Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease
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Thorax 2000;55:643–649 643
Capsaicin responsiveness and cough in asthma
and chronic obstructive pulmonary disease
M J Doherty, R Mister, M G Pearson, P M A Calverley
Abstract Chronic cough is one of the commonest symp-
Background—Chronic cough is associ- toms of patients with persistent asthma1 and
ated with an increased sensitivity to may be the sole presenting feature of this
inhaled capsaicin in a number of condi- disease.2 Cough is frequently the first symptom
tions but there are no data for patients reported by patients with chronic obstructive
with more severe asthma or chronic pulmonary disease (COPD)3 and a cough pro-
obstructive pulmonary disease (COPD). ductive of sputum is the cardinal feature of the
Moreover, the relationships between the subset of COPD patients defined as having
capsaicin response (expressed as the con- chronic bronchitis.4 However, sputum produc-
centration of capsaicin provoking five tion is often scanty or absent as COPD
coughs, C5), self-reported cough, and progresses, yet cough remains a troublesome
routine medication is not known. problem.5
Methods—The cough response to capsai- Objective attempts to assess cough sensitiv-
cin in 53 subjects with asthma, 56 subjects ity have yielded conflicting results. When
with COPD, and 96 healthy individuals capsaicin, the pungent extract of red pepper, is
was recorded and compared with a inhaled it induces cough reproducibly without
number of subjective measures of self- tachyphylaxis.6 Patients with asthma have an
reported cough, measures of airway ob- increased sensitivity to capsaicin which is most
struction, and prescribed medication. In marked in those who complain of cough.7
asthmatic subjects the relationships be- When tested with citric acid, patients with
tween the cough response to capsaicin and COPD also have an increased cough response
mean daily peak flow variability and non- but this has not been reported with capsaicin.7 8
specific bronchial hyperresponsiveness to These diVerences could reflect the use of
histamine were also examined. diVerent tussive agents, diVering patterns of
Results—Subjects with asthma (median symptoms, or diVerences in disease severity.
C5 = 62 mM) and COPD (median C5 = Unfortunately, there are few specific data on
31 mM) were similarly sensitive to capsai- spirometry or other symptoms available from
cin and both were more reactive than the original capsaicin study which examined
normal subjects (median C5 >500 mM). only 11 patients with COPD.7 We hypothesised
Capsaicin sensitivity was related to symp- that the presence of chronic airflow limitation,
tomatic cough as measured by the diary whether due to asthma or COPD, would be
card score in both asthma and COPD (r = associated with an increased capsaicin cough
–0.38 and r = –0.44, respectively), but only response, that the cough response would be
in asthma and not COPD when measured related to the degree of airflow obstruction, and
using a visual analogue score (r = –0.32 that the sensitivity to capsaicin would be
and r = –0.05, respectively). Capsaicin altered by changing airway calibre. Moreover,
sensitivity was independent of the degree we anticipated that there would a relationship
Aintree Chest Centre, of airway obstruction and in asthmatics between the capsaicin cough threshold and the
University Hospital was not related to PEF variability or PC20 perceived severity of the cough.
Aintree, University for histamine. The response to capsaicin In the absence of an agreed symptomatic
Department of measure of cough severity, we have compared
Medicine, Liverpool was not related to treatment with inhaled
corticosteroids but was increased in those several methods of assessing cough as a symp-
and Department of
Biological Sciences, using anticholinergic agents in both con- tom to the capsaicin response measured in
Salford University, UK ditions. groups of stable chronic asthmatic and COPD
M J Doherty Conclusions—These data suggest that an patients and have compared the objective data
R Mister increased cough reflex, as measured by with our previously determined normal range
M G Pearson of capsaicin responsiveness.
