THERE is "convincing evidence" to indicate that a mysterious outbreak of severe hepatitis which sickened hundreds of young children worldwide last year was caused by a virus not previously known to cause disease.
New research led by Glasgow University, and published today in the prestigious journal Nature, also reveals that children with a specific gene variant linked to immunity appeared to be at higher risk.
The findings are based on an analysis of 32 children - mostly under five - who presented to hospitals in Scotland between March 14 and August 20 2022 with symptoms including vomiting, abdominal pain and fatigue.
READ MORE: The inside story of Scotland's child hepatitis outbreak
All were diagnosed with acute hepatitis - a severe and potentially deadly inflammation of the liver - but there was no obvious cause.
The rate of admissions was much higher than would normally be seen, leading clinicians to raise the alarm with Public Health Scotland.
Scotland was the first country in the world to launch an investigation, but to date there have been at least 1,010 probable cases reported in 35 countries as far afield as the United States, Japan, and Argentina.
A preliminary study involving nine patients pointed to a so-called bystander virus known as adeno-associated virus 2 (AAV2) as a probable culprit.
However, today's study is the first peer-reviewed and detailed investigation into the outbreak.
Of the 32 children studied - who were compared against 74 'control' patients - four required treatment in a specialist liver unit and one received a liver transplant.
All of the youngsters recovered following treatment but recovery took several months, even for the least unwell children.
The researchers were able to confirm the presence of AAV2 in the liver of all the patients who were ill with acute hepatitis.
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In addition, 81 per cent of the children with acute hepatitis had AAV2 antibodies present in their blood, compared to only 7% of children in the control group.
READ MORE: Covid Scotland and the strange viral consequences of lockdown
AAV2 was first identified by scientists in 1965 and infects up to 90% of the population.
Most people have developed immunity by the age of 18.
AAV2 has not previously been associated with causing disease.
Known as a 'bystander' virus, it lies dormant in cells and is only "activated" in the presence of other viruses including herpes and adenoviruses - a family of bugs which cause gastroenteritis and cold or flu-like symptoms.
It can also be spread as a co-infection, for example with adenovirus.
The scientists note that a spike in adenovirus diagnoses among young children in Scotland had "directly preceded the outbreak of unexplained hepatitis".
In contrast they found "no direct link between Covid-19 and the outbreak of acute hepatitis", based on antibody testing which indicated that exposure levels in the affected group were lower than expected based on community prevalence at the time.
In addition, none of the children with acute hepatitis had received a Covid vaccine.
However, genetic analysis of 27 of the affected children revealed unusually high rates of a variant called DRB1*04:01 - a form of the Human Leukocyte Antigen gene, which codes for proteins involved in the immune response.
Of the 27 children tested, 25 were positive for at least one copy of this variant.
The frequency was around five times higher compared to the general population.
The team believe this genetic variant could explain why some children were more susceptible to serious illness.
Dr Antonia Ho, a consultant in infectious diseases Glasgow University's Centre for Virus Research (CVR), said there was now "convincing evidence that AAV2, along with a genetic predisposition play an important role in the onset of acute hepatitis in children".
A version of AAV is currently used as a vector in gene therapies, including haemophilia treatment, and hepatitis is a common side-effect.
However, doctors tend to prescribe steroids before and for several weeks after therapy to prevent liver inflammation from becoming serious.
READ MORE: Scots study reveals how testing for Hepatitis C in pharmacies 'could beat the disease'
Professor Emma Thomson, an expert in infectious diseases at the CVR and senior author on the Nature study, said AAV2 may be the direct cause of acute hepatitis or "a useful biomarker of recent adenovirus infection", with adenovirus as the true pathogen.
She added: “There are many unanswered questions and larger studies are urgently needed to investigate the role of AAV2 in paediatric hepatitis cases, particularly the role of the immune response in the disease process.
"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 [genetically] susceptible young children.”
While cases of unexplained acute paediatric hepatitis pre-date the pandemic, it is thought that the surge in adenovirus after Covid restrictions lifted led to a clustering effect - whereby an unusual number of cases occurred in a short time.
By triggering a public health alert, it enabled scientists for the first time to identify a link between the illness, AAV2, and adenovirus.
Co-author Professor Calum Semple, an expert in outbreak medicine and child health at Liverpool University, said paediatric liver centres in the UK would typically see only a "handful of children each year with unexplained hepatitis", but that such cases had "virtually disappeared" when social mixing reduced.
Prof Semple, who contributed to the UK Government's SAGE and NERVTAG advisory groups during the pandemic, stressed that new collaborative ways of working developed during the pandemic by doctors, scientists, and public health teams had "led to the rapid discovery of the cause of this mystery disease".
He added: "It would be a lazy mistake to blame covid restrictions for causing this disease.”
Thomas Baumert, head of the Inserm Research Institute for Viral and Liver Diseases at the University of Strasbourg, said it was "good to see that the cause of these outbreaks has been finally elucidated".
He added that similar findings by three independent studies "give strong credibility to the results".
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