American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 961-964, (2002)
© 2002 American Thoracic Society
Sex-related Differences in Cough Reflex Sensitivity in Patients with Chronic Cough
Jack A. Kastelik,
Rachel H. Thompson,
Imran Aziz,
Josephine C. Ojoo,
Anthony E. Redington and
Alyn H. Morice
Academic Department of Medicine, University of Hull, Castle Hill Hospital, Cottingham, United Kingdom
Correspondence and requests for reprints should be addressed to Professor Alyn H. Morice, Academic Department of Medicine, University of Hull, Castle Hill Hospital, Castle Road, Cottingham HU16 5JQ, UK. E-mail: a.h.morice{at}hull.ac.uk
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ABSTRACT
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Among patients attending specialist cough clinics there is an excess of females, but the reason for this sex difference is unknown. We tested the hypothesis that the sensitivity of the cough reflex is greater in female compared with male patients with chronic cough. Inhalation cough challenges with capsaicin and citric acid were performed in a large group of patients with chronic cough. The concentrations of tussive agent causing two (C2) and five (C5) coughs were calculated. Measurements of capsaicin cough reflex sensitivity (median [interquartile range]) were significantly lower for female patients compared with male patients (C2: 1.9 [0.5 to 5.5] versus 5.3 [2.2 to 11.5] µM, p = 0.0026; C5: 8.6 [2.2 to 34.0] versus 51.2 [7.2 to > 100] µM, p = 0.0007). Similarly for citric acid challenge, values were significantly lower for female compared with male patients (C2: 53.5 [17.3 to 145.4] versus 118.1 [41.4 to 381.7] mM, p = 0.0064; C5: 300.0 [97.1 to > 1,000] versus 830.4 [300.0 to > 1,000] mM, p = 0.032). There were significant correlations between capsaicin and citric acid C2 values (rs = 0.54, p < 0.0001) and C5 values (rs = 0.57, p < 0.0001). These findings indicate a sex difference in cough sensitivity in patients with chronic cough, as previously reported in healthy volunteers. This may explain the female preponderance in cough clinics.
Key Words: capsaicin • citric acid • cough • sex
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INTRODUCTION
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Chronic cough is a common and distressing symptom (1, 2). Surveys of patients attending specialist clinics have consistently reported a higher number of women among patients with chronic cough (3). Similarly, angiotensin-converting enzyme inhibitor-induced cough has been observed more frequently in female patients (4, 5). The reason for this female preponderance is unknown. Studies of healthy volunteers have shown that women are more sensitive to various inhaled tussigenic stimuli, including capsaicin (6–8), citric acid (9), and tartaric acid (10). However, there are no data on whether a similar sex-related difference in cough reflex sensitivity exists in patients with chronic cough.
In this study, we tested the hypothesis that the sensitivity of the cough reflex is greater in female compared with male patients with chronic cough. To address this, we performed inhalation challenge with capsaicin and citric acid in a large unselected group of patients with chronic cough. In addition, we evaluated whether there were correlations between citric acid and capsaicin cough responses in these patients.
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METHODS
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Subjects
Cough reflex sensitivity to capsaicin and citric acid was measured as a part of the routine diagnostic evaluation of patients attending the Hull Cough Clinic (Cottingham, UK) between September 1998 and November 2000. A total of 118 (68 female) patients aged 58.4 ± 12.6 years underwent citric acid inhalation cough challenge. Of these, 101 (60 female) patients aged 57.8 ± 12.9 years also underwent capsaicin cough challenge. All patients gave informed consent.
Measurement of Cough Reflex Sensitivity
Inhalation cough challenges were performed according to a modified version of our previously published protocol (11, 12). Briefly, concentration–response challenges to inhaled capsaicin and citric acid were undertaken with a compressed air-driven nebulizer controlled by a breath-activated dosimeter (Mefar MB3 CE; Mefar, Bresia, Italy) preset to limit the nebulization time to 1 second. The output of the dosimeter was 0.125 ml per inhalation. A 1 mM stock solution of capsaicin (Sigma Chemicals, Poole, Dorset, UK) was made up in 100% ethanol. The nebulizer solutions were then prepared by serial dilution of 1 mM capsaicin in sterile 0.9% saline solution to produce incremental concentrations ranging from 0.1 to 100 µM. The highest concentration of capsaicin contained less than 10% ethanol. For citric acid challenge, solutions were prepared by serial dilution of 1 M citric acid (Production Pharmacy, Royal Hallamshire Hospital, Sheffield, UK) in sterile 0.9% saline solution to obtain concentrations ranging from 1 to 1,000 mM.
