Is the Symptom of Cough in Chronic Obstructive Pulmonary Disease Important?

Abstract

Chronic obstructive pulmonary disease (COPD) is a common disease and a significant burden worldwide. The clinical symptoms of this disease include progressive dyspnea, cough, expectoration, and wheezing, among others. At present, the primary focus has been on reducing the frequency of acute exacerbations and improving lung function and dyspnea symptoms, and limited attention has been paid to cough and expectoration symptoms, which may be associated with a decrease in lung function, more acute exacerbations, and hospitalizations. Therefore, this outcomes in patients with COPD.

Keywords:

• COPD
• cough
• quality of life
• mortality

Introduction

Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide. According to the World Health Organization, COPD ranks fifth among all-cause deaths, and many scholars predicted that it would rise to third by 2020 [1]. The mortality rate of COPD ranks third among chronic diseases in China, and disability and morbidity rates are increasing every year, seriously affecting patients’ quality of life and increasing the economic burden on society [2,3]. The prevention and treatment of this disease has, therefore, become an urgent problem [4]. The clinical symptoms of COPD include progressive dyspnea, cough, expectoration, and wheezing, among others. At present, most of the focus has been on reducing the frequency of acute exacerbations and improving lung function and dyspnea symptoms; limited attention has been paid to cough and expectoration symptoms.

The duration of cough can be divided into three categories: acute (<3 weeks), subacute (3–8 weeks), and chronic cough (>8 weeks). One potential cause of chronic cough is COPD [5,6]. Chronic cough and the hypersecretion of mucus have been reported to be associated with an accelerated decline in lung function, more frequent deterioration, and hospitalizations, all of which affect patients’ quality of life. This article aimed to review cough-related outcomes in patients with COPD.

Methods

We searched PUBMED, EMBASE, CENTRAL, LILACS, CBM, CNKI, and VIP from 1998 to 2020 for clinical studies concerning epidemiology and the effect of cough on COPD patients. The following keywords were used: ‘COPD’, ‘cough’, and ‘expectoration’, AND ‘lung function’, ‘quality of lives’, ‘acute exacerbation’, ‘evaluation of cough’ or ‘cough treatment’. The reference lists of identified articles were also searched to find additional relevant publications. Only articles published in English on adult patients with COPD were considered. Of the 447 studies identified, 247 were excluded after applying the exclusion criteria to the Title or Abstract. A further 155 articles were excluded after fully screening the text. A total of 45 articles were thus included in this review (Figure 1).

Figure 1. PRISMA flow diagram explaining the screening process of citations and number of articles included in the review.

Epidemiology of COPD

COPD is characterized by respiratory symptoms and persistent airflow limitations; therefore, lung function testing is an essential tool for diagnosing and evaluating its severity [2]. According to ‘The Global Burden of Disease 2015’, from 1990 to 2015, the incidence of COPD increased by 44%, and the death rate increased by almost 11%, indicating that the prevalence and mortality of COPD are rapidly increasing worldwide [7]. With this trend, COPD will be the third leading cause of death worldwide by 2020 [1].

The Spanish guidelines concerning COPD propose four different phenotypes: infrequent exacerbators with either chronic bronchitis or emphysema (non-exacerbator, NON-AE), frequent exacerbators with emphysema predominant, frequent exacerbators with chronic bronchitis predominant (FE-CB), and asthma-COPD overlap (ACO) [8]. FE-CB is a common and important clinical phenotype in COPD and is classically defined as chronic cough and sputum production for 3 months per year, for two consecutive years [9]. Multiple studies have shown that the FE-CB phenotype may be associated with increased mortality and an increased risk of exacerbations [10,11]. Additionally, numerous studies have shown that chronic cough and expectoration in COPD patients are associated with worse lung function [12–14] and quality of life [15–20], more frequent acute exacerbations [21–23], and higher mortality [14,24,25]. Therefore, for COPD patients, focusing on cough symptoms is hugely important.

The effect of cough on COPD

Frequency of cough and expectoration in COPD

Cough and expectoration are common symptoms of COPD, with an incidence of 14–74% [15,21,26], they usually persist for many years and sometimes occur before dyspnea. A survey in the Asia-Pacific region found that nearly half of COPD patients visited the hospital for the first time because of cough and sputum symptoms [27].

