Introduction
The outbreak of novel coronavirus disease 2019 (COVID-19) quickly turned into a pandemic, and Europe and U.S.A. have been particularly affected [Zhou et al. 2020b]. Sex differences are emerging in terms ofcase fatality (deaths/reported cases), and sex disaggregated data are now starting to be available for many countries. Looking at male/female ratio for death in confirmed cases it appears that the ratio is always above 1.1 in 34 out of the 35 countries that provide sex disaggregated data (only for Pakistan, the ratio is 0.9). Many European countries (Spain, Italy, England, Belgium, Greece, Denmark and The Netherlands) have a male/female ratio for death in confirmed cases equal or above 1.7 (https://globalhealth5050.org/covid19/, accessed on May 13th 2020). In particular, on May 11, 28.903 COVID-19 positive patients had died in Italy (Table 1). Their mean age was 80 years (median 81, range 0-100, IQR 74 -87) (https://www.iss.it/coronavirus, accessed on May 13th2020). Deceased women were 10.934 (lethality 9.6%), whereas men were 17.018 (lethality 17.1%). For 951 Italian deaths, sex was not reported. The difference in lethality between sexes seems to suggest that women are less prone to develop severe complications that ultimately lead to death. The reasons for this sex-based tolerance are still unknown. Among Italian patients in the range 10-49 years, deceased women were about 84 over 32.345 (0.26% lethality), while in the range age of 50-90 years they were 7975/67.263 (11.9% lethality). Of note, men had a 0.89% lethality (225 deaths over 25276 cases) in the range 10-49 years and 21.8% (15236/69844) in the range 50-90 years. Therefore, lethality seems to increase with age in both sexes, but it is 3.42 folds higher in young men than young women (10-49 years), and 1.84 folds in older men than in older women (50-90 years) (https://www.iss.it/coronavirus, accessed on May 13th 2020).
Although these are cumulative/raw data, they confirm that there is a reduced susceptibility of females to severe COVID-19 infection. Due to the differences between pre and post-menopausal phases [Horstman et al. 2012], it is reasonable to speculate that the potential role played by hormones may be present in protecting against severe outcome, but it is not the only factor. Therefore, we need to consider other possible reasons for this difference in sex-related lethality. First, is this difference confirmed also in populations from other countries? According to the latest publications, such differences in lethality between the 2 sexes have been shown elsewhere (see Table 1 andhttps://globalhealth5050.org/covid19/). For instance, in a number of different articles from China, similar data are reported [Chen et al. 2020a; Chen et al. 2020b; Guan et al. 2019; Huang et al. 2020; Wang et al. 2020; Zhou et al. 2020a]. In these studies, severe or deceased patients admitted to intensive care units (ICUs) were prevalently men, while women ranged between 30% [Huang et al. 2020] and 42.2% [Guan et al. 2019]. In the largest study available from China [Guan et al. 2019;], quite similar percentages to those reported for deceased women in Italy have been observed. Yet, in this latter study, the median age of patients was 47 years (IQR, 35-58), and the distribution between sexes according to age was not reported. For the US, sex disaggregated data on case fatality are not available, but deaths were 57% for males and 43% for women (https://globalhealth5050.org/covid19/, accessed on May 13th 2020).
To sum up, currently available studies suggest that both young and older females are less susceptible to severe infection outcomes, regardless of their nationality. Both hospitalization in ICUs and death rates are different between sexes (https://globalhealth5050.org/covid19/ and Table 1). Similar observations were already reported for other coronavirus epidemics [Channappanavar et al. 2017].
Despite this striking evidences for this infection, very few studies consider different therapeutic approaches for the two sexes. As no specific therapeutics are yet proposed to treat Covid-19 and control disease evolution, a better understanding of the pathogenic mechanisms in the two sexes induced by SARS-CoV-2 is mandatory to characterize new targets.