Covid itself is not to blame for a mysterious hepatitis outbreak affecting children around the world, researchers confirmed today.
However, pandemic-era barriers may have played a role.
Scientists have today identified a normally harmless virus as the main culprit behind an unusual liver disease that has sickened 200 people in the UK and left dozens needing transplants.
Two separate studies concluded that adeno-associated virus 2 (AAV2) plays an “important role.”
The virus, which usually does not cause any illness, infects most Britons by the age of 10.
But AAV2 can’t replicate without a “helper” pathogen like adenovirus—which often causes cold-like symptoms. Adenoviruses have increased according to the hepatitis cluster, experts say, because children have weakened immunity after returning to pre-pandemic levels of exposure.
Therefore, a group of academics supported by the UK’s Health Safety Agency believe that dual infection of these two viruses can best explain the outbreak.
Until now, scientists have been investigating the root cause of the disease, with theories blaming either Covid itself or a mutation in the adenovirus strain.
Q&A: What is the mysterious global hepatitis disease 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 from alcohol consumption.
Some cases resolve on their own, there are no problems, but some can be fatal, and patients need a liver transplant to survive.
What are the symptoms?
People with hepatitis often experience fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, pale stools, and joint pain.
They can also suffer from jaundice — a yellowing of the skin and the whites of the eyes.
Why are experts concerned?
Hepatitis is usually rare in children, but experts have seen more cases in the current outbreak than expected a year later.
According to the World Health Organization, the origin of the diseases is unknown and severe.
What are the higher theories?
Adeno-associated virus 2 (AAV2)
Adeno-associated virus 2 (AAV2) appears to be behind hepatitis, according to two separate studies in the UK that looked at dozens of children across the country.
The virus, which usually does not make people sick, often accompanies an adenovirus infection, similar to the flu.
British experts tasked with investigating widespread outbreaks believe the endless cycle of lockdowns may have played a role.
Restrictions can weaken children’s immunity because they are at higher risk of adenovirus.
This means that even a “normal” adenovirus can have serious consequences because children don’t respond to it the way they used to.
According to other scientists, this adenovirus may have “unique mutations”.
This means it can be contagious or can get the better of children’s natural immunity.
Overall, two studies of dozens of children across the UK found that 96 per cent of children with unexplained hepatitis had “high levels” of AAV2.
In comparison, only four percent of healthy young adults tested positive for AAV2, and at much lower levels.
The study’s lead author, Dr Antonia Ho, said that Covid-19 lockdowns and restrictions had led to a “significant reduction in the circulation of seasonal viruses”.
“Equilibrium” now needs to be restored as young people mingle in pre-pandemic ways, which has led to “different types of circulation” of viruses, he said.
The victims of the strange disease were mostly children under the age of five, which first started with diarrhea, vomiting and stomach pain, followed by jaundice – yellowing of the skin.
Some were hospitalized for between one and 11 weeks with liver inflammation, and 40 percent were admitted to intensive care.
The World Health Organization (WHO) has reported at least 1,010 cases in 35 countries. About 50 liver transplants have been required worldwide, and 22 have died.
Preprints, not yet peer-reviewed but published on the MedRxiv website, suggest that AAV2 may be involved in hepatitis outbreaks.
The first study, led by MRC University of Glasgow’s Center for Viral Research (CVR), examined nine children in Scotland with hepatitis, with an average age of four.
They were all admitted to hospital between March 14 and April 4 and spent an average of 10 days under NHS care. No one needs a liver transplant.
Their DNA was extracted from blood, liver, stool and food samples and the results were compared to 58 healthy young adults.
AAV2 was detected in all nine hepatitis patients but none in the control groups.
In a separate analysis, the researchers examined the genetics of hepatitis patients.
They found that nearly nine in 10 (89 percent) of young children with hepatitis had the human leukocyte antigen gene, compared to less than two in 10 (16 percent) in the general population.
The finding may offer another part of the answer to why some children become so ill, the team said.
Professor Emma Thomson, Clinical Professor and Consultant in Infectious Diseases, CVR and senior author of the Scottish study, explained: ‘The gene itself is important because it codes for a receptor that gives viruses or other pathogens to the immune system.
“So this suggests that viral hepatitis has an immune-related cause.”
However, he said more research is needed to confirm that this gene is involved.
A second study, led by Great Ormond Street Hospital (GOSH) and the UK’s Healthcare Safety Agency, looked at 28 children in Britain with hepatitis.
Their analysis included liver samples from five children who required transplants and blood samples from other young children.
Almost all of the children tested positive for AAV2. By comparison, AAV2 was “only very rare” outside this group – in six percent of healthy children – and at “significantly lower levels”.
And sequencing of the liver samples showed that AAV2 was present and spread throughout the organ.
Both studies ruled out recent or previous Covid infection as a cause of hepatitis.
Tests showed that only two-thirds of hepatitis patients had Covid antibodies – as was common among Scottish children at the time – and the virus was not present in any of the liver samples. None of the young people had received the Covid vaccine.
Scientists do not know why hepatitis occurs now.
However, they said the peak of adenovirus infections in the general population after the lockdown “may have been comparable”.
Scientists have long warned that the Covid-19 restrictions put in place to stop the spread of the virus are stopping the spread of other infections in the population, leaving people with less immunity to them.
Professor Thomson said AAV2 itself could be the cause, or it could act as a “useful biomarker” of recent adenovirus infection, which may be behind cases of hepatitis.
He 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 the seasonal circulation of AAV2, which is not always controlled—the peak of adenovirus infection may coincide with the peak of AAV2 exposure, leading to an unusual presentation of hepatitis in susceptible young children. .’
GOSH virologist Professor Judy Brewer said the results “may reassure parents concerned about Covid, as neither found a direct link to SARS-CoV-2 infection groups”.
“However, our data point to AAV2 in the liver and/or blood as the strongest biomarker of hepatitis,” he added.