The impact of cough and expectoration on quality of life in COPD patients

The Saint George’s respiratory questionnaire (SGRQ) total score is a recognized scale for evaluating quality of life in COPD patients.

Deslee et al. found in their multicenter study that the more severe the cough and expectoration symptoms were in COPD patients, the higher their total SGRQ score and the worse their quality of life [20]. Koo et al. also found that among the 1613 patients with COPD studied, 37.6% had cough and/or expectoration and their total SGRQ scores and scores of all sections higher than those of COPD patients without cough and expectoration, indicating a significant decline in quality of life [16].

In a study by Stephenson et al., more than two-thirds of the patients studied complained that cough, which appeared in the morning and night, was the most common symptom, and more than half of the patients described sleep disturbance and anxiety due to cough intolerance. Additionally, approximately one-third of the patients could not concentrate on work because of symptoms such as coughing [17]. Similar findings by Kessler et al. have also been reported [28].

In addition, multiple studies have also shown that urinary incontinence is more common among COPD patients than among the general population [18–20], with an odds ratio (OR) ranging from 1.53 to 5.55 [29]. To clarify the relationship between cough and urinary incontinence in COPD patients, Hrisanfow et al. enrolled 728 patients with COPD (female/male: 391/337) and found that 30.3% of the female and 49.6% of the male patients had urinary incontinence. The clinical COPD questionnaire (CCQ) used in this study showed that COPD patients with urinary incontinence had more severe cough and sputum symptoms than patients without urinary incontinence [30]. Therefore, the authors hypothesized that severe coughing leads to increased abdominal pressure, which is the main cause of stress urinary incontinence in COPD patients. Therefore, for COPD patients with stress urinary incontinence, it is particularly important to control cough [31].

The effect of cough and expectoration on lung function

Bridevaux et al. randomly enrolled 8282 non-asthmatics and tested their lung function. After 11 years of follow-up, they tested the subjects’ lung function again. The results showed that the decrease in FEV1 in patients with stage 1 COPD without cough and sputum was not significantly different from that in healthy people, while it was significant in patients with symptomatic stage 1 COPD. However, there was no significant difference in the decrease in FEV1 in patients with stage 2–4 COPD regardless of the presence of cough and sputum. It is evident, therefore, that cough and expectoration accelerates the decline in FEV1 in patients with early COPD [19]. Therefore, additional attention should be paid to the control of cough and sputum symptoms in such patients.

De Marco et al. found that the incidence of COPD in normal people with chronic cough was three times higher than that in asymptomatic people. Moreover, the FEV1 in COPD patients with cough and expectoration was significantly lower than that in COPD patients without cough and expectoration. Therefore, the authors pointed out, the appearance of chronic cough and sputum may be an early sign of those at high-risk of developing COPD, and symptom appearance could accelerate the decline in FEV1 [13]. Putcha et al. found that the decrease in FEV1 was greater when cough and expectoration were both present compared to that in asymptomatic COPD patients, even though the individual symptoms were not associated with the decrease in FEV1 [14].

Effects of cough and sputum on acute COPD exacerbation

In their study, Koo et al. included 1613 COPD patients, of which 18.2% had cough and expectoration symptoms, 14.3% had only sputum, 5.2% had only a cough, and 62.4% had no cough or expectoration symptoms. Through univariate and multivariate analyses, the OR values of acute COPD exacerbation (AECOPD) caused by cough and expectoration were found to be 1.52 and 1.56, respectively [10]. Additionally, other studies have also shown that accompanying cough and expectoration symptoms increase the risk of AECOPD [21–23]. Therefore, cough and expectoration may be risk factors for AECOPD.

Why are COPD patients with cough and sputum more prone to acute attacks than those without these symptoms? In one study, Berkhof et al. treated stable COPD patients with low-dose azithromycin, and cough-related quality of life improved after treatment, accompanied by a decrease in the contents of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in sputum [32]. Putcha et al. also showed that COPD patients with cough and sputum symptoms have an increased likelihood of suffering from lower respiratory tract infections [14]. Therefore, we believe that cough may be associated with the colonization of bacteria in the lower airway. During the stable phase, such patients have a small amount of bacteria in the lower airway, resulting in chronic cough and expectoration, and acute attacks occur once the bacteria proliferate to a certain extent. Landt et al. found that COPD patients with cough and expectoration have elevated levels of inflammatory mediators, such as C-reactive protein, leukocytes, neutrophils, and eosinophils, in the peripheral blood and have an increased likelihood of suffering from acute exacerbations of chronic bronchitis, pneumonia, and other diseases over a 10-year period [23]. We speculate, therefore, that the elevated levels of inflammatory cells and inflammatory factors in peripheral blood may be a response to bacterial colonization of the lower airway.

