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Why are men more likely than women to die from COVID-19?

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Written by Paul Taylor

QUESTION: I’ve heard that men are more likely than women to die from COVID-19.  Is this true and what accounts for the difference?

ANSWER: We have known for some time that older folks and those with pre-existing medical conditions – such as heart disease, diabetes and obesity – face an elevated risk of suffering a severe and potentially fatal reaction if they become infected with the novel coronavirus which causes COVID-19.

But a growing body of evidence from COVID-19 hotspots around the world suggests that a person’s sex is also a significant factor in determining the chances of survival.

In China, 64 per cent of the recorded deaths were among men, compared with only 36 per cent among women. A similar pattern has emerged in other countries. In Italy, for instance, men accounted for 71 per cent of deaths, while in Germany, males represented 66 per cent.

Officially known as SARS-CoV-2,  this cornonavirus is so new that researchers can’t say with any certainty why infected men are at a greater risk of death than women.

“This is all very speculative,” says Dr. Cara Tannenbaum, scientific director of the Institute of Gender and Health at the Canadian Institutes of Health Research in Montreal.

Even so, some experts believe that the reason for the stark divergence in mortality rates might be found in the fact that the immune systems of men and women are not actually identical.

Previous research has clearly identified sex-based immune-system differences, says Juan Carlos Zuniga-Pflucker, a senior scientist at Sunnybrook Health Sciences Centre and Chair of the Department of Immunology at the University of Toronto.

One key reason for sex-based differences is pregnancy – a time when a woman essentially has a foreign entity growing inside her body.  Without the ability to modify, or dampen down its response, the immune system would reject the developing fetus, he explains.

Overall, “women tend to have a more distinctly regulated version of the immune system,” he says. This tendency can sometimes increase a woman’s chances of getting certain diseases such as lupus and multiple sclerosis. “But it may be beneficial in responding to a virus like this one,” he adds.

Indeed, an overactive, or overly aggressive immune response appears to be contributing to many COVID-19 deaths – and that may account for a higher number of fatalities among men. It might also explain why some relatively young and apparently healthy individuals are brought down by the illness.

At this point, it’s worth reviewing what we do know about COVID-19.

The infection usually starts when the virus enters the upper airway. It will invade a cell and then take over the cellular machinery to start churning out copies of itself.

In some patients there may be limited viral replication in the upper airway, but in others replication may include the lungs and be associated with more severe disease.

The lungs are extremely vulnerable. The virus can damage the air sacs called alveoli where blood normally picks up oxygen to be distributed to the rest of the body.

As the infection is gaining steam, the immune system starts marshalling its resources for a counterattack.

The immune system is made up of numerous specialized cells.  Many of them produce cytokines, which are chemical messengers that help direct a co-ordinated assault on the microbial invader.

But for reasons that are not fully understood, the immune system sometimes produces too many cytokines leading to what is called a cytokine storm”.

As more and more immune cells converge on the lungs, they generate additional cytokines that then call for reinforcements.  They create a “feedback loop” that intensifies the immune response, says Dr. Zuniga-Pflucker.

“Under these circumstances, the cytokines end up causing collateral damage and normal cells end up being harmed,” says Dr. Samira Mubareka, an infectious diseases physician and virologist at Sunnybrook.

At the same time, cytokines cause vascular leakage from surrounding tissues and fluid begins filling the lungs.

“It becomes harder and harder for patients to get enough air into their lungs,” says Dr. Mubareka. Some of these people will develop a life-threatening condition called acute respiratory distress syndrome (ARDS).

But the lungs are not the only parts of the body harmed by the virus. Many patients experience heart, kidney and liver problems as well as gastrointestinal and central nervous system abnormalities.  Whether the virus is directly invading these other tissues isn’t yet clear. They might be compromised simply because oxygen levels in the blood are plummeting.   Whatever the cause, patients can develop another potentially life-threatening condition – multi-organ system failure.

Although men, in general, are more likely than women to succumb to COVID-19, there is still a lot of individual variability.  After all, some infected men die, some don’t.   So, that suggests the infected person’s genetics may play a role.

“We won’t know which (genetic) variants are important until we do large-scale population-wide genome studies where we compare a lot people who had serious outcomes to those with mild disease,” says Dr. Mubareka.

Plans are already underway to do such studies. But it will take some time before we have a full understanding of why this illness is not an equal opportunity killer.

About the author

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Paul Taylor

Paul Taylor, Sunnybrook’s Patient Navigation Advisor, provides advice and answers questions from patients and their families, relying heavily on medical and health experts. Email your questions to AskPaul@sunnybrook.ca
and follow me on Twitter @epaultaylor