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Department of Respiratory Medicine, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, FranceUniversité de Paris, Institut Cochin, Inserm U1016, Paris, France
Frequent productive cough was present across physician-assigned asthma and/or COPD.
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Prevalence of this clinical trait increased with higher physician-assessed severity.
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The trait was associated with reduced FEV1 and pollutant exposure in all diagnoses.
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Frequent productive cough was associated with higher risk of greater disease burden.
Abstract
Introduction
Persistent cough with sputum production is an important clinical trait in chronic obstructive pulmonary disease (COPD). We defined “frequent productive cough” based on 2 questions from the St George's Respiratory Questionnaire (SGRQ) and sought to determine its occurrence and associated outcomes in patients with physician-assigned asthma and/or COPD from the NOVELTY study.
Methods
Frequent productive cough was defined as cough and sputum production most or several days/week for the past 3 months (scoring ≥3 for both SGRQ questions). Relationships with baseline disease characteristics and exacerbations over 12 months’ follow-up were examined using logistic regression.
Results
Baseline SGRQ data were available for 7125 patients, of whom 31.3% had frequent productive cough. It was more common in asthma+COPD (38.8%) and COPD (38.1%) than asthma (25.0%), increasing with physician-assessed severity, and in current versus former and never smokers. Patient-reported symptomatic worsening was more common in patients with versus without frequent productive cough. Reduced post-bronchodilator FEV1 (odds ratio [OR] per 10% decrement 1.14 [95% confidence interval 1.11–1.16]) and history of pollutant exposure at home/work (OR 1.50 [1.33–1.69]) were associated with frequent productive cough in all diagnoses. Patients with baseline frequent productive cough were more likely to have ≥1 exacerbation over the subsequent 12 months (OR 1.71 [1.52–1.93]), including exacerbations requiring hospital admission and those treated with oral corticosteroids.
Conclusions
Frequent productive cough represents an important indicator of adverse clinical outcomes across asthma and/or COPD. Research into the underlying pathologic mechanisms is required to support targeted therapy development.
], but these symptoms are not specific to either asthma or chronic obstructive pulmonary disease (COPD). The combination of chronic cough and sputum production, described as chronic bronchitis, was recognized in the 1959 Ciba Foundation symposium [
Terminology, definitions and classification of chronic pulmonary emphysema and related conditions: a report of the conclusions of a Ciba guest symposium.
] as present in both asthma and emphysema. Subsequently, chronic bronchitis was formally defined as persistent cough with sputum production for at least 3 months of the year, in at least 2 consecutive years [
Definition and classification of chronic bronchitis for clinical and epidemiological purposes. A report to the Medical Research Council by their Committee on the Aetiology of Chronic Bronchitis.
]. More recently, in patients with COPD, chronic cough and sputum production have been associated with lung function decline, exacerbation risk, and increased risk of mortality [
]. Patients with COPD who have symptoms of chronic bronchitis typically have more respiratory symptoms, more frequent exacerbations, and worse clinical trajectories than those without chronic bronchitis [
The St. George's Respiratory Questionnaire definition of chronic bronchitis may be a better predictor of COPD exacerbations compared with the classic definition.
Chronic bronchitis is associated with severe exacerbation and prolonged recovery period in Chinese patients with COPD: a multicenter cross-sectional study.
Until recently, chronic cough and sputum production have been mainly associated with COPD. Less is known about the characteristics of patients with asthma with these symptoms. Mucus plugging has long been recognized as a feature associated with more severe eosinophilia [
]. However, these terms infer that symptoms are fixed and long-standing or that patients have excessive mucus production. We propose that the term “frequent productive cough” provides a more appropriate descriptor that is applicable across asthma and COPD, is clearly distinguished from the historical definition of chronic bronchitis, and advances the characterization of this clinical problem and potential for symptom variability across asthma and/or COPD without inferring a specific pathology.
Frequent productive cough can be assessed using the St George's Respiratory Questionnaire (SGRQ) [
], which asks patients about the frequency of cough and sputum (phlegm) production over the previous 3 months. The SGRQ criteria have been used previously when describing chronic mucus hypersecretion in patients with and without COPD [
The St. George's Respiratory Questionnaire definition of chronic bronchitis may be a better predictor of COPD exacerbations compared with the classic definition.
