Key factors that determine the severity of COVID-19 infection include age, genetic makeup, underlying health issues including hypertension, diabetes and obesity, lifestyle, access to healthcare, socioeconomic status, work conditions, and, as evidenced by the outcome disparities reported between men and women, sex, though further investigation of the impact of sex remains to be done.

To infect a host cell, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), relies on a protein present on the host cell surface called angiotensin-converting enzyme 2 (ACE2). ACE2 is epigenetically regulated and is expressed in various tissues and cell types, including the heart, lungs, skin and small intestine, and plays a key role in regulating cardiovascular and pancreatic functions. In a recent study, it was found that males with a cardiac condition had higher levels of ACE2 present in the bloodstream compared to healthy males, who themselves had higher levels of ACE2 in the bloodstream than females. This differential expression of ACE2 between sexes may be one of the biological reasons that males are more susceptible to COVID-19.

In terms of immunity, females generate stronger immune responses compared to males, consistent with the fact that the X chromosome—of which women have two and men have one—contains a high number of immune-related genes. While this may result in an enhanced immune response in women, the downside is a higher susceptibility to autoimmune diseases—conditions in which the immune system attacks the body instead of invading pathogens.

Biology may not be the only factor contributing to differences in COVID-19 disease outcomes between males and females. Studies have shown that men were less likely to wear masks, maintain safe distances from others, wash hands and seek medical help compared to women, and men were more likely to engage in risky behaviour, such as join a protest. While the majority of health workers are women, other frontline essential positions, including manufacturing, construction and transportation, are dominated by men. This means more men are exposed to gatherings and jobs requiring travelling. In the time of mandate social distancing, this could be another contributing factor to this disparity in infection rate.

Strategies to decrease COVID-19-related death rates for men may include public health outreach initiatives to encourage men to engage in healthy behaviour and to access primary health care when needed. While there is still on-going research to determine the impact of COVID-19 on the sex gap, it is important that studies also include individuals from the transgender and non-binary (TGNB) community.