P M A Calverley capsaicin responsiveness, is an important
contributor to the presence of cough in
Correspondence to: asthma and COPD, rather than cough
Professor P M A Calverley, Methods
being simply secondary to excessive air-
University Clinical SUBJECTS
Departments, University way secretions. The lack of any relation-
We recruited 53 patients with chronic asthma
Hospital Aintree, Longmoor ship between capsaicin responsiveness
Lane, Liverpool L9 7AL, UK and 56 with COPD from our outpatient clinics.
and airflow limitation as measured by the
email: All the asthmatic patients met the conventional
FEV1 suggests that the mechanisms pro-
pmacal@liverpool.ac.uk diagnostic criteria,9 as did those with COPD10
ducing cough are likely to be diVerent
(table 1). The presence of a persistent cough
Received 30 April 1999 from those causing airways obstruction, at
Returned to authors was not necessary for inclusion in the study. All
least in patients with COPD.
9 July 1999
(Thorax 2000;55:643–649)
patients were clinically stable and any patient
Revised version received with a history of respiratory tract infection
19 April 2000
Accepted for publication Keywords: asthma; chronic obstructive pulmonary dis- in the preceding four weeks, symptoms or
19 April 2000 ease; cough reflex investigations suggestive of oesophageal reflux,
www.thoraxjnl.com644 Doherty, Mister, Pearson, et al
Table 1 Demographic features, medication, and physiology of subjects studied volume in one second (FEV1) and forced vital
capacity (FVC) traces from three technically
Normal subjects Asthma COPD
satisfactory attempts were used. Data are
No. of subjects 96 53 57 expressed as percentage predicted values.11
Median (range) age (years) 38 (20–65) 51 (22–73) 65 (45–88)
Sex (% male) 34 62 75
Smoking habits (%) Capsaicin cough challenge
Current smokers 17 17 40 Capsaicin (Sigma Chemical Co, St Louis, Mis-
Ex-smokers 20 40 60 souri, USA) was dissolved in absolute ethanol
Non-smokers 63 43 0
Drug treatment (%) to make a stock solution of 10–2 M which was
â agonists 0 100 100 further diluted with 0.9% saline to produce
Anticholinergics 0 21 83
Theophylline 0 8 19
nine doubling concentrations from 2 to
Inhaled corticosteroids 0 100 35 500 µM. Doses were administered from an
Lung function Acorn nebuliser powered from a dosimeter
Mean (SE) FEV1 (l) 3.7 (0.48) 2.1 (0.12) 1.1 (0.1)
Mean (SE) FVC (l) 4.4 (0.62) 3.4 (0.16) 2.6 (0.1)
calibrated to deliver 0.009 ml in each inhala-
% Predicted FEV1 (SE) 107 (14) 71 (3) 42 (2) tion at a maximum flow rate of 0.75 l/s and a
Mean (SE) PEF variability (%) — 15.9 (1.2) 17.0 (1.8) mass median particle diameter of 5.2 µm. Sub-
(n=53) (n=18)
Mean (SE) PC20 (mg/ml) — 1.9 (0.46) — jects were asked to take a single slow inhalation
(n=43) from the dosimeter beginning with saline con-
trol and then, with a minimum of 30 second
FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; PEF = peak expira-
tory flow; PC20 = concentration of histamine provoking a fall in FEV1 of 20% or more. intervals, increasing strengths of capsaicin until
Values are numbers of subjects except when otherwise stated. a given inhalation caused five coughs (C5).
This dose was repeated to ensure that a repro-
subjects taking angiotensin converting enzyme ducible C5 response had been attained and, if
inhibitors, or those less than 18 years of age so, that the value was recorded as the patient’s
were excluded, although there was no upper value (C5 capsaicin).
age limit. No patient had clinical or radio-
graphic features suggestive of co-existing bron- COPD: additional tests
chiectasis. We excluded patients with a history Subjects with COPD then completed the
of allergic rhinitis, post nasal drip, and those following additional tests:
being treated for nasal symptoms. The data (1) Diary cards: these were completed at
were compared with those derived from our home over a two week period during which the
normal subject population recruited from hos- subject recorded symptom scores or daily cough
pital staV, free from respiratory disease, who on a five point scale ranging from 1 = no cough
denied cough and were not receiving any to 5 = distressing cough most of the day. The
medication. All subjects gave written informed score over the 14 day recording period was used
consent to the study which was approved by to calculate the mean daily diary cough score.
our institutional ethical committee. Peak expiratory flow (PEF) was self-recorded
using a mini Wright peak flow meter four times
PROCEDURES a day in a standard fashion, the best of three
Subjects omitted short acting inhaled â ago- measurements being taken. Peak flow variation
nists and anticholinergic agents for six hours for any particular day was taken as the diVerence
before attendance and longer acting drugs such between the highest and lowest peak flow
as oral theophylline or inhaled long acting â divided by the highest measure. For patients
agonists for 12 hours on all test days. All with more than nine days of complete data the
subjects underwent the following tests. mean daily PEF variability was calculated.
