Why Is There a COVID-19 Gender Gap?

Most people know that the novel coronavirus has killed older people in far higher numbers and disproportionately affected people of color. But the gender gap in COVID-19 deaths is less well known—and understood.

“It is being reported across China, Italy, Spain, Iran, and Germany that the number of men testing positive and dying from COVID-19 is double that of women,” said Cummings School associate professor Janetrix Hellen Amuguni, VG11. “In Italy, men have accounted for 71 percent of the deaths.”

But why are men dying in higher numbers than women—and are both sexes being similarly affected?

“This question requires an extensive analysis from both a gender and sex perspective,” said Amuguni, an expert on the relationship between gender roles and infectious disease in global health.

“It might be that the men’s immune systems are built in a different way from women’s,” she said. “Or it could be that gender roles linked to behaviors of men and women—access and control over resources and opportunities, power dynamics, and cultural norms that determine what men or women do daily—are playing an underlying role in determining who contracts this infection.”

To study the many factors potentially at play, Amuguni has assembled a team of researchers from Cummings School and the Tufts School of Medicine. The scientists have been awarded $50,000 in COVID-19 Rapid Response Seed Funding from Tufts University and Tufts Medical Center to study sex differences and gender disparities in COVID-19.

The Viral Battles of the Sexes

Michael R. Jordan, A94, M98, an assistant professor at the School of Medicine, has cared for scores of people with COVID-19 as an attending physician in the Division of Geographic Medicine and Infectious Diseases at Tufts Medical Center.

“Several studies suggest that men with COVID-19 do less well, and we know that many diseases can affect men and women differently,” said Jordan. He noted that biological differences between men and women may affect how severe or deadly COVID-19 is for them.

Higher fatality rates were seen in men than women with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), two other deadly infections caused by coronaviruses, said Tess Gannaway, V16, a Ph.D. candidate in infectious disease and global health at Cummings School and member of the Tufts research team.

One hypothesis about COVID-19’s higher fatality rates in men is that the female hormone estrogen “may be protective in some way,” said Jordan. And some scientists suspect that male hormones called androgens, such as testosterone, may be to blame for men’s poorer outcomes.

Genetic differences linked to the X chromosome—of which women inherit two versus men’s one—also may lead to different immune responses or host environments for the infection in men and women, Jordan said.

Gannaway noted that a 2017 study of mice infected with the virus that causes SARS pointed to important sex differences. The male mice were more likely to die than female mice when infected with that coronavirus.

Higher amounts of virus accumulated in the lungs of the males. And “the male mice had a different immunological response to the SARS virus that ended up making them more susceptible to the development of disease,” said Gannaway.

Estrogen appeared to counter both these mechanisms in the female mice infected with SARS, she said. When scientists reduced or eliminated estrogen levels in female mice, for example, the female mice had mortality rates from SARS that were closer to the rates of the male mice.

With that in mind, “it’s really important to characterize how the immune system is responding to COVID-19 in the two sexes, so you can target interventions more accurately for males and females,” Gannaway explained. “It may even help determine what we need to target within the male subset for better drug development and other new therapies.”

To isolate any sex-based differences for SARS-CoV-2, the virus causing COVID-19, the Tufts researchers will conduct studies in mice at the Tufts New England Regional Biosafety Laboratory. The team also plans to draw on a new Tufts resource—the Tufts Medical Center/Tufts University COVID-19 Biorepository and Comprehensive COVID-19 Database.

The biorepository is collecting blood and other samples from up to 400 hospitalized patients with COVID-19 who consent to have these used for research. Meanwhile, the database will collect anonymous data on all individuals testing for COVID-19 at Tufts Medical Center, regardless of their results.

“Specimens for the biorepository are taken from patients at multiple time points,” said Jordan, the director of the COVID-19 biorepository and database. “So we’ll be able to look at the viral loads in the nose and throat, as well as the evolution of antibodies over time in male and female human patients, and we can compare that with what we see in the mice.”

