pH monitor
Lung milk
Scan/salivagram
Interstitial
lung
disease
• rheumatic
diseases
• cytotoxics
• drugs
• radiation
• etc
Autoimmune
markers
HRCT chest
Lung biopsy
Cardiac
• pulmonary
hypertension
• cardiac
oedema
Paediatric
cardiologist
Echo
cardiac
catheter
COUGH IN CHILDREN
Exploring the effects of the cough on the child includes how the child deals with the cough in school,
exercise and other activities. Children are sometimes
requested to leave the class and prevented from participating in physical activity, and these negative elements
may perpetuate or intensify cough. In our clinical experience, parents usually restrain their child’s physical activities and we suspect that this can lead to ‘sick child’
syndrome.
Investigative assessment
Investigation for a child with a cough may be appropriate and intensive, depending on history and examination of the clinical setting (pathway III, Fig. 7.2c). The
majority of children with cough will, however, have
cough of short duration and the cough is ‘expected’ or
within the limits of normality of childhood illness [4].
In the primary care setting, the majority of children
with cough do not require further investigations. The
approach in a tertiary setting would clearly be different.
In children with persistent cough, however, the minimum investigations are spirometry (if over 6 years old)
and a chest radiograph. The more controversial and
research-based investigations are described below.
Is AHR determination useful in children?
In paediatrics, unlike work on adults, the demonstration of AHR in a child with isolated cough is unhelpful
in predicting the later development of asthma [70] or
the response to asthma medications [30]. However
others who have stated that the presence of AHR in
children with cough is representative of asthma did not
use placebo-controlled studies, or confounders were
not adjusted for, or an unconventional definition of
AHR was used [35,71]. In a randomized placebocontrolled trial on the use of inhaled salbutamol and
corticosteroids in children with recurrent cough, the
presence of AHR could not predict the efficacy of these
medications for cough [30]. A recent study has shown
that AHR to hypertonic saline is significantly associated with wheeze and dyspnoea but not associated with
dry cough or nocturnal cough once confounders were
accounted for [72]. Koh et al. suggested that children
with ‘cough-variant asthma’ (CVA) required a greater
amount of methacholine to induce a wheeze which was
only audible when their FEV1 was lower, when compared with children with classical asthma [73]. However in their study the investigators were not blinded to
the category of the child and wheeze was determined
subjectively. The concept that children with CVA require a greater fall in FEV1 to induce a wheeze is interesting but questionable. Moreover, if this was so, a
decrease in FEV1 should still be detectable despite the
absence of wheeze during a coughing episode in those
with ‘CVA’, given that PC20 (the concentration of
methacholine that caused a 20% fall in FEV1) was not
different between the two groups [73].
Airways resistance by the interrupter technique (Rint)
This measurement, not yet established in clinical practice, may prove to be useful in detecting isolated cough
associated with asthma [74]. Despite its application in
research, there are still problems with intersubject variability and hence validity of its measurements when
undertaken by different investigators [75].
Is cough sensitivity determination clinically useful?
The concept of ‘hyperresponsiveness of cough receptors’ in childhood respiratory disease was first raised by
Mitsuhashi et al. [76]. Using acetic acid to assess cough
reflex sensitivity (CRS), the study described a group of
children with asthma who had increased CRS. However the groups were not matched for age and apart
from atopy no clinical associations were made [76].
Later, using nebulized citric acid in a group of children
who had been questioned 2 years before the cough
challenge test, Riordan et al. studied the relationship
between CRS and respiratory symptoms, and found
no relationship [77]. Since then several other studies
have described altered CRS in different diseases
using better methods of measuring CRS and symptom
ascertainment [14,21,41].
Adults with chronic cough that are subsequently well
controlled demonstrate invariably a normalization of
their pretreatment-enhanced capsaicin tussive response [78]. This has not been shown in children but
normalization of the cough sensitivity has been shown
in children with asthma [41] and recurrent cough [14]
upon resolution of their cough. Although children
grouped into different respiratory illnesses have significantly different cough sensitivities (Fig. 7.3) [13], this
test has not been evaluated on an individual basis to
identify its role in the clinic.
Are inflammatory markers useful?
Several groups have examined airway indices in
children with cough. Fitch et al. examined the
67
Mean log [capsaicin] +/– 95% CI
CHAPTER 7
3
2.5
Recurrent cough
Asthma
Cystic fibrosis
Controls
2
1.5
1
0.5
0
C2
C5
Fig. 7.3 Cough receptor sensitivity (CRS) outcome measures
in children with recurrent cough, asthma, cystic fibrosis and
controls. Means and CI are adjusted for age, sex and FEV1.
C2 and C5 of children with recurrent cough were significantly
lower (P = 0.00001) when compared with all groups. CRS
was similar in children with asthma and controls. Children
with recurrent cough have an enhanced cough sensitivity
(thus lower threshold to cough in the capsaicin cough sensitivity test) when compared with those with asthma, cystic fibrosis and controls [13]. While differences in cough
sensitivity can be found in cohorts of children grouped according to disease process [13,14], their relevance for an individual child is not yet defined. Reproduced from Arch Dis
Child 1997; 77: 331–4, with permission from the BMJ Publishing Group.
bronchoalveolar lavage in children with untreated
unexplained persistent cough and showed that only a
minority of children had asthma-type airway inflammation [29]. Zimmerman et al. [79] studied children
with postinfectious cough and treated and untreated
children with asthma, and concluded that postinfectious cough in children has different pathophysiological features than allergic asthma and represents a
different disease. Although 6 of the 11 children with
postinfectious cough had AHR, airway eosinophils
and eosinophil cationic protein were normal [79]. In a
community-based survey of children with chronic respiratory symptoms, Gibson et al. examined airway
markers of four groups of children (wheeze, cough, recurrent chest colds and controls), and found elevated
eosinophils (> 2.5%) in all children with wheeze and
AHR, but only in half of the children with wheeze
alone. Other airway cell differentials were similar in all
three symptom groups and sputum eosinophil cationic
protein (ECP) levels were non-discriminatory between
the groups [27].
In a longitudinal prospective study, children with
68
asthma and chronic cough were found to have elevated serum ECP and urinary eosinophil protein X
(EPX) when compared with controls [80]. However,
the authors failed to control for atopy, an important
confounder. Also ECP may be elevated in neutrophilic
inflammation, a known association in children with
chronic cough [29,79].
When comparing data between groups in a cohort,
differences may be found but application in the clinical
setting for individual patients has not yet been shown in
paediatrics. As single markers are context- and timedependent, inflammatory markers are unlikely to be
useful clinically if used in isolation [81]. This is in contrast to adults where examination of airway cells has a
role in the clinical setting for evaluation of eosinophilic
bronchitis.
Measurement of cough in children
In the clinic, the severity and progress of cough is determined historically. Cough, however, can be measured
and defined in other ways, most of which are used in research but not yet clinically. Cough measurements can
be broadly divided into objective and subjective methods, but only some methods have been used in children.
Of the objective methods that evaluate physical aspects
of the cough (frequency, flow, amplitude), only cough
frequency (static cough devices such as tape recorders
and ambulatory cough meters) [82,83] have been used
in children. Cough sensitivities or cough thresholds to a
variety of stimuli (capsaicin, citric acid, osmotic agents,
tartaric acid, etc.) are the only other objective measurements used in children. The many other objective measurements of cough in adults (e.g. airflow, cough sounds
and spectrographs) have not yet been tested in children,
which is necessary given the difference between adults
and children in frequency of sound and airflow generation. Subjective measurements include measurement of
‘cough tendency’ (recording a number expressing a
need or wish to cough but not actually coughing) [84]
and diary cards using a variety of scales (Likert, visual
analogue) and can be completed by parent or child.
Which of these objective and/or subjective measurements are most clinically relevant is, however, yet to be
defined. It is possible that the most relevant outcome
measure may depend, at least in part, on the reason for
performing the measurement, like determinants of
asthma severity and types of airway hyperresponsive-
COUGH IN CHILDREN
ness. Unlike the adult literature, a cough-specific
quality of life measurement is unavailable in children.
There are also few data on how these measurements
relate to one another. Daytime cough severity subjectively reported correlates to objectively measured
cough, but the confidence intervals for the correlation
coefficients were wide (0.11–0.74). Thus the severity of
cough defined on diary cards does not necessarily represent cough frequency [85]. Such data are unavailable
in adults. Thus the different outcomes of cough would
most likely reflect different aspects of cough. Various
methods of measuring cough are described in more
detail below.
The need to objectively measure cough in clinical research is reflected in the several documented limitations
when cough is used as an outcome measure. Firstly,
questions on isolated cough are largely poorly reproducible [86]. The k-value relating the chance-corrected
agreement between answers to questions on cough
ranges from 0.14 to 0.57 [86,87]. In contrast, questions
on wheeze and asthma attacks are highly reproducible
with k-values of 0.7–1.0 [86]. Secondly, nocturnal
cough is unreliably reported when compared to objective measurements [32,85]. Thirdly, cough is subjected
to the period effect (spontaneous resolution of cough
when studied) [88]. Thus non-placebo-controlled intervention studies have to be interpreted with caution.
Fourthly, cough is also subjected to psychological influences [64]. In adults with cough, subjective scoring of
cough does not correlate with cough frequency over a
20-min period but correlates with mood scores [89].
Rietveld et al. showed that children were more likely to
cough under certain psychological settings [64].
Furthermore, subjective perception of cough severity
depends on the population studied [12]. Finally, ‘normal’ children do cough as described in two studies that
objectively measured cough [11,12].
Measuring cough sensitivity in children
The method in general has been outlined by Fuller
(Chapter 6). In paediatrics, several tussive agents
(acetic acid [21], capsaicin [90], citric acid [77]) and
methods (astrograph, nebulizer with [90] and without
dosimeter [77]) have been used. Cough receptors are
unevenly distributed in the airways [9] and hence
standardization of airway deposition is important for
test validity. This is arguably more important in children who have smaller airways and who are less likely
to comply with complex respiratory manoeuvres like
maintaining an open glottis throughout nebulizer delivery. For measurements to be interpretable, measures
of repeatability within the laboratory are important.
Inspiratory flow has been shown to influence repeatability of measurements of cough sensitivity [90] and
hence should be regulated. Gender is known to influence cough sensitivity in adults but not in children [13].
Other influences on cough sensitivity are airway calibre
and age [13]. A full description of a standardized reliable method of measuring cough sensitivity to capsaicin is available elsewhere [90].
The commonly used outcome measures for cough
sensitivity are C2 (the lowest concentration required
to stimulate two or more coughs) and C5 (the lowest
concentration required to stimulate five or more
coughs). Other outcome measures that have been described are number of coughs within a specific time period (e.g. 10 s) and cough latency. Unlike the C2 and C5
measurements, no repeatability studies have been performed on these other outcome measurements. Control
solutions (diluent) should be used initially since hypoand hyperosmolar solutions can stimulate cough, and
doubling concentration of the chosen stimulant is then
used. The coughs following the challenge should be
objectively monitored or counted by an independent
observer.
Cough meters
The traditional method of recording cough is the audio
tape recorder [32], which limits portability. The first
ambulatory cough meter developed by the Brompton
Unit used in adults [91] was also codeveloped in
children [83]. Adopting the Brompton method, a
cheaper alternative was described [82] and this was
later utilized for an intervention study [30]. To date
there have been no other studies that have objectively
measured ambulatory cough frequency as an outcome,
probably because of the time and expense in using this
method. Until such meters become more assessable,
their application will most likely be limited to research.
Cough diary cards
Traditionally, in studies on children questionnaires and
diary cards are parent-filled [32,92]. In quality of life
questionnaires there is an increasing trend for children
to fill their own questionnaires since child-completed
69
CHAPTER 7
Table 7.3 Verbal descriptive score for paediatric use. From [85].
Cough score
Day of month
Daytime score (0–5)
1st
2nd
3rd
4th
5th
6th
7th
Daytime score
0 No cough during the day
1 Cough for one or two short periods only
2 Cough for more than two short periods
3 Frequent coughing which does not interfere with school or other daytime activities
4 Frequent coughing which does interfere with schoolwork or some daytime
activities
5 Severe coughing that prevents most usual daytime activity
responses have been shown to be significantly different
to those completed by parents [93]. In cough-specific
diary cards, the difference in parent-completed vs.
child-completed diary cards is small in subjects
(children with recurrent cough) and moderate in
controls [85].
Cough-specific diary cards can be related to cough
severity in general (Likert scale, visual analogue scale)
or categorical, based on limitation or effect on activity
(verbal category descriptive score). In a study that compared these scores with objective monitoring, the most
valid subjective method of scoring cough in children
over 6 years old was the verbal category descriptive
score completed by children with parental assistance.
The verbal category descriptive score (Table 7.3) used
was that modified from the diary described by the
Brompton group [91]. Nocturnal cough diary cards
have been repeatedly shown to be inaccurate and are
hence invalid [32,85]. Indeed despite the wide use of
cough as an outcome measure there is only one validated cough-specific diary card for children [85]. However, this study and others [32,91] comparing objective
and subjective scores for cough assume that subjects
and parents judge the severity of cough on the frequency of cough. However, it is possible that some parents may assess the severity of cough on the length of
the paroxysms or the loudness of the cough, which
would not necessarily correlate to the frequency of
cough. Although the frequency of cough is forseeably
the only objective ambulatory measurement available,
it is likely that the severity of cough as defined on diary
cards is not interchangeable with cough frequency
measurements [85].
70
Acknowledgement
Dr I. Brent Masters is gratefully acknowledged for his
critical review of the manuscript and for his valued
mentorship.
References
1 Clough JB, Williams JD, Holgate ST. Effect of atopy on the
natural history of symptoms, peak expiratory flow, and
bronchial responsiveness in 7- and 8-year-old children
with cough and wheeze. Am Rev Respir Dis 1991; 143:
755–60.
2 Ninan TK, Macdonald L, Russel G. Persistent nocturnal
cough in childhood: a population based study. Arch Dis
Child 1995; 73: 403–7.
3 Robertson CF, Heycock E, Bishop J, Nolan T, Olinsky A,
Phelan PD. Prevalence of asthma in Melbourne schoolchildren: changes over 26 years. Br Med J 1991; 302:
1116–8.
4 Bush A. Paediatric problems of cough. Pulm Pharmacol
Ther 2002; 15: 309–15.
5 Chang AB, Asher MI. A review of cough in children. J
Asthma 2001; 38: 299–309.
6 Chung KF, Lalloo UG. Diagnosis and management of
chronic persistent dry cough. Postgrad Med J 1996; 72:
594–8.
7 Phelan PD, Olinsky A, Oswald H. Asthma: classification,
clinical patterns and natural history. Bailliere’s Clin Paediatr 1995; 3: 307–18.
8 Irwin RS, Boulet LP, Cloutier MM et al. Managing cough
as a defense mechanism and as a symptom. A consensus
panel report of the American College of Chest Physicians.
Chest 1998; 114: 133S–81S.
COUGH IN CHILDREN
9 Chang AB. State of the art: cough, cough receptors, and
asthma in children. Pediatr Pulmonol 1999; 28: 59–70.
10 Campanella SG, Asher MI. Current controversies: sinus
disease and the lower airways. Pediatr Pulmonol 2001;
31: 165–72.
11 Munyard P, Bush A. How much coughing is normal? Arch
Dis Child 1996; 74: 531–4.
12 Chang AB, Phelan PD, Robertson CF, Newman RG,
Sawyer SM. Frequency and perception of cough severity. J
Paediatr Child Health 2001; 37: 142–5.
13 Chang AB, Phelan PD, Sawyer SM, Del Brocco S,
Robertson CF. Cough sensitivity in children with asthma,
recurrent cough, and cystic fibrosis. Arch Dis Child 1997;
77: 331–4.
14 Chang AB, Phelan PD, Sawyer SM, Robertson CF. Airway
hyperresponsiveness and cough-receptor sensitivity in
children with recurrent cough. Am J Respir Crit Care Med
1997; 155: 1935–9.
15 National Health Survey — summary of results. Canberra,
Australia: Government Publishing Service, 1997: Catalog
no. 4364.
16 Kogan MD, Pappas GYuSM, Kotelchuck M. Over-thecounter medication use among preschool-age children.
JAMA 1994; 272: 1025–30.
17 Grigg J, Riedler J, Robertson CF. Bronchoalveolar lavage
fluid cellularity and soluble intercellular adhesion
molecule-1 in children with colds. Pediatr Pulmonol
1999; 28: 109–16.
18 Martinez FD, Taussig LM, Morgan WJ. Infants with
upper respiratory illnesses have significant reductions in
maximal expiratory flow. Pediatr Pulmonol 1990; 9:
91–5.
19 Curley FJ, Irwin RS, Pratter MR, Stivers DH, Doern GV,
Vernaglia PA, Larkin AB, Baker SP. Cough and the common cold. Am Rev Respir Dis 1988; 138: 305–11.
20 O’Connell F, Thomas VE, Studham JM, Pride NB, Fuller
RW. Capsaicin cough sensitivity increases during upper
respiratory infection. Respir Med 1996; 90: 279–86.
21 Shimizu T, Mochizuki H, Morikawa A. Effect of influenza
A virus infection on acid-induced cough response in children with asthma. Eur Respir J 1997; 10: 71–4.
22 Kelly YJ, Brabin BJ, Milligan PJM, Reid JA, Heaf D,
Pearson MG. Clinical significance of cough and wheeze
in the diagnosis of asthma. Arch Dis Child 1996; 75:
489–93.
23 McKenzie S. Cough — but is it asthma? Arch Dis Child
1994; 70: 1–2.
24 Thomson F, Masters IB, Chang AB. Persistent cough
in children — overuse of medications. J Paediatr Child
Health 2002; 38: 578–81.
25 Siersted HC. Population based study of risk factors for underdiagnosis of asthma in adolescence: Odense schoolchild study. Br Med J 1998; 316: 651–7.
26 Wright AL, Holberg CJ, Morgan WJ, Taussig L, Halonen
M, Martinez FD. Recurrent cough in childhood and its relation to asthma. Am J Respir Crit Care Med 1996; 153:
1259–65.
27 Gibson PG, Simpson JL, Chalmers AC, Toneguzzi RC,
Wark PAB, Wilson A, Hensley MJ. Airway eosinophilia is
associated with wheeze but is uncommon in children with
persistent cough and frequent chest colds. Am J Respir
Crit Care Med 2001; 164: 977–81.
28 Powell CVE, Primhak RA. Stability of respiratory symptoms in unlabelled wheezy illness and nocturnal cough.
Arch Dis Child 1996; 75: 385–91.
29 Fitch PS, Brown V, Schock BC, Taylor R, Ennis M, Shields
MD. Chronic cough in children: bronchoalveolar lavage
findings. Eur Respir J 2000; 16: 1109–14.
30 Chang AB, Phelan PD, Carlin J, Sawyer SM, Robertson
CF. Randomised controlled trial of inhaled salbutamol
and beclomethasone for recurrent cough. Arch Dis Child
1998; 79: 6–11.
31 Davies MJ, Fuller P, Picciotto A, McKenzie SA. Persistent
nocturnal cough: randomised controlled trial of high dose
inhaled corticosteroid. Arch Dis Child 1999; 81: 38–44.
32 Archer LNJ, Simpson H. Night cough counts and
diary card scores in asthma. Arch Dis Child 1985; 60:
473– 4.
33 Finder JD. Primary bronchomalacia in infants and children. J Paediatr 1997; 130: 59–66.
34 McFadden ER. Exertional dyspnea and cough as preludes
to acute attacks of bronchial asthma. N Engl J Med 1975;
292: 555–8.
35 Cloutier MM, Loughlin GM. Chronic cough in children: a
manifestation of airway hyperreactivity. Pediatrics 1981;
67: 6–12.
36 Stevens MW, Gorelick MH. Short-term outcomes after
acute treatment of pediatric asthma. Pediatrics 2001; 107:
1357–62.
37 Johnston SL, Pattemore PK, Sanderson G et al. Community study of role of viral infections in exacerbations of
asthma in 9–11 year old children. Br Med J 1995; 310:
1225–9.
38 Chang AB, Harrhy VA, Simpson JL, Masters IB. Gibson
PG. Cough, airway inflammation and mild asthma exacerbation. Arch Dis Child 2002; 86: 270–5.
39 Karlsson J-A, Sant’Ambrogio G, Widdicombe J. Afferent
neural pathways in cough and reflex bronchoconstriction.
J Appl Physiol 1988; 65: 1007–23.
40 Chang AB, Gibson PG. Relationship between cough,
cough receptor sensitivity and asthma in children. Pulm
Pharmacol Ther 2001; 15: 287–91.
41 Chang AB, Phelan PD, Robertson CF. Cough receptor
sensitivity in children with acute and non-acute asthma.
Thorax 1997; 52: 770–4.
42 Lalloo UG, Barnes PJ, Chung FK. Pathophysiology and
71
CHAPTER 7
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
72
clinical presentations of cough. J Allergy Clin Immunol
1996; 98: S91–7.
Rosier MJ, Bishop J, Nolan T, Robertson CF, Carlin J,
Phelan PD. Measurement of functional severity of asthma
in children. Am J Respir Crit Care Med 1994; 149:
1434–41.
Schwartz J, Timonen KL, Pekkanen J. Respiratory effects
of environmental tobacco smoke in a panel study of asthmatic and symptomatic children. Am J Respir Crit Care
Med 2000; 161: 802–6.
Mertsola J, Ziegler T, Ruuskanen O, Vanto T, Koivikko A,
Halonen P. Recurrent wheezy bronchitis and viral respiratory infections. Arch Dis Child 1991; 66: 124–9.
Clough JB, Holgate ST. Episodes of respiratory morbidity
in children with cough and wheeze. Am J Respir Crit Care
Med 1994; 150: 48–53.
Frischer T, Studnicka M, Neumann M, Gotz M. Determinants of airway response to challenge with distilled water
in a population sample of children aged 7–10 years old.
Chest 1992; 102: 764–70.
Pattemore PK, Asher MI, Harrison AC, Mitchell EA, Rea
HH, Stewart AW. The interrelationship among bronchial
hyperresponsiveness, the diagnosis of asthma, and asthma
symptoms. Am Rev Respir Dis 1990; 142: 549–54.
Lombardi E, Morgan WJ, Wright AL, Stein RT, Holberg
CJ, Martinez FD. Cold air challenge at age 6 and subsequent incidence of asthma. Am J Respir Crit Care Med
1997; 156: 1863–9.
Johnston BT, Gideon RM, Castell DO. Excluding gastroesophageal reflux disease as the cause of chronic cough. J
Clin Gastroenterol 1996; 22: 168–9.
Ferrari M, Olivieri M, Sembenini C et al. Tussive effect of
capsaicin in patients with gastroesophageal reflux without
cough. Am J Respir Crit Care Med 1995; 151: 557–61.
Laukka MA, Cameron AJ, Schei AJ. Gastroesophageal reflux and chronic cough: which comes first? J Clin Gastroenterol 1994; 19: 100–4.
Treem WR, Davis PM, Hyams JS. Gastroesophageal
reflux in the older child: presentation, response to treatment and long-term follow up. Clin Pediatr 1991; 30:
435–40.
Lombardi E, Stein RT, Wright AL, Morgan WJ, Martinez
FD. The relation between physician-diagnosed sinusitis,
asthma, and skin test reactivity to allergens in 8-year-old
children. Pediatr Pulmonol 1996; 22: 141–6.
Diament MJ, Senac MO, Gilsanz V, Baker S, Gillespie T,
Larsson S. Prevalence of incidental paranasal sinuses
opacification in pediatric patients: a CT study. J Comput
Assist Tomogr 1987; 11: 426–31.
Shopfner CE, Rossi JO. Roentgen evaluation of the
paranasal sinuses in children. AJR 1973; 118: 176–86.
Nishino T, Hasegawa R, Ide T, Isono S. Hypercapnia enhances the development of coughing during continuous
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
infusion of water into the pharynx. Am J Respir Crit Care
Med 1998; 157: 815–21.
Gormley PK, Colreavy MP, Patil N, Woods AE. Congenital vascular anomalies and persistent respiratory symptoms in children. Int J Pediatr Otorhinolaryngol 1999; 51:
23–31.
Wood RE. Localised tracheomalacia or bronchomalacia
in children with intractable cough. J Pediatr 1997; 116:
404–6.
Grathwohl KW, Afifi AY, Dillard TA, Olson JP, Heric BR.
Vascular rings of the thoracic aorta in adults. Am Surg
1999; 65: 1077–83.
Stick S. Pediatric origins of adult lung disease. The contribution of airway development to paediatric and adult lung
disease. Thorax 2000; 55: 587–94.
Vedal S, Petkau J, White R, Blair J. Acute effects of ambient inhalable particles in asthmatic and nonasthmatic children. Am J Respir Crit Care Med 1998; 157: 1034–43.
Wamboldt MZ, Wamboldt FS. Psychiatric aspects of respiratory syndromes. In: Taussig LM, Landau LI, eds. Pediatric Respiratory Medicine. St Louis: Mosby, Inc., 1999:
1222–34.
Rietveld SBI, Everaerd W. Psychological confounds in
medical research: the example of excessive cough in
asthma. Behav Res Ther 2000; 38: 791–800.
Fuller P, Picciotto A, Davies M, McKenzie SA. Cough and
sleep in inner-city children. Eur Respir J 1998; 12: 426–31.
Wu-Williams AH, Samet JM. Environmental tobacco
smoke: exposure–response relationships in epidemiologic
studies. Risk Anal 1990; 10: 39–48.
Couriel JM. Passive smoking and the health of children.
Thorax 1994; 49: 731–4.
Stott NC. Management and outcome of winter upper respiratory tract infections in children aged 0–9 years. Br
Med J 1979; 1: 29–31.
Mellis CM. Can we reduce acute asthma attendances to
hospital emergency departments? Aust NZ J Med 1997;
27: 275–6.
Galvez RA, McLaughlin FJ, Levison H. The role of the
methacholine challenge in children with chronic cough. J
Allergy Clin Immunol 1987; 79: 331–5.
Paganin F, Seneterre E, Chanez P, Daures JP, Bruel JM,
Michel FB, Bousquet J. Computed tomography of the
lungs in asthma: influence of disease severity and etiology.
Am J Respir Crit Care Med 1996; 153: 110–4.
Strauch E, Neupert T, Ihorst G, Van’s-Gravesande KS,
Bohnet W, Hoeldke B, Karmaus W, Kuehr J. Bronchial hyperresponsiveness to 4.5% hypertonic saline indicates a
past history of asthma-like symptoms in children. Pediatr
Pulmonol 2001; 31: 44–50.
Koh YY, Chae SA, Min KU. Cough variant asthma is associated with a higher wheezing threshold than classic
asthma. Clin Exp Allergy 1993; 23: 696–701.
COUGH IN CHILDREN
74 McKenzie SA, Bridge PD, Healy MJ. Airway resistance
and atopy in preschool children with wheeze and cough.
Eur Respir J 2000; 15: 833–8.
75 Klug B, Nielsen KG, Bisgaard H. Observer variability of
lung function measurements in 2–6-yr-old children. Eur
Respir J 2000; 16: 472–5.
76 Mitsuhashi M, Mochizuki H, Tokuyama K, Morikawa A,
Kuroume T. Hyperresponsiveness of cough receptors in
patients with bronchial asthma. Pediatrics 1985; 75:
855–8.
77 Riordan MF, Beardsmore CS, Brooke AM, Simpson H.
Relationship between respiratory symptoms and cough
receptor sensitivity. Arch Dis Child 1994; 70: 299–304.
78 O’Connell F, Thomas VE, Pride NB, Fuller RW. Capsaicin
cough sensitivity decreases with successful treatment of
chronic cough. Am J Respir Crit Care Med 1994; 150:
374–80.
79 Zimmerman B, Silverman FS, Tarlo SM, Chapman KR,
Kubay JM, Urch B. Induced sputum: comparison of
postinfectious cough with allergic asthma in children. J Allergy Clin Immunol 2000; 105: 495–9.
80 Labbe A, Aublet-Cuvelier B, Jouaville L, Beaugeon G,
Fiani L, Petit I, Ouchchane L, Doly M. Prospective longitudinal study of urinary eosinophil protein X in children
with asthma and chronic cough. Pediatr Pulmonol 2001;
31: 354–62.
81 Martinez FD. Context dependency of markers of disease.
Am J Respir Crit Care Med 2000; 162: 56S–57.
82 Chang AB, Newman RG, Phelan PD, Robertson CF. A
new use for an old Holter monitor: an ambulatory cough
meter. Eur Respir J 1997; 10: 1637–9.
83 Munyard P, Busst C, Logan-Sinclair R, Bush A. A new device for ambulatory cough recording. Pediatr Pulmonol
1994; 18: 178–86.
84 Ng-Man-Kwong G, Proctor A, Billings C, Duggan R, Das
C, Whyte MK, Powell CV, Primhak R. Increasing prevalence of asthma diagnosis and symptoms in children is
confined to mild symptoms. Thorax 2001; 56: 312–4.
85 Chang AB, Newman RG, Carlin J, Phelan PD, Robertson
CF. Subjective scoring of cough in children: parentcompleted vs child-completed diary cards vs an objective
method. Eur Respir J 1998; 11: 462–6.
86 Brunekreef B, Groot B, Rijcken B, Hoek G, Steenbekkers
A, de Boer A. Reproducibility of childhood respiratory
symptom questions. Eur Respir J 1992; 5: 930–5.
87 Clifford RD, Radford M, Howell JB, Holgate ST. Prevalence of respiratory symptoms among 7 and 11 year old
schoolchildren and association with asthma. Arch Dis
Child 1989; 64: 1118–25.
88 Evald T, Munch EP, Kok-Jensen A. Chronic non-asthmatic cough is not affected by inhaled beclomethasone dipropionate. A controlled double blind clinical trial. Allergy
1989; 44: 510–4.
89 Hutchings HA, Eccles R, Smith AP, Jawad MSM. Voluntary cough suppression as an indication of symptom severity in upper respiratory tract infections. Eur Respir J 1993;
6: 1449–54.
90 Chang AB, Phelan PD, Roberts RGD, Robertson CF. Capsaicin cough receptor sensitivity test in children. Eur
Respir J 1996; 9: 2220–3.
91 Hsu JY, Stone RA, Logan-Sinclair RB, Worsdell M, Busst
CM, Chung KF. Coughing frequency in patients with persistent cough: assessment using a 24 hour ambulatory
recorder. Eur Respir J 1994; 7: 1246–53.
92 van Essen-Zandvliet EE, Hughes MD, Waalkens HJ,
Duiverman EJ, Kerrebijn KF, and the Dutch CNSLD Study
Group. Remission of childhood asthma after long-term
treatment with an inhaled corticosteroid (budesonide):
Can it be achieved? Eur Respir J 1994; 7: 63–8.
93 Juniper EF, Guyatt GH, Dolovich J. Assessment of
quality of life in adolescents with allergic rhinoconjunctivitis: development and testing of a questionnaire
for clinical trials. J Allergy Clin Immunol 1994; 93:
413–23.
94 Weinberg G. ‘Honking’: psychogenic cough tic in children. S Afr Med J 1980; 57: 198–200.
73
8
The quality of life in coughers
Richard S. Irwin, Cynthia L. French & Kenneth E. Fletcher
Introduction
The methods of assessing the impact of cough on
patients have been categorized as subjective and
objective [1]. Subjective measures such as healthrelated quality of life (HRQoL) instruments are likely
to be the ones that best reflect the severity of cough
from the patient’s standpoint because a subjective response most likely integrates both cough frequency
and intensity. We use the term HRQoL to define a patient’s perception of the impact of health and disease
on multiple domains of his or her life (e.g. physical
function, psychosocial state). HRQoL can be distinguished from QoL in that it is primarily concerned with
factors that fall under the responsibility or concerns of
health care providers and health care systems. In this
chapter, we review the state of the art regarding the
HRQoL in patients who seek medical attention complaining of cough by posing and answering a series of
questions.
Does cough adversely affect the
health-related quality of life?
While cough is an important defence mechanism that
helps clear excessive secretions and foreign material
from the airways, it also is a very common symptom. In
fact, over the past decade, cough of undifferentiated
duration has been the most common complaint for
which patients have sought medical attention from primary care physicians in the US [2,3]. Moreover, referrals of patients with persistently troublesome chronic
cough of at least 8 weeks’ duration have been shown to
account for up to 38% of a pulmonologist’s outpatient
practice [4].
Chronic cough
To better understand why patients with chronic cough
seek medical attention so frequently, French et al. [5]
performed a prospective study to determine whether
chronic cough was associated with adverse psychosocial or physical effects on the HRQoL and to determine
whether the elimination of chronic cough with specific
therapy for the underlying cause(s) improved these adverse effects. Chronic cough has been defined as one
that is persistently troublesome to the patient for at
least 8 weeks in duration [6]. To characterize the complications of cough, the investigators used an adverse,
cough-specific outcome survey (ACOS) that reflected
physical and psychosocial complications of cough. The
ACOS is a fixed-alternative, yes/no, self-administered,
29-item questionnaire. To assess the effects of cough on
HRQoL, the sickness impact profile (SIP) was used. It
had been previously shown to be a reliable and valid,
generic (i.e. non-illness-specific) measure of healthrelated dysfunction in non-coughing disease states.
From this study, five important findings emerged.
First, chronic cough was significantly associated with
meaningful adverse psychosocial and physical effects
on HRQoL. Second, successful treatment of chronic
cough was associated with resolution of patients’ deterioration in HRQoL. Third, the HRQoL induced by
chronic cough was more likely to be psychosocial than
physical in nature. While previous publications have
emphasized the physical consequences of cough [7],
this was the first study to highlight and show that pa75
CHAPTER 8
Table 8.1 Spectrum and frequency of cough-associated adverse occurrences before
and after specific treatment in patients (n = 28) cured of their coughs.
Adverse occurrence
Before
treatment (%)
After
treatment (%)
P value
Needs reassurance nothing is serious
Concerned something is wrong
Frequent retching
Exhaustion
Others think something is wrong
with me
Embarrassment
Self-consciousness
Difficulty speaking on the telephone
Hoarseness
Had to change lifestyle
Cannot sleep at night
Can no longer sing in church
Spouse cannot tolerate cough
Wetting pants
Concerned something is seriously
wrong
Dizziness
Excessive sweating
Achiness
Hurts to breathe
Stopped going to movies
Headaches
Fear of AIDS or TB
Concern of cancer
Absences from school or work
Loss of appetite
Nausea or vomiting
Soiling of pants
Broken ribs
Loss of job
75
68
57
61
46
19
11
8
15
19
< 0.001
< 0.001
< 0.001
< 0.001
0.03
46
46
43
46
36
43
29
27
32
68
11
14
22
15
11
15
8
8
7
11
< 0.004
0.01
0.10
0.01
0.03
0.02
< 0.05
0.08
0.02
< 0.001
18
29
21
18
18
15
11
14
11
11
7
7
7
4
0
7
0
15
4
4
0
4
19
0
7
0
0
4
0.02
0.04
0.01
0.76
0.09
0.16
0.08
0.17
0.40
0.08
0.97
0.16
0.16
0.97
AIDS, acquired immune deficiency syndrome; TB, tuberculosis.
In the 28 patients in whom before and after treatment data were available, c2 analyses
revealed a significant reduction in adverse occurrences. As shown above, 16 of the 29
adverse occurrences had significantly decreased; the reduction in an additional 4
approached significance. With successful treatment, the average (± SD) number of
complaints had decreased from 8.6 ± 4.8 to 1.9 ± 3.2 (P < 0.0001).
tients are most troubled by the psychosocial complications (Table 8.1). Fourth, the ACOS and SIP appeared
to be valid tools in assessing the impact of chronic
cough on patients. Fifth, based upon lack of correlation
between adverse cough occurrences and the specific
76
causes of chronic cough, it appeared that the adverse
occurrences identified in this study were specific to
chronic cough in general and not to chronic cough due
to any specific disease. Because of this and because there
was no difference in other characteristics of patients
QUALITY OF LIFE IN COUGHERS
(e.g. the ages, gender distribution, duration and spectra
and frequencies of the causes of chronic cough) in this
study compared with the results of other prospective
studies, it was concluded that the HRQoLs observed in
this study could be generalized to other adult patients
who seek medical attention complaining of cough.
Using a cough-specific HRQoL questionnaire, the
CQLQ, French et al. [8] prospectively confirmed that
chronic cough does indeed adversely affect the HRQoL
of patients who seek medical attention because of this
complaint. Before treatment, total CQLQ scores in
chronic coughers were significantly higher (i.e. the
higher the scores, the worse the HRQoL) than in the
control group, which did not complain of cough. After
specific treatment, the total CQLQ scores of chronic
coughers had significantly decreased to the control
group level.
Acute cough
By studying acute coughers as well as chronic coughers
in their study, French et al. [8] prospectively showed
that acute cough as well as chronic cough adversely effects the HRQoL of subjects complaining of cough.
Acute cough has been defined as cough that is troublesome to the patient for less than 3 weeks [6]. Using the
CQLQ, it was demonstrated that the HRQoL of acute
coughers was adversely affected overall and to a similar
degree as for chronic coughers, and it was significantly
more affected than the control group which did not
complain of cough. A comparison of the six subscale
and 28 individual item pretreatment scores revealed
that acute coughers complained of similar adverse occurrences related to cough as chronic coughers.
How should the health-related quality
of life of coughers be measured?
In general, HRQoL instruments can be classified as disease- or symptom-specific, generic, or preference-based
[9]. Disease-specific measures focus on the symptoms
of the specific disease while generic measures assess
how the varied aspects of patients’ lives are affected.
Because they focus on the symptoms of the specific disease, disease-specific instruments have the potential to
be able to detect smaller, clinically important changes in
health status than generic instruments. Moreover, compared with generic instruments, disease-specific meas-
ures may be more sensitive because they contain a
higher percentage of directly relevant content to the
specific disease being evaluated. On the other hand,
disease-specific instruments are not as comprehensive
in their approach as generic measures, and diseasespecific instruments are not able to compare health status among different diseases as generic measures can.
Unlike disease-specific and generic HRQoL instruments, preference-based measures can also gather information that reflects health benefits of interventions.
This is because they can assess the willingness of subjects to undergo risk to reduce suffering.
While there is no general agreement about what QoL
means and which class of measure is best [10], we contend that all will agree that the best instrument is one
that has been shown to be reliable and valid by a battery
of psychometric assessments. It should also be shown
to have dimensionality, which means it is composed of
subscales that assess the underlying dimensions of
quality of life related to health problems. With respect
to evaluating the HRQoL in coughers, only one instrument, the CQLQ, has been appropriately evaluated [8].
The CQLQ has been determined to have dimensionality that is consistent with a cough-specific HRQoL instrument. Moreover, it has been determined to be an
internally consistent, reliable and valid instrument by
which to assess the impact of HRQoL in chronic and
acute coughers. It is a 28-item, symptom-specific, paper
and pencil survey, scored on a 4-point Likert-type scale.
There is an overall or total score, scores for six separate
subscales, and 28 individual item scores. The lowest
possible achievable total score indicating no adverse effects of cough on HRQoL is 28, the highest possible
total score is 112. The six subscales were identified by
factor analysis and named according to their content as
follows: physical complaints (e.g. headache), psychosocial issues (e.g. family and/or close friends cannot
tolerate it any more), functional abilities (e.g. prolonged absences from important activities such as
work, school or volunteer services), emotional wellbeing (e.g. ‘I have a fear that I might have AIDS or tuberculosis’), extreme physical complaints (e.g. ‘I wet
my pants’), and personal safety fears (e.g. ‘I want to be
reassured that I do not have anything seriously the matter with me’). While the ACOS and the SIP had been
useful in determining the impact of chronic cough on
the health status of patients, thereby demonstrating
their construct validity, they have not been fully evaluated as HRQoL measures for cough.
77
CHAPTER 8
What have we learned by
using the CQLQ?
To date, we have learned that the CQLQ can be used as
an outcome measure to assess the severity of acute and
chronic cough [8] and to assess the efficacy of cough
therapies for chronic cough [8]. While the ability of the
CQLQ to assess the efficacy of cough therapies in acute
coughers has not yet been evaluated, the following reasons suggest that it will likely be shown to be a valid
means of doing so in future studies: (i) the CQLQ was
developed with data from both acute and chronic
coughers [8]; (ii) it has been determined that pretreatment total CQLQ scores in acute coughers are similar
to those of chronic coughers [8]; and (iii) a comparison
of pretreatment subscale scores between acute and
chronic coughers has revealed that both groups complain of similar types of adverse occurrences related to
cough and both complain significantly more than a
control group [8]. Therefore, it is reasonable to speculate that when cough goes away as a complaint, the
CQLQ scores will drop in similar fashion, whether they
reflect the impact of an acute or a chronic cough.
The CQLQ also has been used to better understand
the reasons for the gender differences in patients complaining of cough [10,11]. Because past studies of patients with chronic cough have consistently established
that more women than men seek medical attention,
French et al. [10] sought to determine whether this difference was due to chronic cough more adversely affecting the HRQoL of women. Using a post hoc
analysis of data collected prospectively from chronic
coughers during the psychometric testing of the
CQLQ, French et al. [8] have reported in abstract form
that the HRQoL of women complaining of chronic
cough is more adversely affected than men. Based upon
their results, these investigators speculated that women
were more adversely affected because they were more
likely to suffer from physical complaints such as urinary stress incontinence and become embarrassed because of it. These same investigators then sought to
determine if there were similar gender-specific data for
women and men seeking medical attention complaining of acute cough. Using a post hoc analysis of data
collected prospectively from acute coughers during the
psychometric testing of the CQLQ [8] to which
prospectively collected data from acute coughers were
added to enhance their database, these investigators
have reported in abstract form [11] that both genders
78
appeared to seek medical attention complaining of
acute cough at approximately the same rate. Based
upon their results, they concluded that the similar frequency was probably related to there being no difference in the overall effects of acute cough on HRQoL
between the genders. In addition, they speculated that
the differences in the few items (e.g. wetting of pants
for women) had the potential to become much more
important when the cough becomes persistent and
chronic.
Clinical and research implications
To optimally evaluate the impact of cough on patients
and to assess the efficacy of cough-modifying agents,
investigators ideally should use both subjective and objective methods because they have the potential to
measure different aspects of cough. Subjective measures are likely to be the ones that will best reflect the
severity of cough from the subject’s perspective, because a subjective response most likely integrates both
cough frequency and intensity. With respect to subjective methods, we believe that the 28-item CQLQ
should be routinely used in adults because, to our
knowledge, it has been shown, in adults, to be the only
reliable, valid, simple, easy-to-use and easy-tounderstand outcome measure that can be selfadministered by patients in a matter of minutes. The
only other reliable and validated subjective instrument
that we are aware of has been developed by Faniran et
al. [12] for use in children for measuring the prevalence,
morbidity and risk factors of persistent cough in epidemiological studies.
References
1 Irwin RS, French CT. Cough and gastroesophageal reflux:
identifying cough and assessing the efficacy of coughmodifying agents. Am J Med 2001; 111 (8A): 45S–50S.
2 Schappert SM. National ambulatory medical care survey:
1991 Summary. Vital Health Stat 1993; 230: 1–20.
3 Woodwell DA. National ambulatory medical care survey:
1998 Summary. Vital Health Stat 2000; 315: 1–25.
4 Irwin RS, Curley FJ, French CL. Chronic cough. Am Rev
Respir Dis 1990; 141: 640–7.
5 French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of
chronic cough on quality of life. Arch Intern Med 1998;
158: 1657–61.
QUALITY OF LIFE IN COUGHERS
6 Irwin RS, Madison JM. The diagnosis and treatment of
cough. N Engl J Med 2000; 343: 1715–21.
7 Irwin RS. Cough. In: Irwin RS, Curley FJ, Grossman RF,
eds. Diagnosis and Treatment of Symptoms of the Respiratory Tract. Armonk, NY: Futura Publishing Co., Inc.,
1997: 1–54.
8 French CT, Irwin RS, Fletcher KE, Adams TM. Evaluation
of a cough-specific quality-of-life questionnaire. Chest
2002; 121: 1123–31.
9 Yusen RD. What outcomes should be measured in patients
with COPD? Chest 2001; 119: 327–8.
10 French C, Irwin RS, Fletcher K, Adams T. Gender differences in quality of life (QoL) in patients complaining of
chronic cough. Am J Respir Crit Care Med 2001; 163:
A58.
11 French CL, Fletcher KL, Irwin RS. Gender differences in
quality of life (QoL) in patients complaining of acute
cough. Am J Respir Crit Care Med 2002; 165: A460.
12 Faniran AO, Peat JK, Woolcock AJ. Measuring persistent
cough in children in epidemiological studies: development
of a questionnaire and assessment of prevalence in two
countries. Chest 1999; 115: 434–9.
79
SECTION 3
Clinical Conditions with Cough
9
Cough in lower airway infections
Wee-Yang Pek & Homer A. Boushey
Introduction
Cough is a common manifestation of acute infections
of the lower respiratory tract, and these infections are
part of a continuum of acute respiratory infections
common in all human populations. The continuum
ranges from rhinosinusitis (the common cold) to laryngitis, tracheobronchitis, bronchiolitis and pneumonia.
These infections are among the most common reasons
for visits to primary care providers and for hospital admissions. In this chapter, ‘acute lower airway infection’
refers to acute tracheobronchitis, acute bronchiolitis
and community-acquired pneumonia (CAP). From a
clinical standpoint, it is sometimes difficult to distinguish these entities from each other, and one condition
may progress into another. They may be due to the same
microbiological agents and share many clinicopathological features. Cough is a common presenting feature
of these conditions, but beyond generally localizing the
infections to the respiratory tract, the symptom is nonspecific, occurring with all conditions from rhinosinusitis (through postnasal drip) to pneumonia.
Epidemiology and aetiology of lower
airway infection
Acute tracheobronchitis and bronchiolitis
Acute tracheobronchitis is commonly diagnosed in
patients presenting with cough of recent onset. In the
US, about a third of the 30 million visits for cough in
1997 were attributed to acute tracheobronchitis [1]. In
the UK, the incidence of acute bronchitis is similarly
high, ranging from 34.5 to 171.4 per 100 000 [2]. The
rate is particularly high during the winter months,
when acute infectious respiratory illnesses are most
prevalent.
Acute tracheobronchitis refers to an acute inflammatory condition of the trachea and bronchi in which
cough, with or without the production of sputum, is a
predominant feature [3,4]. It is usually caused by acute
respiratory infection. The infection is typically viral
in origin, and is usually self-limited. All symptoms,
including cough, usually resolve within 3 weeks.
Exceptions to this benign course are numerous, and
may reflect differences in host or pathogen. An example
of the importance of differences in the host is the difference in the clinical presentation of infection with
respiratory syncytial virus (RSV) in infants and in
older children or adults. In all but infants, infection
with this organism typically causes nasopharyngitis
frequently associated with acute bronchitis. In infants
under the age of 2 years, it causes bronchiolitis. This
acute inflammatory condition of the terminal, bronchiolar airways may be associated with respiratory distress from airway narrowing from oedema, smooth
muscle contraction and mucus secretion. Viral bronchiolitis is one of the most common reasons for hospitalization in infancy [5–7], and RSV is its major cause,
accounting for 45–75% of cases; parainfluenza virus is
responsible for up to 30% [6]. Another potentially lifethreatening respiratory infection due predominantly to
parainfluenza virus (types 1, 2 and 3) and also RSV is
acute laryngotracheobronchitis or croup [8,9]. These
viruses cause inflammation and swelling of the subglottic tissues as well as the tracheal and bronchial mucosa
resulting in upper airway narrowing and obstruction.
83
CHAPTER 9
Table 9.1 Aetiological agents of acute tracheobronchitis.
Viruses
Influenza virus A and B
Rhinovirus
Parainfluenza virus
Respiratory syncytial virus
Adenovirus
Coronavirus
Coxsackievirus A21
Bacteria
Mycoplasma pneumoniae
Chlamydia pneumoniae
Bordetella pertussis
The infection peaks in the second year of life and is
associated with a hospitalization rate in up to a quarter
of patients [10]. In addition to their importance as respiratory pathogens in infants and young children, RSV
and parainfluenza viruses are also important respiratory pathogens in elderly adults, in whom they commonly cause moderate to severe acute inflammation
of the lower respiratory tract [11,12]. Another respiratory pathogen, rhinovirus — the most common
pathogen in humans— also causes different clinical presentations at the two extremes of age. Compared to the
typically limited rhinorrhoea, sneezing and sore throat
of common colds caused by rhinovirus infections in
adolescents and in young and middle-aged adults,
acute otitis media occurs much more commonly in children [13] and prolonged lower respiratory tract symptoms prompting physician consultation occur more
commonly in people over 60 years of age [14].
Differences in the infecting pathogen also cause different clinical presentations. This is most infamously
illustrated by influenza, which so characteristically
provokes fever, rigors, myalgias and malaise in addition to cough and sputum production that ‘the flu’ has
entered the English language as a generic term for an
acute febrile respiratory illness with systemic symptoms. But influenza can also cause pneumonia, a complication thought to be responsible for deaths in the
1918 pandemic, which caused the greatest total mortality from any acute epidemic in human history
[15,16]. The differences in rates of pneumonia and in
mortality among influenza epidemics from year to year
illustrate another cause of variation in clinical presen84
tation and consequence: genetic variations among
strains of the same species of viruses.
The aetiological agents that cause acute tracheobronchitis are identified only in a minority of cases but
are likely to be non-bacterial (Table 9.1). The supplementation of classical but insensitive techniques of
viral culture with modern molecular techniques, like
PCR (polymerase chain reaction), has shown that respiratory viruses account for more than 90% of acute
respiratory illness in which an agent is identified
[11,17,18].
The viruses identified include those that involve
primarily the lower respiratory tract, like influenza A,
influenza B, parainfluenza 3 and the respiratory syncytial virus. Other viruses like rhinovirus, adenovirus
and coronavirus infections predominantly affect the
upper respiratory tract, but also commonly involve the
lower airways [11,17,19,20]. Because of the temperature dependence of some strains of rhinovirus, growing
best in culture at 33 °C, rhinovirus infections were
thought to be limited to the upper airways, causing
lower airway symptoms only indirectly, through postnasal drip of inflammatory secretions. But rhinovirus
has now been demonstrated by the in situ hybridization
technique in bronchial mucosal biopsies from infected
patients [21], proving that it can directly infect the
subglottic, or ‘lower’ airways as well. While severe
tracheobronchitis occurs in a smaller proportion of
patients infected by rhinovirus than by influenza,
parainfluenza and respiratory syncytial virus, the total
number of infections by the > 100 serotypes of rhinovirus is so great that this common virus likely contributes most to the overall burden of lower respiratory
infection in the community [20,22], particularly in the
elderly. In addition, rhinovirus infection is now recognized as the most common cause of exacerbations of
asthma in people with the disease [23,24]. It is now also
emerging as a major cause of acute exacerbations of
chronic obstructive bronchitis (AECB) [25–27] and of
cystic fibrosis [28].
Bacterial infections account for only about 5–10%
of all cases of acute tracheobronchitis in previously
healthy adults. Aetiological agents include Bordetella
pertussis, Mycoplasma pneumoniae and Chlamydia
pneumoniae. In recent years, infection with B. pertussis
has been recognized as an important cause of acute but
persistent tracheobronchitis. It has been identified in as
many as 26% of cases presenting with prolonged cough
[29,30]. The reasons for the apparent increase in the
COUGH IN LOWER AIRWAY INFECTIONS
prevalence of B. pertussis include the waning of immunity in previously vaccinated individuals and an
increased awareness of this infection in the adult population. The role of C. pneumoniae as an important aetiological agent in acute tracheobronchitis has been
better defined in recent years, and is now thought to
account for between 5 and 20% of cases of persistent
cough [31,32]. Again, the use of PCR to detect this
organism in airway biopsies and secretions is changing the appreciation of the organism’s importance.
The aetiological role of common bacterial causes of
community-acquired pneumonia, like Streptococcus
pneumoniae, Haemophilus influenzae and Moraxella
catarrhalis in uncomplicated acute bronchitis in previously healthy patients remains uncertain.
The overwhelming predominance of viral infections
in causing acute tracheobronchitis has not kept the
condition from being an important reason for the inappropriate prescription of antibiotics. Despite the
lack of evidence supporting their routine use, antibiotics are prescribed to a large majority of the patients
with acute tracheobronchitis who present for care [33].
The Ambulatory Medical Care Survey in the US in
1992 showed that 66% of patients diagnosed as having
bronchitis were treated with antibiotics [34]. The
antibiotic prescription rate in patients diagnosed as
having ‘colds’ or upper respiratory tract infections
was slightly lower, at around 50%. The rate of antibiotic use by primary care physicians for patients with
cough of recent onset has remained high, actually increasing from 1980 to 1994 [35]. This excessive use
of antibiotics in outpatient respiratory infections is
believed to be an important determinant of the recent
rise in antibiotic resistance among common respiratory pathogens.
Pneumonia
Community-acquired pneumonia (CAP) is one of the
most common causes of hospitalization and death from
infectious diseases in adults. About 4–6 million cases of
CAP occur each year in the US, and up to 25% of these
require hospital admission [36,37]. Most cases present
with acute cough in association with other respiratory
and systemic symptoms. Community-acquired pneumonia accounts for about 6% of all ambulatory visits
with a chief complaint of cough [35].
The aetiology of CAP is identified in only half of all
cases using currently available diagnostic methods
Table 9.2 Microbial pathogens that cause pneumonia.
Viruses
Influenza virus
Cytomegalovirus
Respiratory syncytial virus
Measles virus
Varicella zoster virus
Hantavirus
Bacteria
Streptococcus pneumoniae
Haemophilus influenzae
Staphylococcus aureus
Mycoplasma pneumoniae
Chlamydia pneumoniae
Chlamydia psittaci
Legionella pneumophila
Moraxella catarrhalis
Oral anaerobes
Enteric aerobic Gram-negative bacilli
Pseudomonas aeruginosa
Nocardia spp.
Mycobacterium tuberculosis
Fungi
Histoplasma
Coccidioides
Blastomyces spp.
(Table 9.2). The most commonly identified organism
is Streptococcus pneumoniae, followed by Haemophilus influenzae and Staphylococcus aureus. Viruses,
Chlamydia pneumoniae, Mycoplasma pneumoniae
and Legionella account for around a quarter of cases in
which an aetiology is identified [38–40]. Enteric Gramnegative bacteria including Pseudomonas aeruginosa
are not common in CAP but can be found more frequently in elderly patients, in patients with chronic lung
diseases and in patients with underlying comorbidities
that suppress immune function [41,42].
Pathophysiology
The pathogenetic mechanism that gives rise to cough
in acute airway infection is not well understood but
is likely to result from one or more of the following
(Table 9.3).
1 Infections limited to the upper airway, like many
85
CHAPTER 9
Table 9.3 Possible mechanisms giving rise to cough in lower respiratory tract
infections.
1 Irritation of nerve endings in the larynx and trachea from ‘postnasal drip’.
2 Release of proinflammatory mediators at the site of viral replication.
3 Exposure of nerve endings secondary to damage and destruction of the airway
epithelium.
4 Enhanced effect of neuropeptides such as substance P secondary to decrease in
neutral endopeptidase on the epithelial cell surface.
5 Deformation of irritant receptors by accumulated secretion and debris.
6 Airway hyperresponsiveness and bronchospasm.
common colds with or without rhinosinusitis, often result in dripping of secretions rich in inflammatory mediators from the nasopharynx down onto the larynx or
trachea (‘postnasal drip’). Irritation of nerve endings at
these sites commonly elicits coughing.
2 Proinflammatory mediators known to be released
in response to rhinovirus infection of the airway
mucosa include chemokines, cytokines, histamine,
bradykinins and prostaglandins [43]. Cough can
result from the stimulation of nerve endings in the
lower airway mucosa by inflammatory mediators
released directly from airway epithelial cells (the site of
rhinovirus infection) or from inflammatory cells attracted to the site of infection by epithelial cell-derived
chemokines, like interleukin-8 and eotaxin [44,45]
(Fig. 9.1).
3 Damage and destruction of the airway epithelium
in the lower respiratory tract is found in infection with
influenza and RSV [46,47]. Necrosis and shedding
of the epithelial layer of the bronchi could expose sensory nerve endings, like rapidly adapting irritant receptors, decreasing the cough threshold to environmental
irritants and inflammatory secretions.
4 Studies of epithelial cells in vitro and of rats and
guinea-pigs in vivo have suggested that some infections
might lower the cough threshold by an indirect mechanism, through reduction in neutral endopeptidase on
the epithelial cell surface [48,49]. This enzyme degrades neuropeptides released from adjacent afferent
nerve endings, so a reduction in its concentration or
activity might amplify the effects of stimulated release
of neuropeptides. One of these effects, most clearly
identified for substance P, is cough, and the administration of exogenous neutral endopeptidase has been
shown to increase the cough threshold to inhalation of
substance P in a guinea-pig model [50,51].
86
5 Together with the increase in mucus production,
the impairment of mucociliary function during infection of the airways leads to accumulation of secretions
and debris in the airway lumen. These secretions
can mechanically deform irritant receptors in the
adjacent bronchial mucosa, triggering cough as a
defensive reflex for clearing the airways of excess
secretions and foreign materials. The accumulation of
secretions in the distal airways is also the mechanism
likely to be responsible for cough in patients with pneumonia, as cough receptors are not present in the lung
parenchyma.
6 Finally, cough in acute lower airway infection may
be a manifestation of airway hyperresponsiveness and
bronchospasm, as is associated with cough in asthma.
The mechanism is presumed to be related to changes in
smooth muscle tone, for bronchodilators are effective
in relieving cough in patients with asthma [52] and in
some patients with cough associated with tracheobronchitis [53–55]. In patients in whom acute infection of
the lower airway is associated with abnormalities in
pulmonary function, cough usually lasts for a longer
period of time, and bronchodilator treatment is more
likely to be effective [18,56].
Clinical presentation
Acute tracheobronchitis
Cough is so consistently present in patients with acute
tracheobronchitis as to be a diagnostic criterion for
the condition [3,4]. A review of 346 adults with selfdiagnosed colds for 48 h or less (82% due to picornavirus infection) found that cough was reported by
75% within the first 2 days and by 25% on the 14th
COUGH IN LOWER AIRWAY INFECTIONS
Mac
(b) Activation of
resident airway
cells
(a) Viral replication
and epithelial
activation
IL-6, IL-8
RANTES
GM-CSF
mediators
Epithelium
IL-11
Lymph
EOS
PMN
Secretions
IL-11
Smooth
muscle
Endothelium
TNFa, IL-1, 8
IFNa, g
Serum proteins
(oedema)
Adhesion
molecules
AHR
(c) Cell recruitment
and activation
(d) Resolution
TNFa, IL-1, 8
IFNa, g
Binding to
epithelium
Neurogenic
and cellular
inflammation
GM-CSF
O2·
degranulation
IL-10
TGFb
CTL
Basement membrane
thickening
AHR
Fig. 9.1 Cellular inflammatory responses to respiratory viral
infection. (a) Respiratory viral infections are initiated when a
virus enters a host epithelial cell, and viral replication causes
the release of new infectious particles and activates secretion
of cytokines, chemokines and mediators by the epithelial
cells. (b) Viral particles released into the airway cause activation of resident cells in the airway, including macrophages,
lymphocytes and granulocytes. Cytokines from epithelial
cells and other resident airway cells increase adhesion molecule expression and increase airway responsiveness. (c) The
combination of chemokine secretion and increased adhesion
molecule expression causes recruitment and activation of additional leucocytes, which further add to airway inflammation and increased responsiveness. (d) Cytotoxic T cells kill
virus-infected cells, and cytokines such as TGFb and interleukin (IL) 10 are likely to play a role in the down-regulation
of airway inflammation after viral infection. Increased numbers of airway lymphocytes and eosinophils may persist for
weeks after the viral infection. The steps illustrated in this
diagram can occur sequentially and/or in parallel, and the
timing depends on factors related to both the host and virus.
Abbreviations: EOS, eosinophil; IFN, interferon; PMN,
polymorphonuclear leucocyte; Mac, macrophage; Lymph,
lymphocyte; CTL, cytotoxic lymphocyte; O ·2 , superoxide;
AHR, airway hyperresponsiveness. Reproduced from:
Folkerts G et al. Virus-induced airway hyperresponsiveness
and asthma. Am J Respir Crit Care Med 1998; 157 (6 Part 1):
1708–20.
87
CHAPTER 9
day. Cough was rated as moderate or severe by 44%,
and as the most troubling symptom in 8% [57].
The symptom usually begins early and becomes
more prominent as the illness progresses. Acute tracheobronchitis can begin as a severe cold or ‘flu-like’
illness with upper respiratory tract symptoms such as
coryza and sore throat, but cough appears shortly
afterwards, progressing to become the predominant
complaint. Specific descriptors of cough in acute tracheobronchitis have not proven useful, but it is often
described as ‘chesty’ and is productive of sputum in
about 50% of cases. The sputum produced is typically
mucoid at the outset, but more purulent in the later
stages of illness. This purulence does not indicate a
bacterial aetiology; it simply indicates the accumulation of inflammatory cells or sloughed mucosal epithelial cells in airway secretions [58]. Another common
symptom of tracheal involvement in acute tracheobronchitis is retrosternal pain, typically worsened by
respiration and coughing. Dyspnoea and cyanosis are
not seen in healthy adults without underlying chronic
lung disease.
Rhonchi and coarse rales may be heard on auscultation indicating the presence of loose intraluminal secretions. Wheezing may be heard but is infrequent except
in patients with prior obstructive airway disease, or
with a predisposition to asthma. Findings of lung consolidation are absent. Wheezing with otherwise unremarkable bouts of tracheobronchitis may be the first
clue to a diagnosis of asthma. With the exception of
influenza and adenovirus infection, fever is typically
absent in acute tracheobronchitis due to viruses.
Although the cough in acute tracheobronchitis typically lasts less than 3 weeks, it may persist up to a month
or longer in some patients [59]. Viral causes still predominate even in these patients, but the proportion
attributable to B. pertussis and C. pneumoniae is increased [30,32,60,61]. In children, the first symptoms
of pertussis are similar to those of a common cold with
coryza: dry cough and mild fever. A week or two after
this innocuous onset, coughing begins to occur in
paroxysms lasting for a minute or even longer. The
child may gasp for air between coughing paroxysms,
with a characteristic ‘whooping’ sound. Coughing
usually continues for at least 2 weeks and may persist
for more than 3 months before gradually improving
[62]. In contrast, adult pertussis usually presents with
relatively mild respiratory complaints, as of simply
prolonged ‘postviral’ cough without the classical
88
paroxysms seen in children. No cluster of clinical features permits a specific diagnosis of pertussis in these
patients, for no pattern of symptoms distinguishes it
from other causes of acute tracheobronchitis [60,63].
Acute bronchiolitis
Cough is usually not the predominant feature of this
condition that affects primarily young children and infants. The key clinical features of viral bronchiolitis are
acute respiratory illness with wheezing and concurrent
fever, coryza or cough in a previously well infant. Auscultation of the lungs reveals bilateral crackles and
expiratory wheezing. Severe cases can present with
respiratory distress with intercostal retraction, hypoxia and respiratory failure. Viral bronchiolitis is
most often due to RSV infection, and peaks in the winter months. Infants diagnosed with viral bronchiolitis
have a higher rate of subsequent wheezing illness
through childhood, with the increase over other children declining toward nil by about the age of 13 [64].
Acute laryngotracheobronchitis
This is an important diagnosis to consider in young
children in the second to third year of life. The classic
signs of this condition — inspiratory stridor, hoarseness
and a peculiar brassy or ‘croupy’ cough — arise from inflammation involving mainly the larynx and trachea.
Most patients have an upper respiratory infection for
several days before cough becomes apparent. Fever is
common. With progressive compromise of the airway,
stridor becomes continuous with a deepening cough.
Suprasternal, infrasternal and intercostal retractions
are frequently observed in severe cases. There may
be diminished breath sounds, rhonchi and scattered
crackles on auscultation. Nevertheless, most patients
with croup have a relatively benign clinical course and
only progress as far as stridor and slight dyspnoea before they start to recover [10]. The differential diagnosis includes other causes of upper airway obstruction in
young children such as acute epiglottitis, aspiration
of foreign body, diphtheria, and peritonsillar and
retropharyngeal abscesses.
Community-acquired pneumonia
Cough is present in about 80% of all cases of
community-acquired pneumonia (CAP) and can be dry
COUGH IN LOWER AIRWAY INFECTIONS
or productive [65]. Other associated features include
fever, sputum production, dyspnoea and pleuritic chest
pain. Elderly patients and patients with impaired
immune response may have few or no respiratory
symptoms. Physical findings on examination include
tachypnoea, crackles, rhonchi and signs of consolidation. Dullness to percussion may suggest the presence
of pleural effusion, but diagnosis often becomes apparent only on chest radiography. While many cases of
CAP are due to viral infection, bacterial causes are
much more prevalent than in tracheobronchitis or
bronchiolitis [40].
Evaluation
A wide variety of inflammatory and infectious conditions of the respiratory system can present as an acute
cough illness. Most common causes of acute cough can
usually be inferred from a detailed history and physical
examination. Acute tracheobronchitis is essentially a
clinical diagnosis characterized by the predominance of
cough in the presence of other symptoms of upper
respiratory tract infection such as sore throat and rhinorrhoea, which help differentiate it from other conditions. However, it is not possible to differentiate
between bacterial and viral tracheobronchitis based on
clinical presentation alone.
The most important objective in the evaluation of
adults with acute cough illness is to exclude the presence of pneumonia. Other serious diseases that should
be kept in mind include congestive heart failure, pulmonary embolism and aspiration. Various studies have
been done to determine the accuracy of the patient’s
history and physical examination for diagnosing
pneumonia in adults with acute cough in the outpatient
and emergency room settings [66–69]. A recent review
of these studies has concluded that in the absence
of abnormalities in the vital signs and chest examination, further diagnostic work-up — as by chest radiography — in an otherwise healthy adult patient with
acute cough is probably not necessary [70]. Nevertheless, the clinician is reminded of the atypical presentations of pneumonia in patients with comorbidities or
immunosuppression, and in elderly patients whose presenting complaints may be of non-respiratory symptoms such as confusion or frequent falls [71].
In the initial evaluation of a patient with new acute
respiratory symptoms, one has to take into account the
patient’s dermographic and epidemiological situation.
B. pertussis infection has to be considered in any
patient with a persistent cough when there is a history
suggestive of a positive contact. Influenza should be
considered a possible cause of acute febrile tracheobronchitis in the winter months or in outbreak settings.
The presence of fever together with sore throat,
headache and myalgia in adult patients presenting with
acute cough illness during the flu season is sufficiently
specific for the clinician to make a definitive diagnosis
of influenza [72–74]. The early diagnosis of these
two conditions is important, as specific antimicrobial
therapy is available. The timely administration of antibiotics in patients with pertussis will help to reduce
the transmission of this highly infectious disease in the
community. In patients with influenza, the early administration of neuraminidase inhibitors such as oseltamivir and zanamivir will shorten the course of the
illness.
Some patients presenting with acute cough illness
due to acute tracheobronchitis may have underlying
asthma. However, the diagnosis of asthma is difficult in
the acute setting because a significant number of patients with otherwise uncomplicated tracheobronchitis
have abnormal pulmonary function. These abnormalities are transient and include a bronchodilatorresponsive decrease in FEV1 and an increase in
bronchial reactivity that can last up to 2 months
[56,75]. It is therefore prudent to defer definitive diagnosis of asthma until at least 2 months after the onset of
acute tracheobronchitis.
Radiographic examination of the chest is strongly
recommended when pneumonia is suspected [36,37].
Standard posteroanterior and lateral chest radiographs
are generally needed for all patients whose symptoms
and physical examination suggest the possibility of
pneumonia. The presence of lung infiltrates excludes
uncomplicated acute tracheobronchitis as the cause of
a patient’s acute cough illness and greatly increases the
possibility of bacterial infection.
Laboratory investigations are usually not helpful in
the diagnosis of acute tracheobronchitis. The yield
from a sputum culture is exceedingly low in this condition and neither Gram stain nor culture is recommended. The role of sputum Gram stain and culture in
the evaluation of pneumonia is controversial. Some
guidelines advocate the tests, whereas others discourage their routine use [36,37,76]. When the clinical suspicion of pertussis is high, a nasopharyngeal smear for
89
CHAPTER 9
direct fluorescent antibody test and culture for B. pertussis should be sent early in the illness. Serological tests
for influenza and B. pertussis may be helpful in the setting of community or seasonal outbreaks. The availability of PCR-based testing for routine use in the future
may shorten the time to detection of these infections.
Cough lasting more than 3 weeks is considered
chronic. It is recommended that chest radiograph be
obtained in all such cases. Irwin and colleague have developed recommendations for the evaluation of such
cases [77]. The term ‘postinfectious cough’ is sometimes used to describe chronic cough developing after
an upper or lower airway infection but should be reserved for those with a normal chest radiograph.
Management
Specific treatment of cough
Antibiotics in acute tracheobronchitis
Randomized controlled trials conducted in the last
20 years have repeatedly failed to demonstrate benefit from the routine use of antibiotic treatment in
uncomplicated acute tracheobronchitis. This is not
unexpected, as the majority of the cases of acute tracheobronchitis are caused by viral infections. While it is
reasonable to expect that patients with acute tracheobronchitis from infection with bacteria such as B. pertussis, M. pneumoniae and C. pneumoniae would
benefit from antibiotic treatment, it is impossible to
differentiate bacterial from viral tracheobronchitis
on clinical grounds, and no method currently allows
prompt detection of bacterial causes of infection.
Methods based on amplification of signature elements
of bacterial DNA (e.g. PCR) may ultimately make this
possible, but until they are developed, it will remain difficult to select patients who may potentially benefit
from antibiotic therapy for treatment.
Trials of antibiotic treatment of uncomplicated
acute tracheobronchitis have been done in sufficient
numbers to permit meta-analyses of their findings. This
approach has confirmed that the routine antibiotic
treatment does not affect the duration of illness, limitation of activity or loss of work [78–82]. With regard to
the specific symptoms of cough and sputum production, two meta-analyses have found a modest benefit
in terms of shorter duration of these symptoms (by
about half a day) in some patients treated with anti90
biotics [81,82]. Using improvement in the healthrelated quality of life as a primary outcome measure, a
recent randomized double blind controlled trial using
the broad-spectrum antibiotic azithromycin failed
to demonstrate any beneficial effect in healthy adults
with acute bronchitis [83]. Clinical practice guidelines
with regard to appropriate antibiotic use have recently
been published [84,85]. These guidelines recommend
that the evaluation of adults with an acute cough illness
or a presumptive diagnosis of uncomplicated acute
bronchitis should focus on ruling out serious illness and
the routine antibiotic treatment of uncomplicated
acute bronchitis is not recommended, regardless of
duration of cough. Patient satisfaction with care for
acute bronchitis depends most on physician–patient
communication than on whether an antibiotic is prescribed. Clinicians caring for patients with uncomplicated acute tracheobronchitis are encouraged to
discuss with their patients the natural course of the disease and the lack of benefit of antibiotics in treating this
condition.
Bronchodilators in acute tracheobronchitis
A few randomized controlled trials have indicated
that the use of bronchodilator agents may be advantageous in selected patient with acute tracheobronchitis
[53–55]. The use of b2-agonists like albuterol has been
shown to shorten the duration of cough in patients with
bronchial hyperresponsiveness, wheezing or an FEV1 <
80% of predicted at the initial visit. No such benefit was
seen in subjects without evidence of airflow limitation
at presentation [53]. A recent Cochrane Database review of the literature concluded that there is no evidence to support the use of b2-agonists in children with
acute cough who do not have evidence of airflow obstruction. There is also little evidence to support their
routine use in adults. While the risk of adverse effects
from b-agonist use is small, it is not nil [86], and the selection of patients for bronchodilator treatment should
rest on the use of objective, simple tests of lung function, like spirometry, when feasible. The duration of
treatment needed in these patients is generally no
longer than 1–2 weeks. In patients with b-agonistresponsive cough persisting for longer than 6 weeks,
follow-up assessment of pulmonary function should
be made.
Antihistamines in acute tracheobronchitis
Antihistamine decongestant therapy has been shown
COUGH IN LOWER AIRWAY INFECTIONS
to reduce postnasal drip and significantly decreases
the severity of cough in patients with uncomplicated
common colds [87]. The impact of this treatment in
cases that have progressed to acute tracheobronchitis is
unknown.
[93]. When these agents are effective only against a particular family of viruses, the question is invited as to the
necessity and cost of making a specific diagnosis early
enough in the course of the illness for the therapy to
make an impact.
Specific considerations
Acute bronchiolitis. Treatment of RSV bronchiolitis is
symptomatic, with emphasis primarily on adequate hydration and oxygenation. Aerosolized ribavirin has
been approved to treat hospitalized infants and young
children with severe lower respiratory infection due to
RSV. Ribavirin is a guanosine analogue with good in
vitro activity against a number of viruses, including
RSV. However, aerosolized ribavirin is costly and the
mode of delivery is elaborate requiring continuous administration with the use of a special nebulization device in a mist tent or hood. There is also concern about
the effect of occupational exposure to ribavirin in
health care workers of childbearing age, as this drug is
known to be teratogenic and even embryocidal in most
animal species. Most importantly, the clinical efficacy
and benefit of this treatment remain uncertain despite
its widespread use in the last two decades [94]. Consequently the American Academy of Pediatrics recommends its use only in patients in specific high-risk
groups [95].
Some clinicians advocate the use of b-agonist bronchodilators, like albuterol, but evidence is lacking
that it reduces admission rates or decreases length of
hospitalization in children with acute bronchiolitis
[96]. With regard to the use of corticosteroids, a metaanalysis using data from six randomized placebocontrolled trials of systemic corticosteroids in the treatment of patients hospitalized with RSV bronchiolitis
reveals a statistically significant improvement of the
clinical symptoms, length of stay and duration of
symptoms [97]. However, two randomized control
trials published later and not included in this metaanalysis show no evidence that corticosteroid treatment alters the course of the disease [98,99].
Pertussis. The one possible exception to antibiotic use
discussed above is when pertussis infection is suspected
in patients with acute tracheobronchitis. Although
studies have identified pertussis in up to 20% of patients with cough longer than 2–3 weeks, there is no
specific clinical feature that identifies persistent cough
due to pertussis [30,60,88]. This is especially true in
adults where the classic features of whooping cough are
not seen. In the setting of a familial or community outbreak of B. pertussis infection, a high index of suspicion
is required and early institution of the appropriate antibiotics can shorten the duration of transmission of
this highly infectious condition by decreasing the shedding of the organism. The most widely used antibiotic
for this infection is erythromycin at 30–40 mg/kg every
6 h for 2 weeks. Nevertheless, there is no evidence to indicate that the natural course of pertussis, including the
duration of cough, can be significantly altered when the
treatment is started 7–10 days after the onset of illness
[88–90].
Influenza. Specific antiviral agents are available for the
treatment and prevention of acute tracheobronchitis
due to influenza. Amantadine, rimantadine and the
newer neuraminidase inhibitors such as oseltamivir
and zanamivir have been shown to be effective in decreasing the duration as well as the severity of symptoms [72,73,91,92]. The caveat is that these agents in
general must be started within 24–48 h to be effective.
The accuracy of a clinical diagnosis of influenza in the
setting of an outbreak is usually good, and laboratory
confirmation may not be necessary before starting
treatment [91]. This consideration is especially important for unvaccinated patients at high risk of complications of influenza infection. Outside of the period of
influenza epidemics, however, diagnosing influenza as a
cause of sporadic cases of acute tracheobronchitis on
clinical grounds alone is difficult.
Antiviral agents effective against other common respiratory viruses, like rhinovirus, have been developed
and tested, but are yet to be approved for clinical use
Acute laryngotracheobronchitis. Specific antiviral
therapy is not available for the treatment of this
infection. Administration of nebulized racemic epinephrine has been demonstrated to be effective in the
treatment of airway obstruction in both outpatients
and hospitalized patients with croup [100–103]. In
patients with moderate to severe laryngotracheobronchitis, parenteral, oral and nebulized corticosteroids
91
CHAPTER 9
have been shown to lessen the symptoms and hospitalizations [104–109]. Oral dexamethasone at a dose of
0.15 mg/kg is also effective for outpatients with less
severe disease [110].
Pneumonia. Most patients with community-acquired
pneumonia are treated empirically with antibiotics initially. Pathogen-specific therapy may be possible in
some patients when blood or sputum culture results become available. The initial choice of antibiotics is usually guided by relevant clinical factors that influence the
likely aetiological pathogens. For example, in outpatients with no risk factors for drug-resistant S. pneumoniae or Gram-negative organisms, macrolide or
tetracycline alone can be used. In patients with risk factors for these organisms, because of either underlying
chronic lung diseases or immunosuppression, the
choice is between a macrolide/b-lactam combination
and an antipneumococcal fluoroquinolone alone. Detailed discussion of the treatment of communityacquired pneumonia is beyond the scope of this
chapter and readers are referred to several guidelines
published recently on this topic [36,37,76,111].
ized controlled trials to reduce cough in patients with
bronchitis [77,112].
The use of protussive therapy is indicated when
cough is deemed to perform a useful function and needs
to be encouraged. Although there is some evidence
that humidified air and guaifenesin are effective expectorants, there is a paucity of good-quality studies on
the use of other protussive agents in the management
of cough secondary to respiratory tract infection. The
role of mucolytic and mucokinetic agents in acute tracheobronchitis remains unclear. While many of these
agents are used widely in cough medications available
over the counter, a recent systemic review of 15 randomized controlled trials involving 2166 adult patients
with acute cough illness due to upper respiratory tract
infections found no convincing evidence that over-thecounter cough preparations were helpful [113].
Although short courses of oral or inhaled corticosteroid have been given to patients in clinical practice
in an attempt to shorten the duration of cough, there is
no published report to suggest that this is effective in
patients without underlying asthma.
References
Symptomatic treatment of cough
Antitussive and protussive therapy
With the exception of pneumonia, the mainstay of
treatment for patients with cough as a troublesome
manifestation of acute lower airway infection will be
the use of non-specific therapies aimed at suppressing
cough or facilitating sputum mobilization and clearance. This is particularly true when specific treatment is
not available, as in most patients with acute tracheobronchitis due to a viral origin.
Antitussive therapy — aimed at controlling or eliminating cough — is often prescribed for nocturnal use,
for patients are often most bothered by cough interrupting sleep, but is also often prescribed for repeated
use throughout the day, on an ‘as needed’ basis. Although inhibition of cough carries the theoretical risk
of allowing accumulation of excessive respiratory
secretions, thus predisposing to bacterial infection, no
association of the use of antitussives and the development of secondary bacterial infections has been
reported in the literature. The effectiveness of
medications such as codeine, dextromethorphan and
diphenhydramine has been demonstrated in random92
1 Schappert SM. Ambulatory care visits of physician offices, hospital outpatient departments, and emergency
departments: United States, 1995. Vital Health Stat 13
1997; 129: 1–38.
2 Ayres JG. Seasonal pattern of acute bronchitis in general
practice in the United Kingdom 1976–83. Thorax 1986;
41 (2): 106–10.
3 Oeffinger KC, Snell LM, Foster BM, Panico KG, Archer
RK. Diagnosis of acute bronchitis in adults: a national
survey of family physicians. J Fam Pract 1997; 45 (5):
402–9.
4 Evan AS. Clinical syndromes in adults caused by respiratory infection. Med Clin North Am 1967; 51: 803–18.
5 Shay DK, Holman RC, Newman RD, Liu LL, Stout JW,
Anderson LJ. Bronchiolitis-associated hospitalizations
among US children, 1980–96. JAMA 1999; 282 (15):
1440–6.
6 Henderson FW, Clyde WA Jr, Collier AM, Denny FW,
Senior RJ, Sheaffer CI et al. The etiologic and epidemiologic spectrum of bronchiolitis in pediatric practice. J Pediatr 1979; 95 (2): 183–90.
7 Welliver RC, Wong DT, Sun M, McCarthy N.
Parainfluenza virus bronchiolitis. Epidemiology and
pathogenesis. Am J Dis Child 1986; 140 (1): 34–40.
8 Denny FW, Murphy TF, Clyde WA Jr, Collier AM,
COUGH IN LOWER AIRWAY INFECTIONS
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Henderson FW. Croup: an 11-year study in a pediatric
practice. Pediatrics 1983; 71 (6): 871–6.
Hall CB. Respiratory syncytial virus and parainfluenza
virus. N Engl J Med 2001; 344 (25): 1917–28.
Sendi K, Crysdale WS, Yoo J. Tracheitis: outcome of
1,700 cases presenting to the emergency department during two years. J Otolaryngol 1992; 21 (1): 20–4.
Nicholson KG, Kent J, Hammersley V, Cancio E. Acute
viral infections of upper respiratory tract in elderly people living in the community: comparative, prospective,
population based study of disease burden. Br Med J
1997; 315 (7115): 1060–4.
Falsey AR, McCann RM, Hall WJ, Tanner MA, Criddle
MM, Formica MA et al. Acute respiratory tract infection
in daycare centers for older persons. J Am Geriatr Soc
1995; 43 (1): 30–6.
Pitkaranta A, Virolainen A, Jero J, Arruda E, Hayden
FG. Detection of rhinovirus, respiratory syncytial virus,
and coronavirus infections in acute otitis media by reverse transcriptase polymerase chain reaction. Pediatrics
1998; 102: 291–5.
Nicholson KG, Kent J, Hammersley V, Cancio E. Risk
factors for lower respiratory complications of rhinovirus
infections in elderly people living in the community:
prospective cohort study. Br Med J 1996; 313: 1119–23.
Van Hartesveldt FR. The 1918–1919 Pandemic of
Influenza: the Urban Impact in the Western World.
Lewiston, NY: E. Mellen Press, 1992.
Crosby AW. America’s Forgotten Pandemic: the Influenza of 1918. Cambridge, UK: Cambridge University
Press, 1989.
Denny FW Jr. The clinical impact of human respiratory
virus infections. Am J Respir Crit Care Med 1995; 152:
S4–12.
Boldy DA, Skidmore SJ, Ayres JG. Acute bronchitis in the
community: clinical features, infective factors, changes
in pulmonary function and bronchial reactivity to histamine. Respir Med 1990; 84 (5): 377–85.
Monto AS. Viral respiratory infections in the community: epidemiology, agents and interventions. Am J Med
1995; 99: 24S–27S.
Monto AS, Sullivan KM. Acute respiratory illness in the
community. Frequency of illness and the agents involved.
Epidemiol Infect 1993; 110 (1): 145–60.
Gern JE, Galagan DM, Jarjour NN, Dick EC, Busse WW.
Detection of rhinovirus RNA in lower airway cells during experimentally induced infection. Am J Respir Crit
Care Med 1997; 155 (3): 1159–61.
Monto AS, Fendrick AM, Sarnes MW. Respiratory illness caused by picornavirus infection: a review of clinical
outcomes. Clin Ther 2001; 23 (10): 1615–27.
Johnston SL, Pattemore PK, Sanderson G, Smith S,
Lampe F, Josephs L et al. Community study of role of
24
25
26
27
28
29
30
31
32
33
34
35
36
viral infections in exacerbations of asthma in 9–11 year
old children. Br Med J 1995; 310: 1225–9.
Nicholson KG, Kent J, Ireland DC. Respiratory viruses
and exacerbations of asthma in adults. Br Med J 1993;
307: 982–6.
Seemungal TA, Harper-Owen R, Bhowmik A, Jeffries
DJ, Wedzicha JA. Detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary
disease. Eur Respir J 2000; 16 (4): 677–83.
Wedzicha JA. Exacerbations: etiology and pathophysiologic mechanisms. Chest 2002; 121 (5 Suppl.):
136S–41S.
Greenberg SB, Allen M, Wilson J, Atmar RL. Respiratory viral infections in adults with and without chronic
obstructive pulmonary disease. Am J Respir Crit Care
Med 2000; 162 (1): 167–73.
Smyth AR, Smyth RL, Tong CY, Hart CA, Heaf DP. Effect of respiratory virus infections including rhinovirus
on clinical status in cystic fibrosis. Arch Dis Child 1995;
73 (2): 117–20.
Mink CM, Cherry JD, Christenson P, Lewis K, Pineda E,
Shlian D et al. A search for Bordetella pertussis infection
in university students. Clin Infect Dis 1992; 14 (2):
464–71.
Nennig ME, Shinefield HR, Edwards KM, Black SB,
Fireman BH. Prevalence and incidence of adult pertussis
in an urban population. JAMA 1996; 275 (21): 1672–4.
Grayston JT, Kuo CC, Wang SP, Altman J. A new
Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections. N Engl J Med 1986; 315 (3):
161–8.
Wright SW, Edwards KM, Decker MD, Grayston JT,
Wang S. Prevalence of positive serology for acute
Chlamydia pneumoniae infection in emergency department patients with persistent cough. Acad Emerg Med
1997; 4 (3): 179–83.
Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the
United States. Clin Infect Dis 2001; 33 (6): 757–62.
Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing
for adults with colds, upper respiratory tract infections,
and bronchitis by ambulatory care physicians. JAMA
1997; 278 (11): 901–4.
Metlay JP, Stafford RS, Singer DE. National trends in the
use of antibiotics by primary care physicians for adult patients with cough. Arch Intern Med 1998; 158 (16):
1813–18.
Niederman MS, Mandell LA, Anzueto A, Bass JB,
Broughton WA, Campbell GD et al. Guidelines for the
management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial
therapy, and prevention. Am J Respir Crit Care Med
2001; 163 (7): 1730–54.
93
CHAPTER 9
37 Bartlett JG, Breiman RF, Mandell LA, File TM Jr.
Community-acquired pneumonia in adults: guidelines
for management. The Infectious Diseases Society of
America. Clin Infect Dis 1998; 26 (4): 811–38.
38 Macfarlane JT, Finch RG, Ward MJ, Macrae AD.
Hospital study of adult community-acquired pneumonia. Lancet 1982; 2: 255–8.
39 Ostergaard L, Andersen PL. Etiology of communityacquired pneumonia. Evaluation by transtracheal aspiration, blood culture, or serology. Chest 1993; 104 (5):
1400–7.
40 Bartlett JG, Mundy LM. Community-acquired pneumonia. N Engl J Med 1995; 333 (24): 1618–24.
41 Ruiz M, Ewig S, Marcos MA, Martinez JA, Arancibia F,
Mensa J et al. Etiology of community-acquired pneumonia: impact of age, comorbidity, and severity. Am J Respir
Crit Care Med 1999; 160 (2): 397–405.
42 Ruiz M, Ewig S, Torres A, Arancibia F, Marco F, Mensa J
et al. Severe community-acquired pneumonia. Risk factors and follow-up epidemiology. Am J Respir Crit Care
Med 1999; 160 (3): 923–9.
43 Gwaltney JM Jr. Rhinovirus infection of the normal
human airway. Am J Respir Crit Care Med 1995; 152:
S36–9.
44 Halperin SA, Eggleston PA, Hendley JO, Suratt PM,
Groschel DH, Gwaltney JM Jr. Pathogenesis of lower
respiratory tract symptoms in experimental rhinovirus
infection. Am Rev Respir Dis 1983; 128 (5): 806–10.
45 Folkerts G, Busse WW, Nijkamp FP, Sorkness R, Gern JE.
Virus-induced airway hyperresponsiveness and asthma.
Am J Respir Crit Care Med 1998; 157: 1708–20.
46 Loosli CG, Stinson SF, Ryan DP, Hertweck MS, Hardy
JD, Serebrin R. The destruction of type 2 pneumocytes by
airborne influenza PR8-A virus; its effect on surfactant
and lecithin content of the pneumonic lesions of mice.
Chest 1975; 67 (2 Suppl.): 7S–14S.
47 Aherne W, Bird T, Court SD, Gardner PS, McQuillin J.
Pathological changes in virus infections of the lower respiratory tract in children. J Clin Pathol 1970; 23 (1):
7–18.
48 Borson DB, Brokaw JJ, Sekizawa K, McDonald DM,
Nadel JA. Neutral endopeptidase and neurogenic inflammation in rats with respiratory infections. J Appl
Physiol 1989; 66 (6): 2653–8.
49 Jacoby DB, Tamaoki J, Borson DB, Nadel JA. Influenza
infection causes airway hyperresponsiveness by decreasing enkephalinase. J Appl Physiol 1988; 64 (6): 2653–8.
50 Kohrogi H, Nadel JA, Malfroy B, Gorman C, Bridenbaugh R, Patton JS et al. Recombinant human enkephalinase (neutral endopeptidase) prevents cough induced by
tachykinins in awake guinea pigs. J Clin Invest 1989; 84
(3): 781–6.
51 Nadel JA, Borson DB. Modulation of neurogenic inflam-
94
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
mation by neutral endopeptidase. Am Rev Respir Dis
1991; 143: S33–6.
Corrao WM, Braman SS, Irwin RS. Chronic cough as the
sole presenting manifestation of bronchial asthma. N
Engl J Med 1979; 300 (12): 633–7.
Melbye H, Aasebo U, Straume B. Symptomatic effect
of inhaled fenoterol in acute bronchitis: a placebocontrolled double-blind study. Fam Pract 1991; 8 (3):
216–22.
Hueston WJ. A comparison of albuterol and erythromycin for the treatment of acute bronchitis. J Fam Pract
1991; 33 (5): 476–80.
Hueston WJ. Albuterol delivered by metered-dose inhaler to treat acute bronchitis. J Fam Pract 1994; 39 (5):
437–40.
Williamson HA Jr. Pulmonary function tests in acute
bronchitis: evidence for reversible airway obstruction. J
Fam Pract 1987; 25 (3): 251–6.
Witek TJ, Doyle C, Hayden FG. The incidence of ‘post
viral cough’ following natural colds in a community setting. Am J Respir Crit Care Med 2002; 165: 8 (2): A130.
Robertson AJ. Green sputum. Lancet 1952; 1: 12–15.
Williamson HA Jr. A randomized, controlled trial of
doxycycline in the treatment of acute bronchitis. J Fam
Pract 1984; 19 (4): 481–6.
Wright SW, Edwards KM, Decker MD, Zeldin MH.
Pertussis infection in adults with persistent cough. JAMA
1995; 273 (13): 1044–6.
He Q, Viljanen MK, Arvilommi H, Aittanen B, Mertsola
J. Whooping cough caused by Bordetella pertussis and
Bordetella parapertussis in an immunized population.
JAMA 1998; 280 (7): 635–7.
Feigin RD, Cherry JD. Pertussis. In: Bralow L, ed.
Textbook of Pediatric Infectious Diseases, 3rd edn.
Pennsylvania: W.B. Saunders, 1992: 1211–12.
Yaari E, Yafe-Zimerman Y, Schwartz SB, Slater PE,
Shvartzman P, Andoren N et al. Clinical manifestations
of Bordetella pertussis infection in immunized children
and young adults. Chest 1999; 115 (5): 1254–8.
Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen
M, Taussig LM et al. Respiratory syncytial virus in early
life and risk of wheeze and allergy by age 13 years. Lancet
1999; 354: 541–5.
Marrie TJ. Community-acquired pneumonia. In:
Niederman MS, ed. Respiratory Infections: a Scientific
Basis for Management. Philadelphia: W.B. Saunders,
1994: 125–38.
Heckerling PS, Tape TG, Wigton RS, Hissong KK, Leikin
JB, Ornato JP et al. Clinical prediction rule for pulmonary infiltrates. Ann Intern Med 1990; 113 (9):
664–70.
Diehr P, Wood RW, Bushyhead J, Krueger L, Wolcott B,
Tompkins RK. Prediction of pneumonia in outpatients
COUGH IN LOWER AIRWAY INFECTIONS
68
69
70
71
72
73
74
75
76
77
78
79
80
with acute cough — a statistical approach. J Chronic Dis
1984; 37 (3): 215–25.
Singal BM, Hedges JR, Radack KL. Decision rules and
clinical prediction of pneumonia: evaluation of low-yield
criteria. Ann Emerg Med 1989; 18 (1): 13–20.
Gennis P, Gallagher J, Falvo C, Baker S, Than W. Clinical
criteria for the detection of pneumonia in adults: guidelines for ordering chest roentgenograms in the emergency
department. J Emerg Med 1989; 7 (3): 263–8.
Metlay JP, Kapoor WN, Fine MJ. Does this patient have
community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997;
278 (17): 1440–5.
Metlay JP, Schulz R, Li YH, Singer DE, Marrie TJ, Coley
CM et al. Influence of age on symptoms at presentation in
patients with community-acquired pneumonia. Arch
Intern Med 1997; 157 (13): 1453–9.
Monto AS, Fleming DM, Henry D, de Groot R,
Makela M, Klein T et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis 1999; 180
(2): 254–61.
Hayden FG, Osterhaus AD, Treanor JJ, Fleming DM,
Aoki FY, Nicholson KG et al. Efficacy and safety of the
neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. Gg167 Influenza Study Group.
N Engl J Med 1997; 337 (13): 874–80.
Dolin R, Reichman RC, Madore HP, Maynard R, Linton
PN, Webber-Jones J. A controlled trial of amantadine
and rimantadine in the prophylaxis of influenza A infection. N Engl J Med 1982; 307 (10): 580–4.
Melbye H, Kongerud J, Vorland L. Reversible airflow
limitation in adults with respiratory infection. Eur
Respir J 1994; 7 (7): 1239–45.
BTS Guidelines for the Management of Community
Acquired Pneumonia in Adults. Thorax 2001; 56 (Suppl.
4): IV1–64.
Irwin RS, Boulet LP, Cloutier MM, Fuller R, Gold PM,
Hoffstein V et al. Managing cough as a defense mechanism and as a symptom. A consensus panel report of the
American College of Chest Physicians. Chest 1998; 114
(2 Suppl. Managing): 133S–181S.
Fahey T, Stocks N, Thomas T. Quantitative systematic
review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults. Br Med J
1998; 316: 906–10.
Orr PH, Scherer K, Macdonald A, Moffatt ME.
Randomized placebo-controlled trials of antibiotics for
acute bronchitis: a critical review of the literature. J Fam
Pract 1993; 36 (5): 507–12.
MacKay DN. Treatment of acute bronchitis in adults
without underlying lung disease. J Gen Intern Med 1996;
11 (9): 557–62.
81 Smucny JJ, Becker LA, Glazier RH, McIsaac W. Are
antibiotics effective treatment for acute bronchitis? A
meta-analysis. J Fam Pract 1998; 47 (6): 453–60.
82 Bent S, Saint S, Vittinghoff E, Grady D. Antibiotics in
acute bronchitis: a meta-analysis. Am J Med 1999; 107
(1): 62–7.
83 Evans AT, Husain S, Durairaj L, Sadowski LS, CharlesDamte M, Wang Y. Azithromycin for acute bronchitis: a
randomised, double-blind, controlled trial. Lancet 2002;
359: 1648–54.
84 Snow V, Mottur-Pilson C, Gonzales R. Principles of appropriate antibiotic use for treatment of acute bronchitis
in adults. Ann Intern Med 2001; 134 (6): 518–20.
85 Gonzales R, Bartlett JG, Besser RE, Cooper RJ,
Hickner JM, Hoffman JR et al. Principles of appropriate
antibiotic use for treatment of uncomplicated acute
bronchitis: background. Ann Intern Med 2001; 134 (6):
521–9.
86 Smucny J, Flynn C, Becker L, Glazier R. Beta2-agonists
for acute bronchitis. Cochrane Database Syst Rev 2001;
(1): CD001726.
87 Curley FJ, Irwin RS, Pratter MR, Stivers DH, Doern GV,
Vernaglia PA et al. Cough and the common cold. Am Rev
Respir Dis 1988; 138 (2): 305–11.
88 Bergquist SO, Bernander S, Dahnsjo H, Sundelof B.
Erythromycin in the treatment of pertussis: a study of
bacteriologic and clinical effects. Pediatr Infect Dis J
1987; 6 (5): 458–61.
89 Sprauer MA, Cochi SL, Zell ER, Sutter RW, Mullen JR,
Englender SJ et al. Prevention of secondary transmission
of pertussis in households with early use of erythromycin. Am J Dis Child 1992; 146 (2): 177–81.
90 Wirsing von Konig CH, Postels-Multani S, Bogaerts H,
Bock HL, Laukamp S, Kiederle S et al. Factors influencing the spread of pertussis in households. Eur J Pediatr
1998; 157 (5): 391–4.
91 Randomised trial of efficacy and safety of inhaled
zanamivir in treatment of influenza A and B virus
infections. The MIST (Management of Influenza in the
Southern Hemisphere Trialists) Study Group. Lancet
1998; 352: 1877–81.
92 Jefferson T, Demicheli V, Deeks J, Rivetti D. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev
2000; (2): CD001265.
93 Rotbart HA. Treatment of picornavirus infections. Antiviral Res 2002; 53 (2): 83–98.
94 Randolph AG, Wang EE. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract.
Cochrane Database Syst Rev 2000; (2): CD000181.
95 American Academy of Pediatrics. Hemophilus influenza
type b and respiratory syncytial virus. In: Peter G, ed. Red
Book: Report of the Committee on Infectious Diseases,
95
CHAPTER 9
96
97
98
99
100
101
102
103
104
96
24th edn. Elk Grove Village, IL: American Academy of
Pediatrics, 1997: 443–7.
Flores G, Horwitz RI. Efficacy of beta2-agonists in
bronchiolitis: a reappraisal and meta-analysis. Pediatrics
1997; 100: 233–9.
Garrison MM, Christakis DA, Harvey E, Cummings P,
Davis RL. Systemic corticosteroids in infant bronchiolitis: a meta-analysis. Pediatrics 2000; 105 (4): E44.
Cade A, Brownlee KG, Conway SP, Haigh D, Short A,
Brown J et al. Randomised placebo controlled trial of
nebulised corticosteroids in acute respiratory syncytial
viral bronchiolitis. Arch Dis Child 2000; 82 (2): 126–30.
Bulow SM, Nir M, Levin E, Friis B, Thomsen LL, Nielsen
JE et al. Prednisolone treatment of respiratory syncytial
virus infection: a randomized controlled trial of 147 infants. Pediatrics 1999; 104 (6): e77.
Ledwith CA, Shea LM, Mauro RD. Safety and efficacy of
nebulized racemic epinephrine in conjunction with oral
dexamethasone and mist in the outpatient treatment of
croup. Ann Emerg Med 1995; 25 (3): 331–7.
Waisman Y, Klein BL, Boenning DA, Young GM,
Chamberlain JM, O’Donnell R et al. Prospective randomized double-blind study comparing 1-epinephrine
and racemic epinephrine aerosols in the treatment
of laryngotracheitis (croup). Pediatrics 1992; 89 (2):
302–6.
Fitzgerald D, Mellis C, Johnson M, Allen H, Cooper P,
Van Asperen P. Nebulized budesonide is as effective as
nebulized adrenaline in moderately severe croup. Pediatrics 1996; 97 (5): 722–5.
Wright RB, Pomerantz WJ, Luria JW. New approaches
to respiratory infections in children. Bronchiolitis and
croup. Emerg Med Clin North Am 2002; 20 (1): 93–
114.
Super DM, Cartelli NA, Brooks LJ, Lembo RM, Kumar
ML. A prospective randomized double-blind study to
105
106
107
108
109
110
111
112
113
evaluate the effect of dexamethasone in acute laryngotracheitis. J Pediatr 1989; 115 (2): 323–9.
Geelhoed GC, Macdonald WB. Oral dexamethasone
in the treatment of croup: 0.15 mg/kg versus 0.3 mg/kg
versus 0.6 mg/kg. Pediatr Pulmonol 1995; 20 (6): 362–8.
Klassen TP, Feldman ME, Watters LK, Sutcliffe T, Rowe
PC. Nebulized budesonide for children with mild-tomoderate croup. N Engl J Med 1994; 331 (5): 285–9.
Johnson DW, Jacobson S, Edney PC, Hadfield P, Mundy
ME, Schuh S. A comparison of nebulized budesonide,
intramuscular dexamethasone, and placebo for moderately severe croup. N Engl J Med 1998; 339 (8):
498–503.
Klassen TP, Craig WR, Moher D, Osmond MH,
Pasterkamp H, Sutcliffe T et al. Nebulized budesonide
and oral dexamethasone for treatment of croup: a
randomized controlled trial. JAMA 1998; 279 (20):
1629–32.
Ausejo M, Saenz A, Pham B, Kellner JD, Johnson DW,
Moher D et al. Glucocorticoids for croup. Cochrane
Database Syst Rev 2000; (2): CD001955.
Geelhoed GC, Turner J, Macdonald WB. Efficacy of a
small single dose of oral dexamethasone for outpatient
croup: a double blind placebo controlled clinical trial. Br
Med J 1996; 313: 140–2.
Heffelfinger JD, Dowell SF, Jorgensen JH, Klugman
KP, Mabry LR, Musher DM et al. Management of
community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant
Streptococcus pneumoniae Therapeutic Working
Group. Arch Intern Med 2000; 160 (10): 1399–408.
Irwin RS, Curley FJ. The treatment of cough. A comprehensive review. Chest 1991; 99 (6): 1477–84.
Schroeder K, Fahey T. Systematic review of randomised
controlled trials of over the counter cough medicines for
acute cough in adults. Br Med J 2002; 324: 329–31.
10
Cough and gastrooesophageal reflux
Alvin J. Ing
Gastro-oesophageal reflux
The primary event in gastro-oesophageal reflux
(GOR) is the movement of acid, pepsin and other
noxious substances from the stomach into the oesophagus [1]. In healthy individuals, reflux is a normal,
mostly asymptomatic event. Gastro-oesophageal reflux disease (GORD) is defined as occurring when
reflux leads to symptoms or physical complications.
In most patients this occurs when there is excessive exposure of the distal oesophageal mucosa to refluxed
gastric contents resulting in heartburn, epigastric or
retrosternal discomfort and chest pain [2]. Prolonged
exposure can lead also to oesophagitis, oesophageal
ulceration and its complications such as bleeding or
stricture formation. However, oesophageal reflux
symptoms can also occur without oesophagitis, and
there can be significant reflux without classical
symptoms [3].
GOR has long been associated with pulmonary
symptoms and diseases, many of which present with
cough. These range from bronchopulmonary dysplasia
in the newborn, bronchial asthma, chronic persistent
cough, chronic bronchitis and diffuse pulmonary fibrosis, through to the pulmonary aspiration syndromes,
including lung abscess, bronchiectasis, aspiration
pneumonitis, recurrent pneumonia and eventually respiratory failure [4]. Pulmonary complications may result from either direct micro- and/or macroaspiration,
as well as from both local and centrally mediated reflex
mechanisms.
