COVID-19: Is there a weaker sex?

Int

Sex is one of the most relevant factors often associated with health, disease severity, mortality, and life expectancy [1]. From neonatal diseases to non-communicable disorders, men often have higher risks and poorer prognosis; however, the causes of these disparities are still subject to debate [[2], [3], [4], [5], [6], [7]]. In this context, the new coronavirus disease of 2019 (COVID-19) has again called attention to these differences, mainly due to the observations of a higher level of complications and fatality rates among men [8]. According to data from the Global Health 50/50 initiative, which collects sex-disaggregated information from COVID-19 cases worldwide, from the 75 countries reporting case and death data by sex, 63 revealed a male:female ratio of mortality over 1, three countries having a value of 1 and only nine a ratio below this mark (Fig. 1). Furthermore, a recent study observed that although the male: female ratio of deaths per 100,000 individuals varied by age, the probability of death remained higher in males across all age categories [9]. In addition, a recently published study from India revealed that the magnitude of the differential risk by sex was higher as age increased, suggesting a role of age in this association [10]. Beyond these population observations, several studies have concluded that male sex is a risk factor for COVID-19 adverse outcomes, even in multivariate analyses after adjusting for potential confounders [[11], [12], [13], [14]]. The association between male gender and adverse outcomes, such as mortality, seems consistent across all geographical areas, as revealed by several meta-analyses [[15], [16], [17], [18]].

Fig. 1

Male to female ratio of deaths in COVID-19 confirmed cases. Source: [44].

The reasons for this trend are likely to be multifactorial, including physiological factors, lifestyle, and socio-cultural behaviors [19] (Fig. 2). The physiological differences between the sexes may initially be directly involved in this differential risk of COVID-19 adverse outcomes [20]. For example, recent evidence has suggested that SARS-CoV-2 expression may induce angiotensin-converting enzyme-2 (ACE-2) downregulation due to the binding of the viral spike protein to its receptor, then promoting a decrease in the angiotensin- [[1], [2], [3], [4], [5], [6], [7]] production [21]. In this context, there is evidence suggesting an important role of sex hormones in the regulation of ACE-2 in a tissue-specific manner [20]. For example, female mice were observed to have a higher expression of ACE-2 in adipose tissue compared with male mice, leading to higher levels of Ang- [[1], [2], [3], [4], [5], [6], [7]], which in turn were associated with lower levels of hypertension, another risk factor for COVID-19 negative outcomes [22,23]. Similarly, higher testosterone levels in males may be related to a higher risk of coagulation disorders, resulting in complications such as venous thromboembolism and systemic embolisms, which are frequently observed in severe COVID-19 patients [24,25].

Fig. 2

Summary of the potential mechanisms and variables involved in the sex differential between men and women regarding COVID-19 adverse outcomes. Source: Authors. Created with BioRender.com

Furthermore, differences in the immune responses against SARS-CoV-2 between sexes may also play an important role. Takahashi et al. observed that men had higher plasma levels of IL-8 and IL-18, along with a more potent induction of non-classical monocytes among patients with moderate COVID-19 who had not received immunomodulatory medications [26]. On the other hand, women had a more robust CD8 T cell activation. In this study, poor T cell responses were associated with disease progression in males, while higher cytokine levels were predictors of worsening of clinical status in females [26]. In addition, females may produce larger amounts of neutralizing antibodies, as evidenced by the study of Zeng et al., in which the concentration of IgG antibodies against SARS-CoV-2 was higher in women, especially during the early phase of the disease [27]. Finally, several studies have supported the direct role of sex hormones in immune responses. For example, the phytoestrogen silibinin was shown to reduce the expression of the pro-inflammatory cytokines IL-17 and TNF-α, potentially reducing the risk of complications such as the cytokine storm observed in cases of severe SARS-CoV-2 infection [28].

On the other hand, lifestyle differences between the two sexes need consideration. Women tend to have a healthier lifestyle than men, with lower frequencies of smoking and heavy drinking [29]. This is reflected in a lower prevalence of classic cardiovascular (CV) risk factors, mostly before the menopausal transition [30]. Furthermore, adipose tissue distribution differences may also impact the outcome of COVID-19, as abdominal adiposity has been identified as an independent predictor of pulmonary function in several studies [[31], [32], [33]]. Nevertheless, recent studies have concluded that CV risk factors may have a stronger association with CV disease in women, highlighting the need for sex-specific analyses to clarify the reason for this trend [34,35].

Finally, socio-cultural variables are paramount to explain these differences. At first, the estimated global ratio of female to male labor force participation for 2020 was around 0.6, positioning work-related transmission as a relevant factor supporting male higher risk in several occupational groups [36]. Similarly, school closures have forced -more often- women to provide care for their children and immediate families, potentially inducing them to stay at home [37]. Furthermore, religious restrictions for women could play a role in the spread of the virus. For example, in certain cultures, facial covering is relatively common; therefore, women are likely to be less exposed to air-borne pathogen transmission, also being less prone to touching their faces [38]. In addition to this, men with voluminous facial hair might have limitations with mask fit, causing increased exposure to the virus and air leakage during non-invasive positive pressure ventilation [39].

From a behavioral perspective, men are usually more likely to engage in health-related risk activities, increasing their exposure to the virus [29]. On the other hand, women tend to be more cautious and tend to have better hygiene knowledge and practice [40]. In addition, women may have a lesser risk of contagion through distancing from men or separation from the broader workforce and community in some cultures. Moreover, women are less inclined to seek medical attention in some settings, which may favor a potential underrepresentation in data collected regarding infection incidence in selected regions [41,42]. Finally, education has been identified as a factor influencing health outcomes in several clinical conditions; however, gender studies have revealed a larger effect on men's mortality than women’ s [43]. Therefore, more research is needed to assess the role of education in COVID-19.

Considering all these differences, it is essential to take a sex- and gender-based approach to the identification, diagnosis, treatment, and overall management in the COVID-19 pandemic to elucidate further additional pathophysiological mechanisms and socio-cultural variables that may play a role in the differential expression of SARS-CoV-2 infection by sex, ultimately leading to an optimal prevention and care.

Contributors

All authors contributed to the writing of this editorial.

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Conflict of interest

The authors have no conflict of interest regarding the publication of this editorial.