Sex-biased clinical presentation and outcomes from COVID-19

Around the world, while males and females are equally likely to test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), males are significantly more likely to be hospitalized, to be admitted into intensive care units, and to die from coronavirus disease 2019 (COVID-19) [1,2]. Although globally the proportions of males and females testing positive for SARS-CoV-2 are similar, a number of gender-associated differences—including behaviour (e.g. acceptance of public health measures that limit virus spread) [3], occupation [4], and access to healthcare for testing [5]— contribute to notable regional differences in SARS-CoV-2 exposure between the sexes [6].

Gender differences (i.e. a social construct that defines norms for men and women) are separate from but complementary to biological sex differences that are mediated by sex chromosome complement, differential reproductive tissues, and differential concentrations of sex steroid hormones. The enrichment of the X chromosome for immune response genes [7], combined with the presence of sex steroid hormone receptors on diverse innate and adaptive immune cells, and the presence of hormone response elements in the promotors of numerous immune response genes, can give rise to sex differences in immunity to viruses [8]. Consequently, there are sex differences in immunity to SARS-CoV-2, control of virus replication, development of immunopathologies, and long-term protection [9]. For example, deleterious mutations in X-linked genes (e.g. TLR7) have been linked to worse COVID-19 outcomes in males [10]. Males consistently have greater proinflammatory cytokine production (e.g. IL-6) than females in the context of COVID-19, although it is unclear whether this difference is a marker of sex differences in disease severity [11,12]. Older males with COVID-19 have lower CD8+ T-cell activity (e.g. IFN-γ production and proliferation) [13], but have greater antibody responses [14] than females. The durability of neutralizing antibodies, however, is lower for males than females over time [15].