Cough in chronic lung disease: a state of the art review

Introduction

Cough is common in a wide range of chronic respiratory diseases (1-5). It is important, not only as a feature of significant disease (such as lung cancer or tuberculosis), but as a symptom due to its effect on the patient. Chronic cough (CC, defined as lasting greater than 8 weeks) of any cause is associated with both significant impairments in quality of life and potentially more severe underlying disease (6-9). Characteristics of cough, such as sputum production and diurnal variation, may vary between diseases, suggesting potentially different underlying mechanisms (10).

Understanding of the physiology of cough has progressed significantly over the last 20 years. The majority of research focused on refractory chronic cough (RCC), defined as CC that persists or has no identifiable cause despite exhaustive investigations and treatment, respectively (11). Important concepts in this context have been cough reflex hypersensitivity (CRH), possibly arising peripherally with sensitisation of airway afferent nerves, and dysregulation of central cough neural networks (12,13). The former is supported by observations of heightened cough reflex sensitivity (CRS) to tussive agents and the symptom profile in RCC, and has led to the hypothesis of cough hypersensitivity syndrome (CHS) (14,15). Meanwhile, recent functional neuroimaging and physiological studies have demonstrated dysfunction of central cough control neuropathways in RCC (16-18).

CRH has also been demonstrated in other chronic respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, interstitial lung disease (ILD) and sarcoidosis (4,19-23). Whilst the mechanism of cough in chronic respiratory disease awaits further evaluation, reports of CRH suggest potential similarities with RCC akin to CHS (12,13,16-18).

The landscape of potentially therapeutic options for RCC is rapidly evolving. Recently, a phase 3 study of the novel antitussive gefapixant, reported very promising results in the disease (16). Gefapixant is a novel antitussive and is postulated to attenuate CRH through direct antagonism of pulmonary C fibres (24). Given the potential mechanistic similarities in cough between RCC and other respiratory diseases, a closer examination of cough in chronic respiratory diseases may reveal shared therapeutic options.

This review will provide an overview of the prevalence, impact on quality of life, mechanism, and management of CC in a range of chronic respiratory diseases. Much effort to date in the understanding of physiology of cough has revolved around CRS, thus this review will focus on CRS mechanistically.

Asthma

Asthma is characterised by airway obstruction, inflammation and hyper-reactivity (25), and affects 12% of the UK general population over their lifetime (26). Of the different asthma phenotypes, cough variant asthma (CVA) and eosinophilic bronchitis (EB) are well described with regards to CC (11,27); what follows will focus more on cough in “classic” asthma rather than focus on CVA and EB.

Prevalence

There is a paucity of studies that report the prevalence of CC in asthma. Studies to date have reported considerably different prevalence of CC in asthma (8% to 58%) (7,28,29) (Tables 1,2). Of note, Osman et al. reported 90 (58%) moderate-severe asthma participants with cough (28), whilst only 70 (8%) of the asthma participants in the Copenhagen General Population Study (CGPS) reported CC (7). The difference in reported prevalence may be attributable to CC definitions employed in these studies. Osman et al. reported cough over 1 week duration whilst the CGPS reported over 8 weeks. In addition, different disease severity, management and study designs may be contributory. Of interest, those with CC were predominantly females in a European study of uncontrolled asthma (n=1,701) (30). This epidemiological similarity with RCC lends support to potential shared mechanistic commonalities with cough in asthma (29,30).

Impact

CC in asthma is associated with increased symptom burden, airway obstruction, exacerbation frequency, and healthcare utilisation (7,29) (Table 3). In the CGPS, asthma participants with CC had higher symptom prevalence (wheeze, dyspnoea, sputum and chest tightness), more severe airway obstruction [forced expiratory volume in 1 second (FEV₁) ≤60%], frequent bronchitis or pneumonia (≥6 episodes in 10 years) and healthcare utilisation [≥3 general practice (GP) consultations in 12 months] compared to those without CC (7). In addition, CC in asthma has been reported to be associated with higher Global Initiative for Asthma (GINA) severity (29), whilst higher objective cough frequency measurements were associated with poorer disease control in a study by Marsden et al. [Asthma Control Questionnaire 6 (ACQ6); r=0.4] (49). The mechanisms of the relationships of cough with exacerbation frequency and healthcare utilisation remain unclear.

Cough in asthma is associated with impaired cough-specific health status, as has been assessed with the Leicester Cough Questionnaire (LCQ, range, 3–21; higher scores indicate better health status) (64). Whilst impaired cough-specific health status in asthma has been reported universally, LCQ health status varies considerably internationally (Table 4). It is unclear why such differences exist though cultural and study design differences may be attributable. Of note, impairment in LCQ health status is similar between asthma patients with CC and non-asthma patients with CC (7,65); from the CGPS, median [interquartile range (IQR)] LCQ 16.8 (14.8–18.9) vs. LCQ 17.4 (15.4–18.9) respectively (7). This suggests that cough is likely an independent contributor to impaired health status in asthma, and has a similar impact on health status to CC in other contexts (28,81). The former is further supported by reports that effective cough management in asthma can yield health status improvement. Fukuhara et al. reported that a reduction in cough frequency (CFreq) with effective treatment was associated with improved LCQ scores (r=0.6) (65). In addition, a separate Japanese study reported improved LCQ with Tiotropium in asthma with CC (66). Taken together, cough in asthma may represent a clinically more severe phenotype with considerable health status impairment, and effective cough-targeted treatment may alter the impact.

