Researchers at Yale University School of Medicine have highlighted the importance of ensuring studies of patients with coronavirus disease 2019 (COVID-19) report data in a sex-disaggregated manner.
Sex differences influence disease incidence and outcomes in COVID-19, with males at a significantly higher risk of death (after the age of 30) than females.
Given that aging is also strongly associated with increased mortality risk across both sexes, older males are the most likely group to succumb to severe disease. The male bias in COVID-19 related death is seen across almost all countries where data that have been disaggregated by sex are available. These data show that the mortality risk among men is around 1.7 times higher than among women.
Reporting COVID-19 data in a sex-disaggregated manner is therefore crucial to establishing differential disease pathogenesis, enhancing understanding of the disease and developing improved prevention and treatment approaches, say the researchers.
Potential mechanisms underlying the bias
In a recently published perspective in the journal Science, researchers Takehiro Takahashi and Akiko Iwasaki outline some of the potential biological mechanisms underlying the male bias towards severe COVID-19 outcomes.
Studies have shown that men often mount weaker immune responses and are more susceptible to infection than women. They have also shown that the immune response to vaccines is generally more robust in females, although this can also lead to immunopathology in cases of infection.
Following infection with a virus, the body launches two lines of defense: antiviral responses mediated by type 1 and type 3 interferons (IFNs) to limit viral replication and the production of cytokines to recruit immune cells such as macrophages and neutrophils that eliminate infected cells.
Importantly, COVID-19 is characterized by a robust innate cytokine response and a disproportionately low IFN-mediated response.
During the early phase of COVID-19, males produce higher levels of key immune cytokines than females, while females produce higher levels of the type 1 interferon IFNα. Interestingly, in a study conducted last year (2020), autoantibodies against type 1 IFN signaling were detected in a group of patients with severe disease, 94% of whom were older males.
Another 2020 study found that during the early phase of COVID-19, T cell activation was robust in older females, whereas it declined in older males. Furthermore, a poor T cell response among males was associated with more severe disease outcomes.
Potential mechanisms underlying the sex differences
The authors say that one potential mechanism underlying these sex differences may involve the sex chromosomes. Many important immune-related genes are found on the X chromosome and while one copy in females is epigenetically silenced or inactivate, some of these genes escape this inactivation. An example is a gene that encodes Toll-like receptor 7, which elicits strong type I IFN production in plasmacytoid dendritic cells (pDCs).
Increased expression of these genes in females leads to a more robust type I IFN response than is seen in males.
Another potential mechanism involves the differential effects that age has on the transcriptomes of immune cells. Aging induces a steeper decline in the level of naïve T cells among men than among women, and the level of B cells only declines in men older than 65 years.
“Males have abrupt and drastic changes in the epigenetic landscape of their immune cells between ages 62 and 64, and subsequently males exhibit an accelerated immunosenescence phenotype,” write the researchers.
On the other hand, females are not affected by significant changes in the epigenetic landscape of immune cells until 5 or 6 years later, with this gap largely corresponding with the difference in lifespan between the sexes.
Sex hormones may also play a role
As the first stage of the infection process, SARS-CoV-2 binds to the human host cell receptor angiotensin-converting enzyme 2 (ACE2). Studies of various cell lines and animal models have shown that ACE2 expression is modulated by the sex hormone estrogen, which is produced at higher concentrations in females than in males.
“Estrogen is a critical regulator of gene expression and functions in innate immune cells, including monocytes, macrophages, and dendritic cells, as well as in lymphocytes such as T helper 1/2 (TH1/2) cells, regulatory T cells (Tregs), and B cells,” write the researchers.
Furthermore, levels of one of the main forms of estrogen, called estradiol, and a marker of the ovarian reserve called anti-Müllerian hormone are inversely correlated with COVID-19 severity, adds the team.
Data on COVID-19 patients should be disaggregated by sex
Takahashi and Iwasaki warn that data on patients with COVID-19 should be reported in a sex-disaggregated manner.
The researchers say this would help “not only to elucidate differential disease pathogenesis but also to enable a deeper understanding of this disease and the eventual development of better treatment and preventive strategies.”
“It should be standard practice to collect and report sex-disaggregated data for this and for all infectious disease and vaccine studies in the future,” concludes the team.