As a cause of chronic cough, GORD has been documented in many series to be one of the most common
aetiologies, across all age groups [5–7].
The normal antireflux barrier
The lower oesophageal sphincter (LOS), the crural diaphragm and the phreno-oesophageal ligament are considered to be the anatomical structures that play a
major role in the normal antireflux barrier [1]. The intraluminal pressure at the gastro-oesophageal junction
reflects the strength of the antireflux barrier, and reflux
only occurs when this pressure is reduced.
The lower oesophageal sphincter is 2.5–3.5 cm in
length, and is probably part intra-abdominal and
part intrathoracic. It consists of a zone of thickened
muscle with evidence of higher neuronal density than
that of the adjacent oesophagus in animals. The end
expiratory pressure at the gastro-oesophageal junction
at rest is due to the smooth muscle activity of the LOS,
but the LOS pressure can also fluctuate with the migrating motor activity of the stomach. The circular muscle
of the LOS can generate tonic activity, which is influenced by neurogenic, hormonal and myogenic factors
[8,9].
The crural diaphragm, phreno-oesophageal ligament and LOS form an anatomical and physiological antireflux barrier which prevents GOR under
both resting conditions and when increased intraabdominal pressure occurs. The transdiaphragmatic
pressure (Pdi) or the pressure difference between the
stomach and the oesophagus is +4–6 mmHg during
tidal volume expiration, while it is +10–18 mmHg
during tidal volume expiration. During maximal inspiratory efforts, e.g. to total lung capacity, the Pdi can
reach values of 60–80 mmHg [1]. However, GOR
does not result from raised transdiaphragmatic pressure alone. This is because as Pdi increases during
97
CHAPTER 10
inspiration, oesophagogastric junction pressure increases due to contraction of the crural diaphragm. For
GOR to occur, therefore, there must be significant defects in the normal antireflux barrier since increases in
Pdi and intra-abdominal pressures are effectively counteracted by intact antireflux mechanisms.
Pathogenesis of gastro-oesophageal reflux disease
It is currently thought that LOS dysfunction is the
major cause of defective gastro-oesophageal competence and thus reflux, with non-sphincteric mechanisms having a secondary role [2]. The majority of
patients with GORD have normal basal LOS tone. Reflux occurs, however, because of transient relaxation of
this tone, a phenomenon termed transient lower oesophageal sphincter relaxation (TLOSR) by Dent et al.
[10].
Simultaneous measurements of oesophageal pH and
motility have found that, under resting conditions,
LOS sphincter pressure has to be absent for reflux to
occur in normal subjects, both adults and children
[10–12]. In the majority of reflux episodes this is due
to TLOSR, with only a minority of episodes due to
chronic absence of LOS pressure, or reduced basal LOS
tone. TLOSR is likely to be neurally mediated, and triggered by gastric distension, and perhaps pharyngeal
activity [13]. There are also non-sphincteric factors related to occurrence of pathological gastro-oesophageal
reflux. Of particular interest in patients with chronic
persistent cough is increased Pdi during the inspiratory
phase of cough, and raised intra-abdominal pressure
during the compressive and expiratory phases of
cough. In healthy subjects, increased Pdi provokes
GOR only if basal LOS pressure is less than or equal
to 4 mmHg [14], normal resting pressure being 10–
26 mmHg. Reflux was not demonstrated when LOS
was normal, and only occurred in the presence of raised
Pdi when there was TLOSR or swallowing [10].
The relationship between cough and oesophageal reflux, with regard to mechanisms by which cough may
aggravate or precipitate reflux episodes, is not known.
There is no doubt that raised transdiaphragmatic pressure occurs as a result of chronic cough, but this alone is
not sufficient to produce reflux on a background of normal basal lower esophageal sphincter tone [1,10]. Possible mechanisms by which cough may precipitate
reflux include cough stimulating either TLOSR or
swallow-induced sphincter relaxation; as yet neither
98
has been proven, although some animal studies are
suggestive.
Chronic persistent cough
Chronic persistent cough has been the most widely
studied entity in the investigation of the role of GORD
in the pathogenesis of cough. It is defined as cough persisting for at least 3 weeks in patients with a normal
chest X-ray and not on angiotensin-converting enzyme
inhibitors. In multiple series, GOR has been documented to be a cause of chronic persistent cough (either
solely or in combination with bronchial asthma and
postnasal drip) in 38–82% of patients [3,5–7,15–17].
GORD, bronchial asthma and postnasal drip account
either singly or in combination for over 90% of patients
with chronic persistent cough. As a consequence, using
evidence-based guidelines, the American College of
Chest Physicians have published a consensus statement
on the management of cough, including an algorithm
on the evaluation of chronic cough in immunocompetent adults (Fig. 10.1) [18]. At the heart of this algorithm is the principle that, in patients with chronic
persistent cough with a normal chest X-ray, the possibility of postnasal drip, bronchial asthma and GORD
should be evaluated in that order to determine the
underlying aetiology of cough.
Role of GOR in the pathogenesis of cough
Chronic cough secondary to GOR has been associated
with a wide range of disease entities. These can be categorized based on the pathogenesis of the cough.
Gross aspiration or macroaspiration has been documented in many pathologies including recurrent aspiration pneumonia, pulmonary abscess, pulmonary
fibrosis including progressive systemic sclerosis and
cryptogenic fibrosing alveolitis, bronchiectasis and
obliterative bronchiolitis in heart–lung transplant
recipients.
Microaspiration has been documented in patients
with laryngeal inflammation (especially posterior
laryngitis), chronic bronchitis and sinusitis.
Vagally mediated distal oesophageal–tracheobronchial reflex mechanisms have been documented in
patients with chronic persistent cough with otherwise
asymptomatic reflux [19], and patients with bronchial
asthma [20].
COUGH AND GASTRO-OESOPHAGEAL REFLUX
Cough
gone
Chronic cough
Hx
PE
Stop ACE-I
ACE-I
Cough
persists
Chest radiograph
Normal
Abnormal
Abnormality
may not be
related to
cough
Avoid irritant
Cough
gone
Order according to likely
clinical possibility
Sputum cytology, HRCT scan,
modified BaE, bronchoscopy,
cardiac studies
Cough
persists
Treat accordingly
Evaluate for three most common
conditions singly in the following
order, or in combination:
1) PNDS 2) Asthma 3) GORD
Cough
gone
Consider
postinfectious
cough
Cough
persists
Cough
gone
Cough
persists
Evaluate for uncommon
conditions
Sputum tests, HRCT scan,
modified BaE, bronchoscopy, cardiac
studies
Fig. 10.1 Guidelines for evaluating
chronic cough in immunocompetent
adults. ACE-I, angiotensin-converting
enzyme inhibitor; BaE, barium examination; GORD, gastro-oesophageal reflux
disease; HRCT scan, high-resolution
computed tomographic scan; Hx, history;
PE, physical examination; PNDS, postnasal drip syndrome. From [18].
In patients with chronic persistent cough whose
cough is unexplained after a standard diagnostic evaluation, including history and examination, chest X-rays,
laryngoscopy, paranasal sinus X-rays, lung function
testing, bronchial provocation testing and home peak
flow monitoring, cough is commonly associated with
Cough
gone
Cough
persists
Reconsider adequacy of treatment
regimens before considering habit
or psychogenic cough
GOR [18]. In this setting, cough has been shown to be a
result of gastric acid stimulating a distal oesophageal
tracheobronchial reflex mechanism with no evidence
of microaspiration or proximal oesophageal reflux
[19,21]. The afferent pathway is inhibited by the oesophageal instillation of local anaesthetic (4% topical
99
CHAPTER 10
lidocaine), while the efferent pathway is inhibited by
nebulized ipratropium bromide [19]. This reflex arc is
the likely mechanism by which GOR leads to cough in
these patients, although intraoesophageal acid may not
be the sole mediator [21].
The nature of this reflex arc has not been fully elucidated in patients with cough, although in patients with
bronchial asthma there is evidence that GOR may initiate airway inflammation from the oesophagus via axonal reflexes [22]. Axonal reflexes are mediated by
nociceptive afferent nerves that release neurotransmitters which act to trigger an inflammatory response.
Tachykinins including substance P and neurokinin A
are associated with nociceptive afferent nerves and are
potent mediators of bronchospasm and mucus secretion. Whether local axonal reflexes such as this have a
role in the pathogenesis of cough associated with GOR
is unknown, although it is likely to play a role in the development of cough secondary to GOR in patients with
asthma.
There is also growing evidence that central nervous
reflexes may be important in the pathogenesis of GORinduced cough in patients with chronic persistent
cough. An animal model has been developed using
Wistar rats, showing that stimulation of their oesophagus by acid and pepsin resulted in an increase in c-Fos
immunoreactivity in brainstem regions [23,24]. In a
randomized controlled fashion, Suwanprathes et al.
[24] perfused the oesophagus of 10 rats with 0.1 mol/L
HCl and pepsin (3200–4500 IU/mL). The brainstem
was then processed immunohistochemically for detection of c-Fos protein, an immediate-early gene with low
basal CNS expression, which is detected maximally in
CNS neurones 30–45 min after stimulation. This study
found that c-Fos immunoreactivity was significantly
increased in a number of brainstem regions in rats including the nucleus of the solitary tract, medial part
(mNTS), Kolliker–Fuse nucleus (KF), central amygdala
nucleus (CeC), nucleus ambiguus (Amb), retroambigualis nucleus (RA) and paratrigeminal nucleus
(PTN). These areas represent the dorsomedial medulla
(mNTS), dorsolateral medulla (PTN), ventrolateral
medulla (Amb and RA) and forebrain (CeC). Other
studies have found that vagal efferent pathways originate from the RA and Amb, and that the PTN is the
initial processing centre for afferent signals, with a
subpopulation of secondary neurones projecting onto
the NTS and then onto the RA and Amb which possibly
represent the cough efferent centre [25,26]. These stud100
ies therefore suggest that acid and pepsin in the distal
oesophagus may stimulate afferent pathways which
project to the brainstem ‘cough centre’ (including the
PTN, NTS, Amb and RA), which in turn may activate
cough efferent pathways. The applicability of this in
humans remains unknown.
The cough–reflux self-perpetuating cycle
GOR precipitates cough via the mechanisms described
above. A number of investigators have proposed a selfperpetuating positive feedback cycle between cough
and oesophageal reflux, whereby cough from any cause
may precipitate further reflux [18,19,25]. The mechanisms by which GOR is worsened or triggered by cough
are still unknown. Evidence for the existence of this
cycle is found in studies showing that the antitussive action of antireflux therapy is prolonged and is present
long after the antireflux therapy has ceased [27,28].
Clinical presentation
Apart from cough, the clinical presentation in adults is
very much dependent on the underlying aetiology. The
most common clinical syndrome is due to distal
oesophageal–tracheobronchial reflex mechanisms,
and in such patients GOR symptoms such as heartburn,
waterbrash and acid regurgitation are unusual. Between 50 and 77% of patients have no reflux symptoms
[15,29], while the remainder have symptoms only after
the development of cough, suggesting cough as the initiating event in the cough–reflux cycle. In one study,
cough was the sole presenting manifestation of GOR in
nine patients [3]. The cough occurs predominantly during the day, with minimal nocturnal symptoms, as reflux occurs generally in the upright position. This is as a
result of the preservation of the normal reflex which
suppresses TLOSR when supine.
The cough may be productive or non-productive and
is generally longstanding with a mean duration of
13–58 months [3,15,29], the majority of patients recalling its onset after an upper respiratory tract infection. Often the cough has not responded to either
non-specific or specific trials of therapy, and investigations including chest X-rays, lung function testing,
bronchial provocation testing and laryngoscopy have
been unhelpful. GOR in this situation needs to be suspected and initial empirical therapy is appropriate and
COUGH AND GASTRO-OESOPHAGEAL REFLUX
cost-effective [18]. There is also evidence to suggest
that chronic cough from any cause may precipitate
GOR via the cough–reflux self-perpetuating cycle, and
thus GOR should be considered as a contributory cause
of cough in any patients with persistent symptoms despite a specific diagnosis and specific therapy. Chronic
cough has been documented to have multiple causes in
over 25% of patients [18].
In patients with microaspiration, symptoms of GOR
are more prominent and may predate the onset of
cough, implying that cough may not be the initiating
event in this group. Laryngeal symptoms such as dysphonia, hoarseness and a sore throat are also prominent, and laryngoscopy may be abnormal. Posterior
vocal cord inflammation is suggestive of microaspiration, but not diagnostic.
Diagnosis
GOR should be considered if there are typical symptoms or if cough remains unexplained after standard investigations. This should include history, examination,
chest X-ray, pulmonary function studies and laryngoscopy. The diagnosis of GORD is usually made on
the basis of clinical grounds. There is evidence that if
cough remains unexplained after the above investigations, and in particular if postnasal drip and bronchial
asthma have been excluded, then an empirical trial of
antireflux therapy is justified [18] (Fig. 10.2). If empirical therapy fails, it cannot be assumed that GORD has
been excluded as a cause of chronic cough, as empirical
therapy may have been inadequate or medical therapy
may have failed. In such a situation, objective investigation for GORD is recommended, and specifically 24-h
ambulatory oesophageal pH monitoring while on
antireflux therapy. Twenty-four-hour ambulatory oesophageal pH monitoring is well recognized as the most
sensitive and specific investigation for GORD, since
significant and/or symptomatic reflux can occur in the
absence of macroscopic mucosal damage at endoscopy,
and patients may have significant reflux without symptoms other than chronic cough. It is recommended that
pH monitoring should be performed during therapy if
there is failure of cough to respond to empirical antireflux treatment, since the presence of significant acid reflux will indicate inadequate therapy, while the absence
of acid reflux would suggest that GOR is not the cause
of the chronic cough.
The other advantages of pH monitoring of the
oesophagus are that it may demonstrate a temporal
relationship between cough and reflux, as well as quantifying the degree of reflux present (Fig. 10.3). It may be
the only method of diagnosing GOR in up
to 32% of patients with cough [5]. There is evidence
that conventionally used diagnostic indices of GORD,
such as those proposed by De Meester [30], may be misleadingly normal in patients with chronic cough, and
GORD
Symptoms
Chronic cough
No
Cough explained after
‘Anatomic Diagnostic
Protocol’ ?
No
Medical
antireflux
therapy
pH monitoring
readily available?
Yes
GOR
Cough
persists
Yes
Rx underlying
cause
Fig. 10.2 Suggested guidelines for the
evaluation of a patient with chronic
cough and suspected gastrooesophageal reflux disease (GORD).
Cough
persists
pH study to evaluate
oesophageal contact
times and refluxinduced episodes
? Antireflux
surgery
Not GOR
Cough resolves
101
CHAPTER 10
S
C
CC C
C
C
CC
CC
pH
8
7
6
5
4
3
2
1
08:00
12:00
16:00
20:00
Time over 24 h
24:00
04:00
08:00
Fig. 10.3 Twenty-four-hour ambulatory oesophageal pH trace in a patient with cough and gastro-oesophageal reflux disease.
Note temporal association between reflux episodes and cough events (C).
analysis of the temporal relationship between cough
episodes and reflux events may be a more sensitive
indicator [3].
Oesophageal pH monitoring is also indicated in
patients with chronic cough with a proven aetiology,
and when there is a poor response to specific therapy,
since GOR may complicate chronic cough of any cause
[8].
Upper gastrointestinal endoscopy, while necessary to
document oesophagitis, may miss GORD without mucosal changes, and the presence of oesophagitis by itself
does not lead to the establishment of this as a cause of
the cough. For this to occur, a temporal relationship between cough and reflux should be demonstrated. Upper
gastrointestinal endoscopy should, however, be performed if there are typical GOR symptoms, or when the
clinical suspicion of GORD is high, to document the
presence of oesophagitis and to exclude concomitant
pathology such as strictures or Barrett’s oesophagus.
In patients with microaspiration, laryngoscopy may
be abnormal with posterior vocal cord inflammation.
However, a diagnosis of proximal GOR is best made
on 24-h ambulatory oesophageal pH monitoring with
both distal (5 cm above LOS) and proximal (20 cm
above LOS) oesophageal pH probes [31]. Upper
gastrointestinal tract endoscopy, although often
performed to exclude complications of GORD, is less
specific for proximal oesophageal or laryngeal acid
reflux.
There is also evidence that proximal oesophageal reflux and laryngeal reflux may be assessed accurately
utilizing fibreoptic endoscopic evaluation of swallow102
ing and sensory testing (FEESST) [32,33]. This technique uses the delivery of a calibrated air pulse administered to the larynx via a specifically manufactured
laryngoscope. This air pulse stimulates the laryngeal
adductor reflex (LAR), with the normal threshold for
this reflex being 2.5–4.0 mmHg air pressure. In patients
with proximal GOR, the threshold for eliciting the
LAR is increased to above 5.0 mmHg, and is often
greater than 10.0 mmHg.
Patients with gross aspiration should be investigated
with upper gastrointestinal endoscopy to document the
presence and degree of oesophagitis, as well as to exclude strictures, Barrett’s oesophagus and achalasia.
Oesophageal motility studies should be performed to
investigate motility disorders, with standard waterperfused manometry being most accurate. Although
techniques for 24-h ambulatory oesophageal motility
monitoring have been reported, their role is predominantly in the diagnosis of atypical chest pain.
Therapy
Therapeutic trials of medical antireflux therapy in patients with chronic persistent cough and proven GOR
are summarized in Table 10.1. Most of these trials are
uncontrolled, unblinded descriptive studies, and report
response rates of between 64.5% and 100%. Early
studies investigated the role of lifestyle measures and
histamine H2-receptor antagonists (H2-antagonists),
with only one of these studies being a randomized controlled study. Treatment regimes using H2-antagonists
COUGH AND GASTRO-OESOPHAGEAL REFLUX
Table 10.1 Summary of therapeutic trials of antireflux therapy in patients with cough and gastro-oesophageal reflux, not
including proton pump inhibitor trials (see text). From [18].
Study
Intervention
Irwin et al. Am Rev Respir Dis
1981; 123: 413–7
Irwin et al. Am Rev Respir Dis
1989; 140: 294–300
Fitzgerald et al. Can Med Assoc J
1989; 140: 520–4
Irwin et al. Am Rev Respir Dis
1990; 141: 640–7
Ing et al. Am Rev Respir Dis
1992; 144: A11
Dordal et al. Allerg Immunol
1994; 26: 53–8
Waring et al. Dig Dis Sci
1995; 40: 1093–7
Smyrnios et al. Chest 1995; 108:
991–7
Antacid
Cimetidine
Metoclopramide
H2-antagonists
Metoclopramide
Cimetidine
Metoclopramide
H2-antagonists
Ranitidine
Cisapride
Domperidone
PPI
H2-antagonists
Prokinetics
Antagonists
No. of
patients
Study design
Response
rate (%)
Evidence grade
5
PUU
100
Descriptive grade II-3
9
PUU
100
Descriptive grade II-3
20
PUU
70
Descriptive grade II-3
28
PUU
100
Descriptive grade II-3
25
PBC
84
Grade I
55
PUU
64.5
Descriptive grade II-3
25
PUU
80
Descriptive grade II-3
20
PUU
97
Descriptive grade II-3
PUU, prospective, unrandomized, uncontrolled; PBC, prospective, blind, controlled; PPI, proton pump inhibitor.
report response rates of 80–100%, with no correlation
between 24-h ambulatory oesophageal pH monitoring
results and response. There are also no important differences on pH monitoring between partial and complete responders.
The antitussive and antireflux effects of H2antagonists are prolonged, with both cough symptoms
and reflux parameters as measured by repeat 24-h
oesophageal pH monitoring being significantly suppressed for more than 6 weeks after the drug is ceased.
This implies that H2-antagonists break the cough–
reflux self-perpetuating cycle in patients with cough
due to distal oesophageal–tracheobronchial reflex
mechanisms [28].
There have been two published randomized, controlled, blinded trials of the effect of proton pump inhibitors in patients with chronic persistent cough and
GOR. Ours et al. [34] studied 17 patients with chronic
persistent cough and proven GOR on ambulatory oesophageal pH monitoring. They randomized 8 patients
to omeprazole 40 mg p.o. b.d. and 9 patients to placebo
for 12 weeks. They reported that 1 of 8 patients receiving omeprazole and 0 of 9 patients on placebo responded. After 12 weeks, all 17 patients received
omeprazole 40 mg p.o. b.d. for another 4 weeks (open
label medication). The authors then reported that 1 of 8
patients in the initial active treatment group responded,
and 5 of 9 in the initial placebo group responded. There
were no differences noted between the active and placebo groups and between the responders and nonresponders for any GOR parameter (including all
oesophageal pH indices), cough duration or GOR
symptoms. All patients who responded did so within 2
weeks of commencing active therapy. Ours et al. concluded that empirical high-dose proton pump inhibitor
therapy for 2 weeks in all patients with chronic persistent cough not secondary to asthma or postnasal drip
syndrome was a ‘practical and simple approach’ [34].
Kiljander et al. [27] investigated 29 patients with
chronic persistent cough and proven GOR: 21 of 29 patients completed a randomized, double-blind, placebocontrolled crossover trial of omeprazole 40 mg p.o.
daily. Each treatment period was for 8 weeks with a 2week washout period. In the group receiving omeprazole in the first period there was a marked reduction in
cough scores when compared with baseline, and this reduction was maintained in the second or placebo period. In the group receiving omeprazole in the second
103
CHAPTER 10
period there was a marked reduction in cough scores
when compared to baseline and when compared to the
initial placebo period. Kiljander et al. [27] concluded
that omeprazole 40 mg p.o. daily for 8 weeks relieved
GOR-related cough and that the reduction in cough
continued after the treatment period. Maximal response in cough occurred after antireflux therapy was
ceased, and Kiljander et al. [27] concluded that this
supported the existence of a cough–reflux positive feedback cycle.
An empirical trial of proton pump inhibitors would
therefore be appropriate in patients with chronic persistent cough, after asthma and postnasal drip have
been excluded. The duration of therapy, however, remains unclear, with some authors recommending a
minimum therapeutic trial of 4 weeks.
Table 10.2 summarizes the studies investigating the
role of antireflux surgery in patients with chronic persistent cough and GOR. Unfortunately all series are
non-randomized, uncontrolled descriptive studies,
though most are prospective. The definitions of response rates for cough are variable, and range from
84% to 100%. One of the more recent series was reported by Novitsky et al. [35]. They investigated 21 patients with cough proven to be secondary to GOR.
Cough was the sole presentation in 53% and persisted
despite intensive medical therapy including high-dose
proton pump inhibitors and antireflux diet. After fundoplication, 62% of patients reported complete resolu-
tion of cough, and another 24% reported significant
improvement in cough.
Irwin et al. [36] reported a subgroup of 8 of the initial
21 patients that had persistent cough despite total or
near-total acid suppression using proton pump inhibitors, prokinetic agents and antireflux diet (omeprazole 20–80 mg p.o. daily and cisapride 40–80 mg p.o.
daily). These 8 patients had 24-h ambulatory oesophageal pH monitoring while on medical therapy,
and in all patients the percentage of 24 h spent at
pH < 4.0 was zero or near zero. Despite this, all 8 patients underwent antireflux surgery with marked reduction in cough scores after surgery (as measured by
visual analogue scale and Adverse Cough Outcome
Survey), which was maintained after 12 months of
follow-up.
These descriptive studies investigating the effect of
antireflux surgery on cough in patients with proven
GOR suggest that surgery may improve cough that is
resistant to medical therapy, and that the improvement
is sustained. In addition, there is a suggestion that acid
reflux disease in patients with cough and GORD may
be a misnomer since non-acid reflux may be responsible
for cough in some patients (volume reflux with gastric
enzymes, bile salts, etc.).
It is unclear at present if antireflux surgery should
be offered to all patients with cough and proven GOR
who fail intensive medical therapy. In the series
published by Novitsky et al. [35], 14% of patients (3 of
Table 10.2 Summary of trials of antireflux surgery in patients with chronic cough and gastro-oesophageal reflux.
Study
Intervention
Pellegrini et al. Surgery 1979; 86:
110–19
De Meester et al. Ann Surg 1990;
211 (3): 337–45
Giudicelli et al. Ann Chir 1990;
44 (7): 552–4
Thoman et al. J Gastrointest Surg
2002; 6 (1): 17–21
Novitsky et al. Surg Endosc
2002; 16 (4): 567–71
Irwin et al. Chest 2002; 121 (4):
1132–40
Fundoplication
No. of
patients
Study design
Response rate (%)
Evidence grade
5
PUU
100
Descriptive grade II-3
Fundoplication
17
PUU
100
Descriptive grade II-3
Fundoplication
13
PUU
84.6
Descriptive grade II-3
Fundoplication
37
RUU
91
Descriptive grade II-3
Fundoplication
21
PUU
86
Descriptive grade II-3
Fundoplication
8
PUU
100
Descriptive grade II-3
PUU, prospective, unrandomized, uncontrolled; RUU, retrospective, unrandomized, uncontrolled.
104
COUGH AND GASTRO-OESOPHAGEAL REFLUX
21) had no response. The reasons are unclear, but failure to address multiple aetiologies remains possible.
There have been no randomized controlled studies on
antireflux surgery in patients with chronic persistent
cough and GORD, and as a result evidence-based
guidelines for management of refractory cough are
lacking.
A recent development that may help predict response
to surgery is the technique of endoscopic implantation
of biopolymer into the LOS. This involves the injection
of a biopolymer such as Enteryx (ethylene vinyl alcohol) into the muscle of the gastric cardia. Although not
reported in patients with cough and GORD, there have
been reports of its efficacy in patients with GORD in
general. Deviere [37] reported 15 patients with proven
GORD on long-term proton pump inhibitors. After
biopolymer injection, LOS pressure increased in 13 of
15 patients at 1 month, and this was sustained for a median of 6 months. Patients were able to cease proton
pump inhibitors, though 4 of 15 resumed this therapy
eventually. This technique has the potential of being
used to predict the response of patients with cough
and GORD to antireflux surgery, but requires further
evaluation in this specific group.
Summary
1 GORD along with bronchial asthma and postnasal
drip syndrome is one of the three most common causes
of chronic persistent cough.
2 Cough may be the only symptom of GORD.
3 GORD most commonly causes chronic cough via
an oesophageal–bronchial reflex mechanism with
both local and central nervous reflexes likely to be
important.
4 Other components of gastric refluxate apart from
acid are likely to be important in the pathogenesis of
cough.
5 Empirical medical antireflux therapy including
proton pump inhibitors is likely to be successful in
treating the cough in over 80% of patients.
6 Patients who do not respond to empirical medical
therapy should have 24-h ambulatory oesophageal
pH monitoring while on therapy.
7 Antireflux surgery may be useful in patients
refractory to medical treatment, even if acid reflux
is not demonstrated on follow-up oesophageal pH
monitoring.
References
1 Mittal RK. Current concepts of the antireflux barrier.
Gastroenterol Clin North Am 1990; 19 (3): 501–17.
2 Dent J. Recent views on the pathogenesis of gastrooesophageal reflux disease. Bailliere’s Clinical Gastroenterol 1987; 1 (4): 727–45.
3 Irwin RS, Zawacki JK, Curley FJ, French CL, Hoffman PJ.
Chronic cough as the sole presenting manifestation of
gastro-oesophageal reflux. Am Rev Respir Dis 1989; 140
(5): 294–300.
4 Mansfield LE. Gastro-esophageal reflux and respiratory
disorders: a review. Ann Allergy 1989; 62: 158–63.
5 Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation and outcomes of specific therapy. Am
Rev Respir Dis 1990; 141: 640–7.
6 Palombi BC, Villanova CAC, Gastal OL, Stolz DP. A
pathogenic triad in chronic cough: asthma, post nasal drip
syndrome, and gastro-oesophageal reflux disease. Chest
1999; 116: 279–84.
7 McGarvey LP, Forsythe P, Heaney LG, McMahon J, Ennis
M. Bronchoalveolar lavage findings in patients with
chronic nonproductive cough. Eur Respir J 1999; 13 (1):
59–65.
8 Liebermann-Meffert D, Allgower M, Schmid P. Muscular
equivalent of the lower esophageal sphincter. Gastroenterology 1979; 76: 31–8.
9 Tottrup A, Forman A, Uldbjerg N et al. Mechanical properties of isolated human esophageal smooth muscle. Am J
Physiol 1990; 21: G329–37.
10 Dent J, Dodds WJ, Friedman RH et al. Mechanisms of
gastro-oesophageal reflux in recumbent asymptomatic
human subjects. J Clin Invest 1980; 65: 256–67.
11 Mittal RK, McCallum RW. Characteristics of transient
lower esophageal sphincter relaxation in humans. Am J
Physiol 1987; 252: G636.
12 Dent J, Holloway RH, Toouli J, Dodds WJ. Mechanisms
of lower esophageal sphincter incompetence in patients
with symptomatic gastro-esophageal reflux. Gut 1988;
29: 1020–8.
13 Holloway RH, Dent J. Pathophysiology of gastroesophageal reflux: lower esophageal sphincter dysfunction in gastroesophageal reflux disease. Gastroenterol
Clin North Am 1990; 19 (3): 517–35.
14 Stanciu C, Bennett JR. Esophageal acid clearing: One factor in production of reflux oesophagitis. Gut 1974; 15:
852–7.
15 Ing AJ, Ngu MC, Breslin ABX. Chronic persistent
cough and gastro-oesophageal reflux. Thorax 1991; 46:
479–83.
16 Irwin RS, Corrao WM, Pratter MR. Chronic persistent
cough in the adult. The spectrum and frequency of causes
105
CHAPTER 10
17
18
19
20
21
22
23
24
25
26
27
and successful outcome of specific therapy. Am Rev Respir
Dis 1981; 123: 413–7.
Poe RH, Harder RV, Israel RH, Kallay MC. Chronic persistent cough: experience in diagnosis and outcome using
an anatomic diagnostic protocol. Chest 1989; 95: 723–8.
American College of Chest Physicians. Managing cough
as a defence mechanism and as a symptom — a consensus
panel report of the American College of Chest Physicians.
Chest 1998; 114 (2): 133S–181S.
Ing AJ, Ngu MC, Breslin ABX. Pathogenesis of chronic
persistent cough associated with gastro-esophageal reflux.
Am J Respir Crit Care Med 1994; 149: 160–7.
Harding SM. The role of gastro-oesophageal reflux in
chronic cough and asthma. Chest 1997; 111: 1389–402.
Irwin RS, French CL, Curley FJ, Zawacki JK, Bennett FM.
Chronic cough due to gastro-oesophageal reflux. Clinical,
diagnostic and pathogenetic aspects. Chest 1993; 104 (5):
1511–17.
Canning BJ. Role of nerves in asthmatic inflammation and
potential influence of gastro-oesophageal reflux disease.
Am J Med 2001; 111 (Suppl. 8A): 13S–17S.
Suwanprathes P, Hunt G, Breslin A, Ing AJ, Ngu MC.
Identification of brainstem regions involved with coughing: a study using c-Fos immunohistochemistry. Am J
Respir Crit Care Med 2000; 161 (8): Abstract B52.
Suwanprathes P, Hunt G, Seow F, Ing AJ, Ngu MC. Cough
and gastro-oesophageal reflux: evidence for a common
centre in the brainstem. Am J Respir Crit Care Med 2001;
163 (8): Abstract F57.
Bieger D. Muscarinic activation of rhombencephalic neurones controlling oesophageal peristalsis in the rat. Neuropharmacology 1984; 23: 1451–64.
Bieger D, Hopkins DA. Viscerotopic representation of the
upper alimentary tract in the medulla oblongata in the rat:
the nucleus ambiguus. J Comp Neurol 1987; 262: 546–62.
Kiljander TO, Salomaa ERM, Hietanen EK, Terho EO.
Chronic cough and gastro-oesophageal reflux: a double
blind placebo controlled study with omeprazole. Eur
Respir J 2000; 16: 633–8.
106
28 Ing AJ. Cough and gastro-oesophageal reflux. Am J Med
1997; 103 (5A): 91–6.
29 Ing AJ, Ngu MC, Breslin ABX. Chronic persistent cough
and clearance of oesophageal acid. Chest 1992; 102:
1668–71.
30 Johnson LF, De Meester TR. Development of the 24-hour
intra-oesophageal pH monitoring composite scoring system. J Clin Gastroenterol 1986; 8 (Suppl. 1): 52–8.
31 Paterson WG, Murat BW. Combined ambulatory oesophageal manometry and dual-probe pH-metry in evaluation of patients with chronic unexplained cough. Dig Dis
Sci 1994; 39 (5): 1117–25.
32 Phua SY, McGarvey LPA, Peters MJ, Breslin ABX, Ing AJ.
Assessing laryngeal sensitivity of patients with chronic
cough and gastro-oesophageal reflux using fibreoptic endoscopic evaluation of laryngeal sensitivity. Am J Respir
Crit Care Med 2002; 165 (8): A406.
33 Aviv JE, Parides M, Fellowes J, Close LG. Endoscopic
evaluation of swallowing as an alternative to 24-hour pH
monitoring for diagnosis of extra-oesophageal reflux.
Ann Otol Rhinol Laryngol 2000; 184 (Suppl.): 25–7.
34 Ours TM, Kavuru MS, Schilz RJ, Richter JE. A prospective evaluation of oesophageal testing and a double blind,
randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol
1999; 94: 3131–8.
35 Novitsky YW, Zawacki JK, Irwin RS, French CT, Hussey
VM, Callery MP. Chronic cough due to gastrooesophageal reflux disease: efficacy of antireflux surgery.
Surg Endosc 2002; 16 (4): 567–71.
36 Irwin RS, Zawacki JK, Wilson MM, French CT, Callery
MP. Chronic cough due to gastro-oesophageal reflux disease: failure to resolve despite total/near total elimination
of oesophageal acid. Chest 2002; 121: 1132–40.
37 Deviere J, Pastorelli A, Louis H, de Maertelaer V, Lehman
G, Cicala M, Le Moine O, Silverman D, Costamagna G.
Endoscopic implantation of a biopolymer in the lower oesophageal sphincter for gastro-oesophageal reflux: a pilot
study. Gastrointest Endosc 2002; 55 (3): 335–41.
11
Cough in postnasal drip,
rhinitis and rhinosinusitis
Bruno C. Palombini & Elisabeth Araujo
Introduction
In 1998 the Consensus Panel Report of the American
College of Chest Physicians (ACCP) stated that ‘the
most common causes of chronic cough in non-smokers
are postnasal drip syndrome (PNDS), asthma and/or
gastro-oesophageal reflux disease (GORD), whether or
not the cough is described as dry or productive’
[1–4].
The incidence of PNDS in chronic cough is disputed,
with published values ranging from 2 to 57% It
seems far more common in the US than in Europe [5].
The reasons for this variation may be social or semantic. Few studies were randomized, and selection of
patients might depend on the reputation and interests
of the investigator. In almost none of the studies was
cough measured, either subjectively or objectively, or
even defined to distinguish between true cough and
huff.
Postnasal drip syndrome
According to the ACCP [3], the diagnosis of PNDS
largely rests on the patient reporting certain symptoms
or sensations. Since PNDS is a syndrome, and since
there are no pathognomonic findings to prove its presence, the diagnosis of postnasal drip-induced cough is
best determined by considering a combination of criteria, including symptoms, physical examination, radiographic findings, and ultimately, response to specific
therapy.
A favourable response to specific therapy for PNDS
with resolution of cough is a crucial step in confirming
that PNDS was present and that it was the aetiology of
the cough.
Cough initiated at the upper respiratory tract is usually produced by stimulation of pharyngeal branch
nerve endings (vagal branches). It is speculated that the
cough in PNDS may be caused by chemical or mechanical irritation of receptors located in the larynx and/or
pharynx [1,2], Proctor [6] claims that, in patients with
purulent rhinosinusitis, secretions are aspirated into
the trachea and bronchi during the night, a process
which is further stimulated by the reduction in mucociliary activity. Bucca et al. [7] have demonstrated an
increase in the extrathoracic reactivity of airways
mediated by pharyngobronchial reflexes following
drainage of upper airway secretions.
Clinical studies suggest that the pathogenesis of
cough from PNDS is due to mechanical or chemical
stimulation of the afferent limb of the cough reflex
in the upper airway. This stimulation is secondary to
secretions emanating from the nose and/or sinuses
dripping down into the hypopharynx. A number of
conditions can cause PNDS. The differential diagnosis includes seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, vasomotor
rhinitis, postinfectious rhinitis, chronic (bacterial)
rhinosinusitis, allergic fungal rhinosinusitis, nonallergic rhinitis due to medication abuse or environmental irritants, and non-allergic rhinitis associated
with pregnancy [6–8].
In addition to this clinical presentation, there is usually a history of rhinosinopathy. These clinical findings
are relatively sensitive, but not specific for diagnostic
purposes [3,4]. In addition to cough (which is productive in 50% of cases), Villanova et al. [8,9] have found
107
CHAPTER 11
that throat-clearing (66.7%) and pharyngeal aspiration (26.7%) are the two most common clinical manifestations in PNDS patients [3,4,8,9].
When chronic cough results from a multicausal association, diagnosis is usually based on the recently described pathogenic triad of chronic cough (asthma,
PNDS and gastro-oesophageal reflux (GOR)) [9,10].
The clinical presentation of patients with PNDS, in
addition to cough, commonly involves complaints of
a sensation of something dripping into the throat
(drainage in posterior pharynx), a need to clear the
throat, a tickle in the throat or nasal congestion and/or
nasal discharge [6]. Patients sometimes complain of
hoarseness. Cough can also occur with talking, but this
is a non-specific complaint associated with essentially
all causes of cough. A history of upper respiratory illness (a cold) is often present. A history of wheeze is also
common. Most patients with PND-induced cough will
have symptoms or evidence of one or more of the following: drainage in posterior pharynx, throat-clearing,
nasal discharge, cobblestone appearance of the
oropharyngeal mucosa and mucus in the oropharynx.
These clinical findings are relatively sensitive, but they
are not specific. They are also found in many patients
with cough due to other causes [1–4].
Pharyngeal aspiration
and throat-clearing
PNDS has been described and discussed in several studies and publications. It is caused by disorders affecting
the nasal fossae, pharynx and paranasal sinuses. Cough
in PNDS may be triggered by numerous stimuli, and in
most cases the aetiopathogenesis is clear. Cough is undoubtedly associated with certain conditions such as
bronchopneumonia, bronchiectasis, bronchial cancer,
tuberculosis, use of angiotensin-converting enzyme
(ACE) inhibitors, lung fibrosis and asthma. However,
cases with multiple or obscure aetiopathogenesis pose a
challenge. For these situations, it is useful to discuss
some recent advances [9,10].
One of the characteristics of non-productive cough is
that it is not associated with expectoration and does not
present the clinical signs of pharyngeal aspiration (PA)
or throat-clearing (TC).
On the other hand, chronic productive cough is frequently observed in smokers, since smoking is often associated with both emphysema and chronic bronchitis.
108
However, this type of productive cough does not present signs of PA, since there is little association between
smoking and chronic rhinosinusitis. In turn, signs of
TC are frequently found in smokers with productive
cough.
Inspiratory signs of PA, even when present in smokers, do not present a cause-and-effect association with
smoking. Signs of PA strongly suggest the presence of
chronic suppurative foci in the upper airway. In other
words, since smoking does not prevent smokers from
having rhinosinusitis, some smokers may simultaneously present signs of PA (due to rhinosinusitis) and
signs of TC (secondary to chronic smoker’s bronchitis).
Figure 11.1 shows cinematography images of pharyngeal aspiration and throat-clearing.
Preliminary results of research concerning the meaning of these clinical signs have already become available. Recent studies in Brazil have employed injection
of barium contrast in the nasal fossae followed by
pharyngeal aspiration and throat-clearing with simultaneous radioscopy with digital subtraction [11].
Concerning the drainage of upper airway secretions,
preliminary impressions suggest that the pharynx may
act as a pump, with inspiration and expiration movements, and its lumen may go from expanded dimensions (inspiration) to a small volume (expiration) (see
Fig. 11.1).
Another major characteristic associated with the
basic physiopathogenic mechanism of PA and TC is the
possibility of airway vibration, also found in other
PND manoeuvres in general. The physical characteristics of such vibration and its role in clearing the airways
are still uncertain.
One of the objectives of the present chapter is to provide tools to general practitioners, pneumologists and
paediatricians to support the diagnosis of chronic
cough using simple rules. Basically, the objective is to
provide further knowledge regarding PA and TC.
Figure 11.1 shows the results of radiological studies
with forced inspiration, characterizing signs of PA, and
forced expiration, constituting signs of TC. The clinical
recognition of these signs is easy, and they have great
diagnostic value, dispensing with expensive diagnostic
procedures that often delay treatment (for example,
computed tomography (CT) of paranasal sinuses and
pharynx and/or fibreoptic nasal endoscopy).
Therefore, the need to train resident physicians
to perform the differential diagnosis of chronic productive cough is underscored, highlighting the dif-
COUGH IN POSTNASAL DRIP
Fig. 11.1 Cinematography images
obtained through digital subtraction
fluoroscopy and schematic illustrations: pharyngeal aspiration and
‘throat-clearing’.
ference between a strong indication of rhinosinusitis
(manifested as signs of PA), and an indication of chronic bronchitis, suggested mainly by the presence of signs
of TC.
Figure 11.2 shows the most common causes of
chronic cough according to clinical presentation, with
emphasis on the signs of PA and of TC.
The signs of PA are the most frequent inspiratory/
vibratory manoeuvres observed in patients with chronic suppuration of paranasal sinuses, especially rhinosinusitis. The soft palate is dislocated backwards and the
patient, taking a deep breath, makes it vibrate, causing
the secretions in this recess to pass into the oropharynx
where they are swallowed or expectorated.
The expiratory/vibratory signs of TC correspond to
an expiratory clearing of the hypopharynx and larynx,
with dislocation of secretions from either the lower respiratory tract (for example, in chronic bronchitis and
bronchiectasis) or the upper respiratory tract (rhinosinusitis and its variants). The resulting action is similar
to that of a ‘force pump.’ After a throat-clearing manoeuvre, the individual swallows the secretions, either
through the nasal cavities or through the mouth
(Fig. 11.1).
It is important to keep in mind that expiratory signs
of TC are typical of smokers with chronic bronchitis
and/or bronchiectasis. However, this sign is also detectable in cases of cough secondary to isolated rhinosinusitis or rhinosinusitis associated with chronic
bronchitis and bronchiectasis.
It is not clear why some individuals presenting with
PNDS have chronic cough and others do not. It is possible that patients who cough also present lesions that
cause hypersensitivity in the afferent limbs of the cough
reflex.
Since a recent publication demonstrates that an
aetiopathogenic triad must be considered in cases of
chronic cough of unknown origin (rhinosinusitis, GOR
and bronchial hyperreactivity), it is important to rely
on laboratory tests for diagnostic purposes in this case
also [9,10].
As discussed above, PNDS is associated with inflammatory processes such as rhinitis, rhinosinusitis and
adenoids, and also with anatomical alterations such
as infected concha bullosa [1–3]. GOR, asthma and
smoking may also lead to PNDS due to the irritating
effect of the reflux on the pharynx [8–14].
In our hospital, we follow some diagnostic guidelines
aimed at helping respiratory disease physicians, general practitioners and paediatricians diagnose PNDS:
1 most patients with chronic productive cough associated with signs of PA have rhinosinusitis;
2 most patients with chronic productive cough associated with signs of TC have chronic bronchitis (with
or without rhinosinusitis);
3 most patients with productive cough associated with
signs of TC and of PA have rhinosinusitis alone or rhinosinusitis associated with bronchitis;
4 patients with non-productive or mildly productive
cough associated with signs of TC may have GOR;
5 patients with wheezy non-productive cough may
have cough-variant asthma.
109
CHAPTER 11
Non-productive
chronic cough
Tuberculosis
Bronchial cancer
Lung fibrosis
Bronchial hyper-reactivity
Use of ACE inhibitors
Productive
chronic
cough
COPD
Bronchiectasis
Lung abscess
Non-productive
chronic cough
Bronchial hyper-reactivity
Gastro-oesophageal reflux
ACE treatment
Chronic cough
With obvious
pathogenic
factors
Sign of pharyngeal aspiration
Present
Absent
Chronic
rhinosinusitis with
chronic bronchitis
Chronic bronchitis
Absent
Productive
chronic cough
Sign of throat clearing
Present
Without obvious
pathogenic
factors
Chronic
rhinosinusitis
Bronchial cancer
Tuberculosis
Fig. 11.2 Pathogenetic routes of the most common types of chronic cough and some accompanying signs.
These clinical findings are relatively sensitive, but
not specific for diagnostic purposes [3,4]. In addition
to chronic cough (which was productive in 50% of
cases of chronic cough, in adults), Villanova et al.
[8,9] have found that the signs of TC were positive in
66.7% and signs of PA in 26.7%. These were the two
most common clinical manifestations in patients with
PNDS.
Rhinitis
The concept of rhinitis implies inflammation of the
nasal mucosa. Clinical diagnosis is based on the pres110
ence of the following symptoms: pruritus, sneezing,
rhinorrhoea and nasal obstruction.
Patients with rhinitis can be divided into ‘sneezers
with a runny nose’ and those with a ‘stuffy nose.’
Cough is more frequently associated with increased
secretion, especially thicker secretion with posterior
drainage. The presence of secretion with inflammatory
mediators results in stimulation of receptors present in
the nasal mucosa that are innervated by the trigeminus
and of receptors found in the posterior pharynx innervated by the glossopharyngeus.
Infectious rhinitis is the most common cause of acute
cough. Viral infections due to rhinovirus, influenza and
parainfluenza induce the activation of several types of
COUGH IN POSTNASAL DRIP
cells, including nasal epithelial cells, and the release of
several types of cytokines. The frequency of cough is
higher in the first 48 h, when it is detected in 83% of the
patients [3], and decreases gradually to 26% on the
14th day. Cough associated with viral infections starts
out ‘short’, dry and infrequent; its intensity and frequency may increase quickly. With evolution of the
viral status, clear and mucoid secretion may appear,
with the cough becoming gradually thicker and assuming a whitish or yellowish colour until spontaneous resolution. Infectious rhinitis is the most common form of
rhinitis. It is caused by the proliferation of microorganisms in the nasal mucosa alone or in association with
other forms of rhinitis. Bacteria such as Streptococcus
pneumoniae and Haemophilus influenzae are the most
common. About 11–25% of the patients complain of
cough more than 3 weeks after upper airway infections;
this is known as postinfectious cough [3].
Allergic rhinitis is induced by IgE-mediated inflammation. It may be reversed spontaneously or with treatment. It may also be subdivided into intermittent or
persistent types. Allergic rhinitis is characterized by
nasal obstruction, rhinorrhoea, sneezing, nasal pruritus and postnasal drip. It is important to identify the exposure to allergens. There may be a history of exposure
to specific allergens, such as pollen or animal fur. The
association of cough with feather pillows, rooms with
curtains or carpeting, and the presence of cats and dogs
must be investigated.
Some situations of cough associated with postnasal
drip result in occupational rhinitis from inhalation of
allergens in work settings.
A careful investigation may reveal rhinitis medicamentosa (drug-induced rhinitis), which may be caused
by misuse of the medication employed to treat rhinitis
[15]. The overuse of topical vasoconstrictors or systemic drugs (especially aspirin and other non-steroidal
antihypertensive agents (such as reserpine, methyldopa
or guanethidine, and nifedipine) can cause rhinitis and
persistent dry cough, possibly because these drugs interfere with a-adrenergic activity [16].
In endocrinological or hormonal rhinitis, nasal
symptoms result from alterations in the nasal blood
flow and/or in glandular reactivity in conditions such as
pregnancy, menopause, puberty or hypothyroidism
[17,18]. The cough usually disappears after delivery or
after hormonal stabilization.
Irritant rhinitis is caused by exposure of the nasal
mucosa to harmful substances such as tobacco smoke
or sulphur dioxide; it can also be induced by exposure
of the nasal mucosa to cold dry air, with the release of
chemical basophil mediators. Irritant rhinitis is characterized by clear rhinorrhoea, postnasal drip with nasal
congestion and minimal sneezing. The duration and
intensity of the cough associated with irritant rhinitis
depends on the inflammatory response, with activation
of mast cells and occurrence of late-phase reaction. In
children, passive smoking may exacerbate chronic
cough.
Idiopathic rhinitis is characterized by nasal symptoms caused by vasomotor/secretory instability in the
absence of a well-defined cause. It may be associated
with either vasoconstriction or enhanced secretion
[12,13]. Non-specific nasal hyperreactivity may be
associated with pharyngeal hyperreactivity, causing
cough due to nasopharyngeal irritation.
Persistent non-allergic rhinitis in association with
eosinophilia is a heterogeneous syndrome consisting
of at least two categories: non-allergic rhinitis with
eosinophilia syndrome, and aspirin intolerance. It is
often characterized by the presence of nasal eosinophilia and perennial symptoms, such as sneezing, itching,
rhinorrhoea, postnasal drip, signs of PA and nasal obstruction, without allergy [19].
Evaluation
The clinical presentation of patients with rhinitis-associated cough includes non-specific signs and symptoms.
Whenever the aetiology of rhinitis is not clear, and in
cases of persistent cough or signs of PA, patients must
undergo laboratory investigation. Laboratory assessment is performed in order to determine atopic status
and to identify the probable aetiological agent as well
as other conditions frequently associated with allergic
rhinitis [20]. The presence of specific IgE antibodies
should be demonstrated by means of in vivo (skin testing) and/or in vitro (radioallergosorbent test, RAST)
testing. Nasal endoscopy using rigid or flexible fibreoptic endoscopes certainly constitutes an important diagnostic tool, and should be performed prior to CT, since
they are complementary procedures [18].
Treatment
The objective of clinical rhinitis treatment is to restore
nasal function in order to maintain the functional integrity of the entire airway. Treatment must be individ111
CHAPTER 11
ualized and extended to associated infectious and
mechanical complications. Important points include
cleanliness of physical environment, pharmacotherapy
and specific immunotherapy.
The drugs used to treat allergic rhinitis-associated
cough include antihistamines, oral and topical vasoconstrictors, ipratropium bromide, disodium chromoglycate, nedochromil sodium, and oral and topical
corticosteroids. These drugs can be used either in isolation or in association [13].
Rhinosinusitis
As previously mentioned, rhinosinusitis is caused by
inflammation of the mucosa lining the nasal cavity
and PNS. Rhinitis may occur in isolation, but cases of
sinusitis without associated rhinitis are rare.
Rhinosinusitis is a major public health problem,
affecting approximately 14% of the worldwide adult
population, and this prevalence has been increasing
[12].
Diagnosis
Acute rhinosinusitis is one of the most common
reasons for medical appointments. Between 0.5% and
5% of the viral infections affecting the upper airways
result in acute rhinosinusitis. A differential diagnosis
with viral infection is often difficult, since most symptoms (nasal obstruction, rhinorrhoea, hyposmia, facial
pressure, PND, signs of PA, cough and fever) are nonspecific. Certain symptoms, such as fever, halitosis and
hyposmia, considered as minor symptoms in adults,
might be the sole indication of rhinosinusitis in children
[13].
In chronic rhinosinusitis, chronic cough (lasting
longer than 3 weeks) and purulent or mucopurulent expectoration, as well as signs of PA, are common findings, without evidence of suppurative foci in the lower
airways [9,10]. The time of the day in which the cough
appears is also an important indication for its origin.
Productive cough appearing at night and on waking
up indicates rhinosinusitis. Between 18 months and 6
years of age, rhinosinusitis is the most frequent cause of
chronic cough. Between 6 and 16 years, it is associated
with asthma-variant cough and psychogenic cough as
the most common causes of chronic cough.
For adults with chronic cough due to PND, rhinosi112
nusitis is the cause in 30–60% of cases. Less frequent
causes are some forms of rhinitis, such as allergic,
postinfectious, vasomotor, perennial, non-allergic and
drug-induced rhinitis [12].
In non-allergic and non-infectious rhinosinusitis, the
common cold (acute coryza) deserves special attention.
Primary symptoms include mouth dryness and nasal
pruritus/itch, followed by dryness and pain in the
throat, sneezing, watery coryza and constitutional
symptoms (febricula, indisposition). After 2 or 3 days,
a secondary infection occurs, with nasal obstruction
and purulent secretions, non-productive cough, febricula and muscle pain lasting for 5–10 days [13].
When chronic cough results from a multicausal
association, diagnosis is usually based on the recently
described [8–10] pathogenic triad of chronic cough
(asthma, PND, GOR) (Fig. 11.3). Over 50% of the
cases of chronic cough are related to this triad. In order
to recognize this condition, in addition to CT of the
PNS, oesophageal pH-metry (detection of oesophageal
reflux) and spirometry with or without bronchoprovocation testing (diagnosis of asthma without wheezing)
should be performed [9,10].
Traditional nasal evaluation with a frontal light
source and nasal speculum provides only limited information. Rigid and flexible fibreoptic endoscopes allow
for a direct and systematic evaluation of nose areas. Endoscopy must be considered whenever the patient presents with severe and persistent cough, despite clinical
treatment [17]. The presence of cough is often related
to drainage of purulent secretions in the nasopharynx
Asthma
12
16
13
Postnasal drip
syndrome
12
4
4
10
Gastro-oesophageal
reflux disease
Fig. 11.3 Aetiological factor in 78 cases of chronic cough:
15.4% of the patients had three simultaneous causes; 26%
had two causes; 35% had one single cause. From [8].
COUGH IN POSTNASAL DRIP
originating at the draining ostia of the maxillary,
ethmoid and sphenoid sinuses. In such situations, our
experience has shown the presence of thick pharyngeal secretion at endoscopy, despite the fact that some
patients refer to having dry cough.
Generally, the diagnostic relevance of simple radiographs is controversial, since radiological abnormalities in the ethmoid and sphenoid sinuses, frontal recess
and osteomeatal complex may go unnoticed. A normal
result in a simple radiograph is not sufficient to rule out
the presence of rhinosinusitis. In children, it is important to underscore that the younger they are the greater
the radiological limitations imposed [17,18].
CT is the preferred method for assessing PNS because it clearly shows the relationship between soft
tissues and bones. CT allows for a specific diagnosis
and for the identification and systematic evaluation of
anatomical areas that are inaccessible to conventional
radiological tests (Fig. 11.4) [18,19].
Approximately 70% of the cases of acute rhinosinusitis are caused by Streptococcus pneumoniae and
Haemophilus influenzae. In chronic rhinosinusitis,
bacteriological studies demonstrate a predominance of
polymicrobial flora and anaerobes, due to the reduced
oxygen concentration in the PNS. Fungi (Aspergillus,
Candida albicans and Alternaria) are isolated in
3–10% of cases of chronic rhinosinusitis [20].
The main aetiological agent of infection in the airways is S. pneumoniae. Recent studies show that ap-
Fig. 11.4 Computed tomography section (coronal view)
showing bilateral ethmoid and maxillary opacification, with
obstruction of the aorta.
proximately 20% of the strains present intermediate
resistance to penicillin; high resistance was observed in
approximately 1%. With regard to other microorganisms, b-lactamase was found in approximately 10%
of H. influenzae strains and in more than 90% of
Moraxella catarrhalis [15,16].
A favourable response to specific therapy, with resolution of cough, is a crucial stage in confirming the
association of bacteria with cough.
Cases of chronic cough caused by chronic rhinosinusitis or sinusitis resistant to treatment should be referred to an otorhinolaryngologist for investigation of
structural abnormalities of the osteomeatal complex,
hypertrophy of adenoids, septal deviation and dental
abscess [15].
References
1 Irwin RS. Cough. In: Irwin RS, Curley FJ, Grossman RF,
eds. Diagnosis and Treatment of Symptoms of the Respiratory Tract. New York: Futura Publishing Co., 1997:
1–54.
2 Irwin RS, Madison JM. The diagnosis and treatment of
cough. N Engl J Med 2000; 343: 1715–21.
3 Irwin RS, Boulet LP, Cloutier MM, Fuller R, Gold PM,
Hoffstein V et al. Managing cough as a defense mechanism
and as a symptom — a consensus panel report of the
American College of Chest Physicians. Chest 1998; 114
(2 Suppl. Managing): 133S–81S.
4 Irwin RS, Curley FJ, French CL. The spectrum and frequency of causes, key components of the diagnostic evaluation and outcome of specific therapy. Am Rev Respir Dis
1990; 141: 640–7.
5 Morice AH. Epidemiology of cough. Pulm Pharmacol
Ther 2002; 15: 253–60.
6 Proctor DF. Nasal physiology and defense of the lung. Am
Rev Respir Dis 1977; 115: 97–102.
7 Bucca C, Rolla G, Scappaticci E, Chiampo F, Bugiani M,
Magnano M et al. Extrathoracic and intrathoracic airway
responsiveness in sinusitis. J Allergy Clin Immunol 1995;
95: 52–9.
8 Villanova CA, Palombini BC, Pereira EA, Stolz DP, Gastal
OL, Alt DC et al. Post-nasal drip syndrome as a cause of
chronic cough: its place among other conditions. Am J
Respir Crit Care Med 1996; 153: A517.
9 Palombini BC, Villanova CA, Araújo E, Gastal OL, Alt
DC, Stolz DP et al. A pathogenic triad in chronic cough —
asthma, postnasal drip syndrome, and gastroesophageal
reflux disease. Chest 1999; 116 (2): 279–84.
10 Palombini BC, Villanova CA, Araújo E, Gastal OL, Alt
113
CHAPTER 11
11
12
13
14
DC, Stolz DP et al. A pathogenic triad in chronic cough —
asthma, post-nasal drip syndrome, and gastroesophageal
reflux disease. Chest 1999; 116 (2): 279–84. (Quotation
in the Journal Watch (General), N Engl J Med 1999; 19
(19): 155.)
Irion KL, Porto NS, Palombini BC, Letti N, Pereira EA,
Fraga JC et al. Documentação radiológica da falência
eventual dos mecanismos supostamente capazes de evitar
aspiração para traquéia das secreções faríngeas durante as
manobras da tosse, da aspiração faríngea e do pigarrear
[abstract]. J Pneumologia 1992; 18 (1): 33.
Madison JM, Irwin RS. Cough. In: Albert R, Spiros S,
Jett J, eds. Comprehensive Respiratory Medicine.
London: Mosby, 1999: 15.1.
Mitchel D. Rhinitis and sinusitis. In: Albert R, Spiros
S, Jett J, eds. Comprehensive Respiratory Medicine.
London: Mosby, 1999: 31.1.
Palombini BC, Pereira EA, Alves MR, Irion KL. The
need to recognize new and accurate symptoms and signs in
the diagnosis of sinobronchitis: the qualification of their
114
15
16
17
18
19
20
sensitivity and specificity [abstract]. Am Rev Respir Dis
1992; 145 (4): 301.
Brandileone MC, Di Fabio JL, Vieira VS, Zanella RC,
Casagrande ST, Pignatari AC et al. Geographic distribution of penicillin resistance of Streptococcus pneumoniae
in Brazil: genetic relatedness. Microb Drug Resist 1998; 4
(3): 209–17.
Naclerio RM, Proud D, Togias AG, Adkinson NF Jr,
Meyers DA, Kagey-Sobotka A et al. Inflammatory mediators in late-phase antigen-induced rhinitis. N Engl J Med
1985; 313: 6570.
McCaffrey TV. Rhinologic Diagnosis and Treatment.
New York: Thieme, 1997.
Mackay I, ed. Rhinitis — Mechanisms and Management.
London: Royal Society of Medicine, 1989.
Kennedy DW. International conference on sinus disease:
terminology staging therapy. Ann Otol Rhinol Laryngol
1995; 104 (10).
Mackay IS, Durham SR. Perennial rhinitis. Br Med J 1998;
316: 917–20.
12
Cough and airway
hyperresponsiveness
Paul M. O’Byrne
Introduction
Asthma is a disease which is identified by the presence
of characteristic symptoms and by the demonstration
of variable airflow obstruction, either spontaneously,
or improving as a result of treatment. The symptoms of
asthma are dyspnoea, wheezing, chest tightness and, in
many patients with persistent asthma, troublesome
cough. Cough has been recognized as a symptom of
asthma since the earliest descriptions of the disease.
Persistent cough in asthma is often, but not always, associated with the presence of airflow obstruction, and
associated with other asthma symptoms. The presence
of persistent cough, with or without sputum production, even when the only asthma symptom, is an indication of poor asthma control [1].
eosinophils have shown morphological features of activation as indicated by heterogeneity of the granular
structure or as eosinophil granules released from
eosinophils lying free in the mucosal interstitium [6].
Increased numbers of activated T lymphocytes have
also been shown in several studies [7], together with increased number of mast cells in the airway mucosa exhibiting various stages of degranulation [8]. The extent
and severity of the airway inflammation increases at
times when asthma is unstable and poorly controlled,
with increased numbers of airway eosinophils and/or
neutrophils [9]. As will be discussed later, the presence
of persistent airway inflammation is likely to be responsible not only for asthma symptoms, including cough,
but also for the structural changes and the associated
physiological abnormalities of asthma.
Airway inflammation and asthma
Airway hyperresponsiveness in asthma
Asthma is an airway inflammatory disease, with inflammation present even when asthma is stable and
well controlled. This has been shown in studies which
have provided information on airway cell populations
in mild stable asthmatics with ongoing and persistent
airway hyperresponsiveness [2,3]. Common findings in
all of these studies are the presence of increased numbers of inflammatory cells such as eosinophils, lymphocytes and mast cells compared with normal control
subjects with normal airway responsiveness. The
eosinophils have shown signs of activation, as indicated by increased airway levels of granular proteins,
major basic protein (MBP) [4] and eosinophil cationic
protein (ECP) [5]. In the bronchial mucosa the
Airway responsiveness is a term which describes the
ability of the airways to narrow after exposure to constrictor agonists. Airway hyperresponsiveness is an
increased ability to develop this response and consists
of the ability of a smaller concentration of an agonist
needed to initiate the bronchoconstrictor response
(increased sensitivity of the airways), a steeper slope of
the dose–response curve (increased reactivity of the airways), as well as a greater maximal response to the agonist (Fig. 12.1). The initial description of an increased
responsiveness of asthmatic airways was made by
Alexander and Paddock in 1921 [10], who demonstrated an ‘asthmatic breathing’ in asthmatic subjects, but
not normals, after subcutaneous administration of the
115
CHAPTER 12
Asthmatic
50
FEV1 (% change)
40
Mild asthmatic
30
(c)
20
(b)
Normal
10
0
(a)
0.25 0.5 1
2 4 8 16 32 64 128 256
Concentration (mg/mL)
Fig. 12.1 The change in FEV1 vs. baseline, induced by increasing doses of a bronchoconstrictor stimulus (methacholine) in mild, moderate and severe asthmatics vs. healthy
individuals. The PC20 value is calculated by interpolating a
20% fall in FEV1 to the log–linear dose–response curve for
each individual. Asthmatic subjects have a reduced threshold
response (a), indicating increased sensitivity of the airways;
an increased slope (b), indicating increased reactivity of the
airways; and an increased maximal response (c).
cholinergic agonist pilocarpine. This observation was
confirmed by Weiss et al. [11], who reported that
asthmatic subjects, but not normals, developed
bronchoconstriction after being given intravenous
histamine. Later Curry [12] described an increased
bronchoconstrictor response to histamine that occurred with intramuscular, intravenous and nebulized
histamine, again only in asthmatic subjects. Tiffeneau
and Beauvallet [13] were the first to describe the use of
acetylcholine inhalation tests to determine the degree of
airway responsiveness in asthmatics. Airway hyperresponsiveness is often considered to be non-specific, in
that asthmatic subjects will develop bronchoconstriction after exposure to many different chemical stimuli
such as histamine [14], the cholinergic agonists methacholine [15] and carbachol [16], cysteinyl leukotrienes
(LT) C4 and D4 [17], and prostaglandins (PG) D2 [18]
and PGF2a [19]. This is to contrast the specific airway responses that develop when subjects inhale substances,
such as allergens [20] or occupational sensitizing agents
[21], to which they have become sensitized. The term
non-specific airway hyperresponsiveness can, however,
be misleading. It suggests that a common mechanism
exists by which these pharmacological or physical
116
stimuli cause bronchoconstriction. This is clearly not
the case, as most of the pharmacological agents act on
specific receptors in the airways, and the mechanisms
by which receptor activation causes bronchoconstriction are different for different agents. However, as each
of these chemical bronchoconstrictors activates specific
receptors, they are considered to be ‘direct-acting’
stimuli. In addition, some stimuli such as exercise [22],
hyperventilation of cold, dry air [23], both hypotonic
and hypertonic solutions [24], and mannitol [25] also
cause bronchoconstriction in asthmatics. In contrast to
the direct-acting stimuli, these cause release of bronchoconstrictor mediators, such as histamine [26] and
cysteinyl leukotrienes [27], in the airways, and therefore are called ‘indirect-acting’ stimuli.
In studies of populations of asthmatic patients, the
severity of airway hyperresponsiveness has been shown
to correlate with the severity of asthma [14] and with
the amount of treatment needed to control symptoms
[28]. A variety of methods of measuring airway responsiveness have been reported, and the clinical significance and the effects of antiasthma medications on
these measurements, and the pathophysiology and
pathogenesis of airway hyperresponsiveness in asthmatic patients have been extensively studied. As a result
of this research, the methods of its measurement have
been standardized, and are widely accepted. Almost all
patients with symptomatic asthma have airway hyperresponsiveness [14], and for this reason the absence of
airway hyperresponsiveness in a patient with symptoms suggestive of asthma should result in an alternative diagnosis being considered.
Mechanisms of airway
hyperresponsiveness
Studies of monozygotic and dizygotic twins have suggested that there is a genetic basis for the development
of airway hyperresponsiveness, but that environmental
factors are more important [29]. Also measurements of
airway hyperresponsiveness in young infants have indicated that airway hyperresponsiveness can be present
very early in life, and that a family history of asthma
and parental smoking were risk factors for its development [30]. More recently, reports of genetic linkage of
airway hyperresponsiveness have been published. One
study has identified genetic linkage between histamine airway hyperresponsiveness and several genetic
COUGH AND AIRWAY HYPERRESPONSIVENESS
markers on chromosome 5q, near a locus that regulates
serum IgE levels [31]. Another study has identified linkage between a highly polymorphic marker of the B subunit of the high-affinity IgE receptor on chromosome
11q and methacholine airway hyperresponsiveness,
even in patients with non-atopic asthma [32]. One specific gene polymorphism (Glu 27) of the nine identified
for the b2-adrenoceptor has also been associated with
increased methacholine airway hyperresponsiveness
[33], while another polymorphism (Gly 16) was associated with the presence of nocturnal asthma [34]. Thus,
a genetic basis for airway hyperresponsiveness seems
very likely; however, the genetic linkage studies need to
be confirmed by other investigators in different patient
populations.
In addition to a possible genetic basis causing airway
hyperresponsiveness in asthma, airway inflammatory
processes are thought to be important (Fig. 12.2).
Mediators released from airway eosinophils have
Myofibroblast
hyperplasia and
fibrosis
Initial antigen recognition,
T-cell orientation
and IgE production
T
been suggested to cause many of the tissue changes
seen in the disease, including epithelial damage and
thickening of the basement membrane. Eosinophils
also produce cysteinyl leukotrienes which cause airway
smooth muscle contraction [35] and exudation of plasma [36], resulting in thickening of the airway wall. It
is likely that airway wall thickening, which has been described in asthmatics of varying degrees of severity,
could explain some of the differences in airway hyperresponsiveness between normal individuals and asthmatic patients. The thickness of the airway wall from
autopsy specimens is greater in fatal asthmatics than in
patients with milder disease and in non-asthmatics
[37]. It is not exactly clear which tissue contributes
mostly to airway wall thickening in asthma. One
factor that may be involved is the subepithelial thickening seen in bronchial biopsy specimens from most
asthmatics. Furthermore, bronchial smooth muscle has
a larger volume in asthmatics [38]. Lastly, exudation of
DC
B
Dendritic cell,
lymphocyte
and mast cell
mediated events
Oedema and
loss of airway
tethering to
parenchyma
MC
T
AHR
Increased smooth muscle
and altered function
Inflammatory
cell production,
recruitment and
mediator release
Goblet cell hyperplasia,
mucus production and
epithelial desquamation
Altered neural
mediators
Fig. 12.2 Potential mechanisms for the development of airway hyperresponsiveness in asthma.
117
CHAPTER 12
plasma can cause oedema, and thus thickening, of the
airway wall. Together these factors may, by geometric
mechanisms, enhance the airway luminal resistance
induced by a certain degree of airway smooth muscle
shortening. Another feature of the asthmatic airway
that correlates with the degree of airway hyperresponsiveness is loss of epithelial structure [6]. Possibly the
partial loss of the epithelial barrier allows greater
amounts of bronchoconstrictor mediators to reach the
smooth muscle or other cells which amplify the bronchoconstricting effect of the inhaled mediators. Alternatively, the release of bronchodilating substances
from the epithelium could be reduced by epithelial
damage, which could enhance bronchial smooth muscle contraction [39]. Indeed, it is possible that a number
of these different mechanisms interact to produce
airway hyperresponsiveness, but it is also likely that
different mechanisms are involved in causing different
components of airway hyperresponsiveness. Thus,
while airway structural changes appear to be responsible for the underlying persisting airway hyperresponsiveness in asthmatic patients, other mechanisms cause
the variable changes in airway hyperresponsiveness
seen in asthmatic subjects during the course of the
disease.
Variable airway hyperresponsiveness can last days
or weeks after experimental allergen inhalation [40],
or during a seasonal allergen exposure [41]. These
changes are temporally related to increases in airway
inflammatory cells, particularly eosinophils and basophils [42]. In addition, the release of cysteinyl
leukotrienes, likely from these cells, is partially responsible for allergen-induced airway hyperresponsiveness.
This has been confirmed by the demonstration that
leukotriene receptor antagonists, such as montelukast
[43] or pranlukast [44], partially attenuate allergeninduced airway hyperresponsiveness, but not the persistent airway hyperresponsiveness of asthma.
Cough-variant asthma
Cough-variant asthma was initially described as a clinical entity in 1979 [45]. It was identified in six patients
who had chronic persistent cough, without airflow
obstruction, but who did have methacholine airway
hyperresponsiveness. These authors argued that the
presence of airway hyperresponsiveness, together with
even one symptom of asthma, established the diagnosis
118
of asthma. In all subjects, the cough improved with regular inhaled bronchodilators. Subsequently, the term
cough-variant asthma was used to indicate a ‘forme
fruste’ of asthma [46]. However, it is now recognized
that in some patients with asthma, cough is the main,
and indeed sometimes the only, symptom and that variable airflow obstruction may not accompany the symptom of cough. Koh et al. [47] have suggested that it is
the level of maximal airway response to inhaled methacholine, rather than the degree of airway hypersensitivity, that may be an important risk factor for the
eventual development of wheezing in patients who initially present with cough as the only symptom of asthma. It has become clear that cough-variant asthma is
rather not a ‘forme fruste’ of asthma, but a clinical manifestation of (usually mild) asthma, with similar pathological changes in the airway wall [48]. Consistent with
this view, Niimi et al. [49] have described that serum
eosinophil cationic protein level and the percentage of
eosinophils in bronchoalveolar lavage (BAL) fluid and
in bronchial biopsy specimens were elevated and comparable to those found in patients with classic asthma
associated with wheeze. The same group found an increased thickness of the bronchial basement membrane
in patients with cough-variant asthma, indicating that
a similar process of airway wall remodelling as observed in classic asthma was present [48].
Eosinophilic bronchitis without airway
hyperresponsiveness
Another clinical entity, identified in 1989 by Gibson
et al. [50], is the presence of troublesome persistent
cough, associated with airway inflammation, as measured by increased numbers of eosinophils in induced
sputum, but without airway hyperresponsiveness
(Fig. 12.3). This was called eosinophilic bronchitis, to
indicate a clinical condition separate from asthma. One
study has suggested that eosinophilic bronchitis is the
cause of troublesome cough in 13% of patients presenting to a speciality clinic [51], and has been described
in an occupational setting [52]. The cough associated
with eosinophilic bronchitis responds to treatment
with inhaled corticosteroids [53], associated with resolution of the eosinophilic airway inflammation. In the
majority of the patients described in the original clinical
description, the cough did not return after treatment.
However, occasionally, the cough did not fully improve
Eosinophils (%)
COUGH AND AIRWAY HYPERRESPONSIVENESS
100
80
60
40
20
0
MCC (%)
2.5
2.0
1.5
1.0
0.5
0.0
Asthma
Non-asthmatic
CS cough
Chronic
bronchitis
Fig. 12.3 Numbers of eosinophils and metachromatic cells in
either spontaneous or induced sputum in patients with asthma (䊉), eosinophilic bronchitis (䊊) or chronic bronchitis (䊏).
Reproduced from [50].
with even high doses of inhaled corticosteroids, and required oral corticosteroids for benefit. Interestingly,
in one case report, inadequately treated eosinophilic
bronchitis resulted in symptomatic asthma, with partially fixed, irreversible airflow obstruction [54]. The
pathological features of eosinophilic bronchitis have
been compared to asthma in airway biopsies [55].
These studies have shown that the main differences
demonstrated were an increased number of mast cells
present in the airway smooth muscle in asthma. Gibson
and colleagues [56] found that sputum cells obtained
from patients with chronic cough, who had normal
spirometry and normal airway responsiveness, and
whose cough responded to inhaled corticosteroids,
expressed interleukin-5 (IL-5) and granulocyte–
macrophage colony-stimulating factor (GM-CSF)
mRNA by in situ hybridization. These patients would
fit into the category of eosinophilic bronchitis, and such
expression has also been observed in patients with asthma indicating that both diseases may be caused by
eosinophils.
Airway hyperresponsiveness and
cough sensitivity
The lack of relationship between airway hyperre-
sponsiveness and capsaicin cough response has been
highlighted by a study of Fujimura and colleagues [57].
They described two groups of patients with chronic
non-productive cough: those with methacholine airway hyperresponsiveness, but with a normal capsaicin
cough threshold, whose cough was responsive to bronchodilator therapy; and those had normal airway responsiveness with a hypertussive response to capsaicin
whose coughs responded to inhaled corticosteroids
or antihistamines. Furthermore, these patients did not
demonstrate any BAL eosinophilia, but had only a
small number of eosinophils in the subepithelium of
the tracheal and bronchial biopsies [58] and in induced
sputum [59]. Thus, it appears that what Fujimura
called ‘atopic’ cough may be part of ‘eosinophilic bronchitis’ or at least at one spectrum of this condition. In
addition, atopic cough, as with eosinophilic bronchitis,
is responsive to inhaled corticosteroid therapy with a
reduction in the capsaicin tussive response [60].
This lack of concordance between airway responsiveness and capsaicin cough response [61] has not
been confirmed by other investigators. Doherty et al.
[62] described a cohort of asthmatic patients, who as
a group showed enhanced capsaicin cough response
when compared to a cohort of non-asthmatic volunteers and capsaicin cough sensitivity was related to
symptomatic cough as measured by diary card score.
Thus, capsaicin cough response may be increased in
some patients with asthma, since some patients may
have a persistent dry cough, even though other asthma
symptoms are well controlled on adequate therapy.
Cough receptor sensitivity in children with uncontrolled asthma, who have troublesome cough, is increased, but decreases when asthma is controlled to
levels similar to those in children with asthma without
cough [63].
Mechanisms of cough in asthma
The mechanisms of cough in asthma are similar to
those causing other symptoms; that is, a consequence
of airway inflammation. In some instances, cough may
occur as a direct result of airway obstruction and increased mucus production that occurs during an asthma exacerbation. As described above, some asthmatics
have also been demonstrated to have an increased
cough reflex as measured by capsaicin inhalation [64],
which suggests that axonal reflexes, the stimulation of
119
CHAPTER 12
airway C fibres and substance P release in the airways
may be abnormal in asthmatics [65]. Sensitization of
the cough response by mediators such as PGE2 or by
bradykinin may occur [66,67]. In addition to peripheral sensitization, central sensitization pathways have
been proposed by integration from various sensory
nerve subtypes in the central nervous system to initiate
exaggerated reflexes and sensation, and substance P
has been proposed as an important central mechanism
for sensitization of the cough reflex, and its persistence
[68]. Interestingly, recent studies have shown that allergen inhalation in atopic asthmatic subjects caused
increases in eosinophilic airway inflammation and
airway hyperresponsiveness, but not in capsaicin sensitivity [69]. This suggests that cough receptor sensitivity
to capsaicin is not associated with airway eosinophilic
inflammation, at least in patients with allergic asthma.
By contrast, Weinfeld et al. [70] described increased
capsaicin sensitivity in allergic asthmatic patients to be
increased during allergen exposure as during the birch
pollen season, and argued that allergic inflammation in
the lower and/or upper airways may trigger neurogenic
mechanisms of significant clinical importance. However, the best evidence for an involvement of airway inflammation, in particular eosinophils, in cough is the
observation that cough associated with eosinophilic inflammation such as asthma, cough-variant asthma and
an eosinophilic bronchitis responds to corticosteroid
therapy which also inhibits eosinophilic inflammation.
Management of cough in asthma
The management of cough in asthma is, generally, the
same as the management of other asthma symptoms
[1]. This means treating airway inflammation, which is
done most effectively with inhaled corticosteroids and
inhaled b2-agonists as needed. Inhaled b2-agonists will
be particularly and rapidly effective if the cough is a result of airflow obstruction. The clinical effectiveness of
inhaled corticosteroids will take days to weeks to
achieve the maximal benefit. Other treatment options
that have been considered for asthmatic cough include
inhaled ipratropium bromide or sodium cromoglycate.
Ipratropium bromide has been shown to reduce
capsaicin-induced bronchoconstriction [64], while
cromoglycate reduces angiotensin-converting enzymeinduced cough [71]. However, only inhaled corticosteroids have been shown to improve the cough
120
threshold in asthmatics [72], while neither cromoglycate [64], nor leukotriene receptor antagonists [73]
have this effect.
Conclusions
Cough is an important symptom in asthmatic patients.
It is often, but not always, associated with airflow obstruction. Occasionally, cough is the only symptom of
asthma, and the diagnosis is established by demonstrating the presence of airway hyperresponsiveness. More
commonly, persistent cough as the only respiratory
symptom is caused by eosinophilic bronchitis, where
airway hyperresponsiveness is absent, but is associated
with eosinophils as in asthma. Some asthmatics have
an enhanced cough reflex as measured by capsaicin inhalation, likely as a consequence of airway inflammation. The treatment of cough in patients with asthma
or eosinophilic bronchitis is the same as with asthma,
with inhaled corticosteroids, with or without inhaled
b2-agonists.
References
1 Global Initiative for Asthma. Global Strategy for Asthma
Management and Prevention, 2002. NIH Publication
02–3659.
2 Kirby JG, Hargreave FE, Gleich GJ, O’Byrne PM.
Bronchoalveolar cell profiles of asthmatic and nonasthmatic subjects. Am Rev Respir Dis 1987; 136: 379–83.
3 Beasley R, Roche WR, Roberts JA, Holgate ST. Cellular
events in the bronchi in mild asthma and after bronchial
provocation. Am Rev Respir Dis 1989; 139: 806–17.
4 Gleich GJ, Frigas E, Loegering DA, Wassom DL,
Steinmuller D. Cytotoxic properties of the eosinophil
major basic protein. J Immunol 1979; 123: 2925–7.
5 Venge P, Bystrom J. Eosinophil cationic protein (ECP). Int
J Biochem Cell Biol 1998; 30 (4): 433–7.
6 Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB.
Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev
Respir Dis 1989; 140: 1745–53.
7 Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans
J, Bentley AM et al. Predominant TH-2 like bronchoalveolar T-lymphocyte populations in atopic asthma. N Engl J
Med 1992; 326: 298–304.
8 Jeffery PK. Comparative morphology of the airways in
asthma and chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 1997; 150: S6–S13.
COUGH AND AIRWAY HYPERRESPONSIVENESS
9 Turner MO, Hussack P, Sears MR, Dolovich J, Hargreave
FE. Exacerbations of asthma without sputum eosinophilia. Thorax 1995; 50: 1057–61.
10 Alexander HL, Paddock R. Bronchial asthma: response to
pilocarpine and epinephrine. Arch Intern Med 1921; 27:
184–91.
11 Weiss S, Robb GP, Ellis LB. The systematic effects of
histamine in man. Arch Intern Med 1932; 49: 360–96.
12 Curry JJ. Comparative action of acetyl-beta-methyl
choline and histamine on the respiratory tract in normals,
patients with hay fever and subjects with bronchial asthma. J Clin Invest 1947; 26: 430–8.
13 Tiffeneau R, Beauvallet P. Epreuve de bronchoconstriction et de bronchodilation par aerosols. Bull Acad Med
1945; 129: 165–8.
14 Cockcroft DW, Killian DN, Mellon JJ, Hargreave FE.
Bronchial reactivity to inhaled histamine: a method and
clinical survey. Clin Allergy 1977; 7: 235–43.
15 Juniper EF, Frith PA, Dunnett C, Cockcroft DW,
Hargreave FE. Reproductibility and comparison of responses to inhaled histamine and methacholine. Thorax
1978; 33: 705–10.
16 Sotomayor H, Badier M, Vervloet D, Orehek J. Seasonal
increase of carbachol airway responsiveness in patients
allergic to grass pollen. Reversal by corticosteroids. Am
Rev Respir Dis 1984; 130: 56–8.
17 Adelroth E, Morris MM, Hargreave FE, O’Byrne PM.
Airway responsiveness to leukotrienes C4 and D4 and to
methacholine in patients with asthma and normal controls. N Engl J Med 1986; 315: 480–4.
18 Hardy CC, Robinson C, Tattersfield AE, Holgate ST.
The bronchoconstrictor effect of inhaled prostaglandin
D2 in normal and asthmatic men. N Engl J Med 1984;
311: 209–13.
19 Thomson NC, Roberts R, Bandouvakis J, Newball H,
Hargreave FE. Comparison of bronchial responses to
prostaglandin F2 alpha and methacholine. J Allergy Clin
Immunol 1981; 68: 392–8.
20 O’Byrne PM, Dolovich J, Hargreave FE. Late asthmatic
responses. Am Rev Respir Dis 1987; 136: 740–51.
21 Chan-Yeung M, Malo JL. Occupational asthma. N Engl J
Med 1995; 333: 107–12.
22 McFadden ER Jr, Gilbert IA. Exercise-induced asthma. N
Engl J Med 1994; 330: 1362–7.
23 O’Byrne PM, Ryan G, Morris M, McCormack D, Jones
NL, Morse JL et al. Asthma induced by cold air and its
relation to nonspecific bronchial responsiveness to methacholine. Am Rev Respir Dis 1982; 125: 281–5.
24 Anderson SD, Schoeffel RE, Finney M. Evaluation of
ultrasonically nebulised solutions for provocation testing
in patients with asthma. Thorax 1983; 38: 284–91.
25 Anderson SD, Brannan J, Spring J, Spalding N, Rodwell
LT, Chan K et al. A new method for bronchial-provocation
26
27
28
29
30
31
32
33
34
35
36
37
38
testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med 1997; 156: 758–65.
Anderson SD, Brannan JD. Exercise-induced asthma: is
there still a case for histamine? J Allergy Clin Immunol
2002; 109 (5): 771–3.
Manning PJ, Watson RM, Margolskee DJ, Williams VC,
Schwartz JI, O’Byrne PM. Inhibition of exercise-induced
bronchoconstriction by MK-571, a potent leukotriene
D4-receptor antagonist. N Engl J Med 1990; 323:
1736–9.
Juniper EF, Frith PA, Hargreave FE. Airway responsiveness to histamine and methacholine: relationship to minimum treatment to control symptoms of asthma. Thorax
1981; 36: 575–9.
Hopp RJ, Bewtra A, Biven R, Nair NM, Townley RG.
Bronchial reactivity pattern in nonasthmatic parents of
asthmatics. Ann Allergy 1988; 61: 184–6.
Young S, Le Souef PN, Geelhoed GC, Stick SM, Turner
KL, Landau LI. The influence of a family history of asthma
and parental smoking on airway responsiveness in early
infancy. N Engl J Med 1991; 324: 1168–73.
Postma DS, Bleeker ER, Amelung PJ, Holroyd KJ, Xu J,
Panhyusen CIM et al. Genetic susceptibility to asthmabronchial hyperresponsiveness coinherited with a major
gene for atopy. N Engl J Med 1995; 333: 894–900.
van Herwerden L, Harrap SB, Wong ZY, Abramson
MJ, Kutin JJ, Forbes AB et al. Linkage of high-affinity IgE
receptor gene with bronchial hyperreactivity, even in the
absence of atopy. Lancet 1995; 346: 1262–5.
Hall IP, Wheatley A, Wilding P, Liggett SB. Association of
Glu 27 beta 2-adrenoceptor polymorphism with lower
airway reactivity in asthmatic subjects. Lancet 1995; 345:
1213–4.
Turki J, Pak J, Green SA, Martin RJ, Liggett SB. Genetic
polymorphism of the beta-2 adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly 16 correlates with the nocturnal phenotype. J Clin Invest 1995; 95:
1635–41.
Dahlen SE, Hedqvist P, Hammarstrom S, Samuelsson B.
Leukotrienes are potent constrictors of human bronchi.
Nature 1980; 288: 484–6.
Cui ZH, Pullerits T, Linden A, Skoogh BE, Lotvall J.
Attenuation of early phase airway response and plasma
exudation due to reduction of leukotrienes production
after repeated allergen exposure. J Allergy Clin Immunol
2000; 105 (1): S294.
Carroll N, Elliot J, Morton A, James AL. The structure
and function of large and small airways in nonfatal and
fatal asthma. Am Rev Respir Dis 1993; 147: 405–10.
Dunnill MS, Massarell GR, Anderson JA. A comparison
of the quantitive anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis and in
emphysema. Thorax 1969; 24: 176–9.
121
CHAPTER 12
39 Manning PJ, Jones GL, Otis J, Daniel EE, O’Byrne PM.
The inhibitory influence of tracheal mucosa mounted in
close proximity to canine trachealis. Eur J Pharmacol
1990; 178: 85–9.
40 Cartier A, Thomson NC, Frith PA, Roberts R, Hargreave
FE. Allergen-induced increase in bronchial responsiveness
to histamine: relationship to the late asthmatic response
and change in airway caliber. J Allergy Clin Immunol
1982; 70: 170–7.
41 Monteseirin J, Guardia P, Delgado J, Llamas E, Palma J,
Conde A et al. Peripheral-blood T-lymphocytes seasonal
bronchial asthma. Allergy 1995; 50 (2): 152–6.
42 Gauvreau GM, Watson RM, O’Byrne PM. Kinetics of allergen-induced airway eosinophilic cytokine production
and airway inflammation. Am J Respir Crit Care Med
1999; 160: 640–7.
43 Leigh R, Vethanayagam D, Yoshida M, Watson RM,
Rerecich T, Inman MD et al. Effects of montelukast and
budesonide on airway responses and airway inflammation in asthma. Am J Respir Crit Care Med 2002; 166 (9):
1212–7.
44 Hamilton AL, Faiferman I, Stober P, Watson RM, O’Byrne
PM. Pranlukast, a leukotriene receptor antagonist, attenuates allergen-induced early and late phase bronchoconstriction and airway hyperresponsiveness in asthmatic
subjects. J Allergy Clin Immunol 1998; 102: 177–83.
45 Corrao WM, Braman SS, Irwin RS. Chronic cough as the
sole presenting manifestation of bronchial asthma. N Engl
J Med 1979; 300 (12): 633–7.
46 Tokuyama K, Shigeta M, Maeda S, Takei K, Hoshino M,
Morikawa A. Diurnal variation of peak expiratory flow in
children with cough variant asthma. J Asthma 1998; 35
(2): 225–9.
47 Koh YY, Park Y, Kim CK. The importance of maximal airway response to methacholine in the prediction of wheezing development in patients with cough-variant asthma.
Allergy 2002; 57 (12): 1165–70.
48 Niimi A, Matsumoto H, Minakuchi M, Kitaichi M,
Amitani R. Airway remodelling in cough-variant asthma.
Med J Aust 2000; 356 (9229): 564–5.
49 Niimi A, Amitani R, Suzuki K, Tanaka E, Murayama T,
Kuze F. Eosinophilic inflammation in cough variant
asthma. Eur Respir J 1998; 11 (5): 1064–9.
50 Gibson PG, Dolovich J, Denburg J, Ramsdale EH,
Hargreave FE. Chronic cough: eosinophilic bronchitis
without asthma. Lancet 1989; 1: 1346–8.
51 Brightling CE, Ward R, Goh KL, Wardlaw AJ, Pavord ID.
Eosinophilic bronchitis is an important cause of chronic
cough. Am J Respir Crit Care Med 1999; 160 (2): 406–10.
52 Lemiere C, Efthimiadis A, Hargreave FE. Occupational
eosinophilic bronchitis without asthma: an unknown
occupational airway disease. J Allergy Clin Immunol
1997; 100 (6): 852–3.
122
53 Gibson PG, Hargreave FE, Girgis-Gabardo A, Morris M,
Denburg JA, Dolovich J. Chronic cough with eosinophilic
bronchitis: examination for variable airflow obstruction
and response to corticosteroid. Clin Exp Allergy 1995; 25:
127–32.
54 Brightling CE, Woltmann G, Wardlaw AJ, Pavord ID.
Development of irreversible airflow obstruction in a patient with eosinophilic bronchitis without asthma. Eur
Respir J 1999; 14 (5): 1228–30.
55 Brightling CE, Bradding P, Symon FA, Holgate ST,
Wardlaw AJ, Pavord ID. Mast-cell infiltration of airway
smooth muscle in asthma. N Engl J Med 2002; 346 (22):
1699–705.
56 Gibson PG, Zlatic K, Scott J, Sewell W, Woolley K, Saltos
N. Chronic cough resembles asthma with IL-5 and granulocyte–macrophage colony-stimulating factor gene expression in bronchoalveolar cells. J Allergy Clin Immunol
1998; 101 (3): 320–6.
57 Fujimura M, Kamio Y, Hashimoto T, Matsuda T. Cough
receptor sensitivity and bronchial responsiveness in patients with only chronic non-productive cough: in view of
effect of bronchodilator therapy. J Asthma 1994; 31:
463–72.
58 Fujimura M, Ogawa H, Yasui M, Matsuda T. Eosinophilic
tracheobronchitis and airway cough hypersensitivity in
chronic non-productive cough. Clin Exp Allergy 2000; 30
(1): 41–7.
59 Fujimura M, Songur N, Kamio Y, Matsuda T. Detection
of eosinophils in hypertonic saline-induced sputum in
patients with chronic nonproductive cough. J Asthma
1997; 34 (2): 119–26.
60 Brightling CE, Ward R, Wardlaw AJ, Pavord ID. Airway
inflammation, airway responsiveness and cough before
and after inhaled budesonide in patients with eosinophilic
bronchitis. Eur Respir J 2000; 15 (4): 682–6.
61 Fujimura M, Kamio Y, Hashimoto T, Matsuda T. Airway
cough sensitivity to inhaled capsaicin and bronchial responsiveness to methacholine in asthmatic and bronchitic
subjects. Respirology 1998; 3: 267–72.
62 Doherty MJ, Mister R, Pearson MG, Calverley PMA.
Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease. Thorax 2000; 55 (8):
643–9.
63 Chang AB, Phelan PD, Robertson CF. Cough receptor
sensitivity in children with acute and non-acute asthma.
Thorax 1997; 52 (9): 770–4.
64 Fuller RW, Dixon CM, Barnes PJ. Bronchoconstrictor response to inhaled capsaicin in humans. J Appl Physiol
1985; 58 (4): 1080–4.
65 Millqvist E, Bende M, Lowhagen O. Sensory hyperreactivity — a possible mechanism underlying cough and asthmalike symptoms. Allergy 1998; 53 (12): 1208–12.
66 Fox AJ, Lalloo UG, Belvisi MG, Bernareggi M, Chung KF,
COUGH AND AIRWAY HYPERRESPONSIVENESS
Barnes PJ. Bradykinin-evoked sensitization of airway
sensory nerves: a mechanism for ACE-inhibitor cough.
Nature Med 1996; 2 (7): 814–7.
67 Nichol GM, Nix A, Barnes PJ, Chung KF. Enhancement of
capsaicin-induced cough by inhaled prostaglandin F2a:
modulation by beta-adrenergic agonist and anticholinergic agent. Thorax 1990; 45: 694–8.
68 Undem BJ, Hunter DD, Liu M, Haak-Frendscho M,
Oakragly A, Fischer A. Allergen-induced sensory neuroplasticity in airways. Int Arch Allergy Immunol 1999;
118: 150–3.
69 Minoguchi H, Minoguchi K, Tanaka A, Matsuo H, Kihara
N, Adachi M. Cough receptor sensitivity to capsaicin does
not change after allergen bronchoprovocation in allergic
asthma. Thorax 2003; 58: 19–22.
70 Weinfeld D, Ternesten-Hasseus E, Lowhagen O, Millqvist
E. Capsaicin cough sensitivity in allergic asthmatic patients increases during the birch pollen season. Ann
Allergy Asthma Immunol 2002; 89 (4): 419–24.
71 Hargreaves MR, Benson MK. Inhaled sodium cromoglycate in angiotensin-converting enzyme inhibitor cough.
Lancet 1995; 345: 13–6.
72 Di Franco A, Dente FL, Giannini D, Vagaggini B, Conti I,
Macchioni P et al. Effects of inhaled corticosteroids on
cough threshold in patients with bronchial asthma. Pulm
Pharmacol Ther 2001; 14 (1): 35–40.
73 Dicpinigaitis PV, Dobkin JB. Effect of zafirlukast on cough
reflex sensitivity in asthmatics. J Asthma 1999; 36 (3):
265–70.
123
13
Cough in chronic obstructive
pulmonary disease
Kian Fan Chung & Peter M.A. Calverley
Introduction
Chronic obstructive pulmonary disease (COPD) is a
leading cause of death and disability throughout the
world, and it is predicted that COPD will increase from
the twelfth to become the fifth most prevalent disease
and from the sixth to become the third most common
cause of death in the world [1]. In the UK, hospital admissions for COPD amounted to just over 200 000 in
1994, with an average hospital stay of 10 days, and the
estimated total direct and indirect costs were £846 million in 1996. Currently, in the US, there are 16 million
patients with COPD, and the estimated direct and indirect costs are $30 billion per year.
COPD is a term that encompasses many conditions
including emphysema and chronic obstructive bronchitis characterized by progressive airflow limitation
that is not substantially reversed by bronchodilators,
usually resulting from an abnormal response of the
lungs to noxious particles or gases [2]. The resulting
endogenous inflammatory response is likely to be
the driving cause for the loss of airway function. The
most common cause of COPD is tobacco smoke, with
its composition of noxious gases and particles.
The causes of airflow limitation in COPD include a
combination of airways inflammation and remodelling, bronchospasm, mucus hypersecretion and loss
of elastic lung recoil. In this chapter, we will overview
the pathophysiology, clinical presentation and treatment of COPD, with emphasis particularly on the importance of cough and the mechanisms underlying
cough.
Cough and COPD — clinical aspects
Before the Global Initiative for Chronic Obstructive
Lung Disease (GOLD) definition of COPD was agreed,
chronic persistent coughing was recognized among
clinicians as a hallmark of at least the early stages of
this illness. This led to the clinical concept of chronic
bronchitis, with its associated sputum production, as
a marker for future ill health and possibly mortality.
When this was tested by the epidemiological studies
of Fletcher and colleagues in the 1970s it became clear
that airflow obstruction and not cough and sputum
production was the best predictor of subsequent mortality [3]. Indeed, inclusion of the data about cough
productive of sputum did not add further to the mortality prediction [4].
This led many clinicians to discount cough in COPD
as being of any importance, apart from its perceived
nuisance value. However this view is now changing
again as further data have accumulated. There is now
better evidence that people who have cough regularly
productive of sputum are more likely to develop pneumonic complications during COPD exacerbations
and subsequently die [5]. Patients spirometrically diagnosed as having COPD are more likely to report any
form of exacerbation if they regularly cough and produce sputum [6]. Even in early COPD there are now
data suggesting that those with persistent infection, associated as it is with regular cough, will have a more
rapid decline in FEV1 than those who do not experience
this problem [7]. This small effect is independent of the
effects of tobacco smoke but its mechanism remains
to be explained.
Thus, there is renewed interest in cough in COPD.
125
CHAPTER 13
Clinically cough does contribute independently to the
reduction in quality of life (better described as health
status) which is typical of patients affected by COPD
[8]. Chronic bronchitis is now recognized as being a
very common complaint reported by over 5 million
people in the US and often associated with undiagnosed
airflow obstruction [9]. This has led the GOLD initiative to propose persistent coughing even without airflow obstruction as a warning sign of the individual’s
potential for developing COPD [2]. This may not be accurate, at least as judged in other population data sets
[10], but it does serve to raise public awareness that a
persistent cough is not something that should be simply
ignored or rationalized as being the result of cigarette
smoking and of no consequence.
Aetiological factors and
amplifying mechanisms
Much thinking has gone into the fact that, although
tobacco smoking induces airway and lung inflammation in all smokers, only 15% of smokers develop
COPD, indicating that there are either host or environmental factors (or both) that may determine the onset
of progressive airflow limitation. Genetic factors are
likely to be important as illustrated by the development
of emphysema in non-smokers, and with accelerated
development of emphysema in smokers associated
with a severe deficiency of a1-protease inhibitor, a
major circulating inhibitor of serine protease [11,12].
Other aetiological or interacting factors with cigarette smoke may be environmental pollution, bacterial
or viral infections, nutritional factors, low birth
weight and bronchial hyperresponsiveness. A growing area of investigation is that of the innate host
response factors to external environmental factors
such as viruses and bacteria, as well as components
of these infective organisms such as viral DNA and
bacterial lipopolysaccharides, and environmental
pollutants.
It has been proposed that latent adenoviral genes
may act as an enhancing transcription factor to enhance the inflammatory response of cigarette smoke
exposure [13]. Furthermore, the propensity of bacterial and viral mucosal infections leading to exacerbations of COPD may themselves damage the epithelial
barrier and enhance the chronic inflammation. Finally,
defence mechanisms of the airways may be impaired
126
primarily, to allow continuing damage such as the
reduction in the production of secretory IgA in the
epithelium of patients with COPD [14], and the impairment of mucociliary clearance in smokers and chronic
bronchitis [15].
The inflammatory process
The close association between tobacco smoking and
the development of emphysema, chronic bronchitis
and the full spectrum of COPD has been known for
many years. Increased numbers of neutrophils,
macrophages and natural killer lymphocytes as compared with values in smokers without airflow obstruction has been described, and each variable inversely
correlated with FEV1 [16]. The association of inflammation and COPD is very complex. Cigarette smokinginduced inflammation is present in the lungs of all
smokers, including those with normal lung function. In
the minority of smokers that develop COPD, the inflammatory process is more pronounced. Airway and
parenchymal inflammation are consistently found in
COPD, and the airways of patients with airflow limitation contain a higher number of inflammatory cells
than do airways of patients with normal FEV1 [16].
However, the inflammation can persist for a long time
after smoking cessation [17].
The inflammatory process in the airways involves
neutrophils, macrophages, CD8+ T cells and epithelial
alterations. The role of overexpressed cytokines
and chemokines is particularly important in the initiation and maintenance of the inflammatory process
[18]. Macrophages can be activated by cigarette smoke
to release inflammatory mediators such as tumour
necrosis factor-a (TNFa), interleukin-8 (IL-8) and
leukotriene B4 (LTB4). These mediators are likely to
contribute to the recruitment of neutrophils to the
lungs. There is also an increase in the number of
macrophages in patients with COPD, and macrophages are localized to the sites of alveolar wall
destruction in patients with emphysema [19], and in the
epithelium of small airways [20]. Part of the inflammatory process or altered tissue repair can lead to large
and small airway wall thickening, together with epithelial squamous and mucous cell metaplasia, excessive
matrix deposition, hypertrophy of the submucosal
glands, and an increased airway smooth muscle mass in
large and small airways.
Neutrophils are increased in the airways of smokers
COUGH IN COPD
and of patients with COPD, especially those with
chronic bronchitis [21], and this is related to the severity of airflow obstruction [16]. Increased neutrophil
elastase activity has been measured in both blood
and lavage from patients with emphysema [22], and
in smokers compared with non-smokers [23]. Other
potential effects of neutrophils include the actions of
neutrophil elastase in causing mucus secretion, epithelial damage and slowing of ciliary beat frequency
[24,25].
Increased numbers of CD8+ T cells in the central and
peripheral airways and lung parenchyma of smokers
with COPD negatively correlated with the degree of
airflow obstruction [26]. These T cells appear activated, expressing surface activation markers IL-2R and
VLA-1 (very late antigen-1) [27]. Interestingly, once established, the number of CD8+ T cells and the expression of these activation markers do not change on
cessation of smoking for up to 1 year [28]. These
CD8+ T cells coexpress interferon-g (IFNg) and the
chemokine receptor, CXCR3; in addition, the ligand
chemokine for this receptor, CXCL10, is overexpressed
in the bronchiolar epithelium of smokers with COPD
[29]. These data indicate that the CXCR3/CXCL10 interaction may lead to the recruitment of CD8+ T cells in
the peripheral airways of smokers with COPD.
Pathophysiological changes in COPD
With biochemical and cellular changes in the small airways and surrounding alveoli, structural damage leads
to a loss of elastic lung recoil [30]. The lungs start to increase in size and forced vital capacity (FVC) increases.
In early stages of COPD, the ratio of FEV1 to FVC may
decrease without any change in FEV1. Both a loss of
elastic lung recoil and an increase in lung resistance
occur when alveoli become damaged or lost, with a reduction in the elastic supporting structure of the lung,
since the airways are no longer tethered by the radial
traction forces of the surrounding alveolar attachments
[31]. Mural inflammation of the small airways and airways remodelling also reduce the airway lumen [32].
The site of airways obstruction in COPD is in the smaller conducting airways including bronchi and bronchioles of less than 2 mm in diameter [33]. Therefore, the
causes of airflow obstruction in COPD are a combination of airways inflammation and remodelling, bronchospasm, mucus hypersecretion and loss of elastic
lung recoil.
Clinical presentation of COPD
The diagnosis of COPD is based on the detection of airflow limitation. Since the umbrella of COPD covers
a range of overlapping conditions such as chronic
bronchitis, bronchiolitis and emphysema, the clinical
presentation can be varied. Many patients who have
smoked for many years may be asymptomatic and the
diagnosis may not be made because spirometry has not
been performed. Otherwise, patients often present with
shortness of breath on effort that is chronic; these patients also often present without cough. Other associated symptoms of COPD may include wheezing and
chest tightness.