]. Notably, these studies did not include patients with asthma.
Here, we present our findings on frequent productive cough across a broad population of patients with asthma and/or COPD enrolled in NOVELTY (NOVEL observational longiTudinal studY; NCT02760329) [
], describing the relationship between frequent productive cough and disease characteristics, disease burden, and exacerbation risk.
2. Methods
2.1 NOVELTY study design
NOVELTY is a global, prospective, 3-year observational study of ∼12,000 patients with a diagnosis or suspected diagnosis of asthma and/or COPD. The NOVELTY study design [
] have been described previously. Patients were enrolled by primary care physicians, pulmonologists, or allergists from active clinical practices in 18 countries. To ensure sufficient representation of subgroups of interest, recruitment was stratified by physician-assigned diagnosis (asthma, asthma+COPD, or COPD) and by physician-assessed severity (mild, moderate, or severe); no diagnostic or severity criteria were prespecified to physicians to avoid prior assumptions about mechanisms and to allow generalizability of the findings to routine clinical practice. The NOVELTY study was approved in each participating country by the relevant institutional review boards and all patients provided written informed consent.
2.2 Frequent productive cough definition
Frequent productive cough was defined using two SGRQ items: “Over the past 3 months, I have coughed …” and “Over the past 3 months, I have brought up phlegm (sputum) …”. Item responses ranged from 0 to 4 (“Not at all” – 0, “Only with chest infections” – 1, “A few days a month” – 2, “Several days a week” – 3, and “Most days a week” – 4). Patients were classified as having frequent productive cough if they answered “most days a week” or “several days a week,” i.e., scored ≥3 on both items. Patients who scored ≤2 for either SGRQ item were classified as not having frequent productive cough.
Separately, to explore the spectrum of possible presentations, patients who scored ≥3 for only one of the SGRQ cough or sputum production items were classified as having frequent cough or frequent sputum production, respectively. Patients who scored ≥3 for the SGRQ cough item and ≤1 for the SGRQ sputum production item were classified as having frequent dry (non-productive) cough. Data for a third smaller subset of patients with frequent cough who scored ≥3 for the SGRQ cough item and scored 2 for the SGRQ sputum production item are not reported.
2.3 Study assessments and outcomes
Data from the baseline and 1-year follow-up clinical study visits were used, as recorded by physicians in electronic case report forms and from patient-reported outcomes completed at baseline. The prevalence of frequent productive cough was evaluated relative to baseline disease characteristics, including physician-assigned diagnosis, physician-assessed severity, comorbidities, medications, biomarkers, spirometry, exacerbation history, patient-reported outcome questionnaires, and exposure history.
Exposure history included ever being exposed to pollutants at home/work and occupational exposure to dust/fumes. Comorbidities were recorded by the physician at baseline. Bronchiectasis was derived from physician diagnosis and/or a record of abnormal computed tomography findings. Allergic rhinosinusitis was defined as allergic, seasonal or perennial rhinitis/sinusitis. Medications were analyzed by class. Biomarkers included blood neutrophil and eosinophil counts from consenting patients and fractional exhaled nitric oxide, as measured per American Thoracic Society (ATS)/European Respiratory Society (ERS) recommendations [
European Respiratory Society, ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.
]. Spirometry measures included bronchodilator responsiveness, post-bronchodilator forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. Predicted and lower limit of normal (LLN) values were based on Global Lung Function Initiative multiethnic reference equations [
An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations. Standardizing endpoints for clinical asthma trials and clinical practice.
] as events “beyond the patient's usual day-to-day variance”.
Baseline patient-reported questionnaires including the SGRQ were undertaken either in person at baseline visit or remotely, via a web-based application or telephone. These included a question on self-reported episodes of symptomatic worsening in the previous 3 months, with patients asked: “During the past 3 months, how many times has your breathing worsened beyond what you usually experience in a typical day (e.g., increased shortness of breath, wheezing, cough, or chest tightness)?”. Response options ranged numerically from “none” to “12+”. This question was separate from how these symptoms were otherwise recorded. Questionnaires were completed at baseline by approximately 60% of patients.
