ارزيابي سرفه

ارزيابي سرفه
Eur Respir J 2007; 29: 1256–1276
DOI: 10.1183/09031936.00101006
CopyrightßERS Journals Ltd 2007
ERS TASK FORCE
ERS guidelines on the assessment
of cough
A.H. Morice*, G.A. Fontana#, M.G. Belvisi", S.S. Birring+, K.F. Chung",
P.V. Dicpinigaitis1, J.A. Kastelik*, L.P. McGarveye, J.A. Smith**,
M. Tatar## and J. Widdicombe""
CONTENTS
Summary of key points and recommendations . . . . . . . . . . .
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Capsaicin and citric acid inhalation cough challenge . . . . .
Cough induced by inhalation of aqueous solutions . . . . . . .
Cough monitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Assessment of quality of life of patients with chronic cough
Animal models of cough . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Design and conduct of clinical trials of antitussive drugs . .
SUMMARY OF KEY POINTS AND
RECOMMENDATIONS
Cough
1) All basic scientific articles should refer to
cough as a three-phase motor act. For the
purposes of acoustic recordings in clinical studies, however, cough should be described as a
forced expulsive manoeuvre or manoeuvres
against a closed glottis that are associated with
a characteristic sound or sounds.
2) All scientific articles should include a clear
definition of what the authors have used as their
definition of cough.
Capsaicin and citric acid inhalation cough
challenge
1) The methodology for the performance of
inhalation cough challenge should be standardised so as to facilitate universal interpretation
and comparison of data generated by different
laboratories.
2) Comprehensive normal ranges need to be
developed using the standardised methodology
advocated in the present document.
3) The single-breath concentration–response
method using a flow-limited dosimeter is recommended for most experimental protocols.
4) Both C2 and C5 should be recorded.
5) Since there is wide inter-individual variation,
cough challenge data have no intrinsic significance, but may usefully be used to follow change
in cough reflex sensitivity in an individual.
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VOLUME 29 NUMBER 6
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Cough induced by inhalation of aqueous
solutions
1) Aerosolised aqueous solutions represent a
useful experimental tool in cough research.
2) The cough challenge with ultrasonic distilled
water (fog) is difficult to standardise since it is
highly dependent upon nebuliser output.
3) Consideration should be given to potential
adverse events, such as bronchoconstriction and
cross-infection.
Cough monitors
1) No cough monitor is currently the gold
standard.
2) Monitors should be developed that are ambulatory, are capable of being digitally processed
and permit prolonged (24-h) recording.
3) There is little to commend any particular
method of quantifying cough over any other.
Assessment of quality of life of patients with
chronic cough
1) Cough can have profound effects on health
status, which can be assessed by cough-specific
health status questionnaires.
AFFILIATIONS
*Cardiovascular and Respiratory
Studies, Respiratory Medicine, Castle
Hill Hospital, Cottingham,
"
National Heart & Lung Institute,
Imperial College London,
+
Kings College Hospital, and
""
University of London, London, and
e
Queen’s University of Belfast,
Belfast, and
**Education and Research Centre,
University of Manchester,
Manchester, UK.
#
University of Florence, Florence,
Italy.
1
Albert Einstein College of Medicine,
and Montefiore Medical Center,
New York, NY, USA.
##
Jessenius Medical School,
Comenius University, Martin,
Slovakia.
CORRESPONDENCE
A.H. Morice, Cardiovascular and
Respiratory Studies, Respiratory
Medicine, Castle Hill Hospital, Castle
Road, Cottingham, East Yorkshire,
HU16 5JQ, UK.
Fax: 44 1482624068
E-mail: a.h.morice@hull.ac.uk
Received:
August 02 2006
Accepted after revision:
December 14 2006
STATEMENT OF INTEREST
Statements of interest for A.H.
Morice, S.S. Birring, K.F. Chung,
J.A. Kastelik, J.A. Smith and M. Tatar
can be found at
www.erj.ersjournals.com/misc/
statements.shtml
2) Cough visual analogue scale (VAS, 0–100 mm)
should be used to assess cough severity in
patients with chronic cough.
3) Patients with chronic cough should be
assessed with cough-specific quality-of-life questionnaires in clinical studies.
European Respiratory Journal
Print ISSN 0903-1936
Online ISSN 1399-3003
EUROPEAN RESPIRATORY JOURNAL
A.H. MORICE ET AL.
Animal models of cough
1) The most useful animal model of cough is the conscious
guinea pig.
2) Both sound and airflow should be used to define a cough
event.
Design and conduct of clinical trials of antitussive drugs
1) The experimental model in which antitussive drugs are
tested depends greatly upon the mode of action of the agent.
2) Normal volunteer studies should be designed in the
knowledge that a large placebo effect is likely.
3) In acute cough, parallel group studies are required.
4) In chronic cough, the patient population studied should be
defined by a diagnostic test.
BACKGROUND
Cough is the most common symptom for which individuals
seek medical advice [1, 2]. An acute cough is often the most
prominent symptom of the common cold, which itself is the
most frequent illness to afflict mankind. In the USA, the direct
and indirect costs of the common cold have been estimated at
US$40 billion per annum [3]. Chronic cough, as the sole
presenting complaint, is known to account for 10–38% of all
referrals made to respiratory physicians [4, 5]. Recently, the
European Respiratory Society (ERS) published guidelines on
the management of cough [6]. The aim of that document, as of
guidelines produced by the American College of Chest
Physicians, was to provide consensus regarding the diagnosis
and treatment of cough in both adults and children [7].
However, little attention has been given to the accurate clinical
and scientific assessment of coughing. In 2004, the ERS
approved the setting up of a task force with the intention of
producing recommendations for cough assessment. The main
objective was to produce a practical document, which would
provide helpful guidance to researchers, clinicians, the
pharmaceutical industry and regulatory authorities. It was
agreed that the scope of this document should include
recommendations on the following key elements: 1) safe
standardised methods of inhalation cough challenge; 2)
reliable, reproducible and relevant clinical cough recording
and analysis; 3) clinical assessment of cough-related quality of
life; 4) appropriate animal models in which to evaluate novel
cough treatments; and 5) areas for future research. It is
envisaged that an effective document would contribute to
improved patient care, enhance the quality of cough research
and ultimately assist in the development of effective new
therapies.
The need for recommendations regarding the assessment
of cough
In addition to the gaps in the existing literature, four major
factors justify the need for such a publication.
1) Since the mid-1960s, there has been a sharp increase in the
number of published manuscripts concerned with various
aspects of cough in human and animal studies. In a PubMed
search ranging 1966–2005 and limited to the keyword ‘‘cough’’,
there were 22,744 citations, more than for other common
respiratory symptoms including the term dyspnoea/dyspnea
EUROPEAN RESPIRATORY JOURNAL
ERS GUIDELINES ON ASSESSMENT OF COUGH
or wheeze. This represents not only an absolute increase but
also a two-fold relative increase in cough publications. The
incremental rise in citations in the four decades spanning this
period is displayed in table 1. The publications are geographically diverse, spanning five continents, and highlight the
importance and frequency with which cough presents as a
clinical problem.
2) The morbidity of cough is not trivial, and the assessment of
cough patients is incomplete without appreciation of the
associated clinical impact. A series of cough-specific quality-oflife questionnaires have been designed to capture this, but
agreement regarding their interpretation and clinical application is needed [8, 9]. New technologies designed to objectively
record and analyse cough events are rapidly being developed.
Recommendations regarding clinical and pharmacologically
relevant end-points for such devices are required.
3) The value of inhalation cough challenge testing as a research
tool in both human and animal studies is established [10, 11].
On review of the existing literature, different methods of
challenge have been identified, with wide variation in the
choice of tussive agents, delivery device and test end-point
employed. Standardisation of cough challenge methodology is
required if reliable comparisons of experimental results
between laboratories are to be made. In order to ensure
continued ethical review board support for cough research, a
standardised approved method of safe inhalation challenge
testing is required.
4) Although specific therapy directed at the underlying cause
of cough is usually successful, there are no particularly
effective nonspecific cough treatments. These are desperately
needed for patients with idiopathic cough, for those troubled
with cough due to pulmonary fibrosis and lung cancer, and
when established treatments for asthma and chronic obstructive pulmonary disease (COPD) are ineffective. Drug development is currently hampered by the lack of consensus as to
the appropriate animal model for testing of putative novel
therapies. Recommendations for the reliable and informative
testing of new therapies in animal models would be a major
step towards effective cough therapy.
Methods
The task force was composed of a number of invited
participants, identified for their particular expertise in the area
of cough assessment and treatment. The initial meeting of task
force members was held at the 2004 ERS Congress in Glasgow,
TABLE 1
Number of citations identified in PubMed
database using the keyword ‘‘cough’’ for the
period 1966–2005
Period
Citations n
1966–1975
2262
1976–1985
2968
1986–1995
6564
1996–2005
10950
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ERS GUIDELINES ON ASSESSMENT OF COUGH
UK, and followed by subsequent meetings in 2005 in
Amsterdam, the Netherlands, and later that year at the ERS
Congress in Copenhagen, Denmark. At the first meeting, it was
agreed that, where possible, recommendations should be
based on the peer-reviewed literature (original publications
and review articles). However, it was apparent that in many
areas of interest, including cough reflex testing, use of qualityof-life questionnaires and new cough recording technologies,
only limited data (such as meeting abstracts) existed.