The association of current cigarette smoking with
cough is well known [34,35], and the risk of cough is
increased with the amount of tobacco smoked. Cough
is frequently the first symptom reported by patients
with COPD [36]. Some patients may have had a history
of chronic bronchitis, with persistent cough and sputum production over a period of months during the
winter, although this may or may not be associated
with airflow obstruction. In fact, cough and sputum
production may precede by many years the development of airflow limitation. Patients with COPD may
have a persistent troublesome cough that is either productive or non-productive.
Given the enormous number of potential variables,
which may play different roles at different stages of the
COPD patient’s clinical progress, it should be no surprise that simple questions about the frequency of
cough and how troublesome it is often yield confusing
results of uncertain value. In one selected series of patients 81% complained of cough but only 12% found
this a very troublesome symptom and only half reported regular sputum production [37]. This illustrates
how limited our knowledge of this important complaint really is in this group of patients. We urgently
need a validated cough questionnaire that can be applied to sufficient numbers of patients for a reliable estimate of the severity, type and natural history of cough
to be obtained. Only then will it be possible to relate
some of the currently rather fragmentary mechanistic
data to recognizable clinical settings.
A further useful development would be to agree a satisfactory acoustic definition of cough and apply it to
COPD patients. Attempts to do this have been made
[38], and studies of objectively recorded overnight
cough suggest that most coughing in COPD occurs
127
CHAPTER 13
FEV1 (per cent predicted)
100
COPD
Asthma
80
60
40
20
0
Saline 2
8
31
125
C5 response (mmol/L)
500 >500
Fig. 13.1 Relationship between FEV1 as a percentage of predicted and directly measured capsaicin cough threshold in
chronic obstructive pulmonary disease (COPD) (䊊) and
chronic asthma (䊉). No significant relationship is present in
either disease. Reproduced with permission from [37].
care settings. The value of Stage 0 is unknown. One
study has suggested that Stage 0 has no predictive value
in detecting subsequent airflow obstruction [10].
The later established stages of COPD are described
according to the degree of airflow obstruction:
Stage I (mild): Early development of airflow obstruction reflected by a reduction in the FEV1/FVC
ratio < 70%, with FEV1 in the normal range (> 80%
predicted).
Stage II (moderate):
A: FEV1 between 50 and 80% of predicted; FEV1/
FVC ratio < 70%; with or without symptoms.
B: FEV1 between 30 and 50% of predicted; FEV1/
FVC ratio < 70%; with or without symptoms.
Stage III (severe): FEV1 less than 30% of predicted,
usually with evidence of current or previous respiratory failure or of right-sided heart failure. Cough and
sputum production may be present at any stage of
COPD.
Exacerbations of COPD
during periods of wakefulness rather than disturbing
sleep, as occurs in other patients with chronic cough
[39]. Measures of lung function like the FEV1 are not
well related to self-reported cough or to measures of
capsaicin sensitivity (Fig. 13.1) [37]. This is another
illustration of how one aspect of the COPD patient’s
disability, in this case expiratory airflow obstruction,
does not capture the extent of their clinical problems
with cough.
Severity of COPD
The severity of COPD is usually categorized by spirometric measurements, as proposed by GOLD. Stage 0 is
early disease usually presenting with persistent cough
with sputum in the absence of airflow obstruction. It
has been proposed that these individuals with persistent cough and sputum have inflammation of the large
airways, as well as the small airways and alveoli, due to
cigarette smoke. The presence of symptoms of cough
and sputum may indicate the presence at sites of pathology which can lead later to airflow limitation. Unfortunately, many smokers consider their cough to be a
‘normal’ accompaniment of smoking, and this may be
the reason why early diagnosis of COPD may be
missed. In addition, the use of spirometry necessary for
the diagnosis of COPD is not prevalent in most primary
128
Patients with severe COPD may deteriorate, with increased dyspnoea and productive cough associated
with increased sputum volume or purulence [40], into
an exacerbation. Cough is sometimes a very prominent
symptom. Other symptoms may include wheeze, sore
throat, nasal discharge or fever. Exacerbations of
OPD that are more common in winter months are often
due to viral or bacterial infections, and sometimes
environmental pollutants, but the cold weather could
be a predisposing trigger. Recurrent exacerbations
are more usual in patients at a more severe stage of the
disease.
Cough reflex sensitivity
Data about the cough reflex in COPD have produced a
somewhat contradictory picture reflecting differences
in the method of selection of the subjects included and
in the technique used to test the reflex (see Chapter 5).
Even when the same stimulus is applied using the same
protocol rather different results can emerge. Thus, a
study of 11 patients with COPD with ‘productive’
cough demonstrated a normal sensitivity of the cough
response to capsaicin [41], and this lends support to the
concept that the cough of COPD was due to clearing of
excessive secretions. However, in a larger cohort of
120
100
Normal
Asthma
COPD
80
60
40
20
15
.6
31
.2
5
62
.5
12
5
25
0
50
0
>5
00
7.
8
3.
9
0
0
1.
95
Cumulative frequency of responders
COUGH IN COPD
Capsaicin concentration (mmol/L)
Fig. 13.2 Cumulative frequency plot of the capsaicin concentration at which the C5 threshold was reached in stable
chronic obstructive pulmonary disease (COPD) patients (䊉),
chronic asthma patients (䉱) and normal individuals (䊏).
Note that at any concentration more patients with airflow
obstruction have a reduced threshold to coughing. Reproduced with permission from [37].
current or ex-smokers with COPD with a mean FEV1 of
42% of predicted values, there was an increase in cough
sensitivity [42]. The capsaicin cough sensitivity was related to the presence of cough, and to the patient’s assessment of cough severity. In general the reduction in
cough threshold was similar to that seen in a group of
chronic asthmatics and significantly lower than that in
a control population of somewhat younger subjects
(Fig. 13.2). One strength of this study is that patients
were not selected on the basis of having a clinically
troublesome cough as in most other investigations.
This may explain why they rated their cough as being of
mild to moderate severity but also suggests that reductions in capsaicin cough threshold are not uncommon
in established COPD. As yet there are no data regarding
cough sensitivity during an exacerbation of COPD, but
one presumes that it is further increased given the
prominence of the cough and the triggering bacterial
or viral infections which are known to increase cough
sensitivity.
The increase in the cough reflex in COPD raises
several interesting issues. First, the basis for the increased cough reflex is not known. Apart from possible
mucus stimulation of cough, chronic smoking may
increase airway sensitivity to capsaicin [43], and cough
sensitivity to capsaicin in awake guinea-pigs [44].
Inflammatory mechanisms may sensitize afferent
nerves in the airways through several mediators such as
prostaglandins, or bradykinin may be implicated. Neurotrophins such as nerve growth factor and ciliary neurotrophic factor induce proliferation of airway sensory
nerves and change their phenotype, with a reduced
threshold of activation and increased expression of
neuropeptides [45]. Substance P levels are elevated in
induced sputum of patients with COPD [46], suggesting a role for neurogenic inflammation. Substance P
may also be an important mechanism for augmentation
and persistence of the cough reflex through ‘peripheral’
and ‘central’ mechanisms which integrate various inputs from sensory nerve subtypes in the central nervous
system to initiate exaggerated reflexes and sensation
[47]. The effect of products of activated neutrophils
such as neutrophil myeloperoxidase or neutrophil elastase on the cough reflex is not known, but neutrophil
elastase can cause goblet cell mucus secretion, epithelial damage and slowing of ciliary beat frequency
[24,25].
Mucus hypersecretion
As noted above, early epidemiological studies failed to
find an association between mucus hypersecretion and
rapid progression of COPD [3], but more recent population-based studies have now reported an association
[48]. These latest epidemiological data support the
concept that the development of cough and sputum in a
smoker may be an early indicator of the development of
COPD. It is also possible that the underlying cause of
mucus hypersecretion and cough may also apply to the
accelerated decline in lung function. Chronic bronchitis is associated with hyperplasia of both epithelial
goblet cells and submucosal glands [20], and with
submucosal gland hypertrophy [49]. Partial or complete occlusion of the airways of less than 2 mm in
diameter with mucus plugs is commonly observed in
COPD [33], with the clinical consequence of impairment of gas exchange, and morphometric measurements of distal airways of patients dying from COPD
showed more mucus in the airway lumen when compared with controls without respiratory disease [49]. A
positive correlation between the amount of submucosal glands and both the amount of mucus in the airway
lumen and the daily sputum volume was reported.
Many COPD patients also have areas of localized
129
CHAPTER 13
bronchiectasis identifiable on computed tomographic
scans but not evident on the ordinary chest radiograph
[50], which could also contribute to the total amount of
sputum produced each day.
Increased mucus production could overwhelm the
normal mucociliary clearance mechanisms and lead
to the pooling of secretions and activation of the cough
reflex. Alternatively the direct ciliotoxic effects of tobacco smoke coupled with delayed or ineffective epithelial healing following infective injury could impair
the capacity of this system to clear more normal
amounts of mucus produced physiologically in the airways. This would yield the same result but might explain why the amount of sputum produced by many
patients is so meagre. Changes in the viscosity and
physical properties of the sputum itself, as well as the
production of this material in more distal airways than
occurs in health due to goblet cell hyperplasia, could
also make it harder to develop sufficiently high expiratory flows to clear mucus effectively. The residual material could act as a chronic irritant that repeatedly
provokes relatively ineffective spells of coughing in the
affected patient.
Whole-lung mucociliary clearance is reduced in
COPD [51,52], and slowing of mucus clearance
was observed to be greatest within the central airways
[53]. In severe airflow obstruction, cough is usually
an ineffective adjunct to mucociliary clearance. However, in asymptomatic smokers, normal values of
mucus transport velocity were found in central
airways with delays in clearance of mucus from peripheral airways [54]. This was reversed by b-agonist
therapy.
Airway mucus is an aqueous solution of glycoconjugates, made predominantly of mucins, in addition
to proteoglycans, enzymes and electrolytes. Mucins
are important in determining the viscoelastic properties
of airway mucus, and up to nine mucin genes have
been identified so far [55]. MUC5AC is a predominant mucin in airway secretions from normal healthy
children and in sputum samples from patients with
chronic bronchitis [56]. In healthy smokers compared
to non-smokers a fourfold increase in mucin-like
material was detected in bronchoalveolar lavage fluid
[57]. Mucus hypersecretion may also be induced by
inflammation in the absence of substantial gland enlargement. For example, neutrophil elastase induces
mucus secretion, together with epithelial damage and
slowing of ciliary beat frequency [24,25]. Cigarette
130
smoke activates C fibres in airways and may result in
mucus hypersecretion and goblet cell discharge [58],
and tachykinins are potent stimuli of mucus secretion
in human airways [59].
The differentiation of epithelial cells into goblet
cells is another aspect underlying mucus hypersecretion and this is determined by the expression of mucin
genes that encode the mucin glycoproteins in epithelial
cells. Mucin genes can be up-regulated by exposure of
epithelial cells to environmental factors including infections and pollutants, and to neutrophil elastase,
while acrolein, a component of cigarette smoke, induces MUC5AC gene expression, and mucus metaplasia in rats [60, 61]. These effects may occur through the
induction of oxidative stress [62], that leads to
the ligand-independent transactivation of epidermal
growth factor receptor (EGFR) and to airway mucin
synthesis. Enhanced EGFR expression in the airway
epithelium on exposure to cigarette smoke has been
observed [63].
Treatment of COPD
The treatment of COPD is mainly aimed towards the
relief of symptoms. Although FEV1 remains the basis
for classification of severity, the change in FEV1 with
treatment is not used as a marker of response because
such change may be small or within the error of the
measurement, yet still be associated with significant
symptomatic relief and improvement in well-being.
Such symptomatic improvement can be obtained by the
use of bronchodilators. The rate of decline in FEV1 is
used as an indication of disease progression, and there
are no treatments that appear to be able to reverse the
accelerated decline in lung function in these patients.
Only cessation of cigarette smoking has been shown to
lead to a normalization of the decline in FEV1 [64].
Therefore, an important therapeutic approach is to get
the patient to cease smoking. Nicotine replacement
therapy with either gum, skin patches or inhaler is beneficial, and addition of buproprion provides additive
effects [65].
In one study, cough markedly decreased in most patients following smoking cessation, with an improvement in the cough noticeable within 4 weeks in more
than 50% of cases [66]. On the basis of this information, one would assume that the cough reflex would be
reduced with smoking cessation.
COUGH IN COPD
Bronchodilators
Bronchodilators, while not modifying the rate of decline in FEV1, provide the most symptomatic relief in
COPD. Although a small bronchodilator response is
usually observed, they may relieve symptoms of effort
dyspnoea probably through a reduction in dynamic hyperinflation. Short-acting b-agonists (e.g. salbutamol
or terbutaline) and short-acting anticholinergic drugs
(e.g. oxitropium or ipratropium) are often used, and
may be used in combination, usually provided on a regular basis up to six times per day. Long-acting bagonists for regular use are more conveniently used
because of their 12-h duration of action, and beneficial
effects on quality of life without significant effect on
FEV1 have been demonstrated [67,68]. Tiotropium
bromide, a long-acting anticholinergic, is now available for the treatment of COPD. This drug is clearly superior to short-acting anticholinergic therapy in terms
of improving FEV1, reducing the number of exacerbations and improving health status [69]. b-Agonists or
anticholinergics may be combined with theophylline.
Although little emphasized in the reports of trials with
all these agents, the self-reported cough score is little influenced in most cases, although occasional studies reporting some benefit can be found [70]. This may reflect
the many different mechanisms underlying cough in
COPD (see above) as well as the insensitive nature of
these questionnaires. However, it is possible that specific mechanisms underlie cough in this disease and
these are not as closely related to those producing airflow obstruction and hence do not change with treatment primarily directed at this endpoint.
There are data suggesting that patients who receive
short-acting anticholinergic drugs have a lower cough
threshold than those on other treatments, while this
test is not influenced by inhaled corticosteroids [37].
However, it is not clear whether this is just a selection
by severity or a true pharmacological effect.
Corticosteroids
The role of anti-inflammatory agents in the treatment
of COPD remains unclear. Several trials of inhaled corticosteroid therapy have shown that these agents do not
slow the decline in lung function, although they do provide slightly more bronchodilator responses to shortacting b-agonists, and they may reduce the number of
exacerbations in severe COPD [71–73]. One reason
put forward for the lack of clinical response to corticosteroid treatment is that the inflammation of COPD is
not steroid responsive [74]. Therefore, other more
specific anti-inflammatory approaches may be necessary, such as those targeted against neutrophils or
macrophage activation.
It is not deemed necessary to use the response to a
course of oral steroids to determine whether a patient
with COPD should be given inhaled corticosteroid
therapy [72]. More severe COPD patients are more
likely to benefit, and a trial of 3–6 months is recommended. Inhaled corticosteroids should be considered
in patients who do not experience benefit from
bronchodilators.
Combination of corticosteroids
and bronchodilators
Recent studies using a combination of fluticasone and
salmeterol have shown a better improvement in FEV1
improvement of the order of 50–70 mL and in dyspnoeic index when compared to placebo or salmeterol
alone; in addition, the combination therapy significantly improved quality of life [75]. These results
provide some optimism for using such combination
therapies in COPD. The combination of inhaled
steroids and inhaled tiotropium will be of interest.
Specific treatment for cough in COPD
If cough is an important part of COPD and contributes
to deterioration in quality of life, it would make sense to
control the symptom. There are two approaches, which
are to suppress the amount of airway secretions and to
reduce the enhanced cough reflex to a ‘normal’ range.
Other potential causes of cough must be looked for
such as rhinosinusitis, gastro-oesophageal reflux, or
being on angiotensin-converting enzyme inhibitor
therapy.
There is no specific treatment of airway mucus
hypersecretion currently available. The currently available anticholinergics do not affect mucus secretion.
Inhaled corticosteroid therapy does not have an
inhibitory effect on goblet cells or on the expression
of mucins in the airways [76–78]. Steroids do not
inhibit the neutrophilic inflammation [74] which
may be responsible for excessive mucus secretion.
Leukotriene receptor antagonists may be tried because the cysteinyl leukotrienes are potent mucus
131
CHAPTER 13
secretagogues, but it is unlikely that these mediators are
involved in COPD.
Mucolytic therapy
There has been a trend in the past to use mucolytic
agents such as N-acetylcysteine or sodium 2mercaptoethane sulphonate, which break down disulphide bonds in mucins, to reduce the viscosity of
mucus, and therefore improve mucus clearance. Nacetylcysteine has been shown to have some beneficial
effects, particularly in reducing exacerbations [79],
although this may result from its antioxidant effects.
However, their efficacy is not good, and there is no
general acceptance of their use in the treatment of
COPD.
Cough suppressants
It is not recommended that centrally acting antitussives
such as opiates be used because of their potential suppressive effect on breathing (although in severe breathlessness opiates are sometimes used), and also because
of the risk of retaining secretions and of infections.
Whether the latter are serious risks is not known. To
what degree the bronchodilators such as b-agonists or
anticholinergics may influence cough in COPD is not
known, although in asthma the reduction in airway
tone achieved by bronchodilators may be a reason why
cough can be controlled. The use of tachykinin receptor
antagonists as antitussives has been proposed particularly for cough in COPD, and this action may result
from suppression of the effects of tachykinin on airways and sputum production.
References
1 Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of
Disease Study. Lancet 1997; 349: 1498–504.
2 Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd
SS. Global strategy for the diagnosis, management, and
prevention of chronic obstructive pulmonary disease.
NHLBI/WHO Global Initiative for Chronic Obstructive
Lung Disease (GOLD) Workshop summary. Am J Respir
Crit Care Med 2001; 163: 1256–76.
3 Fletcher C, Peto R. The natural history of chronic airflow
obstruction. Br Med J 1977; 1: 1645–8.
132
4 Peto R, Speizer FE, Cochrane AL, Moore F, Fletcher CM,
Tinker CM et al. The relevance in adults of air-flow obstruction, but not of mucus hypersecretion, to mortality
from chronic lung disease. Results from 20 years of
prospective observation. Am Rev Respir Dis 1983; 128:
491–500.
5 Prescott E, Lange P, Vestbo J. Chronic mucus hypersecretion in COPD and death from pulmonary infection. Eur
Respir J 1995; 8: 1333–8.
6 Seemungal TA, Donaldson GC, Paul EA, Bestall JC,
Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality
of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 1418–22.
7 Kanner RE, Anthonisen NR, Connett JE. Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive
pulmonary disease: results from the lung health study. Am
J Respir Crit Care Med 2001; 164: 358–64.
8 Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A
self-complete measure of health status for chronic airflow
limitation. The St. George’s Respiratory Questionnaire.
Am Rev Respir Dis 1992; 145: 1321–7.
9 Mannino DM, Gagnon RC, Petty TL, Lydick E. Obstructive lung disease and low lung function in adults in the
United States: data from the National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med
2000; 160: 1683–9.
10 Vestbo J, Lange P. Can GOLD Stage 0 provide information
of prognostic value in chronic obstructive pulmonary disease? Am J Respir Crit Care Med 2002; 166: 329–32.
11 Eriksson S. A 30-year perspective on alpha 1-antitrypsin
deficiency. Chest 1996; 110: 237S–42S.
12 Sandford AJ, Weir TD, Spinelli JJ, Pare PD. Z and S
mutations of the alpha1-antitrypsin gene and the risk of
chronic obstructive pulmonary disease. Am J Respir Cell
Mol Biol 1999; 20: 287–91.
13 Retamales I, Elliott WM, Meshi B, Coxson HO, Pare PD,
Sciurba FC et al. Amplification of inflammation in emphysema and its association with latent adenoviral infection.
Am J Respir Crit Care Med 2001; 164: 469–73.
14 Pilette C, Godding V, Kiss R, Delos M, Verbeken E,
Decaestecker C et al. Reduced epithelial expression of
secretory component in small airways correlates with
airflow obstruction in chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 2001; 163: 185–94.
15 Wanner A. Clinical aspects of mucociliary transport. Am
Rev Respir Dis 1977; 116: 73–125.
16 Di SA, Capelli A, Lusuardi M, Balbo P, Vecchio C,
Maestrelli P et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers.
Am J Respir Crit Care Med 1998; 158: 1277–85.
17 Rutgers SR, Postma DS, ten Hacken NH, Kauffman HF,
Der Mark TW, Koeter GH et al. Ongoing airway inflam-
COUGH IN COPD
18
19
20
21
22
23
24
25
26
27
28
29
30
mation in patients with COPD who do not currently
smoke. Thorax 2000; 55: 12–8.
Chung KF. Cytokines in chronic obstructive pulmonary
disease. Eur Resp J 2001; 18 (Suppl. 34): 50s–59s.
Finkelstein R, Fraser RS, Ghezzo H, Cosio MG. Alveolar
inflammation and its relation to emphysema in smokers.
Am J Respir Crit Care Med 1995; 152: 1666–72.
Saetta M, Turato G, Baraldo S, Zanin A, Braccioni F,
Mapp CE et al. Goblet cell hyperplasia and epithelial
inflammation in peripheral airways of smokers with
both symptoms of chronic bronchitis and chronic airflow
limitation. Am J Respir Crit Care Med 2000; 161:
1016–21.
Confalonieri M, Mainardi E, Della PR, Bernorio S,
Gandola L, Beghe B et al. Inhaled corticosteroids reduce
neutrophilic bronchial inflammation in patients with
chronic obstructive pulmonary disease [see comments].
Thorax 1998; 53: 583–5.
Yoshioka A, Betsuyaku T, Nishimura M, Miyamoto K,
Kondo T, Kawakami Y. Excessive neutrophil elastase in
bronchoalveolar lavage fluid in subclinical emphysema.
Am J Respir Crit Care Med 1995; 152: 2127–32.
Abboud RT, Fera T, Johal S, Richter A, Gibson N. Effect of
smoking on plasma neutrophil elastase levels. J Lab Clin
Med 1986; 108: 294–300.
Sommerhoff CP, Nadel JA, Basbaum CB, Caughey GH.
Neutrophil elastase and cathepsin G stimulate secretion
from cultured bovine airway gland serous cells. J Clin
Invest 1990; 85: 682–9.
Smallman LA, Hill SL, Stockley RA. Reduction of ciliary
beat frequency in vitro by sputum from patients with
bronchiectasis: a serine proteinase effect. Thorax 1984;
39: 663–7.
Saetta M, Baraldo S, Corbino L, Turato G, Braccioni F,
Rea F et al. CD8+ve cells in the lungs of smokers with
chronic obstructive pulmonary disease. Am J Respir Crit
Care Med 1999; 160: 711–7.
Saetta M, Di Stefano A, Maestrelli P, Ferraresso A, Drigo
R, Potena A et al. Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am Rev Respir Dis 1993; 147: 301–6.
Turato G, Di Stefano A, Maestrelli P, Mapp CE, Ruggieri
MP, Roggeri A et al. Effect of smoking cessation on airway
inflammation in chronic bronchitis. Am J Respir Crit Care
Med 1995; 152: 1262–7.
Saetta M, Mariani M, Panina-Bordignon P, Turato G,
Buonsanti C, Baraldo S et al. Increased expression of the
chemokine receptor CXCR3 and its ligand CXCL10 in
peripheral airways of smokers with chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2002;
165: 1404–9.
Petty TL, Silvers GW, Stanford RE. Mild emphysema is associated with reduced elastic recoil and increased lung size
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
but not with air-flow limitation. Am Rev Respir Dis 1987;
136: 867–71.
Mead J, Turner JM, Macklem PT, Little JB. Significance of
the relationship between lung recoil and maximum expiratory flow. J Appl Physiol 1967; 22: 95–108.
Matsuba K, Thurlbeck WM. The number and dimensions
of small airways in emphysematous lungs. Am J Pathol
1972; 67: 265–75.
Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of
airway obstruction in chronic obstructive lung disease. N
Engl J Med 1968; 278: 1355–60.
Barbee RA, Halonen M, Kaltenborn WT, Burrows B. A
longitudinal study of respiratory symptoms in a community population sample. Correlations with smoking, allergen skin-test reactivity, and serum IgE. Chest 1991; 99:
20–6.
Cullinan P. Persistent cough and sputum: prevalence and
clinical characteristics in south east England. Respir Med
1992; 86: 143–9.
Burrows B, Earle RH. Course and prognosis of chronic
obstructive lung disease. A prospective study of 200
patients. N Engl J Med 1969; 280: 397–404.
Doherty MJ, Mister R, Pearson MG, Calverley PM.
Capsaicin responsiveness and cough in asthma and
chronic obstructive pulmonary disease. Thorax 2000; 55:
643–9.
Power JT, Stewart IC, Connaughton JJ, Brash HM,
Shapiro CM, Flenley DC et al. Nocturnal cough in patients
with chronic bronchitis and emphysema. Am Rev Respir
Dis 1984; 130: 999–1001.
Hsu J-Y, Stone RA, Logan-Sinclair R, Worsdell M, Busst
C, Chung KF. Coughing frequency in patients with persistent cough using a 24-hour ambulatory recorder. Eur Resp
J 1994; 7: 1246–53.
Anthonisen NR, Manfreda J, Warren CP, Hershfield ES,
Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann
Intern Med 1987; 106: 196–204.
Choudry NB, Fuller RW. Sensitivity of the cough reflex
in patients with chronic cough. Eur Respir J 1992; 5:
296–300.
Doherty MJ, Mister R, Pearson MG, Calverley PM.
Capsaicin induced cough in cryptogenic fibrosing alveolitis. Thorax 2000; 55: 1028–32.
Bergren DR. Enhanced lung C-fiber responsiveness in sensitized adult guinea pigs exposed to chronic tobacco
smoke. J Appl Physiol 2001; 91: 1645–54.
Bergren DR. Chronic tobacco smoke exposure increases
cough to capsaicin in awake guinea pigs. Respir Physiol
2001; 126: 127–40.
Carr MJ, Hunter DD, Undem BJ. Neurotrophins and
asthma. Curr Opin Pulm Med 2001; 7: 1–7.
Tomaki M, Ichinose M, Miura M, Hirayama Y, Yamauchi
133
CHAPTER 13
47
48
49
50
51
52
53
54
55
56
57
58
59
H, Nakajima N et al. Elevated substance P content in induced sputum from patients with asthma and patients
with chronic bronchitis. Am J Respir Crit Care Med 1995;
151: 613–7.
Canning BJ. Interactions between vagal afferent nerve
subtypes mediating cough. Pulm Pharmacol Ther 2002;
15: 187–92.
Vestbo J, Prescott E, Lange P. Association of chronic
mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City
Heart Study Group. Am J Respir Crit Care Med 1996;
153: 1530–5.
Aikawa T, Shimura S, Sasaki H, Takishima T, Yaegashi H,
Takahashi T. Morphometric analysis of intraluminal
mucus in airways in chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 140: 477–82.
O’Brien C, Guest PJ, Hill SL, Stockley RA. Physiological
and radiological characterisation of patients diagnosed
with chronic obstructive pulmonary disease in primary
care. Thorax 2000; 55: 635–42.
Camner P, Mossberg B, Philipson K. Tracheobronchial
clearance and chronic obstructive lung disease. Scand J
Respir Dis 1973; 54: 272–81.
Wanner A. Clinical aspects of mucociliary transport. Am
Rev Respir Dis 1977; 116: 73–125.
Smaldone GC, Foster WM, O’Riordan TG, Messina MS,
Perry RJ, Langenback EG. Regional impairment of
mucociliary clearance in chronic obstructive pulmonary
disease. Chest 1993; 103: 1390–6.
Foster WM, Langenback EG, Bergofsky EH. Disassociation in the mucociliary function of central and peripheral
airways of asymptomatic smokers. Am Rev Respir Dis
1985; 132: 633–9.
Rose MC, Gendler SJ. Airway mucin genes and gene products. In: Rogers DF, Lethem MI, eds. Airway Mucus: Basic
Mechanisms and Clinical Perspectives. Boston, MA:
Birkhauser-Verlag, 1997: 41–66.
Hovenberg HW, Davies JR, Carlstedt I. Different mucins
are produced by the surface epithelium and the submucosa
in human trachea: identification of MUC5AC as a major
mucin from the goblet cells. Biochem J 1996; 318 (1):
319–24.
Steiger D, Fahy J, Boushey H, Finkbeiner WE, Basbaum
C. Use of mucin antibodies and cDNA probes to quantify
hypersecretion in vivo in human airways. Am J Respir Cell
Mol Biol 1994; 10: 538–45.
Kuo HP, Rohde JAL, Barnes PJ, Rogers DF. Cigarette
smoke-induced airway goblet cell secretion: dose dependent differential nerve activation. Am J Physiol 1992;
L161–L167.
Rogers DF, Aursudkij B, Barnes PJ. Effect of tachykinins
on mucus secretion on human bronchi in vitro. Eur J Pharmacol 1989; 174: 283–6.
134
60 Borchers MT, Wert SE, Leikauf GD. Acrolein-induced
MUC5ac expression in rat airways. Am J Physiol 1998;
274: L573–L581.
61 Voynow JA, Young LR, Wang Y, Horger T, Rose MC,
Fischer BM. Neutrophil elastase increases MUC5AC
mRNA and protein expression in respiratory epithelial
cells. Am J Physiol 1999; 276: L835–L843.
62 Takeyama K, Dabbagh K, Jeong SJ, Dao-Pick T, Ueki IF,
Nadel JA. Oxidative stress causes mucin synthesis via
transactivation of epidermal growth factor receptor: role
of neutrophils. J Immunol 2000; 164: 1546–52.
63 Barsky SH, Roth MD, Kleerup EC, Simmons M, Tashkin
DP. Histopathologic and molecular alterations in
bronchial epithelium in habitual smokers of marijuana,
cocaine, and/or tobacco. J Natl Cancer Inst 1998; 90:
1198–205.
64 Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey
WC, Buist AS et al. Effects of smoking intervention and the
use of an inhaled anticholinergic bronchodilator on the
rate of decline of FEV1. The Lung Health Study. JAMA
1994; 272: 1497–505.
65 Jorenby DE, Leischow SJ, Nides MA, Rennard SI,
Johnston JA, Hughes AR et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for
smoking cessation. N Engl J Med 1999; 340: 685–91.
66 Wynder EL, Kaufman PL, Lesser RL. A short-term followup study on ex-cigarette smokers. With special emphasis
on persistent cough and weight gain. Am Rev Respir Dis
1967; 96: 645–55.
67 Jones PW, Bosh TK. Quality of life changes in COPD
patients treated with salmeterol. Am J Respir Crit Care
Med 1997; 155: 1283–9.
68 Dahl R, Greefhorst LA, Nowak D, Nonikov V, Byrne
AM, Thomson MH et al. Inhaled formoterol dry powder
versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164:
778–84.
69 Vincken W, van Noord JA, Greefhorst AP, Bantje TA,
Kesten S, Korducki L et al. Improved health outcomes in
patients with COPD during 1 year’s treatment with
tiotropium. Eur Respir J 2002; 19: 209–16.
70 Boyd G, Morice AH, Pounsford JC, Siebert M, Peslis N,
Crawford C. An evaluation of salmeterol in the treatment
of chronic obstructive pulmonary disease (COPD). Eur
Respir J 1997; 10: 815–21.
71 Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K.
Long-term effect of inhaled budesonide in mild and
moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999; 353: 1819–23.
72 Burge PS, Calverley PM, Jones PW, Spencer S, Anderson
JA, Maslen TK. Randomised, double blind, placebo
controlled study of fluticasone propionate in patients
with moderate to severe chronic obstructive pulmonary
COUGH IN COPD
disease: the ISOLDE trial. Br Med J 2000; 320: 1297–
303.
73 Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP,
Postma DS, Pride NB. Long-term treatment with inhaled
budesonide in persons with mild chronic obstructive
pulmonary disease who continue smoking. European
Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Med 1999; 340: 1948–53.
74 Culpitt SV, Maziak W, Loukidis S, Nightingale JA,
Matthews JL, Barnes PJ. Effect of high dose inhaled
steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 1999; 160: 1635–9.
75 Calverley PMA, Pauwels RA, Vestbo J, Jones PW,
Pride NB, Gulsvik A, Anderson J, Maden C.
Combined salmeterol and fluticasone in the treatment of
chronic obstructive pulmonary disease: a randomised
controlled trial. Lancet 2003; 361: 449–56.
76 Laitinen LA, Laitinen A, Haahtela T. A comparative study
of the effects of an inhaled corticosteroid, budesonide, and
a beta 2-agonist, terbutaline, on airway inflammation in
newly diagnosed asthma: a randomized, double-blind,
parallel-group controlled trial. J Allergy Clin Immunol
1992; 90: 32–42.
77 Fahy JV, Boushey HA. Effect of low-dose beclomethasone
dipropionate on asthma control and airway inflammation. Eur Respir J 1998; 11: 1240–7.
78 Groneberg DA, Eynott PR, Lim S, Oates T, Wu R,
Carlstedt I et al. Expression of respiratory mucins in fatal
status asthmaticus and mild asthma. Histopathology
2002; 40: 367–73.
79 Boman G, Backer U, Larsson S, Melander B, Wahlander L.
Oral acetylcysteine reduces exacerbation rate in chronic
bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. Eur J Respir Dis 1983; 64:
405–15.
135
14
Cough in suppurative
airway diseases
Robert Wilson
Introduction
Airway suppurative diseases are characterized by production of purulent sputum containing large numbers
of bacteria and neutrophils. They usually occur because the local host defences are in some way deficient,
permitting inhaled bacteria to persist and multiply.
Neutrophils are attracted into the airway lumen by
the products of bacteria themselves and also by mediators released from host cells, e.g. interleukin-8 (IL-8),
C5a and leukotriene B4 (LTB4). Serum levels of the
adhesion molecules E-selectin, ICAM-1 and VCAM-1
are elevated, suggesting that endothelial activation
occurs, probably within the lung [1]. The failure of
the inflammatory response to eradicate the infection
once it is established is due partly to the impaired
defences but also to the number of bacteria present
and their pathogenic determinants [2]. Chronic neutrophilic inflammation has the potential to cause tissue
damage via spillage of proteolytic enzymes such as
elastase and reactive oxygen species. Immune complexes are formed between antibodies that are produced locally and those arriving via transudation, and
bacterial antigens. These stimulate other inflammatory
processes. Infection and inflammation may spread to
involve adjacent areas of normal bystander lung. The
lung defences are further weakened by the tissue damage caused by inflammation, and this in turn promotes
continued infection, which perpetuates the inflammatory response. Epithelial cells, lymphocytes and
macrophages release cytokines and other factors which
orchestrate this sequence of events which has been
termed ‘a vicious circle’ (Fig. 14.1).
Bronchiectasis results from loss of structural pro-
teins such as elastin from the bronchial wall, and
the muscle and cartilage layers also show signs of
damage. These changes lead to abnormal chronic
dilatation of the affected bronchi. Copious secretions
produced by increased numbers of goblet cells and hypertrophic submucosal glands partially obstruct the
airway lumen. Mucus is poorly cleared from the
bronchiectatic airways for several reasons: there is
pooling of excess secretions in the abnormal dilated
airways; ciliated cells are lost when the epithelium is
damaged; and the mucus is less elastic and more viscous
making it difficult to clear by ciliary beat or cough.
Side branches of the tortuous airways are frequently
obliterated, and there may be complete fibrosis of small
airways. There may be peribronchial pneumonic
changes with evidence of parenchymal damage. Lymphocytes predominate in the bronchial wall, which
contains lymphoid follicles and nodes, whereas
neutrophils are abundant in the lumen. As well as B
lymphocytes, plasma cells and CD4+ T lymphocytes in
the follicles, there is a well-developed cell-mediated
immune response, with increased numbers of activated
T lymphocytes, mainly of the suppressor/cytotoxic
CD8+ phenotype, antigen processing cells and mature
macrophages [3].
What is often difficult to establish is the starting
point of the pathological processes described above.
Bronchiectasis can occur as a result of an acute insult
which damages the bronchial wall, e.g. inhalation of
a toxic gas, or following a serious infection, e.g. tuberculosis or whooping cough. In other cases, there may be
a recognized deficiency in the local host defences, e.g.
primary ciliary dyskinesia or cystic fibrosis; or there
may be a deficiency of the systemic host defences, e.g.
137
CHAPTER 14
ment of cough in suppurative airway diseases may have
wider application in some COPD patients.
Impaired host
defences
Cough in bronchiectasis
Bacterial
infection
Tissue damage
Inflammation
Fig. 14.1 A vicious circle of events which begins because impaired host defences predispose the airway to bacterial infection. Persistent infection provokes chronic inflammation
which damages lung tissue and further impairs host defences
promoting continued infection.
hypogammaglobulinaemia, and in these cases damage
is caused by repeated pneumonias. However, in
many cases the origin of the bronchiectasis is much less
clear. There may be a history of childhood pneumonia,
but the significance of this when the patient presents
in adult life with widespread bronchiectasis is uncertain. A history of wheezy bronchitis in childhood
is also common. In some patients a particularly bad
viral-like illness occurs at the onset of their problems,
and the resultant cough and sputum never resolve.
Persistent viral infection might in some way alter the
host defences causing permissive conditions for what
follows [4].
Patients with smoking-related chronic obstructive
pulmonary disease (COPD) are prone to exacerbations
caused by bacterial infection, sometimes preceded by a
viral illness which impairs the airway defences by
destroying ciliated cells and altering mucus rheology. A
proportion of patients, about one-third in several studies, have lower airway bacterial colonization in the
stable state which can be associated with chronic neutrophilic airway inflammation [5]. One communitybased study has suggested that the prevalence of
bronchiectasis in this population is much higher than
had previously been recognized [6], and was present in
29% of patients. This is also suggested by the occurrence of Pseudomonas aeruginosa as a significant
pathogen in COPD patients with severe airflow obstruction [7]. Therefore various aspects of the manage138
Cough in bronchiectasis may be contributed by several
factors, of which the continuous presence of sputum
and airway secretions, often containing bacteria, is
likely to be the most important. Excessive production
of mucus and damage to mucociliary clearance mechanisms both contribute to mucus stasis in damaged airways of bronchiectasis. The induction of cough itself is
a powerful additional mechanism for clearing mucus
from the lungs. This cough clearance is independent of
the action of cilia, but cough efficiency is dependent on
the volume of liquid on the airway surface and the
viscosity of the intraluminal material [8]. Although
patients with primary ciliary dyskinesia have
abnormalities in ciliary structure that leads to absent or
slow ciliary beating and defective mucociliary clearance [9], their cough clearance is well preserved [10]
and mucus clearance is entirely achieved by repetitive
coughing. This illustrates the important therapeutic
role of coughing (e.g. when performing physiotherapy)
in conditions associated with bronchiectasis. The
importance of cough as a clearing mechanism in
bronchiectasis is also emphasized by a group of patients
in whom cough suppression had an adverse effect on
their clinical condition [11]. In cystic fibrosis, it has
been hypothesized that the reduction of periciliary
liquid surface is associated with both an inefficiency
of mucociliary and of cough clearance, and perhaps
results in a more severe disease phenotype when
compared to primary ciliary dyskinesia [12]. One
possibility is that this loss of periciliary liquid fluid may
cause increased attachment between certain mucin
components, to cause bonding between mucus and the
epithelial surface.
Capsaicin cough reflex
In a small group of bronchiectatic patients, the cough
response to inhaled capsaicin was found to be comparable to that of normal subjects, but the severity of the
bronchiectasis was not specified [13]. There may be
several reasons why there could be an enhanced cough
reflex in patients with more severe bronchiectasis. First,
COUGH IN SUPPURATIVE AIRWAY DISEASES
the presence of severe neutrophilic bronchial inflammation and damage may be expected to stimulate
cough receptors. Second, the occurrence of concomitant diseases such a rhinosinusitis and gastrooesophageal reflux may contribute to or exacerbate
cough. These associated conditions, of course, need to
be treated specifically.
Clinical features
The most common symptoms are cough and sputum
production. Patients suffer from recurrent bronchial
infections or may have chronic infection causing regular production of purulent sputum that can total several hundred millilitres in a day. Although most often an
exacerbation is associated with increased purulent
sputum production, sometimes the volume decreases
because it becomes more sticky and difficult to expectorate. High temperature is unusual and may indicate
an acute viral infection or pneumonia if it occurs.
Chronic rhinosinusitis is very common. There is a positive correlation between the severity of airflow obstruction present and the severity of bronchiectasis [14].
There may be some reversibility indicating an asthmatic component, but most of the obstruction is usually
fixed. Over half of patients have airway hyperresponsiveness to methacholine [15].
Chest pains and discomfort are common and increase during exacerbations. Joint pains also occur.
Haemoptysis when present is usually small. Undue
tiredness and difficulty concentrating usually reflects
poorly controlled disease. Symptoms of anxiety and/or
depression may be present as in any chronic illness. We
have found that depression correlates with severity of
disease, but the level of anxiety may be much higher
than is appropriate. This is important to recognize,
because it may not improve with treatment of the lung
disease, and would therefore need to be dealt with
separately [16]. Exercise tolerance, the frequency of
exacerbations, requirement for hospital admission and
the presence or absence of P. aeruginosa infection are
the best predictors of quality of life in bronchiectasis
[17,18].
There may be coarse inspiratory crackles heard over
the site of bronchiectasis, but sometimes there are no
signs in the lung to suggest the diagnosis. Wheezes and
squeaks may be heard due to obstructed airways. Clubbing is quite unusual nowadays, because severe cases
with cystic bronchiectasis are seen infrequently. Weight
should always be recorded because it often falls during
a spell of poor control. Patients’ description of their
sputum colour and volume is often inaccurate and a 24h sputum collection is very informative. Mucus plugs
that form a cast of the airway may indicate allergic
bronchopulmonary aspergillosis (ABPA).
The prevalence of severe cystic bronchiectasis has
decreased because of the introduction of vaccination
against childhood infections, improved socioeconomic
conditions and the availability of antibiotics, but in
parts of the world where social conditions are poor and
health care less available bronchiectasis remains a
much more common cause of morbidity and mortality.
The availability of high-resolution computed tomography has increased the recognition of milder forms of
disease. This cylindrical or tubular form has been
termed ‘modern’ bronchiectasis [19]. The disease is
usually bilateral and may be diffuse, although the lower
lobes are usually worst affected. Progression of disease
may be bimodal, with most patients stable or declining
slowly, whereas a smaller number progress more rapidly for reasons that may not be clear. It is important to
identify those patients that are deteriorating in order
that treatment can be given in an attempt to halt the
decline.
Investigations
Suspicion of the presence of bronchiectasis should lead
to investigation of possible causes (Table 14.1) and associated conditions (Table 14.2). The protocol of investigations performed in our unit is given in Table 14.3. In
a study of 150 patients, Pasteur et al. [20] found that
similar intensive investigation influenced management in 44 instances: 12 had immunological defects, 11
ABPA, 6 aspiration or reflux, 5 Young’s syndrome, 4
cystic fibrosis, 3 primary ciliary dyskinesia, 2 ulcerative
colitis and 1 diffuse panbronchiolitis. Younger patients, those with associated conditions, e.g. infertility,
and those in whom respiratory function is deteriorating
and/or infective exacerbations are becoming more
frequent or prolonged should be seen by a respiratory
physician with a special interest in bronchiectasis who
has access to all of the investigations listed.
A chest radiograph is a relatively insensitive test
for bronchiectasis. In one study less than 50% of patients who subsequently had positive bronchography
139
CHAPTER 14
Table 14.1 Causes of bronchiectasis.
Congenital, e.g. defective bronchial wall, pulmonary sequestration
Postinfective, e.g. tuberculosis, whooping cough, non-tuberculous mycobacteria especially Mycobacterium avium complex
Mechanical obstruction within lumen (e.g. tumour or foreign body) or external compression (e.g. lymph node), bronchial
stenosis
Deficient immune response, e.g. common variable hypogammaglobulinaemia, disorders of phagocyte function, human
immunodeficiency virus
Inflammatory pneumonitis, e.g. aspiration of gastric contents, inhalation of toxic gases
Excessive immune response, e.g. allergic bronchopulmonary aspergillosis, lung transplant rejection, chronic graft vs. host
disease
Abnormal mucociliary clearance, e.g. primary ciliary dyskinesia, cystic fibrosis*, Young’s syndrome
Fibrosis, e.g. cryptogenic fibrosing alveolitis, sarcoidosis, radiation pneumonitis
*Note: Delayed mucociliary clearance in cystic fibrosis may be part of the primary defect or could be secondary to infection.
Other mechanisms are likely to cause bacterial infection in cystic fibrosis, e.g. altered bacterial adherence to airway epithelium or
defective bacterial killing by defensins due to high sodium content of airway fluids.
Table 14.2 Conditions associated with bronchiectasis.
Infertility, e.g. primary ciliary dyskinesia, cystic fibrosis, Young’s syndrome
Inflammatory bowel disease, e.g. ulcerative colitis, Crohn’s disease, coeliac disease
Connective tissue disorders, e.g. rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome
Malignancy, e.g. acute or chronic lymphatic leukaemia
Diffuse panbronchiolitis. Predominantly seen in Japanese
Yellow nail syndrome. Discoloured (usually yellow) nails, lymphoedema and pleural effusions
a1-Antiproteinase deficiency. More commonly causes emphysema
Mercury poisoning. May cause Young’s syndrome (obstructive azospermia, sinusitis and bronchiectasis)
were detected [21]. High-resolution thin-section (1–2
mm) computed tomography scans, performed with a
fast scan time (1 s or less) to reduce artefacts from respiratory motion and cardiac pulsation, have replaced
bronchography in establishing the diagnosis and assessing the extent of the disease. The whole of the lung
should be examined with 10 mm intersection spacing.
Characteristic findings are illustrated in Fig. 14.2.
Although certain features may suggest a cause of
bronchiectasis, e.g. cystic fibrosis (upper lobe disease),
ABPA (proximal disease), non-tuberculous mycobacteria (mild disease with peripheral nodules that may be
cavitating) or diffuse panbronchiolitis (widespread
small nodules), they do not usually allow a confident
diagnosis [22].
Lung function tests provide a measure of functional
impairment and an assessment of change with time.
Airflow obstruction, which is largely fixed, and gas
trapping are very common. Gas transfer values that
140
have been adjusted for alveolar volume are usually well
preserved unless the disease is severe. Antibody deficiency is a relatively common cause of bronchiectasis.
Immunoglobulin G subclass deficiency by itself is not a
cause of susceptibility to infection. Specific antibody
levels should be measured, and if these are low the
ability to respond appropriately to vaccination with
polysaccharide (pneumococcal and Haemophilus
influenzae type b) and protein (tetanus) antigens
should be tested. All cases of immune deficiency may
be secondary to malignancy, particularly of the lymphoreticular system, so a high index of suspicion must
be maintained.
Sputum should be examined by microscopy as well
as culture for respiratory pathogens including fungi
and mycobacteria, since eosinophils may cause
purulence, and their presence may indicate asthma
and/or ABPA. H. influenzae, H. parainfluenzae and
Pseudomonas aeruginosa (which develops a mucoid
COUGH IN SUPPURATIVE AIRWAY DISEASES
Table 14.3 Investigation of bronchiectasis.
All patients
Chest radiograph (PA and lateral)
Sinus radiographs
High-resolution thin-section computed tomography scan
Respiratory function tests
Blood investigations*
Sputum microscopy including eosinophils
Sputum culture and sensitivities
Sputum smear and culture for acid-fast bacilli
Skin tests (atopy, Aspergillus)
Sweat test (nasal potential difference, genotyping)
Nasal mucociliary clearance and exhaled nasal nitric oxide
Proceed to cilia studies if these tests are abnormal
Selected patients
Fibreoptic bronchoscopy
Barium swallow (video fluoroscopy)
Respiratory muscle function
Semen analysis
Tests for associated conditions
Blood tests for rarer immune deficiencies
*To include: differential white cell count; erythrocyte
sedimentation rate and C-reactive protein; total
immunoglobulin (Ig) levels of IgG, IgM, IgA, IgE and IgG
subclasses; specific antibodies; protein electrophoretic strip;
Aspergillus radioallergosorbent test and precipitins;
rheumatoid factor and antinuclear antibodies;
a1-antiproteinase.
phenotype after chronic infection) are the species identified most frequently.
The saccharin test can be used as a simple screening
test to determine if there is a mucociliary clearance
problem [23]. We use exhaled nasal nitric oxide, which
is very low in patients with primary ciliary dyskinesia,
as another screening test. When a ciliary problem is suspected a sample of epithelium is taken from the inferior
turbinate of the nostril using a cytology brush. The ciliary beat frequency and the pattern of ciliary beating
are assessed under light microscopy, and the rest of the
sample is processed for electron microscopy and study
of ultrastructure [24].
Specific causes of bronchiectasis
We remain ignorant of many of the underlying causes
of bronchiectasis, and about half of cases are still con-
D
B
A
C
Fig. 14.2 High-resolution thin-section computed tomography scan of a patient with bronchiectasis. Several characteristic features are demonstrated: a non-tapering bronchus (A);
airway wall thickening (B); the signet ring sign in which the
airway is larger than the accompanying pulmonary artery
(C); mucus filled bronchi which appear as branching tubes or
nodules (D).
sidered idiopathic. Some of the more important causes
are briefly described in this section. Microorganisms
causing severe lung infections that are particularly associated with subsequent bronchiectasis are Mycobacterium tuberculosis, M. avium complex, Bordetella
pertussis, measles virus and adenovirus. A history of
chronic cough and sputum production follows the severe illness. Localized bronchiectasis may occur due to
infection occurring distal to a bronchial obstruction
from any cause, and this can either be in the lumen or
due to compression from outside. Acquired common
variable hypogammaglobulinaemia is the most common immunological deficiency discovered in adults
[25]. ABPA is caused by an immune reaction to Aspergillus fumigatus fungus colonizing the airway
involving eosinophils. Atelectasis occurs due to
obstruction by plugs of inspissated secretions containing fungal hyphae. Acute episodes of fever, wheeze, expectoration of viscid sputum plugs and pleuritic pain,
sometimes associated with fleeting shadows on the
chest radiograph, merge insidiously over time as
bronchiectasis develops into chronic purulent sputum
production where exacerbations of ABPA are difficult
to distinguish from infective exacerbations of
bronchiectasis.
Three different forms of impaired mucociliary
clearance result in chronic bacterial infection and
141
CHAPTER 14
bronchiectasis. Cystic fibrosis is caused by a recessive
mutation of a gene on the long arm of chromosome 7,
which codes for CFTR (cystic fibrosis transmembrane
conductance regulator), a cyclic AMP-dependent chloride channel, which has wide-ranging effects in addition to mucociliary clearance. Childhood infections
with Staphylococcus aureus and non-typeable H. influenzae progress inexorably to severe bronchiectasis
and chronic P. aeruginosa infection and death in early
adult life due to respiratory failure. Primary ciliary
dyskinesia is rare and is thought to be an autosomal recessive condition with incomplete penetrance. Ultrastructural abnormalities in the cilia cause them to be
immotile or move in a slow disorganized fashion.
About half of patients have dextrocardia, and a smaller
percentage full situs inversus. They may present in the
neonatal period with segmental collapse due to mucus
impaction. Cough is incessant, as it is the only way the
patient has to clear mucus. Diffuse bronchiectasis is associated with chronic sinusitis, middle ear disease and
often, but not invariably, in men infertility due to immotile sperm. Young’s syndrome is a combination of
bronchiectasis, chronic sinusitis and azoospermia due
to functional blockage of sperm in the caput epididymis. The condition has been linked to mercury positioning, the incidence of which has fallen since
mercurous chloride was removed from teething powders and worm medication in the UK.
Non-antibiotic treatment
Poor clearance of mucus from bronchiectatic airways
is probably the fundamental reason that patients become infected. Therefore physiotherapy exercises to
clear secretions are a critical aspect of management. Patients are advised to perform postural drainage at least
once daily, and increase the frequency to twice or three
times daily if they suffer an exacerbation. Patients
should be taught by a trained physiotherapist to adopt
the correct position to drain affected areas, and clear
mucus by controlled breathing techniques, sometimes
aided by chest clapping by the patient or partner. About
10 min in any one productive position is required. Understandably compliance with physiotherapy is poor,
because of the nature of the process and the time involved, so medical staff should regularly remind the patient of its importance. Physical exercise should also be
encouraged.
142
Any asthmatic component of bronchiectasis should
be treated in the usual way. Systemic corticosteroids
have unacceptable side-effects when used long-term to
reduce airway inflammation, although they are used
for short periods during severe exacerbations; however,
in some patients systemic corticosteroids are required.
Treatment of ABPA with high-dose inhaled corticosteroids may prevent exacerbations. The antifungal
antibiotic itraconazole may act as a steroid sparing
agent [26]. Inhaled corticosteroids are commonly given
to bronchiectasis patients in an attempt to reduce
airway inflammation and relieve airflow obstruction [27]. However, there is little evidence that this is
beneficial, and an objective assessment of symptoms
and lung function tests should be made after their
introduction.
Acid reflux and rhinosinusitis should be treated if
present. Influenza (annual) and pneumococcal vaccination should be encouraged. Nebulized saline may be
given in an attempt to promote cough clearance by
liquefying secretions. Nebulized recombinant human
DNase gives some benefit to cystic fibrosis patients
in this way, but not in other forms of bronchiectasis,
and other mucolytic agents have no proven benefit.
Patients with chronic respiratory failure due to
bronchiectasis are managed in the usual way. Nasal
intermittent positive pressure ventilation is often surprisingly well tolerated despite sinusitis and excess
bronchial secretions [28].
The only curative treatment of bronchiectasis is surgical resection. Cylindrical bronchiectasis is usually bilateral and surgery is rarely considered for this reason.
Palliative surgical resection may be considered if a localized area of severe bronchiectasis defies medical
management and acts as a sump for infection, even if
less severe bronchiectasis is present elsewhere. Emergency surgical resection may be necessary for lifethreatening haemoptysis, but embolization of the
appropriate bronchial artery is usually attempted first.
Lung transplantation (usually two lungs or heart–lung
otherwise infection in the remaining lung may spread to
the new organ) has been used to treat end-stage respiratory failure due to bronchiectasis.
Antibiotic management
When bronchiectasis is mild to moderate, antibiotics
can reduce the bacterial numbers in the airway to low
COUGH IN SUPPURATIVE AIRWAY DISEASES
levels leading to resolution of the symptoms of the exacerbation. The lung defences are then able to control
bacterial numbers at levels which do not attract an
overt inflammatory response. The next exacerbation
occurs either when a new bacterial infection occurs or
when an event, such as a viral infection, impairs the
host defences, so that bacterial numbers can increase.
When lung damage is more severe, the bronchial tree is
usually chronically infected and the patient’s symptoms
may return soon after stopping the antibiotic. In these
different circumstances, antibiotics may be needed only
during an infective exacerbation when there is a change
in sputum production, breathlessness and malaise, or
at the other end of the spectrum continuously if relapse
following antibiotic treatment is rapid.
The choice of antibiotic is influenced by the high
frequency of b-lactamase production by strains of H.
influenzae and Moraxella catarrhalis, isolated from
bronchiectasis patients who have taken frequent antibiotic courses in the past, and the presence or absence
of P. aeruginosa which is resistant to most oral antibiotics. Co-amoxyclavulanate and ciprofloxacin are
our first-line choices. If patients are severely unwell
at presentation and/or are infected by resistant strains,
intravenous antibiotics are used. Ceftriaxone (nonPseudomonas patients) and ceftazidime plus an aminoglycoside (Pseudomonas patients) are our first-line
antibiotics in these circumstances, with piperacillintazobactam and meropenem second line. Intravenous
antibiotics should be commenced in hospital where
supportive treatment such as physiotherapy can also be
given, but increasingly patients are being taught to
administer their own injections, so that when they are
improving their hospital stay can be shortened by
finishing the course at home.
Patients with frequent exacerbations who relapse
quickly following intravenous treatment may be
considered for long-term prophylactic antibiotics. This
decision should only be taken after careful consideration, and only after other aspects of management have
been optimized. There are several concerns about
this approach: development of antibiotic resistance in
the strains already present, promotion of infection by
more antibiotic-resistant species, e.g. P. aeruginosa,
and side-effects of antibiotics, e.g. Clostridium difficile
infection. Three different approaches to antibiotic
prophylaxis have been used: oral antibiotics, which
can either be with a single antibiotic, or a rotation of
several antibiotics from different classes [29]; inhaled
antibiotics given as an isotonic solution via a nebulizer
[30]; and regular pulsed courses of intravenous antibiotics [31]. Each approach has been shown to reduce
exacerbation frequency, as well as having other benefits. In broad terms we use oral prophylaxis in patients
not infected with Pseudomonas, nebulized antibiotics
for patients with chronic Pseudomonas infection, and
pulsed intravenous antibiotics for patients with the
most severe disease in whom other forms of prophylaxis have failed.
Continuous treatment with macrolide antibiotics
has been used effectively to treat diffuse panbronchiolitis, even when there is chronic bronchial infection
involving P. aeruginosa. This condition was first described in Japan, where it seems to be much more common. There are unique radiological and histological
features, but it bears some resemblance clinically to
idiopathic bronchiectasis. The benefit of macrolides
is unlikely to involve bacterial killing, although
macrolides do influence P. aeruginosa virulence determinants; it is more likely that the anti-inflammatory
properties of the macrolide class are responsible [32].
A recent study has shown promising results in cystic
fibrosis, and further studies in bronchiectasis are under
way [33].
Treatment of cough in bronchiectasis
Because cough clearance is important in bronchiectasis, antitussive therapy is relatively contraindicated.
If cough appears to be a debilitating symptom for
the patient, then various treatment approaches directed
at the airway may well reduce the burden of cough.
This is illustrated by treatments for the infective exacerbations of bronchiectasis. Corticosteroid therapy
may reduce cough by inhibiting the inflammatory
process in bronchiectatic airways, and inhaled bagonist bronchodilator therapy by reversing airway
smooth muscle tone and by improving mucociliary
clearance. However, evidence is lacking that either
of these two approaches is beneficial in non-asthmatic
patients [34]. Macrolide antibiotics have been shown
to reduce sputum volume and to normalize mucus
rheology in two small studies [35,36], to suppress secretion of respiratory glycoconjugates from human airway cells [37], and to reduce neutrophil accumulation
and activation [38]. In the future, demonstration of
sensitization of the cough reflex may be a justification
143
CHAPTER 14
to intensify anti-inflammatory and mucus inhibitory
approaches.
References
1 Zheng L, Tipoe G, Lam WK et al. Up-regulation of circulating adhesion molecules in bronchiectasis. Eur Respir J
2000; 16: 691–6.
2 Wilson R, Dowling R, Jackson AD. The biology of bacterial colonization and invasion of the respiratory mucosa.
Eur Respir J 1996; 9: 1523–30.
3 Lapa e Silva JR, Jones JAH, Cole PJ, Poulter LW. The
immunological component of the cellular inflammatory
infiltrate in bronchiectasis. Thorax 1989; 44: 668–73.
4 Elliot WM, Hayashi S, Hogg JC. Immunodetection of adenoviral EIA proteins in human tissue. Am J Respir Cell
Mol Biol 1995; 12: 642–8.
5 Wilson R. Bacterial infection and chronic obstructive
pulmonary disease. Eur Respir J 1999; 13: 233–5.
6 O’Brien C, Guest PJ, Hill SL et al. Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax
2000; 55: 635–42.
7 Miravitlles M, Espinosa C, Ferandez-Laso E et al. Relationship between bacterial flora in sputum and functional
impairment in patients with acute exacerbations of
COPD. Chest 1999; 116: 40–6.
8 King M, Zahm JM, Pierrot D, Vaquez-Girod S, Puchelle E.
The role of mucus gel viscosity, spinnability, and adhesive
properties in clearance by simulated cough. Biorheology
1989; 26: 737–45.
9 Camner P, Mossberg B, Afzelius BA. Measurements of
tracheobronchial clearance in patients with immotile-cilia
syndrome and its value in differential diagnosis. Eur J
Respir Dis Suppl 1983; 127: 57–63.
10 Noone PG, Bennett WD, Regnis JA, Zeman KL,
Carson JL, King M et al. Effect of aerosolized uridine-5¢triphosphate on airway clearance with cough in patients
with primary ciliary dyskinesia. Am J Respir Crit Care
Med 1999; 160: 144–9.
11 Wells A, Rahman A, Woodhead M, Pfeiffer J, Wilson R,
Cole PJ. Voluntary cough suppression associated with
chronic pulmonary suppuration: a new syndrome. Eur
Respir J 1992; 5 (Suppl. 15): 141S.
12 Knowles MR, Boucher RC. Mucus clearance as a primary
innate defense mechanism for mammalian airways. J Clin
Invest 2002; 109: 571–7.
13 Choudry NB, Fuller RW. Sensitivity of the cough reflex
in patients with chronic cough. Eur Respir J 1992; 5:
296–300.
14 Hansell DM. Imaging of obstructive pulmonary disease.
Bronchiectasis. Radiol Clin N Am 1998; 36: 107–28.
144
15 Bahous J, Cortier A, Pineau L et al. Pulmonary function
tests and airway responsiveness to metacholine in chronic
bronchiectasis of the adult. Bull Eur Physiopathol Respir
1984; 20: 375–80.
16 O’Leary CJ, Wilson CB, Hansell DM, Cole PJ, Wilson R,
Jones PW. Relationship between psychological well-being
and lung health status in patients with bronchiectasis.
Respir Med 2002; 96: 686–92.
17 Wilson CB, Jones PW, O’Leary CJ et al. Health status assessment in bronchiectasis using the St George’s Respiratory Questionnaire. Am J Respir Crit Care Med 1997;
156: 536–41.
18 Wilson CB, Jones PW, O’Leary CJ et al. Effect of sputum
bacteriology on the quality of life of patients with
bronchiectasis. Eur Respir J 1998; 12: 820–4.
19 Cole PJ. Bronchiectasis. In: Brewis RAL, Corrin B, Geddes
DM, Gibson GJ, eds. Respiratory Medicine, 2nd edn.
London: W.B. Saunders, 1995: 1286–317.
20 Pasteur MC, Helliwell SM, Houghton SJ et al. An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med 2000; 162: 1277–84.
21 Currie DC, Cooke JC, Morgan AD et al. Interpretation of
bronchograms and chest radiographs in patients with
chronic sputum production. Thorax 1987; 42: 278.
22 Reiff DB, Wells AU, Carr DH et al. CT findings in
bronchiectasis: limited value in distinguishing between
idiopathic and specific types. Am J Roentgenol 1995; 165:
261–7.
23 Stanley P, MacWilliam L, Greenstone M et al. Efficacy of a
saccharin test for screening to detect abnormal mucociliary clearance. Br J Dis Chest 1984; 78: 62–5.
24 Rutland J, Dewar A, Cox T, Cole PJ. Nasal brushing for
the study of ultrastructure. J Clin Pathol 1982; 35: 357–9.
25 Watts WJ, Watts MB, Dai W et al. Respiratory dysfunction
in patients with common variable hypogammaglobulinaemia. Am Rev Respir Dis 1986; 134: 699–703.
26 Stevens DA, Schwartz HJ, Lee JY et al. A randomised trial
of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 2000; 342: 756–62.
27 Tsang KWT, Ho PL, Lam WK et al. Inhaled fluticasone reduces sputum inflammatory indices in severe bronchiectasis. Am J Respir Crit Care Med 1998; 158: 723–7.
28 Gacouin A, Desrues B, Lena H et al. Long-term nasal intermittent positive pressure ventilation (NIPPV) in sixteen
consecutive patients with bronchiectasis: a retrospective
study. Eur Respir J 1996; 9: 1246–50.
29 Rayner CFJ, Tillotson G, Cole PJ, Wilson R. Efficacy and
safety of long term ciprofloxacin in the management of
severe bronchiectasis. J Antimicrob Chemother 1994; 34:
149–56.
30 Mukopadhyay S, Singh M, Cater JL et al. Nebulised antipseudomonal antibiotic therapy in cystic fibrosis: a metaanalysis of benefits and risks. Thorax 1996; 51: 364–8.
COUGH IN SUPPURATIVE AIRWAY DISEASES
31 Szaff M, Holby N, Flensborg FW. Frequent antibiotic therapy improves survival of cystic fibrosis patients with
chronic Pseudomonas aeruginosa infection. Acta Paediatr
Scand 1983; 72: 651–7.
32 Kudoh S, Uetake T, Hagiwara K et al. Clinical effects of
low dose long-term erythromycin chemotherapy on diffuse panbronchiolitis. Jpn J Thorac Dis 1987; 25: 632–42.
33 Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack
J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 2002; 57: 212–6.
34 Elborn JS, Johnston B, Allen F, Clarke J, McGarry J,
Varghese G. Inhaled steroids in patients with bronchiectasis. Respir Med 1992; 86: 121–4.
35 Tamaoki J, Takeyama K, Tagaya E, Konno K. Effect of
clarithromycin on sputum production and its rheological
properties in chronic respiratory tract infections. Antimicrob Agents Chemother 1995; 39: 1688–90.
36 Rubin BK, Druce H, Ramirez OE, Palmer R. Effect of clarithromycin on nasal mucus properties in healthy subjects
and in patients with purulent rhinitis. Am J Respir Crit
Care Med 1997; 155: 2018–23.
37 Goswami SK, Kivity S, Marom Z. Erythromycin inhibits
respiratory glycoconjugate secretion from human airways
in vitro. Am Rev Respir Dis 1990; 141: 72–8.
38 Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol 2001; 429:
209–29.
145
15
Cough in cancer patients
Sam H. Ahmedzai & Nisar Ahmed
Prevalence and epidemiology
Cough is a normal basic mechanism for self-preservation, and is experienced by all people frequently and
often subconsciously. In respiratory diseases, cough is
sometimes necessary to expectorate excess mucus, but
its frequency and severity may increase to the point that
it impinges on normal daily activities. In the cancer patient, who is usually already burdened by several physical and psychological symptoms, cough can become a
major source of distress.
The cancers that are most commonly associated with
cough and other respiratory symptoms such as dyspnoea and haemoptysis are, naturally, those arising from
the airways, lungs, pleura and other mediastinal structures. However, cancers from many other primary sites
can metastasize to the thorax and produce the same
symptoms. As discussed below, the various anticancer
treatments given for all types of malignancy can themselves be a potent cause of cough, amongst many other
side-effects. For these reasons, it is difficult to state the
exact prevalence of cough in cancer patients, as this
varies between different primary types, their stage and
therapies used.
At presentation, cough is one of the commonest
symptoms of lung cancer. Cumulative experience of
650 patients entering the UK Medical Research Centre’s multicentre lung cancer trials shows that, overall,
cough was the fourth commonest symptom reported at
presentation [1]. The actual frequency of cough was
80% in small cell lung cancer (SCLC) and in 70% of
non-small cell lung cancer (NSCLC). Male patients reported 7% more cough, and 12% more coughing up of
blood (haemoptysis), than females. A survey of patients
with a variety of other cancers attending a large US cancer hospital found that cough was a troublesome symptom for 22% of patients with colon cancer, 26% with
prostate cancer, 28% with ovarian cancer and 37%
with breast cancer [2]. The overall prevalence of cough
was 29%.
Much of the literature on the palliation of cough
in lung and other primary cancers focuses on the
‘advanced’ stages of disease. Usually this means that
the cancer has failed to respond to first-line curative
treatment and has progressed either locally or metastatically. The reporting of cough in these patients is
therefore subject to bias from the impact of prior anticancer therapies as well as intercurrent respiratory
infections that are increasingly common in patients
with increasing frailty and reduced immunity. Another
cause for lack of precision in stating the frequency of
cough — as well as most other symptoms in cancer patients — is that standardized and validated measures,
ideally rated by patients themselves, are not directly
comparable. Indeed, in much of the older oncological
literature, symptoms were evaluated by attending clinicians rather than the patients.
A standard quality of life (QoL) questionnaire commonly used in lung cancer studies is the European Organization for Research and Treatment of Cancer
(EORTC) Lung Cancer 13-item Module (LC-13). Two
international studies, conducted for the validation of
this patient-rated instrument, which included 883 patients with inoperable NSCLC who were about to start
palliative radiotherapy or chemotherapy, found that
the prevalence of cough which was scored as ‘quite a
bit’ or ‘very much’ was altogether 39% [3]. In contrast,
combined data on a total of 673 patients from two US
147
CHAPTER 15
studies in advanced (stage III and IV) NSCLC which
used another self-rated tool, the Lung Cancer Symptom
Scale (LCSS), showed the baseline prevalence of cough
overall to be much higher (86%) [4]. The difference
probably arises because the EORTC study only reported those who reported the more severe grades of cough.
This assumption is backed up by a later study using the
LCSS, which confirmed that cough was the least severe
of the self-reported symptoms [5].
Several surveys of patients referred to palliative care
services have measured symptom prevalence on admission. One US teaching hospital study found cough to be
present in 52% of 100 consecutively admitted patients
[6]. Of this series, 59 had cancer, 22 AIDS and the rest a
variety of terminal conditions. In contrast, a UK palliative care team investigating the problems presented by
heart failure and cancer patients at referral found the
former were more likely to report cough as a troublesome symptom (44% compared with 26%, respectively) [7].
Table 15.1 summarizes the evidence on the prevalence of cough in cancer and palliative care patients.
The prevalence of cough in children with cancer was
assessed in an Australian study which used another selfrated instrument, the Memorial Symptom Assessment
Scale [8]. In 160 children aged 10–18, cough fell into
the group of symptoms experienced by > 35% of the
sample. However, it was not amongst the symptoms
that the patients identified as causing severe distress.
Does the presence of cough have prognostic significance in cancer patients? A multivariate analysis of sev-
eral factors concerning 260 patients with surgically
resected stage I and II NSCLC did indeed show that
median survival in patients with cough was 39 months,
compared with 57 months for patients without cough
(P = 0.04) [9]. In a further analysis of this series, using
the Cox proportional hazards model, cough was a significant predictor of shorter survival (present vs. absent, P = 0.01) [10]. Furthermore, the presence of cough
was a significant (P = 0.02) predictor of disease-free survival. A Japanese study has also revealed that during
the course of hospice care, cough frequency rose from
29% on admission to 48% nearer to death [11]. However, many other symptoms also deteriorated during
the hospice stay, and the analysis did not reveal whether
cough was an independent prognostic factor.
When is cough in cancer patients a new symptom of
that disease? This is a relevant question, as most patients who present with lung cancer are smokers who
may already have a chronic cough. A case-control study
of Czech women with newly diagnosed lung cancer
(140 cases, 280 matched controls) investigated this
issue. It found that chronic cough and sputum (defined
as occurring at least 3 months per year) was associated
with an excess risk of lung cancer (odds ratio = 6.07),
but only if the cough was of less than 2 years in duration
[12]. Thus it was argued that the cough associated with
lung cancer patients, at least, was a new symptom resulting from preclinical changes arising from the malignancy. A further epidemiological study from Sweden
which investigated 364 new cases of lung cancer supports this interpretation [13]. Only 7% of the patients
Table 15.1 Prevalence of cough in cancer and palliative care patients.
Source
Primary site
Stage of disease
n
Cough (%)
Haemoptysis (%)
Dyspnoea (%)
[1]
[1]
[3]
[4]
[2]
[2]
[2]
[2]
[11]
[7]
SCLC
NSCLC
NSCLC
NSCLC
Breast
Colon
Prostate
Ovary
Mixed
Mixed
Advanced
Advanced
Inoperable
Advanced
Mixed
Mixed
Mixed
Mixed
Terminal
Terminal
232
423
833
673
70
60
63
50
350
213
81
87
—
86
37
22
26
29
29–48*
26
26
36
—
41
nr
nr
nr
nr
nr
nr
87
86
—
87
26
29
25
25
33–66*
49
* First figure is at admission; second figure is near death.
SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; nr, not recorded.
148
COUGH IN CANCER PATIENTS
were asymptomatic at diagnosis, and cough was the
most common first symptom to be reported.
It is not altogether clear why cough should be such a
sensitive indicator of a new lung cancer and may also
signify a poorer outcome. One possible explanation
comes from a study of the rheological properties of
mucus taken by bilateral paired sampling in patients
being bronchoscoped for a unilateral radiological abnormality [14]. Eight of the 20 patients studied were
found to have lung cancer. Mucus from the side with the
radiological abnormality had a lower value for the loss
tangent tan d100 (P = 0.004), indicating greater mucus
recoil. This would be consistent with poor mucus clearability on the affected side. All of the eight cancer patients had a low tan d100 value (P = 0.007), and two of
those who were initially negative from bronchoscopy
but had abnormal mucus values were later diagnosed
with cancer on follow-up. These interesting findings
need to be confirmed, but may have implications for
therapeutic management as well as their diagnostic
value.
Causes and consequences of cough in
cancer patients
The study by Zayas et al. [14] described above sheds
light on one of the possible causes of cough as a troublesome symptom in cancer patients. If the presence of
malignant change in the bronchial tree can induce
changes which lead to mucus that is more difficult to
clear and expectorate, then it is evident that the patient
could complain of difficulty in coughing.
Several other causative and associated factors also
need to be considered [15,16]. Table 15.2 gives a summary of the conditions which may initiate or provoke
cough in cancer patients. Infection of the respiratory
tract is naturally a major suspect, as is chronic obstructive pulmonary disease, since most patients with lung
cancer, at least, have a longstanding smoking history. It
is important to consider unusual pathogens, especially
in immunocompromised patients. In one series of such
patients, invasive pulmonary aspergillosis was accompanied by cough in 54% of cases, fever in 54%,
haemoptysis in 30% and dyspnoea in 8% [17]. Since
cancer in adults is a disease that is commoner in the
middle-aged and elderly, it is important to consider comorbidity as a causative factor. Heart failure, the use of
angiotensin-converting enzyme (ACE) inhibiting drugs
for cardiac disease, systemic inflammatory diseases and
pulmonary thromboembolism should be excluded.
The latter is particularly relevant in view of the
increased blood coaguability associated with some
cancers, and the insidious nature of recurrent
thromboembolic episodes which may be individually
subclinical.
Complications of lung cancer and sometimes other
malignancies which give rise to increased coughing include pleural or pericardial effusion, superior vena
cava obstruction, bronchopleural fistula and lymphangitis carcinomatosa. These are usually evident clinically or on routine chest radiographs or computed
tomography (CT) scan, although lymphangitis may be
difficult to diagnose in a patient with pre-existing pulmonary disease or heart failure.
Unfortunately, cough is a common consequence of
many of the treatments which are used against cancer
itself. Studies of long-term survivors of cancer have reported cough as one of the symptoms which both children and adults suffer long after the disease has been
treated. The Childhood Cancer Survivor Study which
investigated 12 390 ex-patients in the USA 5 years or
more after their illness found that, compared with siblings, survivors had significantly increased relative risk
of chronic cough as well as recurrent pneumonia, lung
fibrosis, pleurisy and exercise-induced breathlessness
[18]. Specifically, the study identified the association of
chronic cough with prior chest radiation therapy (RR =
2.0, P < 0.001); with bleomycin exposure (RR = 1.9, P <
0.001); and with cyclophosphamide therapy (RR = 1.3,
P = 0.004). The propensity for these anticancer therapies to cause pulmonary damage has been known for a
long time, although cyclophosphamide-induced lung
damage is relatively rare [19].
A recent study in Sweden has investigated the relatively new approach of allogeneic haematopoietic stem
cell transplantation (HSCT) in adult cancer patients
[20]. Twenty-five patients who had received HSCT 2–4
years previously were surveyed using a variety of symptom and health-related QoL measures. More than half
the patients reported cough, dry mouth and eye problems, as well as tiredness, sexual difficulties and anxiety. It should be noted that, in spite of these reported
problems, 80% of the cancer survivors estimated their
general health as ‘quite good’ or ‘excellent’. In contrast,
another Swedish follow-up study of 277 men who had
been cured of testicular teratoma, compared with 392
controls, revealed that they reported significantly less
149
CHAPTER 15
Table 15.2 Conditions that may initiate or provoke cough in cancer patients.
System
Site
Pathology/mechanism
Respiratory
Upper airways
Laryngeal tumour
Tracheal tumour
Iatrogenic, e.g. radiation tracheitis
Lung cancer
Metastatic cancer
Infection
Chronic obstructive pulmonary disease
Infection
Lymphangitis carcinomatosa
Iatrogenic, e.g. pneumonitis and/or fibrosis after radiation, chemotherapy, biological
therapies
Mesothelioma
Pleural effusion
Bronchi
Lung
parenchyma
Pleura
Cardiovascular
Heart
Pericardial effusion
Pulmonary congestion
Pulmonary thromboembolism
Iatrogenic, e.g. angiotensin-converting enzyme inhibitor
Gastrointestinal
Oesophagus
Tracheo-oesophageal fistula
Reflux
cough, as well as less backache, leg pains and eye problems than the controls [21].
Autologous peripheral blood stem cell transplantation which uses busulphan chemotherapy can also
cause an acute or subacute idiopathic pneumonia syndrome (IPS) characterized by cough, hypoxaemia and
pulmonary infiltrates, sometimes with pleural effusions. Although IPS only arose in 10 out of a series of
271 patients, it was fatal in eight of these [22]. A more
insidious form of this condition has also been described
as delayed pulmonary toxicity syndrome (DPTS),
following the use of high-dose chemotherapy with
cyclophosphamide/cisplatin/BCNU and autologous
bone marrow transplantation [23].
Table 15.3 gives a summary of the common treatments used for cancer that have been shown to be associated with pulmonary damage, cough and dyspnoea.
Many ‘traditional’ anticancer drugs can cause interstitial pneumonia, leading to pulmonary fibrosis. Among
the newer agents that are being used for cancers of the
breast and thorax are the taxanes. Six out of 30 NSCLC
and mesothelioma patients who received paclitaxel
with concurrent chest radiotherapy developed significant lung injury manifested by a persistent cough [24].
150
Table 15.3 Common treatments used for cancer that have
been shown to be associated with pulmonary damage, cough
and dyspnoea.
Type of therapy
Pathology
Radiation
Acute lymphocytic alveolitis
Acute pneumonitis
Bronchiolitis obliterans
organizing pneumonia (BOOP)
Late pulmonary fibrosis
Anticancer
chemotherapy
Acute idiopathic pneumonia
syndrome (IPS)
Delayed pulmonary toxicity
syndrome (DTPS)
Interstitial pneumonitis
Late pulmonary fibrosis
Biological therapies
Idiopathic cough — herceptin;
interleukin
COUGH IN CANCER PATIENTS
Irinotecan is another new antineoplastic agent which is
increasingly being used in the management of colorectal cancer. Cumulative evidence from clinical trials in
Japan and the US suggests that up to 20% of patients
may develop pulmonary toxicity, causing dyspnoea
and cough. The drug initiates an interstitial pneumonitis that may not respond to corticosteroids and can be
fatal [25]. It is claimed that patients with pre-existing
lung disease may be at a higher risk of irinotecan pulmonary toxicity.
Amplification of the human epidermal growth factor
receptor 2 protein (HER2) correlates with poor prognosis in breast cancer, and herceptin is a recombinant
humanized monoclonal immunoglobulin antibody
that binds to the HER2 receptor. It is being increasingly
used in breast cancer trials. One of its commoner sideeffects is cough, along with fever and chills, pain and
tiredness [26]. Interleukin-2 (IL-2) is used as an anticancer agent for metastatic melanoma. One of its many
dose-dependent side-effects is cough [27].
Radiation therapy may causes an acute lymphocytic
alveolitis or hypersensitivity pneumonitis, which is associated with dyspnoea and cough within weeks or a
few months of the dose [28]. In a study of 256 lung cancer patients receiving radical doses of radiotherapy,
49% developed acute radiation pneumonitis although
it was severe in only 13% [29]. Late radiation damage is
evident as pulmonary fibrosis, and may take several
months or years to develop. The fibrosis results from
the effects of tissue repair mechanisms following pneumonitis within the irradiated area, which involve the
activation of fibroblasts by transforming growth factor-b, fibronectin and platelet-derived growth factor
[28]. For longer-term survivors of cancer, radiation
fibrosis is a sinister development as it can lead to severe
symptoms and terminal respiratory failure. There is
evidence that a smoking history can protect patients
from developing radiation-induced pneumonitis [30].
Apart from lung cancer, breast cancer is another
malignancy that often involves thoracic radiation. The
syndrome of bronchiolitis obliterans organizing
pneumonia (BOOP) has been described as a rare (2.5%)
complication of postoperative radiotherapy following
breast-conserving surgery [31]. These patients develop
fever, non-productive cough and patchy unilateral or
bilateral pulmonary infiltrates 5–6 months after
radiotherapy. Postradiation BOOP is a serious condition which tends to recur even after long-term corticosteroidtherapy.Modern radiation planning techniques,
which limit the total dose to normal lung, have minimized the risk of BOOP and IPS, but they may still be a
risk for patients requiring radiation therapy, who have
pre-existing chronic pulmonary disease.
There are some other less common but interesting
iatrogenic causes of disordered or diminished cough in
cancer patients. For example, with concurrent radiotherapy and chemotherapy for head and neck cancer,
14% of patients in one study exhibited aspiration prior
to treatment, 65% soon after therapy and 62% in the
late post-therapy stage (aspiration rates pre-therapy vs.
post-therapy P = 0.0002) [32]. This typically silent aspiration was a result of disordered epiglottal and pharyngeal muscle coordination, leading to a diminished
cough reflex or cough which was delayed or ineffective
in expectorating the aspirated material. Reduced cough
effectiveness is also seen after unilateral vocal cord
paralysis, which is often the result of mediastinal
encroachment of a bronchial cancer, but may also
result iatrogenically during thoracic surgery for the
disease [33].
Assessment of cough in cancer patients
The formal methods of assessing cough are covered
elsewhere in this volume. Specific symptom measurement tools devised for cancer patients, which could
be useful for evaluating the impact of cough on functioning and QoL include the EORTC LC-13; the Lung
Cancer Symptom scale; and the Functional Assessment
of Cancer Treatment (FACT) lung cancer module.
Investigations used in determining the source of
cough in cancer patients are the same as for other disease groups. Thus, the most useful tests will include
thoracic imaging by X-ray or CT scan; ultrasound in
the case of suspected pleural or pericardial effusion;
and ventilation/perfusion scanning for suspected pulmonary thromboembolism. Bronchoscopy is rarely
necessary once a diagnosis of cancer is made, unless an
endobronchial metastasis from a remote primary site is
being considered.
Management of cough in
cancer patients
This topic will be approached under the following
sections — specific anticancer therapies; laser and
151
CHAPTER 15
photodynamic therapy; palliative drug therapies; and
management in terminal care. Table 15.4 summarizes
these methods of managing cough. One of the difficulties of presenting and comparing different methods of
cough palliation is that most studies have used a variety
of outcome measures, timescales and definitions of
‘successful’ palliation. The UK Medical Research
Council has also found that success depends on the
starting point: whereas 90% of patients with lung cancer who had severe or moderate grades of cough at
baseline reported improvement after treatment, only
53% who started with mild cough did so [34].
treatment 23% of patients had cough [35]. However,
the paper does not reveal to what extent radiotherapy
relieved the cough. The analysis did show that the presence of cough prior to treatment was associated with a
higher local failure rate.
A European EORTC study, however, did investigate
respiratory symptoms as well as QoL changes in 164
patients with NSCLC receiving a radical (60 Gy) dose
of radiotherapy [36]. This study showed that there was
a significant association between objective tumour
response and the palliation of pain and physical functioning. During radiation treatment, many general
symptoms and QoL deteriorated. However, after treat-
Anticancer therapies
Radiation therapy
Radiotherapy may be offered to the cancer patient for
two reasons — with the primary aim of curing disease or
extending survival (radical treatment), or with the primary aim of palliating symptoms (palliative treatment). Table 15.5 gives a summary of the results of
radiotherapy for palliation of respiratory symptoms.
Most of the radiation studies have concentrated on the
former, until recent years. Unfortunately, symptom relief was often considered of less importance compared
with survival and tumour response in the case of radical
treatment, and so the earlier research shed little light on
subjective response. Thus, a US review of 156 patients
with clinical stage I NSCLC, who were medically inoperable and therefore treated with radical intent (median
dose 64 Gy) between 1980 and 1995, states that before
Table 15.4 Methods used to manage cough in cancer
patients.
Type of therapy
Examples
Anticancer chemotherapy
Single agents, e.g. gemcitabine
Combination regimens
Radiotherapy
Hypofractionated regimens
Laser therapy
Nd-YAG laser
Photodynamic therapy
Palliative drugs
Anti-inflammatory, e.g.
corticosteroid
Suppressant, e.g. opioid
Antimuscarinic, e.g. hyoscine,
glycopyrrolate
Table 15.5 Summary of the results of radiotherapy for palliation of respiratory
symptoms in non-small cell lung cancer (figures quoted are response rates for each
symptom).
Dose
Study
Cough (%)
Haemoptysis (%)
Dyspnoea (%)
Radical (curative)
60 Gy
Conventional
palliation
Hypofractionated
17 Gy
Hypofractionated
17 Gy
Hypofractionated
20 Gy
[36]
31
83
37
[39]
49
79
3
[37]
48
95
46
[42]
24
60
55
[41]
68
77
42
Gy, Gray.
152
COUGH IN CANCER PATIENTS
ment, cough improved in 31% of patients, haemoptysis
in 83% and dyspnoea in 37%. Global QoL improved
in 36%.
In order to improve tumour response to radical radiotherapy, there has been a move towards increasing
the number of doses given daily (hyperfractionation).
Continuous hyperfractionated radiotherapy (CHART)
is being used in potentially curable cancer patients who
are unable to have surgical resection. Studies of
CHART have focused, not surprisingly, on long-term
objective outcomes. However, short-term monitoring
of patients with head and neck cancer having CHART
has revealed that cough and hoarseness were improved,
compared with conventional dose radiotherapy, at 6
weeks [38].
Studies of palliative regimens for radiotherapy have
naturally focused on symptom control as a key endpoint. The same EORTC group just mentioned above
also reported on palliative responses in patients with locally advanced and metastatic NSCLC [39]. In comparison with their radical treatment study, cough was
relieved in 49% of patients, haemoptysis in 79% and
dyspnoea in 39%. Once again, global QoL improved in
37% of patients after completion of radiotherapy and
there was a tendency for patients who had an objective
tumour response to have a symptomatic benefit.
A Cochrane systematic review examined 10 published randomized trials of palliative radiotherapy for
lung cancer. Meta-analysis of the results was not possible because of great heterogeneity in the doses, patient
characteristics and outcome measures used. There was
no convincing evidence that any particular regime gave
a better symptom resolution. The conclusion from this
review was that most patients should be treated with
minimum doses delivered in one or two fractions (hypofractionation) [40]. This approach would be specially useful for patients who are ill, cannot be admitted to
hospital or cannot attend for long outpatient courses.
In India a study examined the effect of giving four small
weekly doses to a total of 20 Gy to 47 inoperable patients with NSCLC [41]. Not only was the regime well
tolerated and convenient for patients who had long distances to travel, but it also gave relief of cough in 68%,
of haemoptysis in 77% and of dyspnoea in 42%. Hypofractionation was also used in a Greek study of 48
NSCLC patients who had two doses of 8.5 Gy 1 week
apart [42]. Cough was palliated in 24% with a median
palliation duration of 70 days; haemoptysis in 60%
over 133 days; and dyspnoea in 55% over 74 days.
Should palliative radiotherapy be offered routinely
at the time of diagnosis, or only as needed when symptoms develop? This question was tackled by the UK
Medical Research Council in an international study involving 230 patients with advanced inoperable
NSCLC, who had no immediate reasons for radiotherapy [43]. The results showed that there was no difference between the immediate or deferred treatment
approaches in terms of symptom relief, psychological
distress or survival. Adverse effects were more likely
after immediate radiotherapy.
When lung cancer recurs after a course of radiotherapy, it is unusual but it may be feasible to offer a second
course of treatment. A retrospective study evaluating
the outcome of reirradiation showed that 60% of patients achieved improvement in cough, 73% in dyspnoea, and all patients with haemoptysis had a reduction
or complete resolution [44]. In recent years, the preferred approach in specialist centres for such patients is
to offer endobronchially delivered intraluminal irradiation (brachytherapy). This involves subjecting the patient to a bronchoscopy and placing a catheter in the
airway down to the level of the tumour. An after-loading device then sends a radioactive source via the
catheter to the tumour site for a short time before
withdrawal [45]. Several recent small studies have
documented
good
palliative
benefit
after
brachytherapy — relief of cough, haemoptysis and dyspnoea occurring in 54%, 74% and 54%, respectively
[46]; 65%, 86% and 64%, respectively [47]; and 43%,
95% and 80%, respectively [48]. One problem with
brachytherapy is that it is only available in a few centres
with the necessary radioisotope equipment; another is
that it has been associated with dose-dependent late
toxicities, especially massive haemoptysis. Tauelle et al.
[46] reported severe or fatal haemoptysis occurring in
7% of their patients; Hatlevoll et al. [47] in 27% (22%
within 6 months); and Anacak et al. [48] in 11%.
Chemotherapy
As with radiation therapy, in the past the emphasis in
research was on achieving ‘cure’, so that the end-points
were usually survival and objective tumour response
rather than symptom relief. In SCLC, chemotherapy
has long been the preferred option as the disease is often
disseminated and, unlike NCSLC, is very sensitive to
antimitotic drugs. It is well established that objective
tumour response in SCLC is associated with symptom
improvement. In various trials of standard combina153
CHAPTER 15
Table 15.6 Summary of the results of chemotherapy for palliation of respiratory
symptoms in non-small cell lung cancer (figures quoted are response rates for each
symptom).
Regimen
Study
Cough (%)
Haemoptysis (%)
Dyspnoea (%)
Cisplatin/vindesine +
mitomycin or
ifosfamide
Mitomycin/ifosfamide/
cisplatin
Gemcitabine alone
Gemcitabine/cisplatin
[51]
45
91
78
[52]
70
92
46
[53]
[50]
44
44
63
75
26
36
tion chemotherapy regimens, relief of cough has been
reported in between 45% and 70% of patients; of
haemoptysis in up to 92%; and of dyspnoea in between
46% and 78% [45]. A recent study in poor prognosis
SCLC patients comparing combination chemotherapy
vs. single-agent carboplatin showed that even in this
very sick population, good symptom palliation could
be achieved [49]. The combination regime (CAV)
gave 21% relief of cough compared with 7% after carboplatin; dyspnoea improved in 66% and 41%, respectively. In terms of toxicity and objective tumour
response, there were few differences.
Gemcitabine is a new anticancer drug which is given
singly or in combination with others. As a single agent
for inoperable NSCLC it has given relief of cough in
44%, of haemoptysis in 63% and of dyspnoea in 26%
[45]. In combination with cisplatin these response rates
were 44%, 75% and 36%, respectively [50]. It is likely
that other new agents such as the taxanes will be used
increasingly for symptom palliation in NSCLC. Singleagent chemotherapy (as well as talc and tetracycline) is
also used to prevent the recurrence of pleural and pericardial effusions [54]. Table 15.6 summarizes the
results of recent studies of palliating respiratory symptoms in NSCLC.
Laser and photodynamic therapy
Laser therapy for the palliation of cough is delivered intraluminally via a bronchoscope. Unlike brachytherapy which was described above, laser therapy works by
macroscopically heating and destroying tissues. Photodynamic therapy (PDT) is a refinement of the laser
process by premedicating patients with tissue sensitiz154
ers which allow greater killing of tumour as compared
with normal cells [15]. Both of these techniques are
much less commonly available than radiotherapy
(either external or endobronchial) or chemotherapy.
Studies of their effectiveness have been relatively small
and mostly uncontrolled. However, a recent randomized controlled trial was performed in 31 patients with
tracheobronchial obstruction due to inoperable
NSCLC [55]. The study directly compared laser resection using an Nd-YAG laser with dihaematoporphyrin
ether and argon dye laser photoradiation. There was no
difference between the two techniques in terms of
symptom relief, but PDT gave a longer time till recurrence of symptoms and a longer median survival.
Drug therapies
The drug management of cough is described in detail
elsewhere in this volume, as well as in palliative medicine texts [15,16], so only a few points specific to cancer
patients will be highlighted. Most palliative care units
use codeine-based drugs for relieving cough. For
patients who are resistant to codeine, other drugs
which have been recommended include hydrocodone
[56], benzonatate [57] and levodropropizine [58].
There are no published trials comparing the relative
benefits or side-effects of these agents in cancer patients. A potential problem arises when a cancer patient
is already receiving a potent opioid (morphine, hydromorphone, fentanyl, etc.) for pain, and then complains
of a cough. It does not make sense pharmacologically
to add a second opioid drug, as there is no evidence
that incomplete cross-tolerance exists between opioids
for cough (unlike the situation with pain modulation).
COUGH IN CANCER PATIENTS
In this situation, it would be appropriate to use another
class of drug or another approach entirely, such as
radiotherapy.
In palliative care centres, nebulized lidocaine or
bupivacaine have sometimes been advocated for the relief of intractable unproductive cough [16]. This
method is thought to work by anaesthesizing sensory
nerve endings in the hypopharynx, larynx and upper
airways that are involved in generating the cough reflex. Other drugs which have theoretical actions on
cough and may be tried in refractory cases include
baclofen and mexilitine [16].
As discussed above, cough can arise as a symptom of
pulmonary toxicity after some anticancer drugs. Recently there have been attempts to prevent or reverse
the pulmonary damage using novel drug approaches.
In an open uncontrolled US study, 63 patients with
breast cancer who were starting high-dose chemotherapy prior to autologous bone marrow transplantation
were given an inhaled corticosteroid — fluticasone propionate [59]. After 12 weeks of taking this drug twice
daily, the study found that, compared with the centre’s
historical controls, DLCO (the diffusing capacity of the
lungs) declined by a smaller amount (21% fluticasone
vs. 33% historical controls). Delayed pulmonary toxicity syndrome developed in 35% of fluticasone patients
compared to 73% of historical controls. Because of
the grave significance of such pulmonary toxicity, further randomized trials of this and similar regimens are
required.
Management in terminal care
In the care of cancer patients, cough may become very
distressing in the terminal stage. The act of coughing
may cause or aggravate pain, it may disturb precious
sleep and it can impede communication between patients and carers. If the cough is productive, it is helpful
to position the patient so that expectoration is assisted,
and gentle chest physiotherapy may be used [15]. It
may be appropriate to offer an antibiotic for a respiratory tract infection, if the symptoms of cough and dyspnoea are very distressing. Patients with cancer are often
prescribed drugs which can cause dry mouth and reduction of tracheobronchial mucus (opioids, anticholinergics, antihistamines) and this can cause
difficulty in expectoration. It may be helpful in such situations to humidify the air or oxygen, if the patient
needs the latter for hypoxaemia.
Some patients develop noisy breathing as they slip
into unconsciousness (so-called death rattle). The cause
of this is thick mucus lying in the major airways or hypopharynx, which partly obstructs the airflow, but
which the patient is unable to cough up. The patient is
usually unaware of the noise, but it can be very upsetting to family carers or others nearby. Suction may help
if there is mucus in or above the larynx. Often the most
practical management is to prevent further mucus production by giving an antimuscarinic agent, preferably
by subcutaneous injections or by continuous infusions.
The best agents for this purpose are hysoscine butylbromide or glycopyrrolate [60].
References
1 Hopwood P, Stephens RJ on behalf of the Medical Research Council (MRC) Lung Cancer Working Party.
Symptoms at presentation for treatment in patients with
lung cancer: implications for the evaluation of palliative
treatment. Br J Cancer 1995; 71: 633–6.
2 Portenoy RK, Thaler HT, Kornblith AB et al. Symptom
prevalence, characteristics and distress in a cancer population. Qual Life Res 1994; 3: 183–9.
3 Bergmann B, Aaronson NK, Ahmedzai S et al. The
EORTC QLC-LC13: a modular supplement to the
EORTC Core Quality of Life Questionnaire (QLC-C30)
for use in lung cancer clinical trials. Eur J Cancer 1994;
30A: 635–42.
4 Hollen PJ, Gralla RJ, Kris MG et al. Normative data and
trends in quality of life from the Lung Cancer Symptom
Scale (LCSS). Support Care Cancer 1999; 7: 140–8.
5 Lutz S, Norrell R, Bertucio C et al. Symptom frequency
and severity in patients with metastatic or locally recurrent lung cancer: a prospective study using the Lung
Cancer Symptom Scale in a community hospital. Palliat
Med 2001; 4: 157–65.
6 Ng K, von Gunten CF. Symptoms and attitudes of 100
consecutive patients admitted to an acute hospice/
palliative care unit. J Pain Symptom Manage 1998; 16:
307–16.
7 Anderson H, Ward C, Eardley A et al. The concerns of patients under palliative care and a heart failure clinic are not
being met. Palliat Med 2001; 15: 279–86.
8 Collins JJ, Byrns ME, Dunkel IJ et al. The measurement of
symptoms in children with cancer. J Pain Symptom Manage 2000; 19: 363–77.
9 Mehdi SA, Etxell JE, Newman NB et al. Prognostic significance of Ki-67 immunostaining and symptoms in resected
stage I and II non-small cell lung cancer. Lung Cancer
1998; 20: 99–108.
155
CHAPTER 15
10 Mehdi SA, Tatum AH, Newman NB et al. Prognostic
markers in resected stage I and II non-small-cell lung
cancer: an analysis of 260 patients with 5 year follow-up.
Clin Lung Cancer 1999; 1: 59–67.
11 Morita T, Tsunoda J, Inoue S et al. Contributing factors to
physical symptoms in terminally-ill cancer patients. J Pain
Symptom Manage 1999; 18: 338–46.
12 Kubik A, Zatloukal P, Boyle P et al. A case-control study of
lung cancer among Czech women. Lung Cancer 2001; 31:
111–22.
13 Koyi H, Hillerdal G, Branden E. A prospective study of a
total material of lung cancer from a county in Sweden
1997–1999; gender, symptoms, type, stage and smoking
habits. Lung Cancer 2002; 36: 9–14.
14 Zayas JG, Rubin BK, York EL et al. Bronchial mucus
properties in lung cancer: relationship with site of lesion.
Can Respir J 1999; 6: 246–52.
15 Ahmedzai SH. Palliation of respiratory symptoms. In:
Doyle D, Hanks GWC, McDonald N, eds. Oxford Textbook of Palliative Medicine, 2nd edn. Oxford: Oxford
University Press, 1998: 583–616.
16 Twycross R, Wilcock A. Respiratory symptoms. In:
Twycross R, Wilcock A, eds. Symptom Management in
Advanced Cancer, 2nd edn. Oxford: Radcliffe Press,
1997: 141–79.
17 Pidhorecky I, Urschel J, Anderson T. Resection of invasive
pulmonary aspergillosis in immunocompromised patients. Ann Surg Oncol 2000; 7: 312–7.
18 Mertens AC, Yasui Y, Liu Y et al. Pulmonary complications in survivors of childhood and adolescent cancer. A
report from the Childhood Cancer Survivor Study. Cancer
2002; 95: 2431–41.
19 Segura A, Yuste A, Cercos A et al. Pulmonary fibrosis induced by cyclophosphamide. Ann Pharmacother 2001;
35: 894–7.
20 Edman L, Larsen J, Hagglund H et al. Health-related quality of life, symptom distress and sense of coherence in adult
survivors of allogeneic stem-cell transplantation. Eur J
Cancer Care (Engl) 2001; 10: 124–30.
21 Rudberg L, Carlsson M, Nilsson S et al. Self-perceived
physical, psychologic, and general symptoms in survivors
of testicular cancer 3–13 years after treatment. Cancer
Nurs 2002; 25: 187–95.
22 Bilgrami SF, Metersky ML, McNally D et al. Idiopathic
pneumonia
syndrome
following
myeloablative
chemotherapy and autologous transplantation. Ann
Pharmacother 2001; 35: 196–201.
23 Wilczynski SW, Erasmus JJ, Petros WP et al. Delayed pulmonary toxicity syndrome following high-dose
chemotherapy and bone marrow transplantation for
breast cancer. Am J Respir Crit Care Med 1998; 157:
565–73.
24 Herscher LL, Hahn SM, Kroog G et al. Phase I study of pa-
156
25
26
27
28
29
30
31
32
33
34
35
36
37
clitaxel as a radiation sensitizer in the treatment of
mesothelioma and non-small-cell lung cancer. J Clin
Oncol 1998; 16: 635–41.
Madarnas Y, Webster P, Shorter AM et al. Irinotecanassociated pulmonary toxicity. Anticancer Drugs 2000;
11: 709–13.
Goldenberg MM. Trastuzumab, a recombinant DNAderived humanized monoclonal antibody, a novel agent
for the treatment of metastatic breast cancer. Clin Ther
1999; 21: 309–18.
Eton O, Rosenblum MG, Legha SS et al. Phase I trial of
subcutaneous recombinant human interleukin-2 in
patients with metastatic melanoma. Cancer 2002; 95:
127–34.
Abratt RP, Morgan GW. Lung toxicity following chest
irradiation in patients with lung cancer. Lung Cancer
2002; 35: 103–9.
Inoue A, Kunitoh H, Sekine I et al. Radiation pneumonitis
in lung cancer patients: a retrospective study of risk factors
and the long-term prognosis. Int J Radiat Oncol Biol Phys
2001; 49: 649–55.
Johansson S, Bjermer L, Franzen L et al. Effects of ongoing
smoking on the development of radiation-induced pneumonitis in breast cancer and oesophagus cancer patients.
Radiother Oncol 1998; 49: 41–7.
Takigawa N, Segawa Y, Saeki T et al. Bronchiolitis obliterans organizing pneumonia syndrome in breast-conserving
therapy for early breast cancer: radiation-induced lung
toxicity. Int J Radiat Oncol Biol Phys 2000; 48: 751–5.
Eisbruch A, Lyden T, Bradford CR et al. Objective assessment of swallowing dysfunction and aspiration after
radiation concurrent with chemotherapy for headand-neck cancer. Int J Radiat Oncol Biol Phys 2002; 53:
23–8.
Abraham MT, Bains MS, Downey RJ et al. Type I thyroplasty for acute unilateral vocal fold paralysis following
intrathoracic surgery. Ann Otol Rhinol Laryngol 2002;
111: 667–71.
Stephens RJ, Hopwood P, Girling DJ. Defining and
analysing symptom palliation in cancer clinical trials: a
deceptively difficult exercise. Br J Cancer 1999; 79:
538–44.
Sibley GS, Jamieson TA, Marks LB et al. Radiotherapy
alone for medically inoperable stage I non-small-cell lung
cancer: the Duke experience. Int J Radiat Oncol Biol Phys
1998; 40: 149–54.
