Angiotensin-Converting Enzyme(ACE)Inhibitors May Moderate COVID-19 Hyperinflammatory Response:An Observational Study with Deep Immunophenotyping

Background:Angiotensin-converting enzyme inhibitors(ACEi)and angiotensin-II receptor blockers(ARB),the most commonly prescribed antihypertensive medications,counter renin-angiotensin-aldosterone system(RAAS)activation via induction of angiotensin-converting enzyme 2(ACE2)expression.Considering that ACE2 is the functional receptor for SARS-CoV-2 entry into host cells,the association of ACEi and ARB with COVID-19 outcomes needs thorough evaluation.Methods:We conducted retrospective analyses using both unmatched and propensity score(PS)-matched cohorts on electronic health records(EHRs)to assess the impact of RAAS inhibitors on the risk of receiving invasive mechanical ventilation(IMV)and 30-day mortality among hospitalized COVID-19 patients.Additionally,we investigated the immune cell gene expression profiles of hospitalized COVID-19 patients with prior use of antihypertensive treatments from an observational prospective cohort.Results:The retrospective analysis revealed that there was no increased risk associated with either ACEi or ARB use.In fact,the use of ACEi showed decreased risk for mortality.Survival analyses using PS-matched cohorts suggested no significant relationship between RAAS inhibitors with a hospital stay and in-hospital mortality compared to non-RAAS medications and patients not on antihypertensive medications.From the analysis of gene expression profiles,we observed a noticeable up-regulation in the expression of 1L1R2(an anti-inflammatory receptor)and RETN(an immunosuppressive marker)genes in monocytes among prior users of ACE inhibitors.Conclusion:Overall,the findings do not support the discontinuation of ACEi or ARB treatment and suggest that ACEi may moderate the COVID-19 hyperinflammatory response.