Consequently, the opportunity to produce evidence-based
guidelines was limited. In such circumstances, recommendations were based on the consensus of experience of task force
participants.
Individuals and small groups were allocated specific topics
and, after conducting a literature review, asked to produce an
article for consideration at the subsequent task force meeting.
Based on the group discussion at these meetings, a series of
recommendations were agreed upon.
Structure of the document
The present document is prefaced with an executive summary
of key points and recommendations. The subsequent sections
address the individual components of cough assessment,
namely cough challenge in humans, cough event recording,
assessment of cough quality of life, animal models of cough,
and the design and conduct of clinical trials of antitussive
drugs. Each section begins with a summary of the existing
literature followed by a concluding statement highlighting
areas for future research and finally the task force recommendations.
Defining cough
Although usually defined in textbooks, a clear definition of
cough is lacking in the majority of scientific papers concerning
cough [12]. For the purpose of the present recommendations,
two possible definitions of cough, which have been used
elsewhere, are provided [13, 14].
1) Cough is a three-phase expulsive motor act characterised by
an inspiratory effort (inspiratory phase), followed by a forced
expiratory effort against a closed glottis (compressive phase)
and then by opening of the glottis and rapid expiratory airflow
(expulsive phase) [13].
2) Cough is a forced expulsive manoeuvre, usually against a
closed glottis and which is associated with a characteristic
sound [14].
Although some similarities exist, the major discrepancy
between these two definitions relates to the respiratory
patterns associated with cough. In particular, the preceding
inspiratory phase, which constitutes the first definition, is
believed to be one of a number of distinguishing features
between cough and another airway defensive reflex, the
expiration reflex [12].
Furthermore, neither definition adequately deals with the
common clinical scenario whereby an initial cough is followed
by a series of cough efforts. For the patient, this is often
described as a cough ‘‘bout’’ or ‘‘attack’’. To the researcher,
they may represent individual coughs or an extended single
cough. Clearly, this is of importance to those concerned with
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A.H. MORICE ET AL.
the accurate recording of cough frequency. For the physician
and, most critically, the patient, a definition that reflects the
sensation associated with an urge to cough, the intensity of the
cough and its impact on health status overrides any such
debate.
For the purpose of the assessment of cough, the present task
force has adopted the following recommendations.
Recommendations
1) All basic scientific articles should refer to cough as a threephase motor act. For the purposes of acoustic recordings in
clinical studies, however, cough should be described as a
forced expulsive manoeuvre or manoeuvres against a closed
glottis that are associated with a characteristic sound or
sounds.
2) All scientific articles should include a clear definition of
what the authors have used as their definition of cough.
CAPSAICIN AND CITRIC ACID INHALATION COUGH
CHALLENGE
Methodology
The inhalation cough challenge permits measurement of the
sensitivity of the cough reflex and assessment of the antitussive
effects of specific therapies. In general, inhalation cough
challenge testing can be divided into methods that use acid
and non-acid tussives. Capsaicin, the most commonly used
non-acid tussive to experimentally induce cough in humans,
was first described in 1984 [15]. Citric and tartaric acid are the
most widely used acid tussigens [16]. Citric acid inhalation
cough challenge was described and formally characterised in
the mid-1950s [16, 17]. Both citric acid and capsaicin can
induce cough in a dose-dependent and reproducible manner
[16, 18].
Unfortunately, because of the lack of standardisation of cough
challenge methodology in terms of equipment, preparation of
solutions, method of administration, nebuliser output, inspiratory flow rate and dose of aerosol per breath, comparisons of
cough sensitivity data currently in the literature from different
institutions are not valid. In the present section, recommendations that will assist in the standardisation of inhalation cough
challenge testing using both acid and non-acid tussigens are
proposed.
Preparation and storage of capsaicin solutions
Capsaicin (30.5 mg) is dissolved in 1 mL pure ethanol and
1 mL polyoxyethylene sorbitan (Tween 80) and then further
dissolved in 8 mL physiological saline solution to yield a
0.01 M stock solution [19, 20]. Without the detergent Tween 80,
a cloudy rather than clear solution results. The solution is
subsequently diluted with saline in order to obtain serial
doubling concentrations ranging 0.49–1,000 mM. If healthy
volunteers are to be tested, the lowest concentration prepared
is 0.98 mM, since, in the authors’ experience, induction of
cough at this concentration is rare.
It is unclear how often fresh stock solution should be prepared.
A recent study concluded that capsaicin solutions of o4 mM
are stable for 1 yr if stored at 4uC and protected from light [21].
EUROPEAN RESPIRATORY JOURNAL
A.H. MORICE ET AL.
Preparation of citric acid
Serial dilution of 3 M citric acid stock solution in sterile 0.9%
saline solution is performed in order to obtain serial doubling
concentrations ranging 1.95–3,000 mM [22–24]. In healthy
volunteers, the lowest concentration prepared is 7.8 mM. For
both capsaicin and citric acid, fresh dilutions from a stock
solution are prepared on each day of testing. The stock solution
is maintained at , -10uC for capsaicin and 4uC for citric acid.
The authors recommend that fresh solutions are prepared for
each challenge.
Capsaicin and citric acid are delivered in serial doubling
concentrations (the lower concentration is unlikely to influence
the higher one), with inhalation of 0.9% saline solution
randomly interspersed to increase challenge blindness [22–24].
Administration of capsaicin and citric acid
The two main methods of capsaicin and citric acid delivery
during cough challenge testing are the single-dose and dose–
response methods [25]. In the former method, a single
concentration of capsaicin or citric acid is employed. The
dose–response method can involve either the administration of
single vital-capacity breaths of incremental concentrations of
capsaicin or citric acid via a dosimeter-controlled nebuliser or
the tidal-breath inhalation of incremental concentrations of
tussive agent, each over a fixed time period, usually 15–60 s.
In most experimental circumstances, the single-breath dose–
response method is preferred because of the accuracy and
reproducibility of the dose delivered and the ease with which a
tussive response can be determined. With capsaicin and citric
acid inhalation occurring over a prolonged time period,
variations in respiratory frequency and tidal volume are likely
to cause significant variations in the amount of aerosol
delivered from subject to subject, as well as from one
concentration to another in an individual subject. This would
be of particular concern during the administration of concentrations that induce significant coughing, thereby preventing
the subject from inhaling the tussive agent for a significant
portion of the fixed time period of aerosol delivery.
Nevertheless, a recently published comparison of the tidal
breathing and dosimeter methods of capsaicin inhalation
challenge demonstrated both to be reproducible, with good
agreement between the two methods [26].
Optimisation of reproducibility of capsaicin and citric acid cough
challenges
Inspiratory flow rate
The rate of inspiratory flow affects the pattern of deposition of
aerosol within the airways. Variations in inspiratory flow rate
have been demonstrated to affect the results of capsaicin [27]
and citric acid [28] cough challenge. For example, lower
inspiratory flow rates (50 versus 150 L?min-1) result in greater
cough response to citric acid [28]. Therefore, the flow rate
needs to be constant regardless of effort, since, unless
inspiratory flow rate is controlled, variable amounts of tussive
agent will be delivered to different subjects, and even breathto-breath variations may occur in a given subject within the
same study. Such potential variability in aerosol delivery may
affect the results of studies in which reproducibility of cough
challenge results are crucial, such as in pharmacological
studies incorporating cough sensitivity measurement before
EUROPEAN RESPIRATORY JOURNAL
ERS GUIDELINES ON ASSESSMENT OF COUGH
and after drug therapy, and in epidemiological studies
comparing different subject populations.
In order to control for inspiratory flow rate, the present authors
recommend the use of a compressed air-driven nebuliser
(model 646; DeVilbiss Health Care, Inc., Somerset, PA, USA)
controlled by a dosimeter (KoKo DigiDoser; nSpire health Inc,
Louisville, CO, USA (formerly Ferraris Respiratory Inc) and
nSpire health Ltd, Hertford, UK (formerly Ferraris Respiratory
Europe) that is modified by the addition of an inspiratory flow
regulator valve (RIFR; nSpire health Inc, Louisville, CO, USA,
formerly PDS Instrumentation, Inc). The valve limits inspiratory flow rate to 0.5 L?s-1 regardless of excessive inspiratory
force, thereby guaranteeing a consistent and reproducible
inspiratory effort with each breath. Thus, with appropriate
instruction to inhale with sufficient force, all subjects achieve
an identical inspiratory flow rate during each inhalation of
aerosol.
Nebuliser characteristics
Significant variation in the amount of aerosol delivered per
inhalation may occur with a standard nebuliser, even in an
individual subject who attempts to maintain a constant
inspiratory flow rate. The second major determinant of aerosol
output is related to the structure of the nebuliser itself. For
example, in the DeVilbiss 646 model, the straw and baffle
assembly is a removable component of the nebuliser. When
this structure is detached for washing and then reattached,
variable distances result between the straw and baffle
assembly and the source of pressurised air, the jet orifice.
