ACE-2 Downregulation and Incidence of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) Infection

To the Editor: Dublin et al. present an excellent manuscript which not only adds to the growing evidence base that prescription of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARBs) is not associated with increased incidence or severity of severe acute respiratory syndrome-coronavirus-2 (SARS- CoV-2) infection but also shows no adverse effect on clinical outcomes, irrespective of the dosage prescribed.1 SARS-CoV-2 utilizes cellular ACE-2 for viral entry.2 Multiple recent publications suggest that ARBs upregulate ACE-2 (albeit with intraclass variations) while ACEi have at most minimal effects.2 Dublin et al.’s study therefore infers, indirectly, that chronically increased ACE-2 does not predispose to SARS-CoV-2 infection or severity despite its high affinity for ACE-2.1,2 The effect of chronically downregulated ACE-2 on susceptibility to SARS-CoV-2 is unknown. There is a signal that inhibiting ACE-2 might be beneficial. Anti-ACE-2 antibodies inhibited SARS-CoV-1 replication in animal models, as did the specific ACE-2-inhibitor N-(2-aminoethyl)-1 aziridine-ethamine.3 The direct renin antagonist aliskiren downregulates ACE-2 in rodent models.4 The authors’ dataset includes over 300,000 patients with detailed medication prescription records; could they provide data on prescription of aliskiren and, if numbers sufficient, incident SARS-CoV-2 infection, hospitalizations and outcomes in those receiving aliskiren? If incidence and hospitalization rate is reduced, this could inform a paradigm shift in focus from ACE-2 amelioration to antagonism in the prevention/limitation of future ACE-2 mediated viral infections including SARS-CoV-2. The authors declared no conflict of interest.