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Author(s): Richard D. Turner [sup.1] [sup.2], Barnaby Hirons [sup.3] [sup.4], Andrea Cortese [sup.5] [sup.6], Surinder S. Birring [sup.3] [sup.4] Author Affiliations: (1) grid.413154.6, 0000 0004 0625 9072, Department of Respiratory [...], Chronic cough is common, and in many cases unexplained or refractory to otherwise effective treatment of associated medical conditions. Cough hypersensitivity has developed as a paradigm that helps to explain clinical and research observations that frequently point towards chronic cough as a neuropathic disorder. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recently described neurological condition whose clinical features include gait ataxia, unsteadiness, peripheral neuropathy, and autonomic dysfunction. Chronic cough is also a common feature of the syndrome, with features of hypersensitivity, often preceding core neurological symptoms by up to 30 years or more. The genetic basis in a majority of cases of CANVAS appears to be biallelic variable repeat intron expansion sequences within RFC1, a gene normally involved in the regulation of DNA replication and repair. The same polymorphism has now been identified at an increased frequency in patients with unexplained or refractory chronic cough in the absence of defining clinical features of CANVAS. This review expands on these points, aiming to increase the awareness of CANVAS amongst clinicians and researchers working with chronic cough. We discuss the implications of a link between RFC1 disease and cough. Improved understanding of CANVAS may lead to an enhanced grasp of the pathophysiology of chronic cough, and new approaches to antitussive treatments.

Author(s): Lorcan McGarvey [sup.1], Jaclyn A. Smith [sup.2], Alyn Morice [sup.3], Surinder S. Birring [sup.4], Kian Fan Chung [sup.5], Peter V. Dicpinigaitis [sup.6], Akio Niimi [sup.7], Michael S. Benninger [sup.8], [...], Introduction To determine the optimal dose of sivopixant, a highly selective P2X3 receptor antagonist, for refractory or unexplained chronic cough (RCC/UCC). Methods In this phase 2b, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial, patients received sivopixant 50, 150, or 300 mg or placebo once daily for 4 weeks. The primary endpoint was a change from baseline in 24-h cough frequency (coughs/h) with sivopixant vs placebo. Results Overall, 390/406 randomized patients completed the study. Placebo-adjusted changes in hourly cough count over 24 h were 13.17% (P = 0.3532), - 1.77% (P = 0.8935), and - 12.47% (P = 0.3241) and in cough severity (visual analog scale) were 1.75 mm (P = 0.5854), - 1.21 mm (P = 0.7056), and - 6.55 mm (P = 0.0433) with sivopixant 50, 150, and 300 mg, respectively. Placebo-adjusted changes from baseline in Leicester Cough Questionnaire total scores were - 0.37 (P = 0.4207), - 0.07 (P = 0.8806), and 0.69 (P = 0.1473) with sivopixant 50, 150, and 300 mg, respectively. Additionally, 61.3%, 78.3%, 86.8%, and 71.4% of patients receiving sivopixant 50, 150, and 300 mg and placebo, respectively, reported any improvements in Patient Global Impression of Change. The incidence of treatment-emergent adverse events (TEAEs) was 25.7%, 32.0%, 49.0%, and 20.6% in sivopixant 50, 150, and 300 mg and placebo groups, respectively; all TEAEs in the sivopixant group were mild-to-moderate. Conclusion Sivopixant did not demonstrate a statistically significant difference vs placebo in change from baseline in 24-h cough frequency. The dose of 300 mg has potential for RCC/UCC, showing the greatest improvements in cough frequency and patient-reported outcomes and dose-related mild to moderate reversible taste disturbance, although further trials are needed. Clinical Trial Registration ClinicalTrials.gov identifier NCT04110054; registered September 26, 2019.