(2) Hospital questionnaire: a detailed history
Spirometry of current respiratory medications was ob-
Spirometric parameters were recorded with a tained with particular note of ‘as needed’
wedge spirometer (Vitalograph, Maidenhead, inhaled â agonists, regular inhaled anticholin-
Berkshire, UK) and the best forced expiratory ergic agents, and inhaled corticosteroids (table
1). Sputum production was recorded as nil,
120 occasional, or frequent. Symptoms of cough
Normal
Cumulative frequency of responders
were recorded in a number of ways:
100 Asthma (a) the presence or absence of cough on most
COPD days;
(b) whether this cough was mild, moderate,
80
or severe;
(c) using a 10 cm visual analogue scale
60 (VAS) marked between no cough at one end
and worst imaginable cough at the other end.
40
Further tests
After the above, patients with asthma and
20 COPD were invited to perform further tests
including lung volume measurement, hista-
0 mine challenge tests, and the eVect of bron-
0 1.95 3.9 7.8 15.6 31.25 62.5 125 250 500 >500 chodilators on the C5 response. Histamine
Capsaicin concentration (µmol/l) challenge tests were performed later the same
Figure 1 Comparison of the cumulative frequency at which subjects reached the C5 day while lung volume estimation and eVect of
response for asthma and for subjects with COPD compared with normal subjects. bronchodilators were measured on separate
www.thoraxjnl.comCapsaicin responsiveness and cough in asthma and COPD 645
study days during the following three weeks. In loop with the largest sum of FEV1 and FVC
those with asthma the subgroup studied was chosen and from this loop PEF, 25–75%
depended solely on the patient’s willingness to forced expiratory flow (FEF25–75), and peak
undergo these investigations. In those with inspiratory flow (PIF) were derived. Static lung
COPD some patients were unable to take a volumes were measured using the helium dilu-
further part as they were about to enrol in tion technique.
another clinical trial, and others were only will- (2) Histamine challenge: 43 asthmatic pa-
ing to some of the extra tests. There was no tients performed histamine challenge testing
diVerence in mean age, percentage predicted 15 minutes after the capsaicin study, inhaling
FEV1, or median C5 response between the from a dosimeter in a standard fashion. The
subgroups who underwent additional tests and FEV1 was recorded before the histamine
their parent cohorts. challenge to ensure that there was no change
(1) Static lung volumes and flow-volume from the pre-capsaicin baseline. The concen-
tration of histamine provoking a fall in FEV1 of
loops: 38 patients with asthma and 20 with
20% or more (PC20) was calculated by linear
COPD performed flow-volume loops and
interpolation from the logarithmic concentra-
measurement of static lung volumes while
tion response curve.
seated using a rolling seal spirometer (PK
(3) EVect of changing airway calibre on the
Morgan Ltd) with standard criteria for an C5 response: 40 patients with asthma and 13
acceptable loop.11 After coaching, each subject with COPD performed a capsaicin challenge
performed repeated loops until three techni- test and spirometric measurements both before
cally satisfactory traces were obtained. The and 30 minutes after each 5 mg nebulised
salbutamol, 500 µg nebulised ipratropium bro-
A
4 mide, and 3 ml 0.9% saline. All solutions were
r = _ 0.38 given using a System 22 Acorn nebuliser on
separate days at the same time of the day in
random double blind order. For each disease
Average daily diary card score
group and for each solution the C5 and FEV1
3
values before and after administration of the
nebulised agents were compared. Twenty three
asthmatics performed a capsaicin challenge
both before and immediately after the hista-
2 mine challenge so that, at the time of the
second histamine challenge, their FEV1 was
reduced by at least 20% from baseline. The
eVects of bronchoconstriction were then stud-
ied by comparing the diVerence between the
1
C5 before and after the histamine challenge
test with the diVerence between each subject’s
C5 response before and after saline.