Langendijk JA, Aaronson NK, de Jong JM et al. Prospective study on quality of life before and after radical radiotherapy in non-small-cell lung cancer. J Clin Oncol 2001;
19: 2123–33.
Medical Research Council Lung Cancer Working Party.
Randomized trial of palliative two-fraction versus more
intensive 13 fraction radiotherapy for patients with inop-
COUGH IN CANCER PATIENTS
38
39
40
41
42
43
44
45
46
47
48
erable non-small cell lung cancer and good performance
status. Clin Oncol 1996; 8: 167–75.
Griffiths GO, Parmar MK, Bailey AJ. Physical and psychological symptoms of quality of life in the CHART randomized trial in head and neck cancer: short-term and
long-term patient reported symptoms. CHART Steering
Committee. Continuous hyperfractionated accelerated
radiotherapy. Br J Cancer 1999; 81: 1196–205.
Langendijk JA, ten Velde GP, Aaronson NK et al. Quality
of life after palliative radiotherapy in non-small cell lung
cancer: a prospective study. Int J Radiat Oncol Biol Phys
2000; 47: 149–55.
Macbeth F, Toy E, Coles B et al. Palliative radiotherapy
regimens for non-small cell lung cancer. [Update of
Cochrane Database Syst Rev 2001; 2: CD002143;
PMID: 11406035.] Cochrane Database Syst Rev Issue 4,
2002.
Bhatt ML, Mohani BK, Kumar L et al. Palliative treatment of advanced non small cell lung cancer with
weekly fraction radiotherapy. Indian J Cancer 2000; 37:
148–52.
Plataniotis GA, Kouvaris JR, Dardoufas C et al. A short
radiotherapy course for locally advanced non-small cell
lung cancer (NSCLC): effective palliation and patients’
convenience. Lung Cancer 2002; 35: 203–7.
Falk SJ, Girling DJ, White RJ et al. Immediate versus delayed palliative thoracic radiotherapy in patients with unresectable locally advanced non-small cell lung cancer and
minimal thoracic symptoms: randomised controlled trial.
Br Med J 2002; 325: 465.
Gressen EL, Werner-Wasik M, Cohn J et al. Thoracic
reirradiation for symptomatic relief after prior radiotherapeutic management for lung cancer. Am J Clin Oncol
2000; 23: 160–3.
Hoskin P, Ahmedzai SH. Assessment and management of
respiratory symptoms of malignant disease. In: Ahmedzai
SH, Muers M, eds. Supportive Care of the Respiratory
Disease Patient. Oxford: Oxford University Press, 2003
(in press).
Taulelle M, Chauvet B, Vincent P et al. High dose rate endobronchial brachytherapy: results and complications in
189 patients. Eur Respir J 1998; 11: 162–8.
Hatlevoll R, Karlsen KO, Skovlund E. Endobronchial radiotherapy for malignant bronchial obstruction or recurrence. Acta Oncol 1999; 38: 999–1004.
Anacak Y, Mogulkoc N, Ozkok S et al. High dose rate en-
49
50
51
52
53
54
55
56
57
58
59
60
dobronchial brachytherapy in combination with external
beam radiotherapy for stage III non-small cell lung cancer.
Lung Cancer 2001; 34: 253–9.
White SC, Cheeseman S, Thatcher N et al. Phase II study of
oral topotecan in advanced non-small cell lung cancer.
Clin Cancer Res 2000; 6: 868–73.
Jassem J, Krzakowski M, Roszkowski K et al. A phase II
study of gemcitabine plus cisplatin in patients with advanced non-small cell lung cancer: clinical outcomes and
quality of life. Lung Cancer 2002; 35: 73–9.
Fernandez C, Rosell R, Abad-Esteve A et al. Quality of life
during chemotherapy in non-small cell lung cancer. Acta
Oncol 1989; 28: 29–33.
Cullen MH. The MIC regimen in non-small cell lung cancer. Lung Cancer Suppl 1993; 2: 81–98.
Thatcher N, Anderson H, Betticher DC et al. Symptomatic
benefit from gemcitabine and other chemotherapy in
advanced non-small cell lung cancer: changes in performance status and tumour-related symptoms. Anticancer
Drugs 1995; 6 (Suppl.): 39–48.
Paz-Ares L, Garcia-Carbonera R. Medical emergencies.
In: Cavalli F, Hansen HE, Kaye SB, eds. Textbook of
Medical Oncology, 2nd edn. Martin Dunitz, 2000:
619–49.
Diaz-Jimenez JP, Martinez-Ballarin JE, Llunell A et al. Efficacy and safety of photodynamic therapy versus NdYAG laser resection in NSCLC with airway obstruction.
Eur Respir J 1999; 14: 800–5.
Homsi J, Walsh D, Nelson KA et al. Pain and symptom
management. Hydrocodone for cough in advanced cancer. Am J Hospice Palliative Care 2000; 17: 342–6.
Doona M, Walsh D. Benzonatate for opioid-resistant
cough in advanced cancer. Palliat Med 1998; 12: 55–8.
Luporini G, Barni S, Marchi E et al. Efficacy and safety of
levodropropizine and dihydrocodeine on nonproductive
cough in primary and metastatic lung cancer. Eur Respir J
1998; 12: 97–101.
McGaughey DS, Nikcevich DA, Long GD et al. Inhaled
steroids as prophylaxis for delayed pulmonary toxicity
syndrome in breast cancer patients undergoing high-dose
chemotherapy and autologous stem cell transplantation.
Biol Blood Marrow Transplant 2001; 7: 274–8.
Bennett M, Lucas V, Brennan M et al. Using antimuscarinic drugs in the management of death-rattle: evidence-based guidelines for palliative care. Palliat Med
2002; 16: 369–74.
157
SECTION 4
Pathophysiology
16
Sensory pathways for the
cough reflex
Stuart B. Mazzone, Brendan J. Canning & John G. Widdicombe
Introduction
The cough reflex is one of several defensive reflexes that
serve to protect the airways from the potentially damaging effects of inhaled particulate matter, aeroallergens, pathogens, aspirate and accumulated secretions.
In some airways diseases, cough may become excessive
and non-productive, and is potentially harmful to the
airway mucosa. An understanding of the neural pathways involved in the cough reflex may facilitate the development of therapeutic strategies that prevent
excessive and non-productive cough, whilst preserving
the important innate defensive role of this respiratory
reflex.
Much of our current understanding of the neural
pathways involved in the cough reflex is derived from
studies in animals. In cats, dogs, rabbits, guinea-pigs
and monkeys it is clear that vagal afferent nerves are
responsible for initiating the cough reflex [1–6]. Although poorly described, afferent nerves innervating
other viscera as well as somatosensory nerves innervating the chest wall, diaphragm and abdominal musculature also likely play an integral role in regulating cough.
In this chapter the broad classes of vagal afferent nerves
innervating the airways and their role in regulating the
cough reflex will be defined.
Defining airway afferent
nerve subtypes
Airway afferent nerve subtypes can be distinguished
based on their physicochemical sensitivity, adaptation
to sustained lung inflation, neurochemistry, origin,
myelination, conduction velocity and sites of termination in the airways. The utility of each of these
approaches for defining airway afferent nerve subtypes
is limited in large part by the lack of specificity of
the various characteristics studied. When used in
combination, however, these physiological and morphological attributes can be used to identify at least
three broad classes of airway afferent nerves: rapidly
adapting mechanoreceptors (RARs), slowly adapting
mechanoreceptors (SARs) and unmyelinated C-fibres
(Fig. 16.1).
The value of this now widely accepted classification
scheme used to define airway afferent nerve subtypes is
confirmed by its established utility in all species thus far
studied. Most airway afferent nerves found in any of
these species are described reasonably well as either
RAR, SAR or C-fibre. The observations that stereotypical reflexes are initiated by stimuli selective (even if not
specific) for these afferent nerve subtypes and that these
reflexes are modulated by interventions that preferentially alter the activity or actions of the afferent nerve
subtypes studied is further evidence for the utility of
this classification scheme. Studies of central nervous
system (CNS) termination sites of the various afferent
nerve subtypes identified also confirm the utility of the
classification scheme [7]. Such analyses reveal the necessary divergence of afferent nerve terminals within the
CNS, divergence that is required to differentially and
specifically control homeostatic and defensive reflexes
initiated from the airways.
The characteristics of the afferent nerve subtypes innervating the airways are described briefly in Table
16.1 and in detail below.
161
CHAPTER 16
C-fibre
RAR
Cap
SAR
Cap
(b)
(c)
10
0
150
0
Pt
(cmH2O)
30
ABP
(mmHg)
AP
Pt
ABP
(mmHg) (cmH2O)
AP
(a)
Cap
150
0
0
10 s
Activity (imp/s)
Cap
Cap
50
40
30
20
10
0
50
40
30
20
10
0
25
20
15
10
5
0
Inflation
Inflation
Activity (imp/s)
2
Inflation
50
40
30
1
20
10
0
–5
0
5
10
Time (s)
15
0
–5
Fig. 16.1 Afferent nerve subtypes innervating the mammalian airways. Representative traces (upper panels) and
mean data (lower panels) obtained from single-fibre recordings of afferent nerve activity in the vagus nerve of anaesthetized rats. (a) Airway C-fibres are generally quiescent
during tidal breathing and relatively unresponsive to lung inflation (peak activity ~ 1 impulse/s). C-fibres, however, respond vigorously to intravenous injections of the vanilloid
capsaicin (peak activity ~ 20 impulses/s). Rapidly adapting
162
Cap
0
5
10
Time (s)
15
140
120
100
80
60
40
20
0
–5
0
5
10
Time (s)
15
receptors (RARs) (b) and slowly adapting receptors (SARs)
(c) are sporadically active during the respiratory cycle (10–
40 impulses/s). Neither subtype of mechanoreceptor responds to capsaicin (Cap), but both fire intensely when the
lungs are inflated (peak activity ~ 40–120 impulses/s). Note
that RARs are easily differentiated from SARs since they rapidly adapt during sustained lung inflation. Modified with permission from [10].
SENSORY PATHWAYS FOR THE COUGH REFLEX
Table 16.1 In vivo properties of vagal afferent nerve subtypes innervating the mammalian airways.
Rapidly adapting receptor
Slowly adapting receptor
C-fibre
Electrophysiological properties
Conduction velocity (m/s)
Fibre type
Eupnoeic activity (impulses/s)
14–23
Myelinated
0–20
15–32
Myelinated
10–40
1.3–1.5
Unmyelinated
0.3–1.5
Physical sensitivity
Lung deflation
Oedema
Increased
Increased
Decreased
No effect
No effect
Increased
Chemical sensitivity
CO2
H+
Capsaicin
Bradykinin
No effect
Increased
Increased*
Increased*
Decreased
No effect
No effect
No effect
Increased
Increased
Increased†
Increased†
Reflex effects
Parasympathetic
Respiratory
Oedema formation
Excitatory
Hyperpnoea
Promote
Inhibitory
Inhibit inspiration
No effect
Excitatory
Apnoea
Promote
Neurokinin positive
No
No
Yes
* Increased RAR activity is prevented by bronchodilator pretreatment, suggesting that activation occurs secondary to
obstruction in the lung.
† Increased C-fibre activity is enhanced by bronchodilator pretreatment, suggesting that bradykinin and capsaicin directly
stimulate C-fibres in the airways. See text for further details and references.
Afferent nerve subtypes innervating
the airways and their role in
regulating cough
Rapidly adapting receptors
Although relatively little is known about the anatomical arrangement of RAR terminations in the airway
wall, functional studies suggest that RARs terminate
within or beneath the epithelium and are localized to
both intra- and extrapulmonary airways [8–11]. RARs
are typically differentiated from other airway afferent
nerves by their rapid (1–2 s) adaptation to sustained
lung inflations (Fig. 16.1) [10–14]. Other distinguishing properties of RARs include their sensitivity to lung
collapse and/or lung deflation, their responsiveness to
alterations in dynamic lung compliance (and thus their
sensitivity to bronchospasm), and their conduction
velocity (4–18 m/s, suggestive of small, myelinated
axons) [8–11,15]. Careful analysis of the responsive-
ness of RARs to mechanical stimulation reveals that
their adaptation to sustained lung inflation is not attributable to an electrophysiological adaptation, as
with sustained, dynamic mechanical stimulation,
RARs are continually activated [16,17]. RARs may
also adapt comparatively slow to lung deflation [10].
Perhaps RARs are thus better defined as dynamic receptors that respond to changes in airway mechanical
properties (e.g. diameter, length, interstitial pressures).
RARs are sporadically active throughout the respiratory cycle, activated by the dynamic mechanical forces
accompanying lung inflation and deflation and becoming more active as the rate and volume of lung inflation
increases [10,16,17]. It follows therefore that RAR activity during respiration correlates to respiratory rate
and is higher in guinea-pigs and rats (16–27 impulses/s)
and almost unmeasurable in larger animals such as
dogs (< 1 impulse/s). It also follows that, at least in
smaller animals, RAR-dependent reflexes require a
heightened activity in the already active RARs. This
163
CHAPTER 16
sensitivity to the dynamic forces associated with lung
inflation and deflation suggests a mechanism by which
stimuli activate RARs. RARs may be insensitive to
many ‘direct’ chemical stimuli (Fig. 16.1). However,
RAR activity can be increased by stimuli that evoke
bronchospasm or obstruction resulting from mucus secretion or oedema [11,18–23]. Not surprisingly, then,
the ability of substances such as histamine, capsaicin,
substance P and bradykinin to activate RARs can be
markedly inhibited or abolished by preventing the local
end-organ effects that these stimuli evoke (e.g. mucus
secretion, bronchospasm).
Activation of RARs increases parasympathetic nerve
activity in the airways [13,21]. RARs also respond to
stimuli that evoke cough in many species including humans (see below), and fulfil all of the accepted criteria
for mediating cough [1,4,13,24]. Further evidence for
their role in the cough reflex comes from studies of
vagal cooling, which blocks cough at temperatures that
selectively abolish activity in myelinated fibres (including RARs) whilst preserving unmyelinated C-fibre
activity [25].
Slowly adapting mechanoreceptors
SARs, like RARs, are active during the respiratory
cycle, their activity increasing sharply during the inspiratory phase and peaking just prior to the initiation of
expiration (Fig. 16.1) [10,26]. SARs are thus believed
to be the primary afferent fibres involved in the Hering–Breuer reflex, which terminates inspiration and initiates expiration when the lungs are adequately inflated
[26]. SARs, however, can be differentiated from RARs
in some species based on action potential conduction
velocity, and in most species by their lack of adaptation
during sustained lung inflations. SARs may also be differentially distributed throughout the airways [26]. In
cats, guinea-pigs and rats, few if any SARs but many
RARs and C-fibres can be found in the extrapulmonary
airways. Rather, SARs appear to be associated with the
smooth muscle of the intrapulmonary airways (in dogs,
SARs may also be localized to extrapulmonary airways). SARs also differ from RARs with respect to the
reflexes they precipitate. SAR activation results in central inhibition of respiration and inhibition of cholinergic drive to the airways, leading to decreased phrenic
nerve activity and decreased airway smooth muscle
tone (due to a withdrawal of cholinergic nerve activity)
[22,26].
164
The role of SARs in the cough reflex is poorly understood. Single-unit recordings from the vagus nerve in
rabbits suggest that SAR activity does not increase
prior to or during ammonia-induced coughing [5]. Although this suggests that SARs are unlikely to play a
primary role in the cough reflex, their profound influence over respiratory pattern makes it likely that they,
in some way, play a role in cough and other airway defensive reflexes. It has been proposed, for example, that
enhancing baseline SAR activity with the loop diuretic
frusemide (furosemide) may account for the reported
antitussive effects of this agent in animals and in human
subjects [27]. In contrast, preloading, which will likely
increase baseline SAR activity, has been reported to increase expiratory efforts during cough [28,29]. Consistent with this latter assertion, experiments performed
on rabbits in which inhaled sulphur dioxide has been
used in an attempt to selectively block SAR activity
show that the cough reflex is coincidentally attenuated
[4,30]. However, it must be noted that the selectivity of
sulphur dioxide for airway SARs is questionable since
several reports indicate an excitatory action of sulphur
dioxide on airway C-fibres [31,32]. C-fibre activation
may be inhibitory to cough (see below).
Studies of CNS processing also suggest that SARs
may facilitate coughing. Shannon and colleagues have
proposed a central cough network in which SARs facilitate cough via activation of brainstem second-order
neurones (termed pump cells) of the SAR reflex pathway [2]. In this model, SARs, through activation of
pump cells, open an as yet unidentified ‘gate’ in the
brainstem that is thought to promote cough. An excitatory role of pump cells in cough, however, is difficult to
reconcile with studies showing that SARs (via pump
cells) inhibit other RAR-mediated reflex pathways
[20,33].
C-fibres
Unmyelinated afferent C-fibres are physiologically and
morphologically similar to the unmyelinated nociceptors of the somatic nervous system and comprise the
majority of afferent nerves innervating the airways
[11,14,34,35]. In addition to their conduction velocity,
afferent C-fibres are distinguished from RARs and
SARs by their relative insensitivity to mechanical stimulation and lung inflation and their responsiveness to
bradykinin and capsaicin (Fig. 16.1) [9–12,21,34]. Cfibre afferent nerves are further distinguished from
SENSORY PATHWAYS FOR THE COUGH REFLEX
RARs by the observation that bradykinin and capsaicin-evoked activation of their endings in the airways
is not inhibited by pretreatment with bronchodilators.
On the contrary, bronchodilators such as prostaglandin E2 (PGE2), adrenaline (epinephrine) and
adenosine may enhance excitability of airway afferent
C-fibres [34,36]. This indicates that unlike RARs, Cfibres are directly activated by substances such as
bradykinin and capsaicin.
Morphological studies in rats and in guinea-pigs indicate that C-fibre afferent nerves innervate the airway
epithelium as well as other effector structures within
the airway wall [9,37–39]. C-fibres may synthesize
neuropeptides that are subsequently transported to
their central and peripheral nerve terminals
[9,37,39,40]. This unique neurochemical property of
bronchopulmonary C-fibres has been exploited to describe the distribution and peripheral nerve terminals
of these unmyelinated airway afferent nerve endings.
Although the expression of neuropeptides in their peripheral afferent nerve terminals may be species dependent, it seems likely that C-fibres innervating the
airways of other species are morphologically (if not
neurochemically) similar to those well characterized in
guinea-pigs and rats [38,41].
In dogs, airway afferent C-fibres may be further
subdivided into bronchial and pulmonary C-fibres, a
distinction based both on sites of termination but also
on responsiveness to chemical and mechanical stimuli
[14]. Notably, pulmonary C-fibres in dogs may be unresponsive to histamine, whilst bronchial C-fibres (in
dogs at least) are activated by histamine. Whether similar physiological distinctions between bronchial and
pulmonary afferent C-fibres can be defined in other
species is unknown.
C-fibre afferent nerves play a key role in airway
defensive reflexes. Although C-fibre afferent endings
are polymodal and thus respond to both chemical and
mechanical stimulation, their threshold for mechanical
activation is substantially higher than that of RARs
and SARs [9,10]. Accordingly, C-fibres are generally
quiescent throughout the respiratory cycle but are
readily activated by chemical stimuli such as capsaicin,
bradykinin, citric acid, hypertonic saline and sulphur
dioxide [9–11,34]. Reflex responses evoked by C-fibre
activation include increased airway parasympathetic
nerve activity and the chemoreflex, characterized by
apnoea (followed by rapid shallow breathing), bradycardia and hypotension [11,14,21,34]. In some species
(particularly rats and guinea-pigs) C-fibre activation
evokes peripheral release of neuropeptides (via an axon
reflex) leading to bronchospasm and neurogenic
inflammation [34,42].
The role of bronchopulmonary C-fibres in the cough
reflex is controversial. Several lines of evidence support
the hypothesis that activation of airway C-fibres precipitates cough. For example, putatively selective stimulants of airway C-fibres such as capsaicin, bradykinin
and citric acid evoke cough in conscious animals and in
humans [3,14,18,43–45]. Furthermore, capsaicin pretreatment, a technique that is used to selectively deplete
C-fibres of neuropeptides, abolishes cough in guineapigs induced by citric acid, but has no effect on cough
evoked by mechanical probing of the airway mucosa in
these same animals [43]. Finally, pharmacological
studies which take advantage of the somewhat unique
expression of neurokinins by airway C-fibres have
shown that citric acid- and capsaicin-induced cough in
cats and guinea-pigs is attenuated if not abolished by
prior treatment with selective neurokinin receptor
antagonists [46].
Although the evidence summarized above supports a
role for C-fibres in the cough reflex, there is also considerable evidence to indicate that airway C-fibres do not
evoke cough and may actually inhibit cough evoked by
RAR stimulation. In anaesthetized animals, for example, C-fibre stimulation has consistently failed to evoke
coughing, even though cough can be readily induced in
these animals by mechanically probing mucosal sites
along the airways [6,24,25,47]. Indeed, systemic administration of C-fibre stimulants has been shown to
inhibit cough evoked by RAR stimulation in various
species [24,25,47]. Given that vagal cooling abolishes
cough and yet preserves C-fibre-dependent reflexes
provides further evidence against a role for C-fibres in
cough [25].
It is unclear why so much conflicting evidence about
C-fibres in cough exists. It is possible that general
anaesthesia in animals selectively disrupts the ability of
C-fibres to evoke cough without adversely affecting
cough induced by RAR stimulation. Consistent with
this notion, general anaesthesia can also inhibit the
cough reflex in human subjects [48]. It is unlikely
that anaesthesia prevents C-fibre activation and Cfibre-mediated reflex effects entirely. C-fibres are
readily activated in anaesthetized animals and
can precipitate profound cardiorespiratory reflexes
[14,21,49–52]. Rather, anaesthesia must selectively
165
CHAPTER 16
inhibit cough-related neural pathways, or may act by
accentuating the inhibitory effects of C-fibre activation
on cough. Alternatively, general anaesthesia may interfere with the conscious perception of airway irritation
and the resulting urge to cough. In this context, it is interesting that capsaicin-evoked cough can be consciously suppressed in human subjects [53]. Yet an
equally viable hypothesis is that C-fibre stimulation
alone is simply insufficient to evoke cough but depends
upon airway afferent nerve interactions both in the periphery and at the level of the central nervous system
(see below).
Other airway afferent nerve subtypes
Not all airway afferent nerves fit into the three classes of
airway afferent nerves described above. In guinea-pigs
(commonly used to study cough), a second type of nociceptor-like afferent nerve has been described in vitro
[9,16,24,39,40]. Extracellular recording in the vagal
sensory ganglia of guinea-pigs indicates that about half
of the tracheal afferent nerves responsive to both
bradykinin and capsaicin are small, myelinated, Adfibres [9]. Physiologically, these myelinated airway
nociceptors resemble the myelinated nociceptors described in somatic tissues [54]. The guinea-pig tracheal
Ad-nociceptors have their cell bodies in the jugular ganglia (superior vagal ganglia, which also contains the
perikarya of bronchopulmonary C-fibres) and are
readily distinguished from RAR-like Ad-fibres innervating the guinea-pig trachea, which have their cell
bodies in the nodose ganglia (inferior vagal ganglia).
Unlike the jugular Ad-fibres, nodose-derived RARs are
utterly unresponsive to direct stimulation by either capsaicin or bradykinin in vitro and are 15-fold more
sensitive to mechanical stimulation than the jugular
Ad-fibres. The adaptation index (a measurement of afferent responsiveness to sustained mechanical stimulation) of these fibres also differs considerably.
McAlexander et al. [16] reported that the nodosederived RARs had an adaptation index that averaged
95 ± 2, whereas the adaptation index of the jugular
Ad-fibres was comparable to the adaptation index of
tracheal/bronchial C-fibres in the preparation, averaging 46 ± 8. Histological analyses reveal that like Cfibres, Ad-nociceptors innervating the guinea-pig
trachea express the capsaicin receptor VR1, but unlike
airway C-fibres, do not synthesize neuropeptides
[9,39,40].
166
The role of Ad-nociceptors in airway homeostatic
and defensive reflexes, and whether these afferent nerve
subtypes are unique to the guinea-pig trachea, is unknown. No such fibres have been described in rats or
dogs. Whether this is reflective of their peculiarity to the
guinea-pig or of the fact that myelinated, nociceptorlike fibres innervating the airways of other species have
been excluded from published analyses is also unknown. It is interesting, however, that only about half
of the RARs studied in other species are responsive to
capsaicin [12,18].
Subtypes of RARs and SARs have also been proposed [10,11,14,26,55,56]. Differences in the airway
segments innervated and not differences in the physiological properties of the SARs and RARs likely account
in part for some of the subtypes described. In other instances, it could be argued that the evidence for SAR
and RAR subtypes is more an argument of semantics
than physiology. For example, Bergren and Peterson
[56] and Ho and colleagues [10] both described a
population of myelinated afferent nerves innervating
the airways of rats that were activated vigorously by
lung deflation yet adapted rapidly to sustained lung
inflation. These afferent nerves, which were active
throughout the respiratory cycle, appeared to be physiologically identical in every way and yet Bergren and
Peterson classified these fibres as SARs while Ho and
colleagues called them RARs [10,56]. Such divergent
interpretations of essentially identical data by experienced investigators highlight the importance of establishing universal criteria for identifying airway afferent
nerve subtypes.
Interactions between afferent nerve
subtypes evoking cough
Peripheral interactions
Activation of airway C-fibres, particularly by capsaicin, evokes axon reflex-dependent peripheral release
of the neuropeptides substance P, neurokinin A and calcitonin gene-related peptide [42]. There are many consequences of axonal reflexes, including bronchospasm,
vasodilatation, oedema, leucocyte recruitment, mucus
secretion, altered parasympathetic nerve activity and
stimulation of endothelial and epithelial cells [57–63].
This peripheral neuropeptide release from C-fibre endings in the lung is prominent in rats and in guinea-pigs,
SENSORY PATHWAYS FOR THE COUGH REFLEX
and can be problematic when studying mechanisms of
airway defensive reflexes in these species.
Peripheral neuropeptide release in the airways may
also activate RARs. Studies in rabbits and in guineapigs have shown that endogenously released or exogenously administered substance P increases RAR
activity [22,23,64]. The neuropeptide-evoked RAR activation is unlikely to be a direct action on the afferent
nerve ending. Rather, it probably occurs secondary
to actions on structural cells in the airway wall that in
turn indirectly activate RARs [13,19,20]. Consistent
with this notion, capsaicin- and bradykinin-induced
stimulation of RARs in anaesthetized guinea-pigs correlates with the increases in pulmonary insufflation
pressure evoked by these agents. The associated increases in RAR activity can be substantially reduced or
abolished by pretreating animals with isoproterenol,
thereby preventing the bronchospastic activity of these
agents [19].
Given the ability of C-fibre stimulants to activate
RARs secondary to axonal reflex-mediated effects, it
is predictable that preventing the axon reflex would
be effective at preventing cough (Fig. 16.2). Indeed,
cough evoked by capsaicin, cigarette smoke, bronchospasm or the neutral endopeptidase inhibitor
phosphoramidon is markedly inhibited in guinea-pigs
pretreated with b-agonists, inhaled neurokinin receptor antagonists or inhaled neutral endopeptidase
(which enzymatically inactivates neurokinins and
bradykinin) [65–69].
Although it is clear that C-fibre stimulants readily
evoke cough, it is unclear whether axon reflexes or any
peripheral interactions between C-fibres and RARs
play any role in defensive reflex responses in the
Cortex
–
General
anaesthesia
SP/NKA
–
Brainstem
EAA
Central sensitization
Fig. 16.2 Highly schematic diagram
showing the potential roles of airway
C-fibres and rapidly adapting receptors
(RARs) in the cough reflex. In vivo, the
brainstem continuously receives input
from RARs as a result of the mechanical effects of breathing. Additional obstruction or mechanical irritation likely
evokes a distinct activity pattern in
RARs which directly promotes coughing. C-fibres may also contribute to
cough by (a) further activating RARs
secondary to either central or axon reflex mediated airways obstruction; (b)
facilitating ongoing RAR activity in the
brainstem via central sensitization; or
(c) directly activating cough pathways
in the brainstem possibly by promoting
the urge to cough through the perception of airway irritation. EAA, excitatory amino acids; NKA, neurokinin A;
SP, substance P.
Respiratory
muscles
COUGH
Central reflex
Acetylcholine
C-fibre
Axon reflex
SP/NKA
Capsaicin
Bradykinin
Inflammation
RAR
Bronchospasm
Mucus secretion
Plasma leakage
Breathing
Obstruction
Irritation
167
CHAPTER 16
airways of humans or in the airways of any species
other than guinea-pigs. In cats and dogs, for example,
bradykinin and capsaicin evoke bronchospasm,
bronchial vasodilatation and mucus secretion, but
these responses can be prevented entirely with atropine
or by vagotomy. Unlike those seen in rats and guineapigs, therefore, parasympathetic reflexes account for
the end-organ effects mediated by airway C-fibre
activation in the airways of dogs and cats [14,70,71].
Similar findings have been reported in humans [72].
Morphological studies also call into question the importance of the axon reflex in humans, as there are few
substance P-containing nerve fibres in human airways,
and there is no evidence that these nerves correspond to
the terminals of capsaicin-sensitive afferent C-fibres
[38]. Although studies in vitro suggest that capsaicin
can evoke contractions of the airway smooth muscle
and enhance mucus secretion in human tissue preparations, these effects are not mediated by neurokinins
[73–75].
The apparent lack of the axon reflex in humans
(and other species) has to be reconciled with data showing that C-fibre stimulants are extremely effective at
evoking cough. This would indicate that other mechanisms must underlie any potential involvement
of C-fibres in coughing. It is possible that peripheral
interactions between C-fibres and RARs may also
proceed independent of axon reflexes (Fig. 16.2). For
example, C-fibre activation evokes CNS-dependent
parasympathetic reflex-induced alterations in airway
and vascular tone and also induces mucus secretion
[14,21,34,71,72]. These end-organ effects are mediated in large part by acetylcholine released from airway
parasympathetic nerves and may be sufficient to activate RARs in the airway wall. This may account in part
for the observation that inhaled anticholinergics have
some antitussive properties in animals and in human
subjects [76,77].
Central interactions
Our understanding of central integration of airway
afferent fibres is somewhat limited. Insights into how
C-fibres and RARs might interact in the brainstem may
be obtained from studies in other systems, particularly
the somatosensory system. C-fibres and mechanoreceptors arising from somatic tissues interact in the
spinal cord in a process known as central sensitization
[35,78]. The consequence of this central interaction
168
manifests as a heightened reflex responsiveness and exaggerated sensations of pain following cutaneous stimulation. Studies of central sensitization in the spinal
cord have revealed two features of the somatosensory
system that facilitate this hyperreflexia. Firstly, C-fibre
and mechanoreceptor nerve terminals appear to converge onto common integrative neurones in the spinal
cord. Secondly, this convergence allows for central amplification of afferent signalling (i.e. synergy) following
the coincident activation of both afferent nerve subtypes. In many systems, this synergy and resulting hyperreflexia is precipitated by neurokinins released from
the central terminals of somatosensory C-fibres. This
results in a long-lasting hyperexcitability of spinal integrative neurones [35,78].
Several lines of evidence suggest that a process
similar to central sensitization may play a role in airway
defensive reflexes. The morphological, electrophysiological and pharmacological properties of airway Cfibres and mechanoreceptors are similar to those in the
somatic nervous system [9,10,14,35,78]. In addition,
anatomical and functional studies have shown considerable convergence of vagal afferents in brainstem
integration sites such as the nucleus of the solitary tract
(nTS) [7,79,80]. In many species, lung mechanoreceptors are sporadically active throughout the respiratory
cycle, whereas C-fibres are typically quiescent, even
during large lung inflations [10–14]. The central processing of C-fibre afferent nerve activity must therefore
be integrated into a reflex pathway that is continuously
receiving input from airway mechanoreceptors. C-fibre
activation, via central interactions with RARs, may
promote coughing by facilitating synaptic transmission
at RAR relay neurones in the brainstem (Fig. 16.2). In
support of this notion, substance P can facilitate synaptic transmission between lung afferents and nTS neurones in guinea-pigs [81].
Direct evidence for central interactions between airway C-fibres and RARs in the regulation of airway
parasympathetic tone has been documented [80]. Activation of C-fibre afferent nerves in the lung evokes profound increases in cholinergic tone in the airways by
facilitating airway mechanoreceptor activity in the
brainstem. In the absence of airway mechanoreceptor
activity, C-fibres are ineffective at evoking reflex responses. The facilitating effects of C-fibres on RAR reflex pathways in the brainstem appear to be mediated
by neurokinins since the central synergistic interactions
are prevented entirely by neurokinin receptor antago-
SENSORY PATHWAYS FOR THE COUGH REFLEX
nists administered intracerebroventricularly. The sensitizing effect of nociceptor stimulation can also be
mimicked, in the absence of C-fibre stimulation, by administering substance P to the brainstem [80]. Given
that neurokinin receptor antagonists also inhibit
cough, at least in part, via central mechanisms [47], it is
tempting to speculate that they are acting to prevent the
central sensitizing effects of C-fibre activation on RAR
pathways.
7
8
9
Concluding remarks
10
Studies that have delineated the afferent neural pathways regulating cough indicate that RARs subserve a
primary role in the cough reflex. There remains some
uncertainty about the role of other afferent nerve subtypes (particularly C-fibres) in this defensive reflex. The
failure to clearly define the role of C-fibres in cough relates in part to the ability of general anaesthesia to selectively prevent cough mediated by C-fibre stimulants.
The effects of general anaesthesia appear to be unique
to the cough reflex, since C-fibres readily evoke other
defensive reflexes under these same conditions. Anaesthesia must therefore selectively disrupt an as yet
unidentified C-fibre-specific cough pathway in the
brain. Further studies are required to identify the afferent pathways responsible for initiating cough, and the
interactions between these pathways and other modulatory afferent nerves regulating this important defensive reflex.
11
12
13
14
15
16
17
References
18
1 Widdicombe JG. Afferent receptors in the airways and
cough. Respir Physiol 1998; 114: 5–15.
2 Shannon R, Baekey DM, Morris KF, Lindsey BG. Ventrolateral medullary respiratory network and a model of
cough motor pattern generation. J Appl Physiol 1998; 84:
2020–35.
3 Karlsson JA. The role of capsaicin-sensitive C-fibre afferent nerves in the cough reflex. Pulm Pharmacol 1996; 9:
315–21.
4 Sant’Ambrogio G, Sant’Ambrogio FB, Davies A. Airway
receptors in cough. Bull Eur Physiopathol Respir 1984;
20: 43–7.
5 Matsumoto S. The activities of lung stretch and irritant receptors during cough. Neurosci Lett 1988; 90: 125–9.
6 Deep V, Singh M, Ravi K. Role of vagal afferents in the re-
19
20
21
22
flex effects of capsaicin and lobeline in monkeys. Respir
Physiol 2001; 125: 155–68.
Kubin L, Davies RO. Central pathways of pulmonary and
airway vagal afferents. In: Hornbein TF, ed. Regulation of
Breathing, Vol. 79. New York: Marcel Dekker, 1995:
219–84.
Bergren DR, Sampson SR. Characterization of intrapulmonary, rapidly adapting receptors of guinea-pigs. Respir
Physiol 1982; 47: 83–95.
Riccio MM, Kummer W, Biglari B, Myers AC, Undem BJ.
Interganglionic segregation of distinct vagal afferent fibre
phenotypes in guinea-pig airways. J Physiol 1996; 496:
521–30.
Ho CY, Gu Q, Lin YS, Lee LY. Sensitivity of vagal afferent
endings to chemical irritants in the rat lung. Respir Physiol 2001; 127: 113–24.
Widdicombe J. Airway receptors. Respir Physiol 2001;
125: 3–15.
Armstrong DJ, Luck JC. A comparative study of irritant
and type J receptors in the cat. Respir Physiol 1974; 21:
47–60.
Sant’Ambrogio G, Widdicombe J. Reflexes from airway
rapidly adapting receptors. Respir Physiol 2001; 125:
33–45.
Coleridge JC, Coleridge HM. Afferent vagal C fibre innervation of the lungs and airways and its functional significance. Rev Physiol Biochem Pharmacol 1984; 99: 1–110.
Jonzon A, Pisarri TE, Coleridge JC, Coleridge HM.
Rapidly adapting receptor activity in dogs is inversely related to lung compliance. J Appl Physiol 1986; 61:
1980–7.
McAlexander MA, Myers AC, Undem BJ. Adaptation of
guinea-pig vagal airway afferent neurones to mechanical
stimulation. J Physiol 1999; 521: 239–47.
Pack AI, DeLaney RG. Response of pulmonary rapidly
adapting receptors during lung inflation. J Appl Physiol
1983; 55 (3): 955–63.
Mohammed SP, Higenbottam TW, Adcock JJ. Effects of
aerosol-applied capsaicin, histamine and prostaglandin
E2 on airway sensory receptors of anaesthetized cats. J
Physiol 1993; 469: 51–66.
Bergren DR. Sensory receptor activation by mediators of
defense reflexes in guinea-pig lungs. Respir Physiol 1997;
108: 195–204.
Morikawa T, Gallico L, Widdicombe J. Actions of moguisteine on cough and pulmonary rapidly adapting receptor
activity in the guinea-pig. Pharmacol Res 1997; 35:
113–8.
Canning BJ, Reynolds SM, Mazzone SB. Multiple mechanisms of reflex bronchospasm in guinea-pigs. J Appl Physiol 2001; 91: 2642–53.
Joad JP, Kott KS, Bonham AC. Nitric oxide contributes
to substance P-induced increases in lung rapidly adapting
169
CHAPTER 16
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
receptor activity in guinea-pigs. J Physiol 1997; 503:
635–43.
Bonham AC, Kott KS, Ravi K, Kappagoda CT, Joad JP.
Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits. J
Physiol 1996; 493: 229–38.
Canning BJ, Reynolds SM, Meeker S, Undem BJ. Electrophysiological identification of tracheal (T) and laryngeal
(LX) vagal afferents mediating cough in guinea-pigs (GP).
Am J Respir Crit Care Med 2000; 161: A434.
Tatar M, Sant’Ambrogio G, Sant’Ambrogio FB. Laryngeal and tracheobronchial cough in anesthetized dogs. J
Appl Physiol 1994; 76: 2672–9.
Schelegle ES, Green JF. An overview of the anatomy and
physiology of slowly adapting pulmonary stretch receptors. Respir Physiol 2001; 125: 17–31.
Sudo T, Hayashi F, Nishino T. Responses of tracheobronchial receptors to inhaled furosemide in anesthetized
rats. Am J Respir Crit Care Med 2000; 162: 971–5.
Hanacek J, Korpas J. Modification of the intensity of the
expiration reflex during short-term inflation of the lungs
in rabbits. Physiol Bohemoslov 1982; 31: 169–74.
Nishino T, Sugimori K, Hiraga K, Hond Y. Influence of
CPAP on reflex responses to tracheal irritation in anesthetized humans. J Appl Physiol 1989; 67: 954–8.
Hanacek J, Davies A, Widdicombe JG. Influence of lung
stretch receptors on the cough reflex in rabbits. Respiration 1984; 45: 161–8.
Atzori L, Bannenberg G, Corriga AM, Lou YP, Lundberg
JM, Ryrfeldt A, Moldeus P. Sulfur dioxide-induced bronchoconstriction via ruthenium red-sensitive activation of
sensory nerves. Respiration 1992; 59: 272–8.
Wang AL, Blackford TL, Lee LY. Vagal bronchopulmonary C-fibers and acute ventilatory response to inhaled
irritants. Respir Physiol 1996; 104: 231–9.
Ezure K, Tanaka I. Lung inflation inhibits rapidly adapting
receptor relay neurons in the rat. Neuroreport 2000; 11:
1709–12.
Lee LY, Pisarri TE. Afferent properties and reflex functions
of bronchopulmonary C-fibers. Respir Physiol 2001; 125:
47–65.
Ma QP, Woolf CJ. Involvement of neurokinin receptors in
the induction but not the maintenance of mechanical allodynia in rat flexor motoneurones. J Physiol 1995; 486:
769–77.
Ho CY, Gu Q, Hong JL, Lee LY. Prostaglandin E(2) enhances chemical and mechanical sensitivities of pulmonary C fibers in the rat. Am J Respir Crit Care Med
2000; 162: 528–33.
Baluk P, Nadel JA, McDonald DM. Substance Pimmunoreactive sensory axons in the rat respiratory tract:
a quantitative study of their distribution and role in neurogenic inflammation. J Comp Neurol 1992; 319: 586–98.
170
38 Lundberg JM, Hokfelt T, Martling CR, Saria A, Cuello C.
Substance P-immunoreactive sensory nerves in the lower
respiratory tract of various mammals including man. Cell
Tissue Res 1984; 235: 251–61.
39 Hunter DD, Undem BJ. Identification and substance P
content of vagal afferent neurons innervating the epithelium of the guinea-pig trachea. Am J Respir Crit Care Med
1999; 159: 1943–8.
40 Myers AC, Kajekar R, Undem BJ. Allergic inflammationinduced neuropeptide production in rapidly adapting afferent nerves in guinea-pig airways. Am J Physiol Lung
Cell Mol Physiol 2002; 282: L775–81.
41 Dey RD, Altemus JB, Zervos I, Hoffpauir J. Origin and
colocalization of CGRP- and SP-reactive nerves in cat airway epithelium. J Appl Physiol 1990; 68: 770–8.
42 Barnes PJ. Neurogenic inflammation in the airways.
Respir Physiol 2001; 125: 145–54.
43 Forsberg K, Karlsson JA. Cough induced by stimulation of
capsaicin-sensitive sensory neurons in conscious guineapigs. Acta Physiol Scand 1986; 128: 319–20.
44 Choudry NB, Fuller RW, Pride NB. Sensitivity of the
human cough reflex: effect of inflammatory mediators
prostaglandin E2, bradykinin, and histamine. Am Rev
Respir Dis 1989; 140: 137–41.
45 Mazzone SB, Mori N, Canning BJ. Bradykinin-induced
cough in conscious guinea-pigs. Am J Respir Crit Care
Med 2002; 165: A773.
46 Bolser DC, DeGennaro FC, O’Reilly S, McLeod RL, Hey
JA. Central antitussive activity of the NK1 and NK2
tachykinin receptor antagonists, CP-99,994 and SR
48968, in the guinea-pig and cat. Br J Pharmacol 1997;
121: 165–70.
47 Tatar M, Webber SE, Widdicombe JG. Lung C-fibre receptor activation and defensive reflexes in anaesthetized cats.
J Physiol 1988; 402: 411–20.
48 Nishino T, Tagaito Y, Isono S. Cough and other reflexes on
irritation of airway mucosa in man. Pulm Pharmacol
1996; 9: 285–92.
49 Roberts AM, Kaufman MP, Baker DG, Brown JK, Coleridge HM, Coleridge JC. Reflex tracheal contraction induced by stimulation of bronchial C-fibers in dogs. J Appl
Physiol 1981; 51: 485–93.
50 Davis B, Roberts AM, Coleridge HM, Coleridge JC.
Reflex tracheal gland secretion evoked by stimulation
of bronchial C-fibers in dogs. J Appl Physiol 1982; 53:
985–91.
51 Pisarri TE, Coleridge JC, Coleridge HM. Capsaicininduced bronchial vasodilation in dogs: central and peripheral neural mechanisms. J Appl Physiol 1993; 74:
259–66.
52 Bergren DR. Enhanced lung C-fiber responsiveness in
sensitized adult guinea-pigs exposed to chronic tobacco
smoke. J Appl Physiol 2001; 91: 1645–54.
SENSORY PATHWAYS FOR THE COUGH REFLEX
53 Hutchings HA, Morris S, Eccles R, Jawad MS. Voluntary
suppression of cough induced by inhalation of capsaicin in
healthy volunteers. Respir Med 1993; 87: 379–82.
54 Szolcsányi J. Actions of capsaicin on sensory receptors. In:
Wood JN, ed. Capsaicin in the Study of Pain. London:
Academic Press, 1993: 1–27.
55 Yu J. Spectrum of myelinated pulmonary afferents. Am
J Physiol Regul Integr Comp Physiol 2000; 279:
R2142–8.
56 Bergren DR, Peterson DF. Identification of vagal sensory
receptors in the rat lung: are there subtypes of slowly
adapting receptors? J Physiol 1993; 464: 681–98.
57 Lundberg JM, Saria A, Brodin E, Rosell S, Folkers K. A
substance P antagonist inhibits vagally induced increase in
vascular permeability and bronchial smooth muscle contraction in the guinea-pig. Proc Natl Acad Sci USA 1983;
80: 1120–4.
58 Kuo HP, Rohde JA, Tokuyama K, Barnes PJ, Rogers DF.
Capsaicin and sensory neuropeptide stimulation of goblet
cell secretion in guinea-pig trachea. J Physiol 1990; 431:
629–41.
59 Manzini S. Bronchodilatation by tachykinins and capsaicin in the mouse main bronchus. Br J Pharmacol 1992;
105: 968–72.
60 Piedimonte G, Hoffman JI, Husseini WK, Snider RM,
Desai MC, Nadel JA. NK1 receptors mediate neurogenic
inflammatory increase in blood flow in rat airways. J Appl
Physiol 1993; 74: 2462–8.
61 Baluk P, Bertrand C, Geppetti P, McDonald DM, Nadel
JA. NK1 receptors mediate leukocyte adhesion in neurogenic inflammation in the rat trachea. Am J Physiol 1995;
268: L263–L269.
62 Ricciardolo FL, Rado V, Fabbri LM, Sterk PJ, Di Maria
GU, Geppetti P. Bronchoconstriction induced by citric
acid inhalation in guinea-pigs: role of tachykinins,
bradykinin, and nitric oxide. Am J Respir Crit Care Med
1999; 159: 557–62.
63 Canning BJ, Reynolds SM, Anukwu LU, Kajekar R,
Myers AC. Endogenous neurokinins facilitate synaptic
neurotransmission in guinea-pig airway parasympathetic
ganglia Am J Physiol Regul Integr Comp Physiol 2002;
283: R320–30.
64 Matsumoto S, Takeda M, Saiki C, Takahashi T, Ojima K.
Effects of tachykinins on rapidly adapting pulmonary
stretch receptors and total lung resistance in anesthetized,
artificially ventilated rabbits. J Pharmacol Exp Ther 1997;
283: 1026–31.
65 Ujiie Y, Sekizawa K, Aikawa T, Sasaki H. Evidence for substance P as an endogenous substance causing cough in
guinea-pigs. Am Rev Respir Dis 1993; 148: 1628–32.
66 Bolser DC, DeGennaro FC, O’Reilly S, Hey JA, Chapman
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
RW. Pharmacological studies of allergic cough in the
guinea-pig. Eur J Pharmacol 1995; 277: 159–64.
Sekizawa K, Ebihara T, Sasaki H. Role of substance P in
cough during bronchoconstriction in awake guinea-pigs.
Am J Respir Crit Care Med 1995; 151: 815–21.
Yasumitsu R, Hirayama Y, Imai T, Miyayasu K, Hiroi J.
Effects of specific tachykinin receptor antagonists on citric
acid-induced cough and bronchoconstriction in unanesthetized guinea-pigs. Eur J Pharmacol 1996; 300:
215–9.
Kohrogi H, Nadel JA, Malfroy B, Gorman C,
Bridenbaugh R, Patton JS, Borson DB. Recombinant
human enkephalinase (neutral endopeptidase) prevents
cough induced by tachykinins in awake guinea-pigs. J Clin
Invest 1989; 84: 781–6.
Russell JA, Lai-Fook SJ. Reflex bronchoconstriction induced by capsaicin in the dog. J Appl Physiol 1979; 47:
961–7.
Ichinose M, Inoue H, Miura M, Yafuso N, Nogami H,
Takishima T. Possible sensory receptor of nonadrenergic
inhibitory nervous system. J Appl Physiol 1987; 63:
923–9.
Fuller RW, Dixon CM, Barnes PJ. Bronchoconstrictor response to inhaled capsaicin in humans. J Appl Physiol
1985; 58: 1080–4.
Baker B, Peatfield AC, Richardson PS. Nervous control of
mucin secretion into human bronchi. J Physiol 1985; 365:
297–305.
Rogers DF, Barnes PJ. Opioid inhibition of neurally mediated mucus secretion in human bronchi. Lancet 1989; 1:
930–2.
Ellis JL, Sham JS, Undem BJ. Tachykinin-independent effects of capsaicin on smooth muscle in human isolated
bronchi. Am J Respir Crit Care Med 1997; 155: 751–5.
Jia YX, Sekizawa K, Sasaki H. Cholinergic influence on
the sensitivity of cough reflex in awake guinea-pigs. J
Auton Pharmacol 1998; 18: 257–61.
Lowry R, Wood A, Johnson T, Higenbottam T. Antitussive
properties of inhaled bronchodilators on induced cough.
Chest 1988; 93: 1186–9.
Woolf CJ, Salter MW. Neuronal plasticity: increasing the
gain in pain. Science 2000; 288: 1765–9.
Jordan D. Central nervous pathways and control of the
airways. Respir Physiol 2001; 125: 67–81.
Mazzone SB, Canning BJ. Synergistic interactions between airway afferent nerve subtypes mediating reflex
bronchospasm in guinea-pigs. Am J Physiol Regul Integr
Comp Physiol 2002; 283: R86–98.
Mutoh T, Bonham AC, Joad JP. Substance P in the nucleus
of the solitary tract augments bronchopulmonary C fiber
reflex output. Am J Physiol 2000; 279: R1215–23.
171
17
Neurogenesis of cough
Donald C. Bolser, Paul W. Davenport, Francis J. Golder,
David M. Baekey, Kendall F. Morris, Bruce G. Lindsey &
Roger Shannon
Introduction
Recent evidence has led to significant advances in our
understanding of the central mechanisms for the production of cough. A single network of neurones appears to mediate both cough and breathing [1–4]. The
neurones in this network have distinct anatomical connections (or functional interactions) with one another
that, in combination with their intrinsic membrane
properties, regulate their discharge patterns to control
temporal and spatial distribution of motor drive to respiratory muscle motoneurones. Clearly, cough and
breathing are different behaviours. The same network
can produce such different behaviours by a process
known as reconfiguration, which can involve dynamic
alteration of the excitability of key elements and/or
recruitment of previously silent elements. We propose
that the excitability of this network during cough is additionally controlled by a ‘gating’ mechanism, which is
sensitive to antitussive drugs [5]. Included here is a review of the evidence supporting these concepts, as well
as the first effort to integrate the detailed understanding
of the brainstem cough generation network with the
emerging knowledge of how this reflex is functionally
organized.
Cough network model
It is well documented that the ventrolateral medullary
respiratory neuronal network that generates the eupnoeic breathing pattern also participates in producing
cough motor patterns [1–4,6–12].
The scheme in Fig. 17.1 represents a model for the
generation and transmission of the eupnoeic and cough
motor patterns to pump and laryngeal muscles by elements of the rostral and caudal ventral respiratory
group (VRG), including Bötzinger and pre-Bötzinger
complex neurones (BÖT/rVRG). Excitatory and inhibitory connections onto respiratory bulbospinal premotor neurones, that drive spinal motoneurones and
upper airway (i.e. laryngeal) motoneurones, arise from
subpopulations in the ‘core’ network (enclosed by
dotted lines). Discussions of evidence supporting the
model and gaps in our knowledge are available in our
previous reports [3,4,12].
This model is based primarily on fictive cough data
obtained in neuromuscular blocked, ventilated cats by
stimulation of the intrathoracic trachea. Tracheobronchial cough is initiated by stimulation of rapidly
adapting receptors (RARs) [13–14]. For the purposes
of this review, these RARs will be defined as ‘cough receptors’, but we recognize that this population of sensory afferents also elicits mucus production.
In response to cough receptor excitatory input, there
are alterations in inspiratory and expiratory timing and
discharge patterns of ‘core’ neurones. These changes
are transmitted via premotor neurones specific for
different muscles. The pathways and connectivity of
‘cough’ receptor second-order neurones in the nucleus
tractus solitarius (NTS) to ‘core’ neurones are unknown. In the model, cough receptor interneurones are
proposed to provide excitatory input to virtually all
elements of the system; this connectivity generated
cough-like motor patterns in computer simulations [3].
Slowly adapting pulmonary stretch receptors (SARs
or PSRs) influence the timing and patterns of inspiratory and expiratory motor activity during eupnoea.
173
CORE NETWORK
Connectivity key
Excitatory
E-Dec
2nd order 'cough'
excitatory
Inhibitory
I-Driver
I-Plat
E-Aug
late
E-Aug
early
NTS
I-Dec
Pump
I-Aug
E-Dec
2nd
order
E-Aug
late
E-Dec
I-Dec
I-Plat
E-Dec
'Cough' receptors
PSR
I-Dec
I-Aug
ILM
E-Dec
Larynx
I-Aug
ELM
E-Aug
late
E-Aug
early
E-Aug
early
E-Aug
late
E-Aug
late
E-Aug
I-Dec
I-Aug
PSR
E-Dec
PREMOTOR
I-Aug
I-Aug
PREMOTOR
Lungs
Intercostals
I-Dec
I-Driver
Insp
Exp
MN
MN
Diaphragm
Abdominals
Fig. 17.1 Cough network model. Scheme of BÖT/VRG respiratory neuronal network connections and hypothesized inputs from nucleus tractus solitarius (NTS) cough receptor
second-order neurones and pulmonary stretch receptor (PSR,
SAR) pump cells. Neurone connections onto respiratory bulbospinal premotor neurones (I-Aug and E-Aug) and laryngeal motoneurones (ILM and ELM) arise from the core
network (enclosed by dotted line box). E-Aug Early and EAug Late, neurones that begin discharging prior to and dur-
ing the latter part of the expiratory phase, respectively. IDriver, inspiratory neurone also active before the expiratory–inspiratory phase transition and with a relatively constant discharge rate throughout the inspiratory phase (I-Plat);
definition specifically limited to BÖT/rVRG neurones with
previously identified excitatory functional links to other inspiratory neurones [15]. I-Dec and E-Dec, inspiratory and expiratory modulated neurones with decrementing patterns.
Other abbreviations have been described in detail in the text.
NEUROGENESIS OF COUGH
These effects are presumed to be due primarily to
monosynaptic connections, via NTS pump cells, onto
rostral ventral respiratory group propriobulbar E-Dec
neurones [16] and paucisynaptic interactions with bulbospinal premotor E-Aug neurones [17]. SARs appear
not to affect inspiratory amplitude and inspiratory and
expiratory phase timing, during multiple cough
episodes [18]. They are, however, necessary for expression of the cough motor pattern [19,20]; their effect
appears to involve both enhancement of cough
excitability as well as central facilitation of expiratory
motor drive.
The following sections are a summary of our working hypotheses on neurone responses and interactions
during a cough (see Figs 17.1 & 17.2). A key to the
abbreviations is in Table 17.1.
Inspiratory phase of cough
There is an increased firing rate and duration of inspiratory motor activity in the diaphragm, intercostal and
laryngeal muscles. Phrenic and intercostal spinal motoneurones are driven by I-Aug premotor neurones,
whose discharge pattern is determined by excitatory
inputs from ‘core’ I-Aug and I-Driver neurones and
inhibitory inputs from I-Dec neurones. Inspiratory
laryngeal motoneurone activity is determined by excitation from ‘core’ I-Aug, I-Dec and I-Plat (not shown)
neurones, resulting in enlargement of the glottis opening. The prolonged duration of the inspiratory phase
results from the activity of I-Driver neurones and inhibitory I-Dec neurones. Expiratory neurones are suppressed by widespread inhibitory actions of ‘core’
I
E
I
COUGH
C
E
I-Driver
‘CORE’
¨
BOT/rVRG
I-Dec
I-Aug
E-Dec
e
l
E-Aug
Fig. 17.2 Graphical representation of
respiratory neurones and their responses during fictive cough. The discharge
profiles were estimated from integrated
neurone signals (in vivo). Each profile
represents an envelope that includes
neurones with similar discharge patterns, but different peak rates, and duration of activities. C, compressive
phase of cough; PILM and PELM, premotor inspiratory and expiratory laryngeal neurones; LUM, lumbar motor
nerve to abdominal expiratory muscles;
PHR, phrenic motoneurones.
ILM
PILM
ELM
PELM
PHR
I-Aug/BS
PREMOTOR
LUM
E-Aug/BS
PREMOTOR
175
CHAPTER 17
Table 17.1 Key to abbreviations.
I-Driver
I-Dec
I-Aug
I-Aug premotor
ILM
ELM
E-Dec
E-Aug (early)
E-Aug (late)
E-Aug premotor
E-Recruit
Pump cell
PSR
‘Cough’ receptors
Inspiratory neurones also active prior to the expiratory–inspiratory phase transition (I–E/I) and with a
relatively constant discharge rate throughout the I phase (I-Plat). Definition specifically limited to rostral
BÖT/VRG neurones with previously identified excitatory functional links to other inspiratory neurones
Inspiratory neurone with decrementing firing rate during the phase
Inspiratory neurone with augmenting firing rate during the phase
Premotor to spinal motoneurones
Inspiratory laryngeal motoneurone
Expiratory laryngeal motoneurone
Expiratory neurone with decrementing firing rate; most active during the early expiratory (postinspiratory)
interval
Expiratory neurone with augmenting discharge pattern; begins activity early in phase and active
throughout
Activity limited primarily to late part of expiratory interval (stage 2 expiration)
Premotor to spinal motoneurones
Silent neurone that is evoked during the E phase of cough
Neurone excited by pulmonary stretch receptors (SARs) during lung inflation
Slowly adapting pulmonary stretch receptors (SARs)
Operationally defined rapidly adapting receptors (RARs)
I-Dec and I-Aug neurones. The inspiratory phase is terminated by inhibitory actions of ‘core’ E-Dec and early
E-Aug cells. The increased E-Dec and E-Aug neurone
activities are due in part to reduced inhibitory actions
of I-Aug and I-Dec neurones and excitation from cough
receptor activity.
enhanced postinhibitory rebound resulting from the
cessation of actions from antecedent I-Dec and I-Aug
neurones. During the compressive and expulsive
phases, inspiratory laryngeal motoneurones are inhibited by decrementing and augmenting expiratory
neurones.
Compressive phase of cough
Expulsive phase of cough
At the transition between the inspiratory and expulsive
phases, there is a coordinated increase in expiratory intercostal, abdominal and laryngeal muscle activity to
produce a large increase in intrathoracic pressure. Intercostal and abdominal spinal motoneurones receive
excitatory drive from bulbospinal premotor expiratory
neurones. The firing rate of premotor (E-Aug) neurones
increases rapidly near the end of the inspiratory phase
due primarily to enhanced excitation from ‘core’ early
E-Aug neurones. Other factors promoting this activity
include reduced inhibition from ‘core’ I-Dec and I-Aug
neurones (postinhibitory rebound), and reduced inhibition from another subpopulation of E-Aug neurones
and SARs.
A short burst of expiratory laryngeal motoneurone activity, and closure of the glottis, are due primarily to excitation from ‘core’ premotor E-Dec neurones.
Other factors that promote this burst of activity include
The glottis is opened quickly due to a rapid decline in
expiratory laryngeal motoneurone activity. This pattern is a consequence of reduced excitation from core
premotor E-Dec neurones and inhibition from other
E-Dec and late E-Aug neurones.
For a short time after the compressive phase, the firing rates of premotor bulbospinal E-Aug neurones, and
thus spinal expiratory motoneurones, continue to increase. As the expiratory phase progresses, discharge
rates decrease in a decrementing pattern shaped by a
decline in excitation from core early E-Aug neurones
and increasing inhibition from late E-Aug neurones.
Expiratory activity is terminated by enhanced activity
in decrementing and augmenting inspiratory neurones
as they are released from inhibition by expiratory
neurones.
176
NEUROGENESIS OF COUGH
Other modulatory influences on the
cough motor pattern
Respiratory neurones of the ventrolateral medulla
(BÖT/rVRG) mutually interact with other respiratory
and non-respiratory modulated neurones in the medulla, pons and cerebellum to form a larger dynamic network. Results from neuronal recordings and lesioning
studies are consistent with a modulatory role of neurones in the medullary midline (i.e. raphe nuclei and adjoining reticular formation) and lateral tegmental field,
pontine respiratory group and cerebellum on generation of the cough pattern by BÖT/rVRG [7,21–25]. Additional studies are needed to elucidate pathways and
connections between these regions and their specific
modulatory roles.
Cough is a gated process
The work of Bolser et al. [5] involved perturbation of
the cough motor pattern and provided evidence for a
gating mechanism in the tracheobronchial cough pattern generator. The location and identity of the gate are
unknown. The gating mechanism is postulated to regulate the behaviour of the cough network by raising its
excitability above a threshold (analogous to apnoeic
threshold for breathing). Single coughs result from
transient excitation of the gating mechanism, whereas
repetitive coughing can occur as long as the cough
threshold is exceeded. Furthermore, this gating mechanism regulates the magnitude of expiratory motor activation during cough.
Evidence supporting the
gating mechanism
Antitussive drugs do not inhibit tracheobronchial
cough by suppression of the entire central cough generation mechanism, rather they have very specific effects
on various components of this system. For example,
low doses of antitussive drugs (administered via the
vertebral artery) specifically decreased the number of
coughs elicited per stimulus trial and the expiratory
muscle electromyogram burst amplitude during tracheobronchial cough [5]. Inspiratory or expiratory
phase durations and inspiratory burst amplitude were
unchanged by these low doses of antitussive drugs.
Therefore, antitussive drugs must inhibit tracheobronchial cough number by an action ‘upstream’ from
the components of the pattern generator that regulate
cough cycle duration (Fig. 17.3a,b). This aspect of the
model accounts for the fact that antitussive drugs do
not decrease breathing frequency at doses that inhibit
cough [5,26].
We propose that afferent input to the pattern generator is transmitted by cough receptor relay interneurones and pump cells through the gating mechanism
(Fig. 17.3a). Direct suppression of pump cell activity by
antitussive drugs is unlikely because in our study these
drugs had no effect on eupnoeic respiratory phase durations or integrated diaphragm EMG amplitude [5].
These drugs can also selectively decrease expiratory
motor activation during cough without reducing inspiratory motor activation. These findings do not support
an action of antitussive drugs on cough receptor interneurones in the NTS. A caveat to this argument is
that the population of NTS cough relay neurones may
be composed of subsets that separately regulate the behaviour of inspiratory and expiratory motor pathways.
The expiratory subset could have a high relative sensitivity to codeine. To our knowledge, no evidence exists
supporting the existence of functional subsets of this
population of NTS neurones. As such, we have depicted in Fig. 17.3(a) what we believe to be the simplest
hypothesis. In this model, pump cells, NTS cough
receptor neurones and the core of the cough network
that controls cough phase durations do not participate
in the gating mechanism (Fig. 17.3a).
Proposed interaction of the
gating mechanism with elements of the
cough network
The model in Fig. 17.1 is specific to tracheobronchial
cough and does not address any differences between
this type of cough and that elicited from stimulation of
the larynx. Furthermore, the model is based on the results of experiments in which single coughs were generated in each stimulus trial, whereas the gating
mechanism (Fig. 17.3) is based largely on experiments
in which repetitive coughing was produced during each
stimulus. The differences in how elements participating
in this network may interact during single and repetitive coughs are currently unknown.
Reconciliation of the gating mechanism with the
177
CHAPTER 17
(a)
(b)
2nd
E-Dec
Pump
cells
order
Tracheobronchial
gate
Cough pattern
generator
PSRs
Cough
receptors
Inspiratory
premotor
Expiratory
premotor
E-Aug
late
E-Aug
early
E-Aug
early
E-Aug
BS
?
Inspiratory
motor
Excitatory
?
Expiratory
motor
Permissive
Tracheobronchial
gate
Excitatory
Spinal
Inhibitory
Fig. 17.3 Proposed relationship of the tracheobronchial gate with elements of the cough pattern generator. (a) A generalized representation of the relationship of the gate to the cough pattern generator. (b) Potential synaptic relationships of the gate with elements of the cough network that control expiratory motor drive. Abbreviations as in Table 17.1.
detailed model of the cough network is challenging because the gate is a functional entity of unknown
anatomical location. In essence, it is difficult to connect
functional elements with specifically identified components of a model in the absence of specific knowledge of
synaptic relationships between them. This problem in
unifying a functional model with a specific network
model highlights an important concept: namely, that it
is at least as important to determine how the gating
mechanism interacts with known elements of the cough
pattern generator as it is to identify the neuronal groups
that make up the gate itself. Our recent work has been
aimed at determining how the gating mechanism interacts with neurones that control expiratory motor drive
during cough [27]. We have not proposed a model of
the specific synaptic mechanisms by which the gate is
proposed to control the number of coughs per stimulus
trial; more information is needed regarding the identity
and activity patterns of neurones participating in the
gate mechanism before this will become possible.
According to the model in Fig. 17.3(a,b), suppression of expiratory motor activity by antitussive drugs is
178
accomplished by inhibition of elements of the tracheobronchial gating system, preventing the excitatory effects of cough receptors from reaching bulbospinal
premotor expiratory neurones. There currently is no
evidence in the literature indicating the mechanism by
which antitussive drugs suppress medullary or spinal
expiratory motor activity during cough. Jakus et al.
[28] have shown that the tracheobronchial coughrelated discharge of caudal VRG expiratory neurones
is reduced after systemic administration of codeine.
These findings could be explained either by an inhibitory action of codeine on medullary expiratory
neurones or by an action of this drug on neurones
presynaptic to medullary expiratory neurones.
The determination of the mechanism by which antitussive drugs decrease the activity of expiratory motor
pathways during cough represents a critical piece of information in determining how the gating mechanism
interacts with specific elements of the cough network.
We have obtained evidence that the responsiveness of
expiratory motor pathways to other inputs is relatively
unchanged after doses of codeine sufficient to almost
NEUROGENESIS OF COUGH
completely eliminate cough [27]. In anaesthetized cats,
we determined the response of abdominal expiratory
EMG to cough and expiratory threshold loading
(ETL). Expiratory loading results in increased activity
of caudal ventral respiratory group expiratory premotor neurones and expiratory spinal motoneurones
[29]. Central (intravertebral arterial) administration of
codeine significantly suppressed expiratory muscle activation during tracheobronchial cough, but had no
effect on the response to ETL [27]. This selective effect
of codeine supports the concept that expiratory motor
pathways activated by both stimuli are not directly inhibited by the drug. These data are consistent with the
hypothesis that codeine inhibits one or more elements
presynaptic to expiratory premotor and motoneurones. In the cough network (Fig. 17.1), a subset of
‘core’ expiratory augmenting neurones (E-Aug early),
caudal medullary expiratory premotor neurones (EAug), and spinal expiratory motoneurones all contribute to increased expiratory muscle activity during
cough, as well as the temporal regulation of the expulsive phase. Based on our evidence, we propose that the
tracheobronchial gate mechanism is presynaptic to the
‘core’ early E-Aug and caudal VRG premotor neurones
(Fig. 17.3b). We also hypothesize that there are, at
least, two subpopulations of early E-Aug neurones.
One subpopulation is involved in the regulation of expiratory phase durations during cough and the other
group receives excitatory input from the tracheobronchial gate and in turn excites E-Aug bulbospinal
(BS) neurones. This hypothesis is supported by evidence that the expiratory phase duration and magnitude of expulsive motor drive during cough are
regulated independently [30].
The proposed interaction between the gate and the
cough network shown in Fig. 17.3(b) is subject to several caveats. The model must be further tested by direct
determination of the excitability of selected elements of
the expiratory network during codeine administration.
A presynaptic action of codeine would be supported by
an unchanged excitability of E Aug BS neurones in the
presence of this drug. However, if the excitability of EAug BS neurones were decreased by codeine, the model
would have to be revised to incorporate these neurones
in the gating mechanism.
Identity of the gate elements
The gate could represent single or multiple groups of interneurones interposed between NTS cough receptor
relay neurones and the cough network. Alternatively,
suppression of selected presynaptic terminals of NTS
cough receptor relay neurones by antitussive drugs
could account for some of our observations. Candidate
populations of neurones may exist in the raphe nuclei
[24], pons [23], interposed nucleus of the cerebellum
[25], reticular formation [31] and/or tegmental field
[22]. We propose that some elements of the gating
mechanism participate in excitation of expiratory premotor neurones during cough. Whether this excitation
occurs by monosynaptic or multisynaptic interactions
is currently unknown. The excitability of neurones participating in the gating mechanism should be decreased
by antitussive drugs, leading to disfacilitation of elements of the cough network with which they interact.
Of the candidate locations listed above, the most information is available on the effect of the cerebellum on
the cough motor pattern [25]. Cerebellectomy or lesion
of the interposed nucleus can elicit relative suppression
of expiratory motor discharge during cough as well as a
decrease in cough number [25]. However, cerebellectomy does not completely eliminate cough as is commonly observed after administration of antitussive
drugs [32]. The role of the cerebellum in mediating proposed functions of the gate should be clarified by further investigation.
Acknowledgements
Work presented in this review was supported by National Heart, Lung, and Blood Institute grant HL49813 and State of Florida Department of Health
Biomedical Research grant BM-040.
References
1 Shannon R, Bolser DC, Lindsey BG. Neural control of
coughing and sneezing. In: Miller AD, Bianchi AL, Bishop
BP, eds. Neural Control of Breathing. Boca Raton: CRC
Press, 1996: 215–24.
2 Shannon R, Baekey DM, Morris KF, Lindsey BG. Brainstem respiratory networks and cough. Pulm Pharmacol
1997; 9: 343–7.
3 Shannon R, Morris KF, Lindsey BG. Ventrolateral
medullary respiratory network and a model of cough
179
CHAPTER 17
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
motor pattern generation. J Appl Physiol 1998; 84:
2020–35.
Shannon R, Baekey DM, Morris KF, Li Z, Lindsey BG.
Functional connectivity among ventrolateral medullary
respiratory neurons and responses during fictive cough in
the cat. J Physiol 2000; 525: 207–24.
Bolser DC, Hey JA, Chapman RW. Influence of central antitussive drugs on the cough motor pattern. J Appl Physiol
1999; 86: 1017–24.
Engelhorn R, Weller E. Zentrale representation hustenwirksamer Afferenzen in der Medulla oblongata der
Katze. Pflug Arch 1965; 284: 224–39.
Jakus J, Tomori Z, Boselova L, Nagyova B, Kubinec V.
Respiration and airway reflexes after transversal brain
stem lesions in cats. Physiol Bohemoslov 1987; 36:
329–40.
Dawid-Milner MS, Lara JP, Milan A, Gonzalez-Baron S.
Activity of inspiratory neurons of the ambiguous complex
during cough in the spontaneously breathing decerebrate
cat. Exp Physiol 1993; 78: 835–8.
Oku Y, Tanaka I, Ezure K. Activity of bulbar respiratory
neurons during fictive coughing and swallowing in the
decerebrate cat. J Physiol 1994; 480: 309–84.
Gestreau C, Milano S, Bianchi AL, Grelot L. Activity of
dorsal respiratory group inspiratory neurons during laryngeal-induced fictive coughing and swallowing in decerebrate cats. Exp Brain Res 1996; 108: 247–56.
Bongianni F, Mutolo D, Fontana GA, Pantaleo T. Discharge patterns of Botzinger complex neurons during
cough in the cat. Am J Physiol 1998; 274: R1015–24.
Baekey DM, Morris KF, Gestreau C, Lindsey BG, Shannon
R. Medullary respiratory neurones and control of laryngeal motoneurones during fictive eupnoea and cough in
the cat. J Physiol 2001; 534: 565–81.
Tomori Z, Widdicombe JG. Muscular, bronchomotor,
and cardiovascular reflexes elicited by mechanical stimulation of the respiratory tract. J Physiol 1969; 200: 25–49.
Widdicombe JG. Afferent receptors in the airways and
cough. Respir Physiol 1998; 114: 5–15.
Balis UJ, Morris KF, Koleski J, Lindsey BG. Simulations
of ventrolateral medullary neural network for respiratory rhythmogenesis inferred from spike train crosscorrelation. Biol Cybern 1994; 70: 311–27.
Hayashi F, Coles SK, McCrimmon DR. Respiratory neurons mediating the Breuer–Hering reflex prolongation of
expiration in rat. J Neurosci 1996; 16: 6526–36.
Ezure K, Tanaka I. Pump neurons of the nucleus of the
solitary tract project widely to the medulla. Neurosci Lett
1996; 215: 123–6.
Bolser DC, Davenport PW. Volume–timing relationships
180
19
20
21
22
23
24
25
26
27
28
29
30
31
32
during cough and resistive loading in the cat. J Appl Physiol 2000; 89: 785–90.
Hanecek J, Davies A, Widdicombe JG. Influence of lung
stretch receptors on the cough reflex in rabbits. Respiration 1984; 45: 161–8.
Sant’Ambrogio G, Sant’Ambrogio FB, Davies A. Airway
receptors in cough. Bull Eur Physiopathol Respir 1984;
20: 43–7.
Jakus A, Stransky A, Poliacek I, Barani H, Boselova L.
Effects of medullary midline lesions on cough and other
airway reflexes in anaesthetized cats. Physiol Res 1998;
47: 203–13.
Jakus J, Stransky A, Poliacek I, Barani H, Boselova L.
Kainic acid lesions to the lateral tegmental field of medulla: effects on cough, expiration and aspiration reflexes in
anesthetized cats. Physiol Res 2000; 49: 387–98.
Baekey DM, Morris KF, Li Z, Nuding SC, Lindsey BG,
Shannon R. Concurrent changes in pontine respiratory
group neuron activities during fictive coughing. FASEB J
1999; 13: A824.
Baekey DM, Morris KF, Nuding SC, Segers LS, Lindsey
BG, Shannon R. Raphe neuron activity during fictive
coughing. FASEB J 2002; 16: 628.
Xu F, Frazier DT, Zhang Z, Shannon R. Influence of the
cerebellum on the cough motor pattern. J Appl Physiol
1997; 83: 391–7.
May AJ, Widdicombe JG. Depression of the cough reflex
by pentobarbitone and some opium derivatives. Br J Pharmacol 1954; 9: 335–40.
Bolser DC, Pampo CA, Ruble MA, Golder FJ. Evidence
for disfacilitation of expiratory premotor pathways by antitussive drugs. Am J Respir Crit Care Med 2001; 163:
A629.
Jakus J, Tomori Z, Stransky A, Boselova L. Bulbar respiratory activity during defensive airways reflexes in cats. Acta
Physiol Hung 1987; 70: 245–54.
Baker JP, Frazier DT. Response of abdominal muscle
to graded mechanical loads. J Neurosci Res 1985; 13:
581–9.
Bolser DC, Davenport PW. Determinants of cough cycle
duration in the cat. FASEB J 2001; 13: 798.
Billig I, Foris JM, Enquist LW, Card JP, Yates BJ. Definition
of neuronal circuitry controlling the activity of phrenic
and abdominal motoneurons in the ferret using recombinant strains of pseudorabies virus. J Neurosci 2000; 20:
7446–54.
Bolser DC, DeGennaro FC, O’Reilly S, McLeod RL, Hey
JA. Central antitussive activity of the tachykinin receptor
antagonists CP 99,994 and SR 48968 in the guinea pig and
cat. Br J Pharmacol 1997; 121: 165–70.
18
Plasticity of vagal afferent fibres
mediating cough
Marian Kollarik & Bradley J. Undem
Introduction
The coughing associated with acute respiratory tract
infections and chronic airway diseases including bronchitis, asthma and chronic obstructive pulmonary disease (COPD) likely arises as a result of production of
various tussigenic agonists in the airway wall. In addition, in these disorders as well as in cough related to
gastro-oesophageal reflux (GOR), angiotensinconverting enzyme inhibitor treatment and idiopathic
cough, the sensitivity of cough reflex pathways may be
increased (Fig. 18.1). That is to say, cough is evoked by
stimuli that are normally subthreshold for initiating the
cough reflex. The increase in cough reflex sensitivity
has been experimentally demonstrated in numerous
studies. However, the molecular mechanisms by which
this sensitization occurs and the structures involved
remain unknown. One likely structure affected by
processes resulting in increased sensitivity is the vagal
afferent nerve.
Afferent nerves are not static entities, but rather are
constantly changing in structure and activity. In general terms the change in structure and function of nerves
is referred to as neuroplasticity [1]. In this chapter we
use the term ‘plasticity’ rather liberally to denote
changes in neuronal excitability, receptor expression,
transmitter chemistry and the structure of the nerve.
Regrettably, little is known about vagal nerve plasticity
in human diseases associated with cough reflex hypersensitivity. Knowledge in this area has been obtained
only by inference from studies on the somatosensory
system, and from functional and electrophysiological
studies of vagal afferent nerves using various cellular,
tissue and animal models. With respect to the so-
matosensory system, the general concept of cough reflex hypersensitivity finds its analogy in the heightened
sensitivity of pain pathways, i.e. hyperalgesia and allodynia associated, for example, with inflammation. A
mechanistic understanding of the cough reflex plasticity may ultimately suggest novel therapeutic strategies
aimed at normalizing the heightened reflex associated
with chronic cough. In this chapter we focus on those
aspects of neuroplasticity that are likely to contribute
to the increases in cough sensitivity. Although not discussed in this chapter, it should be noted that increases
in cough sensitivity may also occur independently of
changes in nerve structure and function. This is exemplified by the convergent interactions among different
types of airway afferent nerves, and is discussed elsewhere in this volume (Chapter 16).
Clinical studies on cough
reflex sensitivity
Cough reflex sensitivity can be quantified by several
methods [2,3]. In general, these methods are based on
the determination of the amount of tussigenic agent
required to evoke a predetermined cough response.
The most common tussive agents used are capsaicin
and citric acid. The use of either of these agents has revealed that some diseases are associated with an appreciable increase in cough reflex sensitivity (i.e. a decrease
in the amount of tussigenic agent required to evoke
cough). Table 18.1 summarizes some studies on cough
sensitivity [4–11].
Cough sensitivity studies need to be cautiously interpreted, because cough reflex hypersensitivity may be
181
Log concentration (mmol/L) of inhaled
capsaicin causing 5 coughs
CHAPTER 18
2
*
*
*
1
0
Controls Idiopathic Asthma
Asthma GOR
cough without
with
persistent persistent
cough
cough
Fig. 18.1 Cough reflex sensitivity to inhaled capsaicin in normal subjects and in patients with diseases presenting with
cough. Cough threshold was determined as the concentration
of capsaicin causing at least 5 coughs (C5). Note that cough
threshold is decreased in the asthma associated with persistent cough but not in the asthma without persistent cough
(see also Table 18.1). *P < 0.05 compared with control. Data
from [2].
stimulus specific. It is possible that more than one subtype of vagal afferents, each with its own stimulus
specificity, are involved in the initiating of cough. Although capsaicin is a useful tool to evaluate an increase
in cough reflexes mediated by nociceptive-type nerves,
it is probably much less useful for the study of cough
reflexes initiated by mechanical stimulation of nerve
fibres with the rapidly adapting receptor (RAR)
phenotype. As discussed below, the mechanisms of afferent nerve plasticity depend on the nerve phenotype.
It would not be surprising, therefore, to find a clinical
setting in which the cough response to mechanical stimuli is altered whereas the capsaicin-induced cough is
unaltered (or vice versa). It will be important in the future to design protocols such that the sensitivity of
cough to disparate stimuli can be quantitatively evaluated. This will be necessary to address the hypothesis of
specificity in the changes of cough sensitivity associated
with various pathologies.
Afferent nerve fibres associated
with the cough reflex
Detailed information on the characteristics of the
subtypes of afferent nerve fibres involved in cough
can be found elsewhere in this volume (Chapter 16). In
Table 18.1 Studies showing increase in cough reflex sensitivity in the disorders
presenting with cough.
Disorder
Tussive agent
Cough reflex
sensitivity
Reference
Asthma with persistent cough
Capsaicin
Increased
Increased
[2]
[4]
Asthma without persistent cough
Capsaicin
Unaffected
[2]
Asthma (unselected populations)
Capsaicin
Unaffected
Increased
Unaffected
[5]
[6]
[7]
Tartaric acid
182
Gastro-oesophageal reflux
Capsaicin
Increased
Increased
[2]
[8]
Chronic obstructive pulmonary disease
Capsaicin
Citric acid
Increased
Increased
[6]
[9]
Acute respiratory infections
Capsaicin
Citric acid
Increased
Increased
[10]
[11]
PLASTICITY OF FIBRES MEDIATING COUGH
the context of the present chapter, however, we would
like to stress the idea that activation of at least two
fundamentally distinct types of afferent fibres can
lead to cough in animal models. The ‘cough fibre’ described by the classical studies of Widdicombe and colleagues is a myelinated fibre that conducts action
potentials in the Ad range [12]. These fibres are very
sensitive to mechanical perturbation. A defining characteristic of these fibres is the rapid adaptation
of their action potential discharge to a prolonged
suprathreshold mechanical stimulus. Accordingly,
these fibres are commonly referred to as rapidly adapting receptors or RARs. The other fibre type involved in
certain types of cough is the nociceptive fibre (nociceptor). These fibres are relatively insensitive to mechanical stimulation, but can be activated by inflammatory
mediators, acid, changes in osmolarity, and chemicals
such as capsaicin and bradykinin [13,14]. Nociceptors
are typically characterized by non-myelinated axons
(i.e. C-fibres); however, nociceptors also comprise a
large number of Ad-fibres [13]. It is worth emphasizing
that in guinea-pig airways, nociceptive Ad-fibres differ
from RAR Ad-fibres in that the latter are exquisitely
mechanically sensitive and do not respond directly to
capsaicin [13].
The RAR fibres and nociceptors are not only activated by different types of stimuli, but also appear
to be situated in different compartments within the
extrathoracic airway. In guinea-pig airways, circumstantial evidence supports the hypothesis that the
nociceptive population of nerves appears to be the primary nerve type that extends into the epithelium,
whereas the RAR type of fibres are situated in the submucosa just beneath the epithelium [15]. These two
types of afferent nerves may also have different embryological origins. This speculation is based on the observation that, in guinea-pig airways, the RAR-type fibres
arise from cell bodies situated in the nodose ganglia,
whereas the nociceptive C and Ad-fibres are derived
from cell bodies in the jugular (supranodose) ganglia
[13]. Embryologically, neurones within the nodose
ganglia are thought to be derived from the epibranchial
placodes, whereas the jugular ganglion neurones are
derived from the neural crest as are the dorsal root ganglia neurones [16]. Thus, based on the nature of the
activating stimuli, location within the airways and
perhaps embryological origin, the RAR fibres and nociceptive fibres represent quite distinct subpopulations of
airway afferent nerves in guinea-pig trachea/bronchus.
The characteristics and mechanisms of plasticity will
likely therefore differ between these two general types
of fibre.
Plasticity
We use the term plasticity here to denote change in the
neuronal excitability, receptor expression, neurotransmitter chemistry and nerve structure. As such, plasticity per se denotes change, and may lead to either
increases or decreases in overall responsiveness of the
afferent nerves. We have chosen to focus our discussion
on those aspects of plasticity that would most likely
lead to an increase in afferent nerve activity and the sensitivity of cough reflex.
Excitability
General principles of excitability
Activators of afferent nerves (mechanical displacement, certain chemicals, changes in osmolarity, etc.) interact with the nerve terminals in a manner that leads to
a membrane depolarization. This initial terminal membrane depolarization is referred to as the generator
potential. The generator potential is electrotonically
conducted along the axon until it reaches the so-called
active zone characterized by a high concentration of
voltage-gated sodium channels. If in the active zone the
magnitude of membrane depolarization is sufficient
(i.e. the threshold for action potential formation is
reached), action potential discharge is evoked. The
greater the amplitude of generator potential, the higher
is the frequency of action potential discharge. These
are theoretical considerations inasmuch as neither the
structure nor location of the generator region and
active zones has been described in vagal afferent nerve
terminals. However, these mechanisms have been
worked out in considerable detail in somatosensory
systems and are likely to be shared with vagal afferent
nerves [17].
Many chemical mediators affect the electrophysiological properties of the afferent nerve membrane without causing a generator potential and activating the
nerve. One might say that these are not activators of the
nerve, but rather are better characterized as modulators of nerve excitability. It is possible that a given stimulus may act both as an activator (causing a generator
183
CHAPTER 18
potential) and as a modulator of neuronal excitability.
As discussed below, this is exemplified by some G-protein-coupled receptor agonists such as bradykinin. An
obvious case of nerve modulation by prostaglandin E2
(PGE2) is illustrated in Fig. 18.2. In this nociceptive Adfibre, bradykinin causes only modest discharge of ac-
Vagal afferent fibre in guinea pig trachea
(conduction velocity = 3.8 m/s)
10 s
bradykinin
1 min
PGE2
10 s
PGE2
bradykinin
Fig. 18.2 Examples of the action of activator and modulator
of nerve excitability. Activation of airway nociceptive afferent nerve fibre by bradykinin (activator) and the sensitizing
effect of prostaglandin E2 (PGE2) (modulator). Extracellular
recording was made from the nociceptive Ad-fibre projecting
to the trachea in guinea-pig isolated perfused airway/nerve
preparation. The tissue was pretreated with indomethacin
(3 μmol/L) to suppress endogenous PGE2 production. Upper
trace: Transient (~3 s) administration of bradykinin
(0.3 μmol/L, 500 μL) directly over the receptive field evoked a
short delayed burst of action potential discharge. The delay in
the onset of bradykinin-induced response is a consistent phenomenon. Middle trace: The tissue was incubated with PGE2
(10 μmol/L, 10 min) that caused by itself no activation. Note
the change in time scale. Lower trace: PGE2-enhanced response to subsequent challenge with bradykinin.
184
tion potentials. Upon application of PGE2, the nerve is
not activated, but the activation by bradykinin is dramatically enhanced.
Mechanisms potentially leading to increased excitablity of afferent nerves are schematically illustrated
in Fig. 18.3. The excitability of a cough fibre may be increased by processes that lead to an increase in the amplitude of the generator potential, an increase in the
efficiency of electronic conduction, and/or a decrease in
the membrane potential change required for action potential formation. The amplitude of the generator potential can be increased by increasing the probability of
a stimulus opening the ion channels responsible for the
generator potential and/or by increasing the average
time the channel stays open. Both of these characteristics can be affected by a modulator acting through various intracellular signalling pathways. The amplitude
of generator potential can also be increased by an increase in the membrane resistance, as the voltage
change is a product of the current and membrane resistance (Ohm’s law).
Decremental electrotonic conduction of generator
potential to the active zone is governed by the time constant and the space constant. The time constant is a
product of membrane resistance and capacitance, and
characterizes the rate of membrane potential decay
with time. The space constant depends on membrane
resistance and resistance of the axoplasm, and characterizes the rate of membrane potential decay with distance. A modulator can affect these properties by, for
example, increasing the membrane resistance. Such an
increase in membrane resistance increases the excitability by the increased efficacy of generator potential conduction to the active zone. The extent to which these
mechanisms participate in excitability changes will depend on the distance between the generator and active
zones in the afferent nerve.
The membrane potential change required for action
potential formation could be decreased by an increase
in resting membrane potential and/or a decrease of the
threshold for action potential discharge. Resting membrane potential largely depends on the potassium channels. The threshold for action potential formation is
regulated by the number and activity of voltage-gated
sodium channels in the active zone. In addition, neuronal excitability can be modulated by processes that
affect the active (action potential) properties of the
nerve. For example, a modulator may affect membrane
repolarization in such a fashion that the refractory
PLASTICITY OF FIBRES MEDIATING COUGH
Stimulus
intensity
Mechanisms of normal
and enhanced neuronal
excitability
Normal excitability
(subthreshold stimulus)
Generator
potential
Active zone
depolarization
Action potential
discharge
Terminal
membrane
'Active
zone'
membrane
Axonal
membrane
threshold
Increased amplitude of generator
potential in response to given
stimulus
Increased passive electrotonic
conduction of generator potential
to the active zone
Decreased threshold for action
potential formation
Alteration in repolarization —
increased frequency of action
potential discharge
(suprathreshold stimulus)
Fig. 18.3 Theoretical mechanisms of normal and enhanced
neuronal excitability. Stimulus interaction with the receptive
field membrane results in membrane depolarization (generator potential). This depolarization propagates passively to
the active zone which is responsible for initiation of action
potentials. If the membrane depolarization at the active zone
is of sufficient magnitude action potential discharge follows.
Excitability of the nerve terminal could be enhanced by several mechanisms: (i) increase in the amplitude of the generator
potential in response to the stimulus of given intensity by
modification of transducer channels (for example by protein
kinase A-mediated phosphorylation of the capsaicin receptor
TRPV1); (ii) enhancement of passive propagation of the gen-
erator potential (for example by increasing membrane resistance through the inhibition of certain potassium channels);
(iii) reduction of threshold for action potential formation (for
example by modification of voltage-gated sodium channels);
or (iv) increase in the frequency of action potential discharge
due to change in repolarization (for example by modification
of voltage-gated potassium channels involved in the membrane repolarization or hyperpolarization). The bars in ‘generator potential’ and ‘active zone depolarization’ columns
denote the amplitude of membrane depolarization. The horizontal dashed lines in the ‘active zone depolarization’ column
denote the threshold for action potential formation.
period is decreased and consequently the frequency of
action potential discharge is increased.
It is important to realize that a single inflammatory
mediator may affect multiple factors regulating neuronal excitability by signalling through divergent intra-
cellular pathways. Moreover, inflammatory disorders
lead to accumulation of numerous mediators at the site
of nerve terminal. Therefore, within the complexity of
airway disease, rather than an isolated change in a particular mechanism, multiple effects on excitability
185
CHAPTER 18
could summate and result in greatly increased responsiveness of airway afferent nerves.
from those involved in excitability changes in airway
nociceptors.
Molecular mechanisms of increased excitability
At a phenomenological level, allergic inflammation or
various inflammatory mediators have been shown to
increase cough reflex sensitivity as well as excitability
of airway afferent nerves. Inhalation of PGE2, for example, enhances capsaicin-induced cough in humans
[18]. In addition to these types of studies, as discussed
above, a large number of clinical studies have demonstrated that certain pathological conditions are accompanied by a substantial increase in cough reflex
sensitivity in humans (Table 18.1). This can also be observed in animal models. For example, in guinea-pigs
allergic inflammation or inhalation of bradykinin
potentiated cough evoked by capsaicin and citric acid,
respectively [19,20]. An increase in the excitability of
the afferent nerve endings in the airways is likely to
contribute to this phenomenon.
Inhalation of inflammatory mediators including
PGE2 and eosinophil major basic protein results in potentiation of capsaicin-induced action potential discharge in pulmonary nociceptive fibres in rats [21,22].
Some of these mediators also decrease the amount of
mechanical force required to activate nociceptive C-fibres in the lungs [21]. Excitability of RAR fibres is also
enhanced by inflammatory conditions. For example,
exposing the trachea isolated from sensitized guineapigs to the antigen causes a substantial increase in the
mechanosensitivity of RAR fibres [23]. Beyond these
types of descriptive studies, there has been relatively little published relating to the mechanisms underlying increases in airway afferent excitability.
The vast majority of studies on the mechanistic basis
of afferent nerve excitability and plasticity have been
carried out on nociceptive-type somatosensory neurones isolated from the dorsal root ganglia [1]. Somatosensory nociceptors share many properties with
airway nociceptive fibres, and thus may provide important clues to the mechanism of airway nociceptor excitability. On the other hand, the RAR phenotype fibre
is not readily paralleled by any type of somatosensory
afferent. Consequently relatively little has been published on the mechanisms by which airway RAR excitability is modulated. It nevertheless should be kept in
mind that, given the phenotypic differences between
RAR and nociceptive fibres, the mechanisms resulting
in changes in RAR excitability will likely be different
Vanilloid receptor (TRPV1) mechanisms. Vagal afferent nociceptors (C-fibres and Ad-fibres) innervating
the airways express the capsaicin receptor, a member of
the transient receptor potential family, currently referred to as TRPV1 [13,14]. This receptor was previously termed vanilloid receptor 1 (VR1). TRPV1 is not
expressed by RAR-type fibres in guinea-pig airways
[24], and therefore the extent to which capsaicin can
lead to RAR activation in vivo is likely through indirect
means.
TRPV1 is an ionotropic receptor that upon activation serves as a non-selective cation channel resulting
in membrane depolarization [25]. In addition to vanilloid compounds, TRPV1 is activated by endogenous
lipid mediators including anandamide and arachidonic
acid metabolites of various lipoxygenase enzymes
[25,26]. Certain metabotrophic receptors may also
activate TRPV1 through intracellular signal transduction mechanisms. For example, evidence from both
somatosensory neurones and airway afferent C-fibres
supports the hypothesis that bradykinin activates
sensory nerves, at least in part, through production of
lipoxygenase products of arachidonic acid and the
subsequent activation of TRPV1 (see below) [26].
TRPV1 can be stimulated by heat, but the temperature
required (> 40°C) is unlikely to be relevant to cough
physiology. More relevant to airways physiology is the
fact that hydrogen ions can activate TRPV1 (pH ~ 6 at
37°C) [25].
A unique feature of TRPV1 is its ability to integrate
disparate stimuli — i.e. action of one TRPV1 agonist
potentiates the action of the other [25]. For example,
hydrogen ions were found to potentiate TRPV1-mediated responses to vanilloids and heat. On the other
hand, increases in temperature increase the TRPV1mediated responses to vanilloids and lipid mediators.
Integration is likely to be an important mechanism of
increased sensitivity of nociceptive airway afferents involved in cough. Under various pathological conditions one or more TRPV1 agonists may accumulate in
the airway wall. For example, airway inflammation in
asthma could lead to TRPV1-mediated responses by increased concentration of hydrogen ions (i.e. decreasing
the pH in the airway wall), bradykinin and certain lipid
mediators.
Biophysical studies on sensory cell bodies show
186
PLASTICITY OF FIBRES MEDIATING COUGH
that inflammatory mediators that stimulate classical Gprotein-coupled receptors can increase conductance
through TRPV1. Agonists of Gq-coupled receptors
have been shown to increase TRPV1 conductance secondary to phospholipase C (PLC) activation and subsequent phosphorylation of TRPV1 by protein kinase
C (PKC) [27]. In addition, activation of PLC has been
shown to release TRPV1 from phosphatidylinositol
[12,13] phosphate inhibition [28]. This mechanism appears to contribute to increases in TRPV1 activity secondary to nerve growth factor (NGF) stimulation of
trk-A receptors and also bradykinin activation of B2
receptors. One might speculate that bradykinin B2receptor activation (a classical Gq-coupled receptor)
may both activate the nerve via lipoxygenasedependent gating of TRPV1, and increase the excitability of the nociceptor via induction of prostaglandin
production and PKC-dependent phosphorylation of
TRPV1.
The amplitude of the TRPV1-mediated generator
potential may also be increased by Gs-coupled receptors. Elevation in cAMP increases capsaicin-induced
conductance in rat nociceptive neurones by a mechanism that can be inhibited by inhibitors of protein kinase A (PKA) [29]. This mechanism likely contributes
to the observation that PGE2 increases the capsaicininduced action potential discharge in rat pulmonary
nociceptors [21]. The generator potential evoked
by TRPV1 agonists could in theory also be increased by
changes in the number of TRPV1 receptors. Neurotrophins such as NGF have been found to increase
the expression of TRPV1 in rat sensory neurones [30].
Although the relative expression of TRPV1 in nociceptors found in normal and diseased airways has not been
studied, it is known that NGF can be elevated at sites of
airway inflammation [31].
Inflammatory mediators may affect nociceptor excitability by mechanisms that do not involve TRPV1.
Non-TRPV1 mechanisms likely contribute to excitability changes in RAR fibres as well as nociceptors.
Various inflammatory mediators have been shown to
decrease the threshold for mechanical stimulation of
airway afferent nerves [21,23]. The mechanisms underlying this response are unknown but likely involve
modulation of various ion channels.
Potassium channels. There are a large number of
different types of potassium channels in sensory nerve
fibres [32]. In general, inhibition of potassium channels
leads to an increase in excitability. Antigen challenge
and mediators such as histamine have been found to inhibit resting potassium current in vagal sensory neurones [33]. Inhibiting potassium channels that are open
under resting condition leads to an increase in membrane resistance and this could lead to an increase in the
amplitude of the generator potential. Increased membrane resistance can also increase the efficacy of electrotonic conduction of the terminal membrane.
Other potassium channels play a key role in determining the refractory period of the nerve. One such
channel is found in vagal sensory neurones and causes a
slow hyperpolarization following the action potential,
referred to as the ‘slow afterspike hyperpolarization’
(AHPslow) [34]. This channel is opened by calcium
that enters the cell during the action potential through
voltage-gated N-type calcium channels. Inhibiting
these channels increases the peak frequency at which
the sensory nerve can fire action potentials. In nodose
ganglion neurones, antigen challenge, bradykinin,
PGD2 and PGI2 effectively inhibit the AHPslow
[34,35]. In addition, any process that leads to elevations in cAMP or inhibition of N-type calcium channels
will inhibit the AHPslow current.
Potassium channels underlying the so-called maxiK current may also affect the excitability of afferent
nerves in the airways. Pharmacological opening of
these channels with drugs such as NS1619 inhibits afferent nerve activity [36]. Similarly, there are various
voltage-gated potassium channels in the airway afferent endings. Drugs that block some of these channels,
such as 4-aminopyridine and certain dendrotoxins, can
lead to increases in excitability of the nerve endings, or
even to overt activation [37]. However, there is little information on how the process of airway inflammation
affects these channels.
Sodium channels. The number and activity of voltagegated sodium channels can affect the threshold for action potential generation, as well as peak frequency of
action potential discharge. Indeed, long before veratrum alkaloids were known to act by increasing sodium
channel activity (by inhibiting their inactivation), they
were used to stimulate airway afferent nerves. There
are a large number of different voltage-gated sodium
channels expressed in mammalian nerves. Based on
the sensitivity to tetrodotoxin (TTX), these channels
have been pharmacologically divided into two families,
the TTX-sensitive (potently blocked by TTX) and
187
CHAPTER 18
TTX-resistant sodium channels. Sodium channels of
each category are present in airway afferent nerves
[32]. However, TTX-resistant channels may be particularly relevant to regulation of excitability because of
their modulation by inflammatory mediators [38]. In
addition, certain TTX-resistant sodium channels are
preferentially localized to afferent nerves. These ‘sensory nerve specific’ (SNS) channels are found mainly
in small-diameter (nociceptor-like) neurones. The
nomenclature of SNS sodium channels is confusing,
with SNS1 also referred to as PN3, while SNS2 is sometimes referred to as the NaN channel. Christian and
Togo noted that the vast majority of neurones in
guinea-pig jugular ganglia (source of nociceptive fibres
innervating the airways), have sufficient TTX-resistant
sodium channels to support action potential generation
[39]. The sodium channels in airway afferent nerves
have not been characterized in detail; however, preliminary data from our laboratory have shown that airway-specific jugular neurone cell bodies have sufficient
TTX-resistant current to support action potential formation [32]. Current through the SNS TTX-resistant
channels can be amplified by inflammatory mediators.
For example, PGE2, adenosine and 5-hydroxytryptamine (5-HT) are effective in enhancing TTX-resistant
sodium current in somatosensory neurones [38]. The
extent to which inflammatory mediators found in
the airways modulate this current remains to be
determined.
Neurotransmitter plasticity
Sensory C-fibres innervating airways characteristically
contain neuropeptides in their peripheral and central
terminals. The most often studied sensory neuropeptides are substance P and related tachykinins, but other
peptides are likely to be found in C-fibres including calcitonin gene-related peptide (CGRP), secretoneurin
and various opioid peptides.
A hallmark of inflammatory disease is the upregulation in production of various sensory neuropeptides. This has been seen both in animal models of
inflammation and in numerous inflammatory diseases,
including COPD [40]. This is often found to be secondary to increases in the expression of the preprotachykinin gene in the sensory neurones [41,42]. It
remains unknown as to how inflammation within the
airway wall sends signals to the distant cell body in the
relevant sensory ganglia to induce the transcription of
188
neuropeptide synthesizing enzymes. A likely mechanism, however, involves the action of various neurotrophins. Neurotrophins are known to interact with
specific tyrosine kinase-linked receptors (trk receptors)
to evoke signals in the cell body. The neurotrophin–trk
receptor complex is thought to be transported from the
nerve terminals to the cell body via axonal transport
mechanisms, and therein to affect transcriptions of
various genes including those involved in the synthesis
of neuropeptides [43]. Adding to the evidence that
neurotrophins may be involved in the up-regulation of
neuropeptide synthesis in airway diseases are the
observations that neurotrophins such as nerve growth
factor (NGF) and brain-derived neurotrophin factor
(BDNF) are found in the airways, and their production
may be increased at sites of allergic inflammation [31].
Sensory neuropeptides are synthesized in the cell
body and transported to both the peripheral and central terminals [1]. Neuropeptides can be released from
the peripheral terminals of afferent nerves by a process
referred to as the axon reflex. In addition, chemical mediators such as TRPV1 agonists and trypsin can cause
neuropeptide release independent of action potential
discharge and reflex activity. Neurokinins released in
the airways can participate in the inflammatory reaction by causing vasodilatation, plasma extravasation
and in some species bronchial smooth muscle contraction [44]. In the guinea-pig these processes may indirectly activate RAR nerves and thereby contribute to
the tussigenic activity of these agents [44,45].
Neuropeptides are released from the central terminal
in the brainstem as a result of action potential invasion
of the central release sites [1]. It is the release of
neurokinins from the central terminals that likely plays
an important role in regulating cough reflex sensitivity.
Neurokinins released in the synapse between primary
and secondary vagal afferent neurones in the nucleus
of the solitary tract can cause an increase in synaptic
transmission. Typically neurokinins cause slow excitatory postsynaptic potentials and/or increases in input
impedance [1]. These events can lead to changes
in synaptic efficacy and neurotransmission in the
NTS. There is evidence that, at least in some instances,
central terminals of RAR fibres converge on the same
secondary neurones as nociceptive C-fibres [46]. This
fact, considered with the electrophysiological effects
of neurokinins on postsynaptic membranes, provides
the conceptual framework for the process referred to
as ‘central sensitization’ [1]. This term is used to
PLASTICITY OF FIBRES MEDIATING COUGH
denote the process by which one type of nerve input
(e.g. nociceptive C-fibre) enhances the synaptic transmission of another type of input (e.g. RAR fibres). This
could lead to a substantive decrease in the amount of
RAR input to the central nervous system (CNS) required to trigger cough. Moreover, such synergy provided by disparate converging inputs in the brainstem
might explain, for example, how activation of nociceptive-type nerves in the oesophagus could affect the
threshold for cough evoked by activation of airwayspecific afferent nerves.
