Coronavirus appears to pose a particular threat to men. Middle-aged and older men, and those with underlying health conditions that affect the immune system, are being especially badly hit by the virus. And while scientists can’t say for certain why the current pandemic is discriminating by sex, it isn’t a total surprise.

Wired UK

This story originally appeared on WIRED UK.

The discrepancy was first seen in China. An analysis of 44,672 confirmed cases from late 2019, when the virus first emerged in the city of Wuhan, up to February 11, found the death rate among men was 2.8 percent, compared to 1.7 percent among women. Italy–whose death toll surpassed China’s on March 19–has followed a similar trend with a case fatality rate of 10.6 percent in men, compared with 6 percent in women, according to the country’s national health institute.

Men were also disproportionately likely to die during the SARS and MERS outbreaks, which were caused by similar coronaviruses. More women than men suffered from severe acute respiratory syndrome (SARS) in Hong Kong in 2003, but an analysis of all 1,755 cases showed that the death rate among men was 50 percent higher. During the influenza pandemic of 1918, which killed an estimated 50 million people, adult men were also more likely to die than women.

While scientists don’t know what’s causing the gender disparity in this current pandemic, smoking and drinking have been floated as possible theories. Historically, men smoke more than women, and the difference is particularly large in China, where nearly 50 percent of men but less than 3 percent of women smoke.

People who smoke are more likely to develop chronic lung and heart diseases, which are tied to worse outcomes if they contract Covid-19. “One of the main reasons for death is that your lungs are no longer working, and if your lungs are already damaged because of smoking, there’s less reserve before the lungs no longer are sufficiently effective at keeping you oxygenated,” says Paul Hunter, a professor in medicine at the University of East Anglia.

A study of 1,099 patients in China with Covid-19, published in The New England Journal of Medicine in February 2020, found that smokers made up about 26 percent of those that ended up in intensive care or died of the disease. Smokers are also more likely to contract the novel Sars-Cov-2 coronavirus in the first place as they transmit it from hand to mouth when touching their lips and because they may share contaminated cigarettes.

In Italy, however, the sex differences among smokers are much smaller than in China, with 28 percent of men and 19 percent of women smoking. This may suggest that there is some other, as yet unidentified, factor at play.

Women mount stronger immune responses than men–except during pregnancy to avoid attacking and rejecting the fetus growing inside them–which could be another plausible explanation for the emerging picture of male susceptibility to the Covid-19 disease. In a series of experiments in 2016 and 2017, microbiologists from the University of Iowa infected male and female mice with the coronavirus that caused SARS, and as had happened in humans, male mice were more likely to die. But when the team removed the ovaries from females, their death rates shot up, suggesting that the hormone estrogen somehow protected them from the disease.

Hormones could also play a part in how the novel coronavirus, whose genetic makeup is around 79 percent similar to the SARS virus, interacts with human airways. Ian Hall, a professor of molecular medicine at the University of Nottingham, explains that Sars-Cov-2 uses a “spike protein” to attach to a receptor protein called ACE2 on the surface of human respiratory cells. “There could be differences in the way in which the virus interacts with its key receptor in the airways, which might make male individuals more susceptible,” he says, noting that it’s just one theory. Research on the shape of this spike protein and all the ways it folds and shifts with the ACE2 receptor could not only shed light on how the virus infects men and women differently but may also offer a route to treatment.