Is gender a risk factor in COVID-19 fatalities?*

Neelam Sen, JNU

Across the globe, equal numbers of  men and women appear to have SARS-CoV-2 infection. However, men seem to be at a higher risk of death from the infection [1, 2]. In order to develop effective treatment strategies, it is critical to understand how and to what extent gender differences determine the severity and fatality in Covid-19 patients. Two recent papers discuss the possible role of gender-specific biological factors in Covid-19 disease outcomes.

The SARS-CoV-2 virus uses its Spike protein to recognize the ACE2 protein on host cells, such as human lung cells, which enables it to  gain entry into the cell. This leads to a successful infection. Higher levels of ACE2 in vital organs including lungs, heart and kidneys is correlated with multi-organ failures observed in Covid-19 patients [3]. Ghazizadeh & colleagues show that the hormones androgens and their partner proteins control the levels of ACE2 on the cells [1]. Though androgens are found in both males and females, their levels are much higher in males. Importantly, they show that abnormal androgen levels are associated with severe COVID-19 infections in males. They also tested several drugs that block androgen partner proteins and found that the drugs reduce ACE2 levels on cells.  The lower levels of ACE2 could eventually reduce SARS-CoV-2 viral entry into cells.

Hormonal differences could affect the susceptibility to COVID-19 infection, but the differences in  the body’s immune response, after the host cells are infected, would significantly impact the outcome of the infection.  Immune response is the body's reaction to defend against invading pathogens by employing various cell types, such as the White Blood Cells (WBCs). Takahashi & colleagues evaluated various differences in the immune responses between men and women during the course of SARS-CoV-2 infection [4]. They found that the immune response against SARS-CoV-2 has marked variations between men and women with a stronger immune response by the T-cells observed in women that resulted in relatively milder outcomes. On the other hand, male patients, especially the elder men, had poor T-cell responses that were associated with a severe progression of disease  [4]. On the contrary, male patients had a higher inflammatory-based immune response than the female patients and such a response in females led to severe disease outcomes. These conclusions on the severity of the progression of the disease were derived from a limited pool of  patients and they need to be studied further.

Though these studies don’t show any additional layers of defense against COVID-19 in women, they conclude that there are important gender-differences in susceptibility to COVID-19 and the severity of the infections. A comprehensive understanding of the role played by gender is essential to develop an effective and nuanced treatment strategy that could be different for male and female patients.
 
* For the ease of reading, throughout this article ‘gender’ is used instead of ‘biological sex’.

[1] Gebhard C, Regitz-Zagrosek V, Neuhauser HK et al., "Impact of sex and gender on COVID-19 outcomes in Europe." Biology of Sex Differences (2020). https://doi.org/10.1186/s13293-020-00304-9
 
[2] Klein SL , Dhakal S, Ursin RL et al., Biological sex impacts COVID-19 outcomes. PLOS Pathogens (2020). https://doi.org/10.1371/journal.ppat.1008570
 
[3] Ghazizadeh Z, Majd H, Mikayla R, et al., Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men. bioRxiv 2020.05.12.091082; 
 https://doi.org/10.1101/2020.05.12.091082
[4] Takahashi, T., Ellingson, M.K., Wong, P. et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature (2020). https://doi.org/10.1038/s41586-020-2700-3

[Last updated 08 October 2020]