Whole lung directed anti-muscarinic therapy improves small airway dysfunction in COPD patients
File(s)
Published version
Author(s)
Usmani, Omar S
Toumpanakis, Dimitrios
Meah, Sally
Mak, Vincent
Biddiscombe, Martyn F
Type
Journal Article
Abstract
Small airway disease is a key feature of COPD that often precedes emphysema, with the small airways representing a major site of airflow limitation [1]. The prevalence of small airway dysfunction (SAD) ranges from 50% to 90% in COPD patients, and correlates with symptoms [2]. SAD is usually well-established before conventional spirometry is abnormal [3], and contributes to patient quality-of-life burden [4] and disease exacerbations [5]. Inhalation therapy is the bedrock of COPD management, yet despite increasingly new inhaler device-drug combinations, COPD remains sub-optimally controlled for many patients. Most prescribed inhalers, in practice, deliver drugs primarily to the large airways [6]. The inability to effectively treat both the large airways and SAD may be a limiting factor in achieving optimal patient benefit [6]. Technological advances in inhaler engineering now allow targeting of the small airways [6], and coupled with contemporary progress in more sensitive physiological assessments for SAD [1], careful investigation of whether therapeutic targeting of small airways leads to improved patient lung function is now possible [5]. We hypothesised that inhaled tiotropium, a long-acting muscarinic antagonist, the mainstay of COPD pharmacological treatment, aerosolised to a high fine-particle fraction (FPF; ∼65-80%, Respimat soft-mist inhaler (RM-SMI)) [7], achieving both large airway deposition and deeper lung penetration to the small airways [8], would improve SAD better than tiotropium at a low FPF (∼19%, Handihaler dry-powder inhaler (HH-DPI)), which would predominantly target the proximal central airways [9]. 45 patients were recruited; two withdrew after study entry, and 43 (20 females, mean age 69 years, range 46-87 years) symptomatic (COPD Assessment Test (CAT) score >10) patients (Global Initiative for Chronic Obstructive Lung Disease stage I-III, mean±SD forced expiratory volume in 1 s (FEV 1) 65.8±17.0% of predicted) using HH-DPI (tiotropium 18 µg daily) for >6 months, and all naïve to RM-SMI, completed all visits. In this open-label sequential treatment, pragmatic real-life study, patients initially received on visit 1 (day 0) HH-DPI (tiotropium 18 μg daily, 14 days), then on visit 2 (day 14) were switched to RM-SMI (tiotropium 5 µg daily, 14 days). We did not undertake drug deposition imaging in this study. At each visit, patients underwent, in order: pre-dose (trough, 24 h after last tiotropium dose) lung physiology assessment (multiple-breath nitrogen washout (MBNW), impulse oscillometry, body plethysmography and spirometry), symptom questionnaires (CAT, modified Medical Research Council (mMRC) dyspnoea scale), inhaler training by an investigator using placebo devices, investigator-observed first-dose active drug inhalation, followed by a 3-h post-dose lung physiology assessment. At closeout visit (day 28), after pre-dose lung physiology assessment, patients expressed their opinions about each inhaler. All patients had stable COPD with no previous (past 2 months) chest infection requiring antibiotics and/or oral corticosteroids. None had received triple therapy, nor a previous diagnosis of asthma. Active drug and placebo training inhalers were supplied by Boehringer Ingelheim, Germany. The study protocol was approved by ethics committee (REC number: 15/LO/0982) and registered at Clinical trials.gov (identifier: NCT02683668). The primary end-point was oscillometry-determined R5-R20 (difference between resistance at 5 Hz and at 20 Hz), a measure of SAD [1]. The Welch's unequal variances t-test was used to compare trough lung
Date Issued
2026-02-01
Date Acceptance
2025-11-11
Citation
European Respiratory Journal, 2026, 67 (2)
ISSN
0903-1936
Publisher
European Respiratory Society (ERS)
Journal / Book Title
European Respiratory Journal
Volume
67
Issue
2
Copyright Statement
©The authors 2025 This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41309266
PII: 13993003.01326-2025
Publication Status
Published
Coverage Spatial
England
Article Number
2501326
Date Publish Online
2025-11-27