Covid itself is not to blame for the mysterious hepatitis outbreak affecting children across the world, researchers insisted today.
However, pandemic-era lockdowns may have played a role.
Scientists today pinpointed a usually-harmless virus as being the main culprit for the unusual liver illness, which has sickened 200 youngsters in the UK and left a dozen needing transplants.
Two separate studies concluded that adeno-associated virus 2 (AAV2) seems to play a ‘significant role’.
The virus, which does not normally cause any illness, infects most Britons by the age of 10.
But AAV2 cannot replicate without a ‘helper’ pathogen, such as an adenovirus — which usually just causes cold-like symptoms. Adenoviruses surged in line with the hepatitis cluster, which experts believe is because children had weaker immunity upon their return to pre-pandemic levels of mixing.
Therefore, a UK Health Security Agency-backed team of academics believe dual infection with these two viruses may offer the best explanation for the outbreak.
Until now, scientists have been flummoxed as to the root cause of the illness, with theories blaming Covid itself or even a mutation in an adenovirus strain.
Q&A: What is the mysterious global hepatitis outbreak and what is behind it?
What is hepatitis?
Hepatitis is inflammation of the liver that is usually caused by a viral infection or liver damage from drinking alcohol.
Some cases resolve themselves, with no ongoing issues, but a fraction can be deadly, forcing patients to need liver transplants to survive.
What are the symptoms?
People who have hepatitis generally have fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, light-colored stools and joint pain.
They may also suffer from jaundice — when the skin and whites of the eyes turn yellow.
Why are experts concerned?
Hepatitis is usually rare in children, but experts have already spotted more cases in the current outbreak than they would normally expect in a year.
Cases are of an ‘unknown origin’ and are also severe, according to the World Health Organization.
What are the top theories?
Adeno-associated virus 2 (AAV2)
Two separate UK studies, which looked at dozens of children across the country, found that adeno-associated virus 2 (AAV2) seems to be behind the hepatitis illness.
The virus, which does not normally make people unwell, often accompanies an infection with flu-like illness adenovirus.
British experts tasked with investigating the spate of illnesses believe the endless cycle of lockdowns may have played a contributing role.
Restrictions may have weakened children’s immunity because of reduced social mixing, leaving them at heightened risk of adenovirus.
This means even ‘normal’ adenovirus could be causing the severe outcomes, because children are not responding to it how they did in the past.
Other scientists said it may have been the adenovirus that has acquired ‘unusual mutations’.
This would mean it could be more transmissible or better able to get around children’s natural immunity.
Overall, the two studies, which looked at dozens of children across the UK, found that 96 per cent of children with unexplained hepatitis had ‘high levels’ of AAV2.
For comparison, just four per cent of healthy youngsters tested positive for AAV2 and at much lower levels.
Dr Antonia Ho, lead author for of the studies, said Covid lockdowns and restrictions led to ‘much reduced circulation of seasonal viruses’.
An ‘equilibrium’ needs to be re-established now that youngsters are mixing in pre-pandemic ways, which has led to ‘different types of circulation’ of viruses, she said.
Sufferers of the strange illness have mainly been under-fives who initially experience diarrhoea, vomiting and stomach pain, followed by jaundice – the yellowing of the skin.
Some have then been hospitalized with liver inflammation one to 11 weeks later, of which 40 per cent are admitted to intensive care.
The World Health Organization (WHO) has reported at least 1,010 cases in 35 countries. Nearly 50 have required liver transplants worldwide and 22 have died.
The pre-prints, which have not yet been peer-reviewed but are published on the MedRxiv website, suggest AAV2 is involved in the hepatitis outbreak.
The first study, led by the MRC-University of Glasgow Center for Virus Research (CVR), examined nine children, aged four on average, suffering from hepatitis in Scotland.
They were all hospitalized between March 14 and April 4 and stayed under NHS care for 10 days, on average. None required liver transplants.
Their DNA was extracted from blood, liver, stool and throat samples and results compared against 58 healthy youngsters.
AAV2 was detected in all nine hepatitis patients but among no one in the control groups.
In a separate analysis, the researchers examined the genetics of the patients with hepatitis.
They detected that nearly nine in 10 youngsters with hepatitis (89 per cent) had the Human Leukocyte Antigen gene, compared to less than two in 10 (16 per cent) in the general population.
This finding may offer another part of the answer as to why some children have become seriously unwell, the team said.
Professor Emma Thomson, a clinical professor and consultant in infectious diseases at the CVR and senior author of the Scottish study, explained: ‘The gene itself is important because it encodes a receptor which presents viruses or other pathogens to the immune system.
‘And so this suggests that there may be a link to an immune-mediated cause of the hepatitis triggered by viruses.’
However, she said more studies were needed to confirm that this gene was involved.
The second study, led by Great Ormond Street Hospital (GOSH) and the UK Health Security Agency, looked at 28 children with hepatitis in Britain.
Their analysis included liver samples from five children who required a transplant and blood samples from the remaining youngsters who did not.
Nearly all of the children tested positive for AAV2. For comparison, AAV2 was present ‘only very rarely’ outside this group — among just six per cent of healthy children and at ‘much lower levels’.
And sequencing of liver samples showed AAV2 was present and had spread within the organ.
Both studies ruled out that a recent or previous Covid infection caused hepatitis.
Tests showed only two-thirds of hepatitis patients had Covid antibodies – similar to the prevalence among Scottish children at the time — and the virus was not present in any of the liver samples. None of the youngsters had had a Covid vaccine.
The researchers still don’t know why the hepatitis outbreak is happening now.
However, they said a peak of adenovirus infections in the general population after lockdowns ‘may have contributed’.
Scientists have long-warned that Covid curbs in place to stop the spread of the virus also stopped other infections from circulating in the population, leaving people with lower immunity against them.
Professor Thomson said AAV2 itself may be the cause, or it may be functioning as a ‘useful biomarker’ of a recent adenovirus infection, which could be behind the hepatitis cases.
She said: ‘There are many unanswered questions and larger studies are urgently needed to investigate the role of AAV2 in pediatric hepatitis cases.
‘We also need to understand more about seasonal circulation of AAV2, a virus that is not routinely monitored – it may be that a peak of adenovirus infection has coincided with a peak in AAV2 exposure, leading to an unusual manifestation of hepatitis in susceptible young children .’
Professor Judy Breuer, a virologist at GOSH, said the results can ‘reassure parents concerned about Covid as neither teams have found any direct link with SARS-CoV-2 infection’.
‘Our data do, however, point to AAV2 in the liver and, or blood of cases as the strongest biomarker for the hepatitis,’ she added.