More Than Just Men’s Issues

The Tufts researchers also will investigate gender-based factors that may contribute to increased susceptibility and mortality in COVID-19.

Men’s increased susceptibility and mortality may reflect other diseases or health conditions, said Jordan. “There’s likely an interplay between the overall health and genetics.” For example, men may be more likely than women to be overweight or to have high blood pressure.

“There’s speculation that men’s lifestyles might predispose them to develop COVID-19,” explained Amuguni. “For example, in China men are more likely to be smokers than women, and so have more compromised lungs.” There’s also evidence that men take longer than women to seek necessary health care.

Men may tend to work in occupations that put them at higher risk, too, noted Marieke Rosenbaum, V14, MG14, VG14, another member of the Tufts’ research team. “Perhaps men are more likely to greet someone by putting their hand on their shoulder or shaking hands,” she said.

“If we can identify what gender-specific behaviors make men at higher risk for COVID-19, we can identify what precautions might help curb transmission and what behavioral changes would reduce other gender-based impacts,” said Rosenbaum.

Even though the early data suggests that men typically have a higher risk of dying from COVID-19 overall, the coronavirus has killed more women than men in Massachusetts. Scientists suspect this may be because women tend to live longer than men, and people living in long-term care facilities were the population hit hardest by COVID-19 in the state.    

The pandemic may also be disproportionately harming women and other individuals in other ways, Amuguni said.

“There are gender-related consequences as a result of confinement related to stay-at-home advisories and orders, and these would differ across the world,” she explained. “We need to consider simple questions such as, has the workload increased for men or women? What does this mean for decision making, access, control over resources, and power dynamics? And if there an increase in domestic violence, who is affected the most?”

Gannaway noted that women may be at higher risk losing their jobs or of contracting COVID-19 as a result of the pandemic. For example, “seventy percent of the care force working within the health-care sector are women, and these women have more exposure to the coronavirus and greater risk of getting the disease,” she said.

Gender roles, distribution of labor, and resources historically have played an important role in the spread of other infectious diseases, as well as in their control and prevention, noted Amuguni.

“Therefore, these issues need to be addressed to understand better the risks for COVID-19—and to develop adequate prevention and control strategies,” she said.

Amuguni pointed to Ebola as one example. When this deadly virus spill overs from animals to people, the first person infected is usually a male. That’s because the index case, as it is called, is often someone who has been going into animals’ habitat—and in Africa, hunters are typically men.

However, Amuguni said that over the first forty-five days of the Ebola outbreak in Liberia, 75 percent of the people who died were women.

“Ebola was being transmitted primarily among women because of their important role in their communities,” she said. “When someone was sick, women cared for that person. And when people died, women were the ones cleaning their bodies and cooking and serving food at their funerals.”

Of course, like the sex differences, the possible gender-related risk factors for COVID-19 are just hypotheses until they’ve been rigorously studied. That’s why the second component of the Tufts team’s study will include interviews to gather more qualitative data on what gender-based factors may increase susceptibility or spread of the infection.

“We need to really dig in and listen to the experiences of all these people to understand their situations and to look for trends,” said Rosenbaum.

With the help of Tufts Medical Center, the researchers will administer online surveys and hold focus groups with people who have recovered from COVID-19.

For example, “public-health policies and programs also may have different impacts on straight men and women, the lesbian, gay and bisexual community, and people who identify as non-binary,” Jordan said. “We want to explore if these affect individuals’ decision-making around health-seeking behavior or testing, or their access to testing and ability to isolate safely at home.”

It’s a different way to approach health care and medical research during an outbreak, said Amuguni. “Most of the time we approach infectious diseases as a medical emergency and focus solely on treating people.”

“But we have to look at other social determinants to figure out what other factors are actually related to the pandemic,” she added. “What role did gender factors play to get us to this situation—and what role can they play to help the response and get us out of this situation?”

Genevieve Rajewski can be reached at genevieve.rajewski@tufts.edu.