Lessons Learned from Coronavirus Disease 2019 Sex Disparities

This issue of the Journal of Women's Health brings to light an important finding from one of the most extensive reports from the early period of the pandemic in New York. The article by Tejpal et al. shows that in the United States, men compared with women have a higher mortality rate when infected with the severe acute respiratory syndrome (SARS)-Cov-2 virus (coronavirus disease 2019 [COVID-19])—they found that women had a 27% lower risk of in-hospital mortality with COVID-19. ¹

Although this finding is new for COVID-19, similar observations have been made of a related infectious disease. As early as 2003, data from China and Hong Kong revealed that men's mortality rate was much higher than that of women infected with SARS after adjusting for age, 21.0% versus 13.2%. ² The biological origin of the sex disparity in clinical outcomes of both SARS and COVID-19 between men and women is likely multifactorial. Sex is expressed through many mechanisms that could play a role in the disparity, including gender-specific behaviors, genetic and hormonal factors, and distinct biological pathways.

Renin–angiotensin–aldosterone system (RAAS), a series of catalytic steps culminating in the formation of angiotensin (Ang) II, is central in the pathogenesis of SARS-CoV-2 disease. Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of RAAS with protective regulatory effects. It regulates the process through Ang II's deactivation and conversion into Ang 1–7, a peptide that subsequently activates the Mas receptor (MasR)—a cascade leading to anti-inflammatory, antifibrotic, and vasodilatory effects. ^3,4 Studies of SARS-CoV-2 reveal that it directly interacts with ACE2 receptors and that the virus relies on ACE2 for cellular entry. Through this process, SARS-CoV-2 infection ultimately reduces the amount of protective ACE2, resulting in a higher viral load and disease severity. ⁴ There may also be soluble forms of ACE2 that may bind to the virus, thereby preventing some of it from binding to the cellular ACE2 receptors, reducing disease severity, and improving outcomes. ⁵

The female advantage may be due to the extra X chromosome, as multiple genes responsible for innate and adaptive immunity, and ACE2, are located on the X chromosomes. ^3,4 Women have been shown to have less pulmonary alveolar type II cells expressing ACE2 compared with men. In addition, some known upregulators of cellular ACE2 expression are also less prevalent in women, specifically smoking and chronic obstructive pulmonary disease. ³

Observed sex differences in COVID severity may also be mediated by transmembrane-serine protease 2 (TMPRSS2), an enzyme involved in viral attachment and membrane fusion, enhancing viral pathogenicity by enabling cellular entry. Androgen is an established TMPRSS2 gene transcription stimulator, which could also worsen the course of the disease in males. ³

Immunologically, compared with men, women have higher antibody production, higher immunoglobulin G concentrations, CD4+ T cells, activated T cells, cytotoxic T cells, and B cells. Women mount better vaccine responses with a more robust T cell response. ^3,6 In contrast, men have higher proinflammatory chemokines and cytokines such as interleukin (IL)-8, IL-18, and chemotactic cytokine ligand 5 (CCL5), factors that could facilitate cytokine storm. ^4,6 In viral signaling, women seem to have an immune advantage, up to a 10-fold higher number of toll-like receptors that upregulate type 1 interferon (IFN), central to the antiviral response. ³ Conversely, testosterone inhibits IFN expression, which may negatively contribute to protection against viral insults in males. ⁴

In addition to biological sex differences in phenotype, psychosocial and behavioral factors may increase men's susceptibility to COVID-19 and death risk. A survey conducted during the pandemic's first wave showed differences in the perceived severity of COVID-19 between men and women. ⁷ In comparison with women, men tend to participate in high-risk behaviors that may potentiate their risk of contracting COVID-19. ^8,9 In several countries, including the United States, more men than women participate in tobacco use and alcohol consumption, linked to increased COVID-19 infection and mortality. ^8,10 Men are also less likely than women to engage in preventive measures such as wearing masks and handwashing. ¹¹ Also, fewer men than women avoided public gatherings or physical contact with others. ⁹

Men have been sociologically conditioned to diminish their fears, possibly downplaying the severity and potential harm of COVID-19. ⁸ In a survey of 2000 adults in Great Britain, 24% of men believed coronavirus is “just like the flu” compared with 16% of women. ¹² The survey also showed that 14% of men believed that COVID-19 only affects older people and those with underlying medical conditions, compared with 8% of women sharing these beliefs. ¹² Socially constructed male behavior patterns may reduce the perception of illness severity and can be problematic in enforcing pandemic restrictions such as social distancing, thus increasing men's vulnerability to COVID-19. ^8,9

Beyond studying sex disparity in COVID-19 mortality among the infected, it is also important to note that the impacts of COVID-19 in the healthy population are also patterned by gender. However, the threat to the healthy population is more apparent for women. Women are more likely than men to develop depression, especially under the added social, familial, and economic stressors of the pandemic. ¹³ Mental illness has increased during the pandemic in all U.S. populations, in tandem with an also steadily increasing prevalence in substance use disorders. ¹⁴ This can be a tragic recipe for domestic abuse and intimate partner violence, of which women are predominantly the victims. Unfortunately, increasing frequency and severity of domestic abuse injuries have been observed in emergency departments. ^15,16

The pandemic and its associated restrictions significantly impacted employment, particularly in the hospitality and foodservice sectors. Women and men of color are over-represented in low-wage jobs and service positions, many of whom were laid off due to the pandemic. ¹⁷ Furthermore, women have typically shouldered the majority of responsibility for childcare, including meals and education. ¹⁷

We concur with the authors of this issue's article titled “Sex-Based Differences in COVID-19 Outcomes” that although women have less mortality risk with COVID-19, we need to exercise caution not to send a message to deliver subpar care to women with COVID-19 or decrease measures to prevent their infection. Our evolving knowledge should not reduce attention paid to women admitted for COVID-19. We should be mindful not to inadvertently take a step back from our progress toward gender equity in health care. Instead, as we better understand the underlying factors for worse disease in males, we should take aggressive action in controlling those risk factors that are modifiable. These actions include emphasizing preventive measures for men, such as better handwashing, decreasing cigarette and alcohol use, and wearing masks appropriately. These measures may save their lives!