Up-regulation of ACE2, the SARS-CoV-2 receptor, in asthmatics on maintenance inhaled corticosteroids

Abstract

Background: The first step in SARS-CoV-2 infection is binding of the virus to angiotensin converting enzyme 2 (ACE2) on the airway epithelium. Asthma affects over 300 million people world-wide, many of whom may encounter SARS-CoV-2. Epidemiologic data suggests that asthmatics who get infected may be at increased risk of more severe disease. Our objective was to assess whether maintenance inhaled corticosteroids (ICS), a major treatment for asthma, is associated with airway ACE2 expression in asthmatics.

Methods: Large airway epithelium (LAE) of asthmatics treated with maintenance ICS (ICS⁺), asthmatics not treated with ICS (ICS^-), and healthy controls (controls) was analyzed for expression of ACE2 and other coronavirus infection-related genes using microarrays.

Results: As a group, there was no difference in LAE ACE2 expression in all asthmatics vs controls. In contrast, subgroup analysis demonstrated that LAE ACE2 expression was higher in asthmatics ICS⁺ compared to ICS‾ and ACE2 expression was higher in male ICS⁺ compared to female ICS⁺ and ICS‾ of either sex. ACE2 expression did not correlate with serum IgE, absolute eosinophil level, or change in FEV1 in response to bronchodilators in either ICS^- or ICS⁺.

Conclusion: Airway ACE2 expression is increased in asthmatics on long-term treatment with ICS, an observation that should be taken into consideration when assessing the use of inhaled corticosteroids during the pandemic.

Keywords: ACE2; Asthma; Gene expression; Large airway epithelium; Maintenance inhaled corticosteroids; SARS-CoV-2.

Fig. 1

Effect of maintenance inhaled corticosteroid (ICS) and sex on ACE2 expression in the large airway epithelium (LAE). A, B All nonsmoker asthmatics (n = 57) vs healthy nonsmoker controls (n = 29). C, D Nonsmoker asthmatics on maintenance ICS (ICS⁺, n = 19) vs nonsmoker asthmatics not on ICS (ICS⁻, n = 38). A All asthmatics vs controls, by phenotype (ANCOVA, with age as a co-variant). B All asthmatics vs controls, by phenotype and sex (ANOVA). C Asthmatics ICS⁺ vs asthmatics ICS⁻, by phenotype (ANCOVA, with sex as a co-variant). D Asthmatics ICS⁺ vs asthmatics ICS⁻, by phenotype and sex (ANOVA). Data is presented as mean ± standard error

Fig. 2

Correlation of absolute eosinophil and serum IgE levels and FEV1 response to bronchodilators with large airway epithelium (LAE) ACE2 expression. A–C Nonsmoker asthmatics not treated with inhaled corticosteroids (ICS, ICS⁻, n = 38). D–F Nonsmoker asthmatics treated with maintenance ICS (ICS⁺, n = 19). A, D Eosinophil level vs ACE2 expression. B, E IgE level vs ACE2 expression. C, F FEV1 response to bronchodilators (FEV1 post- vs pre-bronchodilators, presented as % change) vs ACE2 expression