Predictors of Objective Cough Frequency in Chronic Obstructive Pulmonary Disease Helen Sumner1,2, Ashley Woodcock1,2, Umme Kolsum1,2, Rachel Dockry1,2, Aili L. Lazaar3, Dave Singh1,2, Jørgen Vestbo1,4, and Jaclyn A. Smith1,2 1 Respiratory Research Group, Faculty of Medicine and Human Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom; 2NIHR Translational Research Facility, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom; 3Clinical Discovery, Respiratory Therapy Area Unit, GlaxoSmithKline, King of Prussia, Pennsylvania; and 4Odense University Hospital/University of Southern Denmark, Odense, Denmark
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 6.7 yr; 67.6% male; 23 smokers; 45 ex-smokers) and 24 healthy volunteers (mean age, 57.5 6 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 ¼ 0.018) and healthy smokers (5.3 [1.2–8.3] coughs/h; P ¼ 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 ¼ 20.36; P ¼ 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 ¼ 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. Keywords: cough; smoking; sputum; neutrophils; capsaicin
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 (Received in original form November 7, 2012; accepted in final form February 1, 2013) 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. Correspondence and requests for reprints should be addressed to Jaclyn A. Smith, M.B.Ch.B., Ph.D., University of Manchester, ERC Building, Second Floor, University Hospital of South Manchester, Manchester M23 9LT, UK. E-mail:
[email protected] This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 187, Iss. 9, pp 943–949, May 1, 2013 Copyright ª 2013 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201211-2000OC on March 8, 2013 Internet address: www.atsjournals.org
AT A GLANCE COMMENTARY Scientific Knowledge on the Subject
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. What This Study Adds to the Field
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.
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
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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).
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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). Capsaicin cough challenge. 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 mm), 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 induction. 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 mg. Samples were placed on ice and cells counted (27).
METHODS For details, see the online supplement.
Subjects We studied 68 subjects with COPD (smokers, n ¼ 23; ex-smokers, n ¼ 45) and 24 healthy volunteers (smokers, n ¼ 12; nonsmokers, n ¼ 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.
Statistical Analysis 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.
Study Protocol 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.
RESULTS Subject Characteristics
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. 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
Procedures Spirometry. Spirometry and flow-volume loops were performed (Spirotrac IV; Vitalograph Ltd.) according to standard criteria (American Thoracic Society and European Respiratory Society guidelines) (20). Objective cough monitoring. 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). Subjective measures of cough. Subjects marked cough severity on a 100-mm Visual Analog Scale (VAS) and a five-point scale for the
TABLE 1. SUBJECT CHARACTERISTICS Post Hoc Comparisons
N (male) Age (SD) FEV1/FVC ratio (SD) FEV1% predicted (SD) Body mass index (SD) Current smoking, cigarettes/d Smoking, pack-years (range) GOLD spirometry grade (1/2/3/4)
COPD CS
COPD CEx
HS
HNS
P Value
CS vs. CEx
CEx vs. HS
HS vs. HNS
23 (12) 61.8 (67.2) 0.50 (60.13) 62.9 (617.7) 24.7 (64.4) 20 (5–30) 45 (15–68) 1/17/6/1
45 (34) 67.5 (65.7) 0.47 (60.14) 56.7 (618.6) 28.8 (65.8) 0 49 (19–108) 5/22/11/5
12 (5) 58.5 (62.3) 0.76 (60.04) 91.9 (615.7) 27.1 (64.3) 15 (5–20) 31 (10–45) —
12 (4) 56.4 (62.3) 0.80 (60.09) 116.5 (616.6) 25.5 (62.5) 0 0 —
,0.001* ,0.001† ,0.001† ,0.001† 0.010† 0.10x ,0.001k 0.56¶
0.01* 0.045‡ 0.045‡ 0.68‡ 0.002 — 0.41x —
,0.001* 0.002‡ ,0.001‡ 0.032‡ 0.323 — ,0.001x —
1.0* ,0.001‡ ,0.001‡ 0.50‡ 0.447 — — —
Definition of abbreviations: CEx ¼ ex-smoker; COPD ¼ chronic obstructive pulmonary disease; CS ¼ current smoker; GOLD ¼ Global Initiative for Chronic Obstructive Lung Disease; HNS ¼ healthy nonsmoker; HS ¼ healthy smoker. * Fisher exact test. y Analysis of variance test. z Independent samples t test. x Mann-Whitney test. k Kruskal-Wallis test. ¶ Chi-squared test.