This variation in distance, albeit minute, results in variation in
nebuliser output. Therefore, in order to optimise reproducibility, two modifications to a nebuliser are suggested. First, an
inspiratory flow regulator valve is installed, as described
above. Secondly, the straw and baffle assembly of the nebuliser
is welded in place, thereby eliminating the variations in
nebuliser output that may occur when these components are
separated and then reattached with resulting variable distances between the jet orifice and straw. After these modifications are performed, the exact output (in mL?min-1) of the
nebuliser is determined (characterised nebuliser; nSpire Health
Inc, formerly PDS Instrumentation, Inc.). When the exact
output of a nebuliser is known, modulation of the duration of
aerosol delivery permits the determination of aerosol output
per inhalation. For example, a nebuliser with an output of
1.007 mL?min-1, programmed to deliver aerosol for 1.2 s,
provides 0.02 mL?breath-1.
Given the potential variations in nebuliser output, it is essential
that research investigations utilise equipment tailored to
optimise reproducibility, and that the same nebuliser, or one
with identical output, is used in studies incorporating serial
cough challenges in individual subjects, or studies comparing
distinct subject populations. Given the reality that different
types of equipment will continue to be used by cough
researchers worldwide, it is recommended that standardisation of cough challenge studies should be attempted by
controlling nebuliser output per breath.
Placebo inhalations
In order to increase cough challenge blindness, inhalations of
physiological saline (placebo) should be randomly interspersed
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between incremental concentrations of capsaicin and citric
acid [25, 29]. This strategy may reduce the effects of
voluntary suppression or conditioned responses in subjects
who would otherwise be anticipating progressively higher
concentrations of tussive agent.
Instructions to subjects
Subjects undergoing cough challenge should be specifically
instructed not to attempt to suppress any coughs and not to
talk immediately after inhalation of tussive agent, since this
may potentially suppress cough. The present authors recommend, for example, the following instruction to subjects:
‘‘allow yourself to cough if you need to, and as much as you
need to’’. Subjects should not be told that the induction of a
specific number of coughs is the end-point of the study (see
Interpretation of cough challenge data section) [11].
A.H. MORICE ET AL.
Significance of capsaicin and citric acid cough sensitivity
measurements
Isolated measurements of capsaicin sensitivity (C2 or C5) have
no intrinsic significance due to the large variation in cough
reflex sensitivity within the normal population (fig. 1). This
contrasts with the assessment of bronchial responsiveness,
where a provocative concentration of drug causing a 20% fall
in forced expiratory volume in one second (FEV1) outside the
normal range is predictive of pathophysiology [34].
Nevertheless, since cough reflex sensitivity to inhaled capsaicin and citric acid is highly reproducible when performed by a
individual investigator or laboratory using appropriate methodology [11, 16–18, 25], these challenges have established
themselves as an important tool in pharmacological studies
incorporating serial challenges, as well as in epidemiological
studies comparing distinct populations.
Determination of tussive response to cough challenge
When employing the single-breath method of capsaicin and
citric acid administration, the tussive response to each dose of
aerosol is immediate and brief. Therefore, only coughs
occurring within 15 s of capsaicin and citric acid delivery
should be counted [10, 25, 30, 31]. Coughs that occur beyond
this time period may not be capsaicin or citric acid induced.
Cleaning of the equipment
The equipment should be sterilised between each subject.
Sterilisation of the equipment should be performed in
accordance with the individual institution’s guidelines. For
example, the present authors’ protocol includes sterilisation for
15 min in Pera1 Safe (Antec International, A DuPont
Company, Sudbury, UK). Afterwards, the equipment is
washed thoroughly with hot water and air dried.
Interpretation of cough challenge data
For each test, the concentrations of capsaicin or citric acid
causing two (C2) and five coughs (C5) are reported. The C2 and
C5 can be obtained by determining the first administered
concentration that results in two or more and five or more
coughs, or by interpolation of logarithmically transformed
concentration–response curve data. Overall, there are minor
differences between these two methods [32]. Interpolated
concentrations are closer to the real C2 and C5, but offer no
particular advantage over the first administered concentration
method. Differing opinions exist among investigators as to
which is the preferred primary end-point, C2 or C5. Published
studies often report both values, but not infrequently C5 alone
is reported. There is evidence that C5 may be the clinically
superior value [11], although other studies have found C2 to be
more reproducible [29]. Until further data are available, the
present authors would recommend that both C2 and C5 are
measured.
Tachyphylaxis and reproducibility
Marked tachyphylaxis occurs to repeated cough challenge in
the short term. Indeed, continual inhalation over 1 min of citric
acid or capsaicin results in a reduction in cough frequency of a
third with capsaicin and complete abrogation with citric acid.
Repeated single-breath cough challenge at 10-min intervals
similarly results in marked tachyphylaxis [35]. The present
authors recommend a minimum of 1 h, and preferably 2 h,
between cough challenge measurements. The high degree of
long-term reproducibility of capsaicin and citric acid cough
challenge testing has been reported by numerous investigators
A small subgroup of individuals with relatively high cough
thresholds may not be able to achieve C5 despite using the
highest concentrations of tussigen. The inhalation of high
concentrations of capsaicin is precluded by a strong burning
sensation in the upper airway, whereas citric acid inhalation
may provoke a choking sensation or pharyngeal discomfort
[18]. The present authors recommend that such subjects be
excluded from comparative clinical trials because a true C5
cannot be discerned, and that the C2 is used in population
studies.
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VOLUME 29 NUMBER 6
2.5
Log C2 mM
A potential problem in serial cough challenges involves the
startle phenomenon [11]. A naive subject undergoing cough
challenge may cough excessively, a phenomenon described
with citric acid in the 1950s [16]. A preliminary familiarisation
challenge may be required, or the C5 may be used, since it is
less likely to succumb to this potential pitfall.
3.5
l
1.5
0.5
l
l
l
l
l
l
ll
ll
ll
ll
ll
lll
l l
l
ll
ll
ll
l
ll
ll
l
l
CVA
GORD
l
ll
ll
l
lll
lll
ll
l l
l
ll
l l
l
-0.5
PND
ICC
l
l
l
l
l
ll
ll
ll
l
l
l
Other
Condition
FIGURE 1.
Cough reflex sensitivity to capsaicin in patients with chronic cough
(&: normal range (derived from 134 healthy subjects)). C2: concentration of
capsaicin inducing two coughs; CVA: cough variant asthma; GORD: gastrooesophageal reflux disease; PND: post-nasal drip (rhinitis); ICC: idiopathic chronic
cough; Other: chronic obstructive pulmonary disease, sarcoidosis, cryptogenic
fibrosing alveolitis, and bronchiectasis. Adapted from [33].
EUROPEAN RESPIRATORY JOURNAL
A.H. MORICE ET AL.
employing the dose–response method and the single dose,
with both the single-breath technique [11, 16, 17, 26, 29, 33, 36–
41] and a fixed time period of capsaicin and citric acid
inhalation [15–18, 26, 35, 42, 43].
Two studies have confirmed the reproducibility of capsaicin
cough challenge over 3 months [44] and .6 months [11]. The
latter demonstrated good reproducibility of cough challenge in
40 healthy volunteers at a mean interval of 16.7 months. The
reproducibility of the recommended citric acid challenge has
recently been demonstrated [45].
Safety
A recent review of the 20-yr clinical experience with capsaicin
failed to uncover a single serious adverse event associated with
capsaicin cough challenge testing in humans [46]. This review
included an examination of 122 studies published since 1984,
describing 4,833 subjects, including healthy adults and
children, as well as patients with pathological cough, asthma,
COPD, hypertension, gastro-oesophageal reflux disease, interstitial lung disease, acute upper respiratory tract infection,
cervical spinal cord injury, heart–lung transplantation and
cystic fibrosis [46]. Side-effects consisted mainly of transient
throat irritation in a minority of subjects.
The safety of citric acid inhalation cough challenge was
reported in the 1950s [16, 17]. However, inhalation cough
challenge using citric acid can result in a small reduction in
FEV1 (,5%), which is unlikely to be of clinical significance [10].
Capsaicin does not induce clinically significant bronchoconstriction in healthy volunteers or asthmatics [15, 47].
However, the present authors would recommend that, when
performing inhalation cough challenge, bronchodilator therapy be available.
Female healthy volunteers and female patients with chronic
cough exhibit increased cough reflex sensitivity to capsaicin
[48, 49] and citric and tartaric acid [22, 50, 51].
The placebo cough response shows a nonlinear increase in
cough suppression, which is most pronounced at 4 h [40]. In
addition, there are suggestions that females may cough more
frequently and exhibit more rapid adaptation of cough than
males.
The contact details of investigators experienced in these
techniques can be found on the International Society for the
Study of Cough website [52].
