These seemingly conflicting data indicate the complexity underlying RAAS responses to pathway modulators and reinforce the concept that findings from preclinical models may not readily translate to human physiology. Such data do suggest that effects on ACE2 should not be assumed to be uniform across RAAS inhibitors or even in response to therapies within a given drug class.41 It is important to note that the plasma ACE2 level may not be a reliable indicator of the activity of the full-length membrane-bound form, in part because ACE2 is shed from the membrane, a process that appears to be separately regulated by an endogenous inhibitor.42 In addition to the degree of expression, the biologic relevance of ACE2 may vary according to tissue and clinical state. Unfortunately, data showing the effects of ACE inhibitors, ARBs, and other RAAS inhibitors on lung-specific expression of ACE2 in experimental animal models and in humans are lacking. Furthermore, even if RAAS inhibitors modify ACE2 levels or activity (or both) in target tissue beds, clinical data are lacking to indicate whether this would in turn facilitate greater engagement and entry of SARS-CoV-2 spike protein. Further mechanistic studies in humans are needed to better define the unique interplay between SARS-CoV-2 and the RAAS network.