What is driving the sex difference in COVID-19?

The current evidence for a male predisposition toward increased risk of severe disease from SARS-CoV-2 infection is consistent across age groups and cultural demographics. Smoking was examined as a possible risk factor based on early studies on COVID-19 epidemiology out of China, where the noticable sex difference in disease severity was paired with a national difference in smoking rates between males and females. Approximately 50% of Chinese men smoke compared to ~2% of women according to the WHO, and this was posited as a potential explanation for the male predisposition to COVID-19 (1). However, data from Italy and Spain have indicated that this sexual disparity persists in countries with less egregious differences in smoking rates between sexes (2,3). Additionally, examination of pediatric COVID-19 cases from the United States and China have found that males are disproportionately represented among children who present COVID-19 symptoms (4,5), suggesting that the origin of this disparity is biological rather than behavioral.

Although it is still too early to tell exactly what is causing this sex difference in susecptibility to SARS-Cov-2, the related virus SARS-CoV-1 has been under investigation for a longer period of time and may shed some light on the potential mechanisms of the current pandemic. The 2002-2004 SARS outbreak in Southeast Asia showed similar sex patterns to the current COVID-19 pandemic, and researchers have been able to develop animal models to examine the infection profile. In a 2017 study, researchers found that male mice infected with a modified version of SARS-CoV-1 had a higher mortality rate than their female counterparts (6).

This pattern was seen in transgenic mice with a Rag1 knockout mutation, which do not produce mature T or B cells, indicating that the sexual disparity exists independently of underlying sex differences in the adapative immune system. However, gonadectomy of female wild-type mice removed this protective survival effect while gonadectomy of male mice did not affect survival rates. This suggests that the relative protection afforded to female SARS-CoV-1 patients is mediated through estrogen receptor signalling, although further research will be needed to validate these findings in SARS-CoV-2 infections and to fully elucidate the responsible mechanism (6).

Written by: Blaine Caslin
Edited by: Jina Zhou and Esther Melamed
4/20/2020