Further research
At present no data are available regarding the short- and longterm reproducibility of the above-mentioned method of citric
acid inhalation cough challenge; however, they are currently
being investigated. The amount of information available
regarding the reproducibility of all cough challenge methods
needs to be increased.
ERS GUIDELINES ON ASSESSMENT OF COUGH
2) Comprehensive normal ranges need to be developed using
the standardised methodology advocated in the present
document.
3) The single-breath concentration–response method using a
flow-limited dosimeter is recommended for most experimental
protocols.
4) Both C2 and C5 should be recorded.
5) Since there is wide inter-individual variation, cough
challenge data have no intrinsic significance, but may usefully
be used to follow change in cough reflex sensitivity in an
individual.
COUGH INDUCED BY INHALATION OF AQUEOUS
SOLUTIONS
In order to evoke cough and other reflex respiratory responses
using aerosolised aqueous solutions, the use of an ultrasonic
nebuliser is mandatory. There are no reports regarding such
responses being obtained using aerosols produced by conventional nebulisers. The technical features and principle of
operation of most widely used ultrasonic nebulisers have been
reviewed elsewhere [53, 54]. Ultrasonic nebulisers generally
produce a much larger solution output per unit volume of air
than conventional nebulisers [53]. Since the tussigenic stimulus
of any aqueous solution is caused by the reduced concentration
of permeant anion, particularly chloride [55], any solution with
a low permeant anion concentration can be used as a coughstimulating agent.
Aerosol delivery
Water aerosols are best delivered during tidal breathing; the
use of a two-way valve [55, 56] or an outlet proximal to the
subject’s airway [57, 58] is required to avoid rebreathing. In
order to ensure constant supply, the aerosol should be
conveyed to a 1.5–2.0-L reservoir bottle [57].
Dosing schedule
Challenges with nebulised aqueous solutions can be performed according to two different methods, the single-dose
and the dose–response method. In the first case, the nebuliser
is set at a predetermined power output (usually the maximum
attainable) and the nebulised agent is inhaled for a predetermined period (usually 1 min) [35, 59–62]. Dose–response
challenges can be performed by the subject inhaling stimuli
of progressively higher intensity, obtained by increasing the
nebuliser output in steps (fig. 2), each corresponding to a
definite fraction of the maximum available output [55, 57].
Alternatively, the stimulus strength can be augmented
progressively with constant nebuliser output, using nebulising
solutions that are progressively lower in anion concentration
[61–63].
Recommendations
1) The methodology for the performance of inhalation cough
challenge should be standardised so as to facilitate universal
interpretation and comparison of data generated by different
laboratories.
Outcome measure/sensitivity
In single-dose challenges, the cough response is assessed in
terms of cough frequency [35, 59–62]; however, cough
frequency seems to be affected by some degree of stimulus
adaptation [35]. In dose–response challenges, cough sensitivity
can be evaluated as the cough threshold, i.e. the lowest
stimulus intensity capable of evoking at least one cough during
two dose–response challenges separated by a 30-min interval
[56–58]. The reliability of other outcome measures, such as C2
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Recommendations
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l
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2) Ultrasonic distilled water (fog) challenge is difficult to
standardise since it is highly dependent upon nebuliser output.
l
l
3) Consideration should be given to potential adverse events,
such as bronchoconstriction and cross-infection.
50
75
100
DC %max
FIGURE 2.
Relationship between ultrasonic nebuliser output (y) and the
corresponding direct current (DC) signal (x) analysed using the least squares
regression method. Data are presented as mean¡SD. The relation fits the linear
model (r50.95; p,0.001), and mean nebuliser output can be calculated from the
following equation (using units shown): y5 -1.90+0.066x. The range of outputs
(means) usually employed is 0.08–4.45 mL?min-1, i.e. 30–100% of the maximum DC
signal.
and C5, i.e. the lowest stimulus intensity capable of evoking at
least two or five coughs, has not been assessed using water
aerosols. Quantitative measures, such as cough expiratory flow
[57, 64] and the force developed by the expiratory muscles
during single cough efforts [56–58, 64], may be useful when the
intensity of motor responses needs to be evaluated.
Reproducibility
Several studies have established the reproducibility of cough
sensitivity [35, 57, 63–65] and cough intensity [57, 66] in dose–
response challenges using ultrasonically nebulised distilled
water [35, 57, 66] and other aqueous solutions [63, 65].
Safety
Ultrasonic nebulisers are obviously not disposable, and are
expensive. Sterilisation of the equipment is, therefore, recommended at every use. This is potentially a major limitation to
the use of ultrasonically nebulised aerosols outside the
research field. Furthermore, hypotonic aerosols are potentially
bronchoconstrictive in susceptible individuals [55].
Cough challenges with aqueous aerosols, however, present
some features that may potentially be useful in cough research.
The stimulus intensity can be increased in small fractional
amounts, such that the cough threshold is assessed relatively
precisely. In addition, since aqueous aerosols are inhaled
during quiet relaxed breathing, it is possible to record several
breathing pattern variables simultaneously, and thus investigate the ventilatory adjustments that may be evoked by airway
receptor stimulation.
Areas for future research
Sensory receptor stimulation by fog may be due to both the
absence of chloride ions (causing cough) and the hypoosmolarity (causing bronchoconstriction in susceptible individuals). Which of these fog-related stimuli is also responsible
1262
for fog-induced changes in the pattern of breathing remains to
be established. The feasibility and reproducibility of measures
such as C2 and C5 for the assessment of cough sensitivity to
aqueous aerosols also needs to be determined.
VOLUME 29 NUMBER 6
COUGH MONITORS
Since the 1950s, researchers have been attempting to objectively measure cough [67–69], i.e. to quantify the amount of
coughing per unit time. Although sound recordings can be
made and cough events counted manually, this process is
extremely laborious. Currently, no standardised method exists,
and there is no adequately validated generic cough monitor
that is commercially available and clinically acceptable.
An objective measure of cough would be of use in clinical
practice, clinical research and the assessment of novel
therapies. It would permit validation of the presence of cough,
grading of severity and monitoring of responses to therapeutic
trials. This is an exciting area of cough research and progress is
being made. Various systems are being developed to automate
cough identification and quantification, taking advantage of
recent technological advances.
The present guidelines aim to inform both developers and
potential users of cough monitors by highlighting the essential
features of an ideal device and clarifying the appropriate
methods for reporting on the performance of cough monitors.
Nonambulatory methods of cough recording
The very first cough monitoring systems to be developed were
nonambulatory; mains-supplied tape recorders with free-field
microphones were used to measure cough in hospital
inpatients or study subjects overnight [67, 70]. Similar systems
can be used for documenting coughing in cough challenge
studies.
Ambulatory methods of cough recording
The most useful systems are ambulatory and can count cough
over a defined period of time (usually 24 h). Advances in
computing and digital storage media have permitted the use of
digital sound recordings. Accurate recognition of the cough
signal remains the limiting step and has been difficult to
achieve. Several groups have applied digital signal processing
techniques to cough sound recordings, but with limited
success [71–74]. Hence, most systems still use manual counting, which is tedious and limits the size and scope of studies.
To date, more than six different systems have been described
that rely on identification of the cough sound [72, 73, 75–79].
One of the first 24-h ambulatory systems used a solid-state
multiple-channel recorder to measure the number of coughs
[75]. Coughs were identified by the simultaneous occurrence of
a digitised cough sound and an electromyographic signal from
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the respiratory muscles. The signals were analysed visually
and counted manually.
Another system transmitted cough sounds from a microphone
to a computer in the subject’s home using telemetry [77].
Digitally stored coughs were counted manually, and also the
cough latency (period between coughs), cough effort (integral
of the acoustic power spectrum), cough intensity (cough effort
divided by cough count) and cough wetness were measured.
In one cough recording system, cough was quantified in terms
of the amount of time spent coughing, i.e. the number of
seconds containing at least one explosive cough [78, 80, 81].
This was used to obtain a more encompassing definition of
cough rather than just measuring the explosive component that
can be heard.
In terms of automation of the cough recognition system,
MORICE and WALMSLEY [73] described a probabilistic neural
network system for differentiating cough from noncough.
Using a Sony Walkman digital audio tape recorder (Sony,
Malaysia), it was demonstrated that this system recorded
similar numbers of coughs to manual counting.
BIRRING and co-workers [82, 83] developed the Leicester Cough
Monitor, which detects coughs in patients with chronic dry
cough using a statistical model and quantifies coughs as
individual events.
Using an ambulatory cardiorespiratory monitoring system
(LifeShirt; Vivometrics, Nahant, MA, USA) with an integrated
unidirectional contact microphone, cough was measured in
eight COPD patients under laboratory conditions and automatically counted using statistical parameters [79]. Compared
with cough counts from video and sound recording, good
correlation was obtained.
Defining cough
Coughing produces a characteristic sound [84]. The sound
results from rapid changes in airflow generated by the
contractions of muscles in the chest wall, abdomen, diaphragm
and larynx. Hence a variety of modalities can be used to detect
coughing (table 2). The definition of a cough depends upon the
signal(s) monitored. Cough counting using sound either alone
or in combination with a second signal has been most
commonly used [75, 76, 79, 85], and the phases of a typical
cough sound are shown in figure 3. It is essential that any
cough monitoring device defines exactly what is recognised as
a cough, from which signal(s) and, furthermore, how coughing
is quantified.
