Rationale: Cough is one of the principal symptoms of chronic obstructive pulmonary disease (COPD) but the potential drivers of cough are likely to be multifactorial and poorly understood.
Objectives: To quantify cough frequency in an unselected group of subjects with COPD and investigate the relationships between cough, reported sputum production, smoking, pulmonary function, and cellular airway inflammation.
Methods: We studied 68 subjects with COPD (mean age, 65.6 ± 6.7 yr; 67.6% male; 23 smokers; 45 ex-smokers) and 24 healthy volunteers (mean age, 57.5 ± 8.9 yr; 37.5% male; 12 smokers; 12 nonsmokers). Subjects reported cough severity, cough-specific quality of life, and sputum expectoration and performed spirometry, sputum induction, cough reflex sensitivity to capsaicin, and 24-hour ambulatory cough monitoring.
Measurements and Main Results: COPD current smokers had the highest cough rates (median, 9 coughs/h [interquartile range, 4.3–15.6 coughs/h]), almost double that of COPD ex-smokers (4.9 [2.3–8.7] coughs/h; P = 0.018) and healthy smokers (5.3 [1.2–8.3] coughs/h; P = 0.03), whereas healthy volunteers coughed the least (0.7 [0.2–1.4] coughs/h). Cough frequency was not influenced by age or sex and only weakly correlated with cough reflex sensitivity to capsaicin (log C5 r = −0.36; P = 0.004). Reported sputum production, smoking history, and current cigarette consumption strongly predicted cough frequency, explaining 45.1% variance in a general linear model (P < 0.001). In subjects producing a sputum sample, cough frequency was related to current cigarette consumption and percentage of sputum neutrophils (P = 0.002).
Conclusions: Ambulatory objective monitoring provides novel insights into the determinants of cough in COPD, suggesting sputum production, smoking, and airway inflammation may be more important than sensitivity of the cough reflex.
Cough is one of the main symptoms of chronic obstructive pulmonary disease. However, little is known about how frequently such patients cough and the potential factors driving cough are poorly understood.
By measuring cough frequency using 24-hour sound recordings, we have quantified cough rate in patients with chronic obstructive pulmonary disease and found that cigarette smoke exposure, mucus hypersecretion, and neutrophilic airway inflammation are more important determinants of cough than the sensitivity of the cough reflex.
Chronic obstructive pulmonary disease (COPD) is a major public health problem, with a lifetime risk in smokers of 35–50% (1). By 2020, it is estimated that more than 200 million people will have COPD, and it will be the third leading cause of death worldwide. Cough (either with or without sputum) is one of the principle symptoms of COPD, along with breathlessness. Epidemiologic studies have found that the reported presence of chronic cough and mucus hypersecretion in established COPD may be linked to accelerated decline in lung function (2), more frequent exacerbations (3), and hospitalizations (4), yet little is known about the mechanisms underlying coughing (5).
The potential drivers for cough in patients with COPD are multifactorial. Excessive airway mucus may provide a mechanical stimulus to coughing, especially in the presence of ciliary dysfunction, airflow obstruction, and airway collapse (caused by destruction of the supporting parenchyma), all of which impair clearance. In addition the inflammation, infection, and in some continuing exposure to cigarette smoke provide chemical stimuli capable of provoking coughing in COPD.
Cough responses to inhaled capsaicin have been used previously to study the sensitivity of the cough reflex in COPD, but there is little agreement among studies about the influences of smoking and COPD on this measure. Although several studies have described diminished sensitivity to capsaicin compared with control subjects in smokers (6–8) and patients with COPD (9), other investigators have found capsaicin responses to be increased in these conditions (10–13). We have developed an ambulatory system for making sounds recordings over 24 hours in ambulatory patients, which allows the objective quantification of coughing (Vitalojak; Vitalograph Ltd., Buckingham, UK). This system has provided novel insights into the predictors of cough in patients presenting with isolated chronic cough (14, 15), asthma (16), and cystic fibrosis (17).
In patients with COPD selected for the symptom of cough, we have previously shown that subjective measures of cough and cough reflex sensitivity are only moderately correlated to objective measures of cough (18), and have insufficient predictive value for understanding the determinants of cough. We therefore aimed to quantify coughing in an unselected group of subjects with COPD (current and ex-smokers), and to ascertain the predictors of cough by investigating associations with reported sputum production, smoking, pulmonary function, and cellular airway inflammation. We also studied cough frequency in two control groups (healthy subjects and healthy smokers) for comparison. Some of the results of these studies have been previously reported in abstract form (19).