To assess the relationship between frequent productive cough at baseline and risk of exacerbations in the subsequent 12 months, outcomes recorded at 1 year included all physician-reported exacerbations during the previous 12 months; exacerbations were further categorized by type of management as those treated with oral corticosteroids (OCS), antibiotics, emergency room/department visit, or resulting in hospital admission.
2.4 Statistical analysis
All patients with complete baseline data for both SGRQ items used to define frequent productive cough were included in the analysis, with results presented for the overall cohort and stratified by physician-assigned diagnosis and physician-assessed severity. Descriptive analyses for the baseline distributions of frequent productive cough, frequent cough, frequent sputum production, and frequent dry cough were performed. Demographics and disease characteristics for patients with versus without frequent productive cough were compared, as were the demographics for patients included versus excluded (due to insufficient baseline SGRQ data) from the analysis.
Associations between frequent productive cough and baseline patient demographic and disease characteristics were assessed within each asthma and/or COPD diagnostic group using multivariate logistic regression, with frequent productive cough as the outcome. Covariates were kept to a minimum to avoid over-adjustment; age, sex, and current smoking status were selected using a directed acyclic graph. Associations with post-bronchodilator FEV1 were assessed per 10% decrement.
The associations between frequent productive cough and exacerbations and exacerbation-related healthcare utilization at 1-year were estimated for each diagnostic label. Associations were assessed using multivariate logistic regression, with odds ratios (ORs) and corresponding 95% confidence intervals (CIs) presented. Exacerbation outcomes were the response variables and frequent productive cough the explanatory variable. Again, age, sex, and current smoking status were selected as covariates.
No adjustment was made for multiple testing. Statistical analysis was performed in Rstudio (R version 3.6.1, Rstudio version 1.2.1086).
3. Results
Overall, 7125 patients with complete SGRQ data were included. Of these, 3754 (52.7%) had asthma, 887 (12.4%) had asthma+COPD, and 2484 (34.9%) had COPD diagnoses. Severity distribution varied considerably among diagnostic groups (Supplementary Table 1). Supplementary Table 2 presents demographics of patients included and excluded (due to lack of SGRQ data) from this analysis. Smoking prevalence varied by region, with the proportion of current smokers ranging from 8.8% in Japan to 23.7% in the USA.
3.1 Distribution of cough types
Frequent productive cough was reported by 31.3% of patients (2229/7125) (Table 1 and Fig. 1); separately, frequent cough was identified in 46.0% of patients (3281/7125), frequent sputum production in 40.4% (2882/7125), and frequent dry cough in 8.1% (574/7125). Frequent cough and/or frequent sputum production were identified in 55.2% of patients (3934/7125) (Supplementary Fig. 1).
Table 1Baseline patient demographics by physician-assessed diagnostic group and frequent productive cough status.
Percentage values for the proportion of patients with and without FPC were calculated using the total number of patients with that demographic/clinical variable in each diagnostic and severity group as the denominator.
Percentage values for the proportion of patients with and without FPC were calculated using the total number of patients with that demographic/clinical variable in each diagnostic and severity group as the denominator.
Percentage values for the proportion of patients with and without FPC were calculated using the total number of patients with that demographic/clinical variable in each diagnostic and severity group as the denominator.
Percentage values for the proportion of patients with and without FPC were calculated using the total number of patients with that demographic/clinical variable in each diagnostic and severity group as the denominator.
Percentage values for the proportion of patients with and without FPC were calculated using the total number of patients with that demographic/clinical variable in each diagnostic and severity group as the denominator.
Current smoker
95/269 (35.3)
174/269 (64.7)
114/210 (54.3)
96/210 (45.7)
340/653 (52.1)
313/653 (47.9)
549/1132 (48.5)
583/1132 (51.5)
Former smoker
316/1191 (26.5)
875/1191 (73.5)
196/582 (33.7)
386/582 (66.3)
541/1672 (32.4)
1131/1672 (67.6)
1053/3445 (30.6)
2392/3445 (69.4)
Never smoker
528/2294 (23.0)
1766/2294 (77.0)
34/95 (35.8)
61/95 (64.2)
65/159 (40.9)
94/159 (59.1)
627/2548 (24.6)
1921/2548 (75.4)
Chronic bronchitis, n (%)
38 (4.0)
47 (1.7)
43 (12.5)
25 (4.6)
75 (7.9)
67 (4.4)
156 (7.0)
139 (2.8)
SGRQ total score
Patients with data available, n
938
2807
344
542
939
1535
2221
4884
Mean (SD)
42.7 (21.2)
25.1 (18.8)
51.3 (21.8)
32.0 (18.7)
51.6 (20.5)
35.7 (20.0)
47.8 (21.4)
29.2 (19.8)
COPD, chronic obstructive pulmonary disease; FPC, frequent productive cough; N, total number of patients in the sample; n, number of patients meeting criteria; N1, number of patients with available data; SD, standard deviation; SGRQ, St George's Respiratory Questionnaire.