TABLE 2
Signals and sensor types for monitoring cough
Sensor
Sound
Free-field microphone
Air-coupled microphone
Contact microphone
Movement
Electromyography
Accelerometer
Induction plethysmography
EUROPEAN RESPIRATORY JOURNAL
Quantification of coughing
One of the difficulties in identifying and quantifying cough is
that a variety of patterns of coughing occur. If the sound signal
is examined, three main patterns have been consistently
described in the literature (figs 3–5) [84, 86, 87], but many
more exist. Coughing can be quantified in a number of
different ways. Figure 6 shows a short sound recording of
coughing and four possible methods of quantification as
follows. 1) Explosive cough sounds (fig. 6a); counting the
characteristic explosive cough sounds is the most intuitive way
of counting cough. 2) Cough seconds (fig. 6b); this is a measure
of the time spent coughing, i.e. the number of seconds per hour
containing at least one explosive cough sound. 3) Cough
breaths (fig. 6c); these are used in a system that continuously
monitors breathing and quantifies cough as the number of
breaths which contain at least one explosive cough sound. 4)
Cough epochs (fig. 6d); continuous coughing sounds without a
2-s pause are counted.
Whether any of these methods is more valid than any other is
not known, but it is fundamental to describe the unit of cough
used. There is a tight linear relationship between cough sounds
and cough seconds in a variety of conditions (fig. 7).
Other end-points in cough monitoring
Other features of the cough signal apart from the number of
coughs are potentially of use as clinical end-points, as follows.
1) The intensity of coughing is likely to be important; subjects
with a small number of coughs may still find the symptom
very distressing if associated with chest pains, retching or
syncope. Both the peak intensity achieved and the overall
energy released in coughs may be valuable measures. 2) The
pattern of coughing (peals versus single coughs) may not only
affect the patient’s experience but also serve different
mechanical purposes. Furthermore, the rates of coughing
throughout the day and night may be related to the stimulus
to cough [81]. 3) The acoustic properties of the cough sounds
are of potential use in identifying the presence of airway
secretions or wheeze.
Automated identification of coughs is necessary to facilitate the
study of these additional parameters. Ambulatory monitoring
over 24 h in the patient’s own environment is necessary as
cough rates can change from hour to hour, show diurnal
variation and may be affected by a nonambulatory setting.
Validation of cough monitors
Validation of cough monitors against a gold standard measure
is obligatory. Manual cough counting from video or sound
recordings is used, and, although extremely laborious [79, 88],
good agreement between observers has been achieved.
Video recordings have the advantage that the movements
associated with coughing can be seen, but monitoring has to be
restricted to the area in view of the camera. It cannot be
assumed that performance is the same in a fully ambulatory
subject. Validation of ambulatory cough monitoring is possible
using a small digital sound recorder and microphone running
simultaneously with the cough monitor [71].
Additionally, the acoustic properties of cough sounds vary in
different diseases [87, 89]; thus validity in one patient group is
not generalisable. Cough detection should therefore be
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FIGURE 3.
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Three-phase cough sound (1: explosive phase; 2: intermediate
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FIGURE 4.
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Time s
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Two-phase cough sound (1: explosive phase; 2: intermediate
phase; 3: voiced phase).
phase).
validated in patients with chronic cough (with a range of
aetiologies) and cough in other respiratory conditions.
ASSESSMENT OF QUALITY OF LIFE OF PATIENTS WITH
CHRONIC COUGH
Chronic cough is often perceived as a trivial problem, but can
be a disabling symptom associated with significantly impaired
quality of life [8, 9]. Until recently, there have been no tools for
measuring cough-specific quality of life. Indeed, there is a
striking paucity of well-validated outcome measures in chronic
cough. There is no consensus regarding the definition of
health-related quality of life, but the World Health
Organization definition of health as ‘‘a state of complete
physical, mental and social well-being, and not merely the
absence of disease’’ is widely quoted [91]. Health status or
health-related quality-of-life measurement is a means of
quantifying the impact of disease or symptoms on patients’
daily life and general well-being in a standardised and
objective manner. Quality-of-life questionnaires are widely
used in clinical studies and are standard end-points in most
randomised controlled trials. This section focuses on the effects
of chronic cough on health status and the measurement of
quality of life in patients with chronic cough.
Sensitivity and specificity
Sensitivity, specificity and positive and negative predictive
values contribute to a description of cough monitor performance. As sounds that could be mistaken for cough (e.g.
speech, throat clearing, laughing and sneezing) may occur
more often than coughs, the number and nature of false
positive results should also be reported. Agreement between
manual and automated cough counts [90] gives a clear
representation as to how much the two measures differ and
whether this difference is related to the magnitude of the
measurement. The reproducibility of the performance of the
cough monitor and responsiveness to change are also
important attributes. The precision of all of these measures
(i.e. 95% confidence intervals) permits assessment of the
consistency of performance.
Future work in cough monitoring
There has been very significant progress towards fully
automated cough counting in recent years, but testing of the
performance of systems needs to be rigorous. Accurate cough
counters will add a new dimension to cough assessment.
Simple cough counts are, however, only one dimension of
cough, and probably explain only part of the patient’s
experiences of the symptom. Further end-points, such as
cough intensity, coughing patterns over both the short and
long term, and acoustic parameters (representing wheeze and
airway secretions), are wide open for development and
investigation.
Recommendations
1) No cough monitor is currently the gold standard.
2) Monitors should be developed that are ambulatory, capable
of being digitally processed and permit prolonged (24-h)
recording.
3) There is little to commend any particular method of
quantifying cough over any other.
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Adverse impact of cough on health status
Cough has wide-ranging effects on health status. The reasons
why patients with chronic cough seek medical advice are
poorly understood, but may relate to worry about the cough,
embarrassment, self-consciousness and the presence of associated symptoms, such as nausea and exhaustion [92]. In acute
cough, health status is impaired transiently. The impact of
chronic cough on health status is varied, being minimal in
some patients who do not seek medical attention to disabling
in others, associated with impairment of quality of life
comparable to that in other chronic respiratory disorders, such
as COPD. The physical, psychological and social domains of
health are commonly affected [9]. Patients with chronic cough
frequently report musculoskeletal chest pains, sleep disturbance and hoarse voice. More marked symptoms, such as
blackouts, stress incontinence and vomiting can occur. Some
patients report adverse symptoms related to the urge and
sensation to cough and the act of cough suppression. The
psychological aspects of health status affected often include
worry about serious underlying diseases, such as cancer and
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patients receive clear instructions regarding the time period
during which cough severity is being assessed. Cough VAS
score is highly repeatable over a 2-week period in patients with
cough due to COPD (within-subject SD 7.8 mm; intra-class
correlation coefficient 0.87) [99]. Cough VAS score is also
highly responsive when used as an outcome measure in
clinical studies of patients with a chronic cough [9, 100, 101].
Cough VAS score relates well to cough-specific quality of life,
but not to cough reflex sensitivity [9]. Its relationship to
objective cough frequency is not known.
Relative amplitude x10-4
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FIGURE 5.
Peal of coughs after a single inspiration with repeated explosive
phases (..........).
tuberculosis. The impact of cough on social well-being
depends upon individual circumstances. The cough may result
in difficulty in relationships, avoidance of public places,
disruption at work and, in severe cases, time off work. The
wide-ranging and potentially profound effects of cough on
health status highlight the importance of a detailed history of
associated symptoms and concerns when assessing a patient
with chronic cough.
Assessment of health status
Cough scores, diaries and visual analogue scales
Cough scores [93], diaries [27, 94, 95], symptom questionnaires
[96, 97] and visual analogue scales (VASs) [98] are commonly
used in clinical studies to evaluate cough severity, but all lack
thorough validation for this purpose. Most symptom-based
tools include questions relating to cough frequency, but
probably measure a combination of aspects of cough severity
that encompass cough frequency and intensity, mood and
quality of life. Very little is known about their relationship to
other parameters of cough severity, such as objective cough
frequency and cough reflex sensitivity. Unlike quality-of-life
questionnaires, the different components of health status
cannot be identified from cough diaries and VASs.
Quality-of-life questionnaires
Quality-of-life measures can be used to facilitate communication with patients and establish information regarding the
range of problems affecting them. The impact of illness on
health and treatment preferences often differ between patient
and physician, and, therefore, quality-of-life considerations
should take the patient’s perspective into account. The
simplest method of assessing quality of life is to ask the
patient [102]. Drawbacks to this are that some observers are
poor judges of patients’ opinions. Assessment of patients using
quality-of-life instruments is essentially similar to a structured
clinical history, although the outcome parameter is an
objective, validated and quantifiable measurement. Qualityof-life domains are usually measured separately to assess
emotional and psychological well-being, as well as the physical
and practical aspects of daily life. Questionnaires can be
generic or disease-specific. Generic instruments are intended
for general use, irrespective of illness. Quality-of-life scores
from patients can be compared with those in other conditions
and even healthy subjects [103]. However, generic instruments
lack specificity, do not focus on issues related to patients’
conditions and are less responsive to specific interventions
compared with disease-specific tools. This has led to the
development of three cough-specific quality-of-life questionnaires for use in patients with chronic cough, the coughspecific quality-of-life questionnaire (CQLQ), Leicester Cough
Questionnaire
(LCQ) and
Chronic
Cough
Impact
Questionnaire (CCIQ) [8, 9, 104].