The increase in sensory neuropeptides associated
with inflammation is thought to be secondary to induction of preprotachykinin genes in nociceptive
neurones. However, recent studies in both the
somatosensory and vagal sensory systems support the
hypothesis that inflammation may also lead to phenotypic changes in the neuropeptidergic innervation
[24,47,48]. Accordingly, exposure to respiratory allergen or virus infection increased the amount of sensory
neurokinins in the airway afferent neurones in guineapigs [24,42,48]. Interestingly, however, the preprotachykinin gene expression and neurokinin production
were found to be increased in neurones that project
non-nociceptive fibres into the airway. The neurones
induced by inflammation to produce neuropeptides
were large-diameter neurones located in the nodose
ganglia and had physiological characteristics consistent with the RAR phenotype. At sites of inflammation,
therefore, neuropeptidergic innervation may consist of
not only nociceptive C-fibres but also RAR fibres. In
addition, histological evidence supports the hypothesis
that the neuropeptides produced in response to airway
inflammation are also transported to central terminals
of the RAR neurones [24]. This raises the possibility
that in allergic inflammation or respiratory virus infection, mechanical activation of the RAR fibres would
lead to neurokinin release in the brainstem. Unlike nociceptors, many RAR fibres are activated during the
breathing cycle. This could lead to central sensitization
during breathing independently of nociceptive stimulation. In the somatosensory system an analogous phenotypic switch in neuropeptide innervation has been
reported to play a role in painful sensation to nonpainful stimuli termed allodynia [47]. It is tempting to
speculate that this process in the airways could contribute to inappropriate or ‘allotussive’ cough sensations, i.e. the urge to cough in the absence of anything in
the airway to productively cough up. The mechanism
underlying this inflammation-induced phenotypic
switch in the neurochemistry of RAR has not been
worked out; however, this effect of allergen challenge
or virus exposure can be mimicked by local injection of
NGF into the airway wall [49].
Changes in the neurotransmitter content in central
terminals of primary afferents, combined with increases in afferent nerve excitability and activity, may lead to
substantive changes in the synaptic input to secondary
neurones (neurones receiving input from sensory afferents) in the central nervous system. This, in turn, can
cause changes in the excitability of the secondary neurones. This is referred to as ‘use-dependent’ plasticity
and has been extensively studied in the somatosensory
system where activation of nociceptive afferent fibres
results in increases in excitability of secondary neurones in the spinal cord, sensitizing them to noxious as
well as innocuous stimuli [50]. The mechanisms of usedependent excitability changes in secondary neurones
are not clear, but several receptors and second messenger cascades may be involved [50]. With respect to
cough-mediating pathways it is interesting to note that
exposing the lungs of non-human primates repeatedly
to allergen resulted in increases in excitability of secondary sensory neurones in the nucleus of the solitary
tract [51]. These observations are consistent with the
hypothesis that allergen inhalation-induced activation
of primary airway afferent nerves can result in usedependent changes in excitability of secondary neurones in the brainstem.
Changes in nerve fibre density
The density of sensory innervation can change in response to its environment [52]. Tissue damage or release of various growth factors can lead to increased
nerve fibre growth and fibre sprouting. The question as
to whether increases in afferent nerve density may participate in increased cough sensitivity has not been extensively studied. To our knowledge only one study has
addressed this issue as it relates to cough [53]. This elegant study was designed such that the nerve density was
determined in biopsies taken from the carina of the
right upper lobe and a subsegmental carina of the right
lower lobe. The tissue was obtained from patients with
persistent idiopathic cough who had increased cough
sensitivity to capsaicin and from controls. There was no
difference in the density of epithelial nerve fibres as
quantified using the non-specific nerve marker PGP
189
CHAPTER 18
9.5, but patients with chronic cough had a higher density of CGRP-positive nerves compared with the control
subjects. This supports the hypothesis of neurotransmitter plasticity contributing to cough sensitivity but
does not favour a role for an increased nerve sprouting
and density. Whether there is a higher nerve density in
the submucosa plexus or near cough regions such as in
the trachea or larynx was not investigated.
Extraneuronal effects
Most afferent nerves in the airways are mechanically
sensitive, and the lungs are exposed to extensive mechanical forces during breathing [13,14]. Each breath
causes discharge in various populations of afferent
mechanosensors. As discussed above, the action potential discharge depends on the amplitude and duration
of the generator potential. It is likely that the amplitude
of the generator potential evoked by mechanical forces
in the lungs will depend not only on the terminal membrane, but also on the viscoelastic properties of the
lung tissue. In airway diseases such as COPD and
asthma, airway tissue destruction and remodelling
will likely affect the extent to which distension of
the tissue in the microenvironment of the mechanosensors is transduced to a generator potential. Cough
reflexes could be increased if changes in airway structure lead to increases in mechanotransduction of
cough-inducing fibres (e.g. RAR-type fibres), or if they
lead to decreases in activity in mechanosensors that are
normally inhibitory to the cough reflex. The hypothesis
that changes in airway structure that accompanies
airway diseases alters the properties of airway
mechanosensors has been studied as it pertains to
COPD, but little information is available as regards
cough [54].
Conclusions
Excessive coughing accompanies many diseases including asthma, respiratory infections, lung cancer, bronchitis, COPD and gastro-oesophageal reflux disease.
The increase in coughing in many cases is likely due to
the production of tussigenic stimuli in the large airways. In addition, however, it is recognized that patients with chronic cough often present with an increase
in the cough reflex sensitivity to tussigenic stimuli. Rational strategies for the treatment of chronic cough may
190
consider therefore both a reduction in the amount of
tussigenic stimuli and a reduction in the heightened sensitivity of the cough reflex. Regrettably, short of nonspecific centrally acting drugs, there are no drugs that
are aimed at decreasing the increased sensitivity of
cough. This is likely because relatively little is known
about the mechanisms underlying this process. The
available data gathered from research on vagal sensory
and somatosensory systems indicate that multiple
mechanisms may lead to hypersensitivity of reflexes
such as cough. These include increases in the excitability of the afferent terminals, changes in the neurotransmitter content and consequent changes in synaptic
transmission in the brainstem, and extraneuronal
changes that may lead to changes in the efficiency of
mechanotransduction in afferent nerves. Adding to the
complexity of this issue is the notion that at least two
disparate types of afferent nerves may participate in
cough reflexes (RARs and nociceptors). Inasmuch as
these nerve subtypes are phenotypically distinct, it is
likely that mechanisms resulting in increases in their activity will also be distinct. Finally, adding height to the
hurdle in front of our understanding of this issue, is the
difficulty in quantifying cough sensitivity in humans.
At present most studies in this area have used classical
nociceptive stimuli to study changes in cough sensitivity. This leaves open the question of the extent to which
the sensitivity of RAR-driven cough is affected in various disease states. A combined effort from studies at
the research bench and bedside will be required before
some semblance of understanding of this complex
area emerges.
References
1 Woolf CJ, Salter MW. Neuronal plasticity: increasing the
gain in pain. Science 2000; 288: 1765–9.
2 Choudry NB, Fuller RW. Sensitivity of the cough reflex in
patients with chronic cough. Eur Respir J 1992; 5 (3):
296–300.
3 Pounsford JC, Birch MJ, Saunders KB. Effect of bronchodilators on the cough response to inhaled citric acid in
normal and asthmatic subjects. Thorax 1985; 40 (9):
662–7.
4 Chang AB, Phelan PD, Robertson CF. Cough receptor
sensitivity in children with acute and non-acute asthma.
Thorax 1997; 52 (9): 770–4.
5 Chang AB, Phelan PD, Sawyer SM, Del Brocco S,
Robertson CF. Cough sensitivity in children with asthma,
PLASTICITY OF FIBRES MEDIATING COUGH
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
recurrent cough, and cystic fibrosis. Arch Dis Child 1997;
77 (4): 331–4.
Doherty MJ, Mister R, Pearson MG, Calverley PM.
Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease. Thorax 2000; 55 (8):
643–9.
Fujimura M, Sakamoto S, Kamio Y, Matsuda T. Cough
receptor sensitivity and bronchial responsiveness in normal and asthmatic subjects. Eur Respir J 1992; 5 (3):
291–5.
Ferrari M, Olivieri M, Sembenini C, Benini L, Zuccali V,
Bardelli E et al. Tussive effect of capsaicin in patients with
gastroesophageal reflux without cough. Am J Respir Crit
Care Med 1995; 151: 557–61.
Wong CH, Morice AH. Cough threshold in patients with
chronic obstructive pulmonary disease. Thorax 1999; 54
(1): 62–4.
O’Connell F, Thomas VE, Studham JM, Pride NB,
Fuller RW. Capsaicin cough sensitivity increases during
upper respiratory infection. Respir Med 1996; 90 (5):
279–86.
Empey DW, Laitinen LA, Jacobs L, Gold WM, Nadel JA.
Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev
Respir Dis 1976; 113 (2): 131–9.
Widdicombe JG. Receptors in the trachea and bronchi of
the cat. J Physiol Lond 1954; 123: 71–104.
Riccio MM, Kummer W, Biglari B, Myers AC, Undem BJ.
Interganglionic segregation of distinct vagal afferent fibre
phenotypes in guinea-pig airways. J Physiol 1996; 496 (2):
521–30.
Fox A. Airway nerves: in vitro electrophysiology. Curr
Opin Pharmacol 2002; 2 (3): 278–9.
Hunter DD, Undem BJ. Identification and substance
P content of vagal afferent neurons innervating the epithelium of the guinea pig trachea. Am J Respir Crit Care
Med 1999; 159 (6): 1943–8.
Fontaine-Perus J, Chanconie M, Le Douarin NM.
Embryonic origin of substance P containing neurons in
cranial and spinal sensory ganglia of the avian embryo.
Dev Biol 1985; 107 (1): 227–38.
Fain GL. Molecular and Cellular Physiology of the
Neurons. Cambridge: Harvard University Press, 1999.
Choudry NB, Fuller RW, Pride NB. Sensitivity of the
human cough reflex: effect of inflammatory mediators
prostaglandin E2, bradykinin, and histamine. Am Rev
Respir Dis 1989; 140 (1): 137–41.
Fox AJ, Lalloo UG, Belvisi MG, Bernareggi M, Chung KF,
Barnes PJ. Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough. Nat
Med 1996; 2 (7): 814–7.
Liu Q, Fujimura M, Tachibana H, Myou S, Kasahara K,
Yasui M. Characterization of increased cough sensitivity
21
22
23
24
25
26
27
28
29
30
31
32
33
34
after antigen challenge in guinea pigs. Clin Exp Allergy
2001; 31 (3): 474–84.
Ho CY, Gu Q, Hong JL, Lee LY. Prostaglandin E(2)
enhances chemical and mechanical sensitivities of pulmonary C fibers in the rat. Am J Respir Crit Care Med
2000; 162: 528–33.
Lee LY, Gu Q, Gleich GJ. Effects of human eosinophil
granule-derived cationic proteins on C-fiber afferents in
the rat lung. J Appl Physiol 2001; 91 (3): 1318–26.
Riccio MM, Myers AC, Undem BJ. Immunomodulation
of afferent neurons in guinea-pig isolated airway. J Physiol
1996; 491 (2): 499–509.
Myers AC, Kajekar R, Undem BJ. Allergic inflammationinduced neuropeptide production in rapidly adapting afferent nerves in guinea pig airways. Am J Physiol Lung
Cell Mol Physiol 2002; 282 (4): L775–81.
Caterina MJ, Julius D. The vanilloid receptor: a molecular
gateway to the pain pathway. Annu Rev Neurosci 2001;
24: 487–517.
Shin J, Cho H, Hwang SW, Jung J, Shin CY, Lee SY et al.
Bradykinin-12-lipoxygenase-VR1 signaling pathway for
inflammatory hyperalgesia. Proc Natl Acad Sci USA
2002; 99 (15): 10150–5.
Premkumar LS, Ahern GP. Induction of vanilloid receptor
channel activity by protein kinase C. Nature 2000; 408:
985–90.
Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE,
Basbaum AI et al. Bradykinin and nerve growth factor
release the capsaicin receptor from PtdIns(4,5)P2mediated inhibition. Nature 2001; 411: 957–62.
Lopshire JC, Nicol GD. The cAMP transduction cascade
mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: whole-cell
and single-channel studies. J Neurosci 1998; 18 (16):
6081–92.
Michael GJ, Priestley JV. Differential expression of the
mRNA for the vanilloid receptor subtype 1 in cells of
the adult rat dorsal root and nodose ganglia and its
downregulation by axotomy. J Neurosci 1999; 19 (5):
1844–54.
Virchow JC, Julius P, Lommatzsch M, Luttmann W, Renz
H, Braun A. Neurotrophins are increased in bronchoalveolar lavage fluid after segmental allergen provocation. Am
J Respir Crit Care Med 1998; 158 (6): 2002–5.
Carr MJ, Undem BJ. Ion channels in airway afferent neurons. Respir Physiol 2001; 125 (1–2): 83–97.
Undem BJ, Hubbard W, Weinreich D. Immunologically induced neuromodulation of guinea pig nodose ganglion
neurons. J Auton Nerv Syst 1993; 44 (1): 35–44.
Cordoba-Rodriguez R, Moore KA, Kao JP, Weinreich D.
Calcium regulation of a slow post-spike hyperpolarization in vagal afferent neurons. Proc Natl Acad Sci USA
1999; 96 (14): 7650–7.
191
CHAPTER 18
35 Undem BJ, Weinreich D. Electrophysiological properties
and chemosensitivity of guinea pig nodose ganglion neurons in vitro. J Auton Nerv Syst 1993; 44 (1): 17–33.
36 Fox AJ, Barnes PJ, Venkatesan P, Belvisi MG. Activation
of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves in the
guinea pig. J Clin Invest 1997; 99 (3): 513–9.
37 McAlexander MA, Undem BJ. Potassium channel blockade induces action potential generation in guinea-pig airway vagal afferent neurones. J Auton Nerv Syst 2000; 78
(2–3): 158–64.
38 Gold MS, Reichling DB, Shuster MJ, Levine JD. Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current
in nociceptors. Proc Natl Acad Sci USA 1996; 93 (3):
1108–12.
39 Christian EP, Togo JA. Excitable properties and underlying Na+ and K+ currents in neurons from the guinea-pig
jugular ganglion. J Auton Nerv Syst 1995; 56 (1–2):
75–86.
40 Tomaki M, Ichinose M, Miura M, Hirayama Y, Yamauchi
H, Nakajima N et al. Elevated substance P content in
induced sputum from patients with asthma and patients
with chronic bronchitis. Am J Respir Crit Care Med 1995;
151: 613–7.
41 Hunter DD, Castranova V, Stanley C, Dey RD. Effects of
silica exposure on substance P immunoreactivity and preprotachykinin mRNA expression in trigeminal sensory
neurons in Fischer 344 rats. J Toxicol Environ Health A
1998; 53 (8): 593–605.
42 Fischer A, McGregor GP, Saria A, Philippin B, Kummer W.
Induction of tachykinin gene and peptide expression in
guinea pig nodose primary afferent neurons by allergic
airway inflammation. J Clin Invest 1996; 98 (10):
2284–91.
43 Klesse LJ, Parada LF. Trks: signal transduction and intracellular pathways. Microsc Res Tech 1999; 45 (4–5):
210–6 [p. ii].
192
44 Advenier C, Emonds-Alt X. Tachykinin receptor antagonists and cough. Pulm Pharmacol 1996; 9 (5–6): 329–33.
45 Joad JP, Kott KS, Bonham AC. Nitric oxide contributes
to substance P-induced increases in lung rapidly adapting
receptor activity in guinea-pigs. J Physiol 1997; 503 (3):
635–43.
46 Mazzone SB, Canning BJ. Synergistic interactions between airway afferent nerve subtypes mediating reflex
bronchospasm in guinea pigs. Am J Physiol Regul Integr
Comp Physiol 2002; 283 (1): R86–R98.
47 Neumann S, Doubell TP, Leslie T, Woolf CJ. Inflammatory
pain hypersensitivity mediated by phenotypic switch in
myelinated primary sensory neurons. Nature 1996; 384:
360–4.
48 Carr MJ, Hunter DD, Jacoby DB, Undem BJ. Expression
of tachykinins in non-nociceptive vagal afferent neurons
during respiratory tract viral infection in guinea pigs. Am J
Respir Crit Care Med 2002; 165: 1071–5.
49 Hunter DD, Myers AC, Undem BJ. Nerve growth factorinduced phenotypic switch in guinea pig airway sensory
neurons. Am J Respir Crit Care Med 2000; 161 (6):
1985–90.
50 Willis WD. Role of neurotransmitters in sensitization of
pain responses. Ann N Y Acad Sci 2001; 933: 142–56.
51 Chen CY, Bonham AC, Schelegle ES, Gershwin LJ,
Plopper CG, Joad JP. Extended allergen exposure in asthmatic monkeys induces neuroplasticity in nucleus tractus
solitarius. J Allergy Clin Immunol 2001; 108 (4): 557–62.
52 Stead RH. Nerve remodelling during intestinal inflammation. Ann N Y Acad Sci 1992; 664: 443–55.
53 O’Connell F, Springall DR, Moradoghli-Haftvani A,
Krausz T, Price D, Fuller RW et al. Abnormal intraepithelial airway nerves in persistent unexplained cough? Am J
Respir Crit Care Med 1995; 152: 2068–75.
54 Mansoor JK, Hyde DM, Schelegle ES. Contribution
of vagal afferents to breathing pattern in rats with lung
fibrosis. Respir Physiol 1997; 108 (1): 45–61.
19
Motor mechanisms and the
mechanics of cough
Giovanni A. Fontana
‘Tussis est offendiculum spiritus in trachea arteria’
(Matteo Plateario, Scuola Medica Salernitana, 12th
century)
pal aspects of respiratory mechanics that are relevant to
the genesis of the high flow rates and gas velocities of
cough. Some related topics will be mentioned, while
others, which are presented elsewhere in this book, will
be omitted.
Introduction
Cough is a modified respiratory act that can be produced voluntarily but, in most instances, it represents a
reflex action evoked by the activation of laryngeal
and/or tracheobronchial receptors. Its main functions
are protecting the lungs against aspiration and helping in the removal of excessive bronchial secretions.
Coughing does not normally occur in healthy individuals, and persistent cough is one of the cardinal signs of
respiratory disease. In health, mucociliary clearance
and alveolar macrophages satisfactorily control minor
insults from exogenous noxious agents. However,
when these systems fail or become overloaded with
foreign matter or excessive bronchial secretions, cough
intervenes as a supplemental mechanism to the
mucociliary escalator.
In his 1937 paper, Coryllos [1] provided a detailed
description of the cough cycle, and noted that ‘cough is
not a simple expiratory act but is composed of three distinctive phases: inspiratory, compressive and expulsive’. He likened the phases of the cough cycle to the
deflagration of a gun: the preparatory inspiration to the
loading of the gun, the compressive phase to the blazing
of the powder and production of gas under high pressure, and the expulsive phase to the ejection of the bullet from the barrel of the gun.
The purposes of this chapter are to describe the
motor characteristics of cough and outline the princi-
Description of cough
When cough is performed voluntarily or initiated by
stimulation of tracheobronchial receptors, it usually
begins with the inhalation of a variable volume of air.
However, if coughing is triggered by stimulation of afferents from the vocal folds, the preparatory inspiration may be absent: this has also been considered a
separate reflex, i.e. the so called ‘expiration reflex’ [2].
Next, the glottis is closed and the expiratory muscles
contract intensely, leading to the build-up of high intrathoracic and abdominal pressures. The glottis is
then actively reopened, and the inspired air volume
forcefully expelled by the sustained contraction of the
expiratory muscles. At the same time the central airways within the thorax are compressed and, for any
given expiratory flow rate, the reduction in their crosssectional area results in higher gas linear velocities than
would have occurred had there been no bronchial narrowing. There may be a fourth phase mainly characterized by the cessation of expiratory muscle activity and
the appearance of some antagonistic activity [3].
During spontaneous coughing, several expiratory
thrusts may follow one another with replication of the
above-mentioned events or with minor variations such
as those characterized by the absence of glottis closure.
The principal muscular and mechanical events that
193
CHAPTER 19
I
C
E
Diaphragm
Abd. muscles
PCA
TA
Flow
PSG
Fig. 19.1 Diagrammatic representation of the motor pattern
of a typical cough effort. The inspiratory (I), compressive (C)
and expiratory (E) phases of cough are delimited by the
dashed lines, and are preceded and followed by periods of
normal breathing. PCA, posterior cricoarytenoid muscle
(laryngeal abductor); TA, tyroarytenoid muscle (laryngeal
adductor); PSG, subglottic pressure. On some occasions
(see [41]), diaphragmatic activity may extend into the early
stages of the expiratory phase. Reprinted with permission
from [17].
characterize a single cough effort are diagrammatically
illustrated in Fig. 19.1.
Inspiratory phase
As with most inspiratory acts, the first event of the inspiratory phase of cough is the contraction of the abductor muscles of the arytenoid cartilage leading to
complete opening of the glottis and facilitating subsequent inhalation of a variable air volume [4]. The inspired air volume may range from a fraction of to
several times the eupnoeic tidal volume.
Studies in which subjects were instructed to cough
voluntarily suggest a high degree of volitional control
over inspired volume, the latter being related to the anticipated forcefulness of the subsequent cough effort. In
a group of normal subjects performing a series of ‘single
gentle coughs’ [5], the mean duration of the inspiratory
phase varied from 0.45 to 1.00 s, with an average value
of 0.75 s. The corresponding inspiratory volume
ranged from 0.09 to 0.53 L (mean 0.39 L), and was
found to correlate with the duration of the preparatory
inspiration [5]. In the study by Ross et al. [6], in which
194
subjects were instructed to perform maximum voluntary cough efforts, the mean duration of the inspiratory
phase was 0.65 s, and resulted in a mean air intake of
about 2.5 L.
Little is known regarding the regulation of inspiratory volume and flow during the inspiratory phase of reflex cough. It may be, however, that the magnitude of
the inspired volume is related, at least in part, to the intensity of the stimulus causing cough (author’s unpublished observations).
During mechanical stimulation of dog trachea, the
typical sequence of cough’s motor acts is often preceded
by a sustained apnoeic period during which the diaphragm shows only minimal activation, and lung volume does not appreciably change [4].
Whatever the regulatory mechanism(s), the augmentation of the inspiratory volume may enhance the
mechanical efficiency of the subsequent expiration
by different means. At high lung volumes, the
tension–length relationship of the expiratory muscles is
optimized [7,8], thus allowing them to produce greater
intrathoracic and abdominal pressures. Furthermore,
activation of pulmonary stretch receptors by lung distension leads to central facilitation of cough [9].
Compressive phase
Closure of the glottis by adduction of the ventricular
folds and covering of the laryngeal inlet by the epiglottis marks the onset of the compressive phase of cough.
Contraction of the expiratory muscles against a closed
glottis leads to the development of high abdominal,
pleural, alveolar and subglottic pressures. When pleural pressure increases, the alveolar gas is compressed
and lung volume decreases. Glottis closure, rather than
gas compression within the respiratory system, is regarded as the phenomenon that mostly differentiates
coughing from a forced expiration. Indeed, marked increases in abdominal and intrathoracic pressures leading to compression of the alveolar gas are known to
occur during expiratory thrusts with an open glottis
due to the resistive properties of the tracheobronchial
tree. Expiratory muscle contraction during the compressive phase is accompanied by the coactivation of
the diaphragm [10] and other inspiratory muscles opposing further development of positive pleural and
alveolar pressures [3].
Since the glottis remains closed for only 0.2 s, although with considerable variability, the rate of change
MOTOR MECHANISMS AND MECHANICS OF COUGH
in alveolar pressure over this brief interval is remarkably high. At the end of the compressive phase, alveolar
pressure may exceed 20 kPa [11,12], i.e. values
50–100% higher than during other expulsive manoeuvres in which the glottis is open. Thus, the corresponding rate of change in alveolar pressure would
approximate 100 kPa/s. Given the relationship between gas pressure and volume changes as dictated by
Boyle’s law, if one assumes a lung volume of 5 L at the
end of the inspiratory phase, and an alveolar pressure
of 20 kPa at the end of the compressive phase (i.e. ~
+20% of the atmospheric value), the corresponding reduction in lung volume will be ~ 1 L. The rate of change
in lung volume during compression would then approximate to 5 L/s. The augmentation of pleural pressure during the compressive phase, as compared to
other expiratory manoeuvres, may be related to a reflex
increase in agonist and decreased antagonist muscle activity, presumably brought about by glottis closure
[13], and/or optimization of the force–length–velocity
relationships of the expiratory muscles [3].
As is the case for all other skeletal muscles, the force
developed by the contracting expiratory muscles is
proportional to their length and inversely related to
their velocity of shortening [8]. Thus, there are mechanically advantageous conditions contributing to
force development during the compressive phase of
cough. In fact, glottis closure prevents significant decreases in lung volume, except for those produced by
gas compression, thus allowing the expiratory muscles
to express their maximal force during contraction at
the length determined by the lung volume attained following the preceding inspiratory phase. In fact, due
to the relatively small changes in lung volume during
compression, the shortening velocity of the expiratory
muscles is minimal, and muscle contraction nearly
isometric.
Although glottic closure is generally considered a
prerequisite for development of the high intrathoracic
pressures of cough, some lines of evidence seem to deny
this. For instance, the study of Gal [14] showed that, in
subjects who performed maximum voluntary cough efforts prior to and following tracheal intubation, cough
pressures were the same or even greater after intubation. Furthermore, neither glottic closure nor high pressures appear to be crucial to effective coughing:
tracheostomized and intubated patients can still expectorate, and even normal subjects need not close the
glottis for airway clearing [15].
Expiratory phase
This is the phase of the cough cycle during which the
airways are cleared of secretions, debris and foreign
material. It is initiated by rapid (20–40 ms) abduction
of the arytenoid cartilages, an active phenomenon involving muscle recruitment [4]. Opening of the glottis
at the onset of expiration is associated with passive oscillations of gas and tissues causing the characteristic
noise of cough and setting up pressure fluctuations that
may play a role in shaking loose secretions. Pressure
within central airways rapidly falls to nearly atmospheric values (Fig. 19.1), while pleural and alveolar
pressures still continue to rise for about 0.5 s. The total
duration of the expiratory phase is variable, but generally comprises between 0.5 and 1.0 s [5,16].
In normal subjects performing a maximum voluntary cough effort starting from near total lung capacity,
expiratory flow sharply rises up to values of more than
10 L/s [17], and the central intrathoracic airways collapse. Airway compression causes rapid, transient displacement of the airway gas volume, and generates high
supramaximal flow rates that superimpose on the airflow coming from the alveolar spaces. More detailed
accounts of the mechanisms contributing to the generation of flow transients during maximum expiratory efforts will be given in a subsequent section. The time
required to achieve these high flow transients (i.e. the
time to peak flow) is approximately 30 ms [17]. After
this short time interval, flow rate falls to much lower
values, approximately 50% of the cough peak flow,
which may be sustained for several milliseconds, up to
half the total duration of the expiratory phase [5,16].
Lung volume and flow rate then decrease exponentially
with time, with a time constant of ~ 0.5 s [3]. During the
last stage of expiration, flow rapidly drops to zero and
expulsion terminates.
The violent muscular activity associated with the expirations of cough may have noxious effects, including
trauma of the larynx and airways, rib fractures and
barotrauma. Indeed, costal fractures and abdominal
muscle tears are well-known complications of intense
cough, but have never been reported to occur with
other expulsive efforts [3,18,19].
Cessation
The cessation phase is associated with relaxation of
expiratory muscle and perhaps onset of antagonistic
195
CHAPTER 19
muscle activity with a fall in pleural and abdominal
pressures. In most instances, the glottis narrows and
the laryngeal structures gradually return to their inspiratory position [5]. The compressed central airways
re-expand.
Mechanics of cough
The development of an effective cough as a clearing
mechanism is thought to be critically dependent upon
the linear velocity of the gas molecules travelling down
the airway lumen [3,20]. It appears that the cough
mechanism is designed to maximally increase the gas
velocity by both generating high expiratory flow rates
and dynamically compressing the airways to reduce
their cross-sectional area. In this section, we will review
the mechanisms implicated in the regulation of the rate
and velocity of flow during the expulsive phase of
cough. Excellent and more detailed descriptions of the
mechanical events of cough, as well as of cough as a
clearing mechanism, can be found in the literature
[3,6,12,20,21].
Regulation of expiratory flow
The high intrathoracic pressures that are generated
during the nearly isometric expiratory muscle contraction of the cough compressive phase are suddenly
released when the glottis opens at the onset of the
expiratory phase. Pressure at the airway opening rapidly falls to atmospheric values, while alveolar and pleural pressures remain constant or may continue to rise
for a short period [3,20]. Sustained expiratory muscle
contraction and concomitant cessation of antagonist
action of the inspiratory muscles allowing full transmission of expiratory muscle force to the pleural and
alveolar spaces are the likely contributing mechanisms
[3]. Due to the elastic recoil of the lungs, alveolar pressure is always greater than pleural pressure, while the
pressure surrounding the outer wall of the airways, the
peribronchial pressure, closely approximates that of
the pleural space [22]. The pressure within the airways,
the intrabronchial pressure, progressively diminishes
as air travels down the airways from the alveolus to the
airway opening. This pressure drop is the result of the
energy expenditure that is required to accelerate flow as
the total airway cross-sectional area decreases and airway resistance increases, as well as the result of laminar
196
and turbulent energy dissipation in the flow [23]. At
some point along the tracheobronchial tree, at the
equal pressure point (EPP), the decrease in intrabronchial pressure equals the elastic recoil of the lung
(Fig. 19.2). Thus, the EPP divides the intrathoracic airways into two segments arranged in series, respectively,
located upstream (i.e. toward the alveoli) and downstream of the EPP. In the upstream segment, the intrabronchial pressure is greater than peribronchial
pressure, and the airways are distended. In the downstream segment, pressure within the airways becomes
lower than the pressure surrounding them, and the airways tend to collapse. Once the maximum expiratory
flow has been achieved, further expiratory efforts only
cause more compression of the downstream segment,
but do not affect flow through the upstream segment. In
fact, since the pressure drop in the upstream segment
equals the elastic recoil, the rate of flow in the upstream
segment is dictated by the ratio between the elastic
recoil of the lungs (PEL) and the resistance (R) of the
upstream (US) segment:
PPL +++
Compressive
phase
PA ++++ ++++
Glottis closed
++++
PPL +++
Expiratory
phase
PA ++++
+++ ++
Glottis open
+
Fig. 19.2 Description of the principal mechanical events of
cough by means of a model of the respiratory system. During
the compressive phase, expiratory muscle activation increases pleural pressure (PPL) that becomes markedly positive
with respect to atmosphere. Alveolar pressure (PA) is always
greater than PPL due to the elastic recoil of the lung (arrows).
Since the glottis is closed, intrabronchial pressure is similar to
PA throughout the airways. When the glottis opens at the beginning of the expiratory phase, air starts to flow rapidly
down the pressure gradient from the alveoli to the mouth.
Thus, there must be a point along the airways at which the intrabronchial pressure and PPL pressures are equal: the equal
pressure point (EPP). Downstream of the EPP, the airways are
distended; upstream of the EPP the intrathoracic airways are
compressed. Reprinted with permission from [17].
MOTOR MECHANISMS AND MECHANICS OF COUGH
.
V = PEL/RUS.
This phenomenon, called flow limitation or autoregulation of flow, is the basic mechanism that sets up the
upper limits to flow during both a forced expiration
and the expiration of cough. It has been likened to the
behaviour of a Starling resistor or a waterfall. The flow
of water upstream of the waterfall depends on the slope
of the terrain that delivers water to the waterfall, but is
independent of the height of the waterfall or the conditions downstream to it. Thus, under conditions of flow
limitation, changes in downstream pressure do not affect flow. When the intrathoracic pressures generated
by the expiratory muscle contraction exceed the modest level necessary to attain maximal expiratory flow,
the excess pressure markedly compresses the downstream segment of the intrathoracic airways, but does
not affect flow. However, narrowing of the downstream airways augments flow velocity and kinetic energy, and this may increase the effectiveness of cough as
a clearing mechanism.
An additional explanation for flow limitation is
based on principles of the wave speed theory [24].
According to this theory, an elastic tube cannot carry a
fluid at a mean velocity greater than the speed at which
pressure waves will propagate along the tube, i.e. the
tube wave speed. By analogy, this is the velocity at
which pulse propagates in the arteries. At the site where
the linear velocity of flow equals the velocity of propagation of pressure waves, a ‘choke point’ develops, and
prevents further increases in flow rate. The tube wave
speed depends on the gas density (r), the tube (i.e. airway) cross sectional area (A) and the specific elastance
.
of the tube wall (A dP/dA). Then, maximum flow (V )
can be expressed as:
.
V = A [r-0.5 (A dP/dA)]0.5.
.
Actual V , however, cannot be determined by using this
equation, since values of A and (A dP/dA) vary with
choke point location, the latter depending on airway
geometry and elasticity, and on lung volume. During an
expiratory thrust performed at a large lung volume, the
choke point resides in the central airways. As lung volume diminishes, the choke point moves in the upstream
direction. In both humans and experimental animals,
simultaneous measurements of pleural and intrabronchial pressures made it possible to estimate that,
above functional residual capacity, the choke point is
located at the level of lobar or segmental bronchi
[20,22]. At lung volumes near residual volume, the
choke point moves down to the fifth- to sixthgeneration branches [20,25]. Thus, when a series of
coughs is initiated at a high lung volume, secretions are
initially cleared from the larger airway; secretions are
then moved from the small to the larger airway as lung
volume progressively diminishes.
Expiratory flow velocity
Given that in any condition flow is the same throughout
the airway, flow velocity must be increased at the level
of the compressed downstream segment. In fact, for
any given flow, the velocity of flow is inversely related
to the airway cross-sectional area:
Velocity = flow/cross-sectional area.
In theory, for a forced expiratory flow of 8 L/s through
an uncompressed tracheal segment with a cross-sectional area of 2.0 cm, the linear velocity of gas would be
approximately 2500 cm/s. Since dynamic airway compression may reduce the tracheal cross-sectional area
by up to one-sixth of its normal value [6], the linear velocity would increase to over 14 000 cm/s. In vivo measurements of linear velocities in the human trachea [22]
have demonstrated velocities close to 12 000 cm/s. The
kinetic energy of a moving airstream increases as the
square of the velocity. Thus, in the example shown, the
force available to remove secretions from the compressed regions of the airways would be approximately
15 times greater than that available in uncompressed
regions.
Supramaximal flow
Dynamic airway compression not only plays a crucial
role in limiting the expiratory flow, but is also implicated in the genesis of the flow transients that characterize
the onset of both coughs and forced expirations (Fig.
19.3). The origin of such flow transients has been clearly understood since the work by Dayman in the early
1950s [26]. However, only the use of more advanced,
fast response devices allowed quantitative analysis of
the flow events generated by manoeuvres such as maximum voluntary cough, forced expirations and coughs
triggered by the rapid release of a solenoid shutter valve
placed at the mouth. Knudson et al. [17] were able to
demonstrate that, during a series of maximum voluntary or triggered expiratory efforts performed from
197
CHAPTER 19
(b)
15
15
1
Forced expiration
10
·
V (L /s)
15
1
2
(a)
3
10
4
10
56
5
3
4
5
7 6
7
5
2
5
0
0
15
0
4
2
Volume (L)
Cough
40
60
80
100
80
100
Time (ms)
10
(c)
15
15
5
1
Triggered transient
·
V (L /s)
0
15
20
6
1
2
10
4
5
10
2
10
3
3
5
6
5
6
5
4
5
0
0
0
Time (10 ms/div)
2
4
Volume (L)
20
40
60
6
Time (ms)
Fig. 19.3 (a) Flow–time representations of forced expiration,
cough and triggered transients performed at the same lung
volume in a normal subject. (b) On the left is the flow–volume
representation of a series of voluntary coughs beginning at
total lung capacity and progressing sequentially down the
vital capacity, superimposed on the subject’s maximum expi-
ratory flow–volume curve. On the right, the numbered
coughs are represented as flow in time. (c) A series of brief,
rapid expiratory efforts are depicted in the same manner as
the coughs. Same subject provided all data shown. Reprinted
with permission from [27].
near total lung capacity to near residual volume, two
distinct components having different sites of origin, different time courses and mechanics contribute to the initial expiratory flow: the airway and the pulmonary
components. The moment at which alveolar pressure
exceeds mouth pressure, air begins to flow from the
lung parenchyma, and this flow represents the pulmonary component. At the same time, since pleural
pressure is greater than that within the central airways,
these are subjected to dynamic compression and collapse abruptly. The flow produced by sudden displacement of the airway gas volume represents the airway
component. This may be detected as a transient flow
‘spike’ at the beginning of the expiratory phase of each
cough or forced expiration (Fig. 19.3), and is referred to
as supramaximal expiratory flow, superimposed on
more sustained flow from lung parenchyma. Transient
peak flow rates, that are particularly evident at low lung
volumes and in patients with airway obstruction [17],
considerably exceed the limits imposed by the standard
maximum expiratory flow–volume (MEFV) curve. If
the expiratory effort is sustained, however, flow rapidly
falls back to within the limits of the MEFV curve. Thus,
with the exception of the initial supramaximal transients, the mechanisms limiting flow during forced expiration also operate to limit flow during cough.
The study by Arora and Gal [11] performed in normal curarized subjects demonstrated that expiratory
198
MOTOR MECHANISMS AND MECHANICS OF COUGH
muscle weakness markedly decreased inspiratory lung
volume and the lung’s ability to generate high pleural
pressures during voluntary coughing. However, the decreased pleural pressure during cough following curarization had minimal effects on the pulmonary
component of flow, whereas it markedly reduced airway compression as judged by the loss of flow transients in coughs initiated at the highest achievable lung
volume [11].
The air volume displaced by dynamic compression is
small, i.e. between 50 and 150 mL, also depending on
the location of the EPP [17]. Volume acceleration (the
ratio of peak flow to the time to peak) during cough and
forced expiration may attain values as high as 300 L/s2.
Volume acceleration values of 1200 L/s2 could be attained when coughing was triggered by a shutter at the
mouth [17,27].
An additional phenomenon occurring during airway
compression is that airway walls undergo substantial
radial acceleration that may facilitate the interaction
between flow and mucus (see below). As Leith et al.
consider in their review on cough [3], during collapse
the airways may behave in a manner similar to a rug
being shaken in the wind. If the airways shake with full
force, as in the case of intense cough or shutter-triggered coughs, more mucus can be shaken from the airways into the rapidly moving airstream of the cough,
thus improving cough effectiveness. However, the possibility that supramaximal flow enhances cough clearance has recently been denied by Bennet and Zeman
[27]. By using radiolabelled aerosols and gamma camera analysis, they compared the efficacy of voluntary
coughs, forced expirations without glottis closure
(‘huffs’) and shutter-triggered coughs for clearing
mucus from the airways of patients with chronic airway obstruction. It was found that increasing supramaximal flow during coughing did not enhance mucus
clearance, and that voluntary coughing was as effective
as huffing in airway clearing [27]. Harris and Lowson
[21] have evaluated the mechanical effectiveness of successive voluntary coughs in healthy young adults by simultaneously recording flow at the airway opening and
changes in tracheal cross section by cine-radiography.
They were able to show that peak flow occurred before
maximum tracheal narrowing, so that maximum linear
velocities were achieved during the period of more sustained but lower-rate flow which occurs after peak flow
had subsided. They concluded that measurements of
sustained flow rates during coughing might be of
greater importance than measurements of peak flow
for assessing the ‘scrubbing action’ of cough. In the
light of these findings [21,27], it appears that both the
time at which cough expiratory flow attains the highest
velocity and the actual relevance of flow velocity to
mucus removal need to be more clearly established.
Flow–mucus interactions
In the airways flow can be either laminar (i.e. obeying
Poiseuilles’s law) or non-laminar (turbulent). Whether
flow is laminar or turbulent can be predicted by the
Reynolds number
. (Re), a dimensionless variable which
depends upon V , gas density (r) and viscosity (h), and
the airway radius (r):
.
Re = 2Vr/prh.
Turbulence is more likely to occur when Re is high, as is
the case in the central airways, particularly the trachea.
Conversely, laminar flow patterns occur only in the
small peripheral airways. When an airway is lined with
mucus, laminar flow exerts only a negligible shearing
force on the lining. However, once flow becomes turbulent, it exercises a force on the lining layer, setting ripples and eventually shearing the mucus off the airway
walls. In such conditions, where airflow exerts a mechanical influence on the mucus lining the airways, then
it is said to be the two-phase cocurrent flow [3,25,28].
This refers to flow of gas and liquid (mucus) in the same
direction within a conduit. For a gas density about that
of air and a liquid viscosity similar to that of mucus,
four main two-phase cocurrent flow regimes exist (Fig.
19.4). The bubble or aerated flow, in which the gas is
dispersed as fine bubbles throughout the liquid, occurs
for gas velocities below 60 cm/s. The piston or slug
flow, in which the gas flows as large plugs, occurs for
gas velocities from 60 to 1000 cm/s. The annular or film
flow, in which the liquid is pumped up the airways as an
annulus and the gas flows as a core, occurs for gas velocities over 1000 cm/s. Finally, for gas velocities over
2500 cm/s, the liquid is carried as fine drops in the gas
phase: the mist flow, probably the most effective one
[25]. Which types of mucus pumping occur in what
parts of the airway depends on the linear velocity of gas
which, as outlined above, is a function of flow rate and
airway cross-sectional area. Air speeds sufficient to
shear mucus from the airway wall typically occur in the
collapsed airway segments downstream from the EPP.
When the lungs are filled to vital capacity, the EPP is at
199
CHAPTER 19
Bubble flow
0–60 cm/s
0–2.16 km/h
Slug flow
60–1000 cm/s
2.16–36 km/h
Annular flow
1000–2500 cm/s
36–90 km/h
Airflow
the level of the trachea, and moves progressively upstream to segmental and smaller bronchi as the lungs
empty. Since flow rate decreases at low lung volumes, it
is doubtful whether the velocity of flow in the smaller
bronchi is high enough to shift mucus, and theoretical
analysis suggests that mist flow is unlikely to occur beyond the sixth-generation branches or for flow rates
lower than 5 L/s [25].
Cough motor mechanisms
The efferent outflows of cough are numerous, the most
important ones being those to the airway smooth muscle, the upper airway and respiratory muscles, and the
mucus-secreting apparatus. The mechanisms subserving mucus secretion during cough will be reviewed in
Chapter 20 of this book.
Airway smooth muscle
Cough and bronchoconstriction can be regarded as a
defensive and protective reflex, respectively, for the respiratory tract [29]. Stimuli to the larynx and the tracheobronchial tree that cause coughing also cause
200
Mist flow
>2500 cm/s
>90 km/h
Fig. 19.4 The four basic regimens in
two-phase cocurrent flow. The range
of associated gas velocities is taken
from engineering literature (see [32]
for references) for large rigid conduits
and Newtonian liquids. Reprinted
with permission from [17].
reflex bronchoconstriction ([30] and references therein). Both these reflex responses appear to be mediated
by the same type of receptor but their afferent neural
pathways may be separate, since they can be induced
individually and suppressed selectively by drugs [29].
In cats, mechanical stimulation of the larynx and tracheobronchial tree causes an increase in total lung resistance that closely corresponds with the inspiratory
and expiratory motoneurone discharge [10]. A simultaneous recording of bronchoconstrictor fibre activity
and of total lung resistance also reveals considerable
correlation in time and magnitude [10].
The physiological meaning of cough-related bronchoconstriction is uncertain. It may, however, enhance
both the sensory and the motor components of cough.
Animal studies [31] have shown that airway rapidly
adapting irritant receptors are stimulated or sensitized
by smooth muscle contraction, and desensitized by
muscle relaxants. Presumably, cough-related bronchoconstriction may also help to limit the progression
of inhaled noxious substances into the lungs, or to stabilize the airway wall during the violent movements of
coughing. In addition, constricted airways are more
rigid than in the relaxed state, and this may prevent
their total collapse when intrabronchial pressure falls
MOTOR MECHANISMS AND MECHANICS OF COUGH
below peribronchial pressure. This phenomenon might
contribute to shifting the EPP upstream, and help to
clear the smaller airways [32].
Upper airway and respiratory muscles
The motor pattern of coughing involves the coordinated activation of several muscles, all having a prevailing
respiratory function and exerting their mechanical action on the chest wall or upper airways. Simultaneous
activation of muscles with an inspiratory or expiratory
discharge pattern during normal breathing occurs during coughing [10]. For clarity, however, their functions
will be analysed separately. Upper airway muscles do
not contribute directly to airflow, but their activation
needs to be synchronized with that of the respiratory
muscles in the production of the normal pattern of
breathing and the cough motor output. To ensure patency of the upper airways, muscles of the oral and
nasal passageways are also recruited during coughing.
They include the alae nasi muscles, muscles lowering
the jaws to open the mouth, and soft palate muscles to
close the nasopharynx. The genioglossus muscle may
also be activated [33].
Laryngeal muscles
The participation of individual laryngeal muscles in
cough has been the object of several endoscopic analyses of the glottal chink [13]. In contrast, the analysis of
laryngeal muscle activation has received considerably
less attention. In humans, invasive electromyographic
(EMG) recordings demonstrated intense activation of
the adductor muscles occurring prior to the onset of the
typical cough sounds, the magnitude of such activation
being greater than that of both normal breathing and
vocalization [34]. The abductor muscle contracted in
reciprocal order to that of the adductors [34].
The study of the temporal relationships between the
pattern of laryngeal muscle activation and the ongoing
mechanical events during cough has recently been undertaken in anaesthetized dogs [4]. These authors
recorded the EMG activity of the laryngeal abductor
and adductor muscles, along with subglottic and intrathoracic pressure changes, during coughing elicited
by mechanical stimulation of the tracheobronchial
tree. The posterior cricoarytenoid (PCA) is the laryngeal abductor muscle, while the thyroarytenoid (TA)
and arytenoid (AR) muscles are adductors. The role of
the cricothyroid (CT) is still controversial, but its pat-
tern of activation during cough closely resembles that
of the abductor muscle [4]. During the inspiratory
phase of cough, the PCA and the CT were activated,
causing a reduction in upper airway resistance and promoting inspiratory flow. During glottal narrowing, the
TA and AR were recruited, while both the PCA and CT
displayed minimal activity. No consistent correlation
was found between the magnitude of TA and RA EMG
activity and intrathoracic and subglottic pressures, suggesting the intervention of additional mechanisms
besides adductor muscle activation in the control of
laryngeal resistance. Finally, during the expiratory
phase, the PCA was recruited and the adductors were
suppressed. These phenomena would open the glottis
and, along with the activation of expiratory muscles,
promote expulsion of air from the lung. Interestingly,
this pattern of motor activation turned out to be unaffected by both isolating the larynx from the intrathoracic airways and sectioning of the internal branches
of the superior laryngeal nerves. Therefore, the wellcoordinated activation of laryngeal abductor and adductor muscles during tracheobronchial cough appears
to be an entirely centrally preprogrammed event that is
uninfluenced by the route of breathing and laryngeal
sensory feedback [4].
Diaphragm and other inspiratory muscles
Studies in cats have demonstrated that, compared with
normal breathing, the EMG activity of the costal and
crural diaphragm, along with that of the parasternal intercostals, is markedly increased during the inspiratory
phase of coughing [35]. Large preparatory inspirations
may optimize the precontractile lengths of the expiratory muscle, which is likely to be an advantageous situation for dynamic airway compression and high gas
velocities during the subsequent expulsive phase of
cough. The electrical activity of these inspiratory muscles also persists into the early expiratory portion of
most mechanically induced cough efforts [10,34]. Tomori and Widdicombe [10] found that, at the beginning
of the expiratory phase, the intensity of diaphragmatic
activity exceeded that of the preceding inspiratory
phase, lasted 0.1–0.2 s, and terminated prior to the attainment of peak positive intrapleural pressure. This
pattern of diaphragmatic activation during cough may
serve to counterbalance the simultaneous, intense activation of the expiratory musculature or delay the transmission of pressure from the abdomen to the thorax
[10].
201
CHAPTER 19
Intercostal muscles
The conventional view of intercostal muscle actions
maintains that, because of muscle fibre orientation, the
external intercostals (EIC) have an inspiratory action,
whereas the internal intercostals (IIC) have an expiratory action ([34] and references therein). Indeed, recent
human studies confirmed that the EIC in many areas
of the rib cage shorten during passive inflation, whereas the IIC lengthen [36]. Thus, in agreement with
Hamberger’s theory ([36] and references therein), the
EIC have an inspiratory advantage, while the IIC have
an expiratory advantage. However, the magnitude of
such mechanical advantages is such that the inspiratory
advantage of the EIC is greatest at the rostral interspaces, and the expiratory advantage of the IEC is
greatest at the ventral portion of the caudal interspaces
[36]. The inspiratory effect of the EIC muscles is maximal at the level of the dorsal half of the second interspace, but decreases rapidly in the caudal direction and
is reversed into an expiratory effect in the ventral half
of the sixth and eighth interspaces. The IIC muscles
in the ventral half of the sixth and eighth interspaces
have large expiratory effects that decrease dorsally and
cranially [36].
Previous EMG studies performed in experimental
animals have demonstrated major differences in the
control of intercostal muscles at different thoracic levels. In anaesthetized cats making respiratory efforts
against an occluded airway, the EIC of the sixth costal
interspace fired during inspiration and the IIC during
expiration. However, both the EIC and the IIC of the
third interspace discharged during inspiration, and
those of the ninth space during expiration [37]. During
coughing elicited by electrical stimulation of the superior laryngeal nerves in the decerebrate cat, midthoracic
external and internal intercostal muscles discharged
synchronously with the diaphragm and the abdominal
muscles, respectively [38]. However, caudal external
and internal intercostals discharged synchronously
with the abdominal muscles [38].
Abdominal and other expiratory muscles
The principal expiratory muscles with significant respiratory function in humans lie in the ventrolateral aspect
of the abdominal wall. The triangularis sternii also
functions as an expiratory muscle. The abdominal
muscles include the transversus abdominis muscle, the
externus and internus obliquus muscles, and the rectus
abdominis muscle [8].
202
The abdominal muscles have an important postural
function as rotators and flexors of the trunk. As expiratory muscles, their contraction pulls the abdominal
wall inward and increases abdominal pressure. As a result, the diaphragm is pushed cranially, lung volume decreases and pleural pressure increases. Due to their
insertions on the rib cage, contraction of the abdominal
muscles contributes to expiration by lowering the
lower ribs. In humans breathing at rest, the abdominal
muscles are silent in the supine position. In the standing
posture, they often display a tonic activity unrelated to
the phases of respiration [8]. Phasic expiratory contraction of these muscles occurs when ventilation reaches
very high levels, or when the expiratory pressure is
higher than 1 kPa [7].
In both humans and experimental animals, intense
activation of the abdominal muscles is an essential
component of cough. When triggered by appropriate
afferent inputs, the respiratory network generating the
cough motor pattern conveys an excitatory drive not
only to the caudal expiratory neurones and, hence, to
the major respiratory motoneurone pools, but also to
the lower lumbar and sacral cord where pudendal motoneurones (nucleus of Onuf) innervating the external
urethral and anal sphincters are located ([39] and references therein). Thus, an excitatory drive to caudal expiratory neurones may play a role also in preventing
incontinence when abdominal pressure is raised by abdominal muscle activation during cough [39].
Tomori and Widdicombe [10] systematically investigated the motor pattern of a single abdominal muscle
during coughing in cats, and showed that the rectus
abdominis was strongly activated during this reflex
and that such activation was associated with large intrathoracic pressures. Electromyographic recordings
performed in humans during either voluntary or capsaicin-induced cough also documented strong activation of the rectus abdominis ([40] and references
therein). The pattern of activation of the anterolateral
abdominal muscles during coughing induced by
mechanical stimulation of the tracheobronchial or laryngeal lumen has recently been studied in anaesthetized cats [40]. During cough, all four abdominal
muscles proved to be simultaneously and vigorously
activated and, unlike during expiratory threshold
loading, the patterns of activation were very similar
to one another [40]. In contrast, by means of surface
EMG recordings performed in humans during voluntary coughing, Floyd and Silver [41] demonstrated
MOTOR MECHANISMS AND MECHANICS OF COUGH
substantial activation of both the internus and externus
obliquus muscles that was associated with relative inactivity of the rectus abdominis muscle. Accordingly, a
subsequent study by Strohl et al. [42] also showed
greater activation of the upper and lower ventrolateral
abdominal muscles compared with the rectus abdominis muscle during voluntary cough efforts in
humans. Measurement of static expiratory airway
pressure during spinal cord stimulation, performed before and after ablation of different expiratory muscle
groups in the anaesthetized dog, confirmed that the
oblique muscles make the largest mechanical contribution to pressure generation, and that the rectus abdominis muscle minimally contributes to pressure
generation [43].
Non-invasive recordings of EMG activity of human
abdominal muscle activity, particularly the obliquus
externus muscle, have been used to assess the intensity
of coughs elicited by inhalation of tussigenic agents
[16,44,45]. Cox et al. [44] were the first to demonstrate
that the sum of the electrical activity generated by each
expiratory muscle contraction (i.e. the ‘true’ integrated
EMG activity) correlated with the volume, flow and
noise of coughs elicited by citric acid inhalation. More
recently, the ‘moving average’ integrated EMG activity
of the obliquus externus muscle has been used to evaluate the intensity of voluntary and reflex cough efforts
[16,45]. These studies showed that the peak and rate of
rise of the obliquus externus integrated EMG activity
correlates with both the intensity of the cough stimulus
[45] and the cough maximum expiratory flow [16,45].
In dogs, both the triangularis sternii and the transversus abdominis are active during normal breathing,
and the peak activity of both these muscles increases
approximately threefold during coughing [46]. De
Troyer et al. [47] found that the triangularis sternii, an
expiratory rib cage muscle, is active during the expiratory phase of coughing in humans. In tetraplegic subjects, contraction of the clavicular portion of the
pectoralis major plays an important expiratory role
during coughing [48].
Cardiovascular implications
of coughing
The intrathoracic pressure generated during both compression and the subsequent expiratory phase may be
high enough to have important cardiovascular effects
([18] and references therein). If these high pressures are
sustained, as may be the case in patients with bronchial
obstruction, venous return, right and left cardiac filling
and afterloads, systemic arterial flow distribution and
vascular reflexes are markedly influenced. In consequence, cardiac output and systemic blood pressure are
reduced, while systemic venous pressure rises. The reduction in blood pressure results in a decreased cerebral
perfusion pressure that, along with the rise in cerebrospinal fluid pressure associated with the augmented
thoracic and abdominal pressures, may eventually
cause loss of consciousness [3,18]. The increase in venous pressure may result in rupture of subconjunctival,
nasal and anal veins. Cough may also be accompanied
by a reflex increase in vagal tone, also leading to bradycardia and heart blocks [18]. Cough has thus been used
as a form of cardiopulmonary resuscitation to restore
a more normal cardiac rhythm in patients with potentially lethal arrhythmia [18].
References
1 Coryllos PN. Action of the diaphragm in cough. Experimental and clinical study on the human. Am J Med Sci
1937; 194: 523–35.
2 Korpas J, Tomori Z. Cough and other respiratory reflexes.
In: Herzog H, ed. Progress in Respiratory Research, Vol.
12. Basel: Karger, 1979: 94–105.
3 Leith DE, Butler JP, Sneddon SL, Brain JD. Cough.
In: Fishman AP, Macklem PT, Mead J, Geiger SR, eds.
Handbook of Physiology. The Respiratory System. Mechanics of Breathing, Sect. 3, Vol. III, Part 1. Bethesda,
MD: American Physiological Society, 1979: 315–36.
4 Sant’Ambrogio G, Kuna ST, Vanoye CR, Sant’Ambrogio
F. Activation of intrinsic laryngeal muscles during cough.
Am J Respir Crit Care Med 1997; 155: 637–41.
5 Yanagihara N, Von Leden H, Werner-Kukuk E. The physical parameter of cough: the larynx in a normal single
cough. Acta Otolaryngol 1966; 61: 495–510.
6 Ross BB, Graniak R, Rahn H. Physical dynamics of the
cough mechanism. J Appl Physiol 1955; 8: 264–8.
7 Agostoni E. Action of respiratory muscles. In: Fenn WO,
Rahn H, eds. Handbook of Physiology, Vol. 1, Sect. 3,
Chapter 12, Respiration. Washington, DC: American
Physiological Society, 1964: 377–86.
8 De Troyer A, Loring SH. Action of respiratory muscles. In:
Fishman AP, Macklem PT, Mead J, Geiger SR, eds. Handbook of Physiology. The Respiratory System. Mechanics
of Breathing, Sect. 3, Vol. III. Bethesda, MD: American
Physiological Society, 1986: 1–67.
203
CHAPTER 19
9 Hanácek J, Davies A, Widdicombe JG. Influence of lung
stretch receptors on the cough reflex in rabbits. Respiration 1984; 45: 161–8.
10 Tomori Z, Widdicombe JG. Muscular, bronchomotor and
cardiovascular reflexes elicited by mechanical stimulation
of the respiratory tract. J Physiol 1969; 200: 25–49.
11 Arora NS, Gal TJ. Cough dynamics during progressive expiratory muscle weakness in healthy curarized subjects. J
Appl Physiol 1981; 51: 494–8.
12 Lavietes MH, Smeltzer SC, Cook SD, Modak RM, Smaldone GC. Airway dynamics, oesophageal pressure and
cough. Eur Respir J 1988; 11: 156–61.
13 Von Leden H, Isshiki N. An analysis of cough at the level of
the larynx. Arch Otolaryngol 1965; 81: 616–25.
14 Gal TJ. Effects of endotracheal intubation on normal
cough performance. Anaesthesiology 1980; 52: 324–9.
15 Young S, Abdul-Settar N, Caric D. Glottic closure and
high flows are not essential for productive cough. Bull
Eur Physiopathol Respir 1987; 23 (Suppl. 10):
11s–17s.
16 Fontana GA, Pantaleo T, Lavorini F, Polli G, Pistolesi M.
Coughing in laryngectomized patients. Am J Respir Crit
Care Med 1999; 160: 1578–84.
17 Knudson RJ, Mead J, Knudson DE. Contribution of airway collapse to supramaximal expiratory flow. J Appl
Physiol 1974; 36: 653–67.
18 Irwin RS, Boulet LP, Cloutier MM et al. Managing cough
as a defence mechanism and as a symptom. A Consensus
Panel Report of the American College of Chest Physicians.
Chest 1998; 114: 113s–81s.
19 Fontana GA, Lavorini F, Pantaleo T, Pistolesi M.
Fisiologia della tosse. In: La Tosse. Fisiopatologia e Clinica. Pisa: Primula Multimedia, 2001: 14–43.
20 Macklem PT. Physiology of cough. Ann Otol 1974; 83:
761–8.
21 Harris RS, Lawson TV. The relative mechanical effectiveness and efficiency of successive voluntary coughs in
healthy young adults. Clin Sci 1968; 34: 569–77.
22 Macklem PT, Wilson NJ. Measurement of intrabronchial
pressure in man. J Appl Physiol 1965; 20: 653–63.
23 Hyatt RE. Expiratory flow limitation. J Appl Physiol
1983; 55: 1–8.
24 Dawson SV, Elliot EA. Wave-speed limitation on expiratory flow — a unifying concept. J Appl Physiol 1977; 43:
498–515.
25 Leith DE. Cough. J Am Phys Ther Assoc 1968; 48:
439–47.
26 Dayman H. Mechanics of airflow in health and emphysema. J Clin Invest 1951; 30: 1175–90.
27 Bennet WD, Zeman KL. Effect of enhanced supramaximal
flows on cough clearance. J Appl Physiol 1994; 77:
1577–83.
28 Clarke SW, Jones JG, Oliver DR. Resistance to two-phase
204
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
gas–liquid flow in airways. J Appl Physiol 1970; 29:
464–71.
Karlsson J-A, Sant’Ambrogio G, Widdicombe JG. Afferent neural pathways in cough and reflex bronchoconstriction. J Appl Physiol 1988; 65: 1007–23.
Widdicombe JG. Respiratory reflexes and defense. In:
Brain JD, Procter DF, Reid LM, eds. Respiratory Defense
Mechanisms, Part II. New York: Marcel Dekker, 1977:
593–630.
Mills JE, Sellick H, Widdicombe JG. Epithelial irritant receptors in the lungs. In: Porter R, ed. Breathing, HeringBreuer Centenary Symposium. London: Churchill, 1970:
77–92.
Olsen CF, Stevens AE, Iroy MB. Rigidity of the trachea and
bronchi during muscular contraction. J Appl Physiol
1967; 23: 27–34.
Tatar M, Webber SE, Widdicombe J. Lung C-fibre receptor activation and defensive reflexes in dogs. J Physiol
1988; 402: 411–20.
Faaborg-Andersen KL. Electromyographic investigation
of intrinsic laryngeal muscles in humans: an investigation
of subjects with normally movable cords and patients with
vocal cord paresis. Acta Physiol Scand 1957; 41: 1–148.
Van Lunteren E, Daniels R, Chandler Deal R, Haxhiou M.
Role of costal and crural diaphragm and parasternal
intercostals during coughing in cats. J Appl Physiol 1989;
66: 135–41.
Wilson TA, Legarnd A, Gevenois P-A, De Troyer A.
Respiratory effects of the external and internal intercostal
muscles in humans. J Physiol 2001; 530.2: 319–30.
Le Bars P, Duron B. Are the external and internal intercostal muscles synergist or antagonist in the cat? Neurosci
Lett 1984; 51: 383–6.
Iscoe S, Grelot L. Regional intercostal activity during
coughing and vomiting in decerebrate cats. Can J Physiol
Pharmacol 1992; 70: 1195–9.
Bongianni F, Mutolo D, Fontana GA, Pantaleo T.
Discharge patterns of Bötzinger complex neurons during
cough in the cat. Am J Physiol 1988; 274: R1015–R1024.
Bolser DC, Reier PJ, Davenport PW. Responses of the anterolateral abdominal muscles during cough and expiratory threshold loading in the cat. J Appl Physiol 2000; 88:
1207–14.
Floyd WF, Silver PHS. Electromyographic study of patterns of activity of the anterior abdominal wall muscles in
man. J Anat 1950; 84: 132–45.
Strohl KP, Mead J, Banzett RB, Loring S, Kosch P. Regional differences in abdominal muscle activity during various
maneuvres in humans. J Appl Physiol 1981; 51: 1471–6.
Di Marco AF, Romaniuk JR, Kowalski KE, Supinski G.
Mechanical contribution of expiratory muscles to pressure generation during spinal cord stimulation. J Appl
Physiol 1999; 87: 1433–9.
MOTOR MECHANISMS AND MECHANICS OF COUGH
44 Cox ID, Wallis PJW, Apps MCP, Hughes DTD, Empey
DW, Osman RCA, Burke CA. An electromyographic
method of objectively assessing cough intensity and use of
the method to assess effects of codeine on the dose–response curve to citric acid. Br J Clin Pharmacol 1984; 8:
377–82.
45 Fontana GA, Pantaleo T, Lavorini F, Boddi F, Panuccio P. A
non-invasive electromyographic study on threshold and
intensity of cough in humans. Eur Respir J 1997; 10:
983–9.
46 Van Lunteren E, Haxhiu MA, Cherniack NS, Arnold SJ.
Role of triangularis sterni during coughing and sneezing in
dogs. J Appl Physiol 1988; 65: 2440–5.
47 De Troyer A, Ninane V, Gilmartin JJ, Lemerre C, Estenne
M. Triangularis sterni muscle use in supine humans. J Appl
Physiol 1987; 62: 919–25.
48 Estenne M, De Troyer A. Cough in tetraplegic subjects: an
active process. Ann Intern Med 1990; 112: 22–8.
205
20
Mucus hypersecretion and mucus
clearance in cough
W. Michael Foster
Introduction
The tracheobronchial airways of the human lung are
largely covered by a liquid lining of mucus. The mucus
is a viscoelastic secretion that serves as a barrier for entrapment of microorganisms and xenobiotic material
and protects the underlying mucosal tissues from dehydration. This fluid lining also acts as an extracellular
surface for immunological and enzymatic action, and
can absorb and neutralize toxic gases [1]. The airway
lining fluid is hyperosmolar and relatively acidic, with
high concentrations of calcium, sodium and potassium
[2,3]. Current understanding is that the liquid lining is
a two-phase model in which the superficial layer is a viscoelastic (mucins, tangled network of high molecular
weight polymers) gel phase that overlays a periciliary
sol phase (serous). The serous layer is approximately
2–4 μm in thickness and bathes the cilia that protrude
from the epithelial surface, and thus the mucus layer
with an estimated depth between 1 and 6 μm is thought
to be propelled by ciliary beating and flows above the
serous layer [1,4]. Recent in vitro studies suggest that
perhaps the periciliary layer is not stationary but may
move unidirectionally via ciliary activity [5]. The velocity of mucus layer transport can be fairly rapid in the
tracheal airway, i.e. velocities observed in humans
range between 4 and 21 mm/min [6], and appears
related in part to the transfer rates of the mucus layer
from the peripheral lung and dependent bronchi into
the lower trachea [7]. Mucociliary transport and replacement of the mucus layer is influenced by several
factors, e.g. secretion rate and viscoelasticity of the
mucus, and synchrony and beat frequency of the cilia.
Cough is a significant stimulus to mucus secretion in
health and a physical adjunct to mucociliary clearance
in hypersecretory airway disease [8,9].
Sources of airway mucus
In humans cellular sources of the mucin component of
the airway liquid layer are the serous and mucous cells
of the submucosal glands, the epithelial goblet cells
and perhaps Clara cells. Submucosal glands are present
throughout the lower respiratory tract in the airways
containing cartilage; whereas goblet cells are located
within all airways and extend to the level of the alveolar
ducts, at which site Clara cells are found. Submucosal
glands, due to their prominence in airway histological
section, are considered to secrete the major contribution of mucus to airway surface liquid. Reid [10] had
estimated that the volume of the glands in the airway
mucosa was 40 times greater than the volume of goblet
cells. This calculation was based on several assumptions and thus the current interpretation is that relative
contributions of goblet cells and glands to the mucin
component of airway mucus are uncertain and likely to
vary with airway level and disease state. The normal
daily output of tracheobronchial secretions does not
exceed 0.5 mL/kg body weight under physiological
conditions [11].
Control of mucus secretion
and transport
Due to the heterogeneity in the cell types that release
secretory products onto the airway surface, control
207
CHAPTER 20
factors are not fully defined for the rate(s) of secretion
or for the composition of products secreted by each cell
type. Mechanisms that regulate the quality and volume
of the respiratory secretions involve, for example, the
transepithelial secretion of the chloride ion across
the airway epithelium with passive diffusion of water,
the stimulation of secretion by a number of mediators
such as arachidonic acid metabolites, and the overall
stability in the numbers of mucus-secreting epithelial
cells present in the airways [12]. The final product, respiratory mucus, can be complex, with differing degrees
of hydration and composition of ion and sugar content,
as well as variation in amino acid, glycoprotein and
lipid moities. Mucin proteins, the major constituents of
airway mucus produced by goblet cells and submucosal
glands, are a high molecular weight mixture of gene
products. At least seven MUC genes are expressed in the
human airways, but three predominate: MUC5B,
MUC1, and MUC5AC [13]. Mucin glycoproteins are
the major determinants for viscoelastic and adhesive properties of mucus [14]. Once synthesized, the
mucin glycoproteins are stored within cytoplasmic
membrane-bound granules; and upon appropriate
stimulation, these granules are released via an exocytotic process in which the granules translocate to the
cell periphery and fuse with the plasma membrane,
followed by mucin release onto the epithelial surface.
Intracellular protein kinases (protein kinase C and
gCMP-dependent protein kinase) appear to be key
determinants in the exocytotic release of mucin [15].
Three of the potential pathologies or airway lesions
that lead to excess mucus are: (i) increased synthesis of
mucus as a result of overexpression of mucin genes; and
(ii) enhanced production of mucus secondary to hyperplasia, hypertrophy or even metaplasia of the secretory
cells; or (iii) hypersecretion of stored mucin granules
from surface goblet cells and submucosal glands.
A wide variety of agents and inflammatory/humoral
mediators can provoke mucin secretion. In healthy subjects, the peripheral airways contain few goblet cells,
but goblet cell metaplasia may occur in respiratory disorders. It is also recognized that surface goblet cells can
quickly discharge vast quantities of mucus in response
to an acute insult; although integral to defence, this
outcome may also precipitate airway diseases associated with hypersecretion of mucus, including bronchitis [16]. Smokers with chronic bronchitis have been
shown to have greater inflammation around gland
ducts in bronchi larger than 4 mm in diameter. One
208
hypothesis is that neutrophil infiltration of the airway
epithelium may mediate hypersecretion by direct
interaction with mucus-producing cells. This concept
is supported by explants of human tracheal tissue in
which integrin binding of neutrophils was required to
induce degranulation of mucus cells [17]. A uniform
airway response following exposure to respirable
irritants, e.g. oxidants or acid aerosols, is a neuralmediated increase in the rate or volume of secretions
from epithelial cells and/or submucosal glands [18]. In
part this is a reflex defence mechanism to enhance the
depth of the airway mucus layer and modify the sensitivity of airway irritant receptors and ameliorate
bronchoconstrictive responses [18–20]. In addition to
stimulation of neural reflexes, toxic agents can often interact with secretions directly. For example, an oxidant
gas like ozone will react with the cross-linking bonds
that hold glycoproteins together and lower viscosity
[21]. Changes in the composition of secreted glycoproteins (either neutral or acid, depending upon specific
sugars in their oligosaccharide side chains) may also
alter the rheological properties of mucus; for example,
an increase in the acidic glycoprotein content of mucins
is associated with an increase in mucus viscosity.
Control of mucociliary clearance
The mucociliary transport system is innervated predominantly by the parasympathetic nervous system;
efferent postganglionic parasympathetic fibres have
been identified in association with submucosal glands
[22]. Airway surface epithelial cells and submucosal
gland cells express muscarinic receptors [23–25]. There
is also a high density of b-adrenergic receptors on surface epithelial cells and submucosal glands [26,27].
Submucosal glands also express a-adrenergic receptors
which are localized mainly to serous cells [26]. Peptidergic receptors (for vasoactive intestinal peptide
(VIP) and substance P) have also been identified on the
airway epithelial cells [28,29]. Mucous glands preserved from bronchial surgical specimens of smokers
with chronic bronchitis demonstrate a significant increase in the density of nerve fibres immunoreactive for
VIP [30] and support the hypothesis for involvement of
neuropeptides in hypersecretion of airway mucus [31].
Mucociliary transport does not appear to be under autonomic control; although it is known that atropine, a
muscarinic antagonist that apparently does not change
MUCUS SECRETION AND COUGH
the rheological properties of mucus, can significantly
reduce the rate of lung mucus transport in humans
[32,33]. Both vagal and sympathetic nerve stimulation
increase the rate of glandular secretion in several
species; and direct stimulation of the airway surface by
exogenous agonists, i.e. adrenergic and cholinergic,
and mediators such as histamine, alter transepithelial
secretory processes [1,16] and in humans increase airway mucociliary clearance [7,34,35].
Cough can be considered as a respiratory reflex with
defensive capabilities and in general its presence is a sentinel of an abnormal condition or an irritant exposure.
For example, an important role in epithelial membrane
homeostasis and continuous effective clearance of the
airway liquid layer is the interaction between mucus
viscosity, periciliary fluid and the ciliary beating. Cough
can signal dysfunction of these components, especially
in chronic bronchitis, and may serve as a back-up and/
or adjunct to the mucociliary clearance system. High
intrathoracic pressures generated during cough serve
to compress intrathoracic airways, thereby giving rise
to high gas velocities within the airway. These high
velocities of airflow supply the shearing forces necessary to dislodge material adherent to the airway epithelial surfaces. It appears likely that two-phase gas–liquid
flow can occur in the human airway under certain conditions. During coughing and rapid breathing (such as
with exercise) and maximal flow manoeuvres the
Reynolds numbers in the large airways will be sufficiently high to result in gas–liquid interaction if the
thickness of the mucus layer at the epithelial surface is in
excess of approximately 300 μm [36]. These depths of
mucus are believed to occur in hypersecretory airway
disease [36] and, although the pathophysiology of persistent cough remains obscure, cough can be a manifestation of hypersecretory airway disease [37].
Cough is a rare occurrence in health (except for
episodes of acute respiratory infection), and only a
few investigations have evaluated the influence of
cough on mucociliary clearance in subjects with normal pulmonary function. In fact, based upon mechanical principles, it has generally been presumed that
voluntary cough manoeuvres are ineffective in the normal airway where moderate depths of the mucus layer
(< 20 μm) exist as compared to the excessive airway secretions and mucus layer thickness found in bronchitis
(> 200 μm) [8,38]. Camner et al. [38] observed no
abrupt changes in airway clearance of a radiomarker
during periods of short vigorous coughing (1–2 min). In
similar fashion, Yeates and coworkers [39] demonstrated that voluntary coughing had no effect on
tracheal velocities of mucus flow in healthy subjects.
However, based upon a physical model with a turbulent stream of airflow through a straight tube and a
non-Newtonian pseudoplastic fluid, Scherer and Burtz
have proposed that cough-related ciliary mucus velocity can be enhanced down to about a 12th airway generation, even in a healthy individual [40]. In this
connection, Bennett and colleagues have investigated
the effects of cough on mucociliary clearance in healthy
subjects during the performance of respiratory manoeuvres (cough-like expiratory, vs. rapid inspiratory,
breathing) [8]. Their objective was to explore the influence of voluntary breathing manoeuvres on the clearance of airway secretions using respiratory efforts
designed to generate directionally opposite, but instantaneous, airflow rates (peak mean airflow measured at
the mouth of 7–10 L/s). The influence of these rapid
breathing manoeuvres on lung mucociliary clearance
is compared with respective control clearance curves
in Fig. 20.1. Somewhat as expected, the cough-like
expiratory manoeuvre significantly increased lung
mucociliary clearance as compared with control clearance (Fig. 20.1a). However, surprisingly, the rapid inspiratory breathing pattern likewise had a stimulatory
influence on transporting mucus out of the lung (Fig.
20.1b). Wolff et al. [41] have shown that both exercise
and resting eucapnic hyperpnoea can enhance the rate
of airway mucociliary clearance in normal subjects,
though exercise provided for a more intense effect.
However, the results with hyperpnoea are consistent
with the results observed by Bennett and colleagues, i.e.
independent of the direction of airflow, airway mucus
clearance was stimulated by high velocity of airflow.
Tracheobronchial neuronal reflexes may be responsible, whereby the velocity of airflow through large
central airways could serve to be a stimulus via rapidly
adapting receptors whose terminals lie within and
under the epithelium of the larger bronchi and which
respond to changes in lung volume (inflation and deflation). Following excitation of these receptors responses
include cough or deep inspirations, bronchoconstriction, mucus secretion and airway vasodilatation [42].
Thus this integrated system is well suited as a neurophysiological line of defence that limits epithelial injury
from respirable irritants. For example, following rapid
lung inflation or deflation or exposure to a respirable
irritant (dust, ozone, smoke, capsaicin) mucus release
209
CHAPTER 20
Particle retention (fraction deposited)
(a)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Normal subjects
Control
Cough
(n = 12)
0 30 60 90 120 150 180 210
(b)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
24 h
Normal subjects
Rapid
Control
(n = 8)
0 30 60 90 120 150 180 210
24 h
Time (min)
Fig. 20.1 Effect of voluntary respiratory manoeuvres on lung
mucociliary clearance. (a) Comparison of high expiratory
airflow (Cough) manoeuvre to relaxed breathing (Control);
(b) Comparison of high inspiratory airflow (Rapid) manoeuvre to relaxed breathing (Control). Number of subjects
studied as indicated and data represent mean and error bars
as ± SEM. Assessment of mucociliary clearance on Control,
Cough and Rapid study days; respiratory manoeuvres (high
expiratory and inspiratory airflow rates, respectively) were
performed voluntarily at 10-min intervals during the first
hour of assessment of mucociliary clearance. Final measure
of radiolabel retention assessed at 24 h post deposition of
radiomarker.
from submucosal glands onto the epithelial surface
would not only act to dilute the specific activity of a
deposited irritant, but would serve to thicken the gel
mucus layer and favour annular-type radial flow of the
mucus layer during the expiratory phase through bronchoconstricted airways (undergoing increased airflow
velocity, secondary to reduced airway diameter).
Animal model studies support stimulation of tracheo210
bronchial gland secretion in response to rapid deflation; an action that is abolished by vagal cooling, vagal
section or anticholinergic treatment [43]. Thus during
expiratory directed airflow (Fig. 20.1) the stimulatory
action on mucociliary clearance may be reflex in nature
and dependent upon cholinergic mechanisms. Support
for this hypothesis arises from a study of stable,
chronic airflow-obstructed patients who had demonstrable increases in mucociliary clearance during voluntary cough manoeuvres. However, pretreatment of
these patients with a cholinergic antagonist that ablated vagal cholinergic efferent innervation of the airway
and reflex responses prevented the cough-related augmentation of mucociliary clearance [44]. Thus during
cough and near-maximal expiratory airflow mucociliary clearance becomes enhanced due to a combination
of factors, i.e. neurally mediated mucus secretion coupled with radial transport of the gel–mucus layer out of
the lung as a result of two-phase gas–liquid interaction
[36,40].
Control of mucociliary clearance in
patients with chronic obstructive
pulmonary disease
The significance of spontaneous cough or its frequency
with regard to the kinetics of mucociliary clearance
within tracheobronchial airways of patients with airflow obstruction is not completely understood [45].
Recently, in patients with chronic spontaneous cough
exposure to isotonic alkaline salt solution that contained bicarbonate ions significantly enhanced airway
mucociliary clearance as assessed with radiomarker
technique [46]. It was hypothesized that replacement
of Cl- by HCO3- facilitated secretion of Cl- into the
airway lumen and promoted hydration of the airway
surface layer that favoured efficiency of cough clearance. Involuntary (spontaneous) cough is essential for
clearance of secretions from the tracheobronchial airways in elderly (over 60 years) patients with obstructive
lung disease [47]. For example, using airway clearance
of an insoluble radiolabelled marker over a 4-h period
as a gauge of lung mucus transport, mucociliary clearance in a small cohort of 16 patients (characterized by
the half-time T50, i.e. time to attain 50% clearance of
the radiolabel) had a mean value of 145 min. Based
upon the T50 index and frequency of spontaneous
cough during the 4-h measurement period the patients
MUCUS SECRETION AND COUGH
were divided into three groupings: (i) six patients had
T50 < 75 min and over the 4 h averaged 23 coughs; (ii)
three patients had T50 > 75 and < 150 min and averaged
13 coughs; and (iii) seven patients had T50 > 150 and
< 300 min and averaged 4 coughs. There were no associations between indices of mechanical lung function of
the patients, i.e. FEV1 or FVC, and the T50 index or the
frequency of cough. These findings suggest that for
elderly patients with obstructive airway disease the
frequency of spontaneous cough is associated with
effective clearance of airway mucus. Thus for patients
with good preservation of their expiratory flow rates,
spontaneous cough is an effective adjunct to mucociliary clearance of mucus from the lung. Submucosal inflammation, a common feature of obstructive airway
disease, is a stimulus for cough [37,48]. Understanding
the linkage in obstructive lung disease between inflammatory cells, mucosal injury, genesis of cough and efficient clearance of airway secretions will require further
study [17,30,44].
Recent epidemiological studies have raised interest
in risk assessment of patients with asthma, chronic
obstructive pulmonary disease (COPD) and cystic
fibrosis, and the presence of airway mucus hypersecretion is now considered to be a risk factor for increased
morbidity. In general, hypersecretion of mucus within
stem bronchi is usually related to cough and sputum;
whereas inflammation and excess mucus discharge in
the distal peripheral airway contribute to airflow obstruction and, as shown by morphological examination of airways (excised or postmortem), correlate with
in vivo tests of small airways function [49,50]. Particularly for COPD patients, chronic hypersecretion of
mucus is a major manifestation of their disease; however, its role in the development of chronic airflow obstruction is unclear. Peto and coauthors suggested that
among males with similar initial airflow obstruction,
age-specific COPD death rates were not significantly
related to initial mucus hypersecretion, and supported
the concept that airflow obstruction and mucus hypersecretion are largely independent disease processes
[51]. However, recent support for a role of mucus
hypersecretion in the development of chronic airflow
limitation was documented by the Copenhagen City
Heart Study [52], an 11-year follow-up study of over
12 000 men and women, that found chronic sputum
production to be associated with both an excessive
FEV1 decline and an increased risk of hospitalization
due to COPD.
Guided by clinical and therapeutic interests, mucociliary clearance has often been studied mechanistically in respiratory disease states (chronic bronchitis,
COPD) to determine whether mucus hypersecretion is
indeed correlated to indices of lung function, i.e. delays
in clearance and thickening of the liquid lining layer
contribute to airflow dysfunction. An examination of
extremes (little or no functional impairment vs. severely obstructed) in these disease states provides insight for the hypothesis that hyperproduction of mucus
is associated with airflow limitation. For example,
asymptomatic bronchitis patients with short smoking
histories and functional values in the predicted normal
range for FEV1 and peak expiratory flow have been
shown to have normal values of mucus transport velocity within central airways (trachea and stem bronchi);
and it was the peripheral bronchi that were first observed to exhibit delays and non-continuous clearance
of airway mucus [53]. This peripheral abnormality in
mucus transport was reversible with b2-adrenergic
therapy, but its presence is consistent with epithelial remodelling, changes in mucosal permeability and inflammatory cellular infiltrates, the triad of abnormal
pathology commonly found in the lung periphery and
respiratory bronchioles of young smokers [54]. By contrast, in patients with advanced airway obstruction, i.e.
diagnosis of COPD, and severely reduced expiratory
flow rates, delays in mucociliary clearance of airway secretions are predominantly found within airways of
central lobar and stem bronchi. For example (Fig.
20.2), Smaldone and coauthors [55] using regional
lung analysis techniques found that patients with
chronic airflow obstruction and flow limitation, i.e.
collapse of major bronchi during the expiratory phase
of a tidal exhalation, exhibited significant slowing of
mucus clearance within central airways. The patients
were compared with normal subjects without airway
obstruction and sufficient expiratory flow reserve, i.e.
capable of increasing expiratory flow rates during tidal
breathing. Mucociliary clearance was also significantly
reduced in the peripheral airways of the patients (Fig.
20.2), although not so impaired as within the central
airway. Although the flow-limited (expiratory) patients
coughed at random during the clearance measures, due
to their severe flow-limitation and low expiratory flow
rates, cough likely would have been an ineffective adjunct to the mucociliary clearance process. Thus these
patients exhibited a pattern of mucus stasis in the lung
that was opposite to the normal situation: central air211
CHAPTER 20
Particle retention (fraction deposited)
(a) Central airways
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Flow-limited (n = 10)
Normal (n = 9)
0
20
40
60
80
100
120
(b) Peripheral airways
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Flow-limited (n = 10)
Normal (n = 9)
0
20
40
60
80
100
120
Time (min)
Fig. 20.2 Regional mucociliary clearance in the lung. Average central (a) and peripheral (b) lung clearance of insoluble
radiolabelled marker in healthy subjects and expiratory airflow-limited COPD patients. Number of subjects studied as
indicated and data represent mean and error bars as ± SEM.
Lung regions located by radio-gas ventilation scan and
divided into central (inner, 30% of total region and centred
over large central airways) and peripheral (outer, remaining
70% of total region) airways. Time zero was at the time point
immediately following inhalation and deposition of the
radiomarker.
ways, that in the healthy airway clear most rapidly and
are assisted by cough and two-phase gas–liquid transport, became rate-limiting. Previous investigations
[56,57] have shown reduced whole-lung clearance in
COPD; however, these studies did not try to assess
whether clearance deficiencies were of a global or a regional nature. In COPD, which diffusely affects lung
parenchyma and airways, there is no reason to suspect
a priori that a rate-limiting clearance defect would
be located in central bronchi. Thus the results of the
212
Smaldone report, disproportionate reduction of mucus
clearance centrally in the lung, certainly support speculation that the prolonged retention and thickening of
the mucus layer may reduce airway diameter and contribute to the mechanical effects causing airflow obstruction as suggested by the Copenhagen City Heart
Study [52]. These findings do not imply that clearance
abnormalities are confined to central airways in
COPD, as significant evidence of peripheral impairment was also apparent (Fig. 20.2). However, the
changes in the periphery were small as compared with
the marked slowing found centrally where the effects of
ineffective cough may be superimposed on a generalized increase in synthesis and release of mucin proteins
onto the airway surface [17].
Therefore in the healthy airway, lung inflation/deflation reflexes, and perhaps shearing forces at the airway
surface during airflow at high velocity, are significant
stimuli for enhancing mucociliary clearance [8,42].
However, in the early stages of smoke-related airway
pathology and mucus hypersecretion in which epithelial remodelling is extended over time, deficiencies in
the mucociliary clearance system seem to predominate
at least initially in the smaller peripheral airways [53].
If there is preservation of expiratory airflow rates
then even with continued exposure to environmental
irritants and cigarette smoke, mucociliary clearance remains effective when assisted by cough and two-phase,
gas–liquid interactions [47,58]. However, for patients
with advanced airway obstruction and incapable of
generating forceful expiratory flows, i.e. expiratory
flow limitation, cough is ineffective and mucociliary
clearance is now disparate with markedly slowed
mucus layer transport within central airways [55]. For
irritant-induced mucus hypersecretion and the later
stages of progressive airway obstruction, improving
clearance of airway secretions may largely depend
upon mucoactive and mucolytic therapies designed to
limit viscous airway secretions, increase cough clearance, and improve ventilation [46,59,60].
Control of mucociliary clearance
in asthma
In bronchial asthma the mucous glands are distributed
throughout the cartilaginous airways as they are in
the normal lung, but also may extend into peripheral
bronchioles where normally they are absent. Hypertro-
MUCUS SECRETION AND COUGH
subjects (severity characterized by FEV1). Based upon
airway epithelial biopsy of mainstem bronchi the
epithelial mucin stores were increased in mild and
moderate asthma and this increase was attributable to
goblet cell hyperplasia (not hypertrophy). Induced sputum collected in the patients suggested that secreted
mucin was increased only in the moderate asthmatics
[65]. An interesting observation in the diathesis of asthma is the finding of a broad range of airway mucociliary
clearance rates. Thus, for example, in severe asthma
(mean FEV1 < 50% of FVC) mucus clearance velocities
in central airways are markedly reduced as compared
to non-asthma subjects; and the patients (Fig. 20.3) in
fact only exhibit measurable velocities of mucus transport within mainstem bronchi and tracheal airways
when stimulated by a b-adrenergic agonist [66]. A corresponding increase in whole-lung clearance was also
observed in the patients following b-adrenergic aerosol
treatment, e.g. on average 53% of the mucus marker
was removed with treatment as compared with 22% on
a control day without treatment. This represented a
1.5-fold increase in lung mucus clearance and transport
of the airway mucus layer was now comparable with
lung clearance observed in unstimulated healthy subjects [53,66]. However, rapid rates of lung mucociliary
clearance have been observed in stable asthma patients
with mild to moderate airflow obstruction (mean
FEV1 of 66% FVC) in which over 40% of the airway
mucus marker was cleared within the initial 30 min of
assessment and on average 60% cleared after a 1-h
time period [67]. These supranormal rates of airway
mucus clearance in mild to moderate asthmatics are
consistent with observations by other laboratories for
0
Trachea
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to
l
bD
ro
nt
Co
b-
D
ila
to
l
ro
nt
Co
ila
to
D
b-
nt
ro
Bronchus
Bronchus
to
0
ila
2
D
2
l
4
b-
4
ro
6
nt
6
Co
8
r
8
r
10
l
10
r
(b) Patients
r
(a) Normal subjects
12
Co
Fig. 20.3 Bronchial and tracheal mucus
transport velocity. (a) Healthy subjects;
(b) asthma patients. Individual values
and means ± SEM of these values are
shown for control (䊉) velocities and
after b-adrenergic aerosol stimulation:
isoproterenol (䊏), or isoetharine (䉱).
Increases in velocity were significant
compared with control tracheal and
bronchial mucus velocities; P < 0.01).
Transport velocity (mm/min)
phy of the submucosal gland mass is thought to
contribute to the presence of excessive mucus production found in fatal asthma. Frequently on pathological examination, there is dilatation of the secretory
ducts leading from the submucosal glands into the
bronchial airway lumen. An increase in the number of
epithelial goblet cells also contributes to the excess of
secretions within the airway in severe asthma [61] and
the excessive secretions present in the larger bronchi
may overwhelm the normal clearance mechanisms
and undergo retrograde flow and/or aspiration into
smaller airways. When mucus secretions are in excess,
as in status asthmaticus, mucus plugs may extend from
the larger second-generation bronchi into the smaller
bronchioles [62].
Marked pathophysiological changes in mucociliary
transport in bronchial asthma have been observed.
Mucociliary transport has been found to be depressed
in experimental as well as human asthma; during acute
antigen challenge, a further reduction in mucociliary
transport is observed. The abnormal mucociliary transport may contribute to physiological abnormalities in
airways function. Cough and residual airways dysfunction found to be present in asthma patients in remission
is partly related to the presence of excessive mucus in
the peripheral airway. This is usually easily observed in
scintigraphy studies of asthma patients by inhomogeneities of radioaerosol deposition in the larger
bronchi and with poor penetration of micron-sized
aerosol into the peripheral airway [63,64].
Fahy and coauthors [14] have recently addressed the
question of whether excessive mucus is an important
cause of morbidity in moderate and mild asthmatic
Trachea
213
CHAPTER 20
non-symptomatic patients at the time of their mucus
clearance evaluation [68,69]. Although in mild asthma
lung mucus clearance can become impaired and be severely compromised during a period of acute exacerbation that requires hospitalization, after recovery and
hospital discharge, a repeat evaluation of lung mucociliary clearance demonstrated remarkable improvement
[70] although at recovery it is difficult to separate out
influences of rescue medications and therapeutic (badrenergics, theophylline, corticosteroids) intervention on mucus clearance. The patients voluntarily
resisted coughing during the assessment periods, so
clearly physical adjuncts to therapy were not responsible for the return of normal clearance at recovery.
Therapeutic approaches [71] to prevent exacerbation
in bronchial asthma are based on long-term control
medications and include corticosteroids, sodium cromoglycate and nedocromil sodium, long-acting b2
adrenoceptor agonists and methylxanthines, all of
which enhance the efficiency of mucociliary function
[72]. As new information becomes available on mechanisms of goblet cell synthesis and release of mucin
granules [15] novel strategies are expected to evolve
to limit factors related to secretion, i.e. inflammatory
cells such as neutrophils [17], or inhibit growth receptors [73] located on epithelial cells and that are key to
secretory cell metaplasia and secretagogue activity.
a powerful adjunct to mucociliary activity for clearance
of airway secretions.
3 In hypersecretory airway disease like bronchitis, tracheal mucus velocities are normal but mucus layer
transport is deficient within the peripheral airways. In
severe stages of COPD, mucus clearance is preferentially impaired within central dependent bronchi. Cough is
an effective adjunct for clearance of secretions when
high velocities of expiratory airflow are preserved and
gas flow and airway liquid interaction favours cough
clearance of secretions.
4 In bronchial asthma, severity of disease in large
measure determines whether airway clearance of secretions is: (i) supranormal; (ii) capable of therapeutic
up-regulation; or (iii) ineffective during states of exacerbation and hypersecretion of mucus.
5 As new information develops on control mechanisms for mucin synthesis and mucin granule release,
therapeutic measures likewise are expected to evolve to
fortify mucociliary clearance and ameliorate mucus
hypersecretion.
Acknowledgements
Preparation of this chapter was supported in part by
awards from National Heart Lung and Blood Institute:
HL-62641 and HL-68072 (Washington, DC, USA).
References
Conclusions
1 The airway surface of the lower respiratory tract is
largely protected by a liquid lining layer composed of
a periciliary phase, adjacent to the luminal surface of
the epithelial lining cells, and a gel phase superimposed
on top. The thickness of this layer depends on transepithelial secretion of Cl- across the epithelial lining cells
with passive diffusion of water, steady-state and stimulated mucin secretion, and overall stability in the numbers of mucus-secreting epithelial cells.
2 Effective transport of the gel phase to the larynx
limits residence time, and removes secretions and
xenobiotic materials from the epithelial surface. Transport results from coordinated ciliary activity of the
epithelial lining cells. Lung inflation/deflation reflexes
and shearing forces at the airway surface during highvelocity airflow, i.e. cough, are stimulatory factors for
increasing mucociliary clearance. Thus in health and
airway disease, spontaneous and/or voluntary cough is
214
1 Kaliner M, Shelhamer JH, Borson B et al. Human respiratory mucus. Am Rev Respir Dis 1986; 134: 612–21.
2 Robinson NP, Kyle H, Webber SE et al. Electrolyte
and other chemical concentrations in tracheal airway
surface liquid and mucus. J Appl Physiol 1989; 66:
2129–35.
3 Knowles M, Gatzy J, Boucher R. Ion composition of airway surface liquid of patients with cystic fibrosis as compared to normal and disease-control subjects. J Clin Invest
1997; 100: 2588–95.
4 Widdicombe J. Airway and alveolar permeability and surface liquid thickness: theory. J Appl Physiol 1997;82:3–12.
5 Matsui H, Randell SH, Peretti SW et al. Coordinated
clearance of periciliary liquid and mucus from airway surface. J Clin Invest 1998; 102: 1125–31.
6 Wolff RK. Mucociliary clearance. In: Parent RA, ed. Comparative Biology of the Normal Lung. Boca Raton, FL:
CRC Press, 1992: 659–80.
7 Foster WM, Langenback EG, Bergofsky EH. Measurement of tracheal and bronchial mucus velocities in man:
MUCUS SECRETION AND COUGH
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
relation to lung clearance. J Appl Physiol 1980; 48:
965–71.
Bennett WD, Foster WM, Chapman WF. Coughenhanced mucus clearance in the normal lung. J Appl
Physiol 1990; 69: 1670–5.
Groth ML, Macri K, Foster WM. Cough and mucociliary
transport of airway particulate in chronic obstructive lung
disease. Ann Occup Hyg 1997: 41 (S): 515–21.
Reid L. Measurement of the bronchial mucous gland layer
a diagnostic yardstick in chronic bronchitis. Thorax 1960;
15: 132–41.
Toremalm NG. The daily amount of tracheo-bronchial
secretions in man. Acta Otolaryngol 1960: 158 (S):43–53.
Jacquot J, Hayem A, Galabert C. Functions of proteins
and lipids in airway secretions. Eur Respir J 1992; 5:
343–58.
Rose MC, Gendler SJ. Airway mucin genes and gene
products. In: Rogers DF, Lethem DI, eds. Airway Mucus:
Basic Mechanisms and Clinical Perspectives. Boston:
Birkhauser-Verlag, 1997: 41–66.
Fahy JV. Airway mucus and mucociliary system. In:
Middleton E, Reed CE, Busse WW, eds. Allergy Principles
and Practice. St Louis, MO: CV Mosby, 1998: 520–31.
Li Y, Martin LD, Spizz G et al. MARCKS protein is a key
molecule regulating mucin secretion in human airway
epithelial cells in vitro. J Biol Chem 2001; 276: 40982–90.
Rogers DF. Airway goblet cell: responsive and adaptable
front-line defenders. Eur Respir J 1994; 7: 1690–706.
Nadel JA. Role of neutrophil elastase in hypersecretion
during COPD exacerbations, and proposed therapies.
Chest 2000; 117: 386S–89S.
Costa DL, Schelegle ES. Inhaled air pollutants. In: Swift
DH, Foster WM, eds. Air Pollutants and the Respiratory
Tract. New York: Marcel Dekker, 1999: 119–45.
King M, Kelly S, Cosio M. Alteration of airway reactivity
by mucus. Respir Physiol 1985; 62: 47–59.
Kim CS, Eldridge MA, Wanner A. Airway responsiveness
to inhaled and intravenous carbachol in sheep: effect of
airway mucus. J Appl Physiol 1988; 65: 2744–51.
Last JA. Mucus production and the ciliary escalator. In:
Witschi H, Nettersheim P, eds. Mechanisms in Respiratory
Toxicology, Vol. 1. Boca Raton, FL: CRC Press, 1982:
247–60.
Laitinen A. Ultrastructural organization of intraepithelial
nerves in human airway tract. Thorax 1985; 40: 488–92.
Barnes PJ, Nadel JA, Roberts JM, Basbaum CB.
Muscarinic receptors in lung and trachea: autoradiographic localization using quinuclidinyl benzilate. Eur J
Pharmacol 1983; 86: 103–6.
Basbaum CB, Barnes PJ, Grillo M et al. Adrenergic and
cholinergic receptors in submucosal glands in ferret
trachea: autoradiographic localization. Eur J Respir Dis
1983; 64: 433–5.
25 Basbaum CB, Grillo M, Widdicombe JH. Muscarinic
receptors: evidence for a non-uniform distribution in
tracheal smooth muscle and exocrine glands. J Neurol Sci
1984; 4: 508–20.
26 Barnes PJ, Basbaum CB. Mapping of adrenergic receptors
in mammalian trachea using an autoradiographic
method. Exp Lung Res 1983; 5: 183–92.
27 Kelsen SG, Mardini IA, Zhou S et al. A technique to harvest viable tracheo-bronchial epithelial cells from living
human donors. Am J Respir Cell Mol Biol 1992; 67:
66–72.
28 Carstairs JR, Barnes PJ. Visualization of vasoactive intestinal peptide receptors in human and guinea-pig lung.
J Pharmacol Exp Ther 1986; 239: 240–55.
29 Basbaum C. Innervation of the airway mucosa and submucosa. Semin Respir Med 1995; 308: 313.
30 Lucchini RE, Facchini F, Turato G et al. Increased VIPpositive nerve fibers in the mucous glands of subjects with
chronic bronchitis. Am J Respir Crit Care Med 1997; 156:
1963–8.
31 Barnes PJ, Barianuk JN, Belvisi MG. Neuropeptides in the
respiratory tract. I. State of art. Am Rev Respir Dis 1991;
144: 1187–98.
32 Groth ML, Langenback EG, Foster WM. Influence of
inhaled atropine on lung mucociliary function in humans.
Am Rev Respir Dis 1992; 145: 215–9.
33 Foster WM, Bergofsky EH, Bohning D et al. Effect of
adrenergic agents and their mode of action on mucociliary
clearance. J Appl Physiol 1876; 41: 146–52.
34 Camner P, Strandberg K, Philipson K. Increased mucociliary transport by cholinergic stimulation. Arch Environ
Health 1974; 29: 220–4.
35 Mussato DJ, Garrard CS, Lourenco RV. The effect of
inhaled histamine on human tracheal mucus velocity
and bronchial mucociliary clearance. Am Rev Respir Dis
1988; 138: 775–9.
36 Clarke SW, Jones JG, Oliver DR. Resistance to two-phase
gas-liquid flow in airways. J Appl Physiol 1970; 29:
464–71.
37 Banner AS. Cough: physiology, evaluation, and treatment.
Lung 1986; 164: 79–92.
38 Camner P, Mossberg M, Philipson K et al. Elimination of
test particles from the human tracheobronchial tract
by voluntary coughing. Scand J Respir Dis 1979; 60:
56–62.
39 Yeates D, Aspin N, Levinson H et al. Mucociliary tracheal
transport rates in man. J Appl Physiol 1975; 39: 47–95.
40 Scherer P, Burtz L. Fluid mechanical experiments relevant
to coughing. J Biomech 1978; 11: 183–7.
41 Wolff RK, Dolovich MB, Obminski G, Newhouse MT.
Effects of exercise and eucapnic hyperventilation on
bronchial clearance in man. J Appl Physiol 1977;43:
46–50.
215
CHAPTER 20
42 Widdicombe JG. Neurophysiology of the cough reflex.
Eur Respir J 1995; 8: 1193–202.
43 Yu J, Schultz HD, Goodman JC, Coleridge JCG, Coleridge
HM, Davis B. Pulmonary rapidly adapting receptors
reflexly increase airway secretion in dogs. J Appl Physiol
1989; 67: 682–7.
44 Bennett WD, Chapman WF, Mascarella JM. The acute
effect of ipratropium bromide bronchodilator therapy on
cough clearance in COPD. Chest 1993; 103: 488–95.
45 Irwin RS, Curley FJ, French CL. Chronic cough: spectrum
and frequency of causes, key components of the diagnostic
evaluation, and outcome of specific therapy. Am Rev
Respir Dis 1990; 141: 640–7.
46 Haidl P, Schonhofer B, Kohler D. Inhaled isotonic alkaline
versus saline solution and radioaerosol clearance in
chronic cough. Eur Respir J 2000; 16: 1102–8.
47 Groth ML, Macri K, Foster WM. Cough and mucociliary
transport of airway particulate in chronic obstructive lung
disease. Ann Occup Hyg 1997; 41(S1): 515–21.
48 Linden M, Ramussen JB, Piitulainen E et al. Airway inflammation in smokers with nonobstructive and obstructive
chronic bronchitis. Am Rev Resp Dis 1993; 148: 1226–32.
49 Wright JL, Lawson LM, Pare PD et al. The detection of
small airways disease. Am Rev Respir Dis 1984;129:
989–94.
50 Peto R, Speizer FE, Cochrane AL et al. The relevance in
adults of air-flow obstruction, but not of mucus hypersecretion, to mortality from chronic lung disease. Am Rev
Respir Dis 1983; 128: 491–500.
51 Cosio M, Ghezo H, Hogg JC et al. The relationship between structural changes in small airways and pulmonary
function tests. N Engl J Med 1978; 298: 1277–81.
52 Vestbo J, Prescott E, Lange P. Copenhagen City Heart
Study Group. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive disease
mortality. Am J Respir Crit Care Med 1996; 153: 1530–5.
53 Foster WM, Langenback EG, Bergofsky EH. Disassociation of mucociliary function in central and peripheral airways of asymptomatic smokers. Am Rev Respir Dis 1985;
132: 633–9.
54 Niewoehner DE, Kleinerman J, Rice DB. Pathologic
changes in the peripheral airways of young cigarette
smokers. N Engl J Med 1974; 153: 629–32.
