Sex Differences in COVID-19

The novel coronavirus disease of 2019 (COVID-19) pandemic caused by SARS-CoV-2 has claimed lives around the globe of both men and women alike. Early reports have shown evidence for gendered impact on health outcomes from COVID-19. Global Health 50/50 is an independent initiative for gender equality in global health, and serves as an important resource for sex-disaggregated data tracking and analysis. Through data collection from official government sources around the world since the onset of the pandemic in March 2020, Global Health 50/50 has provided disease distribution and outcomes information essential to the study of sex differences in COVID-19. While current global data does not appear to reveal sex predilection in disease contraction, gender differences in outcomes once infected have been found.^1,2 

Data from 166 countries indicate a strong signal for worse outcomes in males compared to females. Almost all of the countries with available sex-disaggregated data showed that the male-to-female ratio of COVID-related deaths was >1, with the highest ratio up to 2.57 in Thailand.

In only 5 countries (Costa Rica, Finland, Slovenia, Nepal, Maldives), the male-to-female ratio of COVID-related deaths was <1. In the United States, where the burden of disease is highest with more than 7 million confirmed cases to date, this gendered pattern also exists, with 55% of deceased patients being male.¹ In earlier studies, males have worse health outcomes in the disease spectrum, also accounting for more cases of hospitalization and intensive care admissions, aside from mortality.³

While the exact mechanisms for sex outcomes in COVID-19 remain poorly understood, the causation is likely multifactorial (Figure 1). The X chromosomes contain genes that modulate immune function, which confers more immune protection in females.⁴ Another proposed mechanism is through the anti-inflammatory response mediated by the angiotensin type 2 receptor (AT₂), which has a higher expression in females, thereby conferring decreased risk.⁵ Reproductive organs and hormonal influences likely play a role in sex differences in COVID-19 as well. The specific hormone effects on angiotensin-converting enzyme 2 (ACE2), the key cellular receptor of SARS-CoV-2, likely mediate this. The testis has high levels of expression of ACE2, which could be the driver for the exaggerated COVID-19 effect in males. Additionally, the hormone 17β-estradiol could be attenuating the pathophysiologic effects of COVID-19; a similar manner of lung ACE2 mRNA downregulation by 17β-estradiol has been seen in influenza studies.⁴ Postmenopausal women may be at higher risk for worse COVID-19 disease.⁶ 

Lifestyle and behavioral factors can also play a role in gendered outcomes from COVID-19. Among the various factors, smoking is of particular interest, a practice that is associated to be more common in males. Lung carcinoma and chronic pulmonary disease, both heavily linked to smoking, also predispose patients to more severe disease through a poorer baseline pulmonary status. Early studies show that smoking increases ACE2 expression, which could contribute to poorer outcomes.⁷

Studies have shown that COVID-19 may be a multiorgan endothelial disease triggered by the viral infection,⁸ resulting in various clinical manifestations that reflect its widespread involvement.  

Risk Factors and Pathophysiology of COVID-19

The presence of low-grade systemic inflammation (elevated IL-6) and endothelial dysfunction increase COVID-19 severity. Risk factors that result in systemic inflammation and endothelial dysfunction include obesity, hypertension, cardiovascular disease, diabetes, and cigarette smoking.⁸ 

ACE2 protects endothelial function and exerts anti-inflammatory effects. ACE2 and ACE imbalances accelerate endothelial dysfunction and worsen the progression of vascular disease. Vascular endothelium activation and damage, which occur as part of COVID-19, result in a microvascular injury syndrome that may create a procoagulant state and explain the systemic nature of the disease.⁸

SARS-CoV-2 induces an inflammatory cytokine storm, multiorgan endothelial dysfunction, and thrombotic complications. Chronic inflammation may result in endothelial dysfunction and thrombotic events, endothelial dysfunction promotes thrombosis, and acute thrombosis can accelerate endothelial dysfunction.⁸ Figure 2 summarizes the risk factors and mechanisms that can cause COVID-19 complications.

Sex Differences in QTc Prolongation During COVID-19

Female sex is a well-known risk factor for QTc prolongation leading to Torsades de Pointes (TdP). TdP is 3 times more likely to occur in women than in men.⁹ Although the mechanisms are not completely understood, it is known that estrogen fluctuations can alter the QTc interval.¹⁰ Baseline differences in early and late repolarization such as corrected QTc are longer in females (by 24 msec, 6% longer) when compared to males.¹¹

Investigative treatments for COVID-19 include QTc-prolonging medications such as hydroxychloroquine with or without azithromycin. Hydroxychloroquine¹² and azithromycin¹³ are individually implicated in prolonging QTc, a predictor of TdP.¹⁴ Many trials administered hydroxychloroquine and azithromycin to COVID-19 patients despite concerns of pro-arrhythmic risks due to QTc prolongation.¹⁴

With this background, the question of pronounced QTc elevation risk in female COVID-19 patients undergoing these treatments remains unanswered, and was explored in a recent article by Grewal et al.¹⁵ Evaluating the data reported and additional shared data from different geographical regions, including the New York metropolitan region¹⁶ and France,¹⁷ as well as other observational COVID-19 trials,¹⁸ their aim was to assess whether sex-mediated disparities in QTc alterations existed in COVID-19 treatments. They found that an increased QTc interval of >500 msec was noted in 20% of the patients receiving hydroxychloroquine and azithromycin. They analyzed a cohort of 251 patients, which showed an average increase of 35 msec in males and 30 msec in females. However, there were no increased deaths due to TdP in females. They concluded that since a greater proportion of COVID-19 patients admitted to the hospitals are males, the sex disproportionality in hospitalizations precluded a distinctive risk association in the female COVID-19 patients, and that their observational commentary lacked statistical validity.¹⁵

To date, there are no studies looking at sex disparities in arrhythmias (ventricular tachycardia, TdP, or atrial fibrillation) outcomes in COVID-19 patients.

Conclusion

Although women are equally vulnerable as men to SARS-CoV-2, men with COVID-19 are more at risk for worse outcomes and higher mortality rates. The reasons for this vulnerability in men is not completely understood but may be due to several biological mechanisms, more risky lifestyle behaviors, and a higher risk of comorbidities. Lifestyle behaviors that contribute to higher risk include smoking, poor handwashing hygiene, and delay in seeking care. Biologically, women have a stronger immune system, and 17β-estradiol has attenuating effects of COVID-19. Finally, higher levels of ACE2 in men may also contribute to the higher mortality risk.

Disclosures: The authors have no conflicts of interest to report regarding the content herein.

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