Cough VASs are 100-mm linear scales on which patients
indicate the severity of their cough; 0 mm represents no cough
and 100 mm the worst cough ever (fig. 8). It is important that
Cough-specific quality-of-life questionnaire
The CQLQ is a recently published 28-item questionnaire that
has been developed and tested in North America [8]. It is
intended for use in adults with acute and chronic cough. The
questionnaire is self-completed and contains a four-point
Likert response scale. The items are divided into six domains:
physical complaints, extreme physical complaints, psychosocial issues, emotional well-being, personal safety fears and
functional abilities. Items for this questionnaire were selected
by the investigators and allocated to domains by factor
analysis. Factor analysis is a psychometric method that is used
to select and allocate items to domains and is based largely on
the structure of correlations between items, although the
investigators must make a number of subjective decisions
throughout the process. Although commonly used in the
development of quality-of-life questionnaires, a weakness of
factor analysis is that it does not take into account the
perception of the clinical relevance of items by the intended
population. Concurrent validity, the comparison of an instrument against other standards that provide an indication of the
true value for measurement, was assessed for a preliminary
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Cough diaries comprise questions relating to cough frequency
[75]. They correlate weakly with objectively measured daytime
cough frequency and there is no relationship with nocturnal
cough counts [75]. The reproducibility and responsiveness of
cough diaries has not been reported and their relationship to
other parameters of cough severity, such as cough reflex
sensitivity, is not known for patients with chronic cough. In
children, the reproducibility of parent-completed cough
symptom questionnaires is poor [97]. Self-completed cough
diaries for children show good responsiveness and correlate
better with objective cough frequency [94]. Interestingly, in
children, self-completed cough diaries relate better to objective
cough frequency than those completed by their parents [94].
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Various methods of quantifying coughing: a) explosive cough sounds; b) cough seconds; c) cough breaths; and d) cough epochs (– – –: units of cough
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FIGURE 7.
A comparison of cough quantification using cough seconds and
explosive cough sounds in different diseases. n: cystic fibrosis; e: idiopathic
pulmonary fibrosis; ,: chronic obstructive pulmonary disease; #: asthma. ..........:
overall line of best fit.
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version of the CQLQ, called the Adverse Cough Outcome
Survey (ACOS) [92]. The ACOS correlated moderately with a
generic quality-of-life questionnaire (Sickness Impact Profile).
The CQLQ is both repeatable and responsive to change in
patients with chronic cough, but this was not tested for
patients with acute cough. The relationship between CQLQ,
cough reflex sensitivity and objective cough frequency is not
known. Studies to determine the minimal important clinical
difference are under way.
Leicester Cough Questionnaire
The LCQ is a brief, easy to administer and well-validated
chronic cough health-related quality-of-life questionnaire
developed in the UK [9]. The LCQ comprises 19 items and
three domains (physical, psychological and social). The
questionnaire is self-completed and contains a seven-point
Likert response scale. One of the key differences between the
LCQ and the CQLQ is that items for the LCQ were chosen
using the clinical impact factor method. This method chooses
items that patients label as a problem and ranks them by the
importance associated to them. Items were categorised into
domains using clinical sensibility. The LCQ was extensively
validated against other quality-of-life questionnaires and
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questionnaires showed good concurrent validity and responsiveness, which suggests that the LCQ and CQLQ may be
adaptable for patients from a different cultural background.
FIGURE 8.
Cough visual analogue scale. Please put a cross on the line to
Conclusions
Chronic cough can have profound effects on quality of life. Its
management should include an assessment of health status.
The LCQ, CQLQ and CCIQ are intended for use in adult
patients with chronic cough. Quality-of-life questionnaires can
be used to assess longitudinal changes in patients with chronic
cough and identify the specific health domains affected.
Quality-of-life questionnaires should be used to supplement
objective markers of disease severity and assess the effectiveness of therapeutic interventions in the clinic and clinical trials,
and be integral to cost utility analysis.
indicate the severity of your cough in the last 2 weeks. (Not to scale.)
measures of cough severity [9]. The LCQ has been shown to be
repeatable and responsive in patients with chronic cough and
responsive in acute cough [9, 105]. Preliminary data suggest
that the LCQ correlates with objectively measured cough
frequency in patients with chronic cough [82]. The minimal
important clinical difference for patients with chronic cough is
LCQ total score 1.3 [106]. A study to determine the minimal
important clinical difference for patients with acute cough is
under way. The LCQ has been a responsive tool when used as
a primary outcome parameter in clinical trials of antitussive
therapy for patients with chronic cough [107]. The LCQ can be
obtained from the online version of [9].
Chronic Cough Impact Questionnaire
The CCIQ is the most recently described cough-specific
quality-of-life measure, developed in Italy [104]. It comprises
a 21-item questionnaire divided into four domains (sleep/
concentration, impact on relationship, impact on daily life and
mood) and contains a five-point Likert response scale. The
CCIQ is brief, simple to administer and validity has been
tested in large numbers of patients. The published report
describing the development of the CCIQ lacks important
validation data [104]. The repeatability and responsiveness of
the questionnaire are not reported, and the minimal important
clinical difference and relationship to other markers of cough
severity are not known.
Health status in chronic cough
Little is known about the effects of cough on health status.
However, preliminary data from studies using cough-specific
quality-of-life questionnaires afford an insight. Quality of life is
significantly impaired in acute cough; this impairment affects
males and females equally [108]. In patients with chronic
cough, quality of life is impaired, to a greater extent in female
patients compared with males [109] and not related to age,
duration or aetiology [92, 110]. The psychological aspects of
health status are particularly affected in patients with chronic
cough, and there is a high prevalence of depressive symptoms
[109–111]. There is good evidence that health status improves
significantly after specific therapy for the cough [8, 9].
Future research
Further work is required to determine the minimal clinically
important difference for cough health status questionnaires
and investigate the relationship between quality of life and
other markers of cough severity. Further clinical trials using
cough-specific quality of life as outcome measure are awaited.
Recommendations
1) Cough can have profound effects on health status, which can
be assessed by cough-specific health status questionnaires.
2) Cough VASs (0–100 mm) should be used to assess cough
severity in patients with chronic cough.
3) Patients with chronic cough should be assessed with coughspecific quality-of-life questionnaires in clinical studies.
ANIMAL MODELS OF COUGH
Cough is a reflex defence mechanism and is a most common
symptom of many inflammatory diseases of the airways [113].
At present, there are no satisfactory treatments for acute cough,
as outlined in a recent review in which over-the-counter cough
medicines were assessed [114]. Therefore, the search is on for
possible novel antitussive therapies. However, prior to
evaluation of such agents in humans, they must be tested in
appropriate animal models. The ultimate goal of an animal
model is to provide a system in which to elucidate mechanisms
and test putative drug candidates. The model needs to be
reliable, robust and reproducible and accurately reflect the
disease in humans as closely as is possible.
Species
Most pre-clinical studies of neural pathways involved in the
cough reflex and the pharmacological regulation of such
pathways have been conducted in mice, rats, guinea pigs,
rabbits, cats and dogs [115], as well as, more recently, in
conscious pigs [116].
A recent study comparing a translated LCQ and CQLQ in
Turkish patients with chronic cough found a moderate
correlation between the questionnaires [112]. Both translated
In rodents, the cough reflex is difficult to study in anaesthetised animals, since anaesthesia suppresses neuronal conduction and activity in the central nervous system (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 [117], there is much
scepticism regarding the ability of these animals to produce a
cough that resembles the reflex seen in humans. Indeed, it is
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thought that, if cough can be elicited in rats, the main
reflexogenic origin of the cough is the larynx rather than the
tracheobronchial tree [13]. 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 [118]. Other studies have
described a murine model of cough [119], but again, certain
reservations exist regarding the use of this model given that
mice do not have rapidly adapting receptors (thought, along
with C-fibre afferents, to play an important role in the cough
reflex) and have been found to be lacking in intra-epithelial
nerve endings and thus are thought to be without a cough
reflex [119]. It has also been shown that mice cannot cough
[13], 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 with regard to not only their purchase price but
also their feeding and housing and the production of 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 in tertiary screening.
The most useful and commonly used model for cough studies
in recent years has been the conscious guinea pig [120, 121].
Much information has been gathered using this model
regarding both the physiological [122] and the pharmacological modulation of the cough reflex. In these experiments,
cough can be detected by putting the guinea pig in a
transparent Perspex chamber, exposing it to aerosols of tussive
stimuli and measuring changes in airflow, observing the
characteristic posture of an animal about to cough and
recording the cough sound [123–125].