For details, see the online supplement.
We studied 68 subjects with COPD (smokers, n = 23; ex-smokers, n = 45) and 24 healthy volunteers (smokers, n = 12; nonsmokers, n = 12). Patients with COPD were not selected for the symptom of cough, and only excluded if they had serious concurrent disease, or a recent exacerbation. Healthy volunteers had no history of significant disease and normal spirometry; nonsmokers also had a smoking history of less than one pack-year and healthy smokers more than 10 pack years. The protocol was approved by the local research ethics committee (05/Q1606/173 and 05/Q1402/41) and all subjects provided written informed consent.
Subjects attended on three occasions. On Visit 1, spirometry was measured and sputum induction performed. Twenty-four–hour cough monitoring was commenced on Visit 2 (7–10 d later). The next day (Visit 3), subjects returned the monitor, completed subjective assessments of cough, and cough reflex sensitivity was measured. Current smokers were permitted to smoke according to their normal habits.
Spirometry and flow-volume loops were performed (Spirotrac IV; Vitalograph Ltd.) according to standard criteria (American Thoracic Society and European Respiratory Society guidelines) (20).
Ambulatory cough sound monitoring was performed using a custom-built device (Vitalojak) (21). Recordings were transferred to a personal computer; silences and background noise removed by validated, custom-written software (22); and cough sounds counted using an audio editing package (Audition version 3; Adobe Systems Inc., San Jose, CA).
Subjects marked cough severity on a 100-mm Visual Analog Scale (VAS) and a five-point scale for the day and night of the cough recording (23). Subjects also completed a cough-specific quality-of-life questionnaire (Leicester Cough Questionnaire [LCQ]) (24), with a higher score indicating better health status. Sputum production was assessed by the question “Over the past 4 weeks I have brought up phlegm (sputum): not at all, only with respiratory infections, a few days a month, several days a week or most days a week,” from the St George’s Respiratory Questionnaire (25).
Cough reflex sensitivity was tested in subjects with FEV1 greater than 25% predicted, using standard methodology (26). Capsaicin (Stockport Pharmaceuticals, Stockport, UK) was inhaled at 1-minute intervals, in ascending doubling concentrations (0.125–125 μm), as 10-µl single breath inhalations (KoKo Dosimeter; De Vilibis Health Care Inc., Somerset, PA). The numbers of coughs in the 15 seconds after each inhalation were counted and the concentrations resulting in at least two and five coughs (C2 and C5) recorded.
Sputum samples were induced using 3% saline (Stockport Pharmaceuticals, Stockport, UK) inhaled from an ultrasonic nebulizer (Sonix 2000; Clement Clarke LD, Essex, UK) after salbutamol, 200 μg. Samples were placed on ice and cells counted (27).
Analyses were performed using SPSS version 15.0 (SPSS Inc., Chicago, IL) and Prism version 5.02 (Graphpad Software, Inc., San Diego, CA). The four subject groups (COPD ex-smoker and smokers, and healthy smokers and nonsmokers) were compared using analysis of variance, chi-square, and Kruskal-Wallis tests. Predictors of objective cough frequency were assessed in patients with COPD only using Pearson and Spearman correlations and general linear models. A subgroup analysis assessed the relationships between cellular inflammation and cough frequency in those in whom sputum induction was successful.
Ninety-two subjects completed the study and a comparison of the characteristics of the study groups is shown in Table 1. Both COPD patient groups were older than healthy volunteers, although the absolute differences in age were small and there was a greater proportion of males in the COPD ex-smokers compared with the other groups.