Pathophysiology

CRS, assessed with standardised tussive inhalation challenges, is heightened in asthma (22,50,51,82,83). In tussive challenges, C2 and C5 are commonly reported endpoints, and refer to concentration thresholds of tussive agent required to elicit at least 2 and 5 coughs in 15 seconds respectively (82).

Doherty et al. demonstrated CRS was heightened in asthma compared to healthy controls; C5: 62.5 vs. >500 µM (P<0.001) respectively. In addition, CRS was associated with cough severity visual analogue scale (VAS) (r=−0.32) and subjective cough frequency (r=−0.38) (22). Findings of CRH in asthma and associations between CRH and objective CFreq have since been replicated by different authors (22,50,51,82,83) (Table 5).

CRH appears to be associated with disease control and a specific phenotype. Satia et al. reported heightened CRS was associated with poorer asthma control (51). In a separate study, CRH was reported to be associated with worse asthma control, frequent exacerbations (≥2 per annum) and hospitalisation but not FEV₁ (84). In addition, Satia et al. and Kanemitsu et al. both reported heightened CRS was more pronounced in non-atopic compared to atopic disease (51,84).

Taken together, CRH appears to play a mechanistic role in cough in asthma and represents a more severe phenotype though the precise mechanism remains under-explored. Peripheral airway afferent neurones can be sensitised by various inflammatory markers, and potentially lead to heightened CRS. Indeed, serum neutrophils, leukocytes and fibrinogen may be higher in asthma patients with CC compared to those without (7). If CRH was secondary to inflammatory sensitisation in asthma, the agent responsible remains elusive. Eosinophilic airway inflammation does not appear to be the sole driver of cough; neither fractional exhaled nitric oxide (FeNO) nor serum eosinophil count was associated with CRS to capsaicin (51). The relationship between FeNO or eosinophil count with CRS to other tussive agents is under explored. In addition, airway neutrophils, immunoglobulin E (IgE), interleukin (IL)-5, IL-8 and tumour necrosis factor α (TNF-α) seem to not be associated with cough in asthma (7,51-54). The precise mechanism of cough likely involves multiple receptors and neuropathways as in RCC (12,13,16-18).

Management

Inhaled corticosteroid (ICS) is an established treatment in asthma and is recommended in CC to assess response (11). The specific therapeutic effect on cough may not be due to attenuation of CRS—there seems to be no change in the threshold of capsaicin-induced cough with the use of ICS in asthma (22).

Tiotropium and leukotriene receptor antagonists (LTRAs) are also established treatment for asthma. In an observational study of patients with asthma and CC unresponsive to combination inhaled treatment with long-acting beta agonist (LABA) and ICS (n=17), tiotropium was associated with substantial improvements in median cough severity VAS (from 53 at baseline to 26 mm following treatment), LCQ scores (12.8 to 16.3) and asthma control test scores (17.6 to 20.5), with no significant change in FEV₁ (66). In this study, tiotropium was associated with a reduction in CRS in those patients demonstrating improvements in cough severity VAS of ≥15 mm; however, the mechanism for CRS attenuation remains unclear (66).

Two LTRAs, zafirlukast and montelukast, have been shown to improve cough severity VAS and objective cough frequency with no significant change to FEV₁ in two small randomised controlled trials (RCTs) (n=8 and 14) and an observational study (91-93). CRS was improved by both LTRAs through an uncertain mechanism (91,92). Further studies are required to assess the efficacy and mechanism of action of long-acting muscarinic antagonist (LAMA) and LTRAs in CC in asthma (Table 6).

Azithromycin is an immunomodulatory and anti-inflammatory antibiotic (25). In a RCT in RCC the drug was associated with improved cough severity VAS and LCQ compared to placebo in patients with concurrent asthma (n=7) (108). Recently, biological therapies, such as mepolizumab (anti-IL-5), are increasingly employed in the management of asthma (25). The impact of biological therapies on cough in asthma has been under explored to date. In an observational study (n=11), Faruqi et al. reported a reduction in mean 24-hour objective CFreq with mepolizumab over 6 months (94).

Summary

CC is prevalent in asthma, and significantly impairs quality of life. The presence of CC is associated with increased disease severity and poor control. CC is associated with the presence of airway inflammation and may improve with anti-inflammatory treatment. There is heightened CRS in patients with asthma. A clear relationship between airway inflammation and sensitisation of the cough reflex has however not yet been established. Further work should particularly evaluate treatments that target airway sensory nerves.