Author(s): Jonathan Schelfhout [sup.1], Allison Martin Nguyen [sup.1], Surinder S. Birring [sup.2], Elizabeth D. Bacci [sup.3], Margaret Vernon [sup.4], David R. Muccino [sup.1], Carmen La Rosa [sup.1], Jaclyn A. Smith [...], Purpose Objective cough frequency is used to assess efficacy of chronic cough (CC) treatments. The objective of this study was to explore the relationship between objective cough frequency and cough-specific patient-reported outcomes (PROs) and estimate a clinically meaningful change threshold (MCT) for objective cough frequency. Methods Data collected in a phase 2b study in participants with refractory or unexplained CC were used to investigate the relationship between 24-h cough frequency (measured using an ambulatory cough monitor) and cough-specific PROs (i.e., cough severity visual analog scale, cough severity diary, Leicester Cough Questionnaire). Convergent validity was assessed using Spearman [rho]. An MCT for 24-h cough frequency was estimated using the patient global impression of change (PGIC) scale as an anchor. Results Correlations between 24-h cough frequency and cough-specific PROs at baseline, Week 4, and Week 12 were significant (P < 0.0001) but low to moderate in strength ([rho] = 0.30-0.58). Participants categorized as very much improved/much improved (i.e., PGIC of 1 or 2) or minimally improved (i.e., PGIC of 3) had mean 24-h cough frequency reductions of 55% and 30%, respectively. Receiver operating characteristic curve analysis suggested that a 24-h cough frequency reduction of 38% optimizes sensitivity and specificity for predicting a PGIC score of 1-3. Conclusion Objective 24-h cough frequency is significantly associated with cough-specific PROs, but cough frequency and PROs most likely capture distinct aspects of CC. A [greater than or equal to] 30% reduction in 24-h cough frequency is a reasonable MCT to define treatment response in CC clinical trials.

Author(s): Jaclyn A. Smith [sup.1], Surinder S. Birring [sup.2], Peter V. Dicpinigaitis [sup.3], Lorcan P. McGarvey [sup.4], Alyn H. Morice [sup.5], Ian D. Pavord [sup.6], Imran Satia [sup.7] [sup.8], Stuart [...], Introduction In phase 3 trials (COUGH-1/COUGH-2), gefapixant 45 mg twice daily significantly reduced 24-h cough frequency vs placebo in refractory or unexplained chronic cough (RCC or UCC). Methods Here, the efficacy of gefapixant 45 mg vs placebo was evaluated across COUGH-1/COUGH-2 in predefined subgroups based on sex, region, age, cough duration, cough severity, cough frequency, and diagnosis (RCC, UCC). Awake cough frequency reductions at Week 12 and LCQ response rates (i.e., [greater than or equal to] 1.3-point improvement) at Week 24 were assessed. Results Among 1360 participants analyzed, gefapixant 45 mg resulted in consistent awake cough frequency reductions overall and across predefined subgroups at Week 12. Gefapixant also resulted in improved LCQ scores across subgroups at Week 24; [greater than or equal to] 70% of participants in each subgroup treated with gefapixant 45 mg had an LCQ response. Conclusion These data suggest gefapixant 45 mg provides consistent objective and subjective efficacy across subgroups of individuals with RCC or UCC.

Background: There is increasing interest in the use of home-based monitoring in people with chronic lung diseases to improve access to care, support patient self-management, and facilitate the collection of information for clinical care and research. However, integration of home-based monitoring into clinical and research settings requires careful consideration of test performance and other attributes. There is no published guidance from professional respiratory societies to advance the science of home-based monitoring for chronic lung disease. Methods: An international multidisciplinary panel of 32 clinicians, researchers, patients, and caregivers developed a multidimensional framework for the evaluation of home-based monitoring in chronic lung disease developed through consensus using a modified Delphi survey. We also present an example of how the framework could be used to evaluate home-based monitoring using spirometry and pulse oximetry in adults with asthma, bronchiectasis/cystic fibrosis, chronic obstructive pulmonary disease, and interstitial lung disease. Results: The PANACEA framework includes seven domains (test Performance, disease mANAgement, Cost, patient Experience, clinician Experience, researcher Experience, and Access) to assess the degree to which home-based monitoring assessments meet the conditions for clinical and research use in chronic lung disease. Knowledge gaps and recommendations for future research of home spirometry and pulse oximetry in asthma, bronchiectasis/cystic fibrosis, chronic obstructive pulmonary disease, and interstitial lung disease were identified. Conclusions: The development of the PANACEA framework allows standardized evaluation of home-based monitoring in chronic lung diseases to support clinical application and future research. [ABSTRACT FROM AUTHOR]

This letter discusses a study that examined chronic cough in patients with cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). The study found that chronic cough affects two-thirds of patients with CANVAS and is associated with sensory neuropathy. The researchers compared the characteristics of chronic cough in CANVAS patients to those with refractory chronic cough and found that CANVAS patients had cough of longer duration, earlier age of onset, and lower body mass index. Anxiety and depression scores were lower in CANVAS patients, while cough severity scores and cough-specific health status scores were higher in patients with refractory chronic cough. The study suggests that CANVAS-associated chronic cough may have a neurally mediated cause. Further research is needed to understand the mechanisms behind this type of cough. [Extracted from the article]

Author(s): Alyn H. Morice [sup.1], Surinder S. Birring [sup.2], Jaclyn A. Smith [sup.3], Lorcan P. McGarvey [sup.4], Jonathan Schelfhout [sup.5], Allison Martin Nguyen [sup.5], Zhi Jin Xu [sup.5], Wen-Chi Wu [...], Purpose This analysis assesses clinical characteristics of patients with refractory chronic cough (RCC) or unexplained chronic cough (UCC) enrolled in a phase 2 study to better understand this patient population. Methods Patients with RCC/UCC lasting for [greater than or equal to] 1 year and cough severity visual analog scale (VAS) score of > 40 mm at screening were eligible. Demographics, clinical characteristics, and medical history were collected at baseline. Cough-related measures included cough severity VAS, Cough Severity Diary (CSD), Leicester Cough Questionnaire (LCQ), and a structured cough-trigger questionnaire. Medication history included all medications 30 days before screening and chronic cough treatments within 1 year before screening. Data were summarized using descriptive statistics. Results Patients (N = 253; female, 76%; mean age, 60 years) had severe (mean cough severity VAS, 57.5 mm) and long-lasting (median duration, 11 years) cough. The most burdensome self-reported aspects included psychological and social factors (LCQ) and cough frequency and intensity (CSD). Patient-reported triggers were consistent with cough hypersensitivity (e.g., 95% to 96% reported irritation or tickle in throat). Common reported comorbidities included gastroesophageal reflux disease (GERD; 56%), allergic rhinitis (47%), and asthma (30%); 12% of patients had been diagnosed with all 3 conditions. The most common prior medications included inhaled or oral steroids (21%), antihistamines (15%), and antacids (15%). Conclusion Patients with RCC/UCC had severe, long-lasting, and burdensome cough with clinical features of cough hypersensitivity. Many patients had been diagnosed with GERD, allergic rhinitis, and asthma but had a persistent cough despite treatment of these conditions. Trial registration: ClinicalTrials.gov, NCT02612610; registered November 20, 2015

Author(s): Peter S. P. Cho [sup.1], Hannah V. Fletcher [sup.2], Richard D. Turner [sup.3], Irem S. Patel [sup.2], Caroline J. Jolley [sup.1], Surinder S. Birring [sup.1] [sup.2] Author Affiliations: (1) [...], Background Cough is predictive of exacerbations of chronic obstructive pulmonary disease (COPD). Little is known about cough reflex sensitivity during exacerbation of COPD and whether it is associated with exacerbation frequency. This pilot study aimed to investigate cough reflex sensitivity during and following recovery from exacerbation of COPD, and its association with the frequency of future exacerbations. In addition, the repeatability of cough reflex sensitivity in stable COPD was investigated. Methods Twenty participants hospitalised with exacerbation of COPD underwent inhaled capsaicin challenge during exacerbation and after 6 weeks of recovery. The frequency of future exacerbations was monitored for 12 months. The repeatability of cough reflex sensitivity was assessed in separate participants with stable COPD, who underwent 2 capsaicin challenge tests, 6 weeks apart. Results Cough reflex sensitivity was heightened during exacerbation of COPD. Geometric mean (SD) capsaicin concentration thresholds to elicit 5 coughs (C5) during exacerbation and after 6 weeks of recovery were 1.76 (3.73) vs. 8.09 (6.25) [mu]mol L.sup.-1, respectively (p < 0.001). The change in C5 from exacerbation to 6-week recovery was associated with the frequency of future exacerbations ([rho] = - 0.687, p = 0.003). C5 was highly repeatable over 6 weeks in stable COPD, and intraclass correlation coefficient was 0.85. Conclusion Cough reflex sensitivity is heightened during exacerbation of COPD and reduces after recovery. The persistence of cough reflex hypersensitivity at recovery was associated with the frequency of future exacerbations.