|Post Hoc Comparisons|
|COPD CS||COPD CEx||HS||HNS||P Value||CS vs. CEx||CEx vs. HS||HS vs. HNS|
|N (male)||23 (12)||45 (34)||12 (5)||12 (4)||<0.001*||0.01*||<0.001*||1.0*|
|Age (SD)||61.8 (±7.2)||67.5 (±5.7)||58.5 (±2.3)||56.4 (±2.3)||<0.001†||0.045‡||0.002‡||<0.001‡|
|FEV1/FVC ratio (SD)||0.50 (±0.13)||0.47 (±0.14)||0.76 (±0.04)||0.80 (±0.09)||<0.001†||0.045‡||<0.001‡||<0.001‡|
|FEV1% predicted (SD)||62.9 (±17.7)||56.7 (±18.6)||91.9 (±15.7)||116.5 (±16.6)||<0.001†||0.68‡||0.032‡||0.50‡|
|Body mass index (SD)||24.7 (±4.4)||28.8 (±5.8)||27.1 (±4.3)||25.5 (±2.5)||0.010†||0.002||0.323||0.447|
|Current smoking, cigarettes/d||20 (5–30)||0||15 (5–20)||0||0.10§||—||—||—|
|Smoking, pack-years (range)||45 (15–68)||49 (19–108)||31 (10–45)||0||<0.001‖||0.41§||<0.001§||—|
|GOLD spirometry grade (1/2/3/4)||1/17/6/1||5/22/11/5||—||—||0.56¶||—||—||—|
As might be anticipated, the healthy smokers had a shorter smoking history compared with COPD current and ex-smokers; however, there was no significant difference between the number of cigarettes consumed per day by subjects currently smoking, with or without COPD. Spirometry in patients with COPD demonstrated typical airflow obstruction of a similar severity in current and ex-smokers. Finally, COPD current smokers had a lower body mass index than the other groups. There were significant increases in the sputum total cell count, and absolute neutrophil and lymphocyte counts in COPD current smokers compared with ex-smokers (Table 2). There was an increase in the neutrophil percentage and a corresponding decrease in the macrophage percentage in COPD current smokers compared with ex-smokers, which was significant for macrophages (P = 0.03).
|COPD CS (n = 14)||COPD CEx (n = 24)||P Value|
|Median total cell count ×106/ml (range)||3.41 (0.00–50.54)||1.50 (0.00–27.20)||0.02†|
|Median count ×106/ml (range)||0.005 (0.000–0.408)||0.014 (0.000–0.379)||0.41†|
|Geometric mean % (95% CI)||1.7% (1.2–1.5)||0.2% (1.4–1.8)||0.23§|
|Median count ×106/ml (range)||0.793 (0.000–20.7)||3.225 (0.000–48.6)||0.04†|
|Mean % (SD)||75.7% (±16.2)||83.0% (±13.2)||0.13§|
|Median count ×106/ml (range)||0.20 (0.000–5.8)||0.19 (0.000–6.97)||0.77†|
|Geometric mean % (95% CI)||16.8% (10.7–26.5)||8.0% (4.7–13.6)||0.03§|
|Median count ×106/ml (range)||0.0009 (0.000–0.068)||0.0081 (0.000–0.167)||0.046†|
|Geometric mean % (95% CI)||0.3% (0.2–0.4)||0.4% (0.3–0.7)||0.11§|
|Median count ×106/ml (range)||0.003 (0.00–0.136)||0.000 (0.00–0.059)||0.28†|
|Geometric mean % (95% CI)||0.4% (0.2–0.9)||0.3% (0.2–0.7)||0.72§|
Of the 92 subjects taking part in the study, 89 completed 24-hour cough monitoring (two declined and one recording failed), and 87 subjects completed the capsaicin cough challenge (five failed to meet the inclusion criteria). All completed the LCQ, cough scores, and cough severity VAS, and subjects with COPD completed the St George’s Respiratory Questionnaire. A summary of all the measures of cough is shown in Table 3. Significant correlations were seen between objective cough frequency and all subjective measures of cough (r = 0.46–0.66) (see Table E1 in the online supplement).