COPD

COPD affects an estimated 2% of the UK population (4.5% aged over 40) and is associated with considerable impairment in health status (109-112).

Prevalence

In the CGPS, 8,181 (19%) participants had COPD, of which 796 (10%) reported CC (6) (Table 1). Meanwhile, chronic bronchitis (daily cough with sputum for ≥3 months of the year for ≥2 years), as a phenotype of COPD, has been more widely investigated. The estimated prevalence of chronic bronchitis in patients with COPD varies considerably at up to 74% (31-33,113) (Table 2). Meanwhile, Burden of Obstructive Lung Disease (BOLD) study reported the prevalence of chronic bronchitis across 33 international centres (0–10.8%) across the population (34). In BOLD, chronic bronchitis was associated with older age, current smoking, family history of chronic respiratory disease and lower education level (34). In a French secondary care study (n=433), 321 (74%) stable COPD patients reported chronic bronchitis (33). The considerably varied prevalence observed may be secondary to cultural differences, disease severity and study designs.

Impact

CC is a predictor of airflow obstruction in smokers (55), and is associated with significant symptom burden in COPD (6). In the CGPS, COPD participants with CC experienced more breathlessness and sputum production, more acute bronchitis or pneumonia, more healthcare utilisation, and had lower FEV₁ compared to those without CC (6). Meanwhile, there is conflicting evidence on whether CC in stable COPD is predictive of exacerbation frequency (114). Burgel et al. and Seemungal et al. reported that patient-reported daily cough is a predictor of frequent exacerbations, whilst Hurst et al. did not find such an association (33,56,57); the difference perhaps relating in part to the shortcomings of subjective assessments in comparison to objective cough frequency monitoring. Recently, Cho et al. reported that the change in CRS between exacerbation and 6-week recovery was associated with future exacerbation rate (ρ=−0.69) (87) (Table 3).

Cough in COPD is associated with considerably impaired health status (1,115-118) (Table 4). Jones et al. reported cough as one of the top five factors contributing towards impaired COPD-specific health status with the COPD Assessment Tool (CAT) (118). Cough-specific health status LCQ appears to be impaired in stable COPD patients with cough (1,67-69) (Table 4). Of note, the extent of cough-specific health status impairment is similar between COPD patients with CC and RCC (3). Smith et al. reported that nocturnal cough frequency was associated with worse cough-specific health status (r=0.50) in COPD, thus suggesting that cough is likely a determinant of health status in COPD (71).

Pathophysiology

COPD is characterised by airway and systemic inflammation and, as is postulated in asthma, inflammatory mediators can sensitise airway afferent neurones and heighten CRS (119-121). Supporting this idea, several authors have documented CRS to be heightened in COPD compared to health (1,19,22,86), with a possible association with objectively-measured CFreq (1,3,71) (Table 5). As in asthma, eosinophilic inflammation does not appear to be the driver of cough in COPD. Two studies have reported an association between cough frequency and sputum neutrophils, but not eosinophils (1,58).

Recently, Cho et al. reported a heightened CRS both in participants with COPD and CC, and in a separate group with isolated RCC, in comparison to a third group of healthy controls. However, those with COPD were able to voluntarily suppress evoked cough to a much greater extent than patients with RCC (3). In inhaled tussive challenges, threshold capsaicin concentrations to induce cough, with and without attempted voluntary cough suppression, were associated with objective daily cough frequency (ρ=−0.42 and −0.43 respectively) (3). Taken together, CRS likely plays a mechanistic role though the mechanism is poorly understood and is likely to involve neuropathway sensitisation. In contrast, the dysfunction of central voluntary inhibitory neuropathways may play much less of a part in CC associated with COPD than in other contexts (3).

Smoking is strongly associated with COPD but there have been limited attempts to investigate the mechanistic role of smoking in CC in COPD (1,122). Sumner et al. reported that current smoker status was associated with a higher objective daily CFreq in patients with COPD, compared to both those with COPD who were ex-smokers, and current smokers without COPD. However, this difference in CFreq was not reflected in CRS to capsaicin, threshold inhaled concentrations of which were not significantly different between these two COPD groups (1). This raises the possibility that ongoing tobacco smoke exposure exerts its observed effect on daily cough frequency through a different mechanism to that governing capsaicin-evoked cough pathways in COPD.

Management

There is a plethora of established COPD-specific pharmacological and non-pharmacological interventions, though a lacuna remains in cough-specific management (110,111) (Table 6). That Sumner et al. reported COPD current smokers had worse objective CFreq, cough severity VAS scores and cough-specific health status (LCQ scores) compared to COPD ex-smokers (1) reiterates the benefits of smoking cessation in all COPD patients (111).