FPC: experienced cough and brought up phlegm several or most days a week (SGRQ cough and sputum scores ≥3) in the past 3 months. Where no denominator is reported, N1 = N.
a Percentage values for the proportion of patients with and without FPC were calculated using the total number of patients with that demographic/clinical variable in each diagnostic and severity group as the denominator.
Frequent cough and frequent sputum production were not mutually exclusive. N, number of patients. NOVELTY, NOVEL observational longiTudinal study; SGRQ, St George's Respiratory Questionnaire.
Frequent productive cough was common across all diagnoses but was more common among patients with asthma+COPD (38.8%) and COPD (38.1%) than asthma (25.0%) (Table 1 and Supplementary Fig. 2). A similar pattern was observed for frequent cough and frequent sputum production but not for frequent dry cough (Supplementary Fig. 2). Generally, the proportion of patients with each type of frequent cough and/or sputum production increased with greater physician-assessed disease severity across diagnostic groups (Fig. 2A–C), comprising over one-third of patients with severe asthma and over 40% of patients with severe COPD; this pattern was not observed for frequent dry cough, which was less common with increasing severity of COPD (Fig. 2D).
Fig. 2Distribution of patients with (A) frequent productive cough, (B) frequent cough, (C) frequent sputum production, and (D) frequent dry cough across physician-assigned diagnostic and severity groups.
See Fig. 1 for classification. Frequent productive cough: cough and sputum production several or most days a week (SGRQ cough and sputum scores ≥3) in the past 3 months. Frequent cough: cough several or most days a week (SGRQ cough score ≥3) in the past 3 months. Frequent sputum production: sputum production several or most days a week (SGRQ sputum scores ≥3) in the past 3 months. Frequent dry (non-productive) cough: cough several or most days a week (SGRQ cough score ≥3) and sputum production only with chest infection or not at all (SGRQ sputum production score ≤1) in the past 3 months. COPD, chronic obstructive pulmonary disease; N, total number of patients in the sample; n, number of patients with data; SGRQ, St George's Respiratory Questionnaire.
3.2 Baseline characteristics of frequent productive cough
Baseline demographics for patients with and without frequent productive cough are reported by diagnostic and diagnostic/severity groups (Table 1 and Supplementary Table 1). Distribution of frequent productive cough by region varied considerably in the asthma+COPD and COPD groups, but less so for asthma; the highest and lowest prevalence of frequent productive cough were seen in the USA (37.1%) and Japan (25.3%), respectively. Overall, frequent productive cough prevalence was higher in current smokers (48.5%) than former/never smokers (30.6% and 24.6%, respectively), but it was more common among non-smokers with COPD (40.9%) than non-smokers with asthma (23.0%).
Among included patients, physicians recorded chronic bronchitis and bronchiectasis diagnoses in 4.1% and 5.9%, respectively; for both conditions, the highest proportion of patients was observed in the asthma+COPD group, and the lowest proportion in the asthma group. Both conditions were more common in patients with versus without frequent productive cough, although only 44.6% of patients (187/419) with bronchiectasis reported frequent productive cough symptoms (Table 1 and Supplementary Table 3).
At baseline, more patients with frequent productive cough, compared to those without it, were receiving triple therapy (inhaled corticosteroids, long-acting β2-agonists, and long-acting muscarinic antagonists) across all diagnostic groups (Supplementary Table 3). A small number of patients were taking targeted medications for chronic cough and sputum production such as roflumilast, chronic antibiotics or mucolytics.