|COPD CS||COPD CEx||HS||HNS||P Value|
|Objective 24-hr cough rate (range), coughs/h*|
|Total||9.0 (0.4–83.1)||4.9 (0.60–27)||5.3 (0.20–13.9)||0.7 (0.13–4.3)||<0.001†|
|Day||12.3 (0.4–130.2)||6.5 (0.8–28.6)||8.0 (0.3–18.8)||1.3 (0.1–6.3)||<0.001‡|
|Night||2.4 (0.0–17.6)||1.4 (0.0–47.8)||0.7 (0.0–5.5)||0 (0.0–0.8)||<0.001§|
|Capsaicin cough challenge (SD)‖|
|Log C5||1.08 (±0.49)||1.12 (±0.54)||1.27 (±0.45)||1.37 (±0.42)||0.479|
|Log C2||0.83 (±0.62)||0.77 (±0.49)||0.94 (±0.31)||1.02 (±0.42)||0.249|
|VAS, mm (range)*|
|Day||45 (15–90)||23 (2–84)||17.5 (2–50)||3.5 (0–9)||<0.001†|
|Night||23.5 (0–82)||15.5 (0–81)||10.5 (1–57)||2 (0–5)||<0.001¶|
|Cough score (range)*|
|Day||3 (0–4)||2 (0–4)||1.5 (0–3)||0.5 (0–1)||<0.001†|
|Night||1 (0–4)||1 (0–4)||1 (0–3)||0 (0–1)||<0.002¶|
|LCQ (range)*||16.8 (10.3–20.6)||18.7 (10.5–21)||20.1 (16.8–20.6)||20.9 (19.6–21)||<0.001**|
There were significant differences in cough rates between study groups (P < 0.001). Paired comparisons showed that COPD current smokers had the highest cough rate, with COPD ex-smokers and healthy smokers having similar cough rates (Table 2, Figure 1). Healthy smokers and COPD ex-smokers coughed significantly more than healthy nonsmokers (P = 0.001 and P < 0.001, respectively); day and night cough rates displayed similar patterns, with cough rates significantly higher during the day compared with night. Interestingly, cough in the first hour after waking was significantly elevated compared with the average hourly rate during daytime in COPD smokers (P = 0.005) and COPD ex-smokers (P = 0.012) but not in the control patients (Figure 2).
There were no significant differences in log C5 or log C2 among the groups. However, females overall had a more sensitive cough reflex than males (median log C5, 1.19 M vs. 0.89 M; median log C2, 0.89 M vs. 0.59 M; P < 0.001). Using a multinomial regression analysis and adjusting for the influence of sex, log C5 was significantly lower in COPD smokers (P = 0.027) and ex-smokers (P = 0.016) compared with healthy control subjects, but not healthy smokers (P = 0.44). Both log C5 and log C2 correlated weakly with cough frequency (r = −0.39, P < 0.001 and r = −0.35, P = 0.001, respectively).
Cough VAS increased with both the presence of COPD and current smoking, with COPD current smokers having the highest VAS for cough for daytime and overnight. Cough scores also increased with both the presence of COPD and current smoking, with COPD current smokers having the highest scores by day (P < 0.001) and by night (P = 0.002) compared with the other groups.
LCQ scores were significantly different among the groups (P < 0.001). Cough-related quality of life was worsened by both the presence of COPD and current smoking, with the lowest scores seen in COPD current smokers (Table 2). The LCQ also differed significantly among groups across the three individual domains: physical (P < 0.001); psychological (P < 0.001); and social (P < 0.001) (see Table E2).
Bringing up phlegm “most days” was reported by 56.7% of patients with COPD, “several days a week” by 8.3%, “a few days a month” by 6.7%, “only with respiratory infections” by 18.3%, and “not at all” by 10%. COPD current smokers reported frequent sputum production more often than ex-smokers (P = 0.035).
Table 4 summarizes the relationships between patient characteristics and objective cough frequency in the univariate analyses and multivariate models.
|Predictors of Cough Frequency||Correlation Coefficient or Variance||P Value|
|Age||r = −0.17||0.18|
|Body mass index||r = −0.16||0.19|
|FEV1% predicted||r = −0.08||0.45|
|FEV1/FVC ratio||r = −0.07||0.59|
|History (pack-years)||r = 0.29||0.02|
|Cigarette consumption (cigs/d, current only)||r = 0.64||0.002|
|Reported sputum production||r = 0.56||0.001|
|CRS to capsaicin|
|Log C2||r = −0.32||0.01|
|Log C5||r = −0.31||0.02|
|% Neutrophils||r = 0.30||0.08|
|% Eosinophils||r = −0.30||0.08|
|Model 1 (n = 57)||R2 = 45.1%||<0.001|
|Past smoking history||0.001|
|Cigarette consumption (cigs/d)||0.002|
|Reported sputum production||0.020|
|CRS to capsaicin (Log C5)|
|Model 2† (n = 38)||R2 = 33.0%||0.002|
|Past smoking history||0.41|
|Cigarette consumption (cigs/d)||0.003|
Age, sex, and body mass index did not significantly influence cough frequency, nor did measures of airflow obstruction. However, current smokers coughed significantly more than ex-smokers and cough rates weakly correlated with past smoking history. Additionally, in current smokers increasing cigarette consumption was associated with higher cough frequency. Although the reported level of sputum production correlated moderately with cough frequency, cough reflex sensitivity to capsaicin correlated only weakly.