55 Smaldone GC, Foster WM, O’Riordan TG et al. Regional
impairment of mucociliary clearance in chronic obstructive pulmonary disease. Chest 1993; 103: 1390–6.
56 Camner P, Mossberg B, Philipson K. Tracheobronchial
clearance and chronic obstructive lung disease. Scand J
Respir Dis 1978; 54: 272–81.
57 Mossberg B, Strandberg K, Philipson K et al. Tracheobronchial clearance and beta agonist stimulation in
patients with chronic bronchitis. Scand J Respir Dis
1976; 57: 281–9.
58 Puchele E, Zahm JM, Girard F et al. Mucociliary transport
216
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
in vivo and in vitro: relations to sputum properties in
chronic bronchitis. Eur J Respir Dis 1980; 61: 254–64.
Ziment I. Help for an overtaxed mucociliary system:
managing abnormal mucus. J Respir Dis 1991; 12: 21–33.
Poole PJ, Black PN. Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review. Br Med J 2001; 322: 1271–83.
Shimure S, Andoh Y, Haraguchi M et al. Continuity of airway goblet cells and intraluminal mucus in the airways of
patients with bronchial asthma. Eur Respir J 1996; 9:
1395–401.
Sheehan JK, Richardson PS, Fung DC et al. Analysis of respiratory mucus glycoproteins in asthma: a detailed study
from a patient who died in status asthmaticus. Am J Respir
Cell Mol Biol 1995; 13: 748–56.
Chopra SK, Taplin GV, Tashkin DP et al. Imaging sites of
airway obstruction and measuring functional responses
to bronchodilator treatment in asthma. Thorax 1979; 34:
493–500.
Agnew JE, Bateman JRM, Pavia D et al. Radionuclide
demonstration of ventilatory abnormalities in mild
asthma. Clin Sci 1984; 66: 525–31.
Ordonez CL, Khashayar R, Wong HH et al. Mild and
moderate asthma is associated with airway goblet cell
hyperplasia and abnormalities in mucin gene expression.
Am J Respir Crit Care Med 2001; 163: 517–23.
Foster WM, Bergofsky EH. Airway mucus membrane: effects of beta-adrenergic and anticholinergic stimulations.
Am J Med 1986; 81 (S5A): 28–35.
Groth ML, Ackner V, Foster WM. Targeting of therapeutic aerosols in asthma: is poor penetration of aerosols associated with mucociliary dysfunction in central airways?
Am Rev Respir Dis 1991; 143: A634.
Mussato DJ, Chakravarthy VS, Masssey VJ et al. Computer generated scintigraphy and mucociliary clearance in
healthy and asthmatic patients. Am Rev Respir Dis 1989;
139: A142.
O’Riordan TG, Zwang J, Smaldone GC. Mucociliary
clearance in adult asthma. Am Rev Respir Dis 1992; 146:
598–603.
Messina MS, O’Riordan TG, Smaldone GC. Changes in
mucociliary clearance during acute exacerbations of
asthma. Am Rev Respir Dis 1991; 143: 993–7.
Bousquet J, Jeffery PK, Busse WW et al. State of the art:
asthma from bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 2000;
161: 1720–45.
Wanner A, Salathe M, O’Riordan TG. State of the art: mucociliary clearance in the airways. Am J Respir Crit Care
Med 1996; 154: 1868–902.
Takeyama K, Fahy JV, Nadel JA. Relationship of epidermal growth factor receptors to goblet cell production in
human bronchi. Am J Respir Crit Care Med 2001; 163:
511–6.
21
Animal models of cough
Maria G. Belvisi & David J. Hele
Introduction
Physiology
The ultimate goal of an animal model is to provide
a system to elucidate mechanisms and test putative
drug candidates. The model needs to accurately reflect
the disease in humans as closely as is possible. If treatments are available for the disease in humans then
demonstrable activity of these treatments in the animal
model of choice greatly enhances the credibility of
that model.
Cough, a reflex defence mechanism, is an extremely
common symptom of many inflammatory diseases of
the airways such as asthma and chronic obstructive
pulmonary disease [1]. At present there are no satisfactory treatments for acute cough as was outlined in a
recent review [2] where over-the-counter (OTC) cough
medicines were assessed. It was concluded that the currently available medicines could not be recommended,
as there was no good evidence for their effectiveness.
It is therefore essential to develop animal models
of cough, models that reflect the disease in humans. A
reliable, robust and reproducible model of cough is
essential to profile, and establish the efficacy of, novel
antitussive therapies under development prior to testing in humans. The chosen model should also allow the
study of the physiology of cough and the mechanisms
and mediators that lead to cough or the exacerbation of
cough.
Therefore a requirement of the animal of choice for
the model is that the physiology should resemble as
closely as possible that of humans, which in models
used to study the cough reflex means not only the structure of the lungs but also the innervation of the trachea,
bronchi and intrapulmonary airways.
The cough reflex can be evoked by mechanical or
chemical stimuli or by changes in ion concentration or
osmolarity in the local mucosal surface. The reflex
composes three parts, the afferent system, which senses
the cough-inducing stimulus, the central nervous
system (CNS), which in turn stimulates the efferent
system that produces the cough [3]. Interference with
the afferent signal is thought to provide the best opportunity for pharmacological intervention as the cough
centre in the brain has not yet been clearly identified
and may be diffuse. Interference with the efferent signal
may affect many other processes, i.e. the gut and
cardiovascular system. The afferent nerves that are
thought to play an important role in the cough reflex
are the myelinated Ad-fibres (also known as rapidly
adapting stretch receptors, RARs) and the nonmyelinated C-fibres.
Model development
Species
In an attempt to accurately reflect the disease in humans
several different species have been used to provide a
variety of models of cough. Most preclinical studies
of neural pathways involved in the cough reflex and
the pharmacological regulation of those pathways
have been conducted in mice, rats, guinea-pigs, rabbits,
cats and dogs [4], and more recently in conscious
pigs [5].
In rodents the cough reflex is difficult to study in
217
CHAPTER 21
anaesthetized animals as anaesthesia suppresses
neuronal conduction and activity in the CNS. However, several investigators have used a conscious rat
model of cough to study the effect of potential antitussive therapies. Although many studies have been performed in conscious rats, and cough sounds recorded
[6], there is much scepticism regarding the ability of
these animals to produce a cough that resembles the reflex seen in humans. In fact, it is thought that if cough
can be elicited in rats it would appear that the main reflexogenic origin of the cough is the larynx rather than
the tracheobronchial tree. Indeed, expulsive events
originating from the larynx can include expiration reflexes, which are difficult to differentiate from cough.
Furthermore, the two reflexes are regulated differently
[7]. Other studies have described a murine model of
cough [8] but again there are certain reservations regarding the use of this model given that mice do not
have RARs (rapidly adapting receptors conducting in
the Ad range, the nerves traditionally believed, along
with C-fibre afferents, to play an important role in the
cough reflex) and have been found to be lacking in intraepithelial nerve endings and thus are thought to be
without a cough reflex [8]. It has also been shown that
mice cannot cough, as they cannot generate the energy
needed to cough. It is therefore probable that investigators using the model are measuring an expiration reflex
rather than a true cough.
The use of large animals such as cats, dogs and pigs
involves a cost element, not only in their purchase price
but also in the cost of feeding and housing and in the
cost of producing large quantities of drug substance for
screening purposes. Although the use of these animals
is thus precluded for routine screening they may be of
value for tertiary screening of a compound selected for
development, and the cat, for example, has played a
useful role in determining the physiology and mechanisms involved in the cough response.
The most useful and commonly used model for
cough studies in recent years has been the conscious
guinea-pig [9,10]. Much information has now been
gathered in this model regarding the pharmacological
modulation of the cough reflex. Various tussive stimuli
have been examined, with the most commonly used
being inhaled citric acid or capsaicin. In these experiments cough can be detected by putting the guineapig in a transparent perspex chamber, exposing it to
aerosols of tussive stimuli and measuring changes in
airflow, observing the characteristic posture of an
218
animal about to cough and recording the cough sound
[11–14]. This method is described in detail below.
Conscious vs. anaesthetized animals
As mentioned earlier, in rodents the cough reflex is difficult to study in anaesthetized animals as anaesthesia
suppresses neuronal conduction and activity in the
CNS. In some species (non-rodent), a suitable depth of
anaesthesia, with respiratory reflexes being essentially
intact, can be obtained and a tussive response easily
measured [4]. An example of this is the anaesthetized
cat, which has been utilized to analyse both the central
effects of antitussives administered intracerebroventricularly [15] and the peripheral effects of compounds
administered intravenously [16]. In these experiments
cough in response to mechanical and chemical stimuli is
characterized by a deep inspiration followed by an active expiratory effort. In other experiments cough has
been defined in anaesthetized animals as a large burst of
electromyogram activity in the diaphragm immediately
followed by a burst of activity in the rectus abdominis
muscle [17]. Interestingly, data recently presented by
Canning et al. (unpublished) demonstrated that capsaicin and bradykinin (C-fibre stimulants) are totally
ineffective at initiating and may actually inhibit the
cough reflex in anaesthetized guinea-pigs even though
the cough reflex initiated by mechanical stimuli (largely
RAR selective) is entirely preserved in the anaesthetized
state. However, these chemical agents do elicit a cough
reflex in conscious guinea-pigs. These data illustrate
the importance of accumulating evidence from different experimental settings before making firm conclusions with regard to the influence of certain fibre types
and their role in respiratory reflexes. Furthermore, even
if cough can be readily elicited in a given preparation,
the work by Canning et al. supports the concept that
the physiological state of the animal (i.e. anaesthetized
or awake) may alter how this defensive reflex is regulated. This further suggests that perhaps anaesthesia is
best avoided when studying the cough reflex in animal
models.
Tussive stimuli
The cough reflex can be elicited by electrical, mechanical (in anaesthetized animals) or chemical stimulation,
as well as by changes in ion concentration or osmolarity in the mucosal surface fluid, or of sensory afferents
ANIMAL MODELS OF COUGH
(in the larynx, trachea or bronchial mucosa), or by
stimulation of the CNS. More recent studies have utilized the irritant capsaicin and low pH solutions (e.g.
citric acid) to study the cough response. Citric acid
confers the advantage of allowing repeated cough
measurements without the occurrence of tachyphilaxis
whereas repeated exposure to capsaicin is known to result in tachyphilaxis thus preventing the production of
a reproducible cough response in the same animal [18].
Different methods of stimulation may involve different populations of sensory afferent and there has been
much discussion in the literature regarding the selectivity of agents for different fibre types, e.g. the use of capsaicin as a selective C-fibre stimulant [12,19].
Different airway levels and the sensitivity
of the cough reflex
The density and type of sensory nerves present at each
airway level determines the sensitivity to tussive
stimuli. The larynx of most species including cat, dog,
guinea-pig and humans is particularly sensitive to mechanical stimulation and even the most gentle pressure
in this region leads to strong expiratory efforts. In the
dog both chemical and mechanical irritation are more
potent tussive stimuli in the tracheobronchial tree than
in the larynx, and C-fibre stimulants such as bradykinin
and capsaicin have little effect when applied to the
larynx which would be consistent with the sparse Cfibre innervation to the canine larynx. Furthermore, the
cat intrapulmonary bronchi are much more sensitive to
chemical irritation and less sensitive to mechanical
stimulation than the larynx or trachea. Interestingly,
studies have been performed in human subjects, which
are in agreement with the studies performed in animal
models in that the tracheobronchial tree is more sensitive to chemical stimuli than the laryngeal region [20].
The guinea-pig model of cough
Similarity to the human cough reflex
As stated above, many different species have been used
to study the cough reflex, in both the anaesthetized and
the conscious state. The electrophysiological and mechanical characteristics of the cough reflex appear to be
conserved across species. The current animal of choice
for studying pharmacological intervention in the cough
reflex is the guinea-pig. This animal has been utilized
extensively, with cough being induced in conscious
animals by inhalation of aerosols of either capsaicin or
low pH solutions such as citric acid [11,14,21–23].
One caveat to the use of guinea-pigs is that they need to
be pretreated with a b-adrenoceptor agonist to suppress bronchoconstriction to ensure that only the
cough reflex is being studied. With this exception the
guinea-pig provides a good model of the human cough
reflex and this has been confirmed by a study showing
the similarity in response to both citric acid and capsaicin in humans and guinea-pig [21]. Furthermore, recent in vitro data suggest that the isolated guinea-pig
vagus nerve depolarizes in response to tussive stimuli
in a similar manner to the human isolated vagus [24],
again providing evidence in favour of using the guineapig cough model.
Experimental design
Male or female guinea-pigs have been used. Animals
should be housed under controlled conditions with frequent changes of bedding as the build-up of ammonia
in cages has been shown to influence the cough response to citric acid [25]. Belvisi et al. (unpublished
data) have shown that the cough response to a given
stimuli varies greatly from guinea-pig to guinea-pig but
that repeated assessments within the same animal are
fairly reproducible. Therefore animals should be prescreened to assess their level of response to the stimuli
of choice before being treated with test or standard
compound. The same authors have not found it necessary to precondition guinea-pigs to accept aerosol exposure in the challenging box.
The assessment should take the form of a prescreening exercise, i.e. exposure to cough stimulus for 10 min,
to establish the basal cough rate (expressed as number
of coughs/min) for each individual animal to be used
in a study. The entire group of animals should then be
ranked by cough response and the non-responders excluded. The remaining animals should be blocked into
high, medium and low responders and randomly assigned to groups from each block to ensure a spread
of high, medium and low responders across the treatment groups. This process allows each animal to be
compared with its own control (prescreening) level by
paired analysis as well as allowing meaningful comparisons between treated groups at the post-treatment
cough screening stage.
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CHAPTER 21
Once the prescreening is complete, animals should
be ‘rested’ for at least 72 h before being re-exposed
to the cough stimulant. Prior to the second exposure,
treatment with test compound or compounds can be
performed at a time and by a route determined by the
pharmacokinetic profile (if available) of the compound
or compounds under scrutiny. The most commonly
used routes of administration in this model are oral,
aerosol inhalation, intraperitoneal or subcutaneous.
The intravenous route may be employed via the marginal ear vein but this route is not without difficulty.
The aim should be to give test substances by a route that
causes the least stress to the animal as any undue stress
may affect the response to the cough stimuli.
Methodology
The procedure for measuring cough in conscious
guinea-pigs has been described and modified by several
authors [9,12–14,21].
The protocol currently in common use involves predosing the guinea-pig with terbutaline (0.05 mg/kg i.p.)
3 min prior to exposure to cough stimuli to inhibit
bronchoconstriction and facilitate cough detection
[14]. The guinea-pig is then placed in a small perspex
box (approximately 1 L in volume) that allows free
movement during exposure to aerosols. Airflow
through the box is provided by compressed medical air
via a flow regulator at 600 mL/min with changes in airflow induced by respiration and coughing detected by
a pneumotachograph, amplified via a pressure transducer and recorded on a chart recorder (see Fig. 21.1).
Cough sounds are amplified and recorded via a microphone sited in the cough chamber and recorded concurrently on the chart recorder (see Fig. 21.2). Tussive
agents (capsaicin, citric acid, etc.) are delivered by
aerosol using an ultrasonic nebulizer with an output of
0.4 mL/min and delivering a median particle diameter
of 0.9 μm connected to the airflow port. The animal
is exposed for a defined period, usually 10 min. A
dose–response curve to the chosen stimuli should be
constructed and a submaximal dose chosen for further
studies.
Coughs are assessed and counted by a trained ob-
Transducer
Flow
regulator
Nebulizer
Compressed
air supply
Chart recorder
Microphone
Challenging chamber
Tape recorder
Exhaust
Fig. 21.1 Experimental set-up for the evaluation of the cough response to aerosolized tussive stimuli in the conscious unrestrained guinea-pig.
220
ANIMAL MODELS OF COUGH
Pressure
Non-cough
Sound
Fig. 21.2 A representative trace showing
both airflow and sound recordings of the
guinea-pig cough response over a 10-min
period.
server using three different methods to ensure that only
coughs are counted and that sneezes and augmented
breaths are excluded. The three methods are as follows:
1 by observation, by an observer trained to differentiate between coughs and sneezes and to recognize the
changes in posture (splaying of the front feet and forward stretching of the neck) and the characteristic
opening of the mouth associated with cough (see
Fig. 21.3);
2 by pressure changes, showing as full- or near fullscale deflections in both directions on the chart
recorder (see Fig. 21.2), reflecting the deep inspiration
and explosive expiration occurring during cough;
3 by sound, the characteristic sound of a guinea-pig
cough.
Results can be expressed as coughs/10 min or as
coughs/min and comparisons made with prescreening cough rate or with postscreening vehicle control
treated animals.
Conclusion
Cough, irrespective of which airways disease it is associated with, represents an unmet clinical need. There
are no efficacious treatments available for cough and
those that are available have been shown to be ineffective [2]. It is therefore essential to identify and develop
new treatments for cough. To achieve this end it is necessary to develop and utilize an animal model of cough
that accurately reflects the condition in humans.
The development of an animal model always re-
Cough
10 min
(a)
(b)
Fig. 21.3 The classic change in posture seen when a guineapig coughs in response to tussive stimuli. (a) Normal posture
at rest; (b) cough posture with front feet splayed, body extended and mouth open.
quires the answering of key questions and cough is no
exception. The key questions for a cough model are:
• The choice of species.
• The choice of tussive stimuli to elicit a functional
response.
• Should the model employ conscious or anaesthetized animals?
• What should the end-point measurement be?
• Is the model reliable and reproducible?
• Does the model represent cough in humans?
It would appear that the ‘citric acid-induced cough in
guinea-pig’ model answers most if not all of these questions. The guinea-pig shows distinct advantages over
other small rodents in that it does cough to given stimuli in the conscious state and that the physiology of the
cough response reflects that in humans. The tussive
stimulus, citric acid, used to elicit cough in this model
also causes cough in humans and acts on C-fibres and
possibly RARs which are thought to be involved in
the cough response pathway in humans. Citric acid also
221
CHAPTER 21
has the advantage of producing reproducible cough responses in the same animal within a short period of time
and unlike repeated administration of capsaicin does
not result in tachyphilaxis. The end-point measurement in this model is cough and as this can be assessed
in three different ways, by observed posture change, by
pressure change and by sound, this adds to the reproducibility and reliability of the model.
In conclusion, citric acid-induced cough in the conscious guinea-pig provides a robust model in which to
test and develop much needed putative treatments for
cough in humans.
References
1 Choudry NB, Fuller RW. Sensitivity of the cough reflex
in patients with chronic cough. Eur Respir J 1992; 5:
296–300.
2 Shroeder K, Fahey T. Systematic review of randomised
controlled trials of over the counter cough medicines for
acute cough in adults. Br Med J 2002; 324: 1–6.
3 Widdicombe JG. Advances in understanding and treatment of cough. Monaldi Arch Chest Dis 1999; 54: 275–9.
4 Karlsson J-A, Fuller RW. Pharmacological regulation of
the cough reflex — from experimental models to antitussive effects in man. Pulm Pharmacol Ther 1999; 12:
215–28.
5 Moreaux B, Beerens D, Gustin P. Development of a cough
induction test in pigs: effects of SR 48968 and enalapril.
J Vet Pharmacol Ther 1999; 22: 387–9.
6 Kamei J, Hukuhara T, Kauya Y. Dopaminergic control of
the cough reflex as demonstrated by the effects of apomorphine. Eur J Pharmacol 1987; 141: 511–3.
7 Korpas J. Differentiation of the expiration and the cough
reflex. Physiol Bohemoslov 1972; 21: 677–80.
8 Karlsson J-A, Sant’Ambrogio G, Widdicombe J. Afferent
neural pathways in cough and reflex bronchoconstriction.
J Appl Physiol 1988; 65: 1007–23.
9 Forsberg K, Karlsson J-A, Theodorsen E, Lundberg JM,
Persson CGA. Cough and bronchoconstriction mediated
by capsaicin-sensitive sensory neurons in guinea pigs.
Pulm Pharmacol 1988; 1: 33–9.
10 Fox AJ, Barnes PJ, Urban L, Dray A. An in vivo study of the
properties of single vagal afferents innervating guinea pig
airways. J Physiol 1993; 469: 21–35.
11 Fox AJ. Modulation of cough and airway sensory fibres.
Pulm Pharmacol 1996; 9: 335–42.
12 Fox AJ, Lalloo UG, Belvisi MG, Bernareggi M, Chung KF,
Barnes PJ. Bradykinin-evoked sensitization of airway
sensory nerves: a mechanism for ACE-inhibitor cough.
Nature Med 1996; 2: 814–7.
222
13 Fox AJ, Barnes PJ, Venkatesan P, Belvisi MG. Activation
of large conductance potassium channels inhibits the
afferent and efferent function of airway sensory nerves in
the guinea pig. J Clin Invest 1997; 99/3: 513–9.
14 Lalloo UG, Fox AJ, Belvisi M, Chung KF, Barnes PJ.
Capsazepine inhibits cough induced by capsaicin and
citric acid but not by hypertonic saline in guinea pigs. J
Appl Physiol 1995; 79: 1082–7.
15 Bolser DC, Hey JA, Chapman RW. Influence of central
antitussive drugs on the cough motor pattern. J Appl
Physiol 1999; 86: 1017–24.
16 Bolser DC, McLeod RL, Tulshian DB, Hey JA. Antitussive
action of nociceptin in the cat. Eur J Pharmacol 2001; 430:
107–11.
17 Bolser DC, Aziz SM, DeGennaro FC, Kreutner W, Egan
RW, Siegel MI, Chapman RW. Antitussive effects of
GABAB agonists in the cat and guinea pig. Br J Pharmacol
1993; 110: 491–5.
18 Morice AH, Kastelik JA, Thompson R. Cough challenge
in the assessment of cough reflex. Br J Clin Pharmacol
2001; 52: 365–75.
19 Widdicombe JG. Sensory mechanisms. Pulm Pharmacol
1996; 9 (5–6): 383–7.
20 Karlsson J-A. The role of capsaicin-sensitive C-fibre afferent nerves in the cough reflex. Pulm Pharmacol 1996; 9:
315–21.
21 Laude EA, Higgins KS, Morice AH. A comparative study
of the effects of citric acid, capsaicin and resiniferatoxin on
the cough challenge in guinea pig and man. Pulm Pharmacol 1993; 6: 171–5.
22 Hay DWP, Giardina GAM, Griswold DE, Underwood
DC, Kotzer CJ, Bush B, Potts W, Sandhu P, Lundberg D,
Foley JJ, Luttmann MA, Grugni M, Raveglia LF, Sarau
HM. Nonpeptide tachykinin receptor antagonists. III. SB
235375, a low central nervous system-penetrant, potent
and selective neurokinin 3 receptor antagonist, inhibits
citric acid-induced cough and airways hyper-reactivity in
guinea pigs. J Pharmacol Exp Ther 2002; 300: 314–23.
23 Emonds-Alt X, Advenier C, Cognon C, Croci T, Daoui S,
Ducoux JP, Landi M, Naline E, Neliat G, Poncelet M,
Proietto V, Van Broeck D, Vilain P, Soubrie P, Le Fur G,
Maffrand JP, Breliere JC. Biochemical and pharmacological activities of SR 144190, a new potent non-peptide
tachykinin NK2 receptor antagonist. Neuropeptides
1997; 5: 449–58.
24 Belvisi MG, Venkatesan P, Barnes PJ, Fox AJ. A comparison of the chemosensitivity of the isolated guinea pig and
human vagus nerves. Am J Respir Crit Care Med 1998;
157: A487.
25 Moreaux B, Nemmar A, Beerens D, Gustin P. Inhibiting
effect of ammonia on citric acid-induced cough in pigs: a
possible involvement of substance P. Pharmacol Toxicol
2000; 87/6: 279–85.
SECTION 5
Therapy
22
Mechanisms of actions of centrally
acting antitussives —
electrophysiological and
neurochemical analysis
Kazuo Takahama
Introduction
Many antitussives have been developed and used in
clinics and as over-the-counter (OTC) drugs. However,
there is still a need for effective antitussives that do not
have adverse effects; synthetic non-narcotic antitussives currently available are not very effective, and narcotic antitussives such as codeine often have adverse
effects. Cough can be produced through activation
of the cough reflex arc consisting of afferent nerves,
‘cough centre’ neurones and efferent nerves, and is regulated by higher brain activity [1] and peripheral regulating systems such as tone of the tracheobronchial
smooth muscle. Therefore, these nerves and regulating
systems are possible targets for antitussives. Evidence
from in vivo pharmacological and electrophysiological
studies indicates that the primary sites of action of
centrally acting antitussives are brain neurones. In particular, evidence from comparison of equieffective
doses administered via such varied routes as the vein,
the common carotid artery, the vertebral artery and
the cerebellomedullary cistern [2] suggests that the primary region of action of centrally acting antitussives is
the so-called ‘cough centre’, which is located in the region that includes part of the nucleus tractus solitarii
and adjacent regions. This hypothesis is supported by
data from analysis of actions of antitussives on evoked
discharges in afferent and efferent nerves of the cough
reflex. In addition, there have been studies of neuronal
circuitry involved in integration of cough response in
the brain [3,4]. However, the precise mechanisms of
centrally acting antitussives have yet to be studied, particularly at the neurone level. In this chapter, I discuss
the results of recent studies (including ours) of neuronal
mechanisms of centrally acting antitussives, focusing
on effects on single neurones.
Glycine and its receptor
Action on glycine-induced currents
in single neurones
Glycine, like g-aminobutyric acid (GABA), is generally
considered to be an inhibitory neurotransmitter in
the mammalian central nervous system (CNS), and is
considered to be of particular importance in the lower
brainstem and spinal cord. However, much remains
unknown about the pharmacological and pathophysiological significance of glycine receptors in the CNS,
whereas much data have been accumulated regarding
the pharmacological significance of GABA receptor–
ionophore complexes in the brain. Toxic doses of antitussives often facilitate convulsions in experimental
animals, possibly due to blockade of the receptors
of inhibitory neurotransmitters such as glycine and
GABA. Therefore, we attempted to determine whether
antitussives influence glycine-mediated responses in
the CNS [5]. In that experiment, we used acutely dissociated single neurones of nucleus tractus solitarii
(NTS). The neurones were freshly dissociated from
7–10-day-old Hartley guinea-pigs, using standard
methods. In those neurones, all of which were voltageclamped to a holding potential (VH) of –50 mV, glycine
induced a strychnine-sensitive inward current (Igly) in a
concentration-dependent manner at concentrations of
3 μmol/L to 3 mmol/L.
Dextromethorphan (Dex) did not induce membrane
225
CHAPTER 22
currents in NTS neurones at a concentration of
0.1 mmol/L. However, Dex depressed Igly induced by
30 μmol/L glycine in a concentration-dependent
manner (Fig. 22.1). The half-maximal inhibitory concentration (IC50) of Dex for Igly was 3.3 μmol/L, 85
times the IC50 of strychnine. It has been reported that
Dex inhibits voltage-dependent Ca2+ and Na+ channels
[6]. However, it is unlikely that the effect of Dex on Igly
is due to action on these channels, because Igly is carried
by Cl- in neurones of the CNS, including the NTS neurones of guinea-pigs. Based on electrophysiological
and pharmacological analysis of the action of Dex on
Igly, we speculate that low concentrations of Dex act on
the glycine receptor–ionophore complex, but not on
the Cl- channel of the complex. However, a relatively
high concentration of Dex may affect the Cl- channel of
the complex. Interestingly, 100 μmol/L Dex had no effect on the current induced by 30 μmol/L GABA. The
fact that GABA-induced current (IGABA) in NTS neurones was depressed by bicuculline indicates that it was
mediated by the GABAA receptor. This in turn indicates
that centrally acting antitussives have little effect on
GABAA receptors, although it has been reported that
GABAB receptor agonists have antitussive action in experimental animals [7]. Other antitussives, both narcotic and non-narcotic, have been found to have
inhibitory action on Igly but not on IGABA, but they are
less potent inhibitors of Igly than Dex [8]. Those studies
were the first to indicate that Igly inhibition is an action
common to several centrally acting antitussives at the
brain neurone level, and their findings raise the question of whether Igly inhibition by antitussives is part of
their mechanism of action.
The ‘cough centre’ and its pharmacology
Prior to studying the action of antitussives on single
brain neurones, we sought the location of the so-called
‘cough centre’ and studied the pharmacology of the
cough centre, using guinea-pigs. We found an area that
produces cough-like responses when electrically stimulated, located within the region from 500 μm rostal to
100 μm caudal to the obex, from 800 μm to 400 μm
from the midline, and from 1000 μm to 600 μm below
the dorsal surface of the medulla oblongata. This area
corresponds to a region that includes the rostal part of
the NTS and adjacent areas, and is nearly the same as
the region in cats reported by Kase et al. [1] and Borison
[2]. The responses produced by electrical stimulation of
226
this area were confirmed to be coughing by the fact that
they were effectively depressed by codeine.
Interestingly, in guinea-pigs, direct administration of
1 μg glycine into the cough centre potentiated cough responses, as indicated by an increase in the amplitude of
respiration curves of cough caused by mechanical stimulation of the mucosa of the tracheal bifurcation. This
finding is of particular interest, because all the other
substances such as 5-hydroxytryptamine (5-HT),
atropine and dl-AP5 in that study inhibited cough
responses [9].
Strychnine-sensitive glycinergic transmission
Results of direct administration of glycine into the
cough centre suggested the possibility that there is
glycinergic transmission in the cough centre; glycine
receptors are distributed in the NTS [10]. To resolve
this question, we performed a patch clamp experiment using brain slice preparations. Coronal sections
of the lower brainstem, including the NTS, 200–
250 μm in thickness, were prepared from 6–9-day-old
male Hartley guinea-pigs. Prior to preparing the slices,
it was confirmed that the region the slices were to be
taken from included the sites where the afferent neurones of the cough reflex reach, using a neuronal tracing technique in which the fluorescent dye diI serves as
a probe.
Out of 70 synaptic currents evoked by electrical stimulation of the solitary tract, 13 were excitatory, 28 were
inhibitory, and the remaining 29 were excitatory
currents followed by inhibitory currents. Of the 28
inhibitory postsynaptic currents (IPSCs), 21 were
blocked by strychnine, suggesting that there is glycinergic transmission in the region of the NTS where the afferent neurones of the cough reflex synapse with their
postsynaptic neurones. Dex inhibited the strychninesensitive IPSCs, but not the bicuculline-sensitive IPSCs
[11]. Results of a microdialysis study (discussed below)
also supported the hypothesis that glycine is involved in
cough responses.
Microdialysis experiment
We attempted to determine whether glycine levels in the
NTS of guinea-pigs are increased during coughing. For
this experiment, we developed a new device for floating
a microdialysis probe. This device keeps the tip of a
microdialysis probe stably within the selected region
MECHANISMS OF ACTIONS OF CENTRALLY ACTING ANTITUSSIVES
Control
Dex
1 mmol/L
Wash
Control
Dex
10 mmol/L
Wash
Dex
100 mmol/L
Wash
Glycine 30 mmol/L
Glycine 30 mmol/L
(a)
Dex
100 mmol/L
Wash
Control
GABA 30 mmol/L
Glycine 30 mmol/L
Control
1 nA
20 s
(b)
100
Fig. 22.1 Concentration-dependent inhibitory effect of dextromethorphan
(Dex) and strychnine in NTS neurones.
(a) A neurone was voltage-clamped at
–50 mV. Dex depressed 30 μmol/L
glycine-induced Cl– current Igly in a
concentration-dependent manner, but
did not change the current induced by
30 μmol/L GABA. An apparent depression of the IGABA was due to a rundown
of the response. All responses were obtained from the same neurone. (b) Concentration response curve for the
inhibitory effects of Dex (䊉) and
strychnine (䊏) on Igly. Each point denotes mean from four to five experiments; vertical lines show SE mean.
IGly (% of control)
80
60
40
20
0
0.001
0.01
0.1
1
10
100
Antagonist concentration ( mmol/L)
227
CHAPTER 22
of the lower brainstem, preventing the microdialysis
probe from moving as a result of fluctuations of the
brainstem. Microdialysis samples were collected every
5 min and analysed for amino acids, including glycine,
using HPLC with electrochemical detection. In the experiments performed under stereotaxic fixation using
lightly anaesthetized guinea-pigs, glycine levels in the
NTS were markedly elevated in the microdialysis
samples collected during a period of coughing caused
by inhalation of an aerosol of 2% citric acid solution.
However, the levels of GABA, alanine, glutamic acid
and glutamine did not change. Taurine levels also significantly increased during coughing. It is unlikely that
these changes in the level of glycine and taurine were
caused by the respiratory excitation and rise in blood
pressure that were observed during coughing, because
dimethylphenylpiperadinium-induced respiratory excitation and phenyrephrine-induced increase in blood
pressure did not cause changes in the level of glycine or
taurine.
The above evidence suggests that glycine and its receptor may be involved in the cough response, although
it is unknown whether increases in glycine levels cause
coughing or are a result of coughing. However, it appears that inhibition of Igly by centrally acting antitussives other than Dex does not necessarily contribute
to antitussive action, because relatively high concentrations were needed to inhibit Igly. Further studies are
needed to resolve these questions.
5-Hydroxytryptamine and its receptors
Studies have found that 5-HT may be involved in the
activity of centrally acting antitussives. Kamei et al.
have reported that the 50% antitussive effective dose
(AtD50) of some antitussives in reserpinized rats is twoto fourfold higher than in normal rats [12]. Similar
results have been obtained when rats treated with
p-chlorphenylalanine (PCPA), which depletes 5-HT
content in the brain, were compared to normal rats. In
contrast, treatment with a-methyl-p-tyrosine, which
depletes catecholamines such as noradrenaline (norepinephrine) and dopamine in the brain, has little effect
on antitussive activity, suggesting that catecholamines
are not involved in antitussive activity. Based on
these findings, Kamei et al. suggested that 5-HT in the
brain plays an important role in antitussive activity
[12], although it is well known that activation of
228
serotonergic neurones in the brain causes respiratory
depression.
An important question is which subtype of 5-HT receptor is involved in antitussive activity. 5-HT1A receptors are distributed throughout the medulla oblongata,
and are reportedly involved in regulation of respiration. Interestingly, systemic administration of 8hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT),
a 5-HT1A receptor agonist, depresses coughing in
guinea-pigs [13] and rats [14], suggesting that direct
activation of 5-HT1A receptors may depress cough responses. Also, it has been reported that the antitussive
effects of Dex and dihydrocodeine, a narcotic antitussive, in rats are inhibited by 5-HT1A receptor antagonists such as spiperone and methysergide, but not
by the 5-HT2 receptor antagonist ketanserine [15].
Therefore, we examined the effect of Dex on 5-HTinduced currents (I5-HT) to determine whether 5-HT1A
receptor-mediated mechanisms are involved in the
action of Dex, using nystatin-perforated and conventional whole-cell recording techniques in acutely dissociated brain neurones. In the dorsal raphe (DR)
neurones,voltage-clamped at a VH of –80 mV, 1 nmol/L
to 1 μmol/L 5-HT induced an inwardly rectifying K+
current in a concentration-dependent manner. This
I5-HT was blocked by spiperone, a 5-HT1A receptor
antagonist, but not by ketanserine, a 5-HT2 receptor
antagonist. We also confirmed that I5-HT was carried by
K+, based on electrophysiological analysis.
Not only 5-HT but also 8-OH-DPAT, a 5-HT1A receptor agonist, induced I5-HT in DR neurones. However, 10 μmol/L Dex did not cause any changes in the
membrane current when administered alone. This suggests that Dex may not act agonistically on the 5-HT1A
receptor. Surprisingly, Dex potently inhibited the
I5-HT [16]. Figure 22.2(a) shows the concentrationdependent inhibitory effect of Dex on I5-HT elicited by
0.1 μmol/L 5-HT. The IC50 and Hill coefficient of the
Dex inhibition were 14.3 μmol/L and 1.0, respectively.
The effect of Dex on the maximum 5-HT response and
the results obtained from the Lineweaver–Burk plot indicated that Dex inhibition was non-competitive [16].
Inhibitory action on GIRK channel
When 5-HT1A receptor agonists are applied to the
recorded DR neurones in the brain slice and acutely dissociated cell preparation, they cause hyperpolarization
MECHANISMS OF ACTIONS OF CENTRALLY ACTING ANTITUSSIVES
(a) 5-HT Dex
10–7 10–6 3 ¥ 10–6
mol/L mol/L
10–5
3 ¥ 10–5
50 pA
10 s
(b)
Relative I5-HT
and cessation of spontaneous firing, This effect is
caused by the activation of the G-protein-coupled
inwardly rectifying K+ (GIRK) channels. It has been
shown that intracellular perfusion with guanosine 5¢-o(3-thiotriphosphate) (GTPgS) causes irreversible 5HT1A receptor-mediated activation of the GIRK
channels, in the conventional whole-cell recording
mode. The irreversible activation of K+ current by intracellular perfusion with GTPgS reminded us of the direct activation of K+ channels by G-protein, and
enabled us to determine whether GIRK channels could
be blocked by Dex even in the absence of the agonist. As
shown in Fig. 22.2(c), when we used a recording electrode filled with pipette solution containing GTPgS,
brief application of 5-HT induced a continuous and
almost irreversible inward K+ current. Dex markedly
inhibited the current activated by intracellular GTPgS
in the absence of 5-HT [16], whereas spiperone, a 5HT1A receptor antagonist, had no effect on this current.
There appeared to be two possible explanations for the
inhibition of the GTPgS-activated currents by Dex, because it has been reported that the activation of GIRK
channels is mediated by the G-protein bg subunit. One
possible mechanism is blocking of the GIRK channel
itself. The other mechanism is blocking the G-proteinmediated activation of the channel by inhibiting the
action of the G-protein bg subunits. Although the site of
action of Dex is not clearly indicated by the available
evidence, the fact that onset and termination of the Dex
response were relatively rapid suggests that Dex may
act at the level of the GIRK channel [16].
We felt it could be instructive to determine whether
Dex also inhibits currents caused by activation of other
neurotransmitter receptors coupled to G protein, because GIRK channels are coupled to other receptors, including adrenergic a2-receptors and GABAB receptors.
Therefore, we examined the effect of Dex on norepinephrine (NE)-induced current, which is mediated by
a2-adrenoceptors [17], in the locus coeruleus neurones.
We found that Dex reversibly inhibits the NE-induced
current, with rapid onset and termination. Although it
is known that GIRK channels are heterotetrameric
channels with two or more subunit isoforms, little is
known about the isoforms of GIRK channels that are
coupled with 5-HT1A receptors and a2-adrenoceptors.
The above results indicate that Dex has no specific
effect on GIRK channels coupled to 5-HT1A receptors
in DR neurones.
An important question is whether blocking of GIRK
1.0
0.8
0.6
0.4
0.2
0
10–7
(c)
10–6
10–5
10–4
Dex (mol/L)
10–3
GTP g s
5-HT
10–7 mol/L
Dex
3 ¥ 10–5 mol/L
100 pA
30 s
Fig. 22.2 Concentration-dependent suppression of I5-HT by
dextromethorphan (Dex). (a) Representative current traces
illustrating the effect of Dex on I5-HT. All recordings were performed in external solution containing 20 mmol/L K+ at a VH
of –80 mV. (b) Concentration–inhibition relationship for the
inhibitory effect of Dex on I5-HT. Each point represents mean
from five to seven neurones; vertical bars show SE mean. The
continuous line was drawn according to the following equation: I = 1 – Cn/(Cn + ICn50) where I is the maximalized current
amplitude, n is the Hill coefficient and C is the concentration
of Dex. (c) Effect of Dex on the I5-HT irreversibly activated by
intracellular GTPgS. The neurones were intracellularly perfused with an internal solution containing 0.1 mmol/L GTPgS
by using the conventional whole-cell patch recording mode.
Current recording was performed in external solution containing 20 mmol/L K+ at a VH of –80 mV.
229
CHAPTER 22
channels by antitussives causes inhibition of coughing.
Interestingly, all centrally acting antitussives that we
studied inhibited I5-HT caused by 5-HT1A receptor activation. IC50 values of various antitussives for the current caused by 0.1 μmol/L 5-HT ranged from 1 μmol/L
to 10 μmol/L. Also, currents irreversibly activated by
intracellular perfusion with GTPgS were also inhibited,
suggesting inhibition of GIRK channels by these antitussives, which included narcotic antitussives. It may
be significant that Dex inhibited GIRK channels, because only a few GIRK channel blockers are currently
available.
Many antitussives have respiratory depressant action in experimental animals. Furthermore, it is well
known that activation of serotonergic neurones in
the brain depresses respiration. Unlike antitussives,
pentobarbital-Na, which has potent respiratory depressant action, had little effect on 5-HT-induced current, suggesting that it had little effect on the GIRK
channels. Thus, it is likely that inhibition of GIRK
channels by antitussive drugs contributes to antitussive
action, although the mechanism by which inhibition of
GIRK channels affects coughing is not known.
As described above, the results obtained from pharmacological studies using 5-HT1A receptor agonists
and antagonists suggest that direct activation of the
5-HT1A receptor may lead to inhibition of cough.
However, a patch-clamp study using acutely dissociated single neurones revealed that Dex did not act directly on the 5-HT1A receptor but rather blocked GIRK
channels coupled to 5-HT1A receptor and a2-adrenoceptor via G protein. Although these findings appear
contradictory, the following discussion and findings
may resolve this dilemma.
Significance of inhibitory action on GIRK channels
Results of a competitive binding assay indicated that
Dex had no effect on 5-HT1A receptors [18]. It is well
known that serotonergic neurones often have autoreceptors that may have an inhibitory influence on the
neurones. It has been reported that a subtype of autoreceptors in serotonergic neurones are 5-HT1A receptors.
Furthermore, activation of 5-HT1A receptors is known
to cause hyperpolarization in these neurones. Therefore, a reasonable working hypothesis is that the effect
of Dex on GIRK channels coupled to 5-HT1A autoreceptors blocks feedback inhibition in serotonergic neurones, in turn augmenting release of 5-HT. In fact, it has
230
been reported that Dex and dihydrocodeine increase
the release of 5-HT from slices prepared from the NTS,
an important relay centre in the modulation of cough
[19]. The agonist sensitivity of autoreceptors is also
known to be rather higher than that of postsynaptic
receptors.
It has also been reported that GABAB receptor agonists such as baclofen and 3-aminopropylphosphinic
acid (3-APPi) have antitussive activity in cats and
guinea-pigs. Based on their study of GABAB receptor
antagonists and comparison of equieffective doses
administered via veins and arteries, Bolser et al. concluded that baclofen inhibits cough by activating
CNS GABAB receptors, whereas 3-APPi inhibits cough
by acting at peripheral sites [7]. GABAB agonists
that act on presynaptic receptors are known to inhibit
glutamate exocytosis from synaptosomes, primary
neuronal cultures and brain slices [20]. Here it is
important to remember that N-methyl-D -aspartate
(NMDA) receptor antagonists have antitussive action
in experimental animals [21], although not all centrally
acting antitussives block NMDA receptors. On the
other hand, GABAB receptors are known to be coupled
to GIRK channels. If antitussives inhibit GIRK channels coupled to GABAB receptors, they should affect the
level of GABA in the brain, because GABAB receptors
are also presynaptic autoreceptors. In turn, cough responses may be modulated via changes in GABA levels
in the brain.
Recently, it has been reported that a d-opioid receptor antagonist exerts antitussive action via a CNS
mechanism [3]. However, Kotzer et al. have recently reported that the selective d-opioid receptor agonist SB
227122 has an antitussive effect in guinea-pigs [22].
They have also reported that the selective d-opioid
receptor antagonist SB 244525 has little antitussive
effect in guinea-pigs when administered alone. It has
also been reported that the d1-opioid receptor agonist
DPDPE has little effect on experimentally induced
cough in animals, but inhibited the antitussive effect of
the μ-opioid receptor agonist DAMGO [23]. In contrast, the d2-opioid receptor agonist [d-Ala2] deltorphin II (DELT-II) potentiated the antitussive effect of
DAMGO [23]. Studies of involvement of d-opioid
receptors in antitussive activity have produced some
conflicting results. Surprisingly, in our preliminary
study, the d-opioid receptor antagonists naltrindole
and naltriben, known to have antitussive action, both
inhibited GIRK channels in single brain neurones.
MECHANISMS OF ACTIONS OF CENTRALLY ACTING ANTITUSSIVES
There have been several reports suggesting involvement of s-receptors in mechanisms of action of antitussive drugs [24]. It has also been reported that there is a
high-affinity binding site for Dex on s-receptors [25].
Other studies suggest that s-receptors are associated
with K+ channels, because some s-ligands modify K+
conductances in some tissues. It has been reported that
s-ligands inhibit ligand-induced hyperpolarization mediated by a2-adrenoceptors and μ-opioid receptors in
locus coeruleus (LC) neurones [26]. As described above,
Dex inhibits not only I5-HT in DR neurones but also
norepinephrine-induced currents in LC neurones. Furthermore, a2-adrenoceptors in LC neurones are known
tobecoupledtoGIRKchannels [17]. Therefore, it is possible that s-ligands exert antitussive action at least partly through inhibition of GIRK channels. A patch-clamp
study by Nguyen et al. revealed no correlation between
binding affinities of antitussives at s1- or s2-binding
sites and potency of inhibition of K+ currents [27].
Coughing is regulated by higher brain areas, and is
under voluntary control to some extent. It may be reasonable to speculate that action of antitussive drugs is
facilitated, at least in part, by a placebo effect [28], since
low doses of some antitussives suppress cough with a
potency little greater than that of a placebo.
Recently, it has been reported that antitussive drugs
may act, at least in part, at a cortical level. Our study
also showed that microelectrophoretically applied
antitussives inhibited spontaneous unit activities recorded from the pyramidal layer of the cerebral cortex
of guinea-pigs in vivo (Fig. 22.3). To our knowledge,
the mechanism of inhibition of unit activities in the
cerebral cortex has not been studied. However, it is possible that inhibition of unit activities is the result of in-
hibition of GIRK channels, because GIRK channels are
found in various regions of the brain, including the
cerebral cortex [29].
NMDA and neurokinin 1 (NK1) receptors
NMDA receptor
Glutamate is often an excitatory neurotransmitter in
primary afferent neurones. Netzer et al. were the first
to report that Dex inhibited NMDA-induced currents
in brain neurones [6]. We confirmed this, and demonstrated that Dex had no effect on kainate-induced current in single brain neurones. Interestingly, codeine and
the non-narcotic antitussive eprazinone did not have an
effect on this current, although Dex and codeine both
have a morphinan structure. These findings indicate
that blocking of NMDA receptors is not essential for
antitussive effects.
Substance P and its receptor
There is a high density of substance P (SP)-containing
nerve terminals in the NTS [30], and there is a parallel
distribution of SP receptors in the postsynaptic neurones of these nerve terminals in the NTS. Also, recent
pharmacological and physiological studies using
guinea-pigs have revealed that SP in the NTS augments
bronchopulmonary C-fibre reflex output, causing
bronchoconstriction and changes in respiration including coughing [31]. Although it is unknown whether
clinically available centrally acting antitussives act on
NK1 receptors in the NTS, it seems likely that drugs
20
10
Spikes per s
Fig. 22.3 Inhibitory effect of microelectrophoretically applied antitussives
on single neurone activities in the cerebral cortex of guinea-pigs. Dextromethorphan (Dex) and codeine
inhibited single neurone activities in a
concentration-dependent manner. Na+
was applied to confirm that the inhibitory effect of antitussives was not due
to the current applied. Numerals under
each record represent the current
intensity in nA.
0
+5
Dex
+10
+10
NaCl
+10
1 min
20
10
0
+5
+10
Codeine
+15
1 min
231
CHAPTER 22
which block NK1 receptors in the NTS have antitussive
action.
Sasaki et al. [32] reported that an increase in the level
of SP significantly lowered the risk of pneumonia due
to aspiration of oropharyngeal bacterial pathogens
among older adults, apparently via recovery (or
strengthening) of cough and swallowing reflexes. They
also suggested that treatment with dopamine analogues or potentiating drugs such as amantadine may
affect the incidence of pneumonia, because production
of SP is regulated by dopaminergic neurones in the cerebral basal ganglia. SP is synthesized in the nodose and
jugular ganglia, and has been shown to be transported
peripherally and released in the airway. Increased release of SP is involved in cough and neurogenic inflammation in the airway. However, there is considerable
morphological and physiological evidence that SP is
also released at central synapses in the NTS [31]. This
suggests that NK1 receptors in the NTS could serve as
target receptors for new antitussive drugs. Finally, studies of the NK1 receptor and glycine receptor may provide useful data for development of a ‘cough recovery’
(or ‘strengthening’) drug for older adults with decreased cough and swallowing reflexes, which increase
susceptibility to aspiration pneumonia.
Opioid receptors and
narcotic antitussives
It is clear that antitussive drugs derived from opium alkaloids act via opioid receptors, because (i) antitussive
action of these drugs is effectively abolished by opioid
receptor antagonists such as levallorphan and naloxone and (ii) the blocking action of opioid receptor
antagonists occurs with a very short latency. Opioid
receptors are classified into three receptor types: μ, d
and k, and μ- and d-receptors are in turn divided pharmacologically into subtypes. Kamei et al. have reported
a series of pharmacological findings on involvement of
opioid receptor groups and subgroups in antitussive
activities of opioid drugs. These findings can be summarized as follows: (i) selective agonists for μ- and
k-receptors have significant antitussive action, but dreceptor agonists have little antitussive action [33,34];
(ii) antitussive action of μ-agonists occurs via μ2- but
not μ1-receptors [35,36]; (iii) antitussive action via
μ2-receptors is depressed via μ1-receptors [37]; (iv)
DPDPE, a d1-receptor agonist, depresses the antitussive
232
action of μ- and k-receptor agonists [34,38]; and (v)
DELT-II, a d2-receptor agonist, inhibits antitussive
action that occurs via μ2-receptors, suggesting that
the relationship between μ- and d-receptors in antitussive action may be different from their relationship
in analgesic action [23]. Although these findings are
suggestive, some are controversial; for example,
Kotzer et al. have recently reported that the selective dreceptor agonist SB 227122 has an antitussive effect in
guinea-pigs [22].
As discussed above, action of narcotic antitussives
such as codeine is thought to occur via opioid receptors.
However, nothing is known about effects of these
antitussives on opioid receptor-mediated responses
in single neurones. Findings of several studies indicate
that activation of opioid receptors inhibits excitability of neurones in various regions of the brain and
spinal cord, while increasing excitability in a few
neurones. In addition, there have been several findings
regarding mechanisms of opioid receptor-mediated inhibition of excitability of single neurones. For example,
it has been reported that a μ-receptor agonist inhibits
Ca2+ currents in dorsal root ganglion (DRG) neurones
[39]. This inhibition occurred via activation of a Gi- or
G(o)-type G protein, but was independent of changes
in adenylate cyclase activity [39]. On the other hand,
a study using DRG neurones in organotypic cultures
revealed that most μ-, d- and k-opioid agonists elicit
dimodal excitatory as well as inhibitory modulation of
the action potential duration (APD) of these neurones
[40]. Excitatory opioid effects have been shown to
be mediated by opioid receptors that are coupled via
Gs to cyclic AMP-dependent ionic conductances that
prolong APD, whereas inhibitory opioid effects are
mediated by opioid receptors coupled via Gi/Go to
ionic conductances that shorten APD [40]. A relatively
recent study of dissociated neurones of the periaqueductal grey of rats has found that a μ-opioid
receptor agonist, DAMGO, inhibits high-voltageactivated (HVA) Ca2+ current [41]. It has been confirmed that this effect is due to inhibition of N-type
HVA Ca2+ channels via pertussis toxin (PTX)-sensitive
G proteins [13]. It has also been reported that μ-opioid
receptor stimulation causes activation of inward rectifying K+ conductance in various brain regions [42].
Thus, signal transduction across cellular membranes
by opioid receptors is mediated by coupling to G proteins. However, the actions and mechanisms of opioids
in individual brain neurones appear to vary among
MECHANISMS OF ACTIONS OF CENTRALLY ACTING ANTITUSSIVES
different types of neurones. Also, recent evidence indicates that a single receptor type can interact with several G proteins [43], which in turn can couple to more
than one effector [44]. In addition, studies of the a2adrenergic receptor indicate that receptor/G-protein
interactions are affected by receptor density [45]. Thus,
actions of opioids in single neurones might be greatly
influenced by the region of the brain that the neurones
are from and the type of G protein involved in the signal
transduction mechanism. This also seems to be the case
for k- and d-opioid receptors. Therefore, when studying the actions of narcotic antitussives at the neurone
level, it is important to use neurones that are involved in
the cough reflex. Rhim et al. [46] found that, in neurones of the NTS, an important relay centre in the
modulation of cough, activation of μ-opioid receptors
inhibited both N- and P/Q-type Ca2+ channels. Because
they found that inhibition of Ca2+ currents by
DAMGO, a μ-receptor agonist, was reduced by treatment with PTX and by a conditioning prepulse to
+80 mV, they suggested that a PTX-sensitive G protein
was involved in inhibition of Ca2+ currents by
DAMGO. Also, they found that DAMGO-induced
inhibition of Ca2+ currents, unlike somatostatininduced inhibition of Ca2+ currents, was not attenuated
by intracellular loading with an antiserum raised
against the amino terminus of the a subunits of Go
(Goa), suggesting that at least two different PTXsensitive G-protein-mediated pathways are involved in
receptor-mediated inhibition of Ca2+ currents in NTS
neurones.
As discussed above, narcotic antitussives such as
codeine inhibit GIRK channel currents in brain neurones at relatively high concentrations. Accordingly,
we have conducted a preliminary study of the actions of
codeine on HVA Ca2+ currents and delayed rectifier K+
currents in acutely dissociated NTS neurones. A high
concentration of 1 mmol/L was needed to inhibit both
currents. In this context, it seems likely that the primary
site of action of clinically available narcotic antitussives
is in opioid receptors such as μ-opioid receptors, but
not ionic channels such as HVA Ca2+ and delayed rectifying K+ channels. However, further study is needed to
determine whether opioid receptor-mediated actions
of narcotic antitussives inhibit cough directly or via
changes in levels of other neurotransmitters. Several
studies have found that μ-opioid receptors decrease
GABA release presynaptically in the brain [47].
A recent study using expression of the Fos-like im-
munoreactivity (FLI) has revealed that many regions of
the brain are involved in laryngeal-induced fictive
cough in cats [48], including the interstitial and ventrolateral subdivisions of the nucleus of the tractus solitarius, the medial part of the lateral tegmental field,
the internal division of the lateral reticular nucleus, the
nucleus retroambiguus, the para-ambigual region, the
retrofacial nucleus and the medial parabrachial nucleus. Furthermore, FLI in these regions was found to be
significantly reduced by treatment with codeine [48].
Also, μ- and k-opioid receptors are densely localized in
the NTS and parabrachial nucleus [49]. However, dreceptorsdonot distribute to those regions in which FLI
increases after cough stimulation, although a very low
density of d-receptors was found in the NTS [49]. These
findings seem to be consistent with findings that μ- and
k-agonists, but not d-agonists, have antitussive actions
in experimental animals. However, further studies are
needed to clarify the neuronal mechanisms of the action
of narcotic antitussives, because (i) μ-, d- and k-opioid
receptors are widely distributed in the brain, including
the cerebral cortex [49] and (ii) coughing is under the
control of both lower and higher brain regions [1].
Conclusions
The centrally acting antitussives currently available
have been derived from various compounds that have
different pharmacological actions, such as analgesic,
anticholinergic and antihistaminergic actions. Because
of this, antitussive drugs are diverse in chemical structure. For some time, researchers studying cough and
antitussives have wondered whether centrally acting
antitussives have a common mechanism or site of action in the brain, despite known differences between receptors for narcotic and non-narcotic antitussives. Our
recent studies have shown that centrally acting antitussives have inhibitory actions on the strychnine-sensitive
glycine receptor–ionophore complex and GIRK channels (Table 22.1). Inhibitory action on the glycine receptor does not appear to be important for the action of
antitussives other than Dex, because relatively high
concentrations are needed to inhibit glycine-induced
current. However, blocking of GIRK channels appears
to contribute at least partly to the action of centrally
acting antitussives. As described above, GIRK channels
are coupled to various receptors. A recent study has
revealed that GIRK channels are also coupled to
233
CHAPTER 22
Table 22.1 Effects of antitussive drugs on receptor-mediated or ion channel-activated currents in single brain neurones.
Narcotic (codeine)
Igly
IGABA
INMDA
IK
I5-HT
INE
GIRK channel
ØØ
Æ
Æ
n.d.
Ø
n.d.
Ø
Non-narcotic
Dextromethorphan
Others*
d-Antagonist or s-agonist
ØØØ
Æ
ØØØ
Æ
ØØØ
ØØØ
ØØØ
Ø
Æ
Æ
n.d.
ØØØ
n.d.
ØØØ
n.d.
n.d.
n.d.
n.d.
ØØ
ØØ
ØØ
A downward arrow indicates the magnitude of the inhibitory effect: the greater the number of arrows, the greater is the
inhibitory action on the currents. IGly, IGABA, INMDA, IK, I5-HT and INE are the currents induced by glycine, GABA, NMDA,
kainate, 5-HT and norepinephrine, respectively.
n.d., not determined.
* For example, eprazinone.
μ-receptors in the cerebral cortex [29]. GIRK channels
are tetramers, and exist as homo- and heteromeric complexes of the following four subunits: GIRK1, GIRK2,
GIRK3 and GIRK4. However, it is not known whether
GIRK channels coupled to different receptors each
have a unique GIRK subunit composition. Detailed
studies on the effects of antitussives on the GIRK channels coupled to various receptors may help clarify
neuronal mechanisms of centrally acting antitussives,
in particular, non-narcotic antitussives, because GIRK
channels are coupled to receptors for many different
transmitters, including acetylcholine, dopamine, 5-HT,
GABA, somatostatin, norepinephrine, ATP and opioids, and because results of an FLI expression study
suggest that multiple sites (even in the brainstem) are
involved in the cough reflex and may be involved in
antitussive action [48].
Narcotic antitussives inhibit various channels, including GIRK channels. However, their primary site of
action appears to be opioid receptors such as μ- and kreceptors, because high concentrations are needed to
inhibit μ- and k-receptor-mediated channels. It is likely
that further understanding of central mechanisms of
narcotic antitussives can be achieved by conducting
studies using neurones that are primarily or secondarily involved in cough responses, and by using preparations such as cough response-related single neurones
with synaptic buttons or brain slices containing neuronal circuits related to cough responses. The use of
234
such methods may also help elucidate the mechanisms
of action of non-narcotic antitussives.
Acknowledgements
The author thanks Professor T. Miyata and Drs H. Kai,
Y. Isohama, H. Ishibashi and T. Shirasaki, Faculty of
Pharmaceutical Sciences, Kumamoto University, for
their collaboration. The author thanks the following
graduate students for their assistance: H. Honda, H.
Fukushima, M. Otsuka, S. Nagayama, Y. Terasako and
F. Soeda, Department of Pharmacology, and K.
Kuwano and K. Abe, Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Kumamoto
University. The author sincerely thanks Emeritus Professor Y. Kase for his continuous encouragement.
References
1 Kase Y, Kito G, Takahama K, Miyata T. Influence of cerebral cortex stimulation upon cough-like spasmodic
expiratory response (SER) and cough in the cat. Brain Res
1984; 306: 293–8.
2 Kase Y. Antitussive agents and their sites of action. Trends
Pharmacol Sci 1980; 1: 237–9.
3 Widdicombe J. Neuroregulation of cough: implications for drug therapy. Curr Opin Pharmacol 2002; 2:
256–63.
4 Baekey DM, Morris K, Gestreau C, Li Z, Lindsey B,
Shannon R. Medullary respiratory neurones and control
MECHANISMS OF ACTIONS OF CENTRALLY ACTING ANTITUSSIVES
5
6
7
8
9
10
11
12
13
14
15
16
17
of laryngeal motoneurones during fictive eupnoea and
cough in the cat. J Physiol 2001; 534: 565–81.
Takahama K, Fukushima H, Isohama Y, Kai H, Miyata T.
Inhibition of glycine currents by dextromethorphan in
neurones dissociated from the guinea-pig nucleus tractus
solitarii. Br J Pharmacol 1997; 120: 690–4.
Netzer R, Pflimlin P, Trube G. Dextromethorphan blocks
N-methyl D-aspartate-induced currents and voltageoperated inward currents in cultured cortical neurons.
Eur J Pharmacol 1993; 238: 209–16.
Bolser DC, DeGennaro FC, O’Reilly S, Chapman RW,
Kreutner W, Egan RW, Hey JA. Peripheral and central
sites of action of GABA-B agonists to inhibit the cough
reflex in the cat and guinea pig. Br J Pharmacol 1994; 113:
1344–8.
Fukushima K, Nagayama S, Otsuka M, Takahama K,
Isohama Y, Kai H, Miyata T. Inhibition of glycine-induced
current by morphine in nucleus tractus solitarii neurones
of guinea pigs. Methods Find Exp Clin Pharmacol 1998;
20: 125–32.
Honda H, Takahama K, Kawaguchi T, Fuchikami J, Kai
H, Miyata T. Involvement of N-methyl-D-aspartic acid
(NMDA) receptor in the central mechanism of cough reflex. Jpn J Pharmacol 1990; 52 (Suppl. I): 308P.
Kubo T, Kihara M. Evidence for the presence of
GABAergic and glycine-like systems responsible for cardiovascular control in the nucleus tractus solitarii of the
rat. Neurosci Lett 1987; 74: 331–6.
Takahama K, Soeda F, Usui S, Isohama Y, Kai H, Miyata T.
Is glycinergic transmission in the nucleus tractus solitarii
(NTS) involved in cough reflex. Naunyn-Schmiedeberg’s
Arch Pharmacol 1998; 358 (Suppl. 1): R64.
Kamei J, Ogawa M, Kasuya Y. Monoamine and the
mechanisms of action of antitussive drugs in rats. Arch Int
Pharmacodyn 1987; 290: 117–27.
Stone RA, Barnes PJ, Chung KF. Effect of 5-HT1A receptor
agonist, 8-OH-DPAT, on cough responses in the conscious
guinea pig. Eur J Pharmacol 1997; 332: 201–7.
Kamei J, Mori T, Igarashi H, Kasuya Y. Effects of 8hydroxy-2-(di-n-propylamino) tetralin, a selective agonist
of 5-HT1A receptors, on the cough reflex in rats. Eur J
Pharmacol 1991; 203: 253–8.
Kamei J, Hosokawa T, Yanaura S, Hukuhara T. Effects of
methysergide on the cough reflex. Jpn J Pharmacol 1986;
42: 450–2.
Ishibashi H, Kuwano K, Takahama K. Inhibition of the 5HT1A receptor-mediated inwardly rectifying K+ current by
dextromethorphan in rat dorsal raphe neurones. Neuropharmacology 2000; 39: 2302–8.
Arima J, Kubo C, Ishibashi H, Akaike N. a2Adrenoceptor-mediated potassium currents in acutely
dissociated rat locus coeruleus neurones. J Physiol (Lond)
1998; 508: 57–66.
18 Craviso GL, Musacchio JM. High affinity dextromethorphan binding sites in guinea pig brain, competition
experiments. Mol Pharmacol 1983; 23: 629–40.
19 Kamei J, Mori T, Igarashi H, Kasuya Y. Serotonin release
in the nucleus of the solitary tract and its modulation by
antitussive drugs. Res Comm Chem Pathol Pharmacol
1992; 76: 371–4.
20 Nicholls DG, Sanchez-Prieto J. Neurotransmitter release
mechanism. In: Stephenson FA, Turner AJ, eds. Frontiers
in Neurobiology 3, Amino Acid Neurotransmission.
London: Portland Press, 1998: 1–24.
21 Kamei J, Tanihara H, Igarashi H, Kasuya Y. Effects of
N-methyl-D-aspartate antagonists on the cough reflex.
Eur J Pharmacol 1989; 168: 153–8.
22 Kotzer CJ, Hay DWP, Dondio G, Giardina G, Petrillo P,
Underwood DC. The antitussive activity of d-opioid receptor stimulation in guinea pigs. J Pharmacol Exp Ther
2000; 292: 803–9.
23 Kamei J, Iwamoto Y, Suzuki T, Nagase H, Misawa M,
Kasuya Y. Differential modulation of μ-opioid receptormediated antitussive activity by d-opioid receptor agonists
in mice. Eur J Pharmacol 1993; 234: 117–20.
24 Kamei J, Iwamoto Y, Misawa M, Kasuya Y. Involvement
of haloperidol-sensitive s-sites in antitussive effects. Eur J
Pharmacol 1992; 224: 39–43.
25 Klein M, Paturzo JJ, Musacchio JM. The effects of prototypic s-ligands on the binding of [3H]dextromethorphan
to guinea pig brain. Neurosci Lett 1989; 97: 175–80.
26 Bobker DH, Shen K-Z, Surprenant A, William JT. DTG
and (+)-3PPP inhibit a ligand-activated hyperpolarization
in mammalian neurons. J Pharmacol Exp Ther 1989; 251:
840–5.
27 Neuyen VH, Ingram SL, Kassiou M, Christie MJ. sBinding site ligands inhibit K+ currents in rat locus
coeruleus neurons in vitro. Eur J Pharmacol 1998; 361:
157–63.
28 Eccles R. The powerful placebo in cough studies? Pulm
Pharmacol Ther 2002; 15: 303–8.
29 Ponce A, Bueno E, Kentros C, Vega-Saenz de Miera E,
Chow A, Hillman D, Chen S, Zhu L, Wu MB, Wu X, Rudy
B, Thornhill WB. G-protein-gated inward rectifier K+
channel proteins (GIRK1) are present in the soma and
dendrites as well as in nerve terminals of specific neurons
in the brain. J Neurosci 1996; 16: 1990–2001.
30 Kawai Y, Mori S, Takagi H. Vagal afferents interact with
substance P–immunoreactive structures in the nucleus of
the tractus solitarius: immunoelectron microscopy combined with an anterograde degeneration study. Neurosci
Lett 1989; 101: 6–10.
31 Mutoh T, Bonham AC, Joad JP. Substance P in the nucleus
of the solitary tract augments bronchopulmonary C fiber
reflex output. Am J Physiol Regul Integr Comp Physiol
2000; 279: R1215–23.
235
CHAPTER 22
32 Yamaya M, Yanai M, Ohrui T, Arai H, Sasaki H. Interventions to prevent pneumonia among older adults. J Am
Geriatr Soc 2001; 49: 85–90.
33 Kamei J, Tanihara H, Kasuya Y. Antitussive effect of two
specific k-opioid agonists, U-50,488H and U-62,066E, in
rats. Eur J Pharmacol 1990; 187: 281–6.
34 Kamei J, Tanihahara H, Kasuya Y. Modulation of μmediated antitussive activity in rats by a d agonist. Eur J
Pharmacol 1991; 203: 153–6.
35 Kamei J, Iwamoto Y, Kawashima N, Suzuki T, Nagase H,
Misawa M, Kasuya Y. Possible involvement of μ2mediated mechanisms in μ-mediated antitussive activity in
the mouse. Neurosci Lett 1993; 149: 169–72.
36 Kamei J, Iwamoto Y, Suzuki T, Misawa M, Nagase H,
Kasuya Y. The role of the μ2-opioid receptor in the antitussive effect of morphine in μ1-opioid receptor-deficient
CXBK mice. Eur J Pharmacol 1993; 240: 99–101.
37 Kamei J, Saitoh A, Morita K, Nagase H. Antagonistic
effect of buprenorphine on the antitussive effect of
morphine is mediated via the activation of μ1-opioid
receptors. Life Sci 1995; 57: 231–5.
38 Kamei J, Tanihahara H, Kasuya Y. Modulation of kmediated antitussive activity in rats by a d agonist. Res
Comm Chem Pathol Pharmacol 1992; 76: 375–8.
39 Moises HC, Rusin KI, Macdonald RL. μ-Opioid receptormediated reduction of neuronal calcium current occurs via
a G(o)-type GTP-binding protein. J Neurosci 1994; 14:
3842–51.
40 Crain SM, Shen KF. Modulatory effects of Gs-coupled
excitatory opioid receptor functions on opioid analgesia,
tolerance, and dependence. Neurochem Res 1996; 21:
1347–51.
41 Kim CJ, Rhee JS, Akaike N. Modulation of high-voltage
236
42
43
44
45
46
47
48
49
activated Ca2+ channels in the rat periaqueductal gray
neurons by μ-type opioid agonist. J Neurophysiol 1997;
77: 1418–24.
Loose MD, Kelly MJ. Opioids act at μ-receptors to
hyperpolarize arcuate neurons via an inwardly rectifying
potassium conductance. Brain Res 1990; 513: 15–23.
Laugwitz K, Offermanns S, Spincher K, Schultz G. μ and d
opioid receptors differentially couple to G protein subtypes in membranes of human neuroblastoma SH-SY-5Y
cell. Neuron 1993; 10: 233–42.
Hescheler J, Rosenthal W, Trautwein W, Schutz G. The
GTP-binding protein, Go, regulates neuronal calcium
channels. Nature 1987; 325: 445–7.
Eason MG, Kurose H, Holt BD, Raymond JR, Liggett SB.
Simultaneous coupling of a2-adrenergic receptors to two
G proteins with opposing effects. J Biol Chem 1992; 267:
15795–801.
Rhim H, Toth PT, Miller RJ. Mechanism of inhibition
of calcium channels in rat nucleus tractus solitarius by
neurotransmitters. Br J Pharmacol 1996; 118: 1341–50.
Alreja M, Shanabrough M, Liu W, Leranth C. Opioids
suppress IPSCs in neurons of the rat medial septum/diagonal band of Broca: involvement of μ-opioid receptors and
septohippocampal GABAergic neurons. J Neurosci 2000;
20: 1179–89.
Gestreau C, Bianchi AL, Grelot L. Differential brainstem
fos-like immunoreactivity after laryngeal induced coughing and its reduction by codeine. J Neurosci 1997; 17:
9340–52.
Mansour A, Khachaurian H, Lewis ME, Akil H, Watson
SJ. Anatomy of CNS opioid receptors. Trends Neurosci
1988; 11: 308–14.
23
Pharmacology of peripherally
acting antitussives
Sandra M. Reynolds, Domenico Spina & Clive P. Page
Introduction
‘Sensory’ regulation of the cough reflex
Cough is a common symptom of a variety of airway
diseases, from upper respiratory tract infections to
chronic illnesses such as asthma, chronic obstructive
pulmonary disease (COPD) and bronchial carcinoma.
Cough is also a protective reflex, which prevents entry
of foreign bodies into the respiratory tract and also aids
the expulsion of mucus. Chronic persistent non-productive cough that lasts for longer than a month, where
no specific cause can be found, occurs in about 30–40%
of patients [1], resulting in significant morbidity in
terms of quality of life. Drugs currently used to treat
cough are among the most widely used over-the-counter drugs in the world, despite a recent analysis suggesting that there is little evidence to suggest that such drugs
produce any meaningful efficacy [2]. In 1999 alone
$750 million was spent on antitussive medications in
the US, Canada and Europe [2]. There is a current
unmet need for the development of safe, effective antitussive therapeutic options in the treatment of persistent cough as alternatives to existing medications.
Antitussive drugs are broadly divided into two
groups based on their site of action. Peripherally acting
drugs act outside the central nervous system (CNS) to
inhibit cough by suppressing the responsiveness of one
or more types of sensory nerves that produce cough [3].
Central antitussive drugs act inside the central nervous
system to suppress the responsiveness to one or more
components of the central reflex pathway of cough [4].
This chapter will discuss existing knowledge of the
peripherally acting antitussive medications that are
currently used in the clinic and the development of
novel antitussives in this area (Fig. 23.1).
The cough reflex can be evoked by mechanical and/or
chemical stimuli in the airways. There are four main
groups of airway receptors which may initiate the
cough reflex: the rapidly adapting stretch receptors
(RARs), nociceptive Ad-fibres, the pulmonary and
bronchial C-fibre receptors, and the slowly adapting
stretch receptors (SARs). All of these groups are located
within the epithelial layer of the trachea and lower airways [5,6]. RARs and C-fibres have also been located in
the larynx [7], and pulmonary C-fibres are located in
the alveolar wall (Fig. 23.1).
It is well documented that RARs can cause cough as
they are activated by the same stimuli that initiate
coughing. Studies in experimental animals have
demonstrated that impulse conduction in these nerves
is activated by mechanical, chemical and osmotic stimuli that are all capable of inducing cough in humans
[8–10]. SARs facilitate the cough reflex by activating
RARs as shown in cats and rabbits via interneurones
called ‘pump cells’, which are believed to open gates
that either permit or augment the cough reflex due to
RAR activity in the larynx and trachea [11]. They are
not believed to be directly involved as their activity is
not altered by stimuli evoking cough. The C-fibres
(pulmonary or bronchial, depending on their location
along the airways) are also activated by the same stimuli, but C-fibres are less sensitive to mechanical stimuli
than are RARs. Non-myelinated C-fibre afferents contain neuropeptides such as substance P (SP), neurokinin
A (NKA) and calcitonin gene-related peptide (CGRP)
and may be indirectly involved in the cough reflex, by
the release of these neuropeptides from peripheral
237
CHAPTER 23
CNS
C-fibres
Jugular
ganglion
Bradykinin
Capsaicin
Citric acid
NS1619, VR-1
antagonists
Opioids,
GABA,
Nociceptin
Local anaesthetics
Bronchodilators
SubP
NKA
Tachykinin
antagonists
Nodose
ganglion
Ad fibres
Epithelium
Bronchospasm, mucus secretion
Vasodilatation, oedema/inflammation
Histamine, eicosanoids
Fig. 23.1 Representation of neuronal innervation of the airways and the potential drug targets in the treatment of cough.
Modified from [6].
nerve terminals. The release of endogenous neuropeptides may also induce bronchospasm and oedema
which indirectly stimulate RARs [4]. Most of the evidence for the direct involvement of C-fibres in cough
has come from the fact that capsaicin, which was
thought to be a selective stimulant of C-fibres, can
evoke coughing in animals and humans [12,13]
although there are also suggestions that stimulation of
C-fibre receptors with capsaicin may actually inhibit
cough [14]. However, it is now regarded that capsaicin
is not selective for C-fibres as it has been reported to activate Ad-fibres also [15]. In addition, recent work has
shown that the vanilloid (VR1) receptor, which is activated by capsaicin, is also found in airway nerves not
containing sensory neuropeptides [16–18]. The implication of these findings is that capsaicin can no longer
238
be considered selective for C-fibre afferents and that
C-fibre involvement in the cough response is more
complex than previously recognized.
Opioids and opioid-like drugs
Opioids, especially morphine and codeine, have been
shown to suppress cough in a number of animal models
[19,20] and in humans [21,22] to a range of different
stimuli including capsaicin and citric acid. Of the
five receptor subtypes known, it is thought that
the antitussive actions of these drugs is via stimulation
of μ-opioid receptors. μ-Opioid receptors are found
within the cough centres of the brain and traditionally
it is believed that opioids exert their antitussive effects
PERIPHERALLY ACTING ANTITUSSIVES
via a central action [21,23]. However, the possibility
that opioids suppress cough also by a peripheral mechanism of action led to the development of BW443C, a
novel peripherally acting μ-opioid receptor agonist for
the treatment of cough.
In the guinea-pig BW443C (H–Tyr–D -Arg–Gly–Phe
(4-NH4)) was shown to inhibit cough by a peripheral
site of action as there appears to be little or no penetration of this drug into the CNS sufficient to cause
respiratory depression, in comparison with codeine
and morphine. Furthermore, the antitussive actions
of BW443C were significantly reduced by Nmethylnalorphine, a salt of nalorphine, and therefore
designed not to penetrate the blood–brain barrier [20].
Follenfant et al. also showed that BW443C was
unable to cross the blood–brain barrier in chemically
induced writhing models [24]. BW443C inhibits activity in airway sensory neurones originating from RARs
and C-fibre receptors [3,4]. BW443C has not been
tested as an antitussive in humans but it failed to
significantly alter hyperresponsiveness in asthmatic
subjects, although the possibility of enzymatic destruction following deposition on the epithelial surface may
account for this result [25].
Nociceptin/orphanin FQ (N/OFQ), is an opioid-like
peptide and is the endogenous ligand for the recently
discovered ORL1 receptor now known as NOP1 [26].
Nociceptin also has low affinity for opioid receptors
but it is not recognized as a member of the opioid
group due to the fact that nociceptin does not have
high binding affinity for opioid receptors and opioid
antagonists such as naltrexone are unable to block the
activity of nociceptin. Nociceptin has been located in
the lung and has been found to inhibit the release of
sensory neuropeptides following depolarization of
C-fibres [27] and to inhibit bronchospasm in the
guinea-pig. This latter effect could be due to the inhibition of the release of sensory neuropeptides from
C-fibres [28]. More recently it has been shown that
N/OFQ inhibited cough induced by mechanical and
capsaicin stimuli in guinea-pigs and cats [29]. This
suggests that NOP1 receptors are involved in the
modulation of the cough reflex. N/OFQ is a peptide
and probably does not cross the blood–brain barrier
when administered by the intravenous route; it also
has similar efficacy when delivered by the intracerebroventricular (i.c.v.) route [26,30]. N/OFQ-selective
agonists that activate NOP1 show promise as potentially novel peripherally acting antitussives, that would
be without the side-effects associated with classical
opioid antitussives.
Local anaesthetics
Local anaesthetics like lidocaine, benzonatate, bupivacaine and mexiletine have been used experimentally
to block cough, and local anaesthetics are the most
consistently effective antitussive medications but their
use is controversial and they are often used as the
drugs of last resort in patients with irritable cough.
If local anaesthetics are applied locally they can reversibly inhibit pulmonary vagal afferent discharge
[31]. The inhibition of action potential generation and
transmission in afferent nerves is thought to be a result
of a use-dependent inhibition of voltage-gated sodium
channels.
Lidocaine given systemically is very effective at
inhibiting cough in animal models and in humans,
although it is subject to tachyphylaxis. However,
high plasma concentrations are necessary for effective
cough suppression in humans [32]. Lidocaine also
has a quite rapid equilibration through the blood–
brain barrier and therefore an inhibition of neural
activity in the CNS may contribute to these antitussive
effects when the drug is administered systemically
[33,34]. Penetration within the CNS may be reduced
by direct application to the lung. Thus, inhaled and
topically administered lidocaine inhibited cough in
humans presumably by an action on afferent nerves in
the lung, but it also has a short duration of action. The
duration of action may be improved following oral
administration.
RSD 931 (carcainium chloride), a quaternary ammonium molecule, has been shown to inhibit citric acid
and aerosolized capsaicin-induced cough in the guineapig, an effect not thought to be due to local anaesthetic
activity [35]. RSD 931 almost completely inhibited citric acid-induced cough at the highest dose used. In rabbits that were pretreated with ozone in order to increase
cough sensitivity to citric acid, this cough response was
distinctly inhibited by RSD 931, an effect equivalent to
intravenous codeine in rabbits. RSD 931 also inhibited
histamine-evoked discharge in Ad-fibres originating
from RARs in the tracheobronchial tree of rabbits in
a similar way to lidocaine, which suggests a peripheral
site of action for this compound [35]. However, RSD
931 differs from lidocaine in that it does not inhibit the
239
CHAPTER 23
spontaneous and capsaicin-evoked discharges in
pulmonary and bronchial C-fibres, which suggests a
novel mechanism of action.
Mexiletine is an orally active local anaesthetic and a
single oral dose reduced histamine-induced reflex bronchoconstriction to the same degree as intravenous lidocaine in subjects with mild asthma [36]. Furthermore, it
has been shown that oral administration of mexiletine
suppressed cough in humans induced by tartaric acid
but not by capsaicin [37]. The implications of these
findings are that these stimuli induce cough by different
pathways which are differentially regulated by blockade of sodium channels. Interestingly it has been reported that carcainium chloride, which is structurally
related to lidocaine and mexiletine but which lacks significant local anaesthetic effects, has a selective effect
on RAR nerves in the rabbit and is considerably more
effective than lidocaine as an antitussive drug [35].
Mexiletine could prove a more long-lasting antitussive
as it has a longer equilibration period.
Bupivacaine administered by the inhaled route reduced cough that was generated by inhalation of citric
acid in humans, an effect that was not observed following intravenous administration. This seems to suggest a
local site of action for this drug [38]. Dyclonine failed to
reduce the cough response to inhaled capsaicin at doses
that did not cause bronchoconstriction in humans, despite adequately causing oral anaesthesia. This suggests
that the inhibition caused by lidocaine may be due to
the difference in rate of penetration of the two different
anaesthetics through the airway mucosa [34].
Tachykinin antagonists
Tachykinins are a group of small peptides, including SP,
NKA and neurokinin B (NKB), found in the peripheral
endings of capsaicin-sensitive primary afferent neurones (C-fibres) which innervate the lung. The local release of tachykinins following activation of C-fibres
may stimulate RARs to enhance the cough reflex [39].
It has also been shown that substance P released from
C-fibre afferents augments the stimulatory effect of
mild pulmonary congestion on RAR activity, by enhancing hydraulically induced microvascular leak [40].
The actions of the tachykinins are mediated through
NK1, NK2 and NK3 receptors, which are located in
both the central and peripheral nervous system. The
predominant sites containing tachykinin peptides are
240
capsaicin-sensitive primary afferents that are found in
various locations including the lung, skin and gastrointestinal tract [41,42]. There are now several potent
tachykinin antagonists available which have proved
effective against cough in a number of experimental
conditions [43,44]. Substance P given at high concentrations does not evoke cough in guinea-pigs, pigs,
healthy humans and asthmatics [45,46]. This may
not be surprising since substance P is rapidly metabolized by neutral endopeptidase present in airway epithelium. However, substance P release seems to play a
sensitizing role on the cough reflex in guinea-pigs
through the stimulation of tachykinin NK1, NK2 and
NK3 receptors [46].
The antitussive effect of NK2 antagonists has been
observed in many studies. An NK2 receptor antagonist
(SR 48968) suppressed the cough reflex in a dosedependent manner and was found to be more potent
than codeine in the guinea-pig [47]. The actions of SR
48968 were not reversed by naloxone implying a lack of
involvement of opioid receptors in the suppression of
cough. Interestingly, both SR 48968 and codeine only
partially inhibited the cough reflex when administered
by the inhaled route [44,48]. Although there are conflicting views on the site of action of tachykinin receptor
antagonists, a direct action on NK receptors on RARs
would indirectly suppress the cough reflex, mediated
following activation by NK receptors by endogenous
tachykinins from stimulated C-fibres [39,48,49].
The antitussive effect of NK1 antagonists is not clear.
FK 888 and CP-99994 (NK1 antagonists) have been
shown to inhibit cough induced by tobacco smoke and
citric acid in guinea-pigs and mechanical stimulation of
the trachea in anaesthetized cats [48,49]. Another NK1
antagonist SR 140333 was reported to have no inhibitory effect on cough, but when it was combined
with SR 48968 it was noted that there was an inhibitory effect more marked than with SR 48968 alone [47].
The different effectiveness by these NK1 antagonists
may be reconciled with the findings that unlike CP99994, SR 140333 does not penetrate the blood–brain
barrier [50].
The role of NK3 receptors in the cough reflex has
received scant attention. The most widely studied NK3
receptor antagonist SR 142801 has high affinity, and is
a selective, reversible and competitive antagonist for
the NK3 receptor [51]. SR 142801 has also been shown
to have an inhibitory effect on citric acid-induced
cough in guinea-pigs and pigs although the possibility
PERIPHERALLY ACTING ANTITUSSIVES
of a central mechanism of action cannot be ruled out
[46,52]. SB 235375, a non-peptide antagonist with
high affinity for NK3 receptors [53], has been found
to have low CNS penetration and inhibited cough induced by citric acid in guinea-pigs, and therefore could
be a useful compound as a future peripheral-acting
antitussive [51].
Capsaicin
Capsaicin is a pungent component of chilli peppers that
has been shown to cause pain by stimulating sensory
nerves and is also able to induce neurogenic inflammation in human skin and eyes and rat hind paw [54].
Whilst it has been shown that low concentrations of
capsaicin are highly selective for sensory C-fibres and
have lower activity on Ad-fibres [55], it is clear that Adfibres that innervate the jugular ganglion are responsive
to capsaicin [15]. Capsaicin stimulates sensory nerves
following binding to and activation of the vanilloid
receptor (VR1) which has recently been cloned [56].
Activation of VR1 in the lung can lead to modest
contraction of human isolated airways [57] and has
been implicated in the development of airways hyperresponsiveness to various stimuli [58]. Moreover, chronic treatment with capsaicin can suppress cough in
animal models [59]. Whilst sensory neuropeptides have
been implicated in this phenomenon, it is clear that
neuropeptides indirectly activate cough via RARs.
However, the demonstration of vanilloid receptors on
non-neuropeptide-containing nerves [16] suggests that
capsaicin may be operating through an additional
mechanism independent of sensory neuropeptide
release to incite cough. The activation of the vanilloid
receptor might explain how a variety of mediators
either induce cough and/or sensitize the cough reflex.
This has recently been demonstrated for bradykinin
[60], and other endogenous activators of the vanilloid
receptor include 12 HPETE and 15 HPETE [61], although whether these lipid mediators induce cough is
not yet known. Nonetheless, targeting the vanilloid receptor may offer a new treatment for cough, since capsazepine, a competitive antagonist of the vanilloid
receptor, was found to inhibit cough induced by capsaicin and citric acid but not by hypertonic saline in
guinea-pigs [62], an observation confirming that preventing the activation of vanilloid-containing afferent
nerves can lead to cough suppression.
Disodium cromoglycate
Disodium cromoglycate (DSCG) and the related drug
nedocromil sodium have both been shown to produce
antitussive effects in humans via an inhibitory activity
on sensory nerves, and to suppress sensory C-fibre
activation by capsaicin [63,64]. Further evidence to
suggest that DSCG and nedocromil sodium inhibit
neuronal activity is that nedocromil sodium induced a
long-lasting chloride-dependent nerve depolarization
and clearly reduced the firing of action potentials following desensitization of the nerve [65]. Nedocromil
sodium was able to delay the onset of cough in dogs
to citric acid [65], and in several clinical studies
nedocromil sodium and sodium cromoglycate have
been shown to reduce the severity of cough in patients
with asthma [66,67].
GABAB receptor agonists
GABA (g-aminobutyric acid) is a major inhibitory
neurotransmitter found in the CNS, although it is
also present in the lung [68]. There are two distinct
receptors for GABA, known as GABAA and GABAB.
Baclofen, a selective GABAB receptor agonist, inhibited
bronchospasm and also cough induced by capsaicin
in healthy normal subjects [69]. In experimental
studies, both baclofen and 3-aminopropylphosphinic
acid (3-APPi) administered by the inhaled route were
potent antitussives in the guinea-pig against cough induced by capsaicin with an efficacy equivalent to that
observed with either codeine or dextromethorphan
[70]. The suppression of cough mediated by activation of GABAB receptors did not involve an opioiddependent mechanism, nor were GABAA receptors
involved in this response [70]. A peripheral site of action for 3-APPi and a central site of action for baclofen
were confirmed with the demonstration that i.c.v. administration of a GABAB receptor antagonist inhibited
cough following systemic administration of 3-APPi but
not baclofen [71].
K+ channel openers
Selective K+ channel openers may also be a novel
class of antitussives, by acting to reduce peripheral
cough reflexes. NS1619 is a selective potassium
241
CHAPTER 23
channel opener of calcium-activated K+ channels
(BKCa) which evokes the efflux of K+ from these
channels and leads to cell hyperpolarization. In the
guinea-pig NS1619 inhibited the activity of sensory
nerve-mediated reflexes [72]. Cough induced by citric
acid in conscious guinea-pigs was inhibited by 60%
after pretreatment with NS1619 [20]. Similarly,
NS1619 effectively inhibited the cough reflex induced
by bradykinin in guinea-pigs [72].
Another family of potassium channels, the KATP
channels, has also been implicated in the regulation of
cough and therefore may also prove to be a novel target
for the treatment of cough independent of bronchodilatation per se [73,74]. The KATP channel opener,
pinacidil, inhibited cough induced by capsaicin in
guinea-pigs, and the effect was inhibited by the sulphonylurea, glibenclamide, an inhibitor of this channel
[74].
Antidiuretics
The loop diuretic furosemide has been shown to have
an inhibitory effect on cough induced by inhalation of
low chloride solutions in normal subjects but had no effect on capsaicin-induced cough [75]. Furosemide acts
by inhibiting the Na+/K+/2Cl– cotransporter in the thick
ascending loop of the kidney that leads to a loss in
sodium, potassium and calcium into the urine. Inhaled
furosemide may act indirectly on sensory receptors in
the airway epithelium and may alter the Cl- concentration around the location of the epithelial cough receptors, although this is still not clear [75]. It has also been
shown to inhibit the discharge of laryngeal irritant
receptors [76]. Furosemide given by the intravenous
route does not suppress cough, which suggests that it
does not act systemically [75]. In mild asthmatics,
furosemide had a much smaller effect on cough induced
by low chloride solutions compared with healthy
subjects [77].
Moguisteine
Moguisteine, (R,S)-2-(2-methoxyphenoxy)-methyl-3ethoxycarbonyl-acetyl 1-1,13 thiazolidine, is a nonnarcotic antitussive. Its antitussive actions are thought
to be via the suppression of RAR rather than C-fibre activity. Moguisteine can suppress the resting discharge
242
of RARs when it is administered by the intravenous
route and it also has an inhibitory effect on the cough
reflex and the excitation of RAR activity due to capsaicin [78,79]. Moguisteine, unlike codeine, does not
suppress cough when it is given into the cerebral ventricles and has a very low impact on respiratory and lung
mechanics after oral administration, which points in
favour of a peripheral site of action [80]. Moreover, it
has been suggested that the antitussive action of moguisteine may be via the opening of KATP channels on
peripheral afferent nerves [74]. Moguisteine has
been reported to be safe and well tolerated in subjects
with chronic dry or slightly productive cough and was
as effective as codeine [81].
Dopamine receptor agonists
There are currently five known dopamine receptors,
including D1, D2, D3, D4 and D5 [82], and the possibility that agonists for these receptors may modulate
cough has been proposed [83]. It has been shown that
dopamine receptor activation inhibited the release of
neuropeptides from peripheral endings on airway
nerves and the activation of RARs in vivo [84,85].
Similarly, dopamine can inhibit vagally induced airway
microvascular leakage, which suggests that dopamine
has the ability to inhibit sensory nerve function [86].
Furthermore, it has recently been demonstrated that
dopamine receptors are present on sensory nerves within the human vagus [86]. Recent clinical studies with
Viozan®, a dual D2/b2-adrenoceptor agonist, suggest
that this type of drug may prove to be effective in suppressing cough in humans, although the side-effects
associated with this drug have precluded further
development.
Conclusion
There remains a clear need to develop a safe alternative
therapy to opiates for the treatment of cough which remains a very significant unmet medical need. A number
of preliminary approaches are under investigation, although to date none of them have matured sufficiently
to see whether this is a therapeutic promise that can
be realized.
PERIPHERALLY ACTING ANTITUSSIVES
References
1 O’Connell F, Thomas VE, Pride NB et al. Capsaicin cough
sensitivity decreases with successful treatment of chronic
cough. Am J Respir Crit Care Med 1994; 150: 374–80.
2 Schroeder K, Fahey T. Systematic review of randomised
controlled trials of over the counter cough medicines for
acute cough in adults. Br Med J 2002; 324: 329–31.
3 Adcock JJ. Peripheral opioid receptors and the cough reflex. Respir Med 1991; 85 (Suppl. A): 43–6.
4 Bolser DC, DeGennaro FC. Effect of codeine on the inspiratory and expiratory burst pattern during fictive cough in
cats. Brain Res 1994; 662: 25–30.
5 Widdicombe JG. Advances in understanding and treatment of cough. Monaldi Arch Chest Dis 1999; 54: 275–9.
6 Undem BJ, Carr MJ, Kollarik M. Physiology and plasticity of putative cough fibres in the guinea pig. Pulm Pharmacol Ther 2002; 15: 193–8.
7 Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am
Rev Respir Dis 1990; 141: 640–7.
8 Widdicombe JG. Respiratory reflexes from the trachea
and bronchi of the cat. J Physiol 1954; 123: 70.
9 Widdicombe JG. Receptors in the trachea of and bronchi
of the cat. J Physiol 1954; 123: 71–104.
10 Sant’Ambrogio G. Nervous receptors of the tracheobronchial tree. Annu Rev Physiol 1987; 49: 611–27.
11 Shannon R, Baekey DM, Morris KF et al. Functional
connectivity among ventrolateral medullary respiratory
neurones and responses during fictive cough in the cat.
J Physiol 2000; 525: 207–24.
12 Collier JG, Fuller RW. Capsaicin inhalation in man and the
effects of sodium cromoglycate. Br J Pharmacol 1984; 81:
113–17.
13 Forsberg K, Karlsson JA. Cough induced by stimulation of
capsaicin-sensitive sensory neurons in conscious guineapigs. Acta Physiol Scand 1986; 128: 319–20.
14 Tatar M, Webber SE, Widdicombe JG. Lung C-fibre receptor activation and defensive reflexes in anaesthetized cats.
J Physiol 1988; 402: 411–20.
15 Riccio MM, Kummer W, Biglari B et al. Interganglionic
segregation of distinct vagal afferent fibre phenotypes in
guinea-pig airways. J Physiol 1996; 496 (2): 521–30.
16 Myers AC, Kajekar R, Undem BJ. Allergic inflammationinduced neuropeptide production in rapidly adapting afferent nerves in guinea pig airways. Am J Physiol Lung
Cell Mol Physiol 2002; 282: L775–81.
17 Kagaya M, Lamb J, Robbins J et al. Characterization of
the anandamide induced depolarization of guinea-pig isolated vagus nerve. Br J Pharmacol 2002; 137: 39–48.
18 Guo A, Vulchanova L, Wang J et al. Immunocytochemical
localization of the vanilloid receptor 1 (VR1): relationship
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
to neuropeptides, the P2X3 purinoceptor and IB4 binding
sites. Eur J Neurosci 1999; 11: 946–58.
Karlsson JA, Lanner AS, Persson CG. Airway opioid
receptors mediate inhibition of cough and reflex bronchoconstriction in guinea pigs. J Pharmacol Exp Ther
1990; 252: 863–8.
Adcock JJ, Schneider C, Smith TW. Effects of codeine,
morphine and a novel opioid pentapeptide BW443C, on
cough, nociception and ventilation in the unanaesthetized
guinea-pig. Br J Pharmacol 1988; 93: 93–100.
Fuller RW. Cough. Br J Hosp Med 1991; 45: 100–1.
Sevelius H, McCoy JF, Colmore JP. Dose–response to
codeine in patients with chronic cough. Clin Pharmacol
Ther 1971; 12: 449–55.
Eddy NB, Friebel H, Hahn KJ et al. Codeine and its alternates for pain and cough relief. 5. Discussion and summary. Bull World Health Organ 1969; 40: 721–30.
Follenfant RL, Hardy GW, Lowe LA et al. Antinociceptive
effects of the novel opioid peptide BW443C compared
with classical opiates; peripheral versus central actions. Br
J Pharmacol 1988; 93: 85–92.
Pavord I, Hall I, Wahedna I et al. Effect of 443c81, an
inhaled mu-opioid receptor agonist in asthma. Clin Exp
Allergy 1994; 24: 144–8.
Meunier JC, Mollereau C, Toll L et al. Isolation and structure of the endogenous agonist of opioid receptor-like
ORL1 receptor. Nature 1995; 377: 532–5.
Shah S, Page CP, Spina D. Nociceptin inhibits non-adrenergic non-cholinergic contraction in guinea-pig airway. Br
J Pharmacol 1998; 125: 510–16.
Corboz MR, Rivelli MA, Egan RW et al. Nociceptin inhibits capsaicin-induced bronchoconstriction in isolated
guinea pig lung. Eur J Pharmacol 2000; 402: 171–9.
McLeod RL, Bolser DC, Jia Y et al. Antitussive effects of
nociceptin/orphanin FQ in experimental cough models.
Pulm Pharmacol Ther 2002; 15: 213–16.
McLeod RL, Parra LE, Mutter JC et al. Nociceptin inhibits
cough in the guinea-pig by activation of ORL(1) receptors.
Br J Pharmacol 2001; 132: 1175–8.
DeJong RH, Robles R, Morikawa KI. Actions of immobilizing drugs on synaptic transmission. Exp Neurol 1968;
21: 213–18.
Yukioka H, Yoshimoto N, Nishimura K et al. Intravenous
lidocaine as a suppressant of coughing during tracheal intubation. Anesth Analg 1985; 64: 1189–92.
Gove RI, Wiggins J, Stableforth DE. A study of the use of
ultrasonically nebulized lignocaine for local anaesthesia
during fibreoptic bronchoscopy. Br J Dis Chest 1985; 79:
49–59.
Choudry NB, Fuller RW, Anderson N et al. Separation of
cough and reflex bronchoconstriction by inhaled local
anaesthetics. Eur Respir J 1990; 3: 579–83.
Adcock JJ, Douglas GJ, Garabret MG et al. RSD 931, a
243
CHAPTER 23
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
novel anti-tussive agent acting on airway sensory nerves.
Br J Pharmacol 2003; 138: 407–16.
Groeben H, Foster WM, Brown RH. Intravenous
lidocaine and oral mexiletine block reflex bronchoconstriction in asthmatic subjects. Am J Respir Crit Care Med
1996; 154: 885–8.
Fujimura M, Kamio Y, Myou S et al. Effect of oral mexiletine on the cough response to capsaicin and tartaric acid.
Thorax 2000; 55: 126–8.
Cross BA, Guz A, Jain SK et al. The effect of anaesthesia of
the airway in dog and man: a study of respiratory reflexes,
sensations and lung mechanics. Clin Sci Mol Med 1976;
50: 439–54.
Widdicombe JG. Neurophysiology of the cough reflex.
Eur Respir J 1995; 8: 1193–202.
Bonham AC, Kott KS, Ravi K et al. Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits. J Physiol 1996; 493
(1): 229–38.
Otsuka M, Yoshioka K. Neurotransmitter functions of
mammalian tachykinins. Physiol Rev 1993; 73: 229–308.
Maggi CA. Tachykinins in the autonomic nervous system.
Pharmacol Res 1996; 33: 161–70.
Advenier C, Lagente V, Boichot E. The role of tachykinin
receptor antagonists in the prevention of bronchial
hyperresponsiveness, airway inflammation and cough.
Eur Respir J 1997; 10: 1892–906.
Advenier C, Emonds-Alt X. Tachykinin receptor antagonists and cough. Pulm Pharmacol 1996; 9: 329–33.
Fox AJ. Modulation of cough and airway sensory fibres.
Pulm Pharmacol 1996; 9: 335–42.
Moreaux B, Nemmar A, Vincke G et al. Role of substance P and tachykinin receptor antagonists in citric acidinduced cough in pigs. Eur J Pharmacol 2000; 408:
305–12.
Girard V, Naline E, Vilain P et al. Effect of the two
tachykinin antagonists, SR 48968 and SR 140333, on
cough induced by citric acid in the unanaesthetized guinea
pig. Eur Respir J 1995; 8: 1110–14.
Yasumitsu R, Hirayama Y, Imai T et al. Effects of specific
tachykinin receptor antagonists on citric acid-induced
cough and bronchoconstriction in unanesthetized guinea
pigs. Eur J Pharmacol 1996; 300: 215–19.
Bolser DC. Mechanisms of action of central and peripheral antitussive drugs. Pulm Pharmacol 1996; 9: 357–64.
Bolser DC, DeGennaro FC, O’Reilly S et al. Central antitussive activity of the NK1 and NK2 tachykinin receptor
antagonists, CP-99,994 and SR 48968, in the guinea-pig
and cat. Br J Pharmacol 1997; 121: 165–70.
Hay DW, Giardina GA, Griswold DE et al. Nonpeptide
tachykinin receptor antagonists. III. SB 235375, a low
central nervous system-penetrant, potent and selective
neurokinin-3 receptor antagonist, inhibits citric acid-
244
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
induced cough and airways hyper-reactivity in guinea
pigs. J Pharmacol Exp Ther 2002; 300: 314–23.
Daoui S, Cognon C, Naline E et al. Involvement of
tachykinin NK3 receptors in citric acid-induced cough
and bronchial responses in guinea pigs. Am J Respir Crit
Care Med 1998; 158: 42–8.
Giardina GA, Sarau HM, Farina C et al. 2-Phenyl-4quinolinecarboxamides: a novel class of potent and selective non-peptide competitive antagonists for the human
neurokinin-3 receptor. J Med Chem 1996; 39: 2281–4.
Jancso N, Jancso-Gabor A, Szolcsanyi J. The role of sensory nerve endings in neurogenic inflammation induced
in human skin and in the eye and paw of the rat. Br J Pharmacol 1968; 33: 32–41.
Holzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol
Rev 1991; 43: 143–201.
Caterina MJ, Schumacher MA, Tominaga M et al. The
capsaicin receptor: a heat-activated ion channel in the pain
pathway. Nature 1997; 389: 816–24.
Spina D, Matera GM, Riccio MM et al. A comparison of
sensory nerve function in human, guinea-pig, rabbit and
marmoset airways. Life Sci 1998; 63: 1629–42.
Spina D, Page CP. Pharmacology of airway irritability.
Curr Opin Pharmacol 2002; 2: 264–72.
Karlsson JA. The role of capsaicin-sensitive C-fibre afferent nerves in the cough reflex. Pulm Pharmacol 1996; 9:
315–21.
Shin J, Cho H, Hwang SW et al. Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. Proc Natl Acad Sci USA 2002; 99: 10150–5.
Hwang SW, Cho H, Kwak J et al. Direct activation of
capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci USA
2000; 97: 6155–60.
Lalloo UG, Fox AJ, Belvisi MG et al. Capsazepine inhibits
cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs. J Appl Physiol 1995; 79:
1082–7.
Dixon M, Jackson DM, Richards IM. The action of sodium cromoglycate on ‘C’ fibre endings in the dog lung. Br J
Pharmacol 1980; 70: 11–13.
Dixon M, Jackson DM, Richards IM. A study of the afferent and efferent nerve distribution to the lungs of dogs.
Respiration 1980; 39: 144–9.
Jackson DM, Pollard CE, Roberts SM. The effect of nedocromil sodium on the isolated rabbit vagus nerve. Eur J
Pharmacol 1992; 221: 175–7.
Barnes PJ. Effect of nedocromil sodium on airway sensory
nerves. J Allergy Clin Immunol 1993; 92: 182–6.