In terms of pharmacological therapy, a Cochrane review reported that mucolytics such as carbocisteine reduce exacerbation risk and may improve COPD-specific health status (123); however, the efficacy of these medications on cough remains unexplored. Cough has been relatively under explored as an endpoint in terms of COPD inhaled therapy. Doherty et al. reported no relationship between CRS and ICS treatment, whilst CRS was heightened with inhaled anti-cholinergic therapy (22). Smith et al. observed the effects of inhaled medications on objective CFreq in COPD (71). Cough counts were reduced with long acting β2-agonists, increased with inhaled anticholinergics, and unchanged by ICS (71). Azithromycin can be used in COPD patients with frequent exacerbations (111). In a RCT (n=84) of stable COPD patients with chronic bronchitis (FEV₁ <80%), LCQ scores modestly improved with azithromycin compared to placebo (mean difference 1.3 points; P=0.01) (69).

There has been limited success with non-COPD specific pharmacological therapies (Table 6). Codeine is commonly used as an anti-tussive but had no significant impact on cough severity VAS, objective CFreq, or CRS in a placebo-controlled study in COPD (96). Meanwhile, in an observational study of stable COPD (n=49), Rebelo et al. reported significant improvement in LCQ and the Cough and Sputum Assessment Questionnaire (CASA-Q) following pulmonary rehabilitation (67). Whilst promising, further studies are required to evaluate the potential benefit from inhaled therapies, azithromycin, and pulmonary rehabilitation in COPD-associated cough.

Summary

CC is prevalent in COPD and significantly impairs quality of life. The presence of CC is associated with increased symptom severity and worse lung function though the relationship with exacerbation risk remains unclear. CRS is heightened in COPD patients with cough, much like in RCC. However, in contrast to RCC in the absence of other lung disease, the ability to suppress evoked cough in COPD appears intact. The limited evidence on CRS in COPD does suggest that inflammation is potentially mechanistic in cough and disease severity. Further studies should investigate the culprit of CRH and its associations with disease severity in COPD. Treating cough in COPD tends to largely involve treating the underlying disease and has variable success whilst smoking cessation remains critical.

Bronchiectasis

Bronchiectasis is a heterogenous disorder characterised by complex interplay between infection, airway inflammation, failure of mucociliary clearance and airway structural damage (124).

Prevalence

Chronic productive cough is the cardinal symptom of bronchiectasis, and guidelines report a prevalence of over 90% (35) (Table 1). Özgün Niksarlioglu et al. reported cough in 109 (82%) of stable bronchiectasis patients in Turkey (36). In contrast, King et al. reported CC in 101 (98%) patients referred to a specialist bronchiectasis clinic in Australia (37) (Table 2). The cause of these disparities is unclear, and may relate to the aetiology of bronchiectasis, disease severity or treatment, and cultural differences. Regardless, the prevalence of cough in bronchiectasis is high.

Impact

In stable bronchiectasis, cough-specific health status is impaired; LCQ score range, 11.7–16.0 (2,23,59,72-74) (Table 4). In addition, Guan et al. reported significantly worse LCQ health status with increased disease duration, high-resolution computed tomography (HRCT) severity, sputum burden (sputum purulence score and 24 h volume), and Bronchiectasis Severity Index (BSI) score (23). Not only do LCQ scores significantly differ with disease severity, the questionnaire is able to discriminate between mild and severe stable disease [area under the curve (AUC) 0.8 and 0.84 respectively] as per microbiological and radiological criteria (75) (Table 3).

Increased CFreq appears to be associated with cough-specific health status and exacerbation frequency (59). Spinou et al. reported higher objective CFreq in consecutive stable bronchiectasis patients (n=54) compared to health, and CFreq was associated with LCQ score (r=−0.52) (59). Objective CFreq was independently associated with patient-reported sputum severity VAS and one-year exacerbation frequency, but not spirometry [FEV₁ or forced vital capacity (FVC)] (59). In addition, cough may be associated with psychological co-morbidities. Gao et al. reported increased risk of anxiety and depression with raised daytime cough symptom scores [odds ratio (OR) 1.64 and 1.57 respectively] in stable bronchiectasis (76).

Pathophysiology

Bronchiectasis is associated with airway inflammation, and appears to lead to peripheral airway afferent nerve sensitisation and heightened CRS. Torrego et al. and Guan et al. reported heightened CRS in stable bronchiectasis compared to health, and this may relate to disease severity (23,88) (Table 5). Heightened CRS was associated with disease duration, disease severity (BSI and HRCT findings), Pseudomonas aeruginosa colonisation, female sex, increased cough symptom score and worse LCQ scores (23). The studies to date have not investigated the relationship of CRS with objective CFreq or validated subjective cough measures, thus the mechanistic role of CRH remains unclear.

Sputum burden is likely to play a mechanistic role in cough in bronchiectasis, but there are a lack of studies directly exploring the mechanical and chemical stimulation of airway sensory nerves by the excessive sputum load in the disease. Such challenging work is awaited.