Acceptable sputum cell counts were obtained in 39 of 68 patients with COPD (14 of 23 current smokers and 25 of 45 ex-smokers). Cough frequency was no different in subjects able to expectorate a sputum sample compared with those unable (P = 0.65); however, these subjects were more likely to report chronic expectoration on the St George’s Questionnaire (Fisher exact test, P = 0.003). There was a trend toward a positive correlation between day cough frequency and the percentage sputum neutrophils and eosinophils.
Significant influences on objective cough rate in COPD were further explored in a multivariate model, including variables significant or near significant in the univariate analyses. A total of 45.1% of the variance in objective cough frequency (adjusted R2, P < 0.001) could be explained by a combination of past smoking history (P = 0.001); current cigarettes per day (P = 0.002); and reported sputum production (P = 0.020). Cough reflex sensitivity was not a significant predictor in this model.
In a second model including only subjects in whom sputum could be induced (n = 38), 33% of the variance (adjusted R2, P = 0.002) in day cough frequency (because sputum was collected during the day) was explained by the percentage of neutrophils (P = 0.006), and current cigarettes per day (P = 0.003). Past smoking history and percentage eosinophils were no longer significant in this model.
This is the first study to measure objective cough frequency in an unselected group of patients with COPD, exploring the predictors of coughing and making comparisons with healthy smokers and nonsmokers. We have shown that current healthy smokers and COPD ex-smokers have similar cough frequencies, both significantly greater than healthy nonsmokers. Furthermore, current smoking with a diagnosis of COPD had an additive effect, giving COPD current smokers double the cough frequency of those with either factor alone. In comparison with other respiratory conditions, patients with COPD generally coughed less frequently than those with chronic cough (28), but more often than patients with asthma (16). Objective cough frequency in patients with COPD was influenced by current smoking habits and past smoking history. In those subjects who provided sputum samples, over a third of the variation in cough rates could be explained by the degree of neutrophilic airway inflammation and current smoking.
Qualitative research has suggested that cough and sputum expectoration may be potent triggers for the stigmatization of patients with COPD (29), yet few previous studies have objectively measured cough in COPD (18, 30). Our data suggest this novel approach can provide new insights into the mechanisms that may drive coughing. Smoking habits seem important, with current cigarette consumption correlating moderately with cough frequency in current smokers. The multivariate analysis suggests that this effect is independent of and therefore not mediated by increased sputum production associated with current smoking. Cigarette smoke inhalation may provoke cough by several mechanisms. Nicotine inhalation induces airway irritation and coughing in healthy nonsmokers (31), and in animal studies activates a range of pulmonary afferent fibers (32). Similarly, aldehydes in cigarette smoke and reactive oxygen species induced by cigarette smoke activate transient receptor potential ankyrin 1 channels (33, 34), known to be expressed by unmyelinated vagal afferent nerves innervating the airway (35) and recently shown to evoke coughing in animals and humans (36). However, whether such mechanisms remain important in provoking cough in chronic cigarette smoke exposure is not known.
Despite the inherent difficulties in estimating the degree of airway mucus hypersecretion, our data demonstrate a moderate correlation between reported frequency of expectoration and cough frequency suggesting clearance of excessive secretions at least in part drives coughing in stable COPD. Notably, we were previously able to show a similar positive relationship between objective cough frequency and weight of expectorated mucus in a small group of patients with cystic fibrosis when their pulmonary disease was stable (17). Airway mucus may provide a direct stimulus for coughing by if changing from via to by then needs to say ‘mediated by’ myelinated “cough receptors” (Aδ fibers) present in the proximal airways and sensitive to mechanical stimuli (37). Clearance of airway mucus after sleep may explain the increased cough frequency we observed in the first hour after waking; this was most marked in patients with COPD still smoking where average cough rate was almost doubled.
