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Christian Kjer Heerfordt,1 Josefin Eklöf,1 Pradeesh Sivapalan,1 Truls Sylvan Ingebrigtsen,1 Tor Biering-Sørensen,2– 4 Zitta Barrella Harboe,4,5 Jesper Koefod Petersen,6,7 Christian Østergaard Andersen,8 Jonas Bredtoft Boel,9 Anne Kathrine Bock,10 Alexander G Mathioudakis,11,12 John R Hurst,13 Shailesh Kolekar,7 Sofie Lock Johansson,14 Jette Marie Bangsborg,9 Jens Otto Jarløv,9 Ram Benny Dessau,15 Christian Borbjerg Laursen,14,16 Michael Perch,4,17 Jens-Ulrik Stæhr Jensen1,4,18 1Section of Respiratory Medicine, Department of Medicine, Copenhagen University Hospital Herlev and Gentofte Hospital, Hellerup, Denmark; 2Department of Cardiology, Herlev and Gentofte Hospital, Cardiovascular Non-Invasive Imaging Research Laboratory, University of Copenhagen, Copenhagen, Denmark; 3Faculty of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark; 4Department of Clinical Medicine Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 5Department of Respiratory Medicine and Infectious Diseases, Copenhagen University Hospital, North Zealand, Denmark; 6Department of Respiratory Medicine, Zealand University Hospital Naestved, Naestved, Denmark; 7Department of Pulmonary Medicine, Zealand University Hospital, Roskilde, Denmark; 8Department of Clinical Microbiology, Hvidovre University Hospital, Hvidovre, Denmark; 9Department of Clinical Microbiology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark; 10Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 11The North West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK; 12Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; 13UCL Respiratory, University College London, London, UK; 14Department of Respiratory Medicine, Odense University Hospital, Odense, Denm

Background: Inhaled corticosteroids (ICS) are associated with an increased risk of clinical pneumonia among patients with chronic obstructive pulmonary disease (COPD). It is unknown whether the risk of microbiologically verified pneumonia such as pneumococcal pneumonia is increased in ICS users. Methods: The study population consists of all COPD patients followed in outpatient clinics in eastern Denmark during 2010–2017. ICS use was categorized into four categories based on accumulated use. A Cox proportional hazard regression model was used adjusting for age, body mass index, sex, airflow limitation, use of oral corticosteroids, smoking, and year of cohort entry. A propensity score matched analysis was performed for sensitivity analyses. Findings: A total of 21,438 patients were included. Five hundred and eighty-two (2.6%) patients acquired a positive lower airway tract sample with S. pneumoniae during follow-up. In the multivariable analysis ICS-use was associated with a dose-dependent risk of S. pneumoniae as follows: low ICS dose: HR 1.11, 95% CI 0.84 to 1.45, p = 0.5; moderate ICS dose: HR 1.47, 95% CI 1.13 to 1.90, p = 0.004; high ICS dose: HR 1.77, 95% CI 1.38 to 2.29, p < 0.0001, compared to no ICS use. Sensitivity analyses confirmed these results. Interpretation: Use of ICS in patients with severe COPD was associated with an increased and dose-dependent risk of acquiring S. pneumoniae, but only for moderate and high dose. Caution should be taken when administering high dose of ICS to patients with COPD. Low dose of ICS seemed not to carry this risk.