Management

Bronchiectasis is a suppurative condition with an increased risk of infection, thus the absolute suppression of cough is not recommended (124). However, much of the excessive cough in the disease may be maladaptive above that which is physiologically helpful to aid sputum clearance. To our knowledge, there is no study that has investigated cough-specific interventions in bronchiectasis and cough severity is perhaps not sufficiently explored as an outcome measure in bronchiectasis. Management of bronchiectasis involves airway clearance, bronchial hygiene, prompt treatment of infections, treatment of any underlying conditions, consideration of regular antibiotics, mucolytics, and pulmonary rehabilitation (124) (Table 6).

Atorvastatin has anti-inflammatory effects and has shown promise in bronchiectasis (97,98). In an RCT (n=82) of stable bronchiectasis, treatment improved LCQ (mean change 1.5) compared to placebo (98). However, in a separate cross-over RCT (n=27) of stable bronchiectasis colonised with Pseudomonas aeruginosa, there was improvement in health status with St George’s Respiratory Questionnaire (SGRQ) but not LCQ scores (97). Further studies incorporating objective cough frequency and cough severity ratings are needed before atorvastatin can be recommended for cough in the disease.

Chest physiotherapy and bronchopulmonary hygiene physical therapy (BHPT) have been shown to benefit cough severity and health status in bronchiectasis (73,74,124); the latter involves patient education and airway clearance technique training. A small RCT of stable bronchiectasis patients naïve to chest physiotherapy (n=20) reported improvements in cough-specific health status after 3-months of twice daily chest physiotherapy using an oscillatory positive expiratory pressure device compared to control (3 months of no chest physiotherapy); median increase (IQR) in LCQ scores 1.3 (−0.17 to 3.25) vs. 0 (−1.5 to 0.5) respectively (P=0.002) (74). In a separate observational study (n=53), cough severity VAS and LCQ scores improved following BHPT; mean difference [95% confidence interval (CI)] VAS 15.8 mm (9.6 to 22 mm) and LCQ 3.1 (2.4 to 3.9) (all P<0.001) (73) (Table 6). Effective airway clearance may therefore lead to an improvement in cough severity and cough-specific health status; however, such therapies should be assessed in larger studies (125).

Summary

CC is highly prevalent in bronchiectasis and significantly impairs quality of life. CC appears associated with increased disease severity and exacerbation risk. There is heightened CRS in patients with bronchiectasis, but the mechanisms of cough remain unclear. There is also limited cough-specific therapy, with chest physiotherapy perhaps having the most evidence.

ILD

ILD encompasses over 300 entities with differing aetiologies and prognoses (126). All ILDs involve a degree of interstitial inflammation and can lead to fibrosis (127). IPF is the most common, accounting for more than 60% of patients (99). To date, most cough literature in ILD relates to IPF.

Prevalence

The reported prevalence of cough in IPF varies between 53% and 89%, and most studies report a rate >80% (8,38-42,127) (Table 1). There are considerable differences in the prevalence of cough amongst different aetiologies of ILD (Table 2). The cause of these disparities remains unexplained but may relate to different definitions of cough and ILD, study design, severity of disease, comorbidities, smoking, and cultural differences. The prevalence of cough in ILD other than IPF is under-investigated. In a cross-sectional study of ILD (n=164), 72% of all participants reported cough; 81% in IPF, 66% in connective tissue disease ILD, and 71% in non-specific interstitial pneumonia (42). In systemic sclerosis-associated interstitial lung disease (SSc-ILD), cough is reported in 61–71% of patients (41,43,44). In a small observational study (n=32), cough was reported in 83% of chronic hypersensitivity pneumonitis (HP) (41).

Impact

CC in IPF is associated with disease severity and health status impairment (8,40,41,60,61,128), though again few studies have explored this in other ILDs (Tables 2,5). CC in IPF and cough severity VAS scores (r=0.2) were associated with impaired SGRQ in an Australian national observational study (n=516) (40). In an US IPF registry analysis, self-reported cough was associated with disease severity according to symptoms, exertional desaturation and lung function, and progression but not prognosis or transplantation (8). In addition, Lan et al. reported participants with ILD and cough had more severe disease as measured by FEV₁, FVC, gas transfer factor [diffusing capacity of the lungs for carbon monoxide (DLCO)], 6-minute walk test and physician assessment compared to ILD participants without cough (42).

Cough-specific LCQ health status is impaired in ILD with a reported range of 14.9–16.5 (maximum possible score 21) (6,43,60,61,77) (Table 4). A UK prospective study of IPF (n=484) reported impaired LCQ scores were associated with higher medical research council (MRC) dyspnoea scores but not lung function or mortality (60). In contrast, Lee et al. reported impaired LCQ was associated with increased mortality, hospitalisation, and lung transplantation in a study of the US Pulmonary Fibrosis Foundation registry (n=1,447; 61% IPF) (61). Every 1-point decrease in LCQ score was associated with a 7.4% increased risk of mortality at 12 months; hazard ratio (HR) (95% CI) 1.074 (1.020–1.130, P=0.006). The different disease groups investigated in the studies may be attributable to the contrasting findings. Of note, LCQ scores were not significantly different between ILDs, and there was no association with lung function decline (61).