Based mainly on studies in the guinea pig, it is thought that Aδ fiber (mechanosensitive) and C fiber (chemosensitive) afferent nerves located in the larynx and proximal airways are responsible for regulating cough (38). However, nerves found in the smaller distal airways can still modulate cough responses by convergence and interactions in the brainstem (39). Therefore, although mucus, inhaled cigarette smoke, and inflammation in the proximal airways may be expected to directly activate cough afferents, the potential influences of inflammatory mucus exudates (40) and disease in the small conducting airways (41) are less clear. Indeed, it has been recently noted that the degree of mucus occlusion in these small airways was unrelated to reported symptoms including cough (42).
In patients in whom an induced sputum sample was obtained (those with more chronic expectoration), we were able to show positive relationships between objective cough frequency and neutrophilic inflammation, independent of the influence of current smoking. Although neutrophilic airway inflammation is considered typical of COPD, it must be acknowledged that this may be a cause or a consequence of coughing, or both. Several studies in diverse patient groups have found neutrophilic airway inflammation to be correlated with measures of objective cough frequency, including children with asthma (43), children with primary ciliary dyskinesia (44), and also a large study of adults presenting with a variety of respiratory conditions (45). In an animal model replicating the airway wall collapse and barotrauma induced by coughing, bronchoalveolar neutrophils were found to be still elevated 6 hours after the mechanical stimulus (46). Moreover, this study also found cough responses to be heightened, proportionate to the neutrophilia, suggesting a possible self-perpetuating cycle where cough provokes neutrophilic inflammation, which in turn may sensitize peripheral airway nerves and therefore the cough reflex. It is also interesting that there was a trend toward lower eosinophil counts in patients with higher cough frequency. However, this relationship was not significant in the multivariate analysis suggesting any relationship may be explained to some extent by current smoking habits.
Cigarette smoke (34, 47) and inflammation (48, 49) have the potential to not only stimulate but also sensitize afferent airway nerves. Our data suggest some sensitization of the cough responses to capsaicin in healthy smokers and those with COPD. However, cough reflex sensitivity only weakly correlated with cough frequency and did not significantly predict cough in the multivariate analysis. These observations suggest that neuronal hypersensitivity plays little role in triggering cough in stable COPD.
This study has some limitations. Our control groups were smaller than the groups of COPD smokers and ex-smokers and therefore cough frequency is less accurately estimated in these groups. Also there were significant differences in age and sex between our groups of subjects, although neither of these parameters significantly influenced cough frequency in this study. Finally, sputum samples could only be obtained in 57% of subjects with COPD, which is lower than in previous studies including similar patients. Therefore, the relationships between inflammatory mediators and cough may have been underestimated because of the limited sample size.
In conclusion, we have provided evidence for some of the determinants of cough in stable patients with COPD. Exposure to past and present cigarette smoke and mucus hypersecretion seem to be more important than sensitization of the cough reflex or degree of airflow obstruction. We have also shown that there is a significant burden of cough in unselected patients with COPD, yet effective therapies are lacking. These findings have important implications for how cough might be best treated in stable COPD, suggesting that in addition to smoking cessation, therapies that reduce sputum production or improve clearance are likely to be most effective and more appropriate than cough suppressants, whereas the potential role of antiinflammatory medicines remains to be elucidated.