Influence of cough and sputum on COPD mortality

Ptucha et al. followed 5887 patients with mild to moderate COPD, divided them into four groups (patients with cough and sputum symptoms, those with no cough or sputum symptoms, patients with only cough symptoms, and those with only sputum symptoms), and followed them up for 12.5 years for mortality. The results showed that, compared with asymptomatic patients, the risk of mortality in patients with chronic cough and expectoration was 27% higher. Additionally, for COPD patients, cough symptoms were associated with a higher risk of mortality compared with dyspnea and asthma symptoms [14]. Lindberg also found that COPD patients with cough and sputum symptoms had a higher risk of mortality than asymptomatic COPD patients [24]. A study by Ekberg-Aronsson showed that, in smoking patients with COPD stage 1–2, the risk of mortality for those with cough and expectoration symptoms was much higher than that for those without cough or expectoration symptoms; however, there was no obvious difference in patients with stage 3–4 COPD. Therefore, we should pay attention to the symptoms of cough and expectoration in patients with early-stage COPD [25].

Evaluation of cough in COPD

Chronic cough has a serious negative impact on COPD patients; therefore, a thorough evaluation of cough symptoms and timely intervention and follow-up can prevent the occurrence of AECOPD and reduce hospitalization and mortality rates.

Cough and sputum assessment questionnaire

The cough and sputum assessment questionnaire (CASA-Q) is used to evaluate the severity of cough and expectoration symptoms of COPD patients and their impact on quality of life. The CASA-Q includes four aspects (20 items), namely, cough severity (3 items) and its impact on quality of life (8 items) and severity of expectoration (3 items) and its impact on quality of life (6 items). The higher the score, the less severe the symptoms of cough and expectoration and the lower their impact on quality of life. Monz and his colleagues confirmed the effectiveness of the CASA-Q in evaluating COPD cough and sputum symptoms [33].

Hull automated cough counter and Leicester cough monitor

The Hull automated cough counter and Leicester cough monitor (HACC/LCM) hybrid cough monitoring system is a cough detection system that functions by recording ambient sound through a remote microphone and analyzing cough frequency through a semiautomatic cough classifier. Crooks and others used this equipment to record changes in cough frequency in AECOPD patients 1, 5, 20, and 45 days after hospital discharge to monitor changes in trends of cough frequency. The authors speculated that by observing the cough frequency in COPD patients, changing conditions in discharged patients could be monitored remotely [34].

Leicester cough questionnaire

The Leicester cough questionnaire (LCQ) was originally created to evaluate the impact of cough symptoms on the quality of life of people with chronic cough; however, Berkhof et al. found that it could also be applied to COPD patients to evaluate the impact of cough and expectoration on their quality of life. The LCQ includes three aspects: physical, psychological, and social. The total score ranges from 3 to 21, and the higher the score, the higher the patient’s quality of life. The study found that the total change in the LCQ score could also predict changes in patients’ health after 12 weeks [35].

Other methods

Breathlessness, cough, and sputum scale

The breathlessness, cough, and sputum scale (BCSS) is a comprehensive evaluation of dyspnea, cough, and expectoration. This questionnaire requires COPD patients or their family members to recall symptoms that occurred one week before an acute exacerbation. For the BCSS, the severity of dyspnea, cough, and expectoration are assessed on a scale from 0 (asymptomatic) to 4 (severe symptoms) [36].

Early morning and nighttime symptoms of COPD

For the early morning symptoms of COPD (EMSCI) and nighttime symptoms of COPD (NISCI), information on the frequency of cough and expectoration symptoms and their impact on quality of life is recorded on daily electronic diaries. By evaluating symptoms such as cough, expectoration, and dyspnea, the EMSCI and NISCI can be used to more effectively prevent AECOPD and guide clinical treatment [37,38].