Patients were instructed to exhale to functional residual capacity and then to inhale through a mouthpiece for 1 second until the nebulization had ceased. The number of coughs in the first 10 seconds after inhalation was recorded. There was a 30-second pause between each inhalation, and each concentration of tussive agent was inhaled four times. Capsaicin and citric acid were delivered in incremental concentrations, with inhalation of 0.9% saline solution randomly interspersed to increase challenge blindness. All cough challenges were performed by the same investigator (R.H.T.), using the same dosimeter and settings.
Log concentration–response curves were constructed for each test, and the concentrations of capsaicin or citric acid causing two coughs per inhalation (C2) and five coughs per inhalation (C5) were calculated by linear interpolation. When the specified number of coughs was not reached with the highest concentration of provocant, values were recorded as > 100 µM for capsaicin and > 1,000 mM for citric acid.
Lung Function Measurements
Spirometry was performed with a Vitalograph compact spirometer (Vitalograph, Buckingham, UK). The subjects performed three forced expiratory maneuvers from total lung capacity to residual volume. FEV1 and FVC were recorded, and the best test value for each was used in the analysis.
Statistical Analysis
Analysis was performed with StatView 4.02 for Macintosh (Abacus Concepts, Berkeley, CA). Data for age and spirometric measurements are expressed as means ± SD. Data for capsaicin and citric acid C2 and C5 values and for cough duration are expressed as medians (interquartile range), as these were not normally distributed. Comparisons between male and female patients were performed by using an unpaired t test or Mann–Whitney test, as appropriate. Correlations between capsaicin and citric acid C2 and C5 values were assessed by the Spearman test. A p value of < 0.05 was regarded as statistically significant.
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RESULTS
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The demographic data, cough characteristics, and spirometric measurements for patients who underwent capsaicin and citric acid challenges are shown in Table 1
. Spirometric volumes were significantly (all p values < 0.0001) lower for female than male patients. There were no other statistically significant differences between male and female patients undergoing either challenge, apart from citric acid inhalation, where female patients were slightly older than male patients (p = 0.03).
Measurements of capsaicin cough reflex sensitivity were significantly lower for female patients compared with male patients (C2: 1.9 [0.5 to 5.5] versus 5.3 [2.2 to 11.5] µM, p = 0.0026; C5: 8.6 [2.2 to 34.0] versus 51.2 [7.2 to > 100] µM, p = 0.0007) (Figure 1)
. Similarly for citric acid challenge, values were significantly lower for female compared with male patients (C2: 53.5 [17.3 to 145.4] versus 118.1 [41.4 to 381.7] mM, p = 0.0064; C5: 300.0 [97.1 to > 1,000] versus 830.4 [300.0 to > 1,000] mM, p = 0.032). Among the 101 patients who had both challenges performed, there were statistically significant correlations between capsaicin and citric acid C2 values (rs = 0.54, p < 0.0001) and C5 values (rs = 0.57, p < 0.0001) (Figure 2)
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Figure 1. Box-and-whisker plots showing C2 and C5 data for capsaicin (upper panels) and citric acid (lower panels) challenges for female and male patients with chronic cough. Boxes represent median and interquartile range values, and whiskers indicate 10th and 90th centiles. Values exceeded the highest dose of provocant in the case of 3 patients for capsaicin C2, 6 patients for citric acid C2, 25 patients for capsaicin C5, and 41 patients for citric acid C5.
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Figure 2. Scatter plot showing correlations between capsaicin and citric acid C2 values (top) (rs = 0.54, p < 0.0001) and C5 values (bottom) (rs = 0.57, p < 0.0001). Data points are for individual female patients (filled circles) and male patients (open circles). When the specified number of coughs was not reached with the highest concentration of provocant, values are shown as 100 µM (capsaicin) and 1,000 mM (citric acid) for the purpose of display.
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C2 and C5 values were not significantly correlated with age or duration of cough, other than capsaicin C5 values, where there were weak inverse correlations with age (rs = -0.32, p = 0.02) and cough duration (rs = -0.28, p = 0.03). Cigarette smoking and type of cough (dry versus productive) did not influence C2 or C5 values. Spirometric measurements, expressed as absolute values or as percentages of predicted values, were not significantly correlated with C2 and C5 values in female or male patients, apart from capsaicin C5 and FEV1 values in male patients (rs = 0.37, p = 0.03). To investigate whether the reproductive status of female patients influenced their cough response, patients were divided into age  55 years, presumed postmenopausal, and < 55 years. There were no statistically significant differences in C2 or C5 values for capsaicin or citric acid between the two age groups (Table 2)
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When patients were considered on the basis of final clinical diagnosis, the two main diagnostic categories were asthma and gastroesophageal reflux disease (Table 3)
. The C2 and C5 values for capsaicin and citric acid were significantly lower for female patients in both groups, with the exception of capsaicin C2 (p = 0.063) and citric acid C5 (p = 0.092) for patients with asthma. Fifty-three patients were not included in this analysis. Of these, 43 patients had miscellaneous conditions (including postnasal drip syndrome/rhinitis, angiotensin-converting enzyme inhibitor treatment, bronchiectasis, interstitial lung disease, and idiopathic cough), 6 were lost to follow-up, and 4 were still undergoing investigation.