More patients with versus without frequent productive cough experienced exacerbations in the 12 months prior to baseline, and patient-reported episodes of symptomatic worsening in the 3 months prior to baseline, in all diagnostic groups (Supplementary Table 3) and across disease severity (Supplementary Tables 4–6). SGRQ-assessed health status was substantially worse in patients with frequent productive cough in all diagnostic groups (Table 1).
3.3 Factors associated with frequent productive cough
Associations between baseline demographic and disease variables and frequent productive cough are presented in Fig. 3. Across all diagnostic groups, frequent productive cough was independently associated with ever being exposed to pollutants at work/home (OR 1.50 [95% CI 1.33–1.69]) and with reduced post-bronchodilator FEV1 (OR per 10% decrement 1.14 [95% CI 1.11–1.16]). Among patients with asthma or COPD, frequent productive cough was associated with persistent airway obstruction (FEV1/FVC < LLN). Patients with asthma or COPD and frequent productive cough, but not those with asthma+COPD, had higher blood neutrophil and eosinophil counts than those without frequent productive cough. Allergic rhinosinusitis was associated with frequent productive cough in patients with asthma+COPD or COPD, whereas non-allergic rhinosinusitis was associated with frequent productive cough in patients with asthma. Increased frequency of other comorbidities among patients with frequent productive cough varied across diagnostic groups; those with asthma or asthma+COPD were more likely to have gastroesophageal reflux disease (GERD) and those with asthma only or COPD only were more likely to have coronary heart disease or heart failure.
Fig. 3Association between baseline variables and frequent productive cough by physician-assigned diagnosis of (A) asthma, (B) asthma+COPD, and (C) COPD.
Multivariate regression analysis adjusted for age, sex, and current smoking status; for “yes versus no,” no means “no or missing.” ATS, American Thoracic Society; BMI, body mass index; CAPTURE, COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk; CHD, coronary heart disease; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ERS, European Respiratory Society; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GERD, gastroesophageal reflux disease; LLN, lower limit of normal; n, number of patients with data; OR, odds ratio; ppb, parts per billion; SD, standard deviation. *Pollutants at home/work was derived from question 1 from the CAPTURE questionnaire [
]: “Have you ever lived or worked in a place with dirty or polluted air, smoke, second-hand smoke, or dust?” †Bronchodilator responsiveness was defined as ≥12% and 200 mL increase in FEV1. ‡Per doubling. §FeNO was unadjusted for smoking status and was measured per ATS/ERS recommendations [
European Respiratory Society, ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.
3.4 Frequent productive cough association with exacerbations
Overall and across diagnoses, having frequent productive cough at baseline was associated with an increased risk of ≥1 exacerbation over the subsequent 12 months (OR 1.71 [95% CI 1.52–1.93]), including those resulting in hospital admission (OR 1.93 [95% CI 1.50–2.48]) (Fig. 4 and Supplementary Fig. 3). This pattern was also observed for categories of exacerbations treated with OCS (OR 1.87 [1.63–2.14]) and with antibiotics (OR 1.86 [1.62–2.14]).
Fig. 4Associations between frequent productive cough at baseline and physician-reported exacerbations and related outcomes over the subsequent year, reported at year 1 visit in the overall patient population (N = 5710).
Multivariate regression analyses adjusted for age, sex, and current smoking status; patients with bronchiectasis were removed from this analysis. ATS, American Thoracic Society; CI, confidence interval; ED, emergency department; ERS, European Respiratory Society; OCS, oral corticosteroid; OR, odds ratio. *Exacerbations were defined based on ATS/ERS recommendations as beyond the patient's usual day-to-day variance [
An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations. Standardizing endpoints for clinical asthma trials and clinical practice.
In our analysis of a large global observational cohort of >7000 real-world patients with a diagnosis of asthma and/or COPD, we have established the concept of “frequent productive cough” as a common clinical trait associated with worse clinical and patient-reported disease and poorer clinical outcomes across asthma and/or COPD. Specifically, our results revealed that nearly one-third of patients with SGRQ data available in this NOVELTY sub-cohort reported symptoms at baseline consistent with frequent productive cough. Frequent productive cough was less common in patients with asthma compared with asthma+COPD and COPD; despite this, frequent productive cough represented a more common clinical presentation than frequent dry cough in patients with asthma (25.0% vs 8.6%). Frequent productive cough was present across all categories of physician-assessed severity, including patients characterized as having mild disease and patients with a diagnosis of COPD but without post-bronchodilator airflow obstruction on spirometry assessment.
