key: cord-0877514-lgd7q3mo authors: Husby, Anders; Pottegård, Anton; Hviid, Anders title: Association between inhaled corticosteroid use and COVID‐19 outcomes date: 2021-08-24 journal: Pharmacoepidemiol Drug Saf DOI: 10.1002/pds.5345 sha: 5566b1a2d01098f699ffe5c31988839bbc2695b6 doc_id: 877514 cord_uid: lgd7q3mo BACKGROUND: Recent evidence has established a beneficial effect of systemic corticosteroids for treatment of moderate‐to‐severe COVID‐19. OBJECTIVE: To determine if inhaled corticosteroid use is associated with COVID‐19 outcomes. METHODS: In a nationwide cohort of hospitalized SARS‐CoV‐2 test‐positive individuals in Denmark, we estimated the 30‐day hazard ratio of intensive care unit (ICU) admission or death among users of inhaled corticosteroids (ICS) compared with users of bronchodilators (β(2)‐agonist/muscarinic‐antagonists), and non‐users of ICS overall, with Cox regression adjusted for age, sex, and other confounders. We repeated these analyses among influenza test‐positive patients during 2010–2018. RESULTS: Among 6267 hospitalized SARS‐CoV‐2 patients, 614 (9.8%) were admitted to ICU and 677 (10.8%) died within 30 days. ICS use was associated with a hazard ratio of 1.09 (95% CI [CI], 0.67 to 1.79) for ICU admission and 0.78 (95% CI, 0.56 to 1.11) for death compared with bronchodilator use. Compared with no ICS use overall, the hazard ratio of ICU admission or death was 1.17 (95% CI, 0.87–1.59) and 1.02 (95% CI, 0.78–1.32), respectively. Among 10 279 hospitalized influenza patients, of which 951 (9.2%) were admitted to ICU and 1275 (12.4%) died, the hazard ratios were 1.43 (95% CI, 0.89–2.30) and 1.11 (95% CI, 0.85–1.46) for ICU admission, and 0.80 (95% CI, 0.63–1.01) and 1.03 (95% CI, 0.87–1.22) for death compared with bronchodilator use and no ICS use overall, respectively. CONCLUSION: Our results do not support an effect of inhaled corticosteroid use on COVID‐19 outcomes, however we can only rule out moderate‐to‐large reduced or increased risks. STUDY REGISTRATION: The study was pre‐registered at encepp.eu (EUPAS35897). • Compared with hospitalized influenza patients in 2010-2018, hospitalized SARS-CoV-2 patients had a similar high overall mortality, despite being younger and healthier, but there was no indication of different effects of inhaled corticosteroid use on disease outcomes. • The findings overall argue for continued use of inhaled corticosteroids according to current guidelines during the COVID-19 pandemic. • Sensitivity analysis of inhaled corticosteroid subtypes suggests a reduced risk of severe COVID-19 outcomes among users of inhaled budesonide. • The protective association between inhaled budesonide and SARS-CoV-2 outcomes is in line with results from the randomized STOIC trial. Taken together, these findings argue for larger randomized trials of inhaled budesonide in early SARS-CoV-2 infection. Infection with the novel coronavirus SARS-CoV-2, the causative agent of the COVID-19 pandemic, has only limited treatment options. [1] [2] [3] [4] [5] [6] [7] Studies report that SARS-CoV-2 infection often leads to severe airway inflammation 8 and recent randomized controlled trials found a substantial beneficial effect of systemic treatment with the corticosteroid dexamethasone in hospitalized COVID-19 patients requiring nasal oxygen or mechanical ventilation. [3] [4] [5] [6] [7] On the other hand, a tendency towards an adverse effect of per oral dexamethasone for patients not requiring oxygen was found in the RECOVERY trial. Nevertheless, the role of inhaled corticosteroids in morbidity of COVID-19 is unclear, with one study finding ambiguous results. 9 Adding to the uncertainty, pre-clinical studies suggests inhaled corticosteroids downregulate the SARS-CoV-2 receptors ACE2/TMPRSS2 10 and inhibit SARS-CoV-2 replication, 11 while there is evidence of more severe disease in COPD patients. 12, 13 Using Danish nationwide population registers on prescription drug use, laboratory-confirmed infectious disease, and hospitalizations, we present a nationwide cohort study of inhaled corticosteroid use and COVID-19 outcomes. To aid in the interpretation of the effects of inhaled corticosteroid use on COVID-19 morbidity in a real-world setting, we conducted a comparison analysis of the effect of inhaled corticosteroid use on influenza morbidity during the 2010-2018 influenza seasons, as randomized controlled trials has not found an association between inhaled corticosteroid use and influenza morbidity. 14 2 | METHODS The Danish Civil Registration System allows individual-level linkage of information from national health registers, in addition to providing demographic information on the entire Danish population. 