Risk of Hospitalized COVID-19 in COPD - Single-Inhaler Triple Versus Dual Bronchodilator Therapy

Sep 29, 2026

Objective: Estimate the effect of initiating an inhaled corticosteroids-containing single-inhaler triple agent (ICS-LABA-LAMA) versus a single-inhaler LABA-LAMA dual bronchodilator on the risk of severe COVID-19 in COPD before vaccine rollout. Methods: Cohort study emulating a randomized trial in UK patients aged ≥40, using fine-stratification propensity-score weighting and Cox models with a 30-day grace period. Results: 876 vs 5010 starters; adjusted incidence 5.6 vs 2.9 per 100 person-years; HR 1.96 (95% CI 1.01–3.77). Conclusions: ICS-containing triple therapy may increase severe COVID-19 risk pre-vaccine era; findings should inform treatment initiation.

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Pharmacoepidemiology and Drug Safety Risk of Hospitalized COVID-19 in COPD: Single-Inhaler Triple Versus Dual Bronchodilator Therapy Simon Galmiche1,2 | Sophie Dell'Aniello1 | Samy Suissa1,2 1Center for Clinical Epidemiology, Lady Davis Institute (LDI), Jewish General Hospital, Montreal, Canada | 2Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada Correspondence: Samy Suissa ([samy.suissa@mcgill.ca](samy.suissa@mcgill.ca)) Received: 5 September 2025 | Revised: 24 November 2025 | Accepted: 20 December 2025 Keywords: drug safety | infection | inhaled corticosteroids | new-user cohort ABSTRACT Purpose: Our objective was to estimate the effect of initiating an inhaled corticosteroids-containing single-inhaler triple agent (ICS-LABA-LAMA) compared with a single-inhaler LABA-LAMA dual bronchodilator in patients with COPD on the risk of severe COVID-19 prior to the roll-out of vaccines. Methods: We conducted a cohort study emulating a randomized trial, among patients with COPD aged 40years or more in the UK, comparing those who initiated a triple inhaler with those who initiated a dual bronchodilator inhaler between March 1 and December 31, 2020. Weighting by fine stratification of the propensity score was used to account for confounders. The risk of hospitalized COVID-19 was compared with a Cox proportional hazards model in an as-treated analysis with a 30-day grace period. Results: The study cohort included 876 patients initiating a triple inhaler and 5010 initiating a dual LABA-LAMA inhaler. The adjusted incidence rate of hospitalized COVID-19 was 5.6 per 100 person-years in the triple inhaler group and 2.9 per 100 personyears in the dual inhaler group, with a corresponding hazard ratio (HR) of 1.96 (95% confidence interval 1.01–3.77) . Sensitivity analyses on the duration of the grace period, using an intent-to-treat exposure classification, or starting follow-up 14 days after treatment initiation (accounting for treatment initiation for an undocumented SARS-CoV-2 infection) were generally consistent with the main analysis. Conclusions: Patients with COPD prescribed an ICS-containing triple inhaler were potentially exposed to an increased risk of severe COVID-19 prior to the vaccine era. As SARS-CoV-2 continues to cause significant burden, these findings should be considered when determining initiation of inhaled treatment in COPD. 1 | Purpose Triple therapy for patients with chronic obstructive pulmonary disease (COPD), combining inhaled corticosteroids (ICS) with long-acting β2-agonists (LABA) and long-acting muscarinic antagonists (LAMA) is recommended for patients with exacerbations and high blood eosinophil count (≥300/μL) [1], or those with high disease burden despite dual LABA-LAMA therapy [2] . Along with the documented benefit of ICS-based triple therapy on the risk of exacerbation in patients with multiple exacerbations, it is also associated with an increased risk of pneumonia [3, 4], potentially due to impairments of interferon responses [5] . The effect of ICS-based triple inhaled therapy on the risk of severe COVID-19, however, remains uncertain, with several observational studies that produced discrepant findings [6–9] . These studies investigated ICS use but all included prevalent users of ICS, and some studied a mix of respiratory diseases and inhaled co-medications [6–10] . We therefore employed a This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2026 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd. Pharmacoepidemiology and Drug Safety, 2026; 35:e70321 1 of 5 [https://doi.org/10.1002/pds.70321](https://doi.org/10.1002/pds.70321) | Key Points
• The impact of inhaled corticoste

FAQs

What comparison does the study make in COPD patients?

It compares initiation of a single-inhaler triple therapy (ICS-LABA-LAMA) with initiation of a single-inhaler dual bronchodilator therapy (LABA-LAMA).

What did the study find about hospitalized severe COVID-19 risk?

Patients starting the triple inhaler had a higher risk of hospitalized severe COVID-19, with an adjusted hazard ratio of 1.96 (95% CI 1.01–3.77).

Why is the timing before COVID-19 vaccine rollout important?

The study targets the pre-vaccine period to estimate risks associated with treatment initiation prior to vaccine effects, focusing on potential exposure patterns in 2020.

Sep 29, 2026

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