Why is virus killing so many more men than women?

It’s one of the most striking things we’re learning about this terrible disease.

AVICIOUS fever, terrifying bouts of breathlessness and excruciating headaches – all culminating in a 999 dash to a hospital in Edinburgh, emergency oxygen and intravenous fluids in an isolation ward.

For Scott Dixon, suffering Covid-19 has been a harrowing ordeal. ‘The memory will never leave me,’ he says.

It is also a state in which he never believed he would find himself.

Just shy of his 50th birthday, Scott is fit and healthy, rarely suffering as much as a cold. He is not overweight, exercises regularly and has none of the underlying risk factors that would have made him an obvious candidate for severe disease.

Apart from one, that is – he is a man. A growing body of evidence now suggests that men are far more likely to be hit hard by the virus.

While infection rates between men and women – based on positive tests – appear equal, men are more likely to end up in intensive care and are far more likely to die.

Scott, who is now recovering at home, notes with some surprise that ‘all the other patients on the ward were men’.

The story of Mark and Kathy Anders, both 57, from Warwickshire in England, is another stark example.

The couple started experiencing mild flu-like symptoms four weeks ago. While Kathy, a GP’s secretary, recovered after a fortnight, the condition of paramedic Mark – a fit non-smoker – worsened and he suffered a relentless fever of almost 40C.

LAST Friday he was rushed to hospital for emergency treatment. ‘He wasn’t getting any better and he’d developed an agonising chest pain every time he breathed in,’ says Kathy, who is now self-isolating at home.

‘At first, he was taken to an acute ward but he quickly deteriorated. Scans showed traces of Covid-19 on his lungs and he had pneumonia.

‘On Sunday I got a call from him saying, “I think they’re taking me into intensive care tomorrow – and I don’t think I’m going to come out.” ’

But in a remarkable turnaround, doctors got Mark’s temperature under control and were able to manage his breathlessness with supplementary oxygen within 24 hours.

‘So far he’s dodged intensive care, but we’ve been told that if his condition deteriorates any further, he’ll have no choice,’ Kathy says.

Unlike Mark, Kathy has been unable to secure a test but she is in no doubt about her diagnosis.

She says: ‘We’re NHS workers so we are exposed to infected patients. We became ill within days of each other. Although my symptoms were mild, I’ve never felt anything like this before.’

And no one is more surprised by how differently their bodies have coped than Kathy.

‘I was convinced that if either of us were going to get it – and suffer badly – it would be me,’ she says.

‘I’ve had treatment for cancer twice and I am the one who picks up bugs, whereas Mark rarely even gets a cold.’

This experience is familiar. As Covid-19 cases surge, a startling report from the UK’s Intensive Care National Audit & Research Centre (ICNARC) reveals that men account for 73% of the more than 2,000 most seriously ill patients admitted to critical care units there.

Outcomes for these patients, aged between 52 and 70, are not yet known as many remain in hospital.

But this is a worldwide phenomenon. Global Health 50/50, an initiative which campaigns for health equality between the sexes, has been collecting information on male and female coronavirus cases.

So far, it has reliable figures from 18 countries. In each, the proportion of men and women testing positive for Covid-19 remains roughly equal. But overwhelmingly more men are dying.

In Greece and Peru, 72% of those who died with the virus are male. In Italy, 68% of the deaths have been men, along with 64% each in China, Denmark and Germany.

Of the 235 recorded deaths in Ireland as of April 8, 148 – or 63%, – were male and 87 were female,

But the Global Health 50/50 report does conclude that men are between 50% and 80% more likely than women to die following a coronavirus diagnosis.

So the obvious question is why? The discrepancy was first noticed in China, the origin of the pandemic. An analysis of 44,672 confirmed cases up to February 11 found the death rate among men was 2.8%, compared with 1.7% among women.

Some experts at the time wondered whether lifestyle factors were to blame.

IN CHINA, 50% of men smoke compared to fewer than 4% of women. Smoking, as is well known, increases the risk of lung and heart disease, high blood pressure and cancer, all of which make suffering severe Covid-19 more likely.

But the explanation did not hold up when the virus moved into Western countries. In Europe, the smoking rate is lower – 29% on average, according to the World Health Organisation. And while men are still more likely to use cigarettes, there are high smoking rates among women, too.

There had to be something else in play. In truth, men have long been known as the frailer sex when it comes to viruses.

It was the same picture with Sars – another coronavirus that rampaged across the world in 2003.

It is known to have killed only 780 people globally, while Covid-19 has already led to more than 104,000 deaths. But Sars was also disproportionately more lethal in men – 21% of infected men died, compared with 13% of women.

In 2012, 63% of those infected with the Mers coronavirus were also men.

‘This is a pattern we’ve seen with many viral infections of the respiratory tract – men can have worse outcomes,’ says Sabra Klein, a scientist who studies sex differences in viral infections and vaccination responses at the Johns Hopkins Bloomberg School of Public Health in Baltimore.

‘We’ve seen this with other viruses. Women fight them off better,’ she says.