The guinea pig model of cough
As stated above, the guinea pig is the most useful laboratory
animal for experimental studies of chemically induced cough,
compared with the rat and rabbit [126]. This animal has been
utilised extensively, with cough being induced in conscious
animals by inhalation of aerosols of either capsaicin or low pH
solutions such as citric acid [10, 123, 127–129]. The guinea pig
provides a good model of the human cough reflex, and this has
been confirmed in a study showing the similarity in response
to both citric acid and capsaicin in humans and the guinea pig
[10]. Furthermore, recent in vitro data suggest that the isolated
guinea pig vagus nerve depolarises in response to tussive
stimuli in a similar manner to the isolated human vagus [130].
However, the guinea pig model differs from humans in certain
respects. Although both guinea pigs and humans respond to
capsaicin in a similar fashion in eliciting cough, capsaicin (and
to a lesser extent citric acid) produces tachypnoea in guinea
pigs [10]. Furthermore, if the local release of substance P from
C-fibre nerve endings contributes in any way to the cough
reflex, this may lead to differences in the cough reflex given the
sparse population of neuropeptide-containing nerves in
human airways. Furthermore, the guinea pig is an obligate
nose breather, which may also introduce species differences in
the cough reflex. Lastly, the demonstrated activity of certain
development molecules with no demonstrated efficacy in
humans in animal models has led to the suggestion that data
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generated from these systems may not be predictive of the
situation in humans.
Conscious versus anaesthetised animals
In rodents, the cough reflex is difficult to study in anaesthetised animals since anaesthesia suppresses neuronal conduction and activity in the CNS. However, in some species, a
suitable depth of anaesthesia, with essentially intact respiratory reflexes, can be obtained and a tussive response easily
measured [115, 131, 132]. An example of this is the anaesthetised cat, which has been utilised to analyse both the central
effects of antitussives administered intracerebroventricularly
[133] and the peripheral effects of compounds administered
intravenously [134]. In these experiments, cough in response to
mechanical and chemical stimuli is characterised by a deep
inspiration followed by an active expiratory effort. In other
experiments, cough has been defined, in anaesthetised
animals, as a large burst of electromyographic activity in the
diaphragm immediately followed by a burst of activity in the
rectus abdominus muscle [135]. Interestingly, data recently
presented by CANNING et al. [131] demonstrated that capsaicin
and bradykinin (C-fibre stimulants) are totally ineffective at
initiating the cough reflex in anaesthetised guinea pigs even
though the cough reflex initiated by mechanical stimuli
(largely rapidly adapting receptor-selective) is entirely preserved in the anaesthetised state. Consistent with this data,
TATAR and PECOVA [136] showed that, in urethane-anaesthetised guinea pigs, cough could be regularly elicited by
mechanical stimulation of the larynx and tracheobronchial
tree. Inhalation of a capsaicin aerosol did not change the
respiratory pattern and did not elicit any cough. However,
these chemical agents elicit a cough reflex in conscious guinea
pigs. This suggests that anaesthesia is perhaps best avoided
when studying the cough reflex in animal models.
Methodology
A procedure for measuring cough in conscious guinea pigs has
been described [10, 120, 124–127]. The guinea pig is placed in a
small Perspex box (,1 L in volume) that allows free movement
during exposure to aerosols. Some investigators have used a
double-chambered body plethysmograph with some success
[137]. Airflow through the box is provided by compressed
medical air via a flow regulator at ,600 mL?min-1, with
changes in airflow induced by respiration and coughing
detected by a pneumotachograph, amplified via a pressure
transducer and recorded on a chart recorder or computer.
Cough sounds are amplified and recorded via a microphone
sited in the cough chamber and recorded concurrently on the
computer. Tussive agents (capsaicin, citric acid, etc.) are
delivered by aerosol using an ultrasonic nebuliser, with an
output of ,0.4 mL?min-1 and delivering a median particle
diameter of ,1 mm, connected to the airflow port. The animal
is exposed for a defined period, usually f10 min, depending
on the tussive agent used. A dose–response curve to the chosen
stimulus should be constructed, and a submaximal dose
chosen for further studies. Other protocols include using citric
acid aerosol in gradually increasing concentrations (0.05–
1.6 M), each for 30 s. Cough is recorded during the 30-s
inhalation of each concentration of the tussigen and during the
subsequent 60-s observation time. Therefore, the interval
between exposures is 1.5 min. The number of coughs elicited
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A.H. MORICE ET AL.
by each concentration is compared with a control group. When
there are significant differences in cough numbers during
inhalation of lower concentrations, it can be concluded that the
cough sensitivity is changed [138].
It can be extremely difficult to differentiate cough from other
upper airway reflexes. Therefore, coughs should be assessed
and counted by a trained observer using three different
methods in order to ensure that only coughs are counted and
that sneezes and augmented breaths are excluded. The three
methods are as follows. 1) Observation (or video recording) by
an observer trained to differentiate between coughs and
sneezes and to recognise the changes in posture (splaying of
the front feet and forward stretching of the neck) and
characteristic opening of the mouth associated with cough. 2)
Pressure or airflow changes reflecting the deep inspiration and
explosive expiration occurring during cough. 3) Sound, i.e. the
characteristic sounds of a guinea pig cough. Results can be
expressed as coughs per minute or coughs per 10 minutes, and
comparisons made with vehicle-control-treated animals.
Tussive stimuli
The cough reflex can be elicited by electrical, mechanical (in
anaesthetised animals) or chemical stimulation, as well as by
changes in ion concentration or osmolarity in the mucosal
surface fluid, of sensory afferents (in the larynx, trachea or
bronchial mucosa) or by stimulation of the CNS. More recent
studies have utilised 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 tachyphylaxis,
whereas repeated exposure to capsaicin is known to result in
tachyphylaxis, preventing the production of a reproducible
cough response in the same animal [25, 138]. 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 [124, 139].
Experimental design
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 [140]. M.G. Belvisi and co-workers (unpublished data)
have shown that the cough response to a given stimulus varies
greatly from guinea pig to guinea pig, but that repeated
assessments within the same animal are fairly reproducible
with citric acid but not with capsaicin. Therefore, it is probably
wise to perform experiments in separate animals with test
group data compared with vehicle-treated animals rather than
in the same animal before and after vehicle/drug treatment.
However the inherent variability in conscious models suggests
that large numbers, of between eight and 12, should be utilised
in studies. The same authors have not found it necessary to
precondition guinea pigs to accept aerosol exposure in the
challenging box.
ERS GUIDELINES ON ASSESSMENT OF COUGH
Allergic models
Most models have been configured in the guinea pig and have
demonstrated increased coughing in response to capsaicin
o1 day after antigen challenge in sensitised animals [141, 142].
The increased tussive response is associated with eosinophilia.
Tachykinins appear to play a role in the augmented cough
response in allergic guinea pigs, since enhanced cough
response to capsaicin, following antigen challenge, has been
shown to be suppressed by neurokinin (NK)1 and NK2 and
dual (NK1/NK2) receptor antagonists [141]. An enhanced
cough response to mechanical stimulation of the trachea has
also been seen in anaesthetised dogs sensitised and challenged
with ragweed antigen [143].
Models of post-nasal drip
Chronic disorders of the nose and sinuses (e.g. allergic and
nonallergic rhinitis, sinusitis and vasomotor rhinitis) are also
common causes of chronic cough [7]. This phenomenon has
been demonstrated in animal models in that stimulation of
nasal afferents with capsaicin has been shown to enhance
experimentally induced cough in cats and guinea pigs
following nasal antigen challenge in sensitised animals [137,
138].
Angiotensin-converting enzyme inhibitors
Chronic systemic treatment with several angiotensin-converting
enzyme inhibitors potentiates the irritant-induced and spontaneous cough in guinea pigs [124, 144, 145].
Cigarette smoke exposure
Chronic mainstream or sidestream cigarette smoke exposure
can lead to an enhanced cough response to tussive stimuli in a
guinea pig model [146–148]. In some cases, this is associated
with airway eosinophilia and neutrophilia [146]. In one study,
environmental tobacco smoke increased citric-acid-induced
cough and bronchoconstriction, and this was blocked, in part,
by an NK1 receptor antagonist injected into the nucleus tractus
solitarius [147].
The inflammatory processes present in some of these models
have been suggested to alter the phenotype and/or the
excitability of sensory airway afferents [149-151], which may
lead to increased sensory input into the central control
mechanisms that elicit cough. The mechanisms involved in
this increased responsiveness have not yet been clearly
defined, but the elucidation of specific pathways that sensitise
this reflex may lead to the development of more effective
therapeutics.
Disease models
It is now recognised that many pulmonary disorders are
associated with enhanced cough. However, the mechanisms
involved in these exaggerated responses are not known.
