Warren Alpert Medical School of Brown University, Providence
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already surpassed the combined mortality inflicted by the severe acute respiratory syndrome (SARS) epidemic of 2002 and 2003 and the Middle East respiratory syndrome (MERS) epidemic of 2013. The pandemic is spreading at an exponential rate, with millions of people across the globe at risk of contracting SARS-CoV-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. In the largest Chinese study to date,1 which included 44 672 confirmed cases, preexisting comorbidities that had high mortality rates included cardiovascular disease (10.5%), diabetes (7.3%), and hypertension (6.0%). 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. Below, we outline the mechanisms by which ACEIs/ARBs may be of benefit in those with COVID-19, what the current recommendations are for their use in infected patients, and suggested areas for further research.
SARS-CoV-2 uses the angiotensin-converting enzyme (ACE) 2 receptor for entry into target cells. ACE2 is predominantly expressed by epithelial cells of the lung, intestine, kidney, heart, and blood vessels. Both ACE and ACE2 belong to the ACE family of dipeptidyl carboxydipeptidases and exert distinct physiological functions. ACE cleaves angiotensin I to angiotensin II, which in turn binds and activates angiotensin II receptor type 1. This activation leads to vasoconstrictive, proinflammatory, and pro-oxidative effects. In contrast, ACE2 also degrades angiotensin II to angiotensin 1-7 and angiotensin I to angiotensin 1-9. When angiotensin 1-9 binds to the Mas receptor, it leads to anti-inflammatory, antioxidative, and vasodilatory effects. It is important to note that 2 forms of ACE2 exists: a structural transmembrane protein with extracellular domain that serves as a receptor for spike protein of SARS-CoV-2 and a soluble form that represents the circulating ACE2. Understanding the relationship between SARS-CoV-2 and membranous and soluble ACE2 may help us better understand the adaptive or maladaptive processes operative in COVID-19 infection.
Animal (mice) studies have shown that expression of ACE2 is substantially increased in patients treated with ACEIs/ARBs.2,3 Similar to these observations, higher urinary ACE2 levels were seen in patients with hypertension treated with the ARB olmesartan. In another study,4 circulating ACE2 levels were increased in patients with diabetes treated with ACEIs. 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.
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 (Table). Furthermore, they do not suggest initiation of ACEIs/ARBs in those without another clinical indication (eg, hypertension, heart failure, diabetes), given the lack of strong evidence showing benefit of these medications in COVID-19. We agree with these recommendations, given the current state of evidence. However, the biological plausibility of salutary effects of ACEIs/ARBs in those with COVID-19 is intriguing. 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 in-patient settings (ClinicalTrials.gov identifier: NCT04312009) is currently being planned. Accordingly, further epidemiological 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 ARDS, both in patients with and without additional clinical indications for ACEIs/ARBs.