0 STATISTICAL ANALYSIS
Saline 2 8 31 125 500 >500 Median C5 values and the frequency distribu-
C5 concentration (µmol/l) tion were used to describe the normal range in
each disease group. These were then compared
using the Kruskal Wallis test followed, if
B significant, by paired Mann-Whitney U tests
5
r = _ 0.44 between the groups.
The relationship between symptoms and
sensitivity to capsaicin was examined in a
Average daily diary card score
4 number of ways. The average daily diary card
cough score and the visual analogue score
derived from the questionnaire were each
related to the C5 of each subject using Spear-
3 man rank correlation coeYcient within each
disease group. Patients were grouped into
those who did and those did not cough on
2 most days and were then compared using
Mann-Whitney U tests. Subjects were also
divided into those who considered their cough
to be mild, moderate, or severe and these
1 groups were compared using the Kruskal Wal-
lis test. Similarly, subjects with asthma and
COPD were subdivided into those who rarely
0 produced phlegm, those who occasionally
Saline 2 8 31 125 500 >500 produced phlegm, and those who usually pro-
C5 concentration (µmol/l) duced phlegm and these groups were again
compared using the Kruskal Wallis test. Lung
Figure 2 Scatter plots with Spearman correlation coeYcients showing the relationship
between self-reported cough measured using the daily diary card cough scores and capsaicin function data are presented as mean (SE). The
responsiveness (C5) for (A) asthma and (B) COPD. relationship between capsaicin sensitivity and
www.thoraxjnl.com646 Doherty, Mister, Pearson, et al
Table 2 Severity of self-reported cough in subjects with asthma and COPD using a variety of measures, and its
relationship to regular treatment
Asthma COPD
Median C5 Median C5
n (µM) n (µM)
Cough present 43 Cough most days 61% 16 57 Cough most days 81% 31
No cough most days 39% 250 No cough most days 9% 31
(p=0.015) (p=0.8)
Severity of cough 43 Mild 54% 125 57 Mild 31% 125
Moderate 37% 63 Moderate 56% 16
Severe 10% 16 Severe 12% 8
(p=0.014) (p=0.1)
Sputum production 43 Usually 51% 16 57 Usually 56% 31
Occasionally 28% 125 Occasionally 26% 31
Rarely 21% 500 Rarely 16% 125
(p=0.014) (p=0.8)
Anticholinergic therapy 53 Prescribed 21% 8 57 Prescribed 82% 31
Not prescribed 79% 125 Not prescribed 18% 250
(p=0.02) (p=0.03)
Inhaled corticosteroid 53 Low dose 26% 93 57 Prescribed 35% 63
therapy Moderate dose 62% 63 Not prescribed 65% 31
High dose 12% 125 (p=0.6)
(p=0.7)
PC20 for histamine was examined using Spear- inhaled corticosteroids taken. However, those
man rank correlation coeYcient as was that for patients using an inhaled anticholinergic drug
the C5 response and lung function. Both pre did have a greater C5 sensitivity (p = 0.002; fig
and post nebuliser C5 and FEV1 values as well 3A). The C5 response of those patients not
as pre and post histamine C5 and FEV1 values treated in this way was still significantly greater
were compared using Mann-Whitney U tests. than that of the normal subjects.
