It has now been long enough since the COVID-19 pandemic broke across the world that we all have some idea about it. For example, we all know that elderly people are the most vulnerable to the virus. People with pre-existing diseases such as diabetes, heart issues etc. are also at great risk. Recently, another major risk factor has emerged: being male.
The world first became aware that there was a sex difference in COVID-19 severity from hospital records in China's Wuhan shortly after the city locked down. On January 30, Shanghai Jiao Tong University School of Medicine published a report on 99 COVID-19 patients who were admitted to Wuhan Jinyintan Hospital from the beginning of January to January 20.
The result suggested that the number of male patients in the hospital was more than double than the female patients. The death rate of men was also higher than in women.
Mortality data from 21 hospitals in Wuhan between January 21 and January 30 revealed that 75 percent of deaths from COVID-19 occurred to male patients.
Not only in China, but the same pattern was also observed in other COVID-19 affected countries too.
For example, around 70 percent of patients in critical condition admitted to intensive care unit in England, Wales and Northern Ireland had been male. Also, men died in a large number than women in these countries.
In a similar study, it was found that around 62 percent of 4000 COVID-19 patients in New York City hospitals were male.
The difference in mortality rate is not caused only by the difference in the number of infected patients. For example, the New York study found that male patients are more likely to progress towards severe conditions or death even if the number of infected men and women are the same.
The effect of smoking and ACE2
Let us look back at history.
Previously there have been two emerging coronavirus diseases, SARS and MERS, which have also been found to affect men more. Despite that, the fact that more men are being affected by COVID-19 is not the case with respiratory infections generally.
The study in England, Wales and Northern Ireland also looked at gender data on patients critically ill with viral pneumonia between 2017 and 2019, mostly due to influenza. There was an excess of men in this case too. However, the ratio was much less significant here – 54 male deaths for every 46 female deaths.
One possible explanation for the sex difference could be the habit of smoking.
In China, over 50 percent of men smoke, where only 5 percent of women do so. Tobacco smoke appears to cause lung cells to produce more quantities of a surface protein called ACE2, which the virus exploits to infect cells. This may mean that smoking makes lung cells more susceptible to the virus.
This is only a hypothesis, though, moreover one which isn't supported by data. According to a study of the University of California, Los Angeles, current smokers only make up about 12.5 percent of people severely ill with COVID-19 in China. The researcher said it is much lower than the proportion of smokers in the general population.
What else could be responsible then? One possibility is that men – particularly older men – tend to be in generally worse health than women of the same age range.
They exhibit COVID-19 co-morbidity factors such as higher rates of obesity, high blood pressure, diabetes, cancer, lung and cardiovascular diseases etc. more than women. After the authors of the New York study factored these conditions into their analysis, the result showed that sex was no longer one of the main risk factors for COVID-19.
"There are substantial differences in the immune system between males and females and these have a significant impact on outcome from a wide range of infectious diseases," said immunologist Philip Goulder at the University of Oxford.
A very basic fact is that women have two X chromosomes per cell whereas men have one. "A number of critical immune genes are located on the X chromosome," said Goulder.
In particular, the X chromosome contains a gene for a protein called TLR7, which detects single-stranded RNA viruses like the coronavirus.
"As a result, this protein is expressed at twice the dose on many immune cells in females compared to males, and the immune response to coronavirus is therefore amplified in females," he said.
While one X chromosome is usually inactivated in each female cell, the TLR7 gene somehow escapes this in some immune cells, which means women produce more of the protein. There is also some evidence that female sex hormones such as oestrogen and progesterone boost the immune system, but this has not been specifically investigated in cases of COVID-19 yet.
"Another possibility is that men are simply less hygienic in nature. They are less likely to comply with basic sanitation measures such as hand washing," said Kunihiro Matsushita of Johns Hopkins University.
A study of sex differences in China found that men with COVID-19 in hospitals were also more likely to be carrying other viruses, including flu, and bacteria, and it is possible that this fact may increase the severity of COVID-19 symptoms in them.