The following are key perspectives from this Viewpoint on coronavirus disease 2019 (COVID-19) infection and renin angiotensin system blockers:

1. The COVID-19 pandemic is spreading at an exponential rate, with millions of people across the globe at risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
2. Initial reports suggest that hypertension, diabetes, and cardiovascular diseases were the most frequent comorbidities in affected patients, and case fatality rates tended to be high in these individuals.
3. Patients with such comorbidities are commonly treated with renin angiotensin system blockers, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs). However, the use of ACEIs/ARBs in patients with COVID-19 or at risk of COVID-19 infection is currently a subject of intense debate.
4. SARS-CoV-2 uses the ACE2 receptor for entry into target cells. ACE2 is predominantly expressed by epithelial cells of the lung, intestine, kidney, heart, and blood vessels.
5. Animal (mice) studies have shown that expression of ACE2 is substantially increased in patients treated with ACEIs/ARBs. Based on these observations, some experts have speculated that use of ACEIs/ARBs leading to increased expression of ACE2 could potentially facilitate infection with COVID-19.
6. On the other hand, it has been postulated that SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity, skewing the ACE/ACE2 balance to a state of heightened angiotensin II activity leading to pulmonary vasoconstriction and inflammatory and oxidative organ damage, which increases the risk for acute lung injury (ALI). Conceivably, renin angiotensin system modulation, either by ACEIs/ARBs or recombinant ACE2, leading to increased expression of ACE2 may help mitigate some of these deleterious effects of angiotensin II.
7. It is also postulated that increased levels of the soluble form of ACE2 may act as a competitive interceptor of SARS-CoV-2 and slow virus entry into the cells and protect from lung injury.
8. Several professional societies have put forward their guidance regarding the use of ACEIs/ARBs in patients with COVID-19. In summary, all guidelines recommend continuing ACEIs/ARBs in patients with COVID-19 unless clinically indicated. Furthermore, they do not suggest initiation of ACEIs/ARBs in those without another clinical indication (e.g., hypertension, heart failure, diabetes), given the lack of strong evidence showing benefit of these medications in COVID-19.
9. A multicenter, double-blind, placebo-controlled phase 2 randomized clinical trial of starting losartan in patients with COVID-19 in outpatient settings (ClinicalTrials.gov identifier: NCT04311177) and in inpatient settings (ClinicalTrials.gov identifier: NCT04312009) is currently being planned and will provide additional insight.
10. Additional studies and prospective trials are urgently needed to investigate if use of ACEIs/ARBs can reduce the incidence or mortality associated with COVID-19–associated ALI or acute respiratory distress syndrome, both in patients with and without additional clinical indications for ACEIs/ARBs.

Clinical Topics: COVID-19 Hub, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Hypertension

Keywords: Angiotensin II, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, COVID-19, Coronavirus, Coronavirus Infections, Diabetes Mellitus, Heart Failure, Hypertension, Losartan, Peptidyl-Dipeptidase A, Renin-Angiotensin System, Respiratory Distress Syndrome, SARS Virus, Secondary Prevention, Vascular Diseases, Vasoconstriction

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