Introduction
The incidence of chronic cough ranges from 9% to 33% of the adult population [
1,
2]. The most common aetiologies for chronic cough in non-smokers are upper airway cough syndrome (UACS), gastro-oesophageal reflux (GERD) and asthma, all of which are empirically treated [
2,
3]. However, the aetiologies of 12% to 42% of coughs are unexplained despite thorough evaluation [
4]. Therefore, it is important to explore other possible aetiologies for chronic cough. A recent study reported four patients with unexplained chronic cough who were found to have obstructive sleep apnoea (OSA). Moreover, a prospective study also reported that of 108 patients being referred to sleep clinics for sleep disordered breathing, 33% had a co-existing cough [
5], which suggests an association between chronic cough and OSA. In addition, another study reported that 44% of patients with chronic cough had OSA, 93% of whom demonstrated a significant improvement in cough with continuous positive airway pressure (CPAP) treatment [
6]. The mechanism between chronic cough and OSA is still not clear, although GERD, UACS and airway inflammation have been proposed to be involved [
7]. However, studies on these topics have lacked an adequate control group or included a small sample size [
5‐
7]. Therefore, the aim of this study was to evaluate the prevalence of chronic cough and the associated factors in patients with OSA, and the effect of CPAP treatment.
Discussion
This study demonstrated that the prevalence of chronic cough was significantly higher in the OSA group. In univariate analysis, AHI and GERD were significantly associated with chronic cough. In multivariate analysis, GERD was the only factor associated with chronic cough, which was significantly improved after CPAP treatment. To the best of our knowledge, this is the first study to report an association between chronic cough and OSA.
The most common etiologies of chronic cough are GERD, rhinosinusitis, and asthma [
13]. Recently, several reports have suggested an association between chronic cough and obstructive apnoea [
5‐
7]. Chan et al. reported that the prevalence rate of chronic cough in OSA patients is up to 33% [
5], which is much higher than that in the general population [
14,
15]. In Chan et al’s study [
5], both GERD and rhinitis played important roles in chronic cough, however, there was no control group and the number of cases was relatively small. In the present study, the prevalence of chronic cough in the patients with OSA was 38.6%, which is similar to the results of Chan et al. [
5]. In addition, the number of cases in the present study was larger, and most importantly, the present study enrolled a control group. Compared to the control group, the incidence of chronic cough was significantly higher in the OSA group. Interestingly, the incidence of GERD was also significantly higher in the OSA group, but not UACS or asthma.
GERD is known to be an important aetiology of chronic cough, and a higher prevalence of GERD is expected in patients with OSA due to large intrathoracic negative pressure swings during apnoea episodes aggravating the severity of GERD [
16]. Several sleep lab-based studies have reported incidence rates of GERD in OSA patients ranging from 64.7% to 100% [
17‐
19]. In a large cross-section epidemiology study, subjects with nocturnal GERD had a significantly higher incidence of OSA than those without nocturnal GERD (16% vs. 5%). Nasal CPAP has been shown to reduce GERD in patients with OSA [
19,
20], suggesting a strong relationship between GERD and OSA. In the present study, only AHI and GERD were associated with chronic cough in univariate analysis, and only GERD was associated with chronic cough in multivariate analysis. This implies that GERD may be the most important aetiology of chronic cough in patients with OSA. However, the present study is a retrospective study, and further large-scale prospective studies are needed to draw a more definitive conclusion.
Nasal obstruction is also associated with OSA, and possible mechanisms such as the Starling resistor model, unstable oral breathing, nasal-ventilatory reflex and nitric oxide have been identified [
21]. In the Wisconsin Sleep Study, subjects with self-reported nocturnal nasal congestion had a three-fold increase in the incidence of snoring [
22]. On the other hand, a prospective study reported that allergic rhinitis is directly associated with OSA [
23]. The use of nasal steroids has been reported to improve sleep quality, but not the severity in patients with severe OSA [
24] or in those who receive nasal surgery [
25]. Therefore, it is reasonable to assume nasal steroids or surgery does not improve chronic cough, which is related to OSA. In the present study, a high percentage of rhinosinusitis was noted in the OSA patients, and most of them were treated with nasal steroids and anti-histamines while only some with nasal surgery. Further, rhinosinusitis was not associated with chronic cough in the present study.
The incidence of asthma in patients with chronic cough has been reported to range from 16% to 41.8%, and coughing has been reported to be significantly improved by inhaled corticosteroid treatment [
26]. However, a significantly higher dose of inhaled corticosteroids is needed to control asthma when sputum coexists with eosinophils and neutrophils [
27]. Moreover, neutrophils are activated and delay apoptosis [
28,
29] during the process of ischemia/reperfusion caused by OSA. Therefore, OSA is an important factor in aggravating asthma control, which can be reversed by CPAP treatment [
30]. In addition, the asthma-related chronic cough, which is aggravated by OSA, can also be improved by CPAP. In the present study, chronic cough was significantly improved in the patients with both OSA and asthma by CPAP treatment compared to those who did not receive CPAP treatment (3/4 (75%) vs. 1/7 (14.3%); p = 0.044). However, asthma was not an independent factor contributing to chronic cough in this study, and the number of case was relatively small. Further large-scale studies are needed to clarify this issue.
The major limitations of the present study are its retrospective nature, which may have led to bias in patient selection. Second, the sample size of the study is small, and therefore the results of the study should be interpreted with caution. A prospective study with a larger sample size is warranted to further confirm the results. Finally, the population in this study was based in a sleep lab, so extrapolation of the results to the general population should be done with caution.
Competing interests
The authors declare that they do not have any financial competing interests in relation to the current manuscript.
Authors’ contributions
T-YW contributed to conceptualization and design of this study; collection, analysis, and interpretation of the data; and preparation of the manuscript. Y-LL contributed to conceptualization and design of this study; collection, analysis, and interpretation of the data; and preparation of the manuscript. T-YW, Y-LL, W-TL, S-ML, T-YL, C-HK, F-TC, P-CC, P-JC, Y-LN, S-CH, H-CL, C-HW, C-TY contributed to collection, analysis, and interpretation of the data and preparation of the manuscript. H-PK contributed to conceptualization and design of the study; collection and interpretation of the data; and preparation of the manuscript. All authors read and approved the final manuscript.