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TABLE 2. CELLULAR INFLAMMATION IN INDUCED SPUTUM SAMPLES FROM PATIENTS WITH COPD, COMPARISON BETWEEN CURRENT AND EX-SMOKERS
Sputum induced Median total cell count 3106/ml (range) Eosinophils Median count 3106/ml (range) Geometric mean % (95% CI) Neutrophils Median count 3106/ml (range) Mean % (SD) Macrophages Median count 3106/ml (range) Geometric mean % (95% CI) Lymphocytes Median count 3106/ml (range) Geometric mean % (95% CI) Epithelial cells Median count 3106/ml (range) Geometric mean % (95% CI)
COPD CS (n ¼ 14)
COPD CEx (n ¼ 24)
P Value
14/23 3.41 (0.00–50.54)
24/45 1.50 (0.00–27.20)
,0.001* 0.02†
0.005 (0.000–0.408) 1.7% (1.2–1.5)
0.014 (0.000–0.379) 0.2% (1.4–1.8)
0.41† 0.23x
0.793 (0.000–20.7) 75.7% (616.2)
3.225 (0.000–48.6) 83.0% (613.2)
0.04† 0.13x
0.20 (0.000–5.8) 16.8% (10.7–26.5)
0.19 (0.000–6.97) 8.0% (4.7–13.6)
0.77† 0.03x
0.0009 (0.000–0.068) 0.3% (0.2–0.4)
0.0081 (0.000–0.167) 0.4% (0.3–0.7)
0.003 (0.00–0.136) 0.4% (0.2–0.9)
0.000 (0.00–0.059) 0.3% (0.2–0.7)
0.046† 0.11x 0.28† 0.72x
Definition of abbreviations: CEx ¼ ex-smoker; CI ¼ confidence interval; COPD ¼ chronic obstructive pulmonary disease; CS ¼ current smoker. * Chi-squared test. y Mann-Whitney test. x Independent samples t test.
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 ¼ 0.03). Measures of Cough
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 ¼ 0.46–0.66) (see Table E1 in the online supplement). Objective cough frequency. 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 ¼ 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
TABLE 3. OBJECTIVE AND SUBJECTIVE COUGH DATA COLLECTED FROM COPD CURRENT SMOKERS, COPD EX-SMOKERS, HEALTHY SMOKERS, AND HEALTHY NONSMOKERS
Objective 24-hr cough rate (range), coughs/h* Total Day Night Capsaicin cough challenge (SD)k Log C5 Log C2 VAS, mm (range)* Day Night Cough score (range)* Day Night LCQ (range)*
COPD CS
COPD CEx
HS
HNS
P Value
9.0 (0.4–83.1) 12.3 (0.4–130.2) 2.4 (0.0–17.6)
4.9 (0.60–27) 6.5 (0.8–28.6) 1.4 (0.0–47.8)
5.3 (0.20–13.9) 8.0 (0.3–18.8) 0.7 (0.0–5.5)
0.7 (0.13–4.3) 1.3 (0.1–6.3) 0 (0.0–0.8)
,0.001† ,0.001‡ ,0.001x
1.08 (60.49) 0.83 (60.62)
1.12 (60.54) 0.77 (60.49)
1.27 (60.45) 0.94 (60.31)
45 (15–90) 23.5 (0–82)
23 (2–84) 15.5 (0–81)
17.5 (2–50) 10.5 (1–57)
3 (0–4) 1 (0–4) 16.8 (10.3–20.6)
2 (0–4) 1 (0–4) 18.7 (10.5–21)
1.5 (0–3) 1 (0–3) 20.1 (16.8–20.6)
1.37 (60.42) 1.02 (60.42) 3.5 (0–9) 2 (0–5) 0.5 (0–1) 0 (0–1) 20.9 (19.6–21)
0.479 0.249 ,0.001† ,0.001¶ ,0.001† ,0.002¶ ,0.001**
Definition of abbreviations: CEx ¼ ex-smoker; COPD ¼ chronic obstructive pulmonary disease; CS ¼ current smoker; HNS ¼ healthy nonsmoker; HS ¼ healthy smoker; LCQ ¼ Leicester Cough Questionnaire. * Kruskal-Wallis. y All comparisons ,0.05 except HS versus CEx. z All comparisons ,0.08 except HS versus CEx. x Only comparison ,0.05 is HNS versus COPD CS/CEx. k Analysis of variance test. ¶ Only comparison ,0.001 HNS versus COPD CS/CEx. ** All comparisons ,0.05.
