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RationaleChronic obstructive pulmonary disease (COPD) is a risk factor for severe COVID-19. Inhaled corticosteroids (ICS) are commonly prescribed for the prevention of acute exacerbations in people with COPD, but their use is associated with increased risk of respiratory infections. The effects of ICS on SARS-CoV-2 susceptibility or COVID-19 severity are currently unknown. ObjectivesTo determine the effects of ICS treatment on the bronchial epithelial cell expression of key SARS-CoV-2-related genes in volunteers with COPD. MethodsWe performed a randomized, open-label, parallel treatment trial of 12 weeks treatment with ICS in combination with long-acting beta-agonist (formoterol/budesonide 12/400 {micro}g twice daily or salmeterol/fluticasone propionate 25/250 {micro}g twice daily), or treatment with LABA only (formoterol 12 {micro}g twice daily), in volunteers with mild to very severe COPD. We obtained bronchial epithelial cell samples via bronchoscopy before and after treatment, and determined transcriptome-wide gene expression by RNA sequencing. Main Results63 volunteers were randomized to receive treatment. Compared to formoterol alone, formoterol/budesonide treatment decreased the expression of the SARS-CoV-2 receptor gene ACE2 and the host cell protease gene ADAM17. These genes were highly co-expressed with innate immune response genes, particularly those of the type I interferon and anti-viral response pathways, which also tended to decrease following ICS treatment. ConclusionsThis is the first randomized controlled trial to show that ICS affect the expression of key SARS-CoV-2-related genes in COPD. Their relation to important anti-viral response genes may have critical implications for SARS-CoV-2 susceptibility or COVID-19 severity in this vulnerable population.
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IntroductionCoronavirus disease 2019 (COVID-19) is a respiratory infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This virus uses the angiotensin converting enzyme II (ACE-2) as the cellular entry receptor to infect the lower respiratory tract. Because individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of severe COVID-19, we determined whether ACE-2 expression in the lower airways was related to COPD and cigarette smoking. MethodsUsing RNA-seq, we determined gene expression levels in bronchial epithelia obtained from cytologic brushings of 6th to 8th generation airways in individuals with and without COPD. We eternally validated these results from two additional independent cohorts, which used microarray technologies to measure gene expression levels from 6th to 12th generation airways. ResultsIn the discovery cohort (n=42 participants), we found that ACE-2 expression levels were increased by 48% in the airways of COPD compared with non-COPD subjects (COPD=2.52{+/-}0.66 log2 counts per million reads (CPM) versus non-COPD= 1.70{+/-}0.51 CPM, p=7.62x10-4). There was a significant inverse relationship between ACE-2 gene expression and FEV1% of predicted (r=-0.24; p=0.035). Current smoking also significantly increased ACE-2 expression levels compared with never smokers (never current smokers=2.77{+/-}0.91 CPM versus smokers=1.78{+/-}0.39 CPM, p=0.024). These findings were replicated in the two eternal cohorts. ConclusionsACE-2 expression in lower airways is increased in patients with COPD and with current smoking. These data suggest that these two subgroups are at increased risk of serious COVID-19 infection and highlight the importance of smoking cessation in reducing the risk.