Patients with asthma and/or COPD and frequent productive cough at baseline were at a greater risk of experiencing exacerbations over the subsequent 12 months compared with those without it, even when adjusted for smoking status. This corroborates previous findings of a link between cough and sputum production symptoms and exacerbation risk [
The St. George's Respiratory Questionnaire definition of chronic bronchitis may be a better predictor of COPD exacerbations compared with the classic definition.
]. Frequent productive cough at baseline was also associated with an increased use of exacerbation-related healthcare resources, as previously reported in patients with COPD and similar symptoms [
]. At baseline, a higher proportion of patients with frequent productive cough had a history of exacerbations in the previous 12 months, as seen previously when using these SGRQ items to assess symptoms described as chronic bronchitis [
The St. George's Respiratory Questionnaire definition of chronic bronchitis may be a better predictor of COPD exacerbations compared with the classic definition.
], a higher proportion of current smokers had frequent productive cough than former and non-smokers. As with previous SGRQ-based studies of symptoms characteristic of frequent productive cough [
The St. George's Respiratory Questionnaire definition of chronic bronchitis may be a better predictor of COPD exacerbations compared with the classic definition.
], a higher proportion of patients with versus without frequent productive cough were current smokers. However, this relationship may be confounded by patients with more severe disease being more likely to quit smoking [
Varying prevalence of frequent productive cough was observed across regions, ranging from 25% of patients in Japan to 37% of patients in the USA. One potential reason for this variance may be differences in smoking prevalence in each region, with current smoking rates ranging from 9% in Japan to almost a quarter of patients in the USA, which could be an interesting topic for future publication. Underlying differences in the populations recruited and the diagnostic criteria used by physicians in the NOVELTY study in each region could also account for some variance. Furthermore, a diagnosis of GERD was reported at a low frequency in NOVELTY when compared with other large studies such as COPDGene [
The St. George's Respiratory Questionnaire definition of chronic bronchitis may be a better predictor of COPD exacerbations compared with the classic definition.
], although this is often under-diagnosed. Nevertheless, frequent productive cough was present in patients from all regions analyzed, suggesting a need to better target this global clinical trait in obstructive lung disease.
Corroborating previous findings in patients with symptoms characteristic of frequent productive cough, patients in NOVELTY with versus without frequent productive cough were more likely to have greater airflow limitation [
The St. George's Respiratory Questionnaire definition of chronic bronchitis may be a better predictor of COPD exacerbations compared with the classic definition.
Chronic bronchitis in the 50-year follow-up of the European cohorts of the Seven Countries Study: prevalence, mortality and association with cardiovascular diseases.
]. Although GERD was associated with cough and sputum production symptoms in patients with asthma or asthma+COPD, this was not the case for patients with COPD, which contrasts with findings by the COPDGene study [
The St. George's Respiratory Questionnaire definition of chronic bronchitis may be a better predictor of COPD exacerbations compared with the classic definition.
]. This may be explained by differences in the patient populations and diagnostic practices, with NOVELTY including patients from regions outside of the USA. Furthermore, unlike many large COPD studies, such as COPDGene, NOVELTY includes a population of never-smokers who were not represented in the COPDGene findings. In asthma, frequent productive cough was associated with non-allergic rhinosinusitis, but not allergic rhinosinusitis, whereas for COPD the opposite was observed. Previous observational study findings on frequent productive cough symptoms in asthma have suggested an association with allergic rhinosinusitis [
], but we were unable to corroborate this within a larger real-world asthma population.
Current drugs and treatment strategies for patients with asthma and/or COPD may have only limited effects on frequent productive cough symptoms, supporting the need to identify specific underlying mechanisms and develop novel therapeutic approaches targeting these symptoms [
The effect of aclidinium on symptoms including cough in chronic obstructive pulmonary disease: a phase 4, double-blind, placebo-controlled, parallel-group study.