Boulet LP, Milot J, Boutet M et al. Airway inflammation in
nonasthmatic subjects with chronic cough. Am J Respir
Crit Care Med 1994; 149: 482–9.
PERIPHERALLY ACTING ANTITUSSIVES
68 Chapman RW, Hey JA, Rizzo CA et al. GABAB receptors
in the lung. Trends Pharmacol Sci 1993; 14: 26–9.
69 Dicpinigaitis PV, Dobkin JB. Antitussive effect of the
GABA-agonist baclofen. Chest 1997; 111: 996–9.
70 Bolser DC, Aziz SM, DeGennaro FC et al. Antitussive
effects of GABAB agonists in the cat and guinea-pig. Br J
Pharmacol 1993; 110: 491–5.
71 Bolser DC, DeGennaro FC, O’Reilly S et al. Peripheral and
central sites of action of GABA-B agonists to inhibit the
cough reflex in the cat and guinea pig. Br J Pharmacol
1994; 113: 1344–8.
72 Fox AJ, Barnes PJ, Venkatesan P et al. Activation of large
conductance potassium channels inhibits the afferent and
efferent function of airway sensory nerves in the guinea
pig. J Clin Invest 1997; 99: 513–9.
73 Poggioli R, Benelli A, Arletti R et al. Antitussive effect of
K+ channel openers. Eur J Pharmacol 1999; 371: 39–42.
74 Morita K, Kamei J. Involvement of ATP-sensitive K(+)
channels in the anti-tussive effect of moguisteine. Eur J
Pharmacol 2000; 395: 161–4.
75 Ventresca PG, Nichol GM, Barnes PJ et al. Inhaled
furosemide inhibits cough induced by low chloride content solutions but not by capsaicin. Am Rev Respir Dis
1990; 142: 143–6.
76 Sant’Ambrogio FB, Sant’Ambrogio G, Anderson JW.
Effect of furosemide on the response of laryngeal receptors to low-chloride solutions. Eur Respir J 1993; 6:
1151–5.
77 Stone RA, Barnes PJ, Chung KF. Effect of frusemide on
cough responses to chloride-deficient solution in normal
and mild asthmatic subjects. Eur Respir J 1993; 6: 862–7.
78 Morikawa T, Gallico L, Widdicombe J. Actions of mogu-
79
80
81
82
83
84
85
86
isteine on cough and pulmonary rapidly adapting receptor
activity in the guinea pig. Pharmacol Res 1997; 35:
113–18.
Sant’Ambrogio G, Sant’Ambrogio FB. Action of moguisteine on the activity of tracheobronchial rapidly adapting
receptors in the dog. Eur Respir J 1998; 11: 339–44.
Gallico L, Borghi A, Dalla RC et al. Moguisteine: a novel
peripheral non-narcotic antitussive drug. Br J Pharmacol
1994; 112: 795–800.
Barnabe R, Berni F, Clini V et al. The efficacy and safety of
moguisteine in comparison with codeine phosphate in patients with chronic cough. Monaldi Arch Chest Dis 1995;
50: 93–7.
Schwartz JC, Diaz J, Bordet R et al. Functional implications of multiple dopamine receptor subtypes: the D1/D3
receptor coexistence. Brain Res Rev 1998; 26: 236–42.
Newbold P, Jackson DM, Young A et al. Dual D2 receptor
and b-adrenoceptor agonists for the modulation of sensory nerves. In: Hansel TT, Barnes PJ, eds. New Drugs for
Asthma, Allergy and COPD. Basel: Karger, 2001: 68–71.
Trevisani M, Tognetto M, Amadesi S et al. D2 dopamine
receptor agonists inhibit neuropeptide release from
human airway sensory nerves. Am J Respir Crit Care Med
2001; 163: A905.
Jackson DM, Simpson WT. The effect of dopamine on the
rapidly adapting receptors in the dog lung. Pulm Pharmacol Ther 2000; 13: 39–42.
Birrell MA, Crispino N, Hele DJ et al. Effect of dopamine
receptor agonists on sensory nerve activity: possible therapeutic targets for the treatment of asthma and COPD. Br J
Pharmacol 2002; 136: 620–8.
245
24
Current and potential future
antitussive therapies
Peter V. Dicpinigaitis
Introduction
Cough is usually distinguished in the medical literature
as acute or chronic, the latter often being arbitrarily defined as cough of greater than 3 weeks’ duration. Antitussive therapy is appropriately classified as specific
therapy, which is aimed at an established or presumed
specific aetiology of cough, and non-specific therapy,
whose goal is to suppress the cough reflex.
The successful treatment of chronic cough is inextricably linked to the establishment of its aetiology. Multiple prospective studies have demonstrated that the use
of a systematic diagnostic protocol will provide a diagnosis in the vast majority of patients [1–3]. A definite diagnosis will allow the initiation of specific antitussive
therapy, which is highly effective [1–3]. Non-specific
therapy, which does not address the underlying mechanism of a patient’s cough, is often ineffective.
Acute cough, most commonly associated with an
upper respiratory tract infection (URTI), is usually
transient and self-limited. For patients seeking relief
from bothersome acute cough, currently available
options are less than satisfactory. Contributing to this
therapeutic void are a dearth of adequately performed
trials of non-prescription cough preparations [4], as
well as a lack of consensus among clinicians regarding
logical and appropriate treatment strategies for dealing
with acute cough [5].
Chronic cough
Specific antitussive therapy (Table 24.1)
Prospective studies have shown that, in the vast
majority of patients (> 80%) who are non-smokers, are
not receiving angiotensin-converting enzyme (ACE) inhibitors, and who do not demonstrate acute pathology
on chest radiograph, chronic cough is explained by one
or more of three aetiologies: postnasal drip syndrome
(PNDS), asthma and gastro-oesophageal reflux disease
(GORD) [1–3,6]. Multiple causes of chronic cough are
present simultaneously in approximately 25% of
patients [1–3,6]. Therefore, the clinician must bear in
mind that a partial response to specific antitussive therapy may indicate that only one of multiple aetiologies
of cough has been eliminated.
Postnasal drip syndrome
Multiple studies have demonstrated PNDS to be
the most common cause of chronic cough in adults
[1–3,6,7]. PNDS may be the result of various processes,
including seasonal and perennial allergic rhinitis,
perennial non-allergic rhinitis, vasomotor rhinitis,
postinfectious (postviral) rhinitis and chronic bacterial
sinusitis. Bacterial sinusitis distinguishes itself from the
other causes of PNDS since it requires aggressive
antibiotic therapy.
The combination of a first-generation antihistamine
and decongestant is regarded as the most consistently
effective sole form of therapy for PNDS-induced cough
not due to sinusitis [8]. These older, potentially sedating
antihistamine/decongestant preparations have been
shown in prospective trials to be effective in treating
chronic cough due to PNDS [1,2,9]. The newer, relatively non-sedating antihistamines, alone or in combination with a decongestant, have been shown to be
ineffective antitussives in controlled trials evaluating
cough due to the common cold [10–12]. The superior247
CHAPTER 24
Table 24.1 Specific antitussive therapy.*
Postnasal drip syndrome
Antihistamine/decongestant†
Nasal corticosteroids
Nasal cromolyn
Nasal ipratropium bromide
Asthma-associated cough
Inhaled bronchodilators (b2-agonists)
Inhaled corticosteroids
Leukotriene receptor antagonists
Systemic (oral) corticosteroids
Gastro-oesophageal reflux disease
Proton pump inhibitors
H2-receptor antagonists
Metaclopramide
Conservative (non-pharmacological) measures‡
Surgery (Nissen fundoplication)§
Postinfectious cough
Oral corticosteroids
Inhaled corticosteroids¶
Inhaled ipratropium bromide**
Cough due to angiotensin-converting enzyme (ACE)
inhibitors
Cessation of ACE inhibitor††
* See text for discussion of supporting evidence.
†First-generation antihistamine/decongestant combination
(see text).
‡Including high-protein, low-fat diet; avoidance of coffee
and tobacco; elevation of head of bed.
§When aggressive medical antireflux therapy eliminates acid
reflux, but cough persists; laparoscopic procedure preferred;
surgery not uniformly effective (see text).
¶Efficacy not demonstrated in adequately performed clinical
trials.
**Efficacy demonstrated in one small randomized placebocontrolled trial (see text).
†† Numerous agents shown partially effective (see text).
ity of the first-generation antihistamines is presumably
due to their greater anticholinergic potency and penetration into the central nervous system.
Because PNDS has been shown to be the most common cause of chronic cough [1–3,6,7], and, since cough
may be the sole presenting symptom of PNDS [2], one
therapeutic strategy shown to be successful is to empirically treat patients with a first-generation antihista248
mine/decongestant combination when they present
with a chronic cough whose aetiology is not evident
from initial history and physical examination [2]. In a
prospective study employing this strategy, 36% of
45 patients achieved complete resolution, and 87%
reported an improvement in cough [2]. Patients
unresponsive or only partially responsive to initial,
empirical PNDS therapy were further managed according to a stepwise diagnostic algorithm [2].
Other effective treatments for rhinitis include nasally
administered corticosteroids, cromolyn, ipratropium
bromide and decongestants, but studies evaluating the
effect of these agents specifically on PNDS-induced
cough are lacking.
Cough associated with asthma
In most asthmatics, cough is associated with other typical features of the disease, including dyspnoea and
wheezing. In a subgroup of patients, however, cough is
the predominant or sole symptom [13]. This condition
has been termed cough-variant asthma (CVA).
In general, the therapeutic approach to CVA is similar to that of typical asthma. An initial, albeit partial,
response is often seen after 1 week of therapy with
an inhaled b2-agonist [14]. Prospective studies have
demonstrated inhaled corticosteroids to be efficacious
in CVA, although up to 8 weeks of therapy may be
necessary to achieve full resolution of cough [14,15].
Inhaled steroids are also effective in the treatment of
eosinophilic bronchitis, a condition that causes chronic
cough in association with sputum eosinophilia, but in
the absence of bronchial hyperresponsiveness characteristic of asthma [16].
An important potential pitfall of inhaled steroid
therapy is the possibility that the medication itself may
induce or exacerbate cough, likely due to a constituent
of the aerosol. For example, the more common occurrence of cough after inhalation of beclometasone
dipropionate compared to triamcinolone acetonide is
thought to be caused by a component of the dispersant
in the former [17].
As with other conditions, there appears to exist
a subgroup of CVA patients whose symptoms are
particularly severe. Such patients, whose cough is
refractory to inhaled steroids, have been described
as having ‘malignant cough-equivalent asthma’
[18]. When cough is severe, or when inhaled steroidinduced cough is suspected, oral corticosteroid therapy
(i.e. prednisone 40 mg or equivalent daily for 7–14
CURRENT AND FUTURE ANTITUSSIVE THERAPIES
days), alone or followed by inhaled therapy [19], is
appropriate.
The leukotriene receptor antagonists (LTRAs) represent the newest drug class available for the treatment
of asthma. Initial anecdotal reports suggested that
LTRAs appeared to be quite effective in asthmaassociated cough [20,21]. Subsequently, a randomized
double-blind placebo-controlled crossover study
demonstrated that a 14-day course of oral zafirlukast,
20 mg twice daily, significantly improved subjective
cough scores and diminished capsaicin-induced cough
in a group of eight patients with CVA whose cough had
been refractory to inhaled bronchodilators and, in five
of eight patients, was refractory to inhaled steroids
[22]. The ability of zafirlukast to suppress cough that
had been refractory to inhaled bronchodilators and inhaled steroids suggests that, in subjects with CVA, the
LTRAs more effectively modulate the inflammatory
milieu of the afferent cough receptors within the airway
epithelium. The mechanism by which this occurs
remains to be elucidated.
Given these recent data, LTRAs appear to be an appropriate choice for asthmatic cough refractory to inhaled bronchodilators and steroids, before escalation
of therapy to systemic steroids. Whether LTRAs should
be used before inhaled steroids in CVA remains unclear.
Subepithelial layer thickening, a pathological feature of
airway remodelling, is present in CVA, although to a
lesser extent than in typical asthma [23]. Therefore,
chronic anti-inflammatory therapy may be beneficial in
CVA as in typical asthma. Long-term comparisons of
inhaled steroids and LTRAs in this setting are required.
Other agents shown in prospective trials to be effective in CVA include inhaled nedocromil sodium [24]
(double-blind placebo-controlled study) and azelastine
hydrochloride [25], a second-generation H1-receptor
antagonist (unblinded, uncontrolled study). The mechanism by which azelastine inhibits cough remains
unclear. An antihistaminic effect is supported by the
drug’s ability to inhibit allergen-induced histamine release in nasal lavage fluid [26]. Furthermore, studies in
guinea-pigs suggest that the antitussive effect of azelastine may be due to inhibition of substance P release
from sensory nerves [27].
Gastro-oesophageal reflux disease
The successful treatment of chronic cough due to
GORD presents a challenge to the clinician since, in up
to 75% of cases, no associated symptoms suggestive of
GORD are present [28]. Further complicating diagnosis and therapy of this condition is the prolonged interval that may be required in some patients before cough
improvement and resolution occur.
Initial studies evaluating the treatment of GORDinduced cough employed conservative measures such
as high-protein, low-fat diet, avoidance of coffee and
tobacco, and elevation of the head while sleeping, in
combination with pharmacological therapy consisting
of histamine H2-receptor antagonists and/or metaclopramide. This strategy led to resolution of cough
in 70–100% of patients. In some cases, however,
initial improvement did not occur for 2–3 months, and
full resolution of cough required up to 6 months of
therapy [8].
The subsequent appearance of more potent acid-suppressing medications in the form of proton pump inhibitors appears to have aided the clinician performing
a diagnostic therapeutic trial of antireflux therapy
for presumed GORD-induced chronic cough by more
promptly and effectively achieving initial improvement
and resolution of cough. For example, a regimen of
omeprazole, 40 mg twice daily, has been shown, in a
randomized double-blind placebo-controlled study,
to achieve significant improvement in cough within 2
weeks [29]. In another placebo-controlled study, which
employed a crossover design, therapy with a once-daily
40 mg dose of omeprazole led to significant improvement within 8 weeks [30].
In a subgroup of patients cough will persist despite
documentation of total or near-total elimination of oesophageal acid with intensive medical therapy [31].
Since such refractory cough often improves after antireflux surgery (Nissen fundoplication), it appears
likely that, at least in some patients, reflux-induced
cough is due to non-acid mediators [31]. Surgical intervention is not uniformly effective, however. One study
prospectively evaluating the results of antireflux surgery in 21 patients with reflux-induced cough refractorytointensivepharmacological therapy demonstrated
postoperative improvement in 86%, and complete resolution of cough in 62%, with symptomatic improvement persisting after 1 year [32].
Postinfectious cough
Although cough associated with an acute URTI is usually transient, in a subgroup of patients a dry cough
may persist for weeks to months after resolution
of other symptoms. Viral infections likely cause most
249
CHAPTER 24
cases of postinfectious cough; in adults, Chlamydia
pneumoniae, strain TWAR, Mycoplasma pneumoniae
and Bordetella pertussis have also been implicated [8].
The harsh, persistent, dry cough that may follow an
acute URTI is a common stimulus for medical attention
and eventual referral to a pulmonary specialist. Postinfectious cough can be particularly difficult to treat.
Even codeine, which has been demonstrated to have antitussive activity in chronic and induced cough, was
shown to be ineffective in the acute phase of URTI [33].
Since infection-induced, persistent airway inflammation is the likely cause of enhanced cough sensitivity
during URTI [34], anti-inflammatory therapy with
steroids for severe, debilitating cough seems logical. Although oral steroids have been shown to be effective in
this setting [35], inhaled steroids, which are commonly
prescribed for postinfectious cough, have not been
properly evaluated in clinical trials. One study of nonasthmatic idiopathic chronic cough, though not specifically postinfectious cough, demonstrated a 2–4-week
course of budesonide to be ineffective [36].
Inhaled ipratropium bromide has been shown in one
small, randomized, placebo-controlled study to be
effective in chronic postinfectious cough [37]. The
combination of an oral H1-antagonist, oxatomide, and
dextromethorphan demonstrated antitussive activity
in a small open-label study [38].
Cough due to ACE inhibitors
The mechanism of ACE inhibitor-induced cough remains unclear. Possible mediators include bradykinin
and substance P, which are degraded by ACE and therefore accumulate in lung tissue when the enzyme is
inhibited. Prostaglandins, whose production may be
enhanced by bradykinin, have also been implicated
[39].
The only uniformly effective intervention for ACE
inhibitor-induced cough is cessation of the offending
agent. Numerous small studies evaluating various
drugs have been performed. Agents demonstrating the
ability to attenuate ACE inhibitor-induced cough in
randomized double-blind placebo-controlled trials
include sodium cromoglycate [40], theophylline [41],
indometacin [42], the calcium channel antagonists
amlodipine and nifedipine [42], the thromboxane receptor antagonist picotamide [43], and ferrous sulphate [44]. In open-label uncontrolled studies, drugs
shown to suppress ACE inhibitor-induced cough include the GABA agonist baclofen [45], the thrombox250
ane synthetase inhibitor ozagrel [46], and aspirin (500
mg daily) [47].
The recently introduced drug class, the angiotensin II
receptor antagonists, theoretically should not induce
cough, since their mechanism of action does not involve
inhibition of ACE with resultant elevation of tissue levels of bradykinin and substance P. Indeed, losartan, the
first angiotensin II receptor antagonist approved for
clinical use, has been associated with a low incidence of
cough, similar to that of the diuretic hydrochlorothiazide [48]. Interestingly, multiple cases of angioedema
associated with the use of angiotensin II receptor antagonists have been reported [49].
Non-specific antitussive therapy
Because specific antitussive therapy is highly effective
[1–3], an aggressive diagnostic evaluation aimed at determining the specific aetiology of a patient’s chronic
cough is always indicated. Non-specific antitussive
therapy, whose goal is to suppress bothersome cough
by inhibiting the cough reflex regardless of the cause of
cough, is appropriate only under particular circumstances: (i) when the specific aetiology of cough cannot
be established (idiopathic); (ii) when severe cough
needs to be suppressed while awaiting the effect of specific antitussive therapy or the resolution of postinfectious cough; and (iii) when the aetiology of cough is
known but the cause is irreversible, such as inoperable
lung cancer or pulmonary fibrosis.
Non-specific antitussive agents are broadly classified
as central or peripheral, based on their site of action
(Table 24.2). The pharmacology of these agents is
discussed in detail elsewhere in this text.
Centrally acting agents
Opioids. Three narcotic opioids, codeine, hydrocodone and hydromorphone, are approved for use
as antitussives. Codeine is the preferred narcotic
antitussive because of its lower potential for abuse
and more favourable side-effect profile. Nevertheless,
codeine in antitussive doses can cause sedation, nausea,
vomiting and constipation.
Codeine has been shown in randomized doubleblind placebo-controlled studies to have antitussive
activity against pathological cough [50,51] as well as
induced cough in healthy volunteers [52,53]. However,
as mentioned above, codeine has been demonstrated to
CURRENT AND FUTURE ANTITUSSIVE THERAPIES
Table 24.2 Non-specific antitussive therapy.*
Centrally acting agents
Opioids
Codeine
Dextromethorphan
Diphenhydramine
Peripherally acting agents
Benzonatate
Levodropropizine
Moguisteine
* Only agents demonstrated in controlled clinical trials to
have antitussive activity against pathological cough are
listed; see text for discussion of other agents.
be ineffective against cough associated with acute respiratory tract infections [33]. The minimal effective
dose of codeine appears to be 20–30 mg.
Dextromethorphan is a non-narcotic opioid that
lacks the sedative, analgesic and respiratory depressant
effects of codeine, although it can cause confusion and
irritability at antitussive doses. It is one of the most
widely used antitussive agents worldwide, either alone
or as a component of numerous non-prescription
cough and cold preparations. The drug most commonly appears in a 20–30 mg dose.
Dextromethorphan has been shown, in randomized
double-blind placebo-controlled studies, to be effective
against pathological cough [50,51]. In a recent metaanalysis of six blinded placebo-controlled studies
containing 710 subjects, a single 30 mg dose of
dextromethorphan demonstrated antitussive efficacy
against cough associated with URTI [54].
Diphenhydramine. Diphenhydramine, a first-generation histamine H1-receptor antagonist, is believed
to have central antitussive activity [55]. Placebocontrolled crossover studies have demonstrated the
ability of diphenhydramine to suppress induced cough
in healthy volunteers [56] as well as chronic pathological cough due to bronchitis [57]. A dose of 25 mg
achieved an antitussive effect in both studies.
Baclofen. Baclofen is an agonist of g-aminobutyric
acid (GABA), a central inhibitory neurotransmitter.
Animal studies initially demonstrated the drug’s central
antitussive mechanism [58]. Subsequently, baclofen
was shown, in randomized double-blind placebocontrolled studies, to inhibit capsaicin-induced cough
in healthy human volunteers at doses as low as 20 mg
daily [59,60]. Baclofen demonstrated antitussive activity when evaluated in a double-blind placebo-controlled manner in two patients with chronic idiopathic
cough [61]. In an open-label study, baclofen effectively
suppressed ACE inhibitor-induced cough [45]. Adequate clinical trials in patients with pathological cough
are required to assess the potential therapeutic role of
baclofen or other GABA agonists.
Peripherally acting agents
Benzonatate. Benzonatate (Tessalon‰ perles), a longchain polyglycol derivative chemically related to
procaine, is an orally administered agent that may act
through inhibition of stretch receptors [62]. Studies
performed soon after the drug’s release in the 1950s
demonstrated its ability to inhibit induced cough as
well as to attenuate subjectively measured pathological
cough [55]. The benzonatate perle must be swallowed
whole to prevent oral anaesthetic effects. Although
more contemporary controlled trials are lacking, benzonatate was recently reported to suppress refractory
opioid-resistant cough in three patients with advanced
cancer [63].
Levodropropizine. Levodropropizine is a non-opioid
agent whose peripheral antitussive action may be due
to its modulation of sensory neuropeptides within the
respiratory tract [64]. It has been shown to inhibit experimentally induced cough in healthy volunteers [65]
and in subjects with obstructive lung disease [66]. In
patients with pathological cough, levodropropizine
has been shown to be superior to placebo [67], and
comparable in antitussive activity to dextromethorphan [68] and dihydrocodeine [69] in randomized
double-blind clinical trials.
Moguisteine. Moguisteine is a novel, non-opioid compound whose peripheral site of action [70], which may
involve ATP-sensitive potassium channels [71], has
been established in animal studies. In human trials involving patients with chronic cough, moguisteine was
found to be superior to placebo in a randomized double-blind study [72], and demonstrated antitussive
activity similar to that of codeine in a double-blind
parallel-group comparison trial [73].
251
CHAPTER 24
Inhaled anaesthetics. Nebulized lidocaine has been
shown to inhibit experimentally induced cough in volunteers [74] and, in multiple case reports and small
studies, to suppress chronic refractory cough [75–77],
alone or in combination with nebulized bupivacaine
[77]. The requirement for nebulization provides a
logistical hurdle to the common use of these agents.
Prospective controlled trials are necessary to evaluate
the potential role of inhaled anaesthetics in the management of cough.
Acute cough
Fortunately, acute cough, which is most commonly associated with a URTI, is usually transient and self-limited. However, if cough is severe, interferes with sleep
or persists, patients will consult their physician or pharmacist. Indeed, cough is the most common complaint
for which outpatient medical attention is sought in the
US [78].
Despite the significance of the problem, very few adequate clinical trials have been performed to evaluate
treatments for acute cough [4]. Of those, only a minority have clearly demonstrated the efficacy of pharmacological therapy. Among non-specific antitussive agents,
the narcotic opioid codeine, as discussed above, has
been shown to be ineffective against acute cough
associated with the common cold [33]. Although a
meta-analysis demonstrated antitussive efficacy of the
non-narcotic opioid dextromethorphan in acute cough
due to URTI [54], two other studies showed little or no
benefit compared to placebo [79,80]. Moguisteine, the
peripherally acting non-specific antitussive agent, likewise demonstrated little if any benefit in patients with
acute cough [81]. The combination of a first-generation
antihistamine and decongestant, considered the most
effective therapy for PNDS-induced chronic cough [8],
should theoretically be of some benefit in acute cough
as well, by attenuating the postnasal drip which may
accompany a URTI. This concept is supported by one
study [82], but, interestingly, not by a subsequent trial
that employed a newer-generation, non-sedating antihistamine in combination with a decongestant [12].
Further complicating the situation is the lack of consensus among clinicians regarding the optimal therapeutic strategy for acute cough [5]. Some physicians
maintain that antitussive therapy should be avoided in
cough associated with acute URTI because of a concern
252
that excessive respiratory secretions may accumulate
within the airways. Although this concept may be relevant in conditions associated with copious sputum production, such as bronchiectasis or cystic fibrosis, acute
cough due to URTI is rarely associated with significant
sputum production. Clearly, adequately performed
clinical trials aimed at evaluating currently available
therapeutic agents, and determining optimal management of acute cough, are required.
Agents other than antitussives are marketed worldwide for the treatment of cough, usually as nonprescription preparations. Often these formulations
contain combinations of agents. As with antitussives,
few adequately performed clinical trials are available to
evaluate these products [4].
Expectorants presumably act by decreasing the viscosity of respiratory secretions, thereby facilitating
their expulsion and decreasing the intensity of cough
with its associated physical discomfort. Guaifenesin,
the only expectorant considered ‘safe and effective’
by the US Food and Drug Administration [83], is a
component of numerous cough and cold preparations.
Studies (performed over two decades ago) evaluating
the effect of guaifenesin on sputum characteristics [84],
rate of mucociliary clearance [85] and cough suppression [86,87] have yielded contradictory results.
Demulcents such as sugar often comprise a significant proportion of many cough products. These agents
are thought to suppress cough by coating the inflamed
oral mucosa [62].
Future antitussive therapies
Since antitussive therapy aimed at a specific aetiology
of cough is highly successful [1–3], the greatest current
need is for more effective non-specific antitussive
medications. Presently available non-specific therapy is
severely limited by lack of effective agents and/or their
unacceptable side-effects. A huge unmet need exists
for safe and more effective non-specific cough inhibition, especially for patients with chronic idiopathic
cough; cough due to irreversible causes such as inoperable lung cancer; severe acute or persistent postinfectious cough associated with URTI; and severe cough
requiring transient relief while specific antitussive
therapy takes effect.
Below is a brief overview of several areas of current
scientific inquiry that may eventually result in the
CURRENT AND FUTURE ANTITUSSIVE THERAPIES
Table 24.3 Potential future antitussive agents.*
Delta-opioid receptor antagonists
Opioid-like orphan (NOP) receptor antagonists
Tachykinin receptor (NK1, NK2, NK3) antagonists
Vanilloid (VR1) receptor antagonists
Endogenous cannabinoids
Antiallergic agents/eosinophil antagonists
GABAB agonists
5-Hydroxytryptamine (5-HT) receptor agonists
Large conductance calcium-activated potassium channel
openers
* See text for discussion; most agents listed have only been
evaluated in animal studies.
development of novel antitussive therapeutic agents
(Table 24.3).
Opioid receptor subtypes and opioid-like
receptor antagonists
Agonists of the μ-opioid receptor (including codeine
and hydrocodone) achieve antitussive effect at the
expense of side-effects, which may include sedation,
respiratory depression, nausea, constipation and
potential for abuse. A compound that could inhibit
cough without these associated adverse effects
would offer a significant advantage over currently
available narcotic antitussives. To that end, selective
agonists of the d-opioid receptor have been developed,
and have demonstrated antitussive activity in animal
trials [88].
Opioid-like orphan (NOP) receptors are present
throughout the mammalian central and peripheral
nervous system, including within the lung. Nociceptin/orphanin FQ (N/OFQ) is an endogenous ligand
for the NOP receptor. Intravenously administered
N/OFQ has been shown to inhibit mechanically stimulated cough in cats [89] and, when given by either a central or peripheral route, inhibited capsaicin-induced
cough in guinea-pigs [90]. Subsequent studies demonstrated the ability of N/OFQ to block capsaicininduced tachykinin release and bronchoconstriction
through a mechanism involving the activation of an
inward-rectifier potassium channel [91].
Tachykinin receptor antagonists
The tachykinins include various neuropeptide transmitters such as substance P, neurokinin (NK) A, NKB,
and calcitonin gene-related peptide (CGRP). Animal
studies have implicated that tachykinins, through
stimulation of three receptor subtypes (NK1, NK2 and
NK3), induce bronchial hyperresponsiveness, neurogenic inflammation and cough [92]. In human airways, inflammatory cells appear to be the major source
of tachykinins [93]. Antagonists of the three NK
receptor subtypes have been isolated, and are being
actively investigated for potential therapeutic effect.
Although clinical trials in asthma and chronic obstructive pulmonary disease have been disappointing
[93], antagonists of all three receptor subtypes have
demonstrated antitussive activity in animal studies
[92–95].
Vanilloid (VR1) receptor
Capsaicin, the pungent extract of red peppers, has
achieved common usage in clinical research because it
induces cough in a reproducible and dose-dependent
manner [96]. Recently, the target receptor of capsaicin, the type 1 vanilloid (VR1) receptor, was discovered on peripheral pain-sensing neurones [97], as
well as throughout the central nervous system [98].
The isolation of the VR1 receptor now provides the
opportunity for the development of potentially useful
antagonists.
Endogenous cannabinoids
Anandamide is an endogenous cannabinoid that has
been shown in rodents to inhibit capsaicin-induced
cough and bronchospasm, while inducing bronchospasm in animals devoid of vagal tone [99]. These
contrasting effects are both mediated through peripheral CB1 cannabinoid receptors present in airway
nerves. The development of more selective cannabinoid
receptor agonists provides a potential source of future
antitussive agents.
Eosinophil antagonists
Recent studies have demonstrated that eosinophilic airway inflammation is an important cause of chronic
non-asthmatic cough [16]. The antiallergic agent, su253
CHAPTER 24
platast tosilate, is a T-helper (Th) 2-cytokine inhibitor
that inhibits interleukin (IL)-4, IL-5 and immunoglobulin E production, as well as local eosinophil accumulation [100]. In guinea-pigs, suplatast tosilate inhibited
antigen-induced cough hypersensitivity and airway
eosinophilia [100]. Agents that prevent eosinophilic
airway inflammation may offer therapeutic benefit to a
particular subgroup of patients suffering from chronic
cough.
GABAB agonists
As discussed above, the central inhibitory neurotransmitter baclofen, an agonist of the GABAB receptor, has
demonstrated antitussive activity against induced
as well as pathological cough [45,59–61]. A common
side-effect of baclofen, especially at high doses, is sedation. The discovery of potent GABAB agonists with less
sedative properties than baclofen may provide clinically useful antitussives.
5-Hydroxytryptamine (5-HT) receptor agonists
5-HT has been shown to suppress induced cough in
healthy volunteers [101]. Furthermore, pretreatment
with pizotifen, a 5-HT receptor antagonist, attenuated
the inhibitory effect of morphine against capsaicin-induced cough, thereby suggesting a role for 5-HT receptors in the antitussive, but not sedative, effect of opiates
[102]. Further insights into 5-HT receptor pharmacology may yield effective antitussive agents that lack the
undesirable side-effects of opiates.
Large conductance calcium-activated
potassium channel openers
Animal studies have provided evidence that modulation of potassium channels can attenuate experimentally induced cough. In guinea-pigs, the benzimidazolone
compound NS1619, an opener of large conductance
calcium-activated potassium (BKCa) channels,
inhibited airway sensory nerve activity (as measured by
single-fibre recording experiments) as well as citric
acid-induced cough [103]. Pinacidil, an ATP-sensitive
potassium channel opener, has been shown to inhibit
cough in guinea-pigs. The antitussive effect of pinacidil, as well as that of moguisteine, were attenuated
by glibenclamide, an ATP-sensitive potassium channel
blocker, thus suggesting a role for ATP-sensitive potas254
sium channels in the mechanism of action of both
agents [71].
References
1 Irwin RS, Curley FJ, French CL. Chronic cough. The
spectrum and frequency of causes, key components of
the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990; 141: 640–7.
2 Pratter MR, Bartter T, Akers S, Dubois J. An algorithmic
approach to chronic cough. Ann Intern Med 1993; 119:
977–83.
3 McGarvey LPA, Heaney LG, Lawson JT et al. Evaluation
and outcome of patients with chronic nonproductive
cough using a comprehensive diagnostic protocol.
Thorax 1998; 53: 738–43.
4 Schroeder K, Fahey T. Systematic review of randomised controlled trials of over the counter cough
medicines for acute cough in adults. Br Med J 2002; 324:
329–31.
5 Morice AH, Widdicombe J, Dicpinigaitis P, Groenke L.
Understanding cough. Eur Respir J 2002; 19: 6–7.
6 Smyrnios NA, Irwin RS, Curley FJ, French CL. From a
prospective study of chronic cough. Diagnostic and therapeutic aspects in older adults. Arch Intern Med 1998;
158: 1222–8.
7 Marchesani F, Cecarini L, Pela R, Sanguinetti CM.
Causes of chronic persistent cough in adult patients: the
results of a systematic management protocol. Monaldi
Arch Chest Dis 1998; 53: 510–14.
8 Irwin RS, Boulet LP, Cloutier MM et al. Managing cough
as a defense mechanism and as a symptom: a consensus
panel report of the American College of Chest Physicians. Chest 1998; 114 (Suppl.): 133S–81S.
9 Smyrnios NA, Irwin RS, Curley FJ. Chronic cough with a
history of excessive sputum production: the spectrum
and frequency of causes and key components of the diagnostic evaluation, and outcome of specific therapy. Chest
1995; 108: 991–7.
10 Gaffey MJ, Kaiser DL, Hayden FG. Ineffectiveness of
oral terfenadine in natural colds: evidence against histamine as a mediator of common cold symptoms. Pediatr
Infect Dis J 1988; 7: 223–8.
11 Berkowitz RB, Tinkelman DG. Evaluation of oral terfenadine for the treatment of the common cold. Ann
Allergy 1991; 67: 593–7.
12 Berkowitz RB, Connell JT, Dietz AJ, Greenstein SM,
Tinkelman DG. The effectiveness of the nonsedating
antihistamine loratadine plus pseudoephedrine in the
symptomatic management of the common cold. Ann
Allergy 1989; 63: 336–9.
13 Corrao WM, Braman SS, Irwin RS. Chronic cough as the
CURRENT AND FUTURE ANTITUSSIVE THERAPIES
14
15
16
17
18
19
20
21
22
23
24
25
26
27
sole presenting manifestation of bronchial asthma. N
Engl J Med 1979; 300: 633–7.
Irwin RS, French CL, Smyrnios NA, Curley FJ. Interpretation of positive results of a methacholine inhalation
challenge and 1 week of inhaled bronchodilator use in
diagnosing and treating cough-variant asthma. Arch
Intern Med 1997; 157: 1981–7.
Cheriyan S, Greenberger PA, Patterson R. Outcome of
cough variant asthma treated with inhaled steroids. Ann
Allergy 1994; 73: 478–80.
Brightling CE, Ward R, Goh KL, Wardlaw AJ, Pavord
ID. Eosinophilic bronchitis is an important cause of
chronic cough. Am J Respir Crit Care Med 1999; 160:
406–10.
Shim CS, Williams MH. Cough and wheezing from
beclomethasone diproprionate aerosol are absent after
triamcinolone acetonide. Ann Intern Med 1987; 106:
700–3.
Millar MM, McGrath KG, Patterson R. Malignant
cough-equivalent asthma: definition and case reports.
Ann Allergy Asthma Immunol 1998; 80: 345–51.
Doan T, Patterson R, Greenberger PA. Cough variant
asthma: usefulness of a diagnostic therapeutic trial with
prednisone. Ann Allergy 1992; 69: 505–9.
Tan RA, Spector SL. Chronic cough. Compr Ther 1997;
23: 467–71.
Nishi K, Watanabe K, Ooka T, Fujimura M, Matsuda T.
Cough-variant asthma successfully treated with a peptide leukotriene receptor antagonist (Japanese). Jpn J
Thorac Dis 1997; 35: 117–23.
Dicpinigaitis PV, Dobkin JB, Reichel J. Antitussive
effect of the leukotriene receptor antagonist zafirlukast
in subjects with cough-variant asthma. J Asthma 2002;
39: 291–7.
Niimi A, Matsumoto H, Minakuchi M, Kitaichi M,
Amitani R. Airway remodeling in cough-variant asthma.
Lancet 2000; 356: 564–5.
North American Tilade Study Group. A double-blind
multicenter group comparative study of the efficacy and
safety of nedocromil sodium in the management of asthma. Chest 1990; 97: 1299–306.
Shioya T, Ito N, Watanabe A et al. Antitussive effect of
azelastine hydrochloride in patients with bronchial asthma. Arzneimittel-Forschung 1998; 48: 149–53.
Jacobi HH, Skov PS, Poulsen LK, Malling HJ, Mygind N.
Histamine and tryptase in nasal lavage fluid after allergen challenge: effect of 1 week of pretreatment with intranasal azelastine or systemic cetirizine. J Allergy Clin
Immunol 1999; 103: 768–72.
Ito N, Shioya T, Watanabe A, Sano M, Sasaki M,
Miura M. Mechanism of the antitussive effect of azelastine in guinea pigs. Arzneimittel-Forschung 2002; 52:
441–7.
28 Irwin RS, French CL, Curley FJ, Zawacki JK, Bennett
FM. Chronic cough due to gastroesophageal reflux:
clinical, diagnostic, and pathogenetic aspects. Chest
1993; 104: 1511–17.
29 Ours TM, Kavuru MS, Schilz RJ, Richter JE. A prospective evaluation of esophageal testing and double-blind,
randomized study of omeprazole in a diagnostic and
therapeutic algorithm for chronic cough. Am J Gastroenterol 1999; 94: 3131–8.
30 Kiljander TO, Salomaa ERM, Hietanen EK, Terho EO.
Chronic cough and gastro-oesophageal reflux: a doubleblind, placebo-controlled study with omeprazole. Eur
Respir J 2000; 16: 633–8.
31 Irwin RS, Zawacki JK, Wilson MM, French CT, Callery
MP. Chronic cough due to gastroesophageal reflux
disease. Failure to resolve despite total/near total
elimination of esophageal acid. Chest 2002; 121:
1132–40.
32 Novitsky YW, Zawacki JK, Irwin RS, French CT, Hussey
VM, Callery MP. Chronic cough due to gastroesophageal reflux disease: efficacy of antireflux surgery.
Surg Endosc 2002; 16: 567–71.
33 Freestone C, Eccles R. Assessment of the antitussive
efficacy of codeine in cough associated with common
cold. J Pharm Pharmacol 1997; 49: 1045–9.
34 O’Connell F, Thomas VE, Studham JM, Pride NB,
Fuller RW. Capsaicin cough sensitivity increases during
upper respiratory infection. Respir Med 1996; 90:
279–86.
35 Poe RH, Harder RV, Israel RH, Kallay MC. Chronic
persistent cough. Experience in diagnosis and outcome
using an anatomic diagnostic protocol. Chest 1989; 95:
723–8.
36 Pizzichini MM, Pizzichini E, Parameswaran K et al.
Nonasthmatic chronic cough: no effect of treatment with
an inhaled corticosteroid in patients without sputum
eosinophilia. Can Respir J 1999; 6: 323–30.
37 Holmes PW, Barter CE, Pierce RJ. Chronic persistent
cough: use of ipratropium bromide in undiagnosed cases
following upper respiratory tract infection. Respir Med
1992; 86: 425–9.
38 Fujimori K, Suzuki E, Arakawa M. Effects of oxatomide,
H1-antagonist, on postinfectious chronic cough; a comparison of oxatomide combined with dextromethorphan
versus dextromethorphan alone (Japanese). Arerugi —
Jap J Allergol 1998; 47: 48–53.
39 Israili ZH, Hall WD. Cough and angioneurotic edema
associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 1992; 117: 234–42.
40 Hargreaves MR, Benson MK. Inhaled sodium cromoglycate in angiotensin-converting enzyme inhibitor cough.
Lancet 1995; 345: 13–16.
255
CHAPTER 24
41 Cazolla M, Matera MG, Liccardi G, De Prisco F,
D’Amato G, Rossi F. Theophylline in the inhibition
of angiotensin-converting enzyme inhibitor-induced
cough. Respiration 1993; 60: 212–15.
42 Fogari R, Zoppi A, Mugellini A, Preti P, Bauderali A,
Salvetti A. Effects of amlodipine, nifedipine GITS,
and indomethacin on angiotensin-converting enzyme
inhibitor-induced cough: a randomized, placebocontrolled, double-masked, crossover study. Curr Ther
Res 1999; 60: 121–8.
43 Malini PL, Strocchi E, Zanardi M, Milani M,
Ambrosioni E. Thromboxane antagonism and cough
induced by angiotensin-converting-enzyme inhibitors.
Lancet 1997; 350: 15–18.
44 Lee S-C, Park SW, Kim D-K, Lee SH, Hong KP. Iron
supplementation inhibits cough associated with ACE
inhibitors. Hypertension 2001; 38: 166–70.
45 Dicpinigaitis PV. Use of baclofen to suppress cough
induced by angiotensin-converting enzyme inhibitors.
Ann Pharmacother 1996; 30: 1242–5.
46 Umemura K, Nakashima M, Saruta T. Thromboxane A2
synthetase inhibitor suppresses cough induced by angiotensin converting enzyme inhibitors. Life Sci 1997;
60: 1583–8.
47 Tenenbaum A, Grossman E, Shemesh J, Fisman EZ,
Nosrati I, Motro M. Intermediate but not low doses of
aspirin can suppress angiotensin-converting enzyme
inhibitor-induced cough. Am J Hypertens 2000; 13:
776–82.
48 Lacourciere Y, Brunner H, Irwin R et al. Effects of modulators of the renin–angiotensin–aldosterone system on
cough. J Hypertens 1994; 12: 1387–93.
49 Chiu AG, Krowiak EJ, Deeb ZE. Angioedema associated
with angiotensin II receptor antagonists: challenging our
knowledge of angioedema and its etiology. Laryngoscope 2001; 111: 1729–31.
50 Aylward M, Maddock J, Davies DE, Protheroe DA,
Leideman T. Dextromethorphan and codeine: comparison of plasma kinetics and antitussive effects. Eur J
Respir Dis 1984; 65: 283–91.
51 Matthys H, Bleicher B, Bleicher U. Dextromethorphan
and codeine: objective assessment of antitussive activity
in patients with chronic cough. J Int Med Res 1983; 11:
92–100.
52 Empey DW, Laitinen LA, Young GA, Bye CE, Hughes
DJD. Comparison of the antitussive effects of codeine
phosphate 20 mg, dextromethorphan 30 mg, and
noscapine 30 mg using citric acid-induced cough in normal subjects. Eur J Clin Pharmacol 1979; 16: 393–7.
53 Dicpinigaitis PV, Dobkin JB, Rauf K. Comparison of
the antitussive effects of codeine and the GABA-agonist
baclofen. Clin Drug Invest 1997; 14: 326–9.
54 Pavesi L, Subburaj S, Porter-Shaw K. Application and
256
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
validation of a computerized cough acquisition system
for objective monitoring of acute cough. Chest 2001;
120: 1121–8.
Ziment I. Agents that affect mucus and cough. In: Witek
TJ, Schacter EN, eds. Pharmacology and Therapeutics in
Respiratory Care. Philadelphia: W.B. Saunders, 1994:
239–57.
Packman EW, Ciccone PE, Wilson J, Masurat T. Antitussive effects of diphenhydramine on the citric acid
aerosol-induced cough response in humans. Int J Clin
Pharmacol Ther Toxicol 1991; 29: 218–22.
Lillienfield LS, Rose JC, Princiotto JV. Antitussive activity of diphenhydramine in chronic cough. Clin Pharmacol Ther 1976; 19: 421–5.
Bolser DC, DeGennaro FC, O’Reilly S et al. Peripheral
and central sites of action of GABA-B agonists to inhibit
the cough reflex in the cat and guinea pig. Br J Pharmacol
1994; 113: 1344–8.
Dicpinigaitis PV, Dobkin JB. Antitussive effect of the
GABA-agonist baclofen. Chest 1997; 111: 996–9.
Dicpinigaitis PV, Dobkin JB, Rauf K, Aldrich TK. Inhibition of capsaicin-induced cough by the g-aminobutyric
acid agonist baclofen. J Clin Pharmacol 1998; 38:
364–7.
Dicpinigaitis PV, Rauf K. Treatment of chronic, refractory cough with baclofen. Respiration 1998; 65: 86–8.
Banner AS. Pharmacologic treatment of cough. In:
Leff AR, ed. Pulmonary and Critical Care Pharmacology
and Therapeutics. New York: McGraw-Hill, 1996:
673–9.
Doona M, Walsh D. Benzonatate for opioid-resistant
cough in advanced cancer. Palliat Med 1997; 12: 55–8.
Lavezzo A, Mellilo G, Clavenna G, Omini C. Peripheral
site of action of levodropropizine in experimentallyinduced cough: role of sensory neuropeptides. Pulm
Pharmacol 1992; 5: 143–7.
Bossi R, Braga PC, Centanni S, Legnani D, Moavero NE,
Allegra L. Antitussive activity and respiratory system
effects of levodropropizine in man. ArzneimittelForschung 1988; 38: 1159–62.
Bariffi F, Tranfa C, Vatrella A, Ponticiello A. Protective
effect of levodropropizine against cough induced by
inhalation of nebulized distilled water in patients with
obstructive lung disease. Drugs Exp Clin Res 1992; 18:
113–18.
Allegra L, Bossi R. Clinical trials with the new antitussive
levodropropizine in adult bronchitic patients.
Arzneimittel-Forschung 1988; 38: 1163–6.
Catena E, Daffonchio L. Efficacy and tolerability of levodropropizine in adult patients with non-productive
cough. Comparison with dextromethorphan. Pulm
Pharmacol 1997; 10: 89–96.
Luporini G, Barni S, Marchi E, Daffonchio L. Efficacy
CURRENT AND FUTURE ANTITUSSIVE THERAPIES
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
and safety of levodropropizine and dihydrocodeine on
nonproductive cough in primary and metastatic lung
cancer. Eur Respir J 1998; 12: 97–101.
Gallico L, Borghi A, Dalla Rosa C, Ceserani R, Tognella
S. Moguisteine: a novel peripheral non-narcotic antitussive drug. Br J Pharmacol 1994; 112: 795–800.
Morita K, Kamei J. Involvement of ATP-sensitive K(+)
channels in the antitussive effect of moguisteine. Eur J
Pharmacol 2000; 395: 161–4.
Aversa C, Cazzola M, Clini V et al. Clinical trial of the
efficacy and safety of moguisteine in patients with cough
associated with chronic respiratory diseases. Drugs Exp
Clin Res 1993; 19: 273–9.
Barnabe R, Berni F, Clini V et al. The efficacy and safety
of moguisteine in comparison with codeine phosphate in
patients with chronic cough. Monaldi Arch Chest Dis
1995; 50: 93–7.
Hansson L, Midgren B, Karlsson JA. Effects of inhaled
lignocaine and adrenaline on capsaicin-induced cough in
humans. Thorax 1994; 49: 1166–8.
Trochtenburg S. Nebulized lidocaine in the treatment of
refractory cough. Chest 1994; 105: 1592–3.
Udezue E. Lidocaine inhalation for cough suppression.
Am J Emerg Med 2001; 19: 206–7.
Peleg R, Binyamin L. Practice tips. Treating persistent
cough. Try a nebulized mixture of lidocaine and bupivacaine. Can Fam Physician 2002; 48: 275.
Schappert SM. Ambulatory care visits to physician offices, hospital outpatient departments, and emergency
departments: United States, 1995. Vital Health Stat 13
1997; 129: 1–38.
Tukiainen H, Karttunen P, Silvasti M et al. The treatment
of acute transient cough: a placebo-controlled comparison of dextromethorphan and dextromethorphanbeta-2-sympathomimetic combination. Eur J Respir Dis
1986; 69: 95–9.
Lee PCL, Jawad MS, Eccles R. Antitussive efficacy of
dextromethorphan in cough associated with acute upper
respiratory tract infection. J Pharm Pharmacol 2000; 52:
1137–42.
Adams R, Hosie J, James I et al. Antitussive activity and
tolerability of moguisteine in patients with acute cough:
a randomized, double-blind, placebo-controlled study.
Adv Ther 1993; 10: 263–71.
Curley FJ, Irwin RS, Pratter MR et al. Cough and the
common cold. Am Rev Respir Dis 1988; 138: 305–11.
Expectorant Drug Products for Over-the-Counter
Human Use: Final Monograph. Washington DC: US
Department of Health and Human Services; Federal
Register, 1989; 54: 8494–509.
Hirsch SR, Viernes PF, Kory RC. The expectorant effect
of glyceryl guaiacolate in patients with chronic bronchitis. Chest 1973; 63: 9–14.
85 Houtmeyers E, Gosselink R, Gayan-Ramirez G,
Decramer M. Effects of drugs on mucus clearance. Eur
Respir J 1999; 14: 452–67.
86 Robinson RE, Cummings WB, Deffenbaugh ER.
Effectiveness of guaifenesin as an expectorant: a cooperative double-blind study. Curr Ther Res 1977; 22:
284–96.
87 Kuhn JJ, Hendley JO, Adams KF, Clark JW, Gwaltney
JM. Antitussive effect of guaifenesin in young adults with
natural colds. Chest 1982; 82: 713–18.
88 Kotzer CJ, Hay DW, Dondio G, Giardina G, Petrillo P,
Underwood DC. The antitussive activity of delta-opioid
receptor stimulation in guinea pigs. J Pharmacol Exp
Ther 2000; 292: 803–9.
89 Bolser DC, McLeod RL, Tulshian DB, Hey JA. Antitussive action of nociceptin in the cat. Eur J Pharmacol
2001; 430: 107–11.
90 McLeod RL, Parra LE, Mutter JC et al. Nociceptin
inhibits cough in the guinea-pig by activation of ORL1
receptors. Br J Pharmacol 2001; 132: 1175–8.
91 Jia Y, Wang X, Aponte SI et al. Nociceptin/orphanin FQ
inhibits capsaicin-induced guinea-pig airway contraction through an inward rectifier potassium channel. Br J
Pharmacol 2002; 135: 764–70.
92 Advenier C, Lagente V, Boichot E. The role of tachykinin
receptor antagonists in the prevention of bronchial
hyperresponsiveness, airway inflammation and cough.
Eur Respir J 1997; 10: 1892–906.
93 Joos GF, Pauwels RA. Pro-inflammatory effects of substance P: new perspectives for the treatment of airway
disease? Trends Pharmacol Sci 2000; 21: 131–3.
94 Moreaux B, Nemmar A, Vincke G et al. Role of substance P and tachykinin receptor antagonists in citric
acid-induced cough in pigs. Eur J Pharmacol 2000; 408:
305–12.
95 Hay DW, Giardina GA, Griswold DE et al. Nonpeptide
tachykinin receptor antagonists. III. SB 235375, a low
central nervous system-penetrant, potent and selective
neurokinin-3 receptor antagonist, inhibits citric acidinduced cough and airways hyperreactivity in guinea
pigs. J Pharmacol Exp Ther 2002; 300: 314–23.
96 Midgren B, Hansson L, Karlsson J-A, Simonsson BG,
Perrson CGA. Capsaicin-induced cough in humans. Am
Rev Respir Dis 1992; 146: 347–51.
97 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA,
Levine JD, Julius D. The capsaicin receptor: a heatactivated ion channel in the pain pathway. Nature 1997;
389: 816–24.
98 Mezey E, Toth ZE, Cortright DN et al. Distribution of
mRNA for vanilloid receptor subtype 1 (VR1), and VR1like immunoreactivity, in the central nervous system of
the rat and human. Proc Natl Acad Sci USA 2000; 97:
3655–60.
257
CHAPTER 24
99 Calignano A, Katona I, Desarnaud F et al. Bidirectional
control of airway responsiveness by endogenous
cannabinoids. Nature 2000; 408: 96–101.
100 Myou S, Fujimura M, Kurashima K et al. Effects of
suplatast tosilate, a new type of anti-allergic agent, on
airway cough hypersensitivity induced by airway allergy
in guinea pigs. Clin Exp Allergy 2001; 31: 1939–44.
101 Stone RA, Worsdell YM, Fuller RW, Barnes PJ. Effects of
5-hydroxytryptamine and 5-hydroxytryptophan infu-
258
sion on the human cough reflex. J Appl Physiol 1993; 74:
396–401.
102 O’Connell F. Central pathways for cough in man —
unanswered questions. Pulm Pharmacol Ther 2002;
15: 295–301.
103 Fox AJ, Barnes PJ, Venkatesan P, Belvisi MG. Activation
of large conductance potassium channels inhibits the
afferent and efferent function of airway sensory nerves
in the guinea pig. J Clin Invest 1997; 99: 513–19.
25
Placebo effects of antitussive
treatments on cough associated
with acute upper respiratory
tract infection
Ronald Eccles
Introduction
Treatment of cough associated with acute upper respiratory tract infection (URTI) is mainly based on the
treatment of cough as a symptom rather than treating
the underlying viral infection. Many cough medicines
for the treatment of cough associated with URTI contain codeine or dextromethorphan, which are believed
to act by inhibiting the central control of cough [1].
However, studies on the antiussive effects of codeine
and dextromethorphan in patients with cough associated with URTI have often failed to demonstrate that
these medicines have any greater effect on cough than
placebo treatment [2–4].
The very large effect of placebo treatment on cough
in clinical trials on antitussive medicines has usually
been perceived as a problem in clinical trial design and
there has been little interest in trying to understand the
nature of this antitussive placebo response.
This chapter will discuss the various factors that influence the severity of cough when a patient is treated
with a cough medicine, and in particular will focus on
the nature of the placebo response on cough associated
with URTI.
Factors that influence changes in cough
severity in a clinical trial
Since the introduction of the double-blind placebocontrolled clinical trial as a standard tool of clinical research, any placebo component of treatment has been
considered more of a nuisance to the investigator than a
benefit to the patient. Clinical trials are designed to test
the superiority of the pharmacological component of
the treatment compared with any placebo component,
and there is little interest in trying to understand or
quantify the placebo effect in clinical trials.
The results of a representative clinical trial to investigate the effects of an antitussive medicine on cough associated with URTI are illustrated in Fig. 25.1 [4]. In
this study the reduction in cough frequency following
treatment with a single dose of 30 mg dextromethorphan in capsule form appears impressive, until it is
compared with the reduction in cough frequency associated with treatment with an identical capsule containing only lactose (placebo). The magnitude and time
course of the changes in cough frequency associated
with placebo treatment are almost identical to those associated with treatment with the active medicine. The
importance of including a placebo control in clinical
trials on antitussive medicines can be clearly seen from
the results of the trial illustrated in Fig. 25.1. Without a
placebo control it would be impossible to determine the
antitussive effect of the dextromethorphan.
The changes in cough frequency associated with
treatment with an antitussive medicine, such as a cough
syrup containing dextromethorphan, can be attributed
to at least four different effects: a pharmacological effect, a physiological effect, a true placebo effect, and a
non-specific effect as illustrated in Fig. 25.2. These four
effects of treatment are discussed below.
Pharmacological effect
The pharmacological effect of treatment with a cough
medicine is related to the active ingredient of the medicine, such as codeine or dextromethorphan. The phar259
CHAPTER 25
Cough frequency per 10 min
60
50
40
30
20
10
Baseline
90
135
180
Time (min)
Fig. 25.1 Median cough frequency for patients with cough
associated with upper respiratory tract infection. A single
dose of 30 mg dextromethorphan powder in a hard gelatin
capsule or matched placebo containing lactose powder was
ingested by the patient with a small amount of water. Treatment groups: placebo (䊊), n = 22; dextromethorphan (䊉),
n = 21 [4].
macologically active ingredient has a high affinity for a
specific pharmacological receptor, such as the interaction of codeine with opioid receptors. Slight changes in
the molecular structure of the active ingredient may
have marked effects on its affinity with the receptor and
its biological activity.
In clinical trials on cough medicines, it is the pharmacological effect of the medicine that is under investigation, and any other effects of the treatment are
controlled by comparison with the effects of a placebo
medication that is identical in appearance, colour,
taste, etc. with the active medication.
Physiological effect
The physiological effects of treatment are the nonpharmacological effects of the treatment such as taste,
smell and colour. Physical and chemical properties of
the medicine such as viscosity, pH and temperature
may also be important. These properties can influence
the magnitude of the placebo effect as they provide sensory information about the nature of the treatment.
260
The physiological component of treatment is usually
included as part of the placebo effect, as it is difficult to
separate some of the physiological effects of treatment
from the placebo effect. However, a case can be made
that some aspects of the physiological effect are quite
separate from the placebo effect of treatment. Since the
majority of cough medicines are sugar-based syrups
there has been some speculation that a demulcent effect
of the sugar may make a major contribution to the antitussive activity of the medicine [5]. Such a demulcent
effect would be in addition to any pharmacological
and placebo effects of the medicine.
The demulcent action of the syrup has been proposed
to exert its antitussive effect by at least three mechanisms according to Fuller [5].
1 The sugar content of the cough mixture encourages
saliva production and swallowing; the act of swallowing may interfere with the cough reflex.
2 The sugar solution may coat sensory nerve
endings in the epipharynx and cause their stimulation;
this stimulation may suppress cough by a ‘gating’
process.
3 The sugar solution may act as a protective barrier
to sensory receptors that can either produce cough or
heighten the cough reflex.
The demulcent effect of antitussive medicines is exploited to the maximum in cough syrups that contain
sapid substances such as sugar and honey, and bittertasting substances such as lemon and citric acid. These
sapid substances promote salivation and may also
promote secretion of airway mucus. Gustatory rhinorrhoea has been shown to occur after eating spicy foods,
and this observation demonstrates a link between gustation and airway secretion of mucus [6]. Many cough
medicines contain capiscum which is a potent gustatory stimulus and which may also promote airway
secretions. The fact that almost all cough medicines
are formulated as a sapid syrup indicates that the
demulcent action of the syrup may contribute to
the antitussive activity of the treatment or make the
medicine more palatable.
Cooling and warming agents are often added to give
extra sensations to the treatment and these agents may
influence the activity of cold and warm receptors. Cooling agents such as menthol are sometimes included as
flavouring agents in cough medicines, although menthol may also have pharmacological activity as a local
anaesthetic [7]. The cooling properties of menthol and
other cooling agents could also be considered as a phar-
PLACEBO EFFECTS OF TREATMENT
ACTIVE
MEDICINE
Pharmacological
PLACEBO
CONTROL
Fig. 25.2 Components of a cough
medicine. The reduction in cough
severity in a clinical trial may be explained by four different effects: pharmacological (related to the active
ingredient); physiological (related to a
demulcent effect, salivation and swallowing); true placebo (related to the
sensory impact of the treatment and
belief about the efficacy of the treatment); and non-specific (related to natural recovery of patients). The figure
illustrates the components in three
treatments: active medicine, placebo
control and ‘no treatment’.
Physiological
Physiological
True placebo
True placebo
NO
TREATMENT
Non-specific
macological component of treatment, as there is some
evidence that cooling properties are determined by
interaction with a menthol type of pharmacological
receptor on sensory nerves [7]. Although menthol is
usually declared as a flavouring agent in cough medicines there is some evidence that it may have specific
antitussive activity [8].
Other medicines apart from cough medicines may
have a physiological effect that can be distinguished
from a pharmacological or placebo effect. The efficacy
of throat lozenges for the treatment of sore throat is
mainly related to the stimulation of salivation, and in
this respect there is some similarity between the effects
of throat lozenges and cough syrups. Many treatments
for common cold are taken as a hot tasty drink, and this
mode of treatment may have a physiological effect by
stimulating salivation and airway secretions.
The physiological effect of a cough syrup may exhibit similar characteristics to a pharmacological effect,
with a time course of action, peak effect, cumulative
effect and carry-over effect, but at present there is no information on the pharmacodynamics of any physiological effect of treatment on cough. In the case of cough
Non-specific
Non-specific
medicines, there is likely to be a large physiological effect with a cough syrup, but little, if any, physiological
effect with a tablet or capsule formulation.
Placebo effect
A major problem in defining the placebo effect of a
cough treatment is that the effects attributed to placebo
treatment often include those effects that could also be
attributed to natural recovery from the disease. Some
definitions of the placebo effect of treatment refer to all
those effects of treatment apart from the pharmacological effects [9]. But this definition is too broad as it includes any changes associated with natural recovery
from the disease, and any physiological effects of the
medicine.
The placebo effect (as measured in a clinical trial) has
been divided into a perceived placebo effect and a true
placebo effect by Ernst and Resch [10]. This division
will be used in the present discussion.
The perceived placebo effect is defined as the total effect of the placebo medicine, which includes the true
placebo effect and other effects such as any physiologi261
CHAPTER 25
cal effect, and non-specific effects such as natural recovery from the disease. The perceived placebo effect is
normally measured in a placebo-controlled clinical
trial, but it is not possible to estimate the contribution
of the true placebo effect to any changes in cough severity from this parameter, as the perceived placebo effect
also includes the physiological effect and non-specific
effect of treatment as shown in Fig. 25.2.
In clinical trials where a ‘no treatment’ group is included in the design, it is possible to control for any
non-specific effects of treatment by subtracting any
changes in the no treatment group from those changes
observed in the placebo treatment group. This leaves us
with a measure of any true placebo effect plus any physiological effect. In the case of cough treatments that use
a tablet or capsule formulation, any physiological effect of treatment will be minimal and the use of a no
treatment group will allow determination of the true
placebo effect. But in the case of a cough syrup there
could be a large physiological effect and it will not be
possible to separate this from any true placebo effect.
The true placebo effect refers to a psychological therapeutic effect of the treatment, and this will depend on
many factors such as the belief in the effectiveness of the
treatment, the attitude of the patient towards the therapist, and what the therapist says to the patient.
The psychological therapeutic effect attributed to the
true placebo effect of treatment with a cough medicine
is related to the patient’s belief about the efficacy of the
medicine [11]. The degree of belief in the treatment will
depend on many factors, such as the healer–patient interaction, cultural beliefs about traditional treatments,
the environment in which the medicine is administered,
the properties of the medicine such as taste, colour and
smell, advertising and claims made about the efficacy of
the medicine, the brand name of the medicine, and sideeffects associated with treatment that may reinforce the
belief of efficacy. This list of factors that may influence
the efficacy of a placebo is not exhaustive, and it
illustrates how difficult it is to properly control and
standardize studies on the true placebo effect.
Non-specific effect
‘Sick people often get better’. In an acute illness natural
recovery may occur and this is not due to any effect of
the treatment [10].
Patients recruited to a clinical trial to determine
the efficacy of an antitussive medicine are screened to
262
determine the severity of cough, as only those patients
with a high subjective score and/or objective measure of
cough are recruited for the study. By recruiting only
those patients with a severe or troublesome cough and
excluding those patients with a mild cough, the population of patients on the trial is skewed towards those
with a severe cough. In these circumstances the cough
severity of the patients on trial is unlikely to increase
during the course of the study and it is more likely that
the cough severity will decrease due to the process of
natural recovery. The mean measure of cough severity
is likely to decline during the course of the clinical trial
and this statistical effect is often referred to as ‘regression to mean’ [9]. The changes in cough frequency illustrated in Fig. 25.1 could be explained by regression to
mean since the patients were recruited with high cough
frequency and this declined in both treatment groups
during the course of the study.
It is not possible to control for the effects of rest and
spontaneous recovery in controlled clinical trials that
involve only placebo and active treatment groups, as
both these treatment groups will be affected by rest and
recovery. However, if a ‘no treatment’ group is included
in the trial design then this will allow direct comparison
with the placebo treatment group [10]. If the ‘no treatment’ group does not show any great change in cough
severity during the course of the study then any change
in the placebo group must be due to a true placebo
effect (plus a physiological effect if the treatment is a
syrup). In a study on patients with cough associated
with URTI comparing the antitussive effects of ‘no
treatment’ vs. placebo treatment, the ‘no treatment’
group had a 7% decrease in cough frequency compared
to a 50% decrease in the placebo treatment group [12].
In this study the placebo medicine was a capsule, rather
than a syrup, so the placebo effect cannot be explained
by a demulcent effect of the treatment, or by rest, and it
may be reasonably defined as a true placebo effect.
Magnitude of the perceived
placebo response
A literature survey found eight placebo-controlled clinical trials on antitussive medicines used in the treatment
of cough associated with URTI [2–4,13–15], and the
results of these studies are given in Fig. 25.3 and Table
25.1. The formulation of the placebo medication was
a syrup in two of the studies [2,13] and a capsule or
Percentage placebo response
relative to active treatment
PLACEBO EFFECTS OF TREATMENT
125
100
75
50
25
0
1
2
3
4
5
6
7
8
Study number
Fig. 25.3 Magnitude of perceived placebo response relative
to active medication in clinical trials on cough associated
with upper respiratory tract infection. The perceived placebo
response is calculated as a percentage relative to the change in
cough observed with the active medication. Therefore a perceived placebo response of 100% means that the change in
cough severity on placebo treatment is equal to that observed
with treatment with the active medicine. The study numbers
refer to those given in Table 25.1 which gives further details
of the studies.
tablet in the remaining studies. Only subjective scores
were used in the early studies [13,14], whereas both
subjective and objective measures of cough were used
in the later studies [2–4,15].
The studies are presented in order to assess the magnitude of the perceived placebo effect rather than
debate the efficacy of the antitussive medications. The
perceived placebo effect is calculated as a percentage
relative to the change in cough observed with the active
medication. Thus in the study by Tukiainen et al. [13] a
perceived placebo effect of 105% indicates that the
placebo treatment was actually more effective than the
active medicine in treating cough. Theoretically, one
would expect the maximum perceived placebo effect to
be equal to or less than 100% of the active treatment
effect as all aspects of the placebo treatment should
be present in the active treatment. A perceived placebo
effect above 100% may be explained by variance in
the measures of cough.
The perceived placebo effect varied from a minimum
of 56% up to a maximum of 105% with a mean of
85%. Six of the eight studies had a perceived placebo effect of over 80%. The three studies by Parvez et al. [15]
had the lowest perceived placebo effects. This may be
because of the relatively greater pharmacological effect
of dextromethorphan in their study population of
Indian patients compared to a European or American
population. The Indian patients had an average body
weight of around 50 kg, with some patients having a
body weight as low as 27 kg. The greater antitussive activity of dextromethorphan demonstrated in the Indian
patients may indicate that higher doses of dextromethorphan will have a similar antitussive efficacy
in the heavier patients in the other studies. However,
the greater efficacy in the Indian patients may also be
explained by side-effects that perhaps reinforce and increase the magnitude of the placebo effect of the active
treatment.
The mean perceived placebo effect of 85% can be attributed to a true placebo effect plus other non-specific
factors such as natural recovery and, in the case of a
cough syrup, a physiological effect.
Mechanism of the true placebo effect
Science and medicine have debated the relevance of
mind and body interactions for over 2000 years and
there has been much debate about the role of the mind
in the onset and treatment of disease. There is very good
evidence which indicates that the mind does influence
many bodily functions. Voluntary control of skeletal
muscle and voluntary control of cough are well-established examples of mind–body interactions. The ‘flight
or fight response’ with activation of the sympathetic
nervous system when a real or imaginary threat is perceived is an example of a mind–body interaction that is
not under voluntary control [16].
Studies on patients with cough associated with URTI
have demonstrated that cough can be voluntarily
suppressed and that there is an inverse relationship
between the duration of cough suppression and the
baseline frequency of cough [17]. In general, one would
expect that any therapeutic effect of treatment would
be greatest in those patients with the most severe illness.
Similarly the magnitude of any placebo effect may be
related to the severity of the illness.
The fact that cough can be initiated and inhibited
voluntarily demonstrates a link between the mind
and the control of cough. However, discussion on
mind–body interactions is limited by the problem that
there is no real understanding of what exactly constitutes the mind. If one accepts that the basis of mind depends on complex neurophysiological activity, then at
263
Study
no.
Investigator
Medication
Dosing
Duration of study
Cough measure
Placebo
response (%)
Patients
1
Tukiainen et al. (1986)
Dextromethorphan
syrup?
30 mg 3 times
daily
4 days
Subjective cough
frequency on day
4 of treatment
105
P > 0.05 n.s.*
108 patients with acute
cough
2
Adams et al. (1993)
Moguisteine tablets
200 mg twice
a day
3.5 days
Subjective cough
severity on day 3
of treatment
88
P > 0.05 n.s.†
108 patients with acute
cough
3
Eccles et al. (1992)
Codeine syrup
30 mg single
dose
Laboratory study
on 1 day
Cough frequency
at 150 min after
treatment
105
P > 0.05 n.s.
91 patients with cough
associated with URTI
4
Parvez et al. (1996)
Study 1
Dextromethorphan
capsules
30 mg single
dose
Laboratory study
on 1 day
Cough bouts at 120–
150 min after
treatment
56
P > 0.05 n.s.
108 patients with cough
associated with URTI
5
Parvez et al. (1996)
Study 2
Dextromethorphan
capsules
30 mg single
dose
Laboratory study
on 1 day
Cough bouts at 120–
150 min after
treatment
55
P < 0.05
134 patients with cough
associated with URTI
6
Parvez et al. (1996)
Study 3
Dextromethorphan
capsules
30 mg single
dose
Laboratory study
on 1 day
Cough bouts at 150–
180 min after
treatment
83
P > 0.05 n.s.
209 patients with cough
associated with URTI
7
Freestone et al. (1997)
Codeine capsule
50 mg single
dose
Laboratory study
on 1 day
Cough frequency at
90 min after
treatment
104
P > 0.05 n.s.
82 patients with cough
associated with URTI
8
Lee et al. (2000)
Dextromethorphan
capsules
30 mg single
dose
Laboratory study
on 1 day
Cough frequency at
180 min after
treatment
82
P > 0.05 n.s.
43 patients with cough
associated with URTI
The probability values (P) refer to the difference between the active treatment and placebo.
n.s., not significant.
* Not significant on any day.
† Main group analysis not significant on any day but some subgroups with high cough scores did show a significant difference on some days.
CHAPTER 25
264
Table 25.1 Magnitude of placebo response relative to active medication in clinical trials on cough associated with upper respiratory tract infection (URTI). The
placebo response is calculated as a percentage relative to the change in cough observed with the active medication. Therefore a placebo response of 100% means that
the change in cough severity is equal to that observed with treatment with the active medication.
PLACEBO EFFECTS OF TREATMENT
some point this neurophysiological activity must link
up via distinct nervous pathways with the area of the
brain that controls cough. It is at this point that we
move from the realms of mind into the more easily understood realms of neuroscience. If the belief that one is
exposed to danger can bring about a range of autonomic nervous responses, then it is reasonable to assume
that belief about the effects of treatment may also
influence bodily functions such as the control of cough.
This interaction can be termed a psychoneuropharmacological response that implies that a mind response
has triggered a distinct nervous pathway with its own
neurotransmitters that can be influenced by pharmacological intervention.
The placebo response associated with the treatment
of pain has been explained on the basis that the belief in
treatment in some way activates nervous pathways that
cause the release of endogenous opioid substances [18].
Treatment with exogenous opioids such as codeine and
morphine may inhibit pain by mimicking the effects of
endogenous opioids. Thus administration of a placebo
may inhibit pain by a placebo effect that causes the
release of endogenous opioids. The analgesic effect of
placebo treatment can be inhibited by administration
of opioid antagonists such as naloxone [19], and this
supports the theory that endogenous opioids are
involved in the placebo response to pain.
There are many similarities between the pharmacology of analgesics and the pharmacology of antitussives,
as codeine and morphine are potent analgesics and antitussives. The hypothesis that the placebo analgesia is
mediated by endogenous opioids may also be relevant
to cough, as the true placebo antitussive response may
also be mediated by endogenous opioids.
Kinetics and dynamics of
true placebo effect
‘In a literal sense, there can be no such thing as the pharmacokinetics of a placebo because there is nothing to be
absorbed, distributed, metabolized, excreted or sought
at specific tissue sites’ [16]. However, ‘placebo-generated perceptions can result in the production or release of
endogenous active materials that may indeed have a
kinetic fate analogous to that of administered active
exogenous drugs’ [16]. A review by Lasagna et al. [20]
on the ‘pharmacology’ of placebo medicines discusses
time–effect curves, peak effects, cumulative effects and
‘carry-over’ effects. All of these properties of the true
placebo effect support the concept that placebo treatment can be studied in terms of pharmacokinetics and
pharmacodynamics. This implies that treatment with a
placebo in some way influences neurotransmitter systems in the brain and that the pharmacology of the true
placebo effect is related to the pharmacology of the
neurotransmitters [21]. The release and actions of the
central neurotransmitters associated with the true
placebo effect is not an ‘on and off’ effect, but an effect
with a definite time course and peak effect, similar to
that obtained by administration of a pharmacologically active medicine.
Cough model
A model illustrating the true placebo effect of cough
treatment is illustrated in Fig. 25.4. The model proposes that cough may be initiated by two separate mechanisms, reflex cough and voluntary cough.
Reflex cough is initiated by airway irritation mediated by the vagus nerve that relays with the cough control
centre in the respiratory area of the brainstem. When
airway irritation reaches a sufficient level, cough is
initiated via a descending pathway from the brainstem
to the respiratory muscles. The descending pathway
controlling cough may be different from that controlling spontaneous breathing [22]. Reflex cough can also
be initiated by the entry of food and fluid into the
airway.
Voluntary cough can be initiated by a sensation of
airway irritation mediated by the vagus nerve, with
central pathways ascending from the cough control
centre in the brainstem to the cerebral cortex. Cough is
initiated from the cortex by descending pathways to the
cough control centre in the brainstem. The pathway
from the cerebral cortex to the cough centre may induce
or inhibit cough, as experimental studies in humans
have shown that cough associated with URTI can be
voluntarily inhibited [17]. The term ‘voluntary cough’
does not necessarily mean a cough that is ‘willed’ or ‘desired’, but a cough that can be voluntarily inhibited,
whereas reflex cough cannot be suppressed. It is possible that all types of human cough involve a sensation of
irritation and involve both cortical and brainstem
mechanisms, but that the relative involvement of cortical control varies from complete control to almost no
influence on the cough response.
265
CHAPTER 25
Placebo treatment
Sensory perception of treatment
Belief in treatment
Cerebral cortex
Voluntary
control
of cough
True placebo effect
Sensation
of
irritation
Cough control
centre
+ve
Endogenous
opioids
–ve
Exogenous
opioids
Respiratory area of brainstem
Vagus
nerve
Airway irritation
Respiratory
muscles
COUGH
Cough can be thought of as varying from a reflex
cough that cannot be inhibited, such as cough in
response to food or fluid entering the airway, to a
voluntary cough that is used as a signal or means of
communicating. In these cases the reflex cough may be
initiated via the brainstem pathway, and the voluntary
cough initiated via the cerebral cortex. Cough associated with URTI may be a mix of reflex and voluntary
cough, as some of the cough can be suppressed by
voluntary control [17].
The cough control model illustrated in Fig. 25.4 indicates that placebo treatment causes a true placebo effect via sensory perception of the placebo treatment.
This assumes that treatment with a placebo medicine
must be perceived by the patient via sensory cues, such
266
Fig. 25.4 Model to illustrate the control of cough, and the mechanism of
the true placebo effect. Airway irritation causes cough via a reflex pathway
in the respiratory area of the brainstem
and may also initiate voluntary cough
via a sensation of irritation and the
cerebral cortex. The cerebral cortex
may induce or inhibit cough via a
pathway that influences the activity of
the cough control centre in the brainstem. The act of taking a placebo
cough medicine initiates a true placebo
response that influences cough via a
pathway from the cerebral cortex to
the cough control centre. This pathway
may involve endogenous opioid
neurotransmitters. Exogenous opioids
such as morphine and codeine may
mimic the inhibitory effects of endogenous opioids.
as sight, taste and smell, if the placebo treatment is to
have any true placebo effect. If the patient is not aware
that they are being treated then it is not possible for the
treatment to exert any psychological effect. The belief
by the patient that they are being treated with an effective medicine may be related to previous experience and
belief in the system of medicine in their culture. If the
patient has little belief in the efficacy of the treatment
then the true placebo effect may be limited.
The true placebo effect represents the interface between mind and body interactions and can be discussed
in terms of psychoneuropharmacology as described
above. At some point the neurophysiological activity
associated with the true placebo effect must link up via
distinct nervous pathways with the area of the brain
PLACEBO EFFECTS OF TREATMENT
that controls cough, and modify cough via a descending
pathway from the cerebral cortex to the brainstem
cough centre. Inhibition of cough via a true placebo effect need not enter consciousness as the true placebo effect could operate outside of consciousness. Although
both voluntary control of cough and the true placebo
effect on cough may share a common final pathway to
influence cough, the sites initiating these responses may
be in different parts of the brain.
The descending pathway from the cerebral cortex
that inhibits cough may do so by the release of endogenous opioid neurotransmitters [21]. This would explain why opioids such as morphine and codeine when
administered exogenously act as antitussives.
Discussion
One definition of the placebo nicely fits in with its effects on cough, and states that the placebo is the ‘most
effective medication known to science, subjected to
more clinical trials than any other medicament yet
nearly always does better than anticipated’ [23]. The
majority of published studies on the effects of antitussive medicines on cough associated with URTI have
demonstrated that placebo treatment is just as effective
as the active medicine, and there must be a large number of clinical studies on file that have never been published in the public domain that support the antitussive
efficacy of placebo treatment. One could criticize some
of the studies on their design, population size, etc., but
the overall impression is that there is little difference in
antitussive activity between placebo treatments and active pharmacological treatments such as codeine and
dextromethorphan when administered in the over-thecounter dose range for treatment of cough associated
with URTI. The present review has concentrated on the
antitussive effect of placebo treatments in clinical trials
on cough associated with URTI, and the results and discussion may not be relevant to other types of cough
such as chronic cough [24,25] and induced cough in
healthy volunteers [26] where antitussives such as
codeine and dextromethorphan appear to have significantly greater efficacy than placebo treatment.
The fact that placebo treatment is often as effective
as treatment with codeine and dextromethorphan for
cough associated with URTI can be interpreted in
several ways. It may indicate that codeine and dextromethorphan are relatively ineffective in treating
cough associated with URTI. A meta-analysis of studies
on dextromethorphan indicates that the average superiority of dextromethorphan above placebo ranges
from 12 to 17% [27]. This indicates that placebo treatment is responsible for 83–88% of the reduction in
cough. In other studies the perceived placebo effect has
been responsible for 100% of the reduction in cough
[2–4]. These results could be interpreted as supporting
a very powerful antitussive placebo effect, but since
there is no comparison with a ‘no treatment’ control
group in these studies, it is also possible that nonspecific effects such as natural recovery have a great
contribution to the perceived placebo effect.
More cough clinical trials are needed that use a ‘no
treatment’ group in order to determine the true placebo
effect and control for factors such as natural recovery.
The vehicle syrup used in many cough medicines for the
treatment of cough associated with URTI has both
physiological and true placebo effects that are likely to
produce a very effective antitussive action. Pharmaceutical companies have developed cough syrups with
powerful physiological and placebo effects. The additional antitussive benefit of the active ingredient such as
codeine or dextromethorphan is only a minor factor in
the antitussive efficacy of the syrup medicine. In a safety vs. benefit analysis, the small extra benefit provided
by dextromethorphan and codeine over that provided
by placebo must be weighed against the risks incurred
by their inclusion in cough medicines, especially when
considering the potential for recreational abuse [28]
and side-effects in children [29].
References
1 Widdicombe JG. Advances in understanding and treatment of cough. Monaldi Arch Chest Dis 1999; 54: 275–9.
2 Eccles R, Morris S, Jawad M. Lack of effect of codeine
in the treatment of cough associated with acute upper
respiratory tract infection. J Clin Pharm Ther 1992;
17: 175–80.
3 Freestone C, Eccles R. Assessment of the antitussive efficacy of codeine in cough associated with common cold. J
Pharm Pharmacol 1997; 49: 1045–9.
4 Lee PCL, Jawad MSM, Eccles R. Antitussive efficacy of
dextromethorphan in cough associated with acute upper
respiratory tract infection. J Pharm Pharmacol 2000; 52:
1137–42.
5 Fuller RW, Jackson DM. Physiology and treatment of
cough. Thorax 1990; 45: 425–30.
267
CHAPTER 25
6 Choudry NB, Harrison AJ, Fuller RW. Inhibition of gustatory rhinorrhea by intranasal ipratropium bromide. Eur J
Clin Pharmacol 1992; 42: 561–2.
7 Eccles R. Menthol and related cooling compounds. J
Pharm Pharmacol 1994; 46: 618–30.
8 Morice AH, Marshall AE, Higgins KS et al. Effect of
inhaled menthol on citric acid induced cough in normal
subjects. Thorax 1994; 49: 1024–6.
9 Kienle G, Kiene H. Placebo effect and placebo concept: a
critical methodological and conceptual analysis of reports
on the magnitude of the placebo effect. Altern Ther 1996;
2: 39–54.
10 Ernst E, Resch KL. Concept of true and perceived placebo
effects. Br Med J 1995; 311: 551–3.
11 Morris D. Placebo, pain and belief: a biocultural model.
In: Harrington A, ed. The Placebo Effect. An Interdisciplinary Approach. Cambridge, MA: Harvard University
Press, 1999: 187–207.
12 Lee PCL, Jawad MSM, Hull JD et al. The effect of placebo
treatment on cough associated with common cold. Br J
Clin Pharmacol 2001; 51: 373P.
13 Tukiainen H, Karttunen P, Silvasti M et al. The treatment
of acute transient cough — a placebo-controlled comparison of dextromethorphan and dextromethorphan-beta2sympathomimetic combination. Eur J Respir Dis 1986;
69: 95–9.
14 Adams R, Hosie J, James I et al. Antitussive activity and
tolerability of moguisteine in patients with acute cough: a
randomized, double blind, placebo-controlled study. Adv
Ther 1993; 10: 263–71.
15 Parvez L, Vaidya M, Sakhardande A et al. Evaluation of
antitussive agents in man. Pulm Pharmacol 1996; 9:
299–308.
16 Weiner M, Weiner GJ. The kinetics and dynamics of
responses to placebo. Clin Pharmacol Ther 1996; 60:
247–54.
17 Hutchings HA, Eccles R, Smith AP et al. Voluntary
cough suppression as an indication of symptom severity
268
18
19
20
21
22
23
24
25
26
27
28
29
in upper respiratory tract infections. Eur Respir J 1993; 6:
1449–54.
ter Riet G, de Craen AJM, de Boer A et al. Is placebo
analgesia mediated by endogenous opioids? A systematic
review. Pain 1998; 76: 273–5.
Benedetti FAM. The neurobiology of placebo analgesia:
from endogenous opioids to cholecystokinin. Prog
Neurobiol 1997; 52: 109.
Lasagna L, Laties V, Dohan J. Further studies on the
‘pharmacology’ of placebo administration. J Clin Invest
1958; 37: 533–7.
Sher L. The placebo effect on mood and behavior: the role
of the endogenous opioid system. Med Hypotheses 1997;
48: 347.
Newsom Davis J, Plum F. Separation of descending
spinal pathways to respiratory motoneurons. Exp Neurol
1972; 34: 78–94.
O’Donnell M. Our oath is hypocritical. Monitor Weekly
1995; March 1: 44.
Aylward M, Maddock J, Davies DE, Protheroe DA,
Leidman T. Dextromethorphan and codeine: comparison
of plasma kinetics and antitussive effects. Eur J Respir Dis
1984; 65: 283–91.
Matthys H. Dextromethorphan and codeine: objective assessment of antitussive activity in patients with chronic
cough. J Int Med Res 1983; 11: 92–100.
Morice AH, Kastelik JA, Thompson R. Cough challenge
in the assessment of cough reflex. Clin Pharmacol 2001;
52: 365–75.
Pavesi L, Subburaj S, Porter-Shaw K. Application and validation of a computerized cough acquisition system for
objective monitoring of acute cough — a meta-analysis.
Chest 2001; 120: 1121–8.
Noonan WC, Miller WR, Feeney DM. Dextromethorphan abuse among youth. Arch Fam Med 2001; 9: 791–2.
Taylor JA, Novack AH, Almquist JR et al. Efficacy of
cough suppressants in children. J Pediatrics 1993; 122:
799–802.
26
Mucoactive agents for the
treatment of cough
Bruce K. Rubin
Introduction
Medications that are used to treat cough or to enhance
cough clearance fall into three broad classes [1]. The
first of these, the cough suppressants, are discussed elsewhere in this book. They are mentioned here only to
note that there are many medications available without
prescription in the US and Canada that contain a combination of a ‘cough suppressant’ and a secretagogue
‘expectorant’. This counterproductive combination
would be potentially harmful to the patient if both of
these medications were effective. Perhaps it is fortunate
for the patient that nearly always either one or both of
the medications in these combination products is ineffective, at least at the dosage provided.
The second and largest class of mucoactive medications used as cough therapy are those agents that are
meant to improve the ability to expectorate secretions.
These, in turn, fall into several subgroups. Expectorants are medications that increase the volume of airway secretion either by inducing mucus secretion or by
increasing the transport of water into the airway. They
are meant to ‘loosen’ secretions and thus make them
easier to expectorate. Medications that are proposed to
add water to the airway can be as simple as fluid ingestion or as complex as gene transfer to enhance the expression of epithelial proteins that control airway ion
and water transport. A second group of mucokinetic
medications are those that alter the biophysical properties of airway secretions making them easier to expectorate. This would include the mucolytic agents that
degrade the mucin polymer network (classic mucolytics) or the DNA and F-actin polymer network derived
from inflammatory cell necrosis (peptide mucolytics).
Mucoactive drugs that reduce the adhesivity of secretions and thus their binding to the epithelium will make
sputum easier to expectorate. Such medications include
surfactant preparations. Medications that enhance expiratory airflow can also be considered as mucokinetic
drugs, as cough clearance is dependent not only on the
properties of the mucus but also on expiratory air
volume and velocity (flow). Thus in patients who have
increased airflow following the use of bronchodilators,
the bronchodilator medication might be considered to
be mucokinetic.
The third class of medications effecting cough clearance are those that are meant to reduce the quantity of
airway secretions. Because airway inflammation leads
to mucus hypersecretion, and chronic infection and inflammation often lead to mucous gland hypertrophy
and hyperplasia of goblet cells, it is assumed that
patients with chronic bronchitis, cystic fibrosis (CF),
diffuse panbronchiolitis (DPB), bronchiectasis and
perhaps asthma have an increased airway secretion
burden [2]. Mucoregulatory medications are meant
to reduce mucus hypersecretion without affecting
constitutive or basal secretion. Examples of these
medications are anti-inflammatory drugs, anticholinergics and some of the macrolide antibiotics.
An overview of these agents and proposed mechanism of action is listed in Table 26.1.
Mucoactive medications
‘Mucoactive’ is a general term used to indicate a medication that is used to reduce mucus secretion or to promote mucus clearance. This would include mucolytic,
269
CHAPTER 26
Table 26.11 Classification of mucoactive medications by proposed mechanisms of
action.
Mucoactive agent
Classical mucolytics
N-acetylcysteine, nacystelyn
Peptide mucolytics
Dornase alfa
Severs disulphide bonds in proteins,
antioxidant
Gelsolin
Thymosin b4
Hydrolyses DNA molecules with
reduction in DNA length
Depolymerizes F-actin
Depolymerizes F-actin
Non-destructive mucolytics
Dextran, low molecular weight heparin
Break hydrogen and ionic bonds
Expectorants
P2Y2 agents
Hypertonic saline, mannitol
Gene therapy, aquaporin activators
Mucoregulatory agents
Anticholinergic agents
Glucocorticoids
Indometacin
Macrolide antibiotics
Mucokinetic agents
Bronchodilators
Surfactants
mucokinetic, mucospissic, mucoregulatory and expectorant medications but not cough suppressants [3].
Expectorants
Expectorants are meant to increase the volume of
airway secretions in order to improve their bulk
mobilization, or medications that add water to airway
secretions and presumably free mucus from attachments to the epithelium.
Oral and intravenous hydration have been studied
as a simple method to increase the hydration of airway
secretions. In animal models of airway hypersecretion
induced by allergy, Wanner and colleagues showed that
270
Potential mechanisms of action
Increase epithelial mucus and chloride
secretion
Reduce ionic bonds and increases
secretion hydration
Normalize secretory cell function (may
increase airway water)
Decrease volume of stimulated secretions
Decrease airway inflammation and mucin
secretion
Decreases airway inflammation
Decrease airway inflammation and mucin
secretion
Can improve cough clearance by
increasing expiratory flow
Decrease sputum adhesiveness (abhesive)
intravenous fluids were of no benefit in altering the
volume or biophysical properties of airway secretions
and that when hyperhydration was provided intravenously, there was deterioration in pulmonary function and gas exchange [4]. In another study, patients
with chronic bronchitis were encouraged to drink large
amounts of water under direct supervision over a specific period of time. This did not improve expectoration, pulmonary function or clinical well-being in these
patients [5].
Hyperosmolar aerosol inhalation has been used to
draw fluid into the airway and induce mucus secretion.
This has been shown to assist expectoration acutely in
patients with asthma, chronic bronchitis and CF [6].
MUCOACTIVE AGENTS AND COUGH
This technique has primarily been used either to obtain
secretions for diagnostic purposes for the bacteriological diagnosis of tuberculosis or Pneumocystis carinii,
or to obtain airway secretions from patients with
asthma or CF for research evaluation [7]. There have
been several short-term clinical trials evaluating the use
of inhaled hyperosmolar saline for the treatment of
CF or chronic bronchitis that have demonstrated increased radioaerosol clearance and improved pulmonary function [8]. Similar short-term benefits
have been demonstrated with the inhalation of dry
powder mannitol [9]. The long-term clinical benefit of
this therapeutic intervention is uncertain.
Transepithelial water flux is primarily regulated by
paracellular epithelial ion and water channels [10].
In health, there is probably a smaller contribution
from transcellular pathways. Luminal chloride secretion through the cystic fibrosis ion transport regulator
(CFTR) protein and the calcium-dependent chloride
channels will tend to draw water into the airway while
sodium resorption through the epithelial sodium channel (ENaC) draws water from the airway into the cell.
Patients with CF have impaired chloride secretion
through the CFTR channel and increased sodium
resorption through the ENaC. Early attempts to block
sodium resorption in order to normalize water transport across the CF airway involved the inhalation of an
aerosol of amiloride, a diuretic that blocks sodium
resorption. These trials produced promising acute
results but long-term trials did not demonstrate a
benefit in pulmonary function or mucus clearance [11].
While tricyclic nucleotides such as UTP have been used
to acutely increase calcium-dependent chloride secretion via the purinergic P2Y2 receptors, the half-life of
inhaled UTP is extremely short so current studies
are focusing on similar compounds with a longer
half-life [12].
Water transport across epithelial surfaces is also
modulated by selective water channels called aquaporins. Initially identified in the renal tubules, there
are several aquaporins expressed in airway epithelium,
in particular, aquaporin 5 (AQP5) [13,14]. Because
these channels selectively transport water, they may
be an attractive target for manipulating airway water
content.
It has been demonstrated, both in cell culture and
in airway and nasal tissue, that it is possible to temporarily replace the abnormal CF gene protein product in
airway cells by means of gene transfer using viral or
liposomal vectors. While gene transfer has successfully
corrected the ion transport defect in transfected cells, at
this time transfer is fairly inefficient and temporary, and
there have been problems with increased inflammation
and immune response directed against the gene transfer
vector [15].
Although theoretically adding water to the airway
lumen can potentially ‘unstick’ secretions from the epithelium making them easier to expectorate, with the
exception of short-term improvements in pulmonary
function and sputum expectoration using hyperosmolar aerosol inhalation, there are no medications in this
class of mucoactive drugs that have been proven to be
clinically effective.
Medications that alter the properties of secretions
Airway mucus is an inhomogeneous, adhesive gel that
has properties both of a liquid (viscosity) and of a solid
(elasticity) (Fig. 26.1). When subjected to an applied
stress, mucus initially stores energy, it then begins to
Stress
or
force
(a) Ideal solid
Strain
or
displacement
(b) Ideal liquid
(c) Viscoelastic
material
Time
Fig. 26.1 Viscoelasticity measures the stress/strain response
of a material. (a) An ideal or Hookian solid responds to a
stress by energy storage or elasticity. This energy is released
when the strain is removed. (b) An ideal or Newtonian
liquid responds to stress by deforming continuously with no
energy storage. This rate of deformation or energy loss is
viscosity. (c) A viscoelastic gel initially stores energy like a
solid and, with continued strain, will then deform more like
a liquid.
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CHAPTER 26
deform, and finally it flows. Energy storage or elasticity
is critical for the efficient transmission of energy from
beating cilia to the mucus layer in order to propel the
mucus by ciliary clearance. Mucus flow is essential for
it to be extruded from submucosal glands and transported up the airway. Mucus with increased viscosity is
more difficult to clear, especially by the ciliary elevator.
It has not been demonstrated that increased viscoelasticity alone will impair cough clearance [16].
Mucolytic medications
Mucolytic medications non-selectively decrease both
the viscosity and elasticity of airway secretions by
degrading the polymer networks that give mucus or
sputum its gel-like structure. Classic mucolytics disrupt
mucin polymers either by severing the disulphide bonds
that covalently link mucin monomers into elongated
and stiff oligomers, or by dispersing the tangled mucin
network by disrupting hydrogen ion bonding or van
der Waals forces through mechanisms such as charge
shielding.
With chronic airway infection and inflammation
there is recruitment of inflammatory cells, predominantly neutrophils, into the airway. These cells release
proinflammatory cytokines and chemokines, serine
proteases such as neutrophil elastase, and reactive
oxygen species all of which further damage the airway
epithelium and recruit more inflammatory cells.
Inflammatory cell necrosis also releases cell wallassociated F-actin and nuclear DNA which copolymerize into a stiff secondary polymer network increasing
secretion viscoelasticity and adhesivity. Peptide mucolytics degrade the secondary network by acting
primarily on DNA (dornase alfa) or by acting on the
actin network and secondarily the DNA polymer
(gelsolin, thymosin b4) [17,18].
The only mucolytic approved for use in the
United States and Canada is dornase alfa, marketed by
Genentech as Pulmozyme®. This is administered as an
inhalation aerosol at a dosage of 2.5 mg/day. Studies
have demonstrated that dornase alfa decreases viscosity and substantially decreases the adhesivity of airway
secretions in patients with CF, and that long-term use in
many patients improves pulmonary function, reduces
the rate of deterioration of pulmonary function, and
reduces the need for hospitalization and antibiotic
therapy [19]. Dornase alfa is administered by jet
nebulization and is not mixed with other medications,
although often patients will inhale a bronchodilator
272
first. Although it is generally administered before chest
physical therapy, there are data to suggest greater deposition and perhaps increased efficacy if it is administered simultaneously with external high-frequency
chest wall oscillation [20]. In vitro studies suggest an
additive effect when dornase alfa is combined with
either gelsolin or thymosin b4 [21].
A vexing problem has been trying to determine a priori which patients are most likely to clinically respond
to dornase alfa Therapeutic response appears to be
unrelated to sputum concentration of DNA. Although
there was initially a concern that dornase alfa might
overliquefy secretions, making them more difficult to
expectorate, especially in patients with severe disease
and compromised airflow, many patients with severe
pulmonary compromise appear to benefit from
dornase alfa. Studies suggest that dornase alfa may also
be beneficial when initiated very early in life, before
there are overt signs of pulmonary infection [22].
Nevertheless many patients fail to improve pulmonary
function even after several months of therapy and a
small number have worsening of pulmonary function.
Anecdotal reports suggest that the most severely affected patients (those with FEV1 < 30% predicted) may obtain benefit but are also at greatest risk for pulmonary
function compromise with the use of this medication.
Dornase alfa can also interact with other medications. For this reason it is always administered alone.
There are in vitro data to suggest that azithromycin
may inactivate dornase alfa [23]. On the other hand,
mucolysis may also allow greater penetration of drugs
into airway secretions [24]. This may be of particular
importance when the patient is using aerosolized
antibiotics.
Side-effects with the use of dornase alfa have generally been mild. Hoarseness and occasional sore
throat have been reported. These will usually disappear
when the medication is stopped and often will not recur
when restarted. Although low levels of anti-DNase
antibodies have been reported in some patients, these
do not appear to lead to adverse outcomes nor does this
appear to reduce the efficacy of inhaled dornase alfa.
Dornase alfa has also been studied for the treatment
of chronic bronchitis, non-CF bronchiectasis and
plastic bronchitis [25–27]. A small study in patients
with severe chronic obstructive pulmonary disease
(COPD) suggested that dornase alfa inhalation may reduce mortality but a much larger study showed no benefit. There are several small studies that suggest that
MUCOACTIVE AGENTS AND COUGH
some patients with less severe chronic bronchitis may
benefit from dornase alfa inhalation. Studies of patients
with non-CF bronchiectasis have generally, and surprisingly, proved disappointing in that no clinical or
pulmonary function benefit has been demonstrated. In
a subset of these patients, those with primary ciliary
dyskinesia, there have been a few case reports that suggest benefit from dornase alfa inhalation [28].
Patients with respiratory syncytial virus (RSV) bronchiolitis have high concentrations of DNA in their
bronchial lavage fluid. In a small study conducted evaluating infants admitted to hospital for severe RSV
bronchiolitis a small improvement in X-ray scores, but
not in hospital length of stay, was seen in those who
were administered dornase alfa [29]. Anecdotal reports
have consistently failed to show benefit in patients with
plastic bronchitis (bronchial casts, often in association
with congenital heart disease) who used dornase alfa.
Pilot studies (unpublished) from our laboratory suggest
that these casts are largely comprised of mucin and are
not affected by in vitro exposure to dornase alfa.
Clinical use of classic mucolytics
Although N-acetyl-L-cysteine (NAC) is available as a
nebulizer solution in North America it is not on formulary as an approved mucolytic drug. Outside of North
America, NAC is the most commonly prescribed mucolytic drug for the treatment of lung diseases and it is
available in both oral and inhalation forms. The free
sulphydryl group in NAC can dissociate the disulphide
bond between adjacent cysteine residues linking mucin
monomers. However, aerosolized NAC has a pH of
2.2 and an unpleasant odour, and both of these can
make inhalation difficult for patients who are sensitive
to odours or who have airway hyperresponsiveness.
Airway irritation, bronchospasm and coughing paroxysms have been reported frequently in patients inhaling
NAC. NAC cannot be detected in plasma or bronchial
lavage even after 2 weeks of oral dosing [30].
Glutathione is an important oxygen scavenger and
its synthesis requires cysteine. Orally administered
NAC has very low bioavailability and is rapidly
deacetylated to cysteine. Therefore NAC has antioxidant properties. Side-effects of oral acetylcysteine are
nausea and diarrhoea.
There have been many studies over the last 40 years
that evaluate the use of NAC in patients with chronic
bronchitis but few of these have been rigorously conducted, randomized and placebo controlled with a
long enough duration of treatment to determine
changes in primary outcomes of clinical relevance such
as lung function. Convincing demonstration of the
effectiveness of either inhaled or orally administered
NAC in improving lung function, sputum properties or
clinical morbidity in patients with chronic bronchitis is
lacking.
Preliminary studies in patients with CF who inhaled
the lysine salt of NAC (called nacystelyn) suggest that
there may be an acute improvement in pulmonary function following the inhalation of 16 actuations from the
pressurized metered dose inhaler (pMDI) [31]. Lysine is
a basic amino acid with mucolytic properties and the
lysine salt of NAC has a pseudoneutral pH making it
better tolerated when administered by aerosol. Longterm trials of this medication for the treatment of CF
presumably await the development of a more convenient dosage form.
A fairly large number of derivatives of NAC with
blocked sulphydryl groups have been developed. These
include carbocysteine (S-carboxymethylcysteine),
erdosteine (N-carboxymethylthilacetyl) the lysine salt
of carbocysteine (carbocysteine-LYS), L-ethylsysteine
and stepronin. None of these medications has direct
mucolytic activity but they may act as scavengers for
reactive oxygen species and may also be metabolized
to active drugs with thiol groups capable of severing
disulphide bonds [32].
Polymer dispersion and charge shielding
The elongated mucus oligomers are loosely held together in what has been termed a tangled network gel
structure by relatively weak hydrogen ion bonding and
van der Waals forces. Low molecular weight dextran
or heparin can reduce the viscosity of both mucus and
sputum in vitro [33] presumably by charge shielding
and disrupting these weak forces. This allows increased
hydration or disentanglement of the mucin network.
Clinical trials of these types of agents have not yet
been reported.
Medications that affect the interaction
between mucus and epithelium
Experimental data strongly suggest that the cough
clearability of mucus or sputum (in other words the
ability for airflow to move secretions) is more strongly
influenced by the adhesive interaction between the
secretions and the epithelium than by the bulk viscosity
273
CHAPTER 26
of the mucus [34]. In fact, viscous mucus would be beneficial for cough clearance as it would present a greater
profile to the propelling air column.
Adhesion is the attractive interaction between two
different substances, generally a liquid and a solid.
Important to this interaction is the ability of the liquid
to wet the solid surface. This is generally measured as
the contact angle, q, at the liquid–solid–vapour interface. One of the best known of the commercial applications of this phenomenon is the use of Teflon™ to coat
surfaces so that substances will not adhere. Teflon™
is very poorly wettable and this is the reason for its
non-stick properties. The other important factor determining this interaction is the interfacial force between
the liquid and the solid. Between liquid and vapour
phases this is referred to as surface tension, and between two liquid phases or between a liquid and a solid
it is called the interfacial tension. The Neumann equation for a sessile drop allows us to calculate the work of
adhesion as g (1 + cos q) where gamma (g ) is the interfacial tension and theta (q) is the vapour–liquid–solid
contact angle [35].
The force of tenacity is the product of adhesivity
(defined above) and cohesivity or the ability of a substance to ‘stick to itself’. An approximation of cohesivity can be measured using the Filancemeter which
evaluates the stringiness of a substance as the maximal
length that a set volume of a liquid can be stretched
before it breaks. Initially developed to measure the
spinnbarkeit of cervical mucus, the application of these
measurements to airway secretions has shown that
high cohesivity significantly impairs both ciliary and
cough clearability by increasing the tethering of secretions [36]. This tethering has also been demonstrated
histologically, and is particularly prominent in the CF
airway and in patients with severe asthma. Thus tenacity can be imagined as similar to sticky chewing gum
spread across the bottom of a shoe and on the flooring
surface, with both the stickiness and the stringiness
contributing to the difficulty in breaking free. In
vitro studies have shown that tenacity is the strongest
determinant of secretion cough clearability and that
medications that have the ability to reduce adhesivity
(abhesives) or cohesivity will improve cough clearability of secretions in a simulated cough machine in vitro
[37] (Fig. 26.2).