Exact-respiratory symptoms evaluation

The EXACT-respiratory symptoms (E-RS) includes 11 respiratory symptoms based on dyspnea, cough and sputum, and chest symptoms. The higher the E-RS score, the more severe the symptoms [39].

Treatment of cough in COPD

Long-acting muscarinic antagonist

Long-acting muscarinic antagonists (LAMAs) are the cornerstone of COPD treatment, but research on the therapeutic effect of LAMAs on cough is limited.

McGarvey et al. enrolled 1792 COPD patients and evaluated daily cough and expectoration symptoms using E-RS scores. They found that, compared with placebo, 12 weeks of aclidinium treatment could effectively reduce the frequency and severity of nighttime cough and increase the number of days without daytime cough and expectoration symptoms [40].

Tagaya et al. used tiotropium (18 μg/day) on 22 COPD patients with cough and sputum symptoms. After 8 weeks of treatment, cough and expectoration symptoms had significantly improved. Additionally, they found that the content of solid components and mucin in the sputum had decreased, so the authors speculated that tiotropium might reduce the occurrence of cough and expectoration by inhibiting airway mucus secretion and increasing the rate of mucociliary clearance [41].

Fluticasone propionate

A multicenter randomized control trial (RCT) included 281 COPD patients who were treated with fluticasone (500 µg twice per day) or placebo for 6 months. The cough score in the steroid treatment group was significantly lower than that in the placebo group, accompanied by a reduction in the number of moderate to severe acute attacks [42]. Calverley et al. found that among salmeterol, fluticasone, and placebo alone, the combined use of salmeterol and fluticasone could provide greater improvement in cough symptoms in COPD patients [43]. Although inhaled corticosteroids (ICSs) are currently recommended only for COPD patients with asthma, recurrent acute exacerbations, and elevated peripheral eosinophil levels, it was found from the above studies that ICSs could be prescribed for COPD patients whose cough was not responsive to other medications, such as dilators. Based on the above research, E-RS guidelines for cough recommend a short-term trial (2–4 weeks) of a combination of ICSs and long-acting bronchodilators in adult COPD patients with chronic cough [5].

Lidocaine and terbutaline

Chong et al. enrolled 62 and 65 COPD patients into two groups who received lidocaine and terbutaline atomization, respectively. Cough in both groups was significantly improved after treatment. However, the incidence of oropharyngeal numbness and bitter side effects in the lidocaine group was significantly higher than that in the terbutaline group, while the incidence of atrial fibrillation and palpitation in the terbutaline group was higher than that in the lidocaine group [44].

Azithromycin

Berkhof et al. studied the effect of low-dose azithromycin on the quality of life of COPD patients with cough and expectoration. The study included 84 patients with stage 2–4 COPD with cough and sputum who were given azithromycin 250 mg/dose (3 times/week) or placebo for 12 weeks. The results showed that the LCQ score in the azithromycin intervention group was significantly higher than that in the control group. It has been suggested that azithromycin can improve cough and expectoration [32]. In addition, independent of their antibiotic properties, macrolides have been shown to reduce neutrophil elastase-induced mucus stasis, suggesting potential benefits for chronic bronchitis.

Potential treatment

DT-0111, a P2X3 receptor antagonist, was found to inhibit the activation of nodose pulmonary vagal afferents by ATP in vitro and relieve ATP-induced cough in guinea pigs. Cough is a common symptom of COPD, therefore, the authors believed that DT-0111 might be an attractive drug-candidate for the treatment of cough in COPD [45].

Conclusion

COPD is a global concern; therefore, the treatment of COPD is a critical topic worldwide. Cough has a significant impact on quality of life and changes in disease status in COPD patients. Chronic cough and expectoration in COPD patients are associated with worse lung function and quality of life, more frequent acute exacerbations, and higher mortality. Therefore, it is crucial that more attention be paid to cough symptoms. At present, its influence on COPD patients is not clear, and the cause-and-effect relationship between cough and COPD prognosis has not been established. Therefore, further research in this area is necessary.

Declaration of interest

The authors declare no conflict of interest.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (No. 82070102 and 81770097), the Project of Science and Technology Commission of Shanghai Municipality (No. 20ZR1451500 and 17411970800), the Fund of Shanghai Youth Talent Support Program, the Fund of Shanghai Municipal Health Commission for Excellent Young Scholars (No. 2018YQ01), and the Shanghai Sailing Program (No. 19YF1444100).