], while multiple clinical studies are underway to investigate “chronic cough”. This, like frequent productive cough, was common across patients with asthma and/or COPD in the NOVELTY cohort. However, many studies of chronic cough do not include any analysis of patients with frequent productive cough and indeed some actively exclude patients with chronic bronchitis [
Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials.
ClinicalTrials.gov Identifier NCT04562155, Clinical study to evaluate the efficacy and safety of three different doses of BAY1817080 compared to placebo in patients with chronic cough (PAGANINI).
Characterization of patients with refractory or unexplained chronic cough participating in a phase 2 clinical trial of the P2X3-receptor antagonist gefapixant.
Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial.
ClinicalTrials.gov Identifier NCT03282591, Study of the efficacy, safety, and tolerability of serlopitant for the treatment of refractory chronic cough.
], which results in many patients with COPD being ineligible. This is despite recent clinical guidelines for chronic cough calling for more investigation into the trait [
As demonstrated in our findings, frequent productive cough was present in patients with asthma and/or COPD in all physician-assessed severity categories and was an indicator of adverse clinical outcomes in these groups. This suggests a need for existing chronic cough clinical trials to include subgroup analysis of patients with versus without frequent productive cough, and for the design of clinical trials of new and existing therapies which specifically target the frequent productive cough trait. In addition, few studies examine cough outside of the context of obstructive lung disease, and the differences between the pathophysiology of respiratory disease and chronic cough are poorly understood.
In terms of the patient populations included in frequent productive cough trials, there is a significant need for studies to include broader patient populations that are more representative of the real world. This in turn will aid in the identification of traits which may be targeted to improve diagnosis, and ultimately treatment. Several groups have previously been identified as requiring greater representation in treatment clinical trials to facilitate understanding of COPD disease trajectory, including patients with COPD aged <50 years and patients with pre-COPD [
Treatment trials in young patients with chronic obstructive pulmonary disease and pre-chronic obstructive pulmonary disease patients: time to move forward.
Chronic bronchitis has been described as a “treatable trait,” with proposed therapies including carbocisteine, long-term low-dose macrolides, and roflumilast [
]. Only a small proportion of patients in our analysis were receiving these medications, and from cross-sectional analysis, their effects on frequent productive cough could not be determined. Of note, these therapies are generally recommended in more severe patient populations [
Global Initiative for Chronic Obstructive Lung Disease Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2022 report.
], whereas frequent productive cough was present at all physician-assessed severity levels. Further, the symptoms described here as frequent productive cough may have heterogeneous underlying pathophysiology, including bronchiectasis and increased mucus production, which would influence treatment approaches. Future analysis of stored biosamples in NOVELTY may allow identification of genetic markers of frequent productive cough, such as variations in MUC5AC and MUC5B [
Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort.
In contrast to the frequent productive cough findings, the proportion of patients with frequent dry cough was similar across diagnostic groups, with no clear pattern observed across severity categories. This suggests that different mechanisms may be involved, with further research needed to investigate the pathobiology of these two clinically heterogeneous traits.
A strength of this analysis is its use of the previously established SGRQ-based definition of chronic bronchitis-like symptoms [
], which requires a much shorter (3-month) period than the 2 years needed for the historical chronic bronchitis definition. Further, this SGRQ-based definition has previously been shown to better predict COPD exacerbations than historically defined chronic bronchitis [
The St. George's Respiratory Questionnaire definition of chronic bronchitis may be a better predictor of COPD exacerbations compared with the classic definition.
] can be useful in research settings and, to some extent, clinical practice, where the presence and severity of patient-reported symptoms are important when identifying and diagnosing patients with obstructive lung disease [
Global Initiative for Chronic Obstructive Lung Disease Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2022 report.
]. The SGRQ is already extensively used in respiratory research; therefore, the presence of frequent productive cough could be used to identify patients at risk of poorer outcomes. Our findings should prompt analysis of data from existing and future randomized clinical trials assessing pharmacologic treatment options for asthma and/or COPD that use the SGRQ to further explore the utility of the frequent productive cough questions for patient stratification and its relationship with clinically relevant outcomes.
Furthermore, this analysis benefits from the inclusion of patients across all physician-assessed severity levels, multiple countries, and several ethnicities. Previous analyses have assessed various definitions of chronic bronchitis in asthma [
The St. George's Respiratory Questionnaire definition of chronic bronchitis may be a better predictor of COPD exacerbations compared with the classic definition.