Surfactants are critical to airway stability and the
free flow of mucus. In the alveolus, surfactant prevents
alveolar collapse and reduces the pressure needed to
expand the airway with each breath. In small airways
surfactant permits free and unidirectional mucus flow,
thus preventing airway obstruction. A thin surfactant
layer between the mucus gel and the periciliary fluid facilitates mucus spreading after it is extruded from submucosal glands, and allows the efficient transfer of
kinetic energy from beating cilia to the mucus layer
preventing ciliary entanglement in the mucus. This airway surfactant is thought to be derived both from the
alveolar type II cells and from submucosal glands.
Airway inflammation can degrade surfactant
50
It is the product of
Adhesivity or
stickiness
and Cohesivity or
stringiness (spinnability)
Cough clearability
45
Tenacity is what
makes mucus difficult
to cough out
Bronchitis
CF
40
35
30
25
20
15
10
5
0
400
800
1200
1600
Tenacity in dynes
Fig. 26.2 Tenacity, the product of adhesivity and cohesivity, is the strongest determinant of sputum cough clearability as measured in the simulated cough machine.
274
MUCOACTIVE AGENTS AND COUGH
through several different mechanisms. Transudate of
proteins such as albumen, the presence of products of
inflammation and cellular necrosis such as DNA, and
hydrolysis of surfactant phospholipids — in particular
dipalmitoyl phosphatidylcholine (DPPC) and phosphatidylglycerol (PG) — by secretory phospholipases
A2 (sPLA2) can all produce surfactant dysfunction.
The lysophospholipids products of surfactant hydrolysis not only lack surfactant function but further impair
proper functioning of airway surfactant [38]. Cell wallassociated phospholipids such as sphingomyelin may
have a similar effect.
There are increased amounts of sPLA2 in bronchial
lavage from patients with asthma and these phospholipases readily hydrolyse surfactant phospholipids.
Sputum from patients with chronic bronchitis or CF
have greater quantities of cell wall-associated phospholipids and lower amounts of surfactant phospholipids
than mucus from healthy individuals. Theoretically,
surfactant administration should reconstitute the airway surfactant and enhance mucus clearance. Such an
effect has been well demonstrated in clinical trials of
aerosolized surfactant in patients with stable CF or
chronic bronchitis. There is a dose-dependent improvement in pulmonary function, a decrease in the volume
of trapped thoracic gas as measured by the ratio of
residual volume to total lung capacity (RV/TLC), and
an increase in the sputum cough clearability in bronchitis patients inhaling a surfactant aerosol [39]. One
of the difficulties in the aerosolization of surfactant
is its low surface tension and therefore its propensity
to foam. Further clinical trials await the development
of more efficient means for generating surfactant
aerosols.
Mucolytic agents may also work, in part, as
abhesives but through a different mechanism than by
altering surface tension. With airway inflammation the
mucus has a greater tendency to entangle in airway cilia
and bind to the airway epithelium. Mucolysis may dissolve some of this mucus surface entanglement, making
it easier for airflow to expel secretions as sputum.
Medications that increase airflow
Cough clearance depends on the biophysical properties
of the airway secretions, the interaction between the
mucus and the airway epithelium, and the force and
volume of expiratory airflow. Any manoeuvre that increases expiratory airflow would thus be expected to
improve cough clearance. This is the basis behind most
chest physical therapy manoeuvres and devices that are
currently in use. The medications most commonly used
to increase the expiratory airflow are inhaled
bronchodilators. These agents are effective in enhancing secretion clearance in those patients with bronchial
hyperresponsiveness who have demonstrable improvement in expiratory flow following their use. Although
the b-agonist bronchodilators have a small stimulatory
effect on ciliary beat frequency, this has a trivial effect
on mucus clearance [40]. A warning is in order, because
bronchodilator medications, by virtue of their ability to
relax airway smooth muscle, may increase the collapsibility of the airway, particularly in patients with bronchomalacia or bronchiectasis [41]. This collapse can
lead to gas trapping and paradoxical decrease in flow.
Therefore if these medications are to be used to assist
with cough it is imperative that the patient first be
tested for bronchodilator responsiveness.
Medications that reduce mucus hypersecretion
(mucoregulatory medications)
Chronic airway inflammation leads to the release of
mediators that damage the epithelium and, presumably
as a protective mechanism, lead to hypertrophy and
hyperplasia of surface goblet (mucous) cells and submucosal glands. The increased volume of airway
submucosal glands is a characteristic of chronic bronchitis reflected in the Reid index. Hypertrophy and
hyperplasia of the secretory apparatus is also characteristic of asthma, CF, bronchiectasis and other
inflammatory airway diseases. This increased number
and volume of secretory cells coupled with an increased
responsiveness to secretagogues, the elaboration of
mucus secretagogues during inflammation (e.g. serine
proteases such as neutrophil elastase), and destruction
of the airway epithelium which impairs mucociliary
clearance, all lead to airway mucus retention. Although
in health, mucus secretion is beneficial, the hypersecretion of chronic airway disease leads to entrapment of
bacteria, airflow obstruction, and deterioration in lung
function and quality of life. Mucoregulatory agents are
meant to reduce hypersecretion usually by modifying
the inflammatory response.
Anti-inflammatory agents are probably the most
commonly used immunomodulatory agents. Adrenal
corticosteroids can reduce airway inflammation and
are the most effective medications currently used to
275
CHAPTER 26
treat chronic asthma. Oral corticosteroids have also
been shown to be beneficial to patients with CF. There is
less clear evidence of benefit for these medications in
patients with chronic bronchitis or bronchiectasis;
nevertheless, inhaled corticosteroids are commonly
used to ‘treat’ these conditions. Other medications such
as ibuprofen or indometacin have been used to treat
airway inflammation. Trials of oral ibuprofen have
demonstrated a slower decline in pulmonary function
and improvement in weight gain in young patients with
CF [42]. Indometacin aerosol has been shown to decrease the hypersecretion commonly seen in patients
who have DPB [43].
Atropine and its derivatives decrease cholinergicmediated secretion through a blockade of the M3
receptor interaction. Atropine has not been demonstrated to decrease the normal or baseline level of airway secretions in vitro, and in animals it does not
appear to increase the viscosity of airway secretions
[44]. Atropine is extremely effective at blocking cholinergic-mediated hypersecretion in vivo. It is less clear
whether there is or is not an effect on secretion viscosity
in healthy individuals who are administered atropine
perioperatively.
Derivatives of atropine with greater specificity include glycopyrrolate and quaternary ammonium derivatives of atropine, ipratropium bromide and
oxitropium bromide. Clinical studies have shown that
these latter medications neither reduce mucociliary
clearance nor alter the biophysical properties of
secretions, but they decrease mucus hypersecretion in
patients with chronic bronchitis when given over an
extended period of time [45].
Bacterial killing and prevention of airway infection
are effective ways to reduce inflammation and hypersecretion. Because of this, antibiotics can be considered
‘mucoregulatory medications’ when used to treat infection. Of great recent interest is the non-antibacterial actions of some antibiotics. The 14- and 15-member
macrolactam ring macrolide antibiotics have profound
immunomodulatory and mucoregulatory activity as
detailed below. There is evidence that some of the
quinolone antibiotics may also have immunomodulatory effects.
The macrolide derivatives of erythromycin A have
significant anti-inflammatory and immunomodulatory
effects and decrease the hyperimmune state associated
with chronic airway inflammation. These effects were
first suspected when it was demonstrated that trolean276
domycin was an effective ‘steroid-sparing’ medication
when given to patients with prednisolone-dependent
asthma [46]. Although initially it was suspected that
this was due to decreased steroid metabolism [47],
many patients who received troleandomycin were able
to completely discontinue steroids while retaining control of their asthma. Steroid-associated side-effects
were generally decreased in patients receiving the
macrolide without any decline in pulmonary function,
suggesting a secondary effect on the inflammatory
response unrelated to steroid metabolism.
Evidence has since accumulated demonstrating the
immunomodulatory effects of the macrolide antibiotics [48]. In the early 1980s it was shown that lowdose and long-term therapy with erythromycin or
clarithromycin made a dramatic difference in morbidity and mortality in patients with DPB [49]. DPB is a
form of chronic sinobronchitis that occurs primarily in
adult non-smokers in Japan and Korea. DPB is generally associated with chronic Pseudomonas infection,
mucus hypersecretion and severe sinusitis. The cause of
this disease is unknown but it has been associated with
HLA haplotypes that differ in Japan, Korea and China.
Before 1985, most patients with DPB died within 5
years of diagnosis, even with antibiotic and corticosteroid therapy. Therapy with erythromycin, clarithromycin or azithromycin, but not the 16-member
macrolides, dramatically improves survival and often
leads to complete resolution of the disease. More recently, studies show similar dramatic improvements in
mucus hypersecretion and airway inflammation in
patients with CF given oral macrolide therapy [50].
In vitro the macrolides have a profound effect on
neutrophil migration, cytokine production and the
oxidative burst [51]. They also appear to have direct
effects on the development of bacterial biofilm,
preventing planktonic organisms from producing the
necessary quorum-sensing peptides to develop a
biofilm and thus rendering them more sensitive to
antibiotics and more susceptible to host defences. The
14- and 15-member macrolides and ketolides also have
direct and specific effects on mucus hypersecretion
[52].
Indications for the use of
mucoactive drugs
Expectorants and mucolytics are widely used in
MUCOACTIVE AGENTS AND COUGH
Europe, South America and Asia although there are
few data that demonstrate efficacy [32]. For the most
part, these drugs are not available in North America as
prescription medications (which requires documentation of efficacy) but many ‘expectorant’ cough medications are sold over the counter as non-prescription
therapy for respiratory tract infections. Iodinated
expectorants such as domiodol, iodinated glycerol or
supersaturated potassium iodide (SSKI) provide little
benefit for acute or chronic airway diseases and pose
a risk of iodide toxicity including skin rash, gastrointestinal upset and thyroid suppression. There is a similar lack of proven efficacy for guaifenesin, glycerol
guaiacolate [53] or the thiol-containing mucolytics
such as N-acetylcysteine (NAC). A recent metaanalysis of published studies evaluating the efficacy of
NAC in patients with chronic bronchitis suggests a
small decrease in the frequency of pulmonary exacerbations of disease for those patients taking NAC [54].
Publication bias for positive studies was acknowledged
and the small benefit was thought to be primarily due
to the antioxidant properties of NAC. Because of the
paucity of established data, European and North
American guidelines for the treatment of chronic bronchitis do not recommend the routine use of expectorants or mucolytic agents. There is a similar lack of
data supporting the use of expectorants and, except
for dornase alfa, mucolytics in the treatment of asthma
or CF. The most likely reason for this lack of demonstrated efficacy for these drugs is the paucity of wellcontrolled clinical studies.
Clinical practice guidelines suggest that dornase alfa
should be used for CF patients who are documented to
have pulmonary function improvement after a 2–3
month trial with this medication [55]. Although this
may exclude some patients with intervening concomitant illness who do not appear to respond or may include other patients who are recovering from illness but
would otherwise have limited response to this medication, these guidelines are probably a useful way to initially identify patients likely to receive benefit. There is
ongoing research into specific markers that may predict
which patients are more likely to benefit from mucoactive medication therapy. The use of dornase alfa in infants and children with CF who are too young to
perform pulmonary function manoeuvres is somewhat
more controversial. Guidelines for the use of dornase
alfa in this age group will require the evaluation of more
longitudinal data.
The indication for dornase alfa use in other diseases
is not as clearly established. Although it is frequently
used in patients with non-CF-associated bronchiectasis, it appears that most patients with bronchiectasis
will not respond to dornase alfa therapy with improved
pulmonary function. There are few data to suggest
efficacy in patients with asthma, chronic bronchitis or
other chronic airway diseases because of the lack of
well-controlled clinical trials [25].
Although in vitro data and limited clinical data suggest a significant benefit for aerosol surfactant therapy
in chronic bronchitis and perhaps in asthma and CF,
these medications are quite expensive. Long-term studies with a greater number of subjects await the development of more easily and consistently administered
formulations.
b-Agonist bronchodilators are indicated for patients
with bronchial hyperresponsiveness who demonstrate
improved airflow following their inhalation. Given the
risk of decreased airflow with airway collapse in
patients with bronchiectasis or bronchomalacia [56], it
is strongly recommended that patients have spirometry
to assess bronchodilator response before these medications are administered on a routine basis. Ipratropium
and oxitropium bromide are used long term for the
treatment of chronic bronchitis, principally as bronchodilator medications. Some of their efficacy may be
rooted in their ability to suppress cholinergic-mediated
hypersecretion. Glycopyrrolate is occasionally given
for long periods to patients who have an artificial airway and mucus hypersecretion, but there are few data
to critically support this use. This class of medication
may become more useful in the future with the development of specific M3 antagonists.
Long-term and low-dose macrolide therapy is
clearly indicated for the treatment of patients with
DPB. There is tremendous interest in and enthusiasm
for this therapy in patients with CF. There are several
ongoing studies evaluating not only the clinical
effectiveness but also potential mechanisms of action
of macrolide antibiotics as immunomodulatory
medications.
There is a theoretical risk of using medications
that thin secretions or loosen them in patients with
profoundly compromised expiratory airflow (generally
those with an FEV1 of less than 20% predicted) as this
could potentially lead to retrograde flow of secretions
in a patient unable to expectorate because of muscle
weakness and diminished expiratory flow.
277
CHAPTER 26
Assessment of therapeutic efficacy
There is a great deal of controversy regarding the
most appropriate therapeutic outcomes to use for the
evaluation of mucoactive therapy both in large clinical
trials and in the individual patient [57]. Although
measurement of expiratory airflow such as FEV1 is
reliable, reproducible and easily obtainable for most
patients, it is generally insensitive for determining the
therapeutic efficacy of mucoactive medications with
the exception being the assessment of bronchodilator
therapy and perhaps the use of dornase alfa in patients
with CF. The measurement of gas trapping such as
the ratio of residual volume to total lung capacity
(RV/TLC) may be more sensitive to recruitment of
volume in association with unplugging small airways
as secretions are mobilized and expectorated [58].
Theoretically other measurements of small airway
function (e.g. inspiratory and expiratory high-resolution computed tomographic scanning for evidence of
gas trapping) may be useful for the assessment of mucus
mobilization in some patients.
It seems simple and thus attractive to measure the
volume of expectorated sputum to assess the efficacy of
mucoactive medications. Unfortunately, expectorated
sputum volume bears no relationship to changes in pulmonary function or objective measurements of patient
well-being. There is extraordinary day-to-day and patient-to-patient variability in sputum expectoration
which may be related to diurnal variability in salivary
volume, variability in secretion swallowing and variability in sputum production, leading to differences in
secretion and expectoration volumes that are unrelated
to the medication being given. There are also cultural
and gender differences in the willingness to expectorate
sputum that will influence this measurement. Even in
patients with CF who have a clear improvement in pulmonary function with inhaled dornase alfa, there is no
difference in expectorated sputum volume when compared with patients who have no response or even a decline in pulmonary function. Similar observations have
been made for other mucoactive medications. The ‘normalization’ of sputum volume by drying in an attempt
to eliminate the effect of salivary contamination does
not improve the accuracy of this measurement as an
assessment for sputum clearance [57].
Quality of life scores have been used in an attempt
to evaluate the efficacy of mucoactive medications.
However, existing scoring systems lack objective
278
validation for this use and tend to be insensitive to
other measurements of clinical improvement such as
pulmonary function changes or functional exercise
capacity [59].
For patients with severe chronic lung disease who
have limitation in their activities of daily living, a
potentially useful efficacy measurement is functional
exercise capacity by means of a 6-min walking test or
a shuttle test. Patient and caregiver training is essential
to obtain the most consistent results for this type of testing, and practice is needed to ensure that the test is valid
and reproducible [60]. However, when this test is conducted under controlled circumstances and in a laboratory that is familiar with functional exercise testing, it
appears to reflect fairly well the subjective feeling of
clinical improvement with medications used to treat
decreased sputum clearance.
Summary
Airway mucus is a mixture of water, mucous glycoproteins, low molecular weight ions, proteins and lipids,
whose properties are important for airway defence.
The factors that contribute to the physical properties of
mucus are complex, and there are various pharmacological strategies that can potentially improve the clearability of airway mucus. Although there are a very large
number of drugs used as mucoactive medications to assist cough clearance and to suppress mucus hypersecretion, with few exceptions unequivocal clinical data
supporting their use are lacking. For this reason, most
guidelines for the management of asthma, chronic
bronchitis, bronchiectasis and CF do not routinely
recommend the use of mucoactive medications. This is
not to say that these medications are ineffective, but
rather that carefully designed and well-powered randomized clinical trials with appropriate controls and
well-selected outcome measurements and of sufficient
duration must be conducted before determining which
groups of patients are most likely to benefit.
References
1 Rubin BK, Tomkiewicz RP, King M. Mucoactive agents:
old and new. In: Wilmott RW, ed. The Pediatric Lung.
Basel, Switzerland: Birkhäuser Publishing Ltd, 1997:
155–79.
MUCOACTIVE AGENTS AND COUGH
2 Wanner A, Salathé M, O’Riordan TG. Mucociliary
clearance in the airways. Am J Respir Crit Care Med 1996;
154: 1868–902.
3 Rubin BK. Frontiers in mucus clearance. In: Goldstein
AL, ed. Frontiers in Biomedicine. New York: Kluwer
Academic/Plenum Publishers, 2000: 237–50.
4 Wanner A, Rao A. Clinical indications for and effects of
bland, mucolytic, and antimicrobial aerosols. Am Rev
Respir Dis 1980; 122: 79–87.
5 Shim C, King M, Williams MH Jr. Lack of effect of hydration on sputum production in chronic bronchitis. Chest
1987; 92: 679–82.
6 Eng PA, Morton J, Douglass JA, Riedler J, Wilson J,
Robertson CF. Short-term efficacy of ultrasonically nebulized hypertonic saline in cystic fibrosis. Pediatr Pulmon
1996; 21: 77–83.
7 Pin I, Freitag AP, O’Byrne PM, Girgis-Gabardo A, Watson
RM, Dolovich J, Denburg JA, Hargreave FE. Changes
in the cellular profile of induced sputum after allergeninduced asthmatic responses. Am Rev Respir Dis 1992;
145: 1265–9.
8 Robinson M, Hemming AL, Regnis JA et al. Effect of
increasing doses of hypertonic saline on mucociliary
clearance in patients with cystic fibrosis. Thorax 1997; 52:
900–3.
9 Daviskas E, Anderson SD, Brannan JD, Chan HK, Eberl
S, Bautovich G. Inhalation of dry-powder mannitol
increases mucociliary clearance. Eur Respir J 1997; 10:
2449–54.
10 Boucher RC. State of the art: human airway ion transport.
Am J Respir Crit Care Med 1994; 150: 581–93.
11 Graham A, Hashani A, Alton EW, Martin GP, Marriott C,
Hodson ME, Clarke SW, Geddes DM. No added benefit
from nebulized amiloride in patients with cystic fibrosis.
Eur Respir J 1993; 6: 1243–8.
12 Noone PG, Bennett WD, Regnis JA, Zeman KL, Carson
JL, King M, Boucher RC, Knowles MR. Effect of
aerosolized uridine-5¢-triphosphate (UTP) on cough
clearance in patients with primary ciliary dyskinesia.
Am J Respir Crit Care Med 1999; 160: 144–9.
13 King LS. Surprises from the airway epithelium. Proc Natl
Acad Sci USA 2001; 98: 14192–4.
14 Song Y, Verkman AS. Aquaporin-5 dependent fluid secretion in airway submucosal glands. J Biol Chem 2001; 276:
41288–92.
15 Rubin BK. Emerging therapies for cystic fibrosis lung disease. Chest 1999; 115: 1120–6.
16 King M, Rubin BK. Mucus rheology, relationship with
transport. In: Takishima T, ed. Airway Secretion: Physiological Bases for the Control of Mucus Hypersecretion.
New York: Marcel Dekker, Inc., 1994: 283–314.
17 Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL.
Recombinant human DNase I reduces the viscosity of
18
19
20
21
22
23
24
25
26
27
28
29
30
cystic fibrosis sputum. Proc Natl Acad Sci USA 1990; 87:
9188–92.
Vasconcellos CA, Allen PG, Wohl M, Drazen JM,
Janmey PA. Reduction in sputum viscosity of cystic
fibrosis sputum in vitro by gelsolin. Science 1994; 263:
969–71.
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM,
Nash ML, Ramsey BW, Rosenstein BJ, Smith AL, Wohl
ME. Effect of aerosolized recombinant human DNase on
exacerbations of respiratory symptoms and on pulmonary
function in patients with cystic fibrosis. N Engl J Med
1994; 331: 637–42.
Dasgupta B, Tomkiewicz RP, Boyd WA, Brown NE,
King M. Effects of combined treatment with rhDNase
and airflow oscillations on spinnability of cystic fibrosis
sputum in vitro. Pediatr Pulmonol 1995; 20: 78–82.
Tomkiewicz RP, Kishioka C, Freeman J, Rubin BK. DNA
and actin filament ultrastructure in cystic fibrosis sputum.
In: Baum G, ed. Cilia, Mucus and Mucociliary Interactions. New York: Marcel Dekker, 1998: 333–41.
Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery
MD, Robinson PJ, Wohl ME, Konstan MW, The
Pulmozyme Early Intervention Trial Study Group. A
two-year randomized, placebo-controlled trial of dornase
alfa in young patients with cystic fibrosis with mild
lung function abnormalities. J Pediatrics 2001; 139:
813–20.
Ripoll L, Reinert P, Pepin LF, Lagrange PH. Interaction of
macrolides with alfa dornase during DNA hydrolysis.
J Antimicrob Chemother 1996; 37: 987–91.
Stern M, Caplen NJ, Browning JE, Griesenbach U, Sorgi F,
Huang L, Gruenert DC, Marriot C, Crystal RG, Geddes
DM, Alton EW. The effect of mucolytic agents on gene
transfer across a CF sputum barrier in vitro. Gene Ther
1998; 5: 91–8.
Rubin BK. Who will benefit from DNase? Pediatric
Pulmonol 1999; 27: 3–4.
Crockett AJ, Cranston JM, Latimer KM, Alpers JH.
Mucolytics for bronchiectasis (Cochrane Review).
Cochrane Database Syst Rev 2001; 1.
Wills PJ, Wodehouse T, Corkery K, Mallon K, Wilson R,
Cole PJ. Short-term recombinant human DNase in
bronchiectasis. Effect on clinical state and in vitro sputum
transportability. Am J Respir Crit Care Med 1996; 154:
413–7.
Desai M, Weller PH, Spencer DA. Clinical benefit from
nebulized human recombinant DNase in Kartagener’s
syndrome. Pediatric Pulmonol 1995; 20: 307–8.
Nasr SZ, Strouse PJ, Soskolne E, Maxvold NJ, Garver KA,
Rubin BK, Moler FW. Efficacy of recombinant human
DNase I in the hospital management of RSV bronchiolitis.
Chest 2001; 120: 203–8.
Cotgreave IA, Eklund A, Larsson K, Moldeus PW.
279
CHAPTER 26
31
32
33
34
35
36
37
38
39
40
41
42
43
No penetration of orally administered N-acetylcysteine
into bronchoalveolar lavage fluid. Eur J Respir Dis 1987;
70: 73–7.
Dasgupta B, King M. Reduction in viscoelasticity in cystic
fibrosis sputum in vitro using combined treatment with
nacystelyn and rhDNase. Pediatr Pulmonol 1996; 22:
161–6.
Rogers DF. Mucolytic and mucoactive drugs for asthma
and COPD. Any place in therapy? Expert Opin Investig
Drugs 2002; 11: 15–35.
Feng W, Garrett H, Speert DP, King M. Improved
clearability of cystic fibrosis sputum with dextran treatment in vitro. Am J Respir Crit Care Med 1998; 157:
710–4.
Rubin BK. Surface properties of respiratory secretions:
relationship to mucus transport. In: Baum G, ed. Cilia,
Mucus and Mucociliary Interactions. New York: Marcel
Dekker, 1998: 317–24.
Neumann AW, Good RJ, Hope CJ, Sejpal M. An equationof-state approach to determine surface tensions of lowenergy solids from contact angles. J Colloid Interfac Sci
1974; 49: 291–304.
King M, Zahm JM, Pierrot D, Vaquez-Girod S, Puchelle
E. The role of mucus gel viscosity, spinnability, and adhesive properties in clearance by simulated cough. Biorheology 1989; 26: 737–45.
Albers GM, Tomkiewicz RP, May MK, Ramirez OE,
Rubin BK. Ring distraction technique for measuring
the surface tension of sputum and relationship of the work
of adhesion to clearability. J Appl Physiol 1996; 81:
2690–5.
Lema G, Enhorning G. Surface properties after a simulated PLA2 hydrolysis of pulmonary surfactant’s main
component, DPPC. Biochim Biophys Acta 1997; 1345:
86–92.
Anzueto A, Jubran A, Ohar JA, Piquette CA, Rennard
SI, Colice G, Pattishall EN, Barret J, Engle M, Perret K,
Rubin BK. Effects of aerosolized surfactant in patients
with stable chronic bronchitis. A prospective randomized
controlled trial. JAMA 1997; 278: 1426–31.
Isawa T, Teshima T, Hirano T, Ebina A, Konno K. Effect of
oral salbutamol on mucociliary clearance mechanisms in
the lungs. Tohoku J Exp Med 1986; 150: 51–61.
Rubin BK. Tracheomalacia as a cause of respiratory compromise in infants. Clin Pulm Med 1999; 6: 195–7.
Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect
of high-dose ibuprofen in patients with cystic fibrosis.
N Engl J Med 1995; 332: 848–54.
Tamaoki J, Chiyotani A, Kobayashi K, Sakai N, Kanemura T, Takizawa T. Effect of indomethacin on bronchorrhea
in patients with chronic bronchitis, diffuse panbronchiolitis, or bronchiectasis. Am Rev Respir Dis 1992; 145:
548–52.
280
44 King M, Viires N. Effect of methacholine chloride on
rheology and transport of canine tracheal mucus. J Appl
Physiol 1979; 47: 26–31.
45 Tamaoki J, Chiyotani A, Tagaya E, Sakai N, Konno K.
Effect of long term treatment with oxitropium bromide
on airway secretion in chronic bronchitis and diffuse
panbronchiolitis. Thorax 1994; 49: 545–8.
46 Zeiger RS, Schatz M, Sperling W, Simon RA, Stevenson
DD. Efficacy of troleandomycin in outpatients with
severe, corticosteroid-dependent asthma. J Allerg Clin
Immunol 1980; 66: 438–46.
47 Szefler SJ, Rose JQ, Ellis EF, Spector SL, Green AW,
Jusko WJ. The effect of troleandomycin on methylprednisolone elimination. J Allerg Clin Immunol 1980; 66:
447–51.
48 Jaffé A, Bush A. Anti-inflammatory effects of macrolides in lung disease. Pediatric Pulmonol 2001; 31:
464–73.
49 Kudoh S, Uetake T, Hagiwara K, Hirayama M, Hus LH,
Kimura H, Sugiyama Y. Clinical effects of low-dose longterm erythromycin chemotherapy on diffuse panbronchiolitis. Jap J Thorac Dis 1987; 25: 632–42.
50 Jaffe A, Francis J, Rosenthal M, Bush A. Long-term
azithromycin may improve lung function in children with
cystic fibrosis. Lancet 1998; 351: 420.
51 Çulic O, Erakovic V, Parnham MJ. Anti-inflammatory
effects of macrolide antibiotics. Eur J Pharmacol 2001;
429: 209–29.
52 Rubin BK, Tamaoki J. Macrolides as biologic response
modifiers. Curr Opin Invest Drugs 2000; 1: 169–72.
53 Jager EG. Double-blind, placebo-controlled clinical evaluation of guaimesal in outpatients. Clin Ther 1989; 11:
341–62.
54 Grandjean EM, Berthet P, Ruffmann R, Leuenberger P.
Efficacy of oral long-term N-acetylcysteine in chronic
bronchopulmonary disease: a meta-analysis of published
double-blind, placebo-controlled clinical trials. Clin Ther
2000; 22: 209–21.
55 Davis PB, Drumm M, Konstan MW. State of the art:
cystic fibrosis. Am J Respir Crit Care Med 1996; 154:
1229–56.
56 Panitch HB, Keklikian EN, Motley RA, Wolfson MR,
Schidlow DV. Effect of altering smooth muscle tone on
maximal expiratory flows in patients with tracheomalacia. Pediatr Pulmonol 1990; 9: 170–6.
57 Rubin BK, van der Schans CP. Determinants of mucociliary and cough clearance and outcome measures for clinical trials. In: Rubin BK, van der Schans CP, eds. Therapy
for Mucus Clearance Disorders. New York: Marcel
Dekker, Inc., 2003 (in press).
58 Regnis JA, Robinson M, Bailey DL, Cook P, Hooper P,
Chan HK, Gonda I, Bautovich G, Bye PT. Mucociliary clearance in patients with cystic fibrosis and in
MUCOACTIVE AGENTS AND COUGH
normal subjects. Am J Respir Crit Care Med 1994; 150:
66–71.
59 Piquette C, Clarkson L, Okamoto K, Kim JS, Rubin BK.
Respiratory related quality of life: relationship with
pulmonary function, functional exercise capacity, and
sputum biophysical properties. J Aerosol Med 2000; 13:
263–72.
60 Nixon PA, Orenstein DM, Kelsey SF, Doershuk CF. The
prognostic value of exercise testing in patients with cystic
fibrosis. N Engl J Med 1992; 327: 1785–8.
281
27
Management of cough
Kian Fan Chung
Most aspects of the management of cough have been
dealt with in this book in separate chapters. This final
chapter presents a resumé of the overall management
of the patient presenting with a cough, and more
detailed aspects can be obtained by referring to the appropriate chapter. Previous reviews on the management of cough have been published [1–3]. Much of the
clinical practice surrounding the management of cough
depends on best current practice according to expert
opinion, and there is a relative lack of good placebocontrolled studies particularly when it comes to the
management of cough.
Approach to the patient with cough
The major aim of the management of a patient presenting with cough is to identify the cause of the cough,
and then to treat the cause. Antitussive therapy that
suppresses cough by inhibiting the cough pathway
without treating the cause (‘symptomatic’ antitussives)
is needed if the cough is very severe, or if treatment of
the cause does not lead to sufficient cough suppression
or is not possible or successful.
Cough may be indicative of trivial to very serious airway or lung pathology. The differential diagnosis of
cough is extensive and includes infections, inflammatory and neoplastic conditions, and many pulmonary
conditions (Table 27.1). The protocol for investigating
cough, particularly for a cough that has persisted for
more than 1 month, takes into account several factors
pertaining to the pathophysiology of cough and the
most common causes of cough. Persistent cough may
be due to the presence of excessive secretions, or to air-
way damage and infection, or to the establishment of a
sensitive cough reflex.
The foremost consideration for the clinician at
the first visit is to (i) assess the cause of the cough and (ii)
determine the severity. Various indicators in the
history and examination of the patient will provide
clues to the diagnosis.
A period of 3 weeks has been taken as a cut-off
point for an acute cough usually due to an upper respiratory virus infection, although some postviral cough
may persist for many weeks or months. The only caveat
to this is that sometimes such a cough may last for
more than 3 weeks and many patients with an ‘idiopathic’ cough often state that their cough was a postinfectious cough that never recovered. A cough that has
lasted for more than 2–3 months is less likely to be due
to an upper respiratory tract infection, and further
investigations in terms of other associated causes must
be looked for.
The separation of the diagnostic categories into a
productive or non-productive cough may be clinically
helpful. Cough with sputum production usually points
towards conditions such as chronic bronchitis and
bronchiectasis or other causes of bronchorrhoea. There
is limited information on the diagnostic value of knowing that the cough is productive. One study indicates
that similar causes are often found for both productive
and dry cough [4]. Against this background, the
assessment of the volume of sputum produced is usually
inaccurate, and coughing itself leads to sputum production. The concept of a dry vs. a productive cough as delineating a cough secondary to an increased cough
reflex for the former, and a cough secondary to excessive mucus production for the latter is not entirely cor283
CHAPTER 27
Table 27.1 Common causes of cough.
Table 27.2 Potential complications from excessive cough.
Acute infections
Tracheobronchitis
Bronchopneumonia
Viral pneumonia
Acute-on-chronic bronchitis
Pertussis
Respiratory
Pneumothorax
Subcutaneous emphysema
Pneumomediastinum
Pneumoperitoneum
Laryngeal damage
Chronic infections
Bronchiectasis
Tuberculosis
Cystic fibrosis
Cardiovascular
Cardiac dysrhythmias
Loss of consciousness
Subconjunctival haemorrhage
Airway disease
Asthma
Chronic bronchitis
Chronic postnasal drip
Central nervous system
Syncope
Headaches
Cerebral air embolism
Parenchymal disease
Chronic interstitial lung fibrosis
Emphysema
Sarcoidosis
Musculoskeletal
Intercostal muscle pain
Rupture of rectus abdominis muscle
Increase in serum creatine phosphokinase
Cervical disc prolapse
Tumours
Bronchogenic carcinoma
Alveolar cell carcinoma
Benign airway tumours
Mediastinal tumours
Foreign body
Middle ear pathology
Cardiovascular
Left ventricular failure
Pulmonary infarction
Aortic aneurysm
Other disease
Reflux oesophagitis
Recurrent aspiration
Endobronchial sutures
Drugs
Angiotensin-converting enzyme inhibitors
rect. An increased cough reflex may be present in both
productive and non-productive cough. However, there
are features that are associated with an increased cough
reflex such as cough triggered by taking a deep breath,
laughing, inhalation of cold air and prolonged talking.
Many cigarette smokers have a chronic cough, but
rarely seek medical advice regarding their cough as
284
Gastrointestinal
Oesophageal perforation
Other
Social embarrassment
Depression
Urinary incontinence
Disruption of surgical wounds
Petechiae
Purpura
they expect that the irritant effect of cigarette smoke
is causing their cough. A change in the pattern of
their cough such as an increase in intensity (usually
after an upper respiratory tract infection), or accompanying haemoptysis may force a smoker to seek medical
attention. A chest radiograph is mandatory in this
situation.
Measuring cough severity
Assessment of cough severity traditionally rests on asking the patient for his or her perception of the symptom.
In very severe cough, complications arising from cough
may be experienced (Table 27.2), and the presence of
these indicate that the intensity of the cough is severe.
MANAGEMENT OF COUGH
Measurement of the cough reflex can be done by counting the cough responses to inhalation of tussive agents
such as capsaicin, the hot extract of peppers, acid or
low-chloride content solutions. Although cough can be
induced directly by airway secretions and irritants, persistent cough may also result from an increase in the
sensitivity of the cough receptor. Most patients with
a non-productive persistent cough due to a range of
causes have an enhanced cough reflex to capsaicin
when compared to healthy non-coughing subjects [5].
Successful treatment of the primary condition underlying the chronic cough often leads to a normalization of
the cough reflex. The degree of the cough responsiveness to inhaled capsaicin may be a reflection of the
severity of the cough, but this has not been examined
yet. Of relevance to the evaluation and treatment
strategies for persistent dry cough is the fact that
the cough response can be augmented by various
mediators of inflammation such as the prostaglandins
PGE2 and PGF2a and bradykinin through a process of
sensitization [6,7].
Direct measurement of the number of coughs as
a measure of severity has not been extensively assessed.
A significant correlation between daytime cough
numbers and daytime cough symptom scores has
been shown for a group of chronic dry coughers [8]. In
patients with cough both of unknown cause and associated with asthma, the number of coughs counted
were highest during the daytime, and very few coughs
were observed at night during sleep. Both ambulatory
monitoring of cough and measurement of the cough
reflex are not routinely used in the clinical setting. A
quality of life questionnaire specific for the evaluation
of the impact of chronic cough has been devised but the
sensitivity of the instrument is not known [9].
Causes of acute and chronic cough
There is a very wide range of respiratory and nonrespiratory causes of cough (Table 27.1). A useful
clinical classification is to consider whether the cough
is acute or chronic.
Acute cough
Acute cough is usually due to a viral or bacterial upper
respiratory tract infection. The cough of the common
cold is usually self-limiting and accompanies the cold
in the majority of sufferers within the first 48 h [10].
Other symptoms of postnasal drip, throat-clearing,
irritation of the throat, sore throat, nasal obstruction
and nasal discharge also accompany the cough which
usually resolves within 2 weeks, although it can be
sometimes prolonged. Pertussis should be considered
in the differential diagnosis, particularly with a whooping characteristic of the cough and often associated
with vomiting. Other causes of acute cough that should
be considered are pneumonia, congestive cardiac failure, exacerbation of chronic obstructive pulmonary
disease (COPD), aspiration or pulmonary embolism.
These conditions are usually accompanied by other
symptoms such as shortness of breath and fever,
but cough may be the predominant or rarely the only
symptom.
Many patients with the common cold usually selfmedicate with various antitussive over-the-counter
preparations if they have a problem with their cough.
However, there are few effective preparations on the
market. Codeine appears to be ineffective compared
with placebo against the acute cough of the common
cold [11], while dextromethorphan has been shown to
have some effect in a meta-analysis [12], but not in two
smaller studies [13,14]. A first-generation antihistamine and decongestant has been proposed for the treatment of cough associated with a postnasal drip in acute
cough [10], but a study using a newer-generation antihistamine, loratidine, in combination with a decongestant showed no effect [15]. Sometimes, the rhinitis
associated with the common cold may become mucopurulent, but this is not an indication for antibiotic
therapy unless this persists for more than 10–14 days.
Chronic cough
Chronic cough (cough that persists for more than 3
weeks) can be caused by many diseases, but it is most
commonly due to asthma, gastro-oesophageal reflux
(GOR), postnasal drip, chronic bronchitis and
bronchiectasis [16–18].
Postnasal drip (rhinosinusitis)
The strong association between postnasal drip
(rhinosinusitis) and chronic persistent cough is based
on epidemiological evidence, and on a prospective
study in adults. In acute cough of the common cold,
postnasal drip is likely to play an important role [10]. In
some studies, postnasal drip has been shown to be the
285
CHAPTER 27
most common cause of a chronic cough [16,19]. Postnasal drip (‘nasal catarrh’) is characterized by a sensation of nasal secretions or of a ‘drip’ at the back of the
throat, accompanied very often by frequent need to
clear the throat (‘throat-clearing’). There may be a
nasal quality to the voice due to concomitant nasal
blockage and congestion, and there may be hoarseness.
Physical examination of the pharynx is often unremarkable, although infrequently a ‘cobblestoning’ appearance of the mucosa and draining secretions are
observed, but these appearances are non-specific. The
diagnosis of rhinosinusitis is made usually on a combination of symptoms, physical examination, radiographic findings, and response to specific therapy.
Computed tomography of the sinuses may reveal mucosal thickening or sinus opacification and air–fluid
levels, and is the best investigation compared to sinus
radiography. Extrathoracic variable upper airway obstruction has been described, presumably arising from
upper airway inflammation but this is not invariably
present [20]. Testing for allergens may be helpful and
presence of allergy to pollens support the presence of
seasonal allergic rhinitis. The presence of house dust
mite allergy may be of value if perennial allergic rhinitis
is being considered.
Topical administration of corticosteroid drops in the
head-down position is the best treatment, sometimes
with the concomitant use of antihistamines. Topical
steroids offer the minimum local effect with the minimum of side-effects. Occasionally, severe symptoms
may be controlled initially by a short course of oral
steroids, followed by topical therapy. Betamethasone
drops have the best penetrance into the nose and have
to be administered in the head-back or dependent position, and are particularly useful in gaining control of
symptoms in the initial phase. It is better to avoid longterm use of betamethasone, and to follow 1–2 months
of treatment with betamethasone by other topical nasal
sprays currently available such as beclometasone
dipropionate, fluticasone, flunisolide, mometasone or
budesonide.
Older-generation antihistamines, probably due to
concomitant anticholinergic effects, may be preferable
to newer-generation antihistamines in treating acute
cough due to upper respiratory tract viral infections.
This beneficial effect has been shown in one study [10].
However, the beneficial effects of older antihistamines
in chronic cough has not been demonstrated, and the
newer antihistamines combined with a topical anti286
cholinergic spray to the nose (such as ipratropium bromide) to dry excessive nasal secretions may provide
benefit.
Topical decongestant vasoconstrictor sprays may be
useful adjunct therapy for a few days, but rebound
nasal obstruction may occur after prolonged use. Antibiotic therapy is advisable and necessary in the presence of acute sinusitis involving bacterial infection with
the presence of mucopurulent secretions that has persisted for at least 10 days.
Asthma and associated eosinophilic conditions
Chronic cough may occur in asthma under different
clinical settings. Asthma may present predominantly
with cough, often nocturnal, and the diagnosis is supported by the presence of reversible airflow limitation
and bronchial hyperresponsiveness [21]. This condition of ‘cough-variant’ asthma is a common type of
asthma in children. Elderly asthmatics may also give a
history of chronic cough prior to a diagnosis of asthma
made on the basis of episodic wheeze. Some studies
have reported that cough has been the only symptom of
asthma from 6.5 to 57% of the time. Cough is often the
most prominent symptom complained of by patients
with chronic asthma [22]. More recently, a condition of
eosinophilic bronchitis characterized by cough without
asthma symptoms or bronchial hyperresponsiveness
but with eosinophilia in sputum has been described
[23]. Cough may also occur as a first sign of worsening
of asthma, usually presenting first at night, associated
with other symptoms such as wheeze and shortness of
breath with falls in early morning peak flows. Some
patients with asthma on the other hand develop a persistent dry cough despite good control of their asthma
with antiasthma therapy.
Patients with asthma do not usually have an
enhanced cough reflex, although a subgroup with a
persistent cough may do so [24]. In these latter patients,
cough receptors may be sensitized by inflammatory
mediators such as bradykinin, tachykinins and
prostaglandins. Another cause of cough in asthma may
be due to the presence of bronchial smooth muscle constriction, which may activate cough receptors through
physical deformation. Indeed, in some patients with
cough-variant asthma, b-adrenergic bronchodilators
are effective antitussives [25]. Induction of sputum by
inhalation of hypertonic saline often reveals a predominance of eosinophils, and bronchial hyperresponsiveness is invariably present. Interestingly, in eosinophilic
MANAGEMENT OF COUGH
bronchitis, cough responsiveness to capsaicin is increased without bronchial hyperresponsiveness [26].
When asthma is suspected as being a cause of cough, the
following investigations should be considered: baseline
spirometry, recording of peak flow measurements
morning and evening, airway responsiveness to methacholine or histamine, and bronchodilator response to
salbutamol. Measurement of capsaicin cough response
and of eosinophil counts in induced sputum are investigations that should now be considered to diagnose
eosinophilic bronchitis. Indeed, these conditions
would come under the umbrella of airway eosinophilic
conditions causing cough, which invariably responds
well to inhaled corticosteroid therapy.
Cough associated with asthma should be treated
with antiasthma medication including inhaled corticosteroid therapy and bronchodilators such as b2adrenergic agonists. It is well to remember that the
particles from the inhaler may in some patients induce
cough, and in such a situation, the side-effect may disappear by changing to an alternative form of delivery.
Usually, such treatment may need to be given over a
prolonged period of time (3–6 months) at a minimum
dose that controls the cough. Often, a trial of oral corticosteroids (e.g. prednisolone 40 mg/day for 2 weeks)
may be recommended, particularly in those asthmatics
who have had a cough despite being on adequate antiasthma medication. More recently, the use of a combination of inhaled corticosteroids and a long-acting
b-agonist has become established as being the best
available maintenance treatment for moderate to severe asthma, but the effect of this combination on
cough alone has not been studied. However, it is likely
that such combination has additive benefits on cough
suppression, as it does on other measures of asthma
control. Treatment with nedocromil sodium can be a
useful addition. Leukotriene receptor antagonists may
control cough-variant asthma in patients in whom
inhaled steroids have not been helpful.
Gastro-oesophageal reflux
GOR, the movement of acid and other components of
gastric contents from the oesophagus into the larynx
and trachea, is one of the most common associated
cause of chronic cough in all age groups. GOR may
lead to symptoms or physical complications such as
heartburn, chest pain, a sour taste or regurgitation,
and also a chronic persistent cough. Not infrequently,
there may be no symptoms associated with GOR or
impaired clearance of oesophageal acid. Prolonged
exposure of the lower oesophagus to acid may lead
to oesophagitis, Barrett’s oesophagus, oesophageal
ulceration and stricture and bleeding. An oesophageal–
tracheobronchial cough reflex mechanism has been
proposed on the basis of studies in which distal
oesophageal acid perfusion induced coughing episodes
in such patients [27]. Local distal oesophageal perfusion of lidocaine suppressed the acid-induced cough in
patients with chronic cough, and the inhaled anticholinergic agent, ipratropium bromide, was also effective. Over 90% of the cough episodes have been shown
to be temporally related to reflux episodes. Significant
reflux occurs in both supine and upright positions. A
high proportion of patients with GOR also appear to
have gastrohypopharyngeal reflux, and there may be a
direct effect of acid reflux on cough receptors in the larynx and trachea. Coughing itself may precipitate reflux, creating a vicious circle of acid-inducing cough
which in turn induces acid reflux. Continuous monitoring of tracheal and oesophageal pH in patients with
symptomatic GOR has demonstrated significant increases in tracheal acidity with pHs falling down to 4
during episodes of reflux [28]. Other components of the
refluxate, apart from acid, such as the content of pepsin
or other enzymes may also contribute to stimulating
cough, but this is not known.
There is no particular pattern of the cough of GOR,
although one small study indicated that the cough occurred predominantly during the day and in the upright
posture, with minimal nocturnal symptoms. The cough
may have been longstanding, and may or may not be
productive. In the presence of reflux and microaspiration, laryngeal symptoms may be present with dysphonia, hoarseness and sore throat; often posterior vocal
cord laryngeal inflammation is visible. There may be associated oesophageal dysmotility characterized by
heartburn, waterbrash and oral regurgitation, worse in
the supine position.
The most specific test to diagnose GOR is a 24-h
ambulatory oesophageal pH monitoring. Episodes of
pH below 4 in the oesophagus are usually looked for
and the temporal relationship between cough and falls
in pH msut be looked for. However, there is a low
frequency of acid reflux episodes associated in time
with cough, with up to 13% of coughs occurring shortly after an acid reflux episode [29]. Twenty-four-hour
pH testing does not predict which patients with atypical symptoms have GOR disease-related complaints.
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CHAPTER 27
Other tests that may be used are oesophageal manometry to measure dysmotility particularly associated with
reflux episodes, upper gastrointestinal contrast series
to detect reflux of barium into the oesophagus, or endoscopy. A trial of antireflux treatment may be used in
patients as a diagnostic measure where ambulatory 24h pH oesophageal monitoring is not available. This
is also indicated in patients with chronic cough that
remains unexplained after diagnostic work-up or
exclusion of other associated causes.
The aim of treatment of GOR is to decrease the frequency and duration of the events. Conservative measures should be advocated for all patients with
significant GOR events diagnosed on a 24-h pH monitoring of the oesophagus. Weight reduction, highprotein, low-fat diet, elimination of food and drinks
of low pH, elevation of the head of the bed, avoidance
of coffee and smoking should be advised. Reduction of
acid production by stomach can be achieved with either
H2-histamine blockers or proton pump inhibitors, but
there has been no comparative studies between the two
classes of acid inhibitors. Given the increasing use of
proton pump inhibitors and their superior effect in acid
suppression and in treating GOR, these drugs will
remain more popular. In a placebo-controlled study,
of 17 patients with a positive pH test, six had improvement or resolution of cough with omeprazole treatment for 12 weeks, within the first 2 weeks of treatment
[30]. In another double-blind, placebo-controlled trial,
omeprazole 40 mg/day for 8 weeks relieved GORrelated cough, and this improvement continued after
the treatment period [31]. A duration of 3 months’
treatment at the highest recommended dose of proton
pump inhibitor is recommended. One of the reasons
for medical failure of therapy is the effect of persistent
non-acid refluxate. Antireflux surgery such as open or
laparoscopic fundoplication may be considered for
patients with proven GOR disease who have failed to
respond to medical therapy [32].
Chronic bronchitis/chronic obstructive
pulmonary disease (COPD)
Given that up to 30–40% of the community smokes,
it may be surprising that chronic bronchitis is only
reported in 5% of patients seeking medical attention
for cough. Chronic bronchitis should be considered in
a patient who produces sputum on most days over at
least 3 consecutive months, particularly during the
winter months, over at least 2 consecutive years. In a
288
smoker, the presence of chronic bronchitis may be
predictive of progressive irreversible airflow obstruction, but there is no evidence for this [33]. The cough
of chronic bronchitis may result from excessive sputum
production associated with mucus cell hyperplasia
and bronchiolar inflammation. The presence of airflow
obstruction diagnosed on the basis of a ratio of FEV1/
FVC of less than 70% or of an FEV1 of less than 70% of
the predicted value would indicate the diagnosis of
COPD [34].
The productive cough in chronic bronchitis is exacerbated by upper respiratory infections with common
viruses, or by exposure to irritating dusts. Other causes
of productive cough should be excluded such as
bronchiectasis or postnasal drip. It is important to
exclude also the presence of an endobronchial tumour.
Cessation of cigarette smoking is usually successful in
reducing the cough, occurring most often within 4–5
weeks of smoking cessation [35]. Various adjuncts such
as nicotine replacement or buprorion tablets may help
smoking cessation [36]. Treatment of any associated
chronic airflow obstruction with short-acting and/or
long-acting b2-adrenergic agonists and anticholinergic
agents may be tried. Suppression of the inflammatory
process in the small airways may be tried with inhaled
corticosteroids, but the inflammation may not be responsive to steroids. However, corticosteroids are more
effective in the treatment of exacerbations of COPD.
Use of indirect antitussive therapies is not recommended in the treatment of COPD and the role of
mucolytic therapy at present is not clear.
Bronchiectasis
The cough of bronchiectasis is associated with excessive secretions from overproduction together with reduced clearance of airway secretions. Usually, the
patient produces 30 mL or more of mucoid or mucopurulent sputum per day, sometimes accompanied by
fever, haemoptysis and weight loss. In early cases of
bronchiectasis, the condition may only present with a
persistent productive cough. Bronchiectasis may be
associated with postnasal drip and rhinosinusitis,
asthma, GOR disease and chronic bronchitis. Common pathogens cultured from sputum include
Haemophilus influenzae, Staphyloccocus aureus and
Pseudomonas aeruginosa. The chest radiograph may
show increased bronchial wall thickening particularly
in the lower lobes in advanced cases, but thin-section
computed axial tomography of the chest can reveal
MANAGEMENT OF COUGH
early changes of intrapulmonary airway wall thickening, dilatation and distortion, with mucus plugging and
evidence of bronchiolitis [37].
The cough of bronchiectasis serves as a useful function in facilitating clearance of excessive mucus. In fact,
it is the most effective mechanism for clearing airway
secretions. The cough during infective exacerbations of
bronchiectasis may become a tiring symptom, but
treatment of the exacerbation will lead to a curbing
of cough. The cough due to bronchiectasis may be
successfully controlled with inhaled b2-agonist which
improves mucociliary clearance and reverses any
associated bronchoconstriction, postural drainage of
airway secretions, and the use of intermittent antibiotic
therapy.
Angiotensin-converting enzyme inhibitor cough
Angiotensin-converting enzyme (ACE) inhibitors are
often prescribed for the treatment of hypertension and
heart failure, and cough has been observed in 2–33% of
patients [38,39]. The cough is typically described as
dry, associated with a tickly irritating sensation in the
throat. It may appear within a few hours of taking the
drug, but may also only become apparent after weeks
or even months. The cough disappears within days or
weeks following withdrawal of drug. Patients with
ACE inhibitor cough demonstrate an enhanced response to capsaicin inhalation challenge. The mechanisms underlying ACE inhibitor cough are not clear but
accumulation of bradykinin and prostaglandins which
sensitize cough receptors directly has been implicated.
The best treatment for ACE inhibitor cough is to discontinue the treatment and to replace it with alternative
therapies such as an angiotensin II receptor antagonist
which does not cause cough. However, sulindac, indomethacin, nifedipine, picotamide or inhaled sodium
cromoglycate can be beneficial in ACE inhibitorinduced cough [40–43].
Postinfectious cough
Postinfectious cough has been reported in 11–25% of
patients with chronic cough [44,45]. A persistent
cough occurs in 25–50% of patients following
Mycoplasma or Bordetella pertussis infection [46]. B.
pertussis infection has now been increasingly recognized as a cause of both acute and chronic cough
[47,48]. In children, respiratory viruses (respiratory
syncytial virus and parainfluenzae), Mycoplasma,
Chlamydia and B. pertussis have been implicated [49].
The cough of B. pertussis usually lasts for only 4–6
weeks and is spasmodic with a typical whoop, but can
last for a longer period of time. In most patients with a
postinfectious cough, the initial trigger is usually an
upper respiratory tract infection, and cough that is expected to have lasted for only a week at most persists for
many months, often severe. Such patients are often referred to the cough clinic and are usually investigated
for the more common associated causes of cough. It is
assumed that there may have been persistent damage to
the cough receptor, or persistent airway inflammation
induced initially by the virus. Bronchial epithelial inflammation and damage is present in children with
chronic cough following lower respiratory tract illness.
Irritants may penetrate more readily through the damaged epithelium. This may represent a vicious circle of
events of coughing-induced damage that maintains and
triggers further cough. Inhaled corticosteroids are
often prescribed, but with variable success. There has
been no controlled trial. Oral steroids may be successful [44]. Inhaled ipratropium bromide has been shown
to be effective in a small study [50].
Other conditions
Other conditions causing cough include bronchogenic
carcinoma, metastatic carcinoma, sarcoidosis, chronic
aspiration, interstitial lung disease or left ventricular
failure, conditions that can be excluded by performing
a chest radiograph. Psychogenic or habit cough is not
uncommon, particularly in children, and is usually a
diagnosis arrived at after exclusion of other causes.
Habit cough is a throat-clearing noise made by a person
who is nervous and self-conscious. Cough may be associated with a depressive illness and long-standing
cough may cause depression. In the paediatric population, other cough aetiologies specific for this age group
need to be considered such as congenital abnormalities,
e.g. vascular rings, tracheobronchomalacia, pulmonary sequestration or mediastinal tumours, foreign
bodies in the airway or oesophagus, aspiration due to
poor coordination of swallowing or oesophageal dysmotility, and heart disease.
Chronic persistent cough
of unknown cause
Identification of a potential cause of cough has been reported in 78–99% of patients presenting at a special289
CHAPTER 27
ized cough clinic [16,51]. Treatment of identifiable
causes may also not be successful; in one study, 31% of
patients did not improve with treatment of the associated cause. These patients with a persistent cough of
unknown cause or not responding to treatment of
associated causes present in a similar way as others in
terms of their cough symptoms where a cause has been
identified. An enhanced cough reflex is usually found,
and this usually improves when the associated cause
has been successfully treated. Patients often complain
of a persistent tickling sensation in the throat that often
leads to paroxysms of coughing. This sensation can
be triggered by factors such as changes in ambient temperature, taking a deep breath, cigarette smoke or other
irritants such as aerosol sprays or perfumes. These
symptoms are typical of a sensitized cough reflex.
Mucosal biopsies taken from a group of non-asthmatic
patients with chronic dry cough showed evidence of
epithelial desquamation and inflammatory cells, particularly mononuclear cells [52]. These changes could
represent the sequelae of chronic trauma to the airway
wall following intractable cough, and could also lead to
sensitization of the cough reflex. It is likely that many
patients with postinfectious cough end up being classified as having cough of unknown cause. Because relatively few effective and safe antitussives are available,
the control of persistent cough without associated
cause remains difficult. Indirect antitussive therapy
should be tried and may be reserved for severe paroxysms of the cough.
Diagnosis and investigations
of chronic cough
The history and examination will often indicate likely
associated diagnosis or diagnoses, and the timing of
various investigations may vary according to presentation. Table 27.3 shows the range of possible investigations. Initial investigation may be limited to a chest
radiograph, particularly if there is a high suspicion of a
tumour in a cigarette smoker. There is no indication as
to how good the yield of a diagnosis of a bronchial
tumour is by routinely performing a chest radiograph
in all patient presenting with a cough that has been persistent for more than a few weeks. Abnormalities have
been reported in 10–30% of chest radiographs, although the yield of tumours is likely to be lower. If there
is high degree of suspicion of a lung tumour, further in290
Table 27.3 Investigations of chronic cough.
1 Chest radiograph.
2 Spirometry and peak expiratory flow measurements over
several days.
3 Bronchoprovocation testing with methacholine or
histamine.
4 Rhinosinus imaging (radiography or computed
tomography).
5 Direct examination of nasal passages and upper airways.
6 24-h oesophageal pH monitoring and oesophageal
manometry.
7 Computed tomography of the lungs.
8 Fibreoptic bronchoscopy and mucosal biopsies.
9 Induced sputum for examination of eosinophils.
vestigations (e.g. computed tomography or fibreoptic
bronchoscopy) must be pursued despite a ‘normal’
chest radiograph.
A period of observation of 3–4 weeks in a patient
who provides a good history of an upper respiratory
tract infection prior to further investigation or therapeutic trial is adequate, although institution of an antiinflammatory therapy such as inhaled corticosteroids
can be useful in controlling this type of cough.
Postnasal drip (‘nasal catarrh’), asthma and GOR
are the three most common conditions associated with
a chronic dry cough. It would be sensible in the diagnostic approach to exclude these conditions first. Examination of the nose and sinuses with a computed
axial tomograph of the sinuses may be indicated with a
history of postnasal drip or rhinosinusitis, and ambulatory oesophageal pH monitoring to exclude the possibility of GOR. The diagnosis of asthma is supported by
the presence of diurnal variation in peak flow measurements, bronchial hyperresponsiveness to histamine or
methacholine challenge and the presence of eosinophils
in sputum. Under the umbrella of ‘asthma’ would also
be included cough-variant asthma and eosinophilic
bronchitis. However, a therapeutic trial may be the best
initial approach, particularly when the history and
examination provide supportive clues. It is important
that effective doses of medication over a sufficient
period of time is given. Often a longer than usual period
of treatment is necessary to control the cough. Postnasal drip is a frequently overlooked condition, and aggressive treatment should consist of corticosteroid
MANAGEMENT OF COUGH
nasal drops with an antihistamine, with the possibility
of adding antibiotic therapy and a short period of treatment with a nasal decongestant. Often more than one
of these conditions may coexist and cough may only respond with concomitant treatment of these. For example, inhaled steroid therapy and acid suppression with
H2-histamine blockers or a proton pump inhibitor
would be indicated for the coexistence of asthma and
GOR. There continues to be some debate as to whether
investigations are necessary, or whether one should
proceed to a therapeutic trial once a diagnosis of the associated cause has been made from the history and
examination.
Bearing in mind that there are a myriad of other less
common causes of a chronic cough, investigations must
proceed further if the above causes have been excluded.
Full lung function tests to include lung volumes and gas
transfer factor, and a computed axial tomograph of the
lungs should be considered in case of bronchiolar or
parenchymal disease or unsuspected bronchiectasis.
Fibreoptic bronchoscopy should be considered, and
apart from excluding small central tumours provides
mucosal biopsies for histological examination. A simple algorithm for investigating patients with chronic
cough is presented in Table 27.4.
Therapies aimed towards
cough suppression
(‘symptomatic’ therapies)
An outline of the treatment approach for specific
underlying causes of cough is presented in Table 27.5.
When the treatment of the cause of cough is not
effective or not available, therapies directed at eliminating the symptom of cough irrespective of the cause
of the cough should be tried. These therapies are also
termed symptomatic. Drugs that affect the complex
mechanism of the cough reflex may act in several
ways (Fig. 27.1). They may act by inhibition of central
mechanisms within the cough centre, or by reducing
the response of cough receptors in the airways. Opiates,
Table 27.4 Diagnostic evaluation of chronic cough.
1 History and physical examination.
2 Chest radiograph, particularly in smokers.
3 Initial evaluation may lead to diagnosis of chronic bronchitis in cigarette smokers,
and of angiotensin-converting enzyme inhibitor cough. Discontinue cigarette
smoking and offending drug.
4 Further diagnostic evaluation on basis of initial evaluation:
(i) If suggestive of postnasal drip, order a computed tomographic scan of sinuses,
and allergy tests.
(ii) If suggestive of asthma, request a record of peak expiratory flow
measurements at home for 2 weeks and a bronchoprovocation test with
histamine or methacholine, and/or a trial of antiasthma treatment.
(iii) If suggestive of gastro-oesophageal reflux disease, request 24-h pH
monitoring, and if necessary, an endoscopic examination of the oesophagus,
or a barium swallow series.
(iv) If the chest radiograph is abnormal, consider examination of sputum and a
fibreoptic bronchoscopy. A computed tomographic scan of the thorax and
further lung function evaluation may be necessary.
5 Treat specifically for associated conditions. The cause(s) of cough is (are)
determined when specific therapies eliminate or improve the cough. There may be
more than one associated cause for the cough.
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Table 27.5 Treatments for cough.
1 Treating the specific underlying cause(s)
Asthma, cough-variant asthma
Bronchodilators and inhaled corticosteroids
Eosinophilic bronchitis
Inhaled corticosteroids; leukotriene inhibitors
Allergic rhinitis and postnasal drip
Topical nasal steroids and antihistamines
Topical nasal anticholinergics (with antibiotics, if indicated)
Gastro-oesophageal reflux
Conservative measures
Histamine H2-antagonist or proton pump inhibitor
Angiotensin-converting enzyme inhibitor
Discontinue and replace with alternative drug such as angiotensin II
receptor antagonist
Chronic bronchitis/chronic obstructive pulmonary
disease (COPD)
Smoking cessation
Treat for COPD
Bronchiectasis
Postural drainage. Treat infective exacerbation and airflow obstruction
Infective tracheobronchitis
Appropriate antibiotic therapy
Treat any postnasal drip
2 Symptomatic treatment (only after consideration of cause of cough)
Acute cough likely to be transient, e.g. upper
respiratory viral infection
Simple linctus
Persistent cough, particularly nocturnal
Opiates (codeine or pholcodeine)
Persistent intractable cough due to terminal
incurable disease
Opiates (morphine or diamorphine)
Local anaesthetic aerosol
Cough in children
Simple linctus (paediatric)
demulcents, expectorants, local anaesthetics and
antiasthma drugs have been used as antitussive agents
with varying degrees of success. More effective antitussive therapies are urgently needed [53].
The use of ‘indirect’ antitussive agents is particularly
relevant for patients with lung cancer. Persistent cough
is experienced in up to 79% of patients with a nonsmall cell carcinoma, of whom 50% rated their cough
as moderate to severe [54]. Lung cancer itself, or its
complications and treatment may be the cause of the
cough, and persistent cough can cause headaches,
insomnia, rib fractures and syncope [55].
Narcotic and non-narcotic antitussives
Opiates including morphine, diamorphine and codeine
are the most effective antitussive agents. At their effective doses they cause physical dependence, respiratory
292
depression and gastrointestinal colic. Morphine and
diamorphine are reserved for the control of cough and
pain of terminal bronchial cancer patients, but codeine,
dihydrocodeine and pholcodeine can be tried in other
cases of chronic cough.
Codeine is the methylether of morphine and has long
been the standard centrally acting antitussive drug
against which the pharmacological and clinical effects
of newer drugs have been measured. Codeine is probably the most commonly prescribed antitussive. It has
good analgesic and antitussive activity when given
orally. Codeine has been shown to possess antitussive
activity against pathological cough [56,57] and against
induced cough in normal volunteers [58]. On the other
hand, it appears to be ineffective against acute cough of
the common cold [11].
It should be used cautiously in patients with reduced
hepatic function, but it can be used without dose modi-
MANAGEMENT OF COUGH
'Peripheral'
Acid pH inhibitors
e.g. PPIs
Central
?Anticholinergic
?Expectorant
Mucolytic
Local
anaesthetic
?Demulcents
CORTEX
CNS
'Cough
receptor'
Mucus
nTS
Periciliary fluid
e
rv
Epithelium
e
sn
u
Goblet cell
Blood
vessel
Eosinophil
g
Va
Phrenic nerves
Spinal motor nerves
Recurrent laryngeal
nerves
Respiratory muscles
Laryngeal muscles
RAR
C-fibres
xon
al a x
Loc refle
Oedema
Volitional control
Baclofen?
NK
antagonists?
Opioids
Mucus
Submucosal
gland
Mast cell
Monocyte
Neutrophil
Histamine, LTD4
Cough
Anti-inflammatory:
Corticosteroids
Leukotriene antagonists
Antihistamines
Airway smooth muscle
Bronchodilator: β2 agonist
Anticholinergics
Fig. 27.1 Afferent pathways of the cough reflex and some
potential sites of action of direct and indirect antitussive
drugs. Drugs may be divided according to their peripheral
effects on airways or their central effects on the central
nervous system (CNS). nTS, nucleus tractus solitarius; LTD4,
leukotriene D4; NK, neurokinin; RAR, rapidly adapting
receptor; PPI, proton pump inhibitor.
fication in patients with renal failure. Drowsiness may
be an incapacitating side-effect, together with nausea,
vomiting and constipation. Rarely allergic cutaneous
reactions such as erythema multiforme have been
described. Codeine can cause physical dependence,
but on a smaller scale than morphine. Dihydrocodeine
has no particular advantage over codeine and may
cause more addiction than codeine. Pholcodeine is
also as effective as codeine but has little or no analgesic
effect. There seems little to choose between codeine and
pholcodeine.
Morphine and diamorphine should only be used for
severe distressing cough which cannot be relieved by
other less potent antitussives, and are therefore usually
confined to patients with terminal illness such as
bronchial carcinoma. These opioids also relieve anxiety
and pain. They cause sedation, respiratory depression
and constipation. Opioids can exacerbate wheezing
through the release of histamine, but this is rare. Diamorphine may be preferred to morphine because of its
lower incidence of nausea and vomiting. Morphine
may be given by mouth every 4 h, and also by suppository. Diamorphine is preferably given by injection.
Non-narcotic antitussives include dextromethorphan which is a synthetic derivative of morphine with
no analgesic or sedative properties and which is usually
included as a constituent of many compound cough
preparations sold over the counter. Dextromethorphan
is a synthetic derivative of morphine with no analgesic
or sedative properties. It is as effective as codeine in suppressing acute and chronic cough when given orally
[57,59], with one study showing its superiority over
codeine [60]. Antitussive efficacy of a single 30-mg
dose has been demonstrated against cough associated
with upper respiratory tract infections [12]. It is commonly used as a constituent of many compound cough
293
CHAPTER 27
preparations which are sold over the counter. Sideeffects are few with the usual dose, but at higher doses
dizziness, nausea and vomiting, and headaches may
occur. It should be avoided in patients with hepatic insufficiency as it undergoes metabolic degradation in the
liver. Dextromethorphan should be used with caution
also in patients on monoamine oxidase inhibitors
as cases of central nervous depression and death have
occurred.
Other non-narcotic preparations include noscapine
and levopropoxyphene, although their antitussive efficacy has not been proven. Levodropropizine, a nonopioid antitussive with peripheral inhibition of sensory
cough receptors, has a favourable benefit–risk profile
compared to dextromethorphan [61]; this is currently
available in several European countries. Other drugs
acting on cough receptors include benzonatate which
inhibits vagal stretch lung receptors, with a possible
central effect. Baclofen, an agonist of g-aminobutyric
acid, an inhibitory neurotransmitter, had demonstrable
inhibitory effects in two patients with chronic cough
[62], and against ACE inhibitor cough [63].
Expectorants and mucolytics
The basis for using these agents as antitussives lies in the
belief that altering the volume of secretions or their
composition will lead to suppression of the cough
reflex. Despite the lack of proof, mucolytic agents such
as acetylcysteine, carbocisteine, bromhexine and
methylcysteine are often used to facilitate expectoration by reducing sputum viscosity in patients with
chronic bronchitis. A small reduction in the exacerbation of bronchitis has ben reported with oral acetylcysteine, accompanied by small improvement in cough, a
decrease in volume of sputum and some ease of expectoration. Aromatic agents such as eucalyptus and menthol have decongestant effects in the nose and can be
useful in short-term relief of cough. Menthol inhibits
capsaicin-induced cough in normal volunteers [64],
and acts on a cold-sensitive receptor. Demulcents also
form an important component of many proprietary
cough preparations and may be useful because the thick
sugary preparation may act as a protective layer on the
mucosal surface.
Local anaesthetics
Lidocaine aerosol inhaled from a nebulizer has been
294
administered in cases of intractable cough with variable results, and should be reserved for such individual
cases [65]. Local anaesthetics work by inhibiting sensory neural activity, but also remove reflexes that protect
the lung from noxious substances. Their effects are
transient and they should be avoided in patients with
asthma or a past history of asthma because they can induce severe bronchoconstriction. There has been no
controlled trials of local anaesthetics, but their efficacy
in controlling cough is not ideal because of the short
duration of effect of these agents. In the author’s experience, this treatment is not very effective. It may be that
we have not understood the best way of targeting the
larynx and large airways with this agent.
Antiasthma therapy
Often antiasthma therapy (b2-agonist and anticholinergic therapy or corticosteroid therapy) may be tried,
even in the absence of symptoms or tests supporting
asthma. Cough may be accompanied by bronchoconstriction, which in turn could worsen cough, an effect
that could be prevented by an inhaled b2-agonist. In addition, airway inflammation may be present in the airways as a contributory factor, and could be controlled
by an inhaled corticosteroid. However, apart from
eosinophilic airway inflammation, it may not respond
to corticosteroids. Such treatment should be instituted
as a trial after diagnostic evaluation has excluded most
causes associated with the cough.
References
1 Chung KF, Lalloo UG. Diagnosis and management of
chronic persistent dry cough. Postgrad Med J 1996; 72:
594–8.
2 Irwin RS, Madison JM. The diagnosis and treatment of
cough. N Engl J Med 2000; 343: 1715–21.
3 Irwin RS, Boulet LP, Cloutier MM, Fuller R, Gold PM,
Hoffstein V et al. Managing cough as a defense mechanism
and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest 1998; 114:
133S–81S.
4 Smyrnios NA, Irwin RS, Curley FJ. Chronic cough with a
history of excessive sputum production. The spectrum and
frequency of causes, key components of the diagnostic
evaluation, and outcome of specific therapy. Chest 1995;
108: 991–7.
5 Choudry NB, Fuller RW. Sensitivity of the cough reflex in
MANAGEMENT OF COUGH
6
7
8
9
10
11
12
13
14
15
16
17
18
patients with chronic cough. Eur Respir J 1992; 5:
296–300.
Nichol GM, Nix A, Barnes PJ, Chung KF. Prostaglandin
F2 alpha enhancement of capsaicin-induced cough in
man: modulation by beta-adrenergic agonist and anticholinergic agent. Thorax 1990; 45: 694–8.
Myers AC, Kajekar R, Undem BJ. Allergic inflammationinduced neuropeptide production in rapidly adapting
afferent nerves in guinea pig airways. Am J Physiol Lung
Cell Mol Physiol 2002; 282: L775–L781.
Hsu J-Y, Stone RA, Logan-Sinclair R, Worsdell M, Busst
C, Chung KF. Coughing frequency in patients with persistent cough using a 24-hour ambulatory recorder. Eur
Respir J 1994; 7: 1246–53.
French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of
chronic cough on quality of life. Arch Intern Med 1998;
158: 1657–61.
Curley FJ, Irwin RS, Pratter MR, Tivers DH, Doern GV,
Vernaglia PA et al. Cough and the common cold. Am Rev
Respir Dis 1988; 138: 305–11.
Freestone C, Eccles R. Assessment of the antitussive efficacy of codeine in cough associated with common cold.
J Pharm Pharmacol 1997; 49: 1045–9.
Pavesi L, Subburaj S, Porter-Shaw K. Application and validation of a computerized cough acquisition system for
objective monitoring of acute cough: a meta-analysis.
Chest 2001; 120: 1121–8.
Tukiainen H, Karttunen P, Silvasti M, Flygare U,
Korhonen R, Korhonen T et al. The treatment of acute
transient cough: a placebo-controlled comparison of dextromethorphan and dextromethorphan-beta 2-sympathomimetic combination. Eur J Respir Dis 1986; 69: 95–9.
Lee PCL, Jawad MS, Eccles R. Antitussive efficacy of
dextromethorphan in cough associated with acute upper
respiratory tract infection. J Pharm Pharmacol 2000; 52:
1137–42.
Berkowitz RB, Connell JT, Dietz AJ, Greenstein SM,
Tinkelman DG. The effectiveness of the nonsedating antihistamine loratadine plus pseudoephedrine in the
symptomatic management of the common cold. Ann
Allergy 1989; 63: 336–9.
Irwin RS, Curley FJ, French CL. Chronic cough: the
spectrum and frequency of causes, key components of the
diagnostic evaluation, and outcome of specific therapy.
Am Rev Respir Dis 1990; 141: 640–7.
O’Connell F, Thomas VE, Pride NB, Fuller RW. Capsaicin
cough sensitivity decreases with successful treatment of
chronic cough. Am J Respir Crit Care Med 1994; 150:
374–80.
McGarvey LP, Heaney LG, Lawson JT, Johnston BT, Scally
CM, Ennis M et al. Evaluation and outcome of patients
with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax 1998; 53: 738–43.
19 Mello CJ, Irwin RS, Curley FJ. Predictive values of the
character, timing, and complications of chronic cough
in diagnosing its cause. Arch Intern Med 1996; 156:
997–1003.
20 Irwin RS, Pratter MR, Holland PS, Corwin RW, Hughes
JP. Postnasal drip causes cough and is associated with reversible upper airway obstruction. Chest 1984; 85:
346–52.
21 Carrao WM, Braman SS, Irwin RS. Chronic cough as the
sole presenting manifestation of bronchial asthma. N Engl
J Med 1979; 300: 633–7.
22 Osman LM, McKenzie L, Cairns J, Friend JA, Godden DJ,
Legge JS et al. Patient weighting of importance of asthma
symptoms. Thorax 2001; 56: 138–42.
23 Gibson PG, Dolovich J, Denburgh J, Ramsdale EH,
Hargreave FE. Chronic cough: eosinophilic bronchitis
without asthma. Lancet 1989; 1: 1246–7.
24 Doherty MJ, Mister R, Pearson MG, Calverley PM.
Capsaicin responsiveness and cough in asthma and
chronic obstructive pulmonary disease. Thorax 2000; 55:
643–9.
25 Fujimura M, Kamio Y, Hashimoto T, Matsuda T. Cough
receptor sensitivity and bronchial responsiveness in patients with only chronic non-productive cough: effect of
bronchodilator therapy. J Asthma 1994; 31: 463–72.
26 Brightling CE, Ward R, Wardlaw AJ, Pavord ID. Airway
inflammation, airway responsiveness and cough before
and after inhaled budesonide in patients with eosinophilic
bronchitis. Eur Respir J 2000; 15: 682–6.
27 Ing AJ, Ngu MC, Breslin AB. Pathogenesis of chronic persistent cough associated with gastroesophageal reflux. Am
J Respir Crit Care Med 1994; 149: 160–7.
28 Jack CIA, Calverley PMA, Donnelly RJ, Tran J, Russell G,
Hind CRK et al. Simultaneous tracheal and oesophageal
pH measurements in asthmatic patients with gastroesophageal reflux. Thorax 1995; 50: 201–4.
29 Paterson WG, Murat BW. Combined ambulatory
esophageal manometry and dual-probe pH-metry in evaluation of patients with chronic unexplained cough. Dig
Dis Sci 1994; 39: 1117–25.
30 Ours TM, Kavuru MS, Schilz RJ, Richter JE. A prospective evaluation of esophageal testing and a double-blind,
randomized study of omeprazole in a diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol
1999; 94: 3131–8.
31 Kiljander TO, Salomaa ER, Hietanen EK, Terho EO.
Chronic cough and gastro-oesophageal reflux: a doubleblind placebo-controlled study with omeprazole. Eur
Respir J 2000; 16: 633–8.
32 Novitsky YW, Zawacki JK, Irwin RS, French CT, Hussey
VM, Callery MP. Chronic cough due to gastroesophageal
reflux disease: efficacy of antireflux surgery. Surg Endosc
2002; 16: 567–71.
295
CHAPTER 27
33 Vestbo J, Lange P. Can GOLD Stage 0 provide information
of prognostic value in chronic obstructive pulmonary disease? Am J Respir Crit Care Med 2002; 166: 329–32.
34 Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd
SS. Global strategy for the diagnosis, management, and
prevention of chronic obstructive pulmonary disease.
NHLBI/WHO Global Initiative for Chronic Obstructive
Lung Disease (GOLD) Workshop summary. Am J Respir
Crit Care Med 2001; 163: 1256–76.
35 Wynder EL, Kaufman PL, Lesser RL. A short-term followup study on ex-cigarette smokers. With special emphasis
on persistent cough and weight gain. Am Rev Respir Dis
1967; 96: 645–55.
36 Jorenby DE, Leischow SJ, Nides MA, Rennard SI,
Johnston JA, Hughes AR et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for
smoking cessation. N Engl J Med 1999; 340: 685–91.
37 Roberts HR, Wells AU, Milne DG, Rubens MB, Kolbe J,
Cole PJ et al. Airflow obstruction in bronchiectasis: correlation between computed tomography features and pulmonary function tests. Thorax 2000; 55: 198–204.
38 Israili ZH, Hall WD. Cough and angioneurotic edema
associated with angiotensin-converting enzyme inhibitor
therapy. A review of the literature and pathophysiology.
Ann Intern Med 1992; 117: 234–42.
39 Berkin KE, Ball SG. Cough and angiotensin converting
enzyme inhibition. Br Med (Clin Res Ed) 1988; 296:
1279.
40 Fogari R, Zoppi A, Tettamanti F, Malamani GD, Tinelli C,
Salvetti A. Effects of nifedipine and indomethacin on
cough induced by angiotensin-converting enzyme inhibitors: a double-blind, randomized, cross-over study.
J Cardiovasc Pharmacol 1992; 19: 670–3.
41 McEwan JR, Choudry NB, Fuller RW. The effect of sulindac on the abnormal cough reflex associated with dry
cough. J Pharmacol Exp Ther 1990; 255: 161–4.
42 Malini PL, Strocchi E, Zanardi M, Milani M, Ambrosioni
E. Thromboxane antagonism and cough induced by
angiotensin-converting-enzyme inhibitor. Lancet 1997;
350: 15–8.
43 Hargreaves MR, Benson MK. Inhaled sodium cromoglycate in angiotensin-converting enzyme inhibitor cough.
Lancet 1995; 345: 13–6.
44 Poe RH, Harder RV, Israel RH, Kallay MC. Chronic persistent cough. Experience in diagnosis and outcome using
an anatomic diagnostic protocol. Chest 1989; 95: 723–8.
45 Hoffstein V. Persistent cough in nonsmoker. Can Respir J
1994; 1: 40–7.
46 Davis SF, Sutter RW, Strebel PM, Orton C, Alexander V,
Sanden GN et al. Concurrent outbreaks of pertussis and
Mycoplasma pneumoniae infection: clinical and epidemiological characteristics of illnesses manifested by cough.
Clin Infect Dis 1995; 20: 621–8.
296
47 Gilberg S, Du Njamkepo ECI, Partouche H, Gueirard P,
Ghasarossian C et al. Evidence of Bordetella pertussis infection in adults presenting with persistent cough in a
French area with very high whole-cell vaccine coverage.
J Infect Dis 2002; 186: 415–8.
48 Birkebaek NH, Kristiansen M, Seefeldt T, Degn J, Moller
A, Heron I et al. Bordetella pertussis and chronic cough in
adults. Clin Infect Dis 1999; 29: 1239–42.
49 Kamei RK. Chronic cough in children. Pediatr Clin North
Am 1991; 38: 593–605.
50 Holmes PW, Barter CE, Pierce RJ. Chronic persistent
cough: use of ipratropium bromide in undiagnosed cases
following upper respiratory tract infection. Respir Med
1992; 86: 425–9.
51 O’Connell F, Thomas VE, Pride NB, Fuller RW. Capsaicin
cough sensitivity decreases with successful treatment of
chronic cough. Am J Respir Crit Care Med 1994; 150:
374–80.
52 Boulet LP, Milot J, Boutet M, St Georges F, Laviolette M.
Airway inflammation in non-asthmatic subjects with
chronic cough. Am J Respir Crit Care Med 1994; 149:
482–9.
53 Chung KF. Cough: potential pharmacological developments. Expert Opin Invest Drugs 2002; 11: 955–63 .
54 Muers MF, Round CE. Palliation of symptoms in nonsmall cell lung cancer: a study by the Yorkshire Regional
Cancer Organisation Thoracic Group. Thorax 1993; 48:
339–43.
55 Dudgeon DJ, Rosenthal S. Management of dyspnea and
cough in patients with cancer. Hematol Oncol Clin North
Am 1996; 10: 157–71.
56 Eddy NB, Friebel H, Hahn KJ, Halbach H. Codeine
and its alternates for pain and cough relief. 3. The antitussive action of codeine — mechanism, methodology
and evaluation. Bull World Health Organ 1969; 40:
425–54.
57 Aylward M, Maddock J, Davies DE, Protheroe DA, Leideman T. Dextromethorphan and codeine: comparison of
plasma kinetics and antitussive effects. Eur J Respir Dis
1984; 65: 283–91.
58 Empey DW, Laitinen LA, Young GA, Bye CE, Hughes DT.
Comparison of the antitussive effects of codeine phosphate 20 mg, dextromethorphan 30 mg and noscapine 30
mg using citric acid-induced cough in normal subjects. Eur
J Clin Pharmacol 1979; 16: 393–7.
59 Eddy NB, Friebel H, Hahn KJ, Halbach H. Codeine and its
alternates for pain and cough relief. 4. Potential alternates
for cough relief. Bull World Health Organ 1969; 40:
639–719.
60 Matthys H, Bleicher B, Bleicher U. Dextromethorphan
and codeine: objective assessment of antitussive activity in
patients with chronic cough. J Intern Med 1983; 11:
92–100.
MANAGEMENT OF COUGH
61 Catena E, Daffonchio L. Efficacy and tolerability of levodropropizine in adult patients with non-productive
cough. Comparison with dextromethorphan. Pulm Pharmacol Ther 1997; 10: 89–96.
62 Dicpinigaitis PV, Rauf K. Treatment of chronic, refractory
cough with baclofen. Respiration 1998; 65: 86–8.
63 Dicpinigaitis PV. Use of baclofen to suppress cough in-
duced by angiotensin-converting enzyme inhibitors. Ann
Pharmacother 1996; 30: 1242–5.
64 Morice AH, Marshall AE, Higgins KS, Grattan TJ. Effect
of inhaled menthol on citric acid induced cough in normal
subjects. Thorax 1994; 49: 1024–6.
65 Udezue E. Lidocaine inhalation for cough suppression.
Am J Emerg Med 2001; 19: 206–7.
297
Index
Note: page numbers in italics refer to figures, those in bold refer to tables.
abdominal muscles 202–3
ACE inhibitor cough 12, 13, 15, 30, 108, 250, 289
acute cough
antitussives 252
causes 285
epidemiology 11–12
physical examination 30
and quality of life 77
acute respiratory infection 59–60
adenovirus 84, 141
adhesion 274
afferent nerve subtypes 161–3, 162, 163
association with cough reflex 182–3
C-fibres 6, 161, 162, 164–6
interactions between
central 168–9
peripheral 166–8, 167
properties of 163
RARs 6, 18–19, 18, 161, 162, 163–4, 173
SARs 19, 161, 162, 164–5
airway hyperresponsiveness
in asthma 115–16, 116
in children 61
and cough sensitivity 119
mechanisms of 116–18, 117
airway inflammation 33
assessment of 43
induced sputum 43–5, 44
airway lesions in children 62
airway remodelling 43
airway smooth muscle 200–1
allergic bronchopulmonary aspergillosis 139
allergic cough 61
allergic rhinitis 111
Alternaria 113
American College of Chest Physicians 107
g-aminobutyric acid see GABA
anandamide 253
angiotensin-converting enzyme inhibitors see ACE
inhibitors
animal models 217–22
conscious/anaesthetized animals 218
guinea-pig 219–21
experimental design 219–20
methodology 220–1, 220, 221
similarity to human cough reflex 219
physiology 217
sensitivity of cough reflex 219
species 217–18
tussive stimuli 218–19
antacids 103
anti-inflammatory agents 275–6
antibiotics
bronchiectasis 142–3
tracheobronchitis 90
anticholinergics 270
antidiuretics 242
antihistamines 112
tracheobronchitis 90–1
antireflux surgery 104
antitussives 7, 19, 92, 247–57
antidiuretics 242
capsaicin 241, 253
centrally acting 225–36, 250–1
5-hydroxytryptamine 228, 254
glycine 225–8
inhibitory action on GIRK channel 228–31, 229
NMDA and NK1 receptors 231–2, 231
opioid receptors 232–3
clinical trials 259–62, 260, 261
non-specific effects 262
pharmacological effects 259–60
physiological effects 260–1
placebo effects 261–2
COPD 132
disodium cromoglycate 241
dopamine receptor agonists 242
eosinophil antagonists 253–4
expectorants 252, 270–1
GABAB receptor agonists 241, 254
local anaesthetics 239–40, 252, 294
moguisteine 242
mucoactive agents 269–81, 270
mucolytics 132, 272–3, 294
narcotic 232–3, 292–4, 293
non-specific 250–2, 251
opioids 238–9
peripherally acting 237–45
placebo effects 259–67
potassium channel openers 241–2, 254
specific 247–50, 258
tachykinin antagonists 240–1, 253
aquaporin activators 270
aquaporins 271
Aspergillus spp. 113
Aspergillus fumigatus 141
aspirin, and rhinitis 111
assessment of cough
airway inflammation 43–5, 44
bronchial mucosal biopsy 45
children 62–8
clinical assessment 63–7, 64, 65, 66
investigative assessment 67–8, 68
cough counts 40–1, 41
299
INDEX
assessment of cough (continued)
and diagnosis 42–3
exhaled nitric oxide test 45
pharmacological 41–2, 42
asthma 28, 115–23
airway hyperresponsiveness 115–16, 116
airway inflammation 115
antitussives 248–9
cough-predominant 12, 13–14, 118, 286–7
in children 60–1
management 120
mechanism 119–20
mucociliary clearance in 212–14, 213
treatment 294
asthma-like syndrome 12, 13
atopic cough 61
atropine 276
autoregulation of flow 197
baclofen 251
beclomethasone, and cough count 41–2
benzonatate 239, 251
Blastomyces spp. 85
Bordetella pertussis 5, 84, 85, 88, 141, 250, 289
treatment 91
bradykinin 86
bronchial carcinoma 108
bronchial mucosal biopsy 45
bronchiectasis 62, 108, 137–45, 288–9
antibiotic management 142–3
causes 140, 141–2, 141
clinical features 139
conditions associated with 140
cough in 138
treatment 143–4
investigations 139–41, 140, 141
non-antibiotic treatment 142
bronchiolitis 83–5, 84
clinical presentation 88
treatment 91
bronchiolitis obliterans organizing pneumonia (BOOP) 151
bronchoconstriction 116
COPD 131
see also asthma
bronchodilators 131, 270
tracheobronchitis 90
bronchomalacia 62
bronchopneumonia 108
bronchoprovocation testing 32
bupivacaine 239, 240
BW443C 239
C-fibre receptors 19
C-fibres 6, 161, 162, 164–6
calcitonin gene-related peptide 7
cancer 147–57
assessment of cough 151
bronchial 108
causes of cough in 149–51, 150
conditions provoking cough in 150
management of cough 151–5, 152, 154
prevalence of cough in 148
300
terminal care cough management 155
treatment causing cough 150
Candida albicans 113
capsaicin 241, 253
capsaicin challenge 7, 50, 51, 53, 119, 129, 182
capsaicin cough reflex 138–9
carcainium chloride 239
cardiovascular implications of coughing 203
causes of cough 284, 285–9
CD8+ T cells 126, 127
cellular response to infection 87
chemokines 86
chemotherapy 153–4, 154
chest radiograph 31, 62
children 57–73
acute respiratory infection 59–60
airway hyperresponsiveness 61, 67
airway lesions 62
airways resistance 67
allergic/atopic cough 61
assessment 62–8
clinical 63–7, 64, 65, 66
investigative 67–8, 68
asthma 60–1
cough-variant 67
causes of cough in 57, 58
chronic suppurative lung disease 62
cough categories 57, 59
non-specific 59
normal/expected 57, 59
specific 59
cough sensitivity determination 67, 68, 69
environmental causes of cough 62
gastro-oesophageal reflux 61
habitual/psychogenic cough 62
inflammatory markers 67–8
measurement of cough 68–70
cough diary cards 69–70, 70
cough meters 69
nasal space disease 61–2
Chlamydia pneumoniae 84, 85, 88, 250
chronic bronchitis 288
chronic cough 5, 12–15
aetiology 112
causes 12–14, 13, 285–9
diagnosis and investigations 290–1, 290, 291
and gastro-oesophageal reflux 98–100, 99
physical examination 30
and quality of life 75–7, 76
treatment 247–52
unknown cause 290
chronic obstructive pulmonary disease 6, 125–35, 288
aetiology 126–7
clinical presentation 127–8, 128
cough in 125–6
cough reflex sensitivity 128–9, 129
exacerbations of 128
inflammatory process 126–7
mucociliary clearance in 210–12, 212
mucus hypersecretion 129–30
pathophysiological changes in 127
severity of 128
INDEX
treatment 130–2
bronchodilators 131
corticosteroids 131
cough suppressants 132
mucolytics 132
cimetidine 103
cisapride 103
citric acid challenge test 7, 53
clinical assessment 27–37
cost-effectiveness 35
diagnosis 27–8
frequency and severity of cough 30–1
history 28–30
cough characteristics 29
cough duration 28–9
drug history 30
occupational history 29–30
smoking history 29
sputum production 29
investigations 31–3, 31
airway inflammation 33
bronchoprovocation testing 32
chest radiograph 31
fibreoptic bronchoscopy 33
gastrointestinal investigations 32–3
psychological assessment 33
sinus imaging 32
spirometry and peak expiratory flow 31–2
thoracic CT scanning 33
upper airway provocation studies 32
physical examination 30
protocol 34
clinical management 51–2, 51
Clostridium difficile 143
codeine 7, 238, 250–1
clinical trials 264
complications of cough 284
compressive phase of cough 176, 194–5
computed tomography 33, 113
continuous hyperfractionated radiotherapy (CHART) 153
COPD see chronic obstructive pulmonary disease
coronavirus 11, 84
corticosteroids 112, 120, 275–6
COPD 131
cough centre 19, 225, 226
cough counts 40–1, 41
cough diary cards 69–70, 70
cough duration 28–9
cough meters 69
cough model 265–7, 266
cough network model 173–6, 174, 175, 176
compressive phase of cough 176
expulsive phase of cough 176
inspiratory phase of cough 175–6
cough provocation tests 49–55
in clinical research 52, 53
cough reflex 6, 49, 50
animal models 219
capsaicin 138–9
in COPD 128–9, 129
plasticity of 21–2
sensitivity 181–2, 182
sensory pathways 161–71
sensory regulation 237–8, 238
cough sensitivity
and airway hyperresponsiveness 119
animal models 219
in children 67, 68, 69
chronic obstructive pulmonary disease 128–9, 129
cough severity 30–1, 284–5
factors affecting 259–62, 260, 261
cough severity tests 40
cough symptom score 40
cough-predominant asthma 12, 13–14, 118, 286–7
in children 60–1
management 120
mechanism 119–20
cough-variant asthma 118
coxsackievirus A21 84
cysteinyl leukotrienes 116, 117
cystic fibrosis ion transport regulator 271
cytokines 44, 86, 87
definition of cough 17
description of cough 193–6
cessation 195–6
compressive phase 176, 194–5
expulsive phase 176, 195
inspiratory phase 175–6, 194
dextran 270
dextromethorphan 42, 225–6, 227, 228, 229, 235, 251
clinical trials 264
diagnosis 51
diaphragm muscles 201
dihydrocodeine 7
mode of action 228
diphenhydramine 251
disodium cromoglycate 112, 120, 241
domperidone 103
dopamine 19
dopamine receptor agonists 242
dornase alfa 270, 272, 277
drug-induced rhinitis 111
dry cough 50
environmental factors 4
in children 62
EORTC LC-13 151
eosinophil antagonists 253–4
eosinophil cationic protein 115
eosinophilia syndrome 44, 111
eosinophilic bronchitis 44
without airway hyperresponsiveness 118–19, 119
eosinophilic cough 45, 286–7
eosinophils 5
role in airway hyperresponsiveness 117
eotaxin 86
epidemiology 11–16, 49–50, 50
European Community Respiratory Health Survey 4
excitability 183–8, 184, 185
potassium channels 187
sodium channels 187–9
vanilloid receptor mechanisms 186–7
exercise-induced bronchoconstriction 116
301
INDEX
expectorants 252, 270–1
expiration reflex 17
expiratory flow 196–7, 196
drugs increasing 275
expiratory flow velocity 197
expulsive phase of cough 176, 195
fibreoptic bronchoscopy 33
flow limitation 197
flow–mucus interactions 199–200, 200
forced expiratory volume 116, 125, 127, 128
forced vital capacity 127
foreign body, inhaled 15, 33, 62
Functional Assessment of Cancer Treatment (FACT) 151
G-protein-coupled inwardly rectifying K+ channels see
GIRK channels
GABA 19
GABAB receptor agonists 241, 254
gastro-oesophageal reflux 5, 12, 13, 14, 28, 44, 97–106,
287–8
antireflux barrier 97–8
antireflux surgery 104
antitussives 249
in children 61
clinical presentation 100–1
and cough 98–100, 99
diagnosis 101–2, 101, 102
pathogenesis 98
therapy 102–5, 103, 104
gastrointestinal investigations 32–3
gating mechanism of cough 177
evidence in support of 177
identity of gate elements 179
interaction with cough network 177–9, 178
gelsolin 270, 272
gene therapy 270
Gilles de la Tourette syndrome 15
GIRK channels 228–31, 229
Global Initiative for Chronic Obstructive Lung Disease 125
glucocorticoids 270
glutamate 19
glycine pathways, antitussive action on 225–7
cough centre 226
glycine-induced currents in single neurones 225
microdialysis experiments 226–8, 227
strychnine-sensitive glycinergic transmission 226
glycopyrrolate 276
granular proteins 115
granulocyte–macrophage colony-stimulating factor 44
guanethidine 111
guinea-pig cough model 219–21
experimental design 219–20
methodology 220–1, 220, 221
similarity to human cough reflex 219
habit cough 15, 33
in children 62
haematopoietic stem cell transplantation 149
Haemophilus influenzae 85, 111, 113, 140, 142, 143
Haemophilus parainfluenzae 140
302
haemoptysis 139
Hering–Breuer reflex 19
histamine 86, 116
Histoplasma 85
history 28–30
cough characteristics 29
cough duration 28–9
drug history 30
occupational history 29–30
smoking history 29
sputum production 29
hormonal rhinitis 111
human epidermal growth factor receptor 2 protein 151
5-hydroxytryptamine 19
5-hydroxytryptamine receptor agonists 228, 254
hypertonic saline 270
idiopathic rhinitis 111
inflammation 126–7, 127
influenza virus 84, 91
inspiratory phase of cough 175–6, 194
intensity of cough 41
intercostal muscles 202
interleukin-5 44
interleukin-8 44, 86, 126, 137
ipratropium bromide 112, 120, 276
irritant rhinitis 111
laryngeal muscles 201
laryngotracheobronchitis
clinical presentation 88
treatment 91–2
laser therapy 154
Legionella pneumophila 85
leukotriene B4 126, 137
levodropropizine 251
lidocaine 100, 239, 252
local anaesthetics 239–40, 252, 294
low molecular weight heparin 270
lower airway infections 83–96
clinical presentation 86, 88–9
epidemiology and aetiology 83–5, 84, 85
evaluation 89–90
management 90–2
pathophysiology 85–6, 86, 87
see also individual infections
Lung Cancer Symptom Scale 151
macrolide antibiotics 270, 276
major basic protein 115
management of cough 283–97, 291– 4, 292
approach to 283– 4
see also antitussives
mannitol 270
measles virus 141
measurement of cough 39– 40, 40
children 68–70
cough diary cards 69–70, 70
cough meters 69
cough sensitivity 69
mechanics of cough 196–200
INDEX
expiratory flow velocity 197
flow–mucus interactions 199–200, 200
regulation of expiratory flow 196–7, 196
supramaximal flow 197–9, 198
mechanisms of cough 17–21
central nervous system 19–20, 20
N-methyl-D-aspartate 19
methyldopa 111
metoclopramide 103
mexiletine 239, 240
moguisteine 242, 251
clinical trials 264
Moraxella catarrhalis 85, 113, 143
morphine 238
motor mechanisms of cough 20–1, 21, 200–3
airway smooth muscle 200–1
upper airway and respiratory muscles 201–3
abdominal muscles 202–3
diaphragm 201
intercostal muscles 202
laryngeal muscles 201
MUC5AC 130
mucoactive agents 269–81
altered properties of secretions 271–3, 271
efficacy 278
expectorants 252, 270–1, 294
increase in airflow 275
indications for use 276–7
interaction between mucus and epithelium 273–5, 274
mucolytics 132, 272–3, 294
mucoregulatory drugs 275–6
mucolytics 132, 272–3, 294
clinical use 273
in COPD 132
polymer dispersion and charge shielding 273
mucoregulatory drugs 275–6
mucus 21, 271–2
clearance 208–14, 210
in asthma 212–14, 213
in COPD 210–12, 212
flow–mucus interactions 199–200, 200
hypersecretion 129–30
secretion and transport 207–8
sources of 207
viscoelasticity 271
Mycobacterium avium 141
Mycobacterium tuberculosis 85, 141
Mycoplasma pneumoniae 84, 85, 250, 289
N-acetylcysteine 132, 270, 273
nacystelyn 270, 273
nasal space disease 61–2
nedocromil sodium 112
neurogenesis of cough 173–80
cough network model 173–6, 174, 175, 176
compressive phase of cough 176
expulsive phase of cough 176
inspiratory phase of cough 175–6
gating mechanism 177
evidence in support of 177
identity of gate elements 179
interaction with cough network 177–9, 178
neurogenic inflammation 18
neurotransmitter plasticity 188–9
nifedipine 111
nitric oxide, exhaled 45
NMDA receptors 231
nociceptin 239
nocturnal cough 4, 12
non-productive cough 4
normal cough pattern 3–4
occupational factors 29–30
omeprazole 103, 288
opioid receptors 232–3
opioids 238–9, 250–1, 292–4, 293
oxitropium chloride 276
parainfluenza virus 84
particulates 4
pathophysiology of cough 6–7
peak expiratory flow measurements 31–2
pharmacological assessment of cough 41–2, 42
pharyngeal aspiration 108–10, 109, 110
pholcodeine 7
photodynamic therapy 154
physical examination 30
placebo effects of antitussives 259–67
cough model 265–7, 266
factors affecting cough severity 259–62, 260, 261
kinetics and dynamics 265
magnitude of 262–3, 263
mechanism of action 263–5, 265
plasticity 183–90
changes in nerve fibre density 189–90
of cough reflex 21–2, 181–2, 182
excitability 183–8, 184, 185
extraneuronal effects 190
neurotransmitter plasticity 188–9
pneumonia, community-acquired 85
clinical presentation 88–9
treatment 92
pollutants 4
postinfectious cough 249–50, 289
postnasal drip 5, 18, 28, 44, 86, 107–8, 285–6
antitussives 247–8
incidence 14
treatment 14
postviral cough 15
potassium channel openers 241–2, 254
potassium channels 187
prevalence of cough 4–5
productive cough 50
prognosis 51
prostaglandins 86
proton pump inhibitors 103, 288
protussives 92
provocation tests 32, 52, 53
Pseudomonas aeruginosa 85, 138, 140, 143
psychogenic cough 33
in children 62
Pulmozyme 270, 272, 276
303
INDEX
quality of life 75–9
acute cough 77
chronic cough 75–7, 76
measurement of 77
radiotherapy 152–3, 152
ranitidine 103
rapidly adapting stretch receptors 6, 18–19, 18, 161, 162,
163–4, 173
RARs see rapidly adapting stretch receptors
RAST test 111
reconfiguration 173
reserpine 111
respiratory syncytial virus 11, 83, 273
rhinitis 12, 13, 14, 110–12
allergic 111
drug-induced 111
endocrine/hormonal 111
evaluation 111
idiopathic 111
irritant 111
treatment 111–12
rhinosinusitis 112–13, 285–6
diagnosis 112, 113
see also postnasal drip
rhinovirus 11, 84
salbutamol, and cough count 41–2, 42
SARs see slowly adapting stretch receptors
sensitized cough reflex 6
sensory mechanisms of cough 18–19, 18
sensory pathways 18–19, 18, 161–71
afferent nerve subtypes 161–3, 162, 163
C-fibres 164–6
properties of 163
rapidly adapting receptors 163–4
slowly adapting receptors 164
interaction between afferent nerve subtypes
central 168–9
peripheral 166–8, 167
sinus imaging 32
304
slowly adapting stretch receptors 19, 161, 162, 164–5
smoking 29, 108
sodium 2-mercaptoethane sulphonate 132
sodium channels 187–8
spirometry 31–2
sputum 4–5
induced 43–5, 44
production 29
Staphylococcus aureus 85, 142
Streptococcus pneumoniae 85, 111, 113
strychnine-sensitive glycinergic transmission 226
substance P 7, 86, 231–2
suppurative airway disease see bronchiectasis
supramaximal flow 197–9, 198
surfactants 270, 274
tachykinin antagonists 240–1, 253
tachykinins 18, 19
tenacity 274
throat-clearing 108–10, 109, 110
thymosin b4 270, 272
tracheobronchitis 83–5, 84
clinical presentation 86, 88
treatment
antibiotics 90
antihistamines 90–1
bronchodilators 90
tracheomalacia 62
treatment 7–8
tuberculosis 108
tumour necrosis factor-a 44, 126
tussiphonogram 42
upper airway provocation testing 32
upper respiratory tract infection 19
vanilloid receptors 186–7, 253
vasoconstrictors 112
Young’s syndrome 142