Inhaled corticosteroids downregulate SARS-CoV-2-related gene expression in COPD: results from a RCT

Milne, Stephen; Li, Xuan; Yang, Chen Xi; Cordero, Ana I Hernandez; Filho, Fernando Sergio Leitao; Yang, Cheng Wei Tony; Shaipanich, Tawimas; Eeden, Stephan F van; Leung, Janice M; Lam, Stephen; Sin, Don D

Rationale: Chronic 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. Objectives: To determine the effects of ICS treatment on the bronchial epithelial cell expression of key SARS-CoV-2-related genes in volunteers with COPD. Methods: We 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 g twice daily or salmeterol/fluticasone propionate 25/250 g twice daily), or treatment with LABA only (formoterol 12 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 Results: 63 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. Conclusions: This 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.