COVID-19 studies should provide sex-disaggregated data, researchers warn

By Sally Robertson, B.Sc.Jun 21 2021Reviewed by Emily Henderson, B.Sc.

Researchers in Greece have warned that studies examining sex-specific responses to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) must provide sex-disaggregated data to help improve understanding of the pathology involved in coronavirus disease 2019 (COVID-19).

SARS-CoV-2. Image Credit: Dotted Yeti/Shutterstock.com

The team – from the Aristotle University of Thessaloniki – conducted a literature review exploring the pathophysiologic and behavioral basis of the disproportionate male morbidity and mortality that occurs in COVID-19.

As reported in the journal Microbes and Infection, the researchers found that the data support the existence of sex-specific responses to SARS-CoV-2.

However, not all studies include a sex-based distinction regarding the data used to monitor the pandemic, says Kalliopi Kotsa and colleagues.

Interpreting intersex differences in immune response to SARS-CoV-2 could lead to a deeper understanding of COVID-19 pathophysiology and enable healthcare professionals to conduct a more accurate patient risk assessment and better predict clinical outcomes of the disease,”

Males are more susceptible, despite a similar infection rate between the sexes

Epidemiologic monitoring of the COVID-19 pandemic has shown that males are more susceptible to morbidity and mortality than females, despite a similar infection rate between the sexes.

Differences in comorbidities, hormonal profiles, chromosomal composition, and behavior have all been proposed as potential factors underlying this sexual dimorphism in susceptibility to SARS-CoV-2.

Kotsa and colleagues say that an in-depth analysis of this sexual dimorphism is essential to understanding COVID-19 pathophysiology.

What did the researchers do?

The researchers set out to review literature covering the pathophysiological and behavioral basis underlying the disproportionate male morbidity and mortality observed in COVID-19.

They searched PubMed, Embase, and Google scholar databases for relevant articles, with the last search performed in April 2021.

The role that comorbidities play

According to a systematic review of seven studies, patients with severe COVID-19 are more likely to have hypertension or cardiovascular disease, says the team.

Multiple studies have also shown that hypertension occurs more commonly in males than among age-matched females throughout middle age, potentially rendering males more susceptible to severe COVID-19. Rates of mortality due to cardiovascular disease have also been shown to be higher among males than females, says Kotsa and colleagues.

It could be argued that the sex-bias regarding COVID-19 morbidity and mortality could be partly attributed to the fact that, overall, males begin at a less favorable health standpoint, presenting with more risk factors for severe COVID-19,”

However, according to some sex-disaggregated data, the difference in case fatality rate between males and females is too large to be accounted for by differences in comorbidity alone, they add.

Estrogen and the immune response

Immune cells such as natural killer cells, neutrophils, B-cells, and T cells are directly affected by circulating estrogen levels, depending on the type of estrogen receptors they express.

For example, in the case of T cells, the expression ratio of the estrogen receptors Erα and Erβ determines the cell’s course of action. Erβ signaling is involved in the differentiation of T regulatory cells and immunosuppression, while Erα signaling stimulates the immune response.

“As estrogen levels fluctuate throughout the menstrual cycle, women may undergo phases of altered immune reactivity,” says the team. “In this context, females may elicit stronger immune responses than their male counterparts.”

The researchers also suggest that estrogen signaling may affect immune responses via induction of endothelial nitric oxide synthase in the presence of inflammation. This increases the production of nitric oxide, which exerts strong vasodilatory effects and increases blood circulation at sites of inflammation. The activation of estrogen receptors also impedes the formation of reactive oxygen species, thereby exerting another anti-inflammatory benefit.

The role that sex chromosomes might play

Other factors that the team says may contribute to the sexual dimorphism seen in the response to SARS-CoV-2 include the sex chromosomes, differences in behavior between men and women, and a sex bias in vaccination.

The X chromosome contains more immune-related genes than the Y chromosome and since females possess two X chromosomes, they have twice the quantity of immune genes that men do.

Studies of gender behavior have shown that women are more likely than men to adhere to preventive measures such as mask-wearing, hand washing, and social distancing. Women have also been shown to be more likely to comply with social distancing practices.

In addition, women have been shown to have a stronger immune response to vaccination than men and to produce higher levels of neutralizing antibodies against viruses.

“Many factors play a role in the sexual dimorphism”

“It is evident that many factors play a role in the sexual dimorphism related to SARS-CoV-2 infection,” says Kotsa and colleagues.

Comorbidities, estrogen levels, sex chromosomes, and behaviors during the pandemic all appear to play a part in making men more vulnerable to infection and less likely to survive.

“However, clinical trials and animal model experiments are not always sex-balanced and tend to include fewer female subjects. In addition, not all countries include a sex-based distinction regarding their epidemiological data used to monitor the course of the pandemic,” writes the team.

The researchers say such a lack of information hinders scientific conclusions.

Thus, it is of utmost importance that henceforward, sex-disaggregated data stand at the epicenter of the research field, thereby shedding more light on COVID-19 pathogenesis and enabling the drawing of more accurate scientific conclusions,”