Results COPD SYMPTOMS AND LUNG FUNCTION
The clinical and physiological data at study Complete symptomatic data were available in
entry are given in table 1. The patients with only 19 cases, the remaining patients having
asthma were older than the normal subjects but been recruited into a study of inhaled cortico-
younger than the patients with COPD steroids where treatment changes might have
(p500 µM, pCapsaicin responsiveness and cough in asthma and COPD 647
A Asthma C COPD
100 100
Cumulative frequency (%)
Cumulative frequency (%)
80 80
60 60
40 40
Ipratropium Ipratropium
20 20
No ipratropium No ipratropium
0 0
Saline 2 8 31 125 500 >500 Saline 2 8 31 125 500 >500
C5 concentration (µmol/l) C5 concentration (µmol/l)
B D
100 100
Cumulative frequency (%)
Cumulative frequency (%)
80 80
60 60
40 40
Low ICS ICS
20
Moderate ICS 20 No ICS
High ICS
0 0
Saline 2 8 31 125 500 >500 Saline 2 8 31 125 500 >500
C5 concentration (µmol/l) C5 concentration (µmol/l)
Figure 3 Comparison of the cumulative frequency at which subjects reached the C5 response by medication for both
asthma and for COPD: (A) asthma: inhaled anticholinergics versus no inhaled anticholinergics; (B) asthma: low versus
moderate versus high dose inhaled corticosteroids; (C) COPD: inhaled anticholinergics versus no inhaled anticholinergics;
(D) COPD: inhaled corticosteroids versus no inhaled corticosteroids.
a mean increase in FEV1 of 0.37 (0.04) l after In the 13 patients with COPD tested before
salbutamol or 0.36 (0.04) l after ipratropium and after bronchodilators the FEV1 rose from
from a baseline of 2.07 (0.13) l did not change 1.2 (0.12) l to 1.37 (0.13) l after salbutamol
the median C5 response. Similarly, the median and to 1.41 (0.14) l after ipratropium, but
C5 values were unchanged in the 23 asthmatic without a significant eVect on the measured C5
patients measured before and after histamine response.
challenge, despite a fall in FEV1 of a mean of
0.6 (0.05) l from a baseline value of
2.1(0.12) l. Discussion
The capsaicin cough challenge test is a simple
and reproducible laboratory method for the
COPD
assessment of cough susceptibility in a wide
Asthma range of diseases.7 12 It tests the aVerent limb of
100 the cough reflex which is thought to be
mediated by rapidly adapting receptors within
the airway wall. It can be increased by inhaling
prostanoids in normal subjects13 or by taking a
80 thromboxane antagonist in patients with
FEV1 (percent predicted)
asthma.14
Studies in a range of conditions associated
with chronic cough have shown an increased
60
capsaicin sensitivity that falls with successful
treatment, which can be achieved in two thirds
of cases.12 However, it is diYcult to extrapolate
40
data from these studies to patients with either
asthma or COPD as the numbers studied, par-
ticularly in the latter group, are relatively small
and data about lung function and bronchial
20
reactivity are scanty. Our data in a large group
of chronic persistent asthmatic subjects extend
earlier observations in mild asthma that
suggested that a reduced C5 cough threshold is
0 a frequent finding which bears some relation-
Saline 2 8 31 125 500 >500 ship to the severity of the patient’s symptoms.
C5 response (µmol/l) Other measures such as percentage predicted
Figure 4 Scatter plot showing the relationship between C5 response and percentage FEV1 have recently been shown not to relate to
predicted FEV1 for both asthma and COPD the severity of cough in asthmatic subjects.15
www.thoraxjnl.com648 Doherty, Mister, Pearson, et al
Similar reductions in cough threshold were The confounding eVects of drug treatment
seen in patients with moderate to severe or smoking are unlikely to explain our findings.
COPD, despite the significant diVerences in Regular use of â agonists does not appear to
the baseline spirometric values and the diVer- modify the C5 response, despite earlier reports
ent mechanisms producing the disease.16 of benefit in cough induced in volunteers,25 and
Several methodological problems should be our patients were asked to omit inhaled therapy
addressed. We performed our capsaicin chal- before attendance. Short term use of oral
lenge as described previously7 with the addi- corticosteroids and longer term use of inhaled
tional feature of repeating the last concentra- corticosteroids are associated with changes in
tion inhaled to confirm the C5 end point. We the frequency of symptomatic cough in
did not report the concentration producing two COPD.26 Specific data about the eVect of these
coughs (C2) as we have found this to be less drugs on cough threshold are lacking. We
reproducible than the C5 response in normal found no relationship between smoking status
subjects and it does not add additional and C5, neither did the regular use of â
information. Others using similar methods agonists or inhaled corticosteroids relate to the
have also found that C2 and C5 data yield recorded response. Likewise, there were no dif-
similar information in other diseases.18 As chal- ferences in the symptom severity of cough,
lenge test dosimeters are not identical, we have however assessed, and the presence of sputum
related changes in our patients to our laborato- production or use of inhaled corticosteroids.
