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

Ann Allergy Asthma Immunol. 2023 Jul;131(1):59-68.e3. doi: 10.1016/j.anai.2023.03.032. Epub 2023 Apr 7.

Abstract

Background: We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting β2 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 5 μg (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 µM) 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/ctr_view.cgi?recptno=R000024253).

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adrenal Cortex Hormones / therapeutic use
  • Adrenergic beta-2 Receptor Agonists / therapeutic use
  • Asthma* / drug therapy
  • Capsaicin / therapeutic use
  • Cough* / drug therapy
  • Drug Therapy, Combination
  • Humans
  • Quality of Life
  • Reflex
  • Theophylline
  • Tiotropium Bromide / therapeutic use

Substances

  • Tiotropium Bromide
  • Capsaicin
  • Adrenergic beta-2 Receptor Agonists
  • Adrenal Cortex Hormones
  • Theophylline

Associated data

  • JPRN/UMIN000021064