Outside of IPF, self-reported cough was associated with impaired LCQ, breathlessness and disease severity (DLCO and radiological features) in two separate studies in SSc-ILD (43,44). Recently, Cheng et al. reported greater patient-reported cough severity (VAS) in IPF compared to both chronic HP and SSc-ILD; median (IQR) VAS 39 [17–65] vs. 29 [11–48] vs. 18 [0–33] mm respectively (P<0.01) (41).In addition, worse lung function (FEV₁, FVC, DLCO) and dyspnoea score were predictors of cough in IPF, chronic HP and SSc-ILD (41). The impact of cough should be investigated in large studies in individual ILDs.

Pathophysiology

ILD is associated with inflammation and interstitial distortion, which may lead to cough through sensitisation and stimulation of both chemoreceptors and mechanoreceptors, respectively (43,129). To our knowledge, there is no study that has directly investigated the role of mechanoreceptors in cough in ILD. However, Jones et al. reported that indirectly activating mechanoreceptors by chest wall percussion evoked cough in 85% of patients with IPF (n=27) compared to 17% of healthy controls (130). As in other respiratory diseases, effort in understanding the mechanisms of cough has largely focused on CRS, and such effort has borne fruit to some extent.

Heightened CRS to inhaled capsaicin and substance P has been observed in IPF and SSc-ILD compared to healthy volunteers (21,89) (Table 5). The mechanism of such CRH in ILD is unclear, though it appears to be associated with pathophysiology of the lung disease itself rather than, for example, generalised systemic inflammation. Supporting this idea, in a study of subjects with progressive systemic sclerosis, Lalloo et al. reported significantly higher cough severity VAS and heighten CRS to capsaicin in participants with associated ILD compared to those without (90).

Despite the demonstration of heightened CRS in ILD, the extent to which hypersensitivity drives cough in this group is not certain. The profile of cough in ILD is similar to that in RCC; similar self-reported laryngeal sensations and triggers are common to both contexts, including airway irritants (smoke, aerosols, fumes), talking, exertion and position change (42,131). On the other hand, the studies above did not explore the associations of CRS with cough severity VAS or objective cough frequency to consolidate the concept of CRH in cough in ILD (21,89).

Management

ILD-associated cough is often refractory to treatment (5,8,132), and in this context most cough-specific therapies have only been investigated in IPF (Table 6). With ILD associated with inflammation and heightened CRS, much effort has understandably been invested in assessing the efficacy of immunomodulatory therapies in ILD-associated cough.

Various immunomodulators have been investigated in IPF-associated cough, and the results have been largely disappointing (133). In a small study of IPF with cough (n=6), prednisolone was associated with improvement in CRS and cough severity VAS (89). However, long-term corticosteroid treatment in IPF does not improve prognosis and is associated with considerable morbidity (134). Thalidomide is a potent immunomodulatory and anti-inflammatory drug, and was associated with improved cough severity VAS, Cough Quality-of-Life Questionnaire (CQLQ), and SGRQ scores in a cross-over study of IPF-associated cough (99). Unfortunately, thalidomide was also associated with substantial adverse event rates (77%), such as constipation and dizziness, which might limit clinical application (99,135). Azithromycin, an immunomodulatory and anti-inflammatory antibiotic, has demonstrated benefit in various cough metrics in sarcoidosis and COPD (69,78). However, a small RCT of the drug in IPF (n=25) demonstrated no improvement in LCQ, cough severity VAS, or objective CFreq (100). Inhaled sodium cromoglycate, a mast cell degranulation inhibitor which can inhibit C-fibre sensory nerve activity, significantly improved cough severity VAS, LCQ and objective CFreq in IPF in an initial small RCT (n=24) (136). However, these findings were not reproduced in a subsequent larger scale study (n=81) of longer duration (12 weeks vs. 14 days) (101). A large initial placebo effect is frequently observed in cough trials which may explain the differing findings in these studies (137). The mostly disappointing findings above perhaps reflect our limited understanding of cough physiology in ILD, thus impeding the development of targeted therapy.

To our knowledge, pirfenidone is the only disease attenuating therapy that has been investigated in relation to cough. Pirfenidone, an antifibrotic agent (138), significantly improved cough severity VAS, LCQ and objective CFreq in IPF in an observational study (n=43) (102), but the findings need to be replicated in larger randomised studies.

Therapies with demonstrated efficacy in isolated RCC have been investigated in IPF, though with limited success (Table 6). Gastro-oesophageal reflux disease (GORD) is a potential cause of CC and a common co-morbidity in ILD (127). However, omeprazole had no significant effect on objective CFreq or patient-reported outcomes, including LCQ scores, in an RCT (n=45) of patients with IPF (77). The P2X3 inhibitor gefapixant improved cough severity diary (CSD) score, but had no effect on cough severity VAS scores, CQLQ score or objective CFreq in a cross-over RCT (n=51) in IPF (103). This suggests the ATP/P2X pathway is less important in CC associated with IPF than in RCC in other contexts. Meanwhile, two separate RCTs are underway, nalbuphine (a mixed opioid agonists/antagonist) and morphine for CC in IPF, and early results are promising (139,140).

