Experts have largely dismissed a study that suggests more men may be dying with the coronavirus due to them having higher levels of an enzyme in their blood.
On the week ending 20 April, nearly two-thirds of the more than 2,400 deaths that occurred in England and Wales were in males.
To learn more, scientists from the University of Groningen in the Netherlands looked at blood samples from over 3,700 heart-failure patients across 11 countries.
Results revealed the men had a higher concentration of angiotensin-converting enzyme 2 (ACE2) than the women.
ACE2 acts as a receptor for the coronavirus on the surface of cells, allowing the infection to take hold.
Other experts have stressed the study was not carried out in people with the coronavirus, calling it “pure speculation” that “should be tempered”.
Early research suggests the infection is mild in four out of five cases, however, it can trigger a respiratory disease called COVID-19.
Coronavirus: Do men have more of a ‘dangerous’ enzyme?
The Groningen scientists were already studying different disease markers in the blood of men and women when the coronavirus emerged at the end of 2019.
“When we found that one of the strongest biomarkers, ACE2, was much higher in men than in women, I realised this had the potential to explain why men were more likely to die from COVID-19 than women”, said co-lead author Dr Iziah Sama.
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The scientists measured ACE2 concentrations in blood samples collected from 1,485 men and 537 women with heart failure.
Heart failure occurs when the organ does not pump blood as efficiently as it should. ACE2 levels are known to be higher in those with the condition.
The experiment was then repeated in 1,123 male and 575 female patients.
Results, published in the European Heart Journal, revealed being male was the “strongest predictor of elevated ACE2 concentrations”.
“ACE2 is a receptor on the surface of cells,” said co-lead author Dr Adriaan Voors.
“It binds to the coronavirus, and allows it to enter and infect healthy cells after it is has been modified by another protein on the surface of the cell, called TMPRSS2.
“High levels of ACE2 are present in the lungs and therefore it is thought to play a crucial role in the progression of lung disorders related to COVID-19.”
ACE2 is also highly expressed in other tissue, including the heart, kidneys, blood vessels and testicles.
“Taken together, these observations demonstrate for the first time that male subjects have delayed viral clearance of [the coronavirus],” they wrote on the online research site medRxiv.
The New York scientists wondered if this expression suggests the testicles may act as a “reservoir” for the virus and play a role in “viral persistence”.
Results ‘should be taken with caution’
Professor Paolo Madeddu, from the University of Bristol, called the Groningen study “interesting” but stressed he does “not agree with the authors’ conclusions”.
He added he “doesn’t understand how they have made any conclusions about COVID-19” when these patients were not included in the research.
In addition, while the difference in ACE2 concentrations between the male and female participants may have been statistically significant, it “was in the order of decimal points”.
“Therefore, any biological or medical interpretation of the difference should be taken with caution,” said Professor Madeddu.
“In their conclusion, the authors state these data might explain the higher incidence and fatality rate of COVID-19 in men.
“It is important to emphasise this is purely speculation and is not supported by the data provided, and should be tempered”.
Professor Ian Hall, from the University of Nottingham, agreed. He said: “The actual difference in ACE2 levels between men and women, whilst statistically significant, is in real terms small, and I believe it likely whilst this might contribute in a small way there must be other explanations as to why men are at increased risk of severe disease.
“One potential explanation would be that differential immune responses to the virus, regulated by genetic differences between men and women, may also underlie this difference in susceptibility”.
Professor Phillip Goulder, from the University of Oxford, previously explained how “the protein by which viruses such as coronavirus are sensed is encoded on the X chromosome”, which women have two of and men just one.
“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.
Regarding the Groningen study, Prof Hall noted ACE2 was measured in the participants’ blood, not their airways.
By only including heart-failure patients, the participants may also “not be entirely representative of the general population”, he added.
Professor John Boyd Chambers, from Guy’s and St Thomas’ Hospitals in London, described the research as “hypothesis-generating” for future investigations.
ACE-inhibitor drugs ‘do not raise COVID-19 risk’
Concerns have previously been raised that heart-failure drugs that target angiotensin may increase the risk of coronavirus complications.
The Groningen results showed, however, patients on these treatments did not have elevated ACE2 levels compared to those taking other medications.
“Our findings do not support the discontinuation of these drugs in COVID-19 patients as has been suggested by earlier reports,” said Prof Voors.
Prof Chambers added this was likely “the most important result” of the research.
Some studies have suggested medication that targets so-called renin-angiotensin-aldosterone system (RAAS) inhibitors might increase ACE2 levels in the plasma, the liquid part of blood.
It was implied this could raise the risk of coronavirus complications.
The Groningen study suggests this is not the case, however, it only looked at ACE2 concentrations in plasma, not tissues.
It also does not provide definitive evidence of the effects of RAAS inhibitors in patients with COVID-19.
There appears to be a lot of confusion surrounding these drugs, with Prof Madeddu even pointing out ACE inhibitors may “protect human cells by sponging and blocking the virus in the circulation, allowing immune cells to kill it”.
“Other researchers are exploiting this possibility to generate drugs that block the virus, while waiting for a vaccine,” he added.
All the experts agreed patients that have been prescribed angiotensin-inhibiting drugs should continue to take them.
“The evidence so far, including in this study, does not support the discontinuation”, said Professor Francesco Cappuccio, from the University of Warwick.
“Patients on these drugs, whether for heart failure or for high blood pressure or diabetes, should not stop them unless advised and under strict medical supervision and with the addition of a suitable replacement medicine.”
What is the coronavirus?
The coronavirus is one of seven strains of a virus class that are known to infect humans.
Others cause everything from the common cold to severe acute respiratory syndrome (Sars), which killed 774 people during its 2002/3 outbreak.
Since the coronavirus outbreak was identified, more than 4.1 million cases have been confirmed worldwide, according to Johns Hopkins University.
Of these cases, over 1.4 million are known to have “recovered”.
Globally, the death toll has exceeded 283,400.
The coronavirus mainly spreads face to face via infected droplets expelled in a cough or sneeze.
Symptoms include fever, cough and slight breathlessness.
The coronavirus has no “set” treatment, with most patients naturally fighting off the infection.
Those requiring hospitalisation are given “supportive care”, like ventilation, while their immune system gets to work.