Dr James Gill, a locum GP and honorary clinical lecturer at Warwick Medical School, believes one reason is that men ‘simply don’t look after their bodies as well’ and, on average, drink more alcohol. Studies suggest that they are less likely to follow healthy diets or seek medical help if they need it.

As a result, men are more likely than women to suffer from chronic conditions such as heart and lung disease, cancer, high blood pressure and type 2 diabetes – all of which can lead to more serious coronavirus symptoms.

Other studies have shown that men are less likely to wash their hands and use soap or abide by public health advice.

This could, in theory, involve ignoring social-distancing policies, although there is no direct evidence for it.

Immunologist Professor Philip Goulder, from Oxford University, says these are important behavioural differences between the sexes which ‘have a huge impact on the outcome from infections such as coronavirus’.

There is also an ongoing debate over whether obesity in itself, rather than as a contributory factor to high blood pressure and diabetes, increases the risk of coronavirus problems. The Health Survey for England 2017 found men are more likely to be overweight or obese than women (67% compared with 61%). The latest ICNARC data does not suggest that those with a Body Mass Index above 25 are any more likely to require hospital treatment with coronavirus than those with a healthy weight.

But those who are obese are more likely to die in critical care.

Based on the more limited data available on outcomes, 57% of people with a BMI over 30 died, compared to 43% of those with a normal BMI.

Duncan Young, Professor of Intensive Care Medicine at Oxford University, says: ‘The numbers are small but there does appear to be an increased risk of death in obese patients admitted to an intensive care unit with a Covid-19 infection.’

DR GILL says one plausible theory is that, in men, the way that their weight is distributed could be having an effect. ‘Broadly, men have an appleshaped weight distribution which means fat will be distributed more widely across their torsos,’ he says. ‘It could put extra pressure on respiratory muscles, which work harder if you’re carrying more weight. You’ll deteriorate faster. It doesn’t matter what put a patient into respiratory distress in the first place.

‘Huge amounts of evidence from anaesthesiology and general surgery tells us that if you’re obese,

I’ve had treatment for cancer twice and always pick up bugs. Mark rarely even gets a cold

then your outcomes are worse on a ventilator.’

Could there also be a genetic explanation for the disparity? Scientists are trawling through DNA databases to try to work out why some people are more susceptible to the worst ravages of the disease than others.

But some already believe that basic differences between male and female immune systems may be a key factor.

Prof Goulder says: ‘It is becoming increasingly recognised that there are substantial differences in the immune system between males and females, and that these have a significant impact on outcome from a wide range of infectious diseases.

‘The immune response throughout life to vaccines and infections is typically more aggressive and more effective in females compared to males.’

Inside the nucleus of every cell, genetic material called DNA is packaged into thread-like structures called chromosomes.

These contain sequences of ‘code’ called genes, which determine how cells function and, as a result, everything from hair and eye colour to blood type.

The usual number of chromosomes in every cell in the body is 46 – or 23 pairs.

We inherit half from our mother and half from our father.

One pair are known as sex chromosomes and they determine whether a person is born male or female.

The sex chromosomes in men and women differ in structure: women have two that are, when looked at under an extremely powerful microscope, shaped like an X. Men have one shaped like an X, and one like a Y.

A number of critical immune genes are located on the X chromosome, says Prof. Goulder.

BECAUSE women have two copies of this chromosome and men only one, it means that women are better equipped to fight infection and viruses. When it comes to coronavirus specifically, there is a protein called TLR7 – again, on the X chromosome – which senses the Covid-19 infection.

This triggers a signal which results in the production of chemicals in the body called type one inferons. These ‘essentially have direct antiviral effects, but also amplify the innate immune response’, according to Prof Goulder.

‘It’s about recognising a threat and instigating a response. The more TLR7 receptors you have, the better that response.’

Men, who have only one X chromosome, therefore naturally have fewer TLR7 receptors to fight off coronavirus.

At first glance, this might seem to be a huge biological mistake. But Prof Goulder explains that this may have had an evolutionary advantage.

In theory, it is more important that women, who have to bear and raise children, are able to fight off infections, including viruses, and stay healthy.

For men, other evolutionary roles, such as attracting a mate and physical strength, were historically more advantageous.

Early man just didn’t need as strong an immune system as women, he says.

Other factors could include sex hormones such as testosterone, which suppresses the immune system.

Testosterone is often known as the male sex hormone as it is responsible for the development of sperm – although women also produce small amounts.

‘There’s a very nice study looking at the response to the flu vaccine in men and women,’ Prof Goulder says.

‘The women had higher antibody responses than the men, but the women with the lowest testosterone had the highest of all, and the worst response was seen in men with the most testosterone.’

Whether testosterone levels can also have an impact on coronavirus severity has yet to be investigated.

Now the big hope in clarifying the difference between the effects of coronavirus in men and women will come from the proposed rollout of antibody testing.

No test has yet proved reliable. Positive tests for coronavirus have appeared to show that men and women are roughly equally likely to be infected – 52% compared with 48%.

But an antibody test involving swathes of the population could reveal the truth, including whether women are more likely to be carriers, develop only mild symptoms, or develop a stronger antibody response than men.

Proof, perhaps, that man flu may not be a myth after all.