Why is Covid-19 killing more men than women? Scientists have 4 theories

As Covid-19 continues to sicken millions, scientists have noticed certain people have more trouble battling the infection and beating the brutal disease. This group includes older people, those with underlying medical conditions like asthma or HIV, and immunocompromised people.

Now, a growing body of research suggests another group is at higher risk of not recovering from Covid-19: men.

Men are more than twice as likely to die from the novel coronavirus, reports the first published study to break down the sex differences in infected patients. In turn, they are more likely to experience a more severe course of the disease than women. Overall, men and women are equally likely to contract Covid-19, the study claims.

This study provides the strongest evidence yet that sex is a risk factor. Case reports spanning different countries increasingly reveal a stark coronavirus gap between the sexes— this research helps to explain why.

It was published Wednesday in the journal Frontiers of Public Health.

“Being male is a risk factor for death from Covid-19, regardless of age,” confirms Sabra Klein, an immunologist, and co-director of the Johns Hopkins Center for Women’s Health, Sex, and Gender Research.

Klein was not involved in the research and describes the study to Inverse as a “detailed and robust analysis.”

In early January of 2020, the study's authors were consumed with treating patients with Covid-19 in Beijing when they noticed that more men appeared to be dying from the disease than women.

"This raised a question: Are men more susceptible to getting or dying from Covid-19?" co-author Jin-Kui Yang, a physician at Beijing Tongren Hospital, tells Inverse. "We found that no one had measured gender differences in COVID-19 patients, and so began investigating."

To see how men and women fare against the disease, the team analyzed 43 Covid-19 patients they treated directly and then analyzed a larger, publicly available data set that included 1,056 Covid-19 patients living across China.

They also examined a 2003 dataset that covered 524 patients who contracted SARS. Studying SARS patients might prove helpful in understanding this current pandemic because both viruses attack cells through the same ACE2 receptor, the study explains. (Some experts believe this receptor is the key to developing a coronavirus vaccine or treatment.)

Overall, they found that older people and those with specific underlying conditions tended to have more severe disease and were more likely to die. When they narrowed it down to men and women, another pattern emerged: While the numbers of infected men and women were similar, men tended to have more severe disease, regardless of age.

In the large COVID-19 dataset, over 70 percent of the patients who died were men. This means that men had almost 2.5 times the death rate of women.

"This study confirms other early reports that men have a worse prognosis with Covid-19 than women," Kathryn Sandberg tells Inverse. "We don't yet know why. There are many factors that could come into play."

Sandberg is the director of the Center for the Study of Sex Differences in Health, Aging, and Disease at Georgetown University. She was not involved in the study.

Among the SARS patients, males were more likely to die than females. This finding makes salient the point that men are at greater risk of death from pathogenic coronaviruses and this not limited to the current pandemic, Klein explains. She notes that a similar trend was previously observed for MERS, which is also a viral respiratory illness.

Why are men more at risk? — When the study authors first observed the strange pattern, they linked the gender imbalance to lifestyle factors like smoking, as men smoked more frequently in places with skewed Covid-19 gender ratios. But international case reports show similar sex differences where men and women are equally likely to smoke, leading them to question what other factors might be at play.

Yang, Sandberg, and Klein all suggest comorbidities — co-existing conditions like diabetes, obesity, or heart disease — could be what's contributing to men's poor outcomes. In the large public data set analyzed in this study, 65 percent of both male and female Covid-19 patients had at least one underlying disorder such as hypertension.

But comorbidities can't explain the sex difference completely since they were prevalent in both men and women in the study.

Instead, the gap may stem from fundamental immune system differences in men and women, the scientists theorize. Research shows generally, women mount greater inflammatory, antiviral, and humoral immune responses than males during viral infections, which may help them clear Covid-19 faster. In the latest study, men showed higher levels of white blood cells, lymphocytes, and neutrophils, suggesting men are pumping out immune cells at different rates than women.

Circulating ACE2 levels are also higher in men than in women and in patients with diabetes or cardiovascular diseases, which the study suggests may put men at a higher risk.

"Therefore, male patients may be more prone to die from SARS-CoV-2 because of the high expression of ACE2, though further research on the mechanism is needed," Yang says. Other preliminary data suggests men's testes may be acting as viral reservoirs when fighting Covid-19 since they are sites of high ACE2 expression.

Hormones may also be swaying immune function, Yang, Sandberg, and Klein theorize: Some data suggests estrogen may inhibit the expression of ACE2 receptors, hampering the virus from reproducing. In the past few weeks, doctors began testing estrogen and progesterone as possible treatments to strengthen men's immune responses to Covid-19.

Larger studies are needed to pull apart the complicated factors driving the gender breakdown. In the meantime, Yang recommends that additional supportive care and prompt access to the intensive care unit (ICU) may be especially necessary for older male patients.

Abstract:

Objective: The recent outbreak of Novel Coronavirus Disease (Covid-19) is reminiscent of the SARS outbreak in 2003. We aim to compare the severity and mortality between male and female patients with COVID-19 or SARS.

Study Design and Setting: We extracted the data from (1) a case series of 43 hospitalized patients we treated, (2) a public data set of the first 37 cases died of COVID-19 and 1019 survived patients in China, and (3) data of 524 patients with SARS, including 139 deaths, from Beijing in early 2003.

Results: Older age and high number of comorbidities were associated with higher severity and mortality in patients with both COVID-19 and SARS. Age was comparable between men and women in all data sets. In the case series, however, men tend to be more serious than women (P=0.035). In the public data set, the number of men is 2.4 times that of women in the deceased group (70.3% vs. 29.7%, P=0.016). In SARS patients, the gender role in mortality was also observed. The percentage of male were higher in the deceased group than in the survived group (P=0.015).

Conclusion: Male gender is a risk factor for worse outcomes independent of age and susceptibility in patients with COVID.