Outside of IPF, there are some early promising findings regarding the efficacy of systemic treatment of cough in ILD. In post-hoc analyses of two studies investigating cyclophosphamide and mycophenolate in SSc-ILD, the drugs were associated with significant improvements in self-reported cough (43,44). These observations however require further confirmation, and neither cyclophosphamide nor mycophenolate are currently recommended for cough in SSc-ILD (133).

Summary

CC is highly prevalent in ILD and significantly impairs quality of life. CC may be associated with increased disease severity, mortality and lung transplantation. The symptom profile of cough and the demonstration of CRH in ILD suggest similar specific underlying physiological processes to those governing cough to in ‘classical’ RCC (in the absence of other lung disease). The lack of therapeutic response to P2X3 antagonist in ILD however casts doubt on this idea. Investigations of therapies for cough in ILD have enjoyed the most success with immune and inflammatory modulating therapies, albeit in early exploratory studies, perhaps suggesting specific immune and inflammatory pathways as culprits for further attention.

Sarcoidosis

Sarcoidosis is an idiopathic multisystem granulomatous disorder which commonly affects the lungs, skin, and eyes. It is more common in African-Caribbean populations with both genetic and environmental factors playing a role in susceptibility (141).

Prevalence

Cough prevalence in sarcoidosis varies geographically, ranging from 3% in Japan, 33% in Finland, to 48–64% in Saudi Arabia and Europe (4,45-48) (Table 1). A paucity of studies investigating the prevalence and predictors of cough in sarcoidosis mean the mechanism of this geographical variation remains unexplained (Table 2).

Impact

Cough in sarcoidosis appears to be associated with other symptoms of the disease. Kovacova et al. reported that self-reported cough was associated with concurrent dyspnoea, fever, and chest pain, but not arthralgia or erythema nodosum in a retrospective study (47). Presence of cough has also been associated with lower FEV₁ and FVC values, but not radiological staging of thoracic sarcoidosis (Scadding), sex, or smoking status (47). Recently, Sinha et al. demonstrated that objective CFreq was higher in patients with sarcoidosis (n=32) compared to healthy volunteers, and correlated with the subjective markers cough severity VAS (r=0.62) and LCQ scores (r=−0.61) (4) (Table 3).

Cough-specific health status is impaired in sarcoidosis; the reported range of LCQ scores is between 14.8 and 16.9 in a secondary care setting (4,78-80) (Table 4). Judson et al. reported more severe cough (VAS) and worse LCQ health status in consecutive black patients compared to white patients, and more severe cough (VAS) in females (80). In addition, cough severity and health status were not associated with age, lung function, radiological severity, or smoking status (80).

Pathophysiology

Few have investigated the mechanisms of cough in sarcoidosis to date. Postulated mechanisms include airway inflammation or hyper-responsiveness, interstitial distortion, vagus nerve disruption, laryngeal and vocal cord involvement, granulomatous infiltration of the pulmonary vasculature, and heightened CRS (63,142).

Kovacova et al. reported that cough in sarcoidosis was associated with more positive endobronchial findings compared to those without cough (43% vs. 12% respectively) in the absence of cough-relevant co-morbidities (47). In addition, cough was associated with airway neutrophilia, but not lymphocyte counts, eosinophils, or CD4⁺:CD8⁺ ratios (47). In a retrospective study of tracheal biopsy in sarcoidosis, Ding et al. reported more self-reported cough in patients with tracheitis compared to those without (92% vs. 49% respectively) (63). Taken together, endobronchial sarcoidosis and airway neutrophilic inflammation are associated with cough though the precise mechanism remains unexplored.

The potential role of levels of serum angiotensin converting enzyme (ACE) in cough is conflicting (4,79). Sinha et al. reported heightened CRS was associated with lower serum ACE level (r=0.72) though there was no association between serum ACE and objective CFreq (4,62). Meanwhile, Gvozdenovic et al. reported lower serum ACE was associated with better LCQ health status in an observational study (n=275) (79).

Heightened CRS may play a mechanistic role in sarcoidosis-associated cough (Table 5). Sinha et al. reported heightened CRS in sarcoidosis compared to health, and capsaicin thresholds were associated with objective CFreq (r=−0.64) (4). Indeed, the profile of cough triggers in sarcoidosis were suggestive of CRH, and included smoky atmosphere (54%), tickle sensation in the throat (49%), perfume and scents (44%). In addition, objective CFreq was not associated with lung function (FEV₁, FVC, DLCO), number of organs involved, immunosuppressive treatment or radiological staging, thus suggesting CFreq and mechanism of cough are independent of disease severity (4).

Management

Few therapeutic options have been investigated in sarcoidosis-related cough (Table 6). Systemic corticosteroid is often indicated in sarcoidosis, although no specific trials for cough exist to our knowledge (143). Meanwhile, ICSs are ineffective in sarcoid-related cough as per three different RCTs (n=21, 29 and 44) (104-106). ICSs are therefore not recommended for cough in the disease (133).