15 19 The Danish National Prescription Registry, which contains individual-level information on all filled prescriptions in Denmark, provides information on pharmaceutical exposures of interest. 20 The Cause of Death Register includes information on all registered deaths in Denmark. 21 All hospitalized individuals aged 40 years or older in Denmark with a positive SARS-CoV-2 PCR test up to July 16, 2020, were included in our COVID-19 cohort from the date of testing or hospitalization, whichever came latest. The COVID-19 cohort was followed up for ICU admission or death within 30 days from cohort entry. Individuals who tested PCR-positive for influenza during 2010-2018 were included in an equivalent influenza cohort from the date of testing or hospitalization, whichever came latest, and followed up for ICU admission or death within 30 days from cohort entry. For sensitivity analyses, we also constructed nationwide cohorts of all individuals aged 40 years or older who tested positive for SARS-CoV-2 or influenza while out-of-hospital to investigate effect of ICS use in the general population. These cohorts were followed up for hospitalization or death within 30 days from the test date. In addition, we constructed cohorts of SARS-CoV-2 or influenza test-positive ICU patients who were followed up for death within 30 days from admission to ICU, to investigate effect of ICS use among patients with severe illness. Exposure groups were categorized as (1) ICS use: individuals with inhaled corticosteroid (ICS) use, defined as one or more filled prescriptions of inhaled corticosteroids within the last 6 months, with or without simultaneous filled prescriptions for other inhaled pharmaceuticals (i.e., β 2 -receptor agonist and/or muscarinic receptor antagonists), or use of combinatory inhalers (e.g., combined ICS and β 2 -receptor agonist inhaler), (2) Patients with bronchodilator use: individuals with β 2 -receptor agonist and/or muscarinic receptor antagonists use 2 defined as one or more filled prescriptions within the last 6 months, but not ICS use, and (3) All patients without ICS use: individuals without ICS use. Prescriptions 2 weeks prior to a positive test were omitted when allocating study participants to exposure groups. Information on other covariates of interest was defined by relevant pharmaceutical, demographic, and diagnostic codes (see Table S1 ). The study aimed to investigate the effect of ICS on disease severity, why admission to ICU and death where chosen as primary endpoints as both outcomes represent severe infection. Information on date of admission to ICU and mechanical ventilation, respectively, was acquired from the Danish National Patient Register. Information on date of death was acquired from the Cause of Death Register. Our main analysis was conducted among hospitalized individuals who tested positive for SARS-CoV-2 (in 2020) and influenza (in 2010-2018), respectively. We followed participants for 30 days from the date of study entry until either ICU admission, or death. We used Cox proportional hazards regression to estimate the hazard ratios of death and ICU admission comparing exposure groups. We estimated 30-day cumulative hazards according to exposure status taking competing risks of respectively ICU admission or death into account using the Nelson-Aalen estimator. In the Cox models, we took potential confounders into account through direct propensity score adjustment, in addition to age, sex, β2-receptor agonist use, and muscarinic receptor antagonist use. We considered the following covariates in the propensity score: atrial fibrillation, dementia, heart failure, hypertension, inflammatory bowel disease, malignancy, renal failure, Charlson Comorbidity index score, number of filled prescription within 90 days, and per oral corticosteroid use. Covariate status was ascertained 6 months before study entry (before exposure ascertainment). Propensity scores were estimated using logistic regression of probability of exposure on the above-mentioned covariates as main effects. We estimated separate propensity scores for each exposure group of interest. Covariate balance was assessed by graphical inspection of propensity score distribution among exposed and non-exposed cohort members and no indications of unbalanced propensity scores were found (distribution of propensity scores by exposure group can be seen in Figures S1-S4 for the COVID-19 cohort and Figures S5-S8 for the influenza cohort in the supplement). Lastly, a graphical overview of the study design is shown in Figure S9 . (Table 1) . Furthermore, COVID-19 patients were slightly younger and had fewer filled prescriptions within the last 90 days compared with influenza