Sex, Renin Angiotensin System Inhibitors, and COVID-19 Severity: Biologic Divergence or Healthcare Disparity?

The renin-angiotensin system (RAS) has received considerable scrutiny for its potential role in the biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia since the beginning of the COVID-19 event. Early in the pandemic, it was discovered that like the SARS-CoV-1 virus, SARS-CoV-2 uses the angiotensin-converting enzyme-2 (ACE-2) protein as a receptor to gain cell entry. This process appears further augmented by cobinding of viral-ACE-2 complexes to either angiotensin-II type-1 receptors (AT1Rs) or vasopressin-V1 receptors (1). Additionally, multiple animal models consistently reported that proinflammatory AT1R signaling played a key mediating role in the development of experimental inflammatory lung injury (2). Further heightening interest in the RAS pertaining to COVID-19, there are already U.S. Food and Drug Administration-approved therapies that modulate the RAS including inhibitors of the ACE-1 enzyme (ACE-Is) as well as AT1R antagonists (AT1R blockade [ARB]) and agonists (synthetic angiotensin-II).

Subsequent biomarker studies demonstrated a dynamic course of RAS markers in severe COVID-19 that closely correlated with organ dysfunction and illness severity (3–6). Although these observations seemingly implicated an important role for the RAS in COVID-19, randomized trials to date consistently show neither benefit nor harm from RAS-inhibiting therapies (7, 8). A caveat to interpreting these trials is that all were conducted in patients with early, mild, or moderate disease. No randomized studies to date have evaluated RAS modulation in critically ill COVID-19 patients who meet criteria for acute respiratory distress syndrome. Still, the relation of the RAS to key early disease events, such as viral cell entry, could indicate that other factors may be at play.

In this issue of Critical Care Medicine, Rocheleau et al (9) offer an intriguing hypothesis informed by another observation from early in the pandemic: that men with COVID-19 tend to develop more severe disease than women.

In a prospectively enrolled multicenter observational study, the authors followed 1686 patients admitted to the hospital with COVID-19 and evaluated whether biological sex was an effect modifier for the association between chronic RAS-modulating therapy and disease severity. They found that males taking preadmission ARBs had lower risk of invasive ventilation and vasopressor use versus those not taking ARBs, an association not seen among females. This association was specific to ARBs and not seen for ACE-Is. Additionally, the authors measured plasma levels of several RAS metabolites in a subset of patients and observed that males had higher plasma ACE-1 levels than females early in the disease course. This difference between sexes subsided over time.

This observational study comparing preillness medication exposures cannot—and should not—be used to inform RAS modulating treatment strategies for critically ill COVID-19 patients. However, from the perspective of understanding the biology of COVID-19, this report raises intriguing questions for future study. Perhaps more importantly, the authors’ findings also highlight underrecognized sex differences that may have impact on equitable care.

One possibility supported by the present study is that the widely hypothesized potential for RAS-modulation to influence viral susceptibility is sex-dependent. The observation that exposure to ARBs, but not ACE-Is, was associated with decreased disease severity supports this notion, given that the AT1R is shown to augment the endocytosis of complexes formed between SARS-CoV-2 and soluble ACE-2: (1) ARBs are direct receptor antagonists, whereas ACE-1 inhibitors do not directly interact with AT1R. The male-specific association reported in the present study, along with the ACE2 gene’s X-chromosomal locus and relatively higher expression in males, is also consistent with this hypothesis. Although lack of a consistent signal for disease modulation from ARB in early disease has lessened enthusiasm for RAS-inhibition, reviewing these trials for evidence of effect-modification by sex may be warranted.

Distinct from whether clinical RAS modulation impacts viral susceptibility is the question of how the RAS interacts with vascular injury and inflammation in COVID-19. Sex-related differences may again prove relevant. Notably, large meta-analyses of RAS-blocking therapy report greater antihypertensive efficacy in male versus female patients (10). Pulmonary ACE-1 shedding is a well-described sequela of acute inflammatory injury (11), including in viral infection, and the higher initial plasma ACE-1 levels seen in this study in males suggest greater pulmonary vascular inflammation. A critical limitation of the present study is the inability to disentangle whether the sex-related association between ARB exposure and COVID-19 severity reflects the drugs themselves or any of the numerous other factors represented by their use: not only underlying chronic cardiorenovascular disease severity but also patients’ longitudinal engagement in healthcare and medication adherence. Although this clearly precludes inferring that chronic RAS-exposure alters COVID-19 disease course, the commonality among these myriad collinear elements is nevertheless greater chronic vascular inflammation and injury.

As to whether these data can directly influence treatment of critically ill patients with COVID-19—the answer is no. First, as discussed above, an observational study of a preillness treatment exposure cannot dictate ICU treatment decisions. Second, it is notable that no randomized trials of ARBs have been conducted in critically ill COVID-19 patients. Hemodynamic tolerability is a key concern in this population given the heavy sedation that life-saving low tidal volume ventilation often requires; the combination of RAS-inhibition, and sedative-hypnotic agents can induce profound and refractory hypotension (12).

Yet, the key implication of this study involves equitable translation of research to practice. More than 60% of study patients were male, hardly atypical of COVID-19 clinical reports. Although the relative overrepresentation of male patients in clinical trials is well-documented across multiple disciplines (13), this disparity appears heightened in COVID-19 literature. Consider that although males comprise 57% of National Institutes of Health-funded trial participants, in the pivotal Randomized Evaluation of COVID-19 Therapy-Dexamethasone Trial (RECOVERY-DEX), which established dexamethasone as standard-of-care in COVID-19 critical illness, 73% of patients were male (14). Similar imbalances occur in major basic and translational advances in COVID-19 biology (e.g., male-only animal experiments), making them vulnerable to missing potential sex-related differences. The higher observed baseline disease severity of male patients in COVID-19 trials suggests sex differences are indeed present. However, the sex-based differences in risk associated with outpatient medication use identified by Rocheleau et al (9) may indicate clinically relevant sex-stratified effects regardless of whether they are biologically intrinsic to COVID-19. These findings may be a canary in the coal mine for mechanisms and treatments we currently accept as sex-agnostic. Whether our clinical knowledge about what works for severe COVID-19 is really just what works for men with severe COVID-19 is an uncomfortable question, but one we need to ask.

In summary, the study by Rocheleau et al (9) proposes and offers preliminary data to support a novel hypothesis on the interaction of sex and the RAS in SARS-CoV-2 infection. It reinforces the increasingly accepted view that vascular injury is a key component of serious COVID-19 illness. However, there remains much to learn about the interaction of the RAS, inflammation, and lung injury. Future mechanistic studies may do well to consider if accounting for the influence of sex can refine our understanding. However, perhaps most importantly, both animal and human COVID-19 studies must ensure equitable representation of the sexes to ensure that new insights benefit all patients without reinforcing preexisting disparities.