|1.||Vestbo J. Chronic cough and phlegm in young adults: should we worry? Am J Respir Crit Care Med 2007;175:2–3.|
|2.||Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Care Med 1996;153:1530–1535.|
|3.||Burgel PR, Nesme-Meyer P, Chanez P, Caillaud D, Carre P, Perez T, Roche N. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest 2009;135:975–982.|
|4.||Vestbo J, Rasmussen FV. Respiratory symptoms and FEV1 as predictors of hospitalization and medication in the following 12 years due to respiratory disease. Eur Respir J 1989;2:710–715.|
|5.||Smith J, Woodcock A. Cough and its importance in COPD. Int J Chron Obstruct Pulmon Dis 2006;1:305–314.|
|6.||Pounsford JC, Saunders KB. Cough response to citric acid aerosol in occasional smokers. Br Med J (Clin Res Ed) 1986;293:1528.|
|7.||Millqvist E, Bende M. Capsaicin cough sensitivity is decreased in smokers. Respir Med 2001;95:19–21.|
|8.||Dicpinigaitis PV. Cough reflex sensitivity in cigarette smokers. Chest 2003;123:685–688.|
|9.||Stravinskaite K, Sitkauskiene B, Dicpinigaitis PV, Babusyte A, Sakalauskas R. Influence of smoking status on cough reflex sensitivity in subjects with COPD. Lung 2009;187:37–42.|
|10.||Wong CH, Morice AH. Cough threshold in patients with chronic obstructive pulmonary disease. Thorax 1999;54:62–64.|
|11.||Doherty MJ, Mister R, Pearson MG, Calverley PM. Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease. Thorax 2000;55:643–649.|
|12.||Blanc FX, Macedo P, Hew M, Chung KF. Capsaicin cough sensitivity in smokers with and without airflow obstruction. Respir Med 2009;103:786–790.|
|13.||Terada K, Muro S, Ohara T, Haruna A, Marumo S, Kudo M, Ogawa E, Hoshino Y, Hirai T, Niimi A, et al. Cough-reflex sensitivity to inhaled capsaicin in COPD associated with increased exacerbation frequency. Respirology 2009;14:1151–1155.|
|14.||Kelsall A, Decalmer S, McGuinness K, Woodcock A, Smith JA. Sex differences and predictors of objective cough frequency in chronic cough. Thorax 2009;64:393–398.|
|15.||Smith JA, Decalmer S, Kelsall A, McGuinness K, Jones H, Galloway S, Woodcock A, Houghton LA. Acoustic cough-reflux associations in chronic cough: potential triggers and mechanisms. Gastroenterology 2010;139:754–762.|
|16.||Marsden PA, Smith JA, Kelsall AA, Owen E, Naylor JR, Webster D, Sumner H, Alam U, McGuinness K, Woodcock AA. A comparison of objective and subjective measures of cough in asthma. J Allergy Clin Immunol 2008;122:903–907.|
|17.||Smith JA, Owen EC, Jones AM, Dodd ME, Webb AK, Woodcock A. Objective measurement of cough during pulmonary exacerbations in adults with cystic fibrosis. Thorax 2006;61:425–429.|
|18.||Smith J, Owen E, Earis J, Woodcock A. Cough in COPD: correlation of objective monitoring with cough challenge and subjective assessments. Chest 2006;130:379–385.|
|19.||Sumner H, Kelsall A, Lazaar AL, Kolsum U, Singh D, Woodcock A. Influences of smoking and COPD on objective cough frequency [abstract]. Thorax 2009;64:A15.|
|20.||Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, et al. Standardisation of spirometry. Eur Respir J 2005;26:319–338.|
|21.||Smith J, Woodcock A. New developments in the objective assessment of cough. Lung 2008;186:S48–S54.|
|22.||Sumner H, Kelsall A, Woodcock A, Smith JA, McGuinness K. A semi automatic method to reduce the time taken for manual cough counting [abstract]. Am J Respir Crit Care Med 2010;181:A5555.|
|23.||Hsu JY, Stone RA, Logan-Sinclair RB, Worsdell M, Busst CM, Chung KF. Coughing frequency in patients with persistent cough: assessment using a 24 hour ambulatory recorder. Eur Respiratory J 1994;7:1246–1253.|
|24.||Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID. Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ). Thorax 2003;58:339–343.|
|25.||Jones PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire. Respir Med 1991;85(Suppl B):25–31; discussion 33–27.|
|26.||Morice AH, Fontana GA, Belvisi MG, Birring SS, Chung KF, Dicpinigaitis PV, Kastelik JA, McGarvey LP, Smith JA, Tatar M, et al. ERS guidelines on the assessment of cough. Eur Respir J 2007;29:1256–1276.|
|27.||Pavord ID, Pizzichini MM, Pizzichini E, Hargreave FE. The use of induced sputum to investigate airway inflammation. Thorax 1997;52:498–501.|
