To the best of our knowledge, this is the first study to examine cough intensity and frequency separately in patients with IIPs, CTD-ILD, or CHP. Cough intensity was greatest in the group containing patients with IIPs; both the intensity and frequency of cough were negatively associated with the DLco and positively with the CPI in these patients. In patients with CTD-ILD, both components of cough correlated significantly with a higher FSSG score. In all patients with ILD, multiple logistic regression analysis revealed independent associations of IIPs and the FSSG score with both the intensity and frequency of cough and a tendency for an independent association of CPI with the frequency of cough. Furthermore, although cough intensity and frequency behaved similarly overall, the total and subdomain LCQ scores were significantly poorer in the cough frequency-dominant group than in the other two groups.
Cheng et al. recently reported that the VAS score for cough severity was higher in patients with IPF or CHP than in those with CTD (SSc)-ILD [5]. In the present study, we demonstrated that patients with IIPs had more intense cough than those with CTD-ILD or CHP (Table 1) and that IIPs but not the CPI was an independent risk factor for intensity of cough (Table 4). Cough intensity in patients with IIPs in the present study (median 31 mm) was similar to the cough severity in patients with IPF reported by Cheng et al. (median 39 mm) [5] and Key et al. (median 32 mm) [8].
In this study, CPI tended to be independently associated with frequency of cough in patients with ILD. Specifically, in patients with IIPs, both the intensity and frequency of cough were associated with the CPI and DLco. Both CPI and DLco reflect the extent of disease seen on computed tomography scans in patients with ILD [25-27], so it is possible that severity of cough may be associated with the extent of the parenchymal lesions in IIPs. When compared with patients with CTD-ILD, there was also a numerically stronger association of both the intensity and frequency of cough with CPI in patients with IIPs (Fig. 1). Like our findings in patients with IIPs, Cheng et al. reported a significant correlation of cough severity with DLco in patients with IPF [5]. Although our results do not indicate a causal relationship between intensity and frequency of cough and CPI, Ryerson et al. showed that cough in patients with IPF is an independent predictor of disease progression, which was defined as a 15% decline in DLco, a 10% decline in FVC, or lung transplantation or death attributable to any cause [3]. Moreover, there is a hypothesis that formation of the fibroblastic foci in IPF may come from stretch injury to the epithelial-mesenchymal interface [28]. It was also found that both the intensity and frequency of mechanical stress-related breathing resulted in activation of transforming growth factor beta-1 in rat fibrotic tissue; when forces of 5–20 mN were applied to fibrotic lung strips, active transforming growth factor beta-1 increased significantly in response to the mechanical stimulus [13]. Therefore, an increase in intensity and frequency of cough that causes mechanical stress may contribute to disease progression, such as an increase in CPI, in patients with IIPs.
Alternatively, cough in patients with IIPs might be a consequence of architectural distortion of the fibrotic lung. Traction bronchiectasis is caused by constriction of the surrounding fibrotic alveolar tissue, and such architectural distortion of the bronchial tree may be involved in activation of rapidly adapting receptors [10, 29], resulting in an exaggerated coughing response, i.e., an increase in cough intensity or frequency. Further studies are required to evaluate the correlation between the extent of disease seen on HRCT and the intensity and frequency of cough in patients with IIPs.
The FSSG score was another independent risk factor for both the frequency and intensity of cough in patients with ILD, and particularly in patients with CTD-ILD. This finding is consistent with that of Tashkin et al., suggesting that frequency of cough relates to the severity of GORD at baseline and declines in parallel with improvement in GORD by treatment for SSc-ILD [11]. Furthermore, a study in patients with SSc-ILD reported a relationship between the degree of pulmonary fibrosis assessed using a validated HRCT score and the number of reflux episodes in the distal and proximal oesophagus [30]. Hence, the well-known interaction between GORD and cough [31] may be closely involved in the pathogenesis of CTD-ILD, particularly SSc-ILD. Meanwhile, FSSG scores were lower in patients with IIPs than those in patients with CTD-ILD, and there was no significant correlation of either intensity or frequency of cough with the FSSG score in patients with IIPs in the present study. Another study found that only 25% of patients with IPF and increased exposure to acid in the oesophagus reported typical reflux symptoms [32]. A further study found no association between GORD and cough in patients with IPF [3]. Therefore, the impact and association of GORD with cough may be weaker in patients with IIPs than in those with CTD-ILD, even though GORD is thought to be involved in the pathogenesis of IIPs [33].
Patients with ILD and frequency-dominant cough had greater impairment of health status than those in the other groups. Numerically, there was a stronger correlation between cough frequency and total LCQ scores than between cough intensity and total LCQ scores. Our results concur with a report by Key et al. that demonstrated a strong correlation between the objective cough count and cough-related HRQoL in patients with IPF [8]. Furthermore, given the tendency for an association between frequency of cough and the CPI in patients with ILD in the present study, it is reasonable to assess the frequency of cough in patients with ILD in a clinical setting. However, we should not neglect cough intensity. The scores in the physical domain of the LCQ were significantly poorer in the cough intensity-dominant group than in the group with equal cough severity (Table 5). Furthermore, the intensity of cough also showed a significant correlation with total LCQ scores in patients with ILD. Finally, in patients with IIPs, cough intensity, which was severest in the three subtypes of ILD, was as significantly associated with DLco and CPI as cough frequency. These findings highlight the need for assessment of both the intensity and frequency of cough in patients with ILD, particularly for patients with IIPs.
The strengths of this study are that it addressed both the intensity and frequency of cough in patients with ILD and included an analysis of subtypes of ILD (i.e., IIPs, CTD-ILD, and CHP). However, the study also has several limitations. First, we could not carry out a detailed analysis in patients with CHP because of the small sample size, which may reflect our stringent study exclusion criteria. Second, we did not investigate whether or not patients had sputum present. Third, the study had a cross-sectional design that precluded identification of a temporal or causal relationship. Prospective and longitudinal studies that include additional characteristics of cough (e.g., production of sputum and duration) are needed.