Covid itself is not to blame for the mysterious outbreak of hepatitis affecting children around the world, researchers insisted today.
However, pandemic-era lockdowns may have played a role.
Scientists today identified a usually harmless virus as the main culprit behind the unusual liver disease which has sickened 200 young people in the UK and left a dozen in need of transplants.
Two separate studies have concluded that adeno-associated virus 2 (AAV2) appears to play a “significant role”.
The virus, which does not normally cause illness, infects most Britons by the age of 10.
But AAV2 cannot replicate without a “helper” pathogen, such as an adenovirus – which usually only causes cold symptoms. Adenoviruses increased alongside the hepatitis cluster, which experts say is due to children having lower immunity as they returned to pre-pandemic mix levels.
Therefore, a team of academics supported by the UK Health Security Agency believe that dual infection with these two viruses may offer the best explanation for the outbreak.
Until now, scientists have been puzzled over the root cause of the disease, with theories blaming Covid itself or even a mutation in a strain of adenovirus.
Q&A: What is the mysterious global hepatitis epidemic and what is behind it?
What is hepatitis?
Hepatitis is an inflammation of the liver that is usually caused by a viral infection or liver damage caused by alcohol consumption.
Some cases resolve on their own with no lingering problems, but a fraction can be fatal, requiring patients to need liver transplants to survive.
What are the symptoms?
People with hepatitis typically experience fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, pale stools, and joint pain.
They can also suffer from jaundice – when the skin and the whites of the eyes turn yellow.
Why are experts concerned?
Hepatitis is generally rare in children, but experts have already spotted more cases in the current outbreak than they would normally expect in a year.
The cases are of “unknown origin” and are also serious, according to the World Health Organization.
What are the best theories?
Adeno-associated virus 2 (AAV2)
Two separate UK studies, involving dozens of children across the country, found that adeno-associated virus 2 (AAV2) appears to cause hepatitis.
The virus, which does not normally make people sick, often accompanies an infection with a flu-like adenovirus.
British experts investigating the wave of illness believe the endless cycle of lockdowns may have played a contributing role.
The restrictions may have weakened children’s immunity due to reduced social mixing, leaving them at increased risk of adenovirus.
This means that even the “normal” adenovirus could be the cause of the serious consequences, because children do not react to it as they did in the past.
Other scientists said it may have been the adenovirus that had acquired “unusual mutations”.
This would mean that it might be more transmissible or better able to circumvent children’s natural immunity.
Overall, the two studies, which looked at dozens of children across the UK, found that 96% of children with unexplained hepatitis had ‘high levels’ of AAV2.
By comparison, only 4% of healthy young people tested positive for AAV2 and at much lower levels.
Dr Antonia Ho, lead author of the studies, said the Covid lockdowns and restrictions have led to “very reduced circulation of seasonal viruses”.
A “balance” needs to be restored now that young people are mixing in a pre-pandemic fashion, which has led to “different types of circulation” of viruses, she said.
People with this strange disease are mostly children under the age of five who initially suffer from diarrhoea, vomiting and stomach pain, followed by jaundice – the yellowing of the skin.
Some were then hospitalized for liver inflammation one to 11 weeks later, 40% of whom are admitted to intensive care.
The World Health Organization (WHO) has reported at least 1,010 cases in 35 countries. Nearly 50 people have required liver transplants worldwide and 22 have died.
The preprints, which have not yet been peer-reviewed but are published on the MedRxiv website, suggest that AAV2 is involved in the hepatitis epidemic.
The first study, led by the MRC-University of Glasgow Center for Virus Research (CVR), looked at nine children, aged four on average, with hepatitis in Scotland.
They were all hospitalized between March 14 and April 4 and remained in NHS care for an average of 10 days. None required a liver transplant.
Their DNA was extracted from blood, liver, stool and throat samples and the results were compared to those of 58 healthy young people.
AAV2 was detected in all nine hepatitis patients but in none of the control groups.
In a separate analysis, the researchers looked at the genetics of patients with hepatitis.
They detected that almost nine out of 10 young people with hepatitis (89%) had the human leukocyte antigen gene, compared to less than two out of 10 (16%) in the general population.
This finding may offer another part of the answer as to why some children became seriously ill, the team said.
Professor Emma Thomson, Clinical Professor and Infectious Diseases Consultant at CVR and lead author of the Scottish study, explained: ‘The gene itself is important because it codes for a receptor that presents viruses or other pathogens to the immune system.
“And so that suggests there may be a link to an immune-mediated cause of virus-triggered hepatitis.”
However, she said more studies were needed to confirm this gene was involved.
The second study, led by Great Ormond Street Hospital (GOSH) and the UK Health Security Agency, involved 28 children with hepatitis in Britain.
Their analysis included liver samples from five children who needed transplants and blood samples from other youngsters who did not.
Almost all of the children tested positive for AAV2. By comparison, AAV2 was present ‘very rarely’ outside of this group – in just 6% of healthy children and at ‘much lower levels’.
And sequencing of liver samples showed that AAV2 was present and had spread through the organ.
Both studies excluded that a recent or previous Covid infection caused hepatitis.
Tests showed that only two-thirds of people with hepatitis had Covid antibodies – similar to the prevalence in Scottish children at the time – and the virus was not present in any of the liver samples. None of the young people had had a Covid vaccine.
Researchers still don’t know why the hepatitis outbreak is happening now.
However, they said a spike in adenovirus infections in the general population after the shutdowns “may have contributed to this”.
Scientists have long warned that the Covid curbs in place to stop the spread of the virus have also prevented other infections from circulating in the population, leaving people with weaker immunity to them.
Professor Thomson said AAV2 itself could be the cause, or it could work as a ‘useful biomarker’ of recent adenovirus infection, which could be behind the hepatitis cases .
She said: “Many unanswered questions remain and larger studies are urgently needed to investigate the role of AAV2 in pediatric hepatitis.
“We also need to know more about the seasonal circulation of AAV2, a virus that is not routinely monitored – a peak in adenovirus infection may have 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 may “reassure parents concerned about Covid as none of the teams found a direct link to SARS-CoV-2 infection”.
“Our data, however, indicate that AAV2 in the liver and/or blood of cases is the most potent biomarker of hepatitis,” she added.