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COVID-19 results in higher case numbers and mortality rates in men than women across age groups, a recently released review article from Harvard Medical School and Beth Israel Deaconess Medical Center showed.

Led by HMS Assistant Professor of Medicine Vaishali R. Moulton, the Frontiers in Immunology study analyzed sex-based physiological differences in COVID-19’s effect.

Moulton, alongside co-authors and Boston University medical students Nirupa Gadi, Samantha C. Wu, and Allison P. Spihlman, stated that the roots of this sex-based difference may include pre-existing determinants such as the increased likelihood of cardiovascular disease and hypertension in men compared to women. Additional behavioral variables, such as the tendency of men to smoke more than women, may also contribute to disparate COVID-19 risk, the study explained.

Beyond those social and environmental factors, the review also highlighted a variety of biological variables underlying divergent immune responses between sexes. Such factors include differences in microbiome control, sex hormones, and sex chromosome-linked genes.

One such gene is ACE2, a receptor that the virus binds to as a mechanism of entering host cells. Variable expression of ACE2 may result in higher viral susceptibility in men compared to women, which could lead to differential clinical outcomes, the review explained.

Additionally, estrogen –– the primary female sex hormone –– contributes to increased bacteria presence, specifically in the gastrointestinal tract. These gut microbiota may underlie the improved immune response of women compared to men.

The study ultimately concluded that sex is an understudied yet vital component in research relating to immunity and infectious disease, including COVID-19.

The authors called for a greater consideration of sex in future research, specifically pointing to implications for vaccine dosage and other protective immunity strategies.

“Vaccine-related research and clinical trials, including those currently underway for COVID-19, must include sex as a key variable when measuring and reporting outcomes,” they stated in the review.

Assistant Professor of Surgery at Massachusetts General Hospital Anahita Dua, who is unaffiliated with the study, commented on the significance of the findings.

“I commend the authors for looking into this. We really need to figure out how we can target our therapies to best serve patients that are the most likely to get severe and potentially die,” Dua said. “As people continue on their quest to figure out COVID, they do give a little bit more focus onto the male-female aspect.”

Dua said that while the exact reasons for the sex-based difference in mortality rates are still unclear, future studies can continue to examine the relationship between biological sex and COVID.

“This highlights yet another piece that may be part of this jigsaw puzzle that is COVID,” Dua said.