Global Initiative for Chronic Obstructive Lung Disease Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2022 report.
]. The inclusion of patients with asthma and/or COPD provides evidence to support further research into frequent productive cough as a phenotype of obstructive lung disease and its association with worse outcomes in these diagnoses. This may support the development of targeted therapies for frequent productive cough, as opposed to treatments guided by diagnostic label only.
Since the prevalence of symptoms characteristic of frequent productive cough seems to increase with age [
], data comparisons between physician-assigned diagnostic groups may be hindered by differences in mean patient age. Curiously, some patients reported frequent sputum production without frequent cough; one possible explanation is that they were referring to the clearing of mucus originating from nasal secretions (previously “post-nasal drip,” now termed “upper airway cough syndrome” [
]), but this remains unclear. This analysis did not include any imaging data, limiting the diagnosis of bronchiectasis and preventing the possibility of examining the relationship between these symptoms and mucus plugging, as investigated recently [
]. Analysis of sputum was not possible due to the size and scope of the study.
5. Conclusion
Frequent productive cough, as self-reported with the SGRQ, represents an important clinical trait that is common across the spectrum of obstructive lung disease. Although asthma and COPD are sometimes simplistically characterized by wheeze and cough, respectively, this analysis confirms that both cough and sputum production are frequent chronic symptoms in patients with asthma and/or COPD. Frequent productive cough was present across all physician-assessed severity levels, was associated with significant disease burden, and was an important indicator of the risk of adverse clinical outcomes. Efforts to reduce frequent cough and sputum production symptoms may, therefore, be an important component of the management strategy for these patients. Further research is required to understand the different pathobiologies underlying frequent productive cough and support the development of targeted therapies that improve patient outcomes rather than conventional treatment strategies based on either diagnostic label or clinical trait alone. Clinical trials investigating frequent productive cough should be designed to include broader populations to ensure that new therapies effectively target this trait.
Rod Hughes: Conceptualization, Methodology, Writing – original draft, Supervision, Writing – review & editing. Eleni Rapsomaniki: Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. Christer Janson: Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing. Christina Keen: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. Barry J. Make: Conceptualization, Methodology, Writing – original draft, Writing – review & editing. Pierre-Régis Burgel: Investigation, Writing – original draft, Writing – review & editing. Erin L. Tomaszewski: Methodology, Writing – original draft, Supervision, Writing – review & editing. Hana Müllerová: Conceptualization, Methodology, Writing – original draft, Supervision, Writing – review & editing. Helen K. Reddel: Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review & editing.
Declaration of competing interest
R.H., E.R., C.K., E.L.T., and H.M. are employees of AstraZeneca; C.J. has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Orion; B.J.M. has received CME personal fees from American College of Chest Physicians, Eastern Pulmonary Society, Integritas Communications, Medscape, National Jewish Health, Novartis, Mt Sinai, Projects in Knowledge, WebMD, and Wolters Kluwer Health; medical advisory board fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Novartis, Phillips, Third Pole, and Verona; personal fees for data safety and monitoring board from Quintiles and Spiration; grants from American Lung Association, AstraZeneca, GlaxoSmithKline; personal fees from AstraZeneca, GlaxoSmithKline, Optimum Patient Care Global Limited, Spiration, and Third Pole; funding from the NHLBI for the COPDGene study; P-R.B. has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Pfizer, Vertex Pharmaceuticals, and Zambon; grants from Boehringer Ingelheim, GlaxoSmithKline and Vertex Pharmaceuticals; H.K.R. has participated in advisory boards for AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, and Sanofi-Genzyme; and has received honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Sanofi, and Teva Pharmaceuticals for independent medical educational presentations; and independent research funding from AstraZeneca, GlaxoSmithKline and Novartis.
Acknowledgments
The authors would like to thank the patients who participated in NOVELTY and the NOVELTY study investigators, who are listed in full in Supplementary Table 7. Medical writing support, under the direction of the authors, was provided by Niall Tyrer, MBiolSci, CMC Connect, McCann Health Medical Communications, and funded by AstraZeneca, Cambridge, UK, in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med 2015; 163:461–464).
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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