Assessing the Burden and Prognostic Value of Cough in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease that mainly affects older adults and males (1). Approximately 6,000 new cases of IPF are diagnosed per year in the United Kingdom, and over 32,000 patients are currently living with the disease (1). Improving symptoms and quality of life (QoL) for patients with IPF remains a challenge, with antifibrotic medications such as pirfenidone and nintedanib currently used to slow disease progression. A U.K. IPF registry found that 66% of patients reported symptoms of exertional breathlessness and/or cough for >12months at diagnosis (1). Ryerson and colleagues conducted a study of 242 patients with IPF and found that 84% of them had cough. They also identified cough as an independent predictor of disease progression (2). Similarly, the Australian IPF Registry showed an association between cough andmortality after adjusting for baseline demographics, including age, sex, body mass index, smoking status, and percent predicted forced vital capacity (FVC) (3). In this issue of AnnalsATS, Saunders and colleagues (pp. 1267–1273) present one of the first prospective, longitudinal cohorts (PROFILE [Prospective Study of Fibrosis in the Lung Endpoints] study) characterizing cough burden and its impact on QoL in patients with IPF. The study recruited 632 patients and assessed them at multiple time points over 3 years (4). The results showed a weak association between cough burden and pulmonary function test results. In contrast to previous large studies, cough was not a significant predictor of disease progression or survival in patients with IPF. This study by Saunders and colleagues differs from the one by Ryerson and coworkers in terms of cough assessment, using the Leicester Cough Questionnaire (LCQ) as a measure of cough-related QoL instead of cough as a dichotomous variable. Moreover, progression data were available for only two-thirds of the cohort in the study by Ryerson and coworkers, and data were assessed at 6months, whereas Saunders and colleagues assessed progression at 12months. A small study of 19 patients with IPF highlighted a strong correlation between objective coughmeasurements and subjective cough scoring (visual analog scale [VAS] and LCQ), suggesting through these tools that the cough perception of patients with IPF can be accurate (5). The study by Saunders and colleagues, therefore, bridges a gap in knowledge, given its large, multicenter longitudinal cohort design and the comprehensive assessment of cough using the LCQ. The study by Saunders and colleagues has limitations, including lack of full examination of the potential impact of comorbidities on cough-related QoL, particularly in relation to gastroesophageal reflux (GER), a comorbidity with a complex relationship with IPF characterized by a “chicken or egg” dilemma, further complicated by confounding factors such as smoking (6). Recent research by Reynolds and colleagues on this complex relationship, using genetic variants to eliminate confounding factors, found that GER increased the risk of IPF (odds ratio, 1.6), but there was no evidence that IPF increased the risk of GER (6). An earlier study suggested this correlation when it found that 87% of patients with IPF had abnormal acid GER on 24-hour pHmonitoring, with 71% of these patients not receiving any treatment with a proton pump inhibitor (PPI) at the time (7). Interestingly, only 47% of those with abnormal acid GER exhibited symptoms of GER, and there was no correlation between acid GER severity and IPF severity as measured by pulmonary function tests (7). Although no large randomized controlled trials have evaluated the efficacy of PPI treatment in patients with IPF, PPI treatment has become a common practice. A small pilot randomized controlled trial evaluating the impact of omeprazole on cough frequency found a reduction in the omeprazole group, but the trial was not sufficiently powered to establish statistical significance (8). A pooled analysis of two observational studies found that antacid medication had no statistically significant effect on disease progression when defined as a 10% or more decline in FVC or 6-minute-walk distance or death (9). The Saunders and colleagues cohort had almost half of the patients diagnosed with GER, but only 27.8% received PPI treatment, raising concerns about potential impacts on LCQ scores. Because the role of GER in IPF remains unclear, further research is needed in this regard. A current U.K.-based study, TIPAL (Treating People with Idiopathic Pulmonary Fibrosis with the Addition of Lansoprazole; ClinicalTrials.gov identifier NCT04965298), aims to address some of these questions through a randomized, placebo-controlled multicenter clinical trial. Effective treatments for IPF-related cough are currently not available as part of the standard of care, and this cough appears to be resistant to conventional therapies. In the Saunders and colleagues study, only a small minority (8.8%) of patients started antifibrotic treatment (53 with pirfenidone, 3 with nintedanib) during the follow-up This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern.