Tiotropium for refractory cough in asthma via cough reflex sensitivity: A randomized, parallel, open-label trial

Background: We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting b2 agonists (ICS/LABA) by modulating capsaicin cough reflex sensitivity (C-CRS). Objective: We sought to determine the antitussive effects of tiotropium for refractory cough in asthma in a randomized, parallel, open-label trial. Methods: A total of 58 patients with asthma having chronic cough refractory to ICS/LABA were randomized in a 2:1 ratio to add tiotropium 5mg (39 patients) or theophylline 400 mg (19 patients) for 4 weeks. Patients underwent workups, including capsaicin cough challenge test and subjective measures such as cough severity visual analog scales (VAS). We adopted C5, the lowest capsaicin concentration to induce at least 5 coughs, as an index of C-CRS. We also performed a posthoc analysis to identify factors predicting tiotropium responders, who found an improvement of at least 15 mm in cough severity VAS. Results: A total of 52 patients (tiotropium, 38; theophylline, 14) completed the study. Both tiotropium and theophylline significantly improved cough severity VAS and cough-specific quality of life. Tiotropium, but not theophylline, significantly increased C5, whereas pulmonary function did not change in either group. In addition, changes in cough severity VAS correlated with changes in C5 values in the tiotropium group. A posthoc analysis revealed that heightened C-CRS (C5 =1.22 mM) before the addition of tiotropium was an independent predictor for tiotropium responders. Conclusion: Tiotropium may alleviate chronic cough in asthma refractory to ICS/LABA by modulating C-CRS. Heightened C-CRS may predict responsiveness to tiotropium for refractory cough in asthma. Trial Registration: Clinical Trials Registry ID: UMIN000021064 (https://center6.umin.ac.jp/cgi-open-bin/ctr/ (c) 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.