Most day-to-day diseases don’t seem to care what sex you are: coughs, colds and stomach bugs latch on regardless.

But there’s clear evidence that Covid-19 is different. Across the world, scientists are reporting that men are much more likely to suffer severe symptoms from the illness, meaning more will succumb.

So what factors could be important? The most obvious are lifestyle-related: If you’re a smoker, you’re already more likely to die from lung or heart disease, which would likely make recovery from Covid-19 more difficult as these are already on the ‘high-risk’ categories established by the UK’s NHS.

Obesity has also been linked to how hard Covid-19 can hit, with Prof Jean-Francois Delfraissy, France’s chief epidemiologist, saying being overweight is a major risk factor for people infected with the novel coronavirus.

Drinking habits might matter, too; alcohol is a causal factor in more than 60 medical conditions, including mouth, throat, stomach, liver and breast cancers; high blood pressure; cirrhosis of the liver; and depression, says Alcohol Change UK. And men drink at problematic levels more than women.

But could something deeper be going on at a cellular level? Nanotechnologist Dr Michelle Dickinson, creator of Nanogirl STEM Adventure subscriptions, says that while mechanisms that underlie differences between the sexes are complex and there are some behaviours seen more in men (such as smoking), how our bodies react to Covid-19 seems to revolve more around immunological, hormonal and genetic factors.

‘This is not the first time we have seen this gender difference,’ says Dr Dickinson. ‘Sars, influenza, Ebola and HIV have all affected men differently to women.

‘Research shows that women’s bodies are better at fighting off infection, thanks to hormones and the many immune function genes that sit on their two X chromosomes; men only have one X chromosome.’

This means women typically have stronger immune responses than men, except during pregnancy, to help them avoid attacking their foetus. This is thought to be related to the female hormone oestrogen, which has been shown to bind to immune cells and activate disease-fighting molecules.

‘When mice were infected with Sars,’ explains Dr Dickinson, ‘male mice were more likely to die, until the researchers removed the ovaries (and therefore oestrogen) from the female mice, after which their death rates skyrocketed.’

University of New South Wales researcher Zoe Xirocostas has just published a hypothesis called the Unguarded X into why women live longer than men generally. She explains why having two matching X chromosomes (as in human females) is advantageous to longevity: ‘The hypothesis suggests that having a small Y chromosome (as in human males) means you would be more likely to express undesirable traits if there was something wrong with a gene on one of your X chromosomes.

‘Whereas in females, having two X chromosomes means if something is wrong with a gene on one chromosome, you are likely to have a functioning version of that gene on your other X chromosome and essentially hide (or mask) any mistakes, and therefore not express the undesirable trait. These undesirable traits could be anything that is housed on the X chromosome.’

As an example, she says, a faulty gene might play a small role in immunity or respiratory function. As explained by the hypothesis, men would be more likely to express this faulty gene than women (because women have an extra X chromosome that would likely have a good copy of this gene) and therefore have the immune/respiratory system function in a way that is not ideal.

Normally, a small genetic error like this would go unnoticed as the body is still able to function normally. However, in the case of coronavirus, it could be a big factor affecting how you are able to fight the disease.

Xirocostas also points out that testosterone has been shown to act as an immunosuppressant, which could also play a role in men dying at higher rates than women for coronavirus.

Meanwhile, oestrogen enhances immune defence and acts as an antioxidant, says a Danish analysis published in the journal PNAS in 2018, which looked into why women live longer than men even during epidemics.

The research team led by epidemiologist Prof Virginia Zarulli points out that many bacterial, viral, parasitic and fungal infectious diseases are higher in men than in premenopausal women.

Plus, autoimmune diseases are more prevalent in women than in men, as is a stronger immune response to vaccinations, although the mechanisms through which sex hormones affect immune responses in humans have not been fully elucidated.

Could innate fitness also matter?

Women process oxygen more quickly than men when they start to exercise, according to a 2017 study from the University of Waterloo. ‘We found that women’s muscles extract oxygen from the blood faster, which, scientifically speaking, indicates a superior aerobic system,’ said Richard Hughson, a professor in the Faculty of Applied Health Sciences, and Schlegel Research Chair in Vascular Aging and Brain Health at Waterloo.

By processing oxygen faster, women are less likely to accumulate molecules linked to muscle fatigue, effort perception and poor athletic performance.

Is it also a question of exposure?

More women seem to be contracting the virus in the first place, with US data showing that while more men are dying of Covid-19, in most states, slightly more women are getting infected.

This could be due to the sex-based nature of health workforces — according to NHS Digital, 77 per cent of the whole NHS workforce is female, with most in lower paid or junior roles.

Another factor where gender matters is a protein called ACE 2. Dr Dickinson explains: ‘Covid-19 prefers to infect and latch on to cells that have this ACE 2 protein on the outside. Recent (though not peer-reviewed) research on Covid-19-infected patients in China showed higher circulating ACE 2 levels in men than in women and in patients with diabetes or cardiovascular diseases.

‘While there is still more research to be done, it does seem that females are designed to have a more robust immune response to Covid-19.’

That would certainly be true for Katherine Baldwin, a 49-year-old coach and author and her husband Bill Burroughs, 54, an engineer. The couple, who live in Dorset, caught the virus when they went skiing in the French Alps in early March.

Katherine says: ‘Bill started feeling unwell on March 12; we thought it was a cold. But we left Val d’Isere two days later anyway. Our whole party of eight felt under the weather.’

By Monday, her husband called in sick to work. He had a temperature and was feeling ‘woolly’, with shivers and aches and pains, but no cough. Then his chest began to hurt and breathing became restricted.

By Sunday, a GP friend suggested they call 111, who advised Burroughs go to hospital the next morning. ‘That night was frightening,’ says Baldwin. ‘I could really hear him struggle to breathe.’

The next day, he was tested for pneumonia and had his oxygen monitored before being sent home to rest, with the advice to keep fluids up and use paracetamol if necessary.

Gradually, he recovered, but it has taken a month for him to feel ‘95 per cent’, as he says, and to feel up to going out for a bike ride. For Baldwin, however, the symptoms were only mild.

‘Was it something innate in our biology or did Bill get a higher viral load at first exposure?’ she says. ‘We just don’t know.’

But perhaps soon we will, and sex-separated research that targets women and men as two biological entities could be the place to start.

The Daily Telegraph

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