|28.||Decalmer SC, Webster D, Kelsall AA, McGuinness K, Woodcock AA, Smith JA. Chronic cough: how do cough reflex sensitivity and subjective assessments correlate with objective cough counts during ambulatory monitoring? Thorax 2007;62:329–334.|
|29.||Berger BE, Kapella MC, Larson JL. The experience of stigma in chronic obstructive pulmonary disease. West J Nurs Res 2011;33:916–932.|
|30.||Smith J, Owen E, Earis J, Woodcock A. Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease. J Allergy Clin Immunol 2006;117:831–835.|
|31.||Hansson L, Choudry NB, Karlsson JA, Fuller RW. Inhaled nicotine in humans: effect on the respiratory and cardiovascular systems. J Appl Physiol 1994;76:2420–2427.|
|32.||Lee LY, Burki NK, Gerhardstein DC, Gu Q, Kou YR, Xu J. Airway irritation and cough evoked by inhaled cigarette smoke: role of neuronal nicotinic acetylcholine receptors. Pulm Pharmacol Ther 2007;20:355–364.|
|33.||Taylor-Clark TE, Undem BJ. Sensing pulmonary oxidative stress by lung vagal afferents. Respir Physiol Neurobiol 2011;178:406–413.|
|34.||Andre E, Campi B, Materazzi S, Trevisani M, Amadesi S, Massi D, Creminon C, Vaksman N, Nassini R, Civelli M, et al. Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J Clin Invest 2008;118:2574–2582.|
|35.||Nassenstein C, Kwong K, Taylor-Clark T, Kollarik M, Macglashan DM, Braun A, Undem BJ. Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lungs. J Physiol 2008;586:1595–1604.|
|36.||Birrell MA, Belvisi MG, Grace M, Sadofsky L, Faruqi S, Hele DJ, Maher SA, Freund-Michel V, Morice AH. TRPA1 agonists evoke coughing in guinea pig and human volunteers. Am J Respir Crit Care Med 2009;180:1042–1047.|
|37.||Canning BJ, Mazzone SB, Meeker SN, Mori N, Reynolds SM, Undem BJ. Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J Physiol 2004;557:543–558.|
|38.||Canning BJ. Functional implications of the multiple afferent pathways regulating cough. Pulm Pharmacol Ther 2011;24:295–299.|
|39.||Mazzone SB, Mori N, Canning BJ. Synergistic interactions between airway afferent nerve subtypes regulating the cough reflex in guinea-pigs. J Physiol 2005;569:559–573.|
|40.||Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645–2653.|
|41.||Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 1968;278:1355–1360.|
|42.||Hogg JC, Chu FS, Tan WC, Sin DD, Patel SA, Pare PD, Martinez FJ, Rogers RM, Make BJ, Criner GJ, et al. Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology. Am J Respir Crit Care Med 2007;176:454–459.|
|43.||Li AM, Lex C, Zacharasiewicz A, Wong E, Erin E, Hansel T, Wilson NM, Bush A. Cough frequency in children with stable asthma: correlation with lung function, exhaled nitric oxide, and sputum eosinophil count. Thorax 2003;58:974–978.|
|44.||Zihlif N, Paraskakis E, Lex C, Van de Pohl LA, Bush A. Correlation between cough frequency and airway inflammation in children with primary ciliary dyskinesia. Pediatr Pulmonol 2005;39:551–557.|
|45.||Yousaf SM, Birring SS, Pavord ID. Factors affecting cough frequency in a mixed population [abstract]. Thorax 2009;2009;64(Suppl IV):A151.|
|46.||Hara J, Fujimura M, Ueda A, Myou S, Oribe Y, Ohkura N, Kita T, Yasui M, Kasahara K. Effect of pressure stress applied to the airway on cough-reflex sensitivity in guinea pigs. Am J Respir Crit Care Med 2008;177:585–592.|
|47.||Lin YS, Hsu CC, Bien MY, Hsu HC, Weng HT, Kou YR. Activations of TRPA1 and p2x receptors are important in ROS-mediated stimulation of capsaicin-sensitive lung vagal afferents by cigarette smoke in rats. J Appl Physiol 2010;108:1293–1303.|
|48.||Kuhad A, Chopra K. Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy. Neuropharmacology 2009;57:456–462.|
|49.||Lee LY, Gu Q. Role of Trpv1 in inflammation-induced airway hypersensitivity. Curr Opin Pharmacol 2009;9:243–249.|
Supported by GlaxoSmithKline (SCO104960, NCT00292552).
Author Contributions: J.A.S., A.L.L., and A.W. conceived and designed the study. H.S., R.D., and U.K. performed the study. H.S. and J.A.S. drafted the manuscript and performed the data analysis. J.V. and D.S. advised on data interpretation. All authors revised the manuscript and approved the final version.
Originally Published in Press as DOI: 10.1164/rccm.201211-2000OC on March 8, 2013
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org