ry’s normal values rather than to those derived We found that the C5 cough threshold was sig-
from the literature, although our normal range nificantly lower in both asthmatic and COPD
overlaps that described elsewhere. We used a patients taking regular inhaled ipratropium,
fixed inspiratory flow rate to minimise diVer- although the patients not using these drugs
ences in cough threshold between subjects.17 In were still more responsive than the control
subjects. Whilst it is tempting to postulate that
our laboratory we have found no evidence of
this may be a pharmacological eVect, it is more
age, sex, or smoking eVects, unlike other
likely to reflect selection of the more severe
reports.18
patients among the asthmatic group9 and the
The reduced C5 in patients with chronic
widespread use of these drugs among COPD
stable asthma was not surprising in view of the
patients.10 Indeed, anticholinergic agents have
earlier reports in milder disease. A range of been shown to decrease rather than increase
possible mechanisms involving diVerent in- the nasal response to capsaicin.27 Prospective
flammatory mediators has been suggested to studies of the capsaicin response before and
explain the enhanced C5 response.13 19 20 How- after the introduction of anticholinergic treat-
ever, given the heterogeneity of FEV1 and PC20 ment would be needed entirely to exclude this
of the asthmatic populations in which this has as an adverse reaction to treatment.
now been reported, it seems likely that Whilst diVerences in the deposition of
increased cough susceptibility is either pro- capsaicin to more central airway receptors
duced by very non-specific means or involves might be hypothesised to explain some of the
an entirely diVerent pharmacological pathway apparent similarities in asthmatic and COPD
from the mechanisms which determine the patients, the absence of any relationship
severity of airways reactivity or resting airway between C5 and the severity of airflow
calibre. This has implications for the modifica- limitation is a pointer against this. None of the
tion of cough as a symptom in asthma. measures of airflow limitation were related to
The reduction in C5 in the patients with C5 in either disease. Moreover, the C5 was
COPD was unexpected as previous reports had unaltered even when the airway calibre was
suggested that the C5 response was normal in varied acutely, suggesting that neither airflow
COPD and that the cough was perhaps related limitation alone nor changes in capsaicin depo-
to increased sputum production and now sition explain the increased level of response in
increased responsiveness of laryngeal our patients with asthma or COPD. A similar
receptors.21 lack of eVect of smaller changes in airway cali-
Studies in patients with chronic bronchitis or bre has been reported in normal subjects,25 but
COPD where lung function data are available our data confirm that this is true in established
have examined less severe disease and/or a disease when baseline FEV1 is reduced.
population diagnosed as having chronic sinus C5 was not related to the level of bronchial
disease,22 neither being representative of unse- hyperreactivity or to the level of PEF variability
lected COPD patients reported here. Our over two weeks, providing further evidence that
patients met the conventional diagnostic crite- the mechanisms underlying cough production
ria for COPD, had limited bronchodilator are not necessarily related to those determining
reversibility and a history of past or current airway calibre.
smoking, making it unlikely that there was a Unlike previous studies, our patients were
significant asthmatic element to their illness. In not selected because of their complaint of
these patients we found no association between cough12 17 but were randomly drawn from our
reported sputum production and either cough outpatient clinics as we did not wish to bias
severity or C5 threshold. our data by patients self-selected by their
Induced sputum studies have shown levels of perception of a subjective complaint. Most
pro-inflammatory cytokines in both asthma patients, whatever the diagnosis, rated their
and COPD.23 24 Persistent airway inflammation cough as being of either mild or moderate
may contribute to the enhanced C5 response severity, but the capsaicin response did not dis-
and merits further investigation. tinguish between these subjective grades. Other
www.thoraxjnl.comCapsaicin responsiveness and cough in asthma and COPD 649
mechanisms may be important in milder 7 Choudry NB, Fuller RW. Sensitivity of the cough reflex in
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