Impact of sex and gender on COVID-19 outcomes in Europe

Abstract

Background: Emerging evidence from China suggests that coronavirus disease 2019 (COVID-19) is deadlier for infected men than women with a 2.8% fatality rate being reported in Chinese men versus 1.7% in women. Further, sex-disaggregated data for COVID-19 in several European countries show a similar number of cases between the sexes, but more severe outcomes in aged men. Case fatality is highest in men with pre-existing cardiovascular conditions. The mechanisms accounting for the reduced case fatality rate in women are currently unclear but may offer potential to develop novel risk stratification tools and therapeutic options for women and men.

Content: The present review summarizes latest clinical and epidemiological evidence for gender and sex differences in COVID-19 from Europe and China. We discuss potential sex-specific mechanisms modulating the course of disease, such as hormone-regulated expression of genes encoding for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) entry receptors angiotensin converting enzyme (ACE) 2 receptor and TMPRSS2 as well as sex hormone-driven innate and adaptive immune responses and immunoaging. Finally, we elucidate the impact of gender-specific lifestyle, health behavior, psychological stress, and socioeconomic conditions on COVID-19 and discuss sex specific aspects of antiviral therapies.

Conclusion: The sex and gender disparities observed in COVID-19 vulnerability emphasize the need to better understand the impact of sex and gender on incidence and case fatality of the disease and to tailor treatment according to sex and gender. The ongoing and planned prophylactic and therapeutic treatment studies must include prospective sex- and gender-sensitive analyses.

Keywords: COVID-19; Gender; Immune system; Renin angiotensin aldosterone system; Sex.

Fig. 1

Sex-disaggregated data of confirmed COVID-19 cases and deaths provided by Global Health 50%50 data tracker as of April 2, 2020 [16]

Fig. 2

Male to female ratios of COVID-19 cases, hospitalizations, intensive care unit (ICU) admissions, deaths, and case-fatality rates in European countries and China as of April 2, 2020. *absolute numbers are provided. Sex-disaggregated data were not available for all indicators

Fig. 3

Male predominance in COVID-19 case fatality (deaths divided by confirmed cases) in Italy, Spain, Germany, and Switzerland by age. A male to female mortality ratio of 1 would reflect gender balance, the red bars reflect male predominance. Pooled data from Italy as of March 30, 2020, Spain as of March 31, 2020, Germany as of April 1, 2020, and Switzerland as of March 31, 2020

Fig. 4

Estrogen and sex regulate components of the renin angiotensin aldosterone system (RAAS). Estrogen-regulated pathways are depicted in green. AT2R angiotensin II type 2 receptor, ACE2 angiotensin converting enzyme 2, NEP neutral endopeptidase neprilysin

Fig. 5

Sexual dimorphism in TMPRSS2-mediated SARS-CoV2 host cell entry. Androgen receptors (ARs) are activated via heat shock proteins (HSPs) release in response to changes in intracellular testosterone concentration. ARs are then phosphorylated and translocated as homodimers into the nucleus, prompting transcriptional activation of TMPRSS2 and translation of the TMPRSS2 protein [149]. At the cell membrane, TMPRSS2 facilitates viral entry and spreads into the host cell by activating the spike proteins [24]