patients. Among COVID-19 patients, 6.5% were registered with a hospital diagnosis for asthma and 8.5% with a chronic pulmonary disease (incl. COPD) diagnosis (Table 1) Table 2 ). Furthermore, examining the 30-day hazard of mechanical ventilation or death, rather than admission to ICU or death, did not lead to different findings (Table S3) . (Figure 1(A) ). In the influenza cohort, death was slightly more common among patients exposed to inhaled corticosteroids (p-value for log-rank test, 0.01) and approximately 10% died within 30 days (Figure 1(B) ). Examining the combined 30-day endpoint of admission to ICU or death by subtype of filled ICS, we observed a stronger reduction in risk among users of budesonide relative to users of fluticasone, compared with users of other inhaled pharmaceuticals and non-users of ICS in the COVID-19 cohort (Table S5) . However, due to low statistical power we were not able to estimate hazard ratios by prescriptions of beclomethasone, ciclesonide, or mometasone. In sensitivity analyses, we looked into the effect of inhaled corticosteroid use by excluding individuals with oral corticosteroid use within the last 6 months, different periods of the COVID-19 epidemic, different influenza seasons, persistency of ICS use, xanthines and leukotriene receptor antagonist use, and effects of prescriptions 2 weeks prior to a positive test (Tables S6-S11), and found no noticeable differences in the hazard of the combined endpoint in different subgroups. In addition, we considered if adjusting for the Charlson Comorbidity index score, beyond individual risk factors, might have led to over-adjustment of our estimates, but found no effect of omitting this factor (Table S12) . Finally, we investigated the 30-day hazard of death among patients admitted to ICU by use of inhaled corticosteroids (Table S13 ). In the COVID-19 cohort, we found no statistically significant difference in risk of death among ICU patients by usage of inhaled corticosteroids compared with users of bronchodilators but not ICS (hazard Furthermore, using hospitalized patients for our main analysis minimized potential selection bias due to potential differential SARS- Furthermore, in parallel with other reports we found COVID-19 to be associated with a markedly high level of overall morbidity and mortality compared with influenza. 23, 24 This finding underscores the severity of COVID-19, since our COVID-19 cohort was both younger and generally healthier than our influenza cohort was. Together with the findings of others, our study supports continued use of inhaled corticosteroid according to current guidelines. Although suggesting no major adverse or beneficial effect of inhaled corticosteroids on COVID-19, our study is no substitution for randomized controlled trials of inhaled corticosteroids in the treatment of COVID-19. As also suggested by others, 25 inhaled corticosteroids could potentially limit both short-term and long-term COVID-19 morbidity and the STOIC trial suggest marked benefits with early treatment. However, larger trials are needed to assess effects on severe outcomes. Taken together, our study found no effect of inhaled corticoste- As the study was based on de-identified information from the Danish national registers and as study participants are never contacted, consent from the Danish research bioethics committees are not required. The study's use of register data was covered by the approval from The Danish Medicines Agency given to A.P. 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A cohort of eight million persons Board of Representatives C. The Danish microbiology database (MiBa) 2010 to 2013 Real-time surveillance of laboratory confirmed influenza based on the Danish microbiology database (MiBa). Stud Health Technol Inform Existing data sources in clinical epidemiology: the danish covid-19 cohort The Danish National Patient Registry: a review of content, data quality, and research potential Data resource profile: the Danish National Prescription Registry The Danish register of causes of death Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial Assessment of Deaths from COVID-19 and from Seasonal Influenza Kondziella D. 30-day mortality and morbidity in COVID-19 versus influenza: a population-based study SUPPORTING INFORMATION Additional supporting information may be found in the online version of the article at the publisher's website. How to cite this article: Husby A, Pottegård A, Hviid A. Association between inhaled corticosteroid use and COVID-19 outcomes Data: Anton Pottegård had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Anders Husby and AntonPottegård. Acquisition, analysis, or interpretation of data: All authors.