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DISCUSSION
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This study of a large group of patients with chronic cough has shown for the first time that women compared with men have a heightened cough reflex sensitivity to both capsaicin and citric acid. A similar difference between the sexes was also evident in the two principal diagnostic categories, asthma and gastroesophageal reflux disease.
These findings are consistent with reports, concerning healthy volunteers, that have demonstrated a sex-related difference in cough response to acid and nonacid tussigenic agents (6–10). Fujimura and coworkers, for example, reported that healthy female subjects had a lower cough threshold to both capsaicin (6, 7) and tartaric acid (10). Similarly, we have previously observed that healthy female volunteers exhibited an increased number of coughs after inhalation of a fixed dose of citric acid (9). Other reports have failed to demonstrate a sex difference in evoked cough in healthy volunteers (13, 14). These results may be explained by methodological differences such as difficulties in achieving cough threshold in a proportion of subjects (14). Studies investigating cough response in disorders such as chronic obstructive pulmonary disease (15, 16), asthma (16), and pulmonary fibrosis (14) have not allowed comparison of cough sensitivity between the sexes because of the small numbers of subjects.
The explanation for the increase in cough reflex sensitivity among female patients with chronic cough (and in healthy female volunteers) is unknown. It has been suggested that female subjects inhale a proportionately higher dose of tussigenic stimulant because of their smaller airway size (8, 10, 17). This may be relevant to studies using long inhalation methods involving tidal breathing (6, 7, 10). However, it is unlikely to explain sex-related differences reported with a single-breath dosimeter-controlled technique, as the relative difference in the volume delivered to male and female volunteers is negligible with this method (8). Furthermore, the absence of correlations between cough reflex sensitivity and spirometric measurements (either absolute or percentage predicted) observed in this report, and in previous studies (9, 13, 14), also suggests that a variation in deposition of tussigenic agent in the airways is unlikely to account for sex-related differences in cough.
Another possible explanation would be an endocrine influence on the cough reflex. In patients with chronic cough there is evidence of persistent airway inflammation, with increased numbers of neutrophils, eosinophils, and mast cells (18–20). Studies have described the expression of estrogen and progesterone receptors on inflammatory cells, including neutrophils (21), eosinophils (22), and mast cells (23). Sex hormones may, therefore, regulate airway inflammation and so influence evoked cough. Previous reports that postmenopausal women have greater cough reflex sensitivity than premenopausal women (6), and more frequently suffer from angiotensin-converting enzyme inhibitor-induced cough (4) would, however, argue against this hypothesis. Similarly, the observation of a sex difference in normal volunteers suggests that inflammatory endocrine modulation may not be important. In our population of patients, interpretation of the effects of menopause on cough reflex sensitivity was limited by the small number of premenopausal patients.
The present report provided data on a large number of patients with chronic cough who underwent both citric acid and capsaicin challenge. We show significant correlations between these two tussigenic agents. Studies of guinea pigs have demonstrated that capsaicin and citric acid activate cough through a single pathway (24). Capsaicin and protons are known to stimulate, in allosteric fashion, the Type 1 vanilloid receptor (25). We suggest that in cough this receptor is responsible for transducing chemical stimulation into afferent sensory impulses. Direct activation of Type 1 vanilloid receptor has been shown to occur not only with exogenous capsaicin but also with 12-(S)-hydroperoxyeicosatetraenoic acid and several other lipoxygenase products (26). Thus these inflammatory mediators have the potential to act as endogenous ligands for this putative cough receptor. In patients with chronic cough, the presence of persistent airway inflammation may result in hyperresponsiveness of Type 1 vanilloid receptor. The altered basal state of the Type 1 vanilloid receptor could explain the correlation between citric acid and capsaicin sensitivity observed in our study of patients with chronic cough and the previously reported lack of any such relation in normal subjects (12, 27), where airway inflammation is presumably absent.
In conclusion, we observed that female patients with chronic cough had heightened responses to inhaled capsaicin and citric acid. This sex difference in the cough reflex is consistent with that previously reported in healthy volunteers and may explain why female patients predominate in cough clinics.
Received in original form September 18, 2001;
accepted in final form July 16, 2002
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Copyright © 2002 American Thoracic Society
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TOP
ABSTRACT
INTRODUCTION
55 years