Further uncontrolled studies of potential treatments for cough in sarcoidosis have shown promise but need RCT evaluation. Nebulised vasoactive intestinal peptide (VIP), a neurotransmitter with anti-inflammatory and immunomodulator properties, appeared to have efficacy in an open label phase 2 study (n=20) (107). Bronchoalveolar TNF-α levels were significantly reduced following inhalation of the drug, and nine (75%) patients who received it reported amelioration of their CC (107). Recently, azithromycin significantly reduced objective CFreq in a non-controlled, open-label clinical trial (n=21); median cough frequency 228 vs. 81 coughs over 24 hours before and after three months of treatment (78). In addition, cough severity (VAS) and LCQ health status improved significantly, and CFreq improvement was associated with improvement in LCQ scores (r=−0.64) (78). The findings from these exploratory studies clearly need confirmation.

Summary

CC is prevalent in patients with sarcoidosis although the range is large and varies with geographical region. The presence of CC impacts on quality of life. There appears to be a relationship between CC and endobronchial disease, and symptoms in sarcoidosis. However, a relationship with disease severity or progression has not been reported. CC is associated with airway inflammation in sarcoidosis. Further studies are needed to evaluate if treating this inflammation improves cough. There is heightened CRS in patients with sarcoidosis. The relationship between this and sarcoidosis outcomes has not been well studied.

Future directions

CC is common in chronic respiratory diseases and frequently associated with impaired health status. Despite this, in chronic respiratory conditions, a paucity of studies have investigated the prevalence and predictors of CC and, unlike isolated RCC in the absence of other respiratory disease (144), no study has investigated cough-related healthcare utilisation and cost. Further investigations may reveal its true burden in a wide breath of respiratory diseases. Such studies will help to effectively direct future research efforts.

In the general field of CC, notable advancements in the understanding of neuropathophysiology have been made (13,18,145). Functional neuroimaging has provided novel insight into central mechanisms (18,122), whilst clinical and preclinical models have illuminated peripheral processes (13,145). In turn, effective pharmacological and non-pharmacological therapies, neuromodulators and speech pathology management respectively, have been developed for the management of RCC (146-149). In contrast, with limited investigations to date in most cases, the specific (additional) mechanisms of cough which may be unique to particular chronic respiratory diseases remain enigmatic. At present this is limiting options for treatment.

Potential avenues for investigating cough associated with chronic respiratory diseases may come about from a closer examination of the mechanisms of RCC. Indeed, such an approach has borne fruit; investigations into CRS have demonstrated an element of CRH in many chronic respiratory diseases (Table 5). Belvisi et al. demonstrated that different respiratory diseases have different cough reflex profiles with different tussive agents, thus proposed the idea of different ‘neurophenotypes’ of cough amongst respiratory diseases (83). Indeed, the differing CRS profiles between diseases may suggest different pathophysiology of cough. Further studies to investigate the CRS profile and mechanism of CRH in different respiratory diseases may provide insight into the potential for novel antitussives such as P2X3 inhibitors (16,150). Further understanding into the phenotypes of cough in different respiratory diseases may also enable individualised disease-specific treatment.

Recently, dysfunctional central voluntary cough suppression has been reported in RCC (13,18). Of note, in contrast to RCC, COPD patients with cough were able to voluntarily suppress an evoked cough despite presence of CRH in both conditions (3). This phenomenon lends further support to the concept of distinct phenotypes of cough, with different mechanisms, in different chronic respiratory diseases. In addition, it is not possible to simply extrapolate our understanding between RCC and other chronic respiratory diseases. Indeed, the central cough neural mechanisms remains enigmatic in both RCC and other diseases.

Conclusions

CC is a common symptom in chronic respiratory disease and is frequently associated with worse disease-specific outcomes and impaired health status. The mechanisms of cough in these diseases remain poorly understood. There is some evidence to suggest CRH may play a mechanistic role in diseases other than RCC. This is of particular interest given the findings of the recent phase 3 study of gefapixant, known to reduce CRS to adenosine triphosphate (16,24). Further studies should investigate the impact of cough in other respiratory diseases, including healthcare cost, to guide more directed interventions. In addition, a better understanding of the neurophysiology of cough in other diseases may help to identify specific avenues of investigation for potential novel therapies, and may extend the useful indications for new drugs developed initially for RCC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Woo-Jung Song and Kian Fan Chung) for the series “Novel Insights into Chronic Cough” published in Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1776/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1776/coif). The series “Novel Insights into Chronic Cough” was commissioned by the editorial office without any funding or sponsorship. SSB has received personal fees for consultancy from Merck, Bellus, Trevi, Genentech, Nerre, Kinevant, Boehringer Ingelheim and Bayer. PSPC reports two ongoing grants: EPSRC and MERCK, outside of the submitted work. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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