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Figure 1. Graph comparing 24-hour cough frequency among chronic obstructive pulmonary disease (COPD) current smokers (CS), COPD ex-smokers (CEx-S), healthy smokers (HS), and healthy nonsmokers (HNS). Note logarithmic scale on y axis. Kruskal-Wallis (P , 0.001); COPD smokers compared with COPD ex-smokers (P ¼ 0.03), COPD smokers compared with healthy smokers (P ¼ 0.03).
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Figure 2. Diurnal variation in cough frequency in chronic obstructive pulmonary disease (COPD) current smokers (CS), COPD ex-smokers (CEx-S), healthy smokers (HS), and healthy nonsmokers (HNS). Median (interquartile range) coughs in the first hour after waking were significantly higher in COPD smokers (P ¼ 0.005) and COPD ex-smokers (P ¼ 0.012) compared with median day hourly rates, with the difference most marked in COPD smokers.
elevated compared with the average hourly rate during daytime in COPD smokers (P ¼ 0.005) and COPD ex-smokers (P ¼ 0.012) but not in the control patients (Figure 2). Cough reflex sensitivity. 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 ¼ 0.027) and ex-smokers (P ¼ 0.016) compared with healthy control subjects, but not healthy smokers (P ¼ 0.44). Both log C5 and log C2 correlated weakly with cough frequency (r ¼ 20.39, P , 0.001 and r ¼ 20.35, P ¼ 0.001, respectively). Subjective measures. 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 ¼ 0.002) compared with the other groups. Cough-specific quality of life. 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). Reported sputum production. 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 ¼ 0.035).
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 ¼ 0.65); however, these subjects were more likely to report chronic expectoration on the St George’s Questionnaire (Fisher exact test, P ¼ 0.003). There was a trend toward a positive correlation between day cough frequency and the percentage sputum neutrophils and eosinophils. Multivariate analyses. 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 ¼ 0.001); current cigarettes per day (P ¼ 0.002); and reported sputum production (P ¼ 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 ¼ 38), 33% of the variance (adjusted R2, P ¼ 0.002) in day cough frequency (because sputum was collected during the day) was explained by the percentage of neutrophils (P ¼ 0.006), and current cigarettes per day (P ¼ 0.003). Past smoking history and percentage eosinophils were no longer significant in this model.
Predictors of Objective Cough Frequency in COPD
DISCUSSION
Table 4 summarizes the relationships between patient characteristics and objective cough frequency in the univariate analyses and multivariate models. Univariate analyses. Age, sex, and body mass index did not significantly influence cough frequency, nor did measures of airflow obstruction. However, current smokers coughed significantly more
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
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TABLE 4. PREDICTORS OF OBJECTIVE COUGH FREQUENCY IN PATIENTS WITH COPD, UNIVARIATE AND MULTIVARIATE ANALYSES
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” (Ad 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 Ad 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.
Predictors of Cough Frequency Univariate analyses Age Sex Body mass index Spirometry FEV1% predicted FEV1/FVC ratio Smoking History (pack-years) Status (current/ex-smoker) Cigarette consumption (cigs/d, current only) Reported sputum production CRS to capsaicin Log C2 Log C5 Cellular inflammation† % Neutrophils % Eosinophils Multivariate analyses Model 1 (n ¼ 57) Past smoking history Cigarette consumption (cigs/d) Reported sputum production CRS to capsaicin (Log C5) Model 2† (n ¼ 38) Past smoking history Cigarette consumption (cigs/d) % Neutrophils % Eosinophils
Correlation Coefficient or Variance r ¼ 20.17
P Value
r ¼ 20.16
0.18 0.25 0.19
r ¼ 20.08 r ¼ 20.07
0.45 0.59
r ¼ 0.29 r ¼ 0.64
0.02 0.02* 0.002
r ¼ 0.56
0.001
r ¼ 20.32 r ¼ 20.31
0.01 0.02
r ¼ 0.30 r ¼ 20.30
0.08 0.08
R2 ¼ 45.1%
,0.001 0.001 0.002 0.020
R2 ¼ 33.0%
0.002 0.41 0.003 0.006 0.33
Definition of abbreviations: cigs ¼ cigarettes; COPD ¼ chronic obstructive pulmonary disease; CRS ¼ cough reflex sensitivity. P values less than 0.05 are shown in bold. * Independent-samples t test. y Analyses refer to predictors of 24-hour cough frequency except for sputum inflammation, which was correlated with daytime cough frequency.
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
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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. Author disclosures are available with the text of this article at www.atsjournals.org.
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