Biological sex has been found to underlie stark differences in COVID-19 patient outcomes, with men comprising approximately 60 percent of COVID-19-related deaths around the world and facing a higher risk of death than women.
To explore the reason behind this phenomenon, a team of Yale researchers –– led by Professor of Immunology Akiko Iwasaki –– conducted an observational study that compared the immune responses of men and women who had been infected with the coronavirus. The study was published in Nature on Aug. 26 and emerged from the Yale COVID-19 IMPACT project, which enrolled a cohort of individuals hospitalized with COVID-19 at the Yale New Haven Hospital between March and May.
“We got consent from these individuals, enrolled them in this study and collected a wide set of samples including nasopharyngeal swabs, oropharyngeal swabs, blood samples, urine samples and stool samples, both at enrollment and then periodically during their stays in the hospital,” said Mallory Ellingson GRD ’25, a Ph.D. student in the Department of Epidemiology and Microbial Diseases at the Yale School of Public Health and one of the co-authors of the study. “We looked at a broad array of immune responses at baseline, but we were also interested in how that correlated with disease progression, so we also looked at how these baseline immune responses were associated with the eventual outcome of the disease.”
Earlier in the course of the disease, relative to women, men were found to mount a more pro-inflammatory response, mediated by immune molecules called cytokines. Women, on the other hand, fared better at harnessing a specific type of immune cell, called T cells, which kill the virus and halt its spread. In the long term, weaker T-cell response was related to worse disease outcomes in men, while stronger cytokine responses prefaced worse disease progression in women. In general, these findings suggest that there are intrinsic differences in how the immune systems of men and women react to the coronavirus.
Back in April, global epidemiological data illustrated significant differences between the mortality rate in men and women: At that point, men were approximately 50 percent more likely to die. At the same time, mounting evidence suggested that abnormal immune responses against the virus were contributing to harmful pathological processes in severe cases of COVID-19, but the mechanistic link between the two remained unexplored.
“Major studies that really focused on and analyzed the differences [in] immune responses in COVID-19 between the sexes were lacking,” Takehiro Takahashi — an associate research scientist in the Iwasaki lab and first author of the study — wrote in an email to the News.
Recognizing this significant void in the literature, the group decided to explore the immunological reasons underpinning these observations. According to Takahashi, this is the first study to show that sex differences in immune responses to COVID-19 are significant and could underlie clinical outcomes observed in both men and women.
Takahashi told the News that even though the patient cohort was relatively small, the group’s findings provide a strong basis for future investigations into how COVID-19 dynamics may differ between men and women. In terms of potential clinical applications, the results also highlight the need to devise differential strategies for treatment and vaccine development in consideration of biological sex.
“We definitely need studies with larger cohorts to validate these findings,” Takahashi wrote to the News. “Our present study itself is an observational study and does not have direct clinical applications, but I hope clinical studies on treatments or vaccines will pay more attention to the differences between sexes, and that this leads to further important findings that are useful for better care for the patients.”
The study also highlighted that age seems to have an impact on immune responses in men and women. Takahashi explained that he was surprised to see that T-cell activation worsened with age in men while women were able to sustain T-cell responses even at older ages. “This clearly correlated with disease progression and aggravation in older male patients,” he wrote.
Duygu Ucar — an assistant professor at the Jackson Laboratory for Genomic Medicine who leads a computational lab and studies how epigenetic programs change with age — recently led a study that examined the impact of age and sex on immunity. Her findings showed that after the ages of 60 to 65, major changes occur in the immune system of men.
“T-cell loss in men is much more significant, and increase in inflammation in men is much more significant,” Ucar said.
According to her, even though the combined impacts of sex and aging on the immune system are not yet fully understood, they do produce differences in life and health spans between men and women. “If you think about it,” Ucar said, “women live much longer.” Worldwide, as of 2019, the life expectancy for women was estimated to be five years longer than it is for men.
Even though there are different possible explanations for why women seem better at fending off infectious diseases, how this fits into the COVID-19 context remains elusive. Current theories range from evolutionary perspectives that maintain that women evolved better immune systems to protect themselves and their offspring from diseases during gestation, to endocrine perspectives that suggest that sex hormones play a key role in regulating immune reactions.
“It has been extensively studied that women generally mount more robust responses against infections of various viruses, and this is in part mediated by estrogen signaling, which enhances the activation and proliferation of T cells,” Takahashi said.
Another hypothesis involves differences in genes expressed by women as compared to men.
“Women have two copies of the X chromosome, while men have only one,” Ucar said. “The X chromosome has a lot of immune-related genes, and it’s probably one of, if not the most, immune-gene dense chromosomes.”
Although the Yale study attempted to understand the biological reasons for why men and women respond differently to the coronavirus, Ellingson emphasized that the role of sociocultural factors on patient outcomes can also be significant.
“The gender gap that we are seeing in COVID-19 outcomes is not 100 percent explained by biology nor 100 percent explained by social and cultural factors, and there’s the possibility that there might be interplay between these two broad categories of explanations,” Ellingson said. “I think it’s interesting, I think they probably both play a factor in some combination of differential risk between men and women.”
The study’s findings suggest that COVID-19 treatment options for men and women might have to look different, Ellingson said. In the paper, the authors suggest that, for men, maybe something that can block the overactivation of pro-inflammatory cytokines and promote a better T-cell response might be more appropriate, whereas for women, dampening innate immune reactions at early stages of the disease could be more effective.
The overarching hope behind this study is that these observations will translate into improved, more tailored approaches to COVID-19 patient care, Takahashi said.
“In this moment, many people in this world are suffering from [COVID-19] or suffering from the loss of their loved ones by this disease,” Takahashi said. “As basic researchers, we sincerely hope that our findings eventually lead to a better understanding of this disease and the establishment of better treatments for the patients.”
According to the Global Health 50/50 COVID-19 data tracker, men account for 48 percent of confirmed coronavirus cases and 53 percent of deaths in the United States at time of writing.
Correction, Sept. 12, 2020: This story has been updated to accurately reflect Ellingson’s degree program. The previous inaccuracy was due to an editing error.