Author(s): Krishna M. Sundar [sup.1] [sup.2] [sup.3] , Alika M. Willis [sup.1] , Sarah Smith [sup.2] , Nan Hu [sup.4] [sup.5] , Jay P. Kitt [sup.6] , Surinder S. Birring [...], Background An association between chronic cough and obstructive sleep apnea (OSA) has been reported in prior studies with resolution or improvement in cough after continuous positive airway pressure (CPAP) therapy. Controlled studies of the benefit of CPAP on cough-quality of life measures have not been conducted. Research Question Does CPAP therapy for OSA improve cough in patients with chronic unexplained cough? Study Design and Methods Patients with unexplained chronic cough (> 2 months duration of cough) and OSA were randomized to receive either CPAP or sham CPAP therapy for 6 weeks. The primary end point was the change in health status assessed with the Leicester Cough Questionnaire (LCQ) in patients treated with CPAP vs. sham CPAP. Secondary end points were changes in exhaled breath condensate markers of airway inflammation (interleukin-6, nitrite/nitrates, hydrogen peroxide and 8-isoprostanes). Results A total of 22 patients with chronic unexplained cough and OSA were randomized of whom18 completed 6 weeks of treatments with either CPAP or sham CPAP. The CPAP vs. sham CPAP-treated group were comparable in terms of sex distribution, body mass index, and OSA severity. Following CPAP therapy, there was a significantly greater improvement in total LCQ scores as compared to those treated with sham therapy (ANCOVA p value 0.016). No significant differences were noted in the exhaled breath condensate marker changes between CPAP-treated vs. sham CPAP-treated groups. Conclusion Treatment of comorbid OSA in patients with chronic cough improved cough quality of life measures following treatment of OSA with CPAP in this pilot study. Larger studies to understand this association and unravel mechanisms of CPAP benefit in chronic cough need to be undertaken. Clinical Trial Registration NCT03172130

Background: Chronic cough, a cough lasting >8 weeks, includes refractory chronic cough (RCC) and unexplained chronic cough (UCC). Patient-reported outcome (PRO) measures are needed to better understand chronic cough impacts that matter most to patients. The 19-item Leicester Cough Questionnaire (LCQ), an existing PRO measure of chronic cough, assesses impacts of cough across physical, psychological, and social domains. However, the content validity of the LCQ evaluating these concepts in patients with RCC/UCC had not been established. Objectives: To evaluate the content validity of the LCQ in patients with RCC/UCC. Design: A cross-sectional, qualitative interview study. Methods: First, previously completed qualitative interview results in adults with RCC/UCC (N = 30) were evaluated and mapped to LCQ concepts. Next, a clinical cough expert reviewed each LCQ item and assessed the salience of its concepts for patients with RCC/UCC. Finally, semistructured interviews—including both concept elicitation and cognitive debriefing—were conducted in adults with RCC/UCC (N = 20) to elicit a comprehensive set of participant experiences and to assess the appropriateness of using the LCQ in this population. Results: Concepts reported in the past and present qualitative interviews were included across all LCQ items, and most impacts reported to be the "most bothersome" were assessed in the LCQ. In the current study, all participants indicated that reduced cough frequency would be an important treatment target. During cognitive debriefing, each LCQ item was endorsed by ⩾70% of participants. Additionally, participants were generally able to understand, recall, and select a response for each LCQ item. All participants and the clinical expert indicated that the LCQ was appropriate and assessed the impacts most relevant to patients with RCC/UCC. Conclusion: Our findings support the content validity of the LCQ and demonstrate that this measure is fit-for-purpose and includes important cough impacts in adults with RCC/UCC. [ABSTRACT FROM AUTHOR]