Conclusion
Cough, irrespective of which airways disease it is associated
with, represents an unmet clinical need. There are no effective
treatments available for cough, and those that are available
have been shown to be ineffective [114]. It is, therefore,
essential to identify and develop new treatments for cough. In
order to achieve this end, it is necessary to develop and utilise
an animal model of cough that accurately reflects the condition
in humans. The guinea pig shows distinct advantages over
other small rodents in that it coughs in response to given
stimuli in the conscious state and that the physiology of the
cough response reflects that in humans, and, for these reasons,
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the present task force recommends the use of this species as an
investigational tool.
Recommendations
1) The most useful animal model of cough is the conscious
guinea pig.
2) Both sound and airflow should be used to define a cough
event.
DESIGN AND CONDUCT OF CLINICAL TRIALS OF
ANTITUSSIVE DRUGS
Since acute cough is so common and chronic cough such a
distressing and disabling symptom, it is unsurprising that
novel antitussive treatments, both specific and nonspecific, are
currently undergoing development. Cough in humans differs
from that in animals, and compounds that may be highly
effective in animal models, e.g. NK receptor antagonists, may
fail in the clinic [152]. The demonstration of efficacy or lack of
efficacy in humans is fraught with difficulties, including the
choice of model, recruitment of subjects, choice of end-point,
applicability to clinical research and overcoming the placebo
effect. This section provides guidance in order to maximise the
chance of providing a genuine result from any clinical
pharmacology study.
Choice of model
Cough in clinical scenarios in which drug therapy is required
differs from evoked cough in normal volunteers because the
cough reflex is sensitised in disease. This is true of both acute
[29] and chronic cough [22, 24], in which cough challenge
dose–response curves are shifted to the left and return towards
normal after either spontaneous resolution [29] or drug
treatment [101, 153, 154]. The molecular cause of this cough
reflex hypersensitivity is unknown. Airway inflammation
leading to peripheral hypersensitivity of cough receptors
would appear to be a reasonable explanation when the airways
are inflamed, such as in acute viral bronchitis. A proliferation
of nerves containing the putative cough receptor transient
receptor potential vallinoid (TRPV)1 has been demonstrated
[155], although expression of this receptor may not be confined
to the sensory neurons [156] Animal work supports the
hypothesis that sensitisation occurs in the vagal ganglia
located in the relay stations of the nodose and jugular
parasympathetic ganglia [157]. Central modulation and hypersensitivity of the cough reflex certainly occurs [31]. Thus, in
designing studies to test for antitussive activity, knowledge of
the putative mode of action is vital. For example, leukotriene
antagonists have been demonstrated to be effective in cough
variant asthma [153], and are one of the mainstays of clinical
treatment when inhaled steroids alone prove ineffective. When
tested in cough challenge models in classic asthma, however,
they are ineffective [158]. This is because the heightened cough
reflex is due to the asthmatic inflammation, particularly the
clustering of mast cells around airway nerves [159]. In the
absence of inflammation, no beneficial effect is seen from these
agents. In contrast, in the development of a TRPV1 capsaicin
receptor antagonist, it would not be unreasonable to assume
that an effective agent should block capsaicin cough challenge
in normal volunteers.
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Cough is a vital protective reflex. Conditions with a demonstrably reduced cough reflex, such as stroke and Parkinson’s
disease, are associated with an increased incidence of aspiration and pneumonia. Care is required, therefore, in the design
of clinical studies looking at nonspecific cough suppression.
Thus, although the suppression of cough due to viral
bronchitis is unlikely to have adverse consequences, suppression of cough in studies in which the patient population has a
chronic productive cough may lead to inspiration of secretions
and clinical worsening. However, even in situations in which
there is increased sputum production, cough reflex sensitivity
may be exaggerated. Whether the suppression of this abnormal
reflex sensitivity to normal levels results in an improvement or
deterioration in clinical status remains to be determined from
future studies.
Normal volunteer studies
Studies in normal volunteers are almost invariably performed
using cough challenge methodologies. Two challenges are
commonly used, citric acid and capsaicin [25]. The challenges
do not measure the same reflex sensitivity since there is little
correlation between the sensitivities of the two challenges in an
individual [23]. There is little to choose between the two
modalities of challenge, and both have been used to demonstrate antitussive effects. Lack of knowledge regarding how
these responses are related to what occurs in the clinic is a
major weakness of cough challenge in normal subjects.
Subject selection should include a screening visit during which
challenge is performed. There is a strong argument for
excluding subjects who show cough responses only at high
challenge concentrations. In these subjects, it is difficult to
demonstrate cough suppression because they are already
approaching the maximum tolerable dose, and nonspecific
effects, such as a burning sensation with capsaicin or a choking
sensation with citric acid, mask any therapeutic effect [18].
The placebo response
In normal volunteer challenge studies, the placebo response is
a major factor. A reduction in cough challenge of .30% can be
seen with placebo, and this effect may continue for several
hours [160]. Indeed, the pharmacokinetics of placebo activity in
cough challenge have been modelled [39]. A number of
strategies have been used in an attempt to minimise this, e.g.
performing a screening experiment with a placebo described as
an antitussive and excluding responders, randomisation of
challenge administration and using subjects previously known
to exhibit a small response to placebo. None of these strategies
appear to be effective. Studies should be designed with the
probability that a considerable placebo response may occur
whatever precautions are taken.
Sex
Females exhibit a heightened cough reflex [49, 51]. On average,
females cough twice as much as males to any given cough
challenge, or, conversely, C2 and C5 are consistently lower in
female subjects. The cause of this sex-related difference is
unknown, but it also occurs in patients attending the cough
clinic [22] and those receiving angiotensin-converting enzyme
inhibitors [161]. Provided this fact is understood in the design of
exclusion criteria, there is no reason for differential treatment of
males and females within normal volunteer studies.
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Normal volunteer studies with airway inflammation
In an attempt to obtain a model that has some of the elements
of clinically relevant cough in normal subjects, smokers with
cough have been recruited to clinical studies [162]. These
subjects provide another end-point, i.e. their smoker’s cough,
and also represent a state in which there is airway inflammation. In the conduct of such studies it should be remembered
that there is a profound effect of cigarette smoking on the
cough reflex [163]. Indeed, smoking reduces cough reflex
sensitivity and approximately halves the number of coughing
episodes per hour. Thus, the key time for observing drug
effects is after overnight abstinence, with the subject refraining
from smoking for the duration of the study.
Although giving a model of ‘‘natural’’ cough, the use of
smokers may confound the study of certain groups of agents.
In particular, the negative effect of smoking on inhaled steroid
efficacy has been well described [164].
Studies in patients
Perhaps the major difficulty in the study of clinically important
cough is defining the study population.
Acute cough
Acute cough is a benign self-limiting condition. Having
recruited a study population, there is an inevitable marked
spontaneous regression back to normality. This, coupled with a
particularly powerful placebo effect [165, 166], makes the study
of subjects with acute cough highly challenging. These factors,
but particularly the daily variation in baseline, make crossover
studies virtually impossible. Since there is individual variability in response, any parallel group study must be of a large
size in order to convincingly show efficacy. Indeed, the only
robust study demonstrating antitussive efficacy in acute cough
is a meta-analysis of .300 subjects [167]. This study undertook
laborious aural analysis of cough data. More recently, digital
cough recorders offer the opportunity for objective cough
frequency measurement, which may become the gold standard
for such studies in future [73, 80, 83, 160]. Until then, subjective
cough scores, VASs and, again more recently, quality-of-life
measurements may be used as end-points [8, 9].
ERS GUIDELINES ON ASSESSMENT OF COUGH
the basis of showing methacholine bronchial hyperresponsiveness or sputum eosinophilia. Similarly, patients with reflux
disease should have a proven diagnosis from objective testing
in the knowledge that many other patients will be excluded
who also have reflux disease, but at least this is a certain entry
criterion. A similar situation exists in studies of classic asthma
where entry into a study is predicated by reversibility testing,
even though only a small percentage of asthmatics fit into
these reversibility criteria. One interesting group of patients for
study are those who fail to meet the diagnostic criteria for a
cough syndrome or fail multiple trials of appropriate therapy.
They have been termed idiopathic cough patients and are
frequently found in cough clinics. Unlike the situation in acute
cough, these patients do not show placebo effects, and, since
cough is reproducible, crossover studies are possible, limiting
the number of subjects required [107].
Recommendations
1) The experimental model in which antitussive drugs are
tested depends greatly upon the mode of action of the agent.
2) Normal volunteer studies should be designed in the
knowledge that a large placebo effect is likely.
3) In acute cough, parallel group studies are required.
4) In chronic cough, the patient population studied should be
defined by a diagnostic test.
Chronic cough
Confusion exists in the categorisation of patients with chronic
cough. This, in part, explains the wide variation in the
proportion of patients diagnosed with the various cough
syndromes in reports from cough clinics [168]. It is thus
perhaps better to define the study population according to the
presence or absence of a particular diagnostic result rather than
use diagnostic labels about which there is disagreement.
Patients with reflux disease may, through aspiration, show
bronchial hyperresponsiveness [169]. Similarly, patients with
asthma may also exhibit reflux symptoms [170]. In the study of
asthmatic cough, it is better to define the study population on
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