A MYSTERIOUS outbreak of hepatitis in young children has been linked to a virus not previously associated with human disease.

Testing of the blood plasma of nine paediatric patients in Scotland who fell ill with unexplained liver inflammation between March and April found that all nine were positive for adeno-associated virus 2 (AAV2), a form of parvovirus.

Most children are exposed to AAV2 around the age of three, but the virus will lie dormant in the cells unless activated by a "helper" virus, such as adenovirus or the herpesvirus, which triggers it to replicate.

Researchers believe that a surge in adenovirus as restrictions eased earlier this year led to an unusual clustering of hepatitis cases, prompting a public health investigation which may have exposed a link with AAV2 for the first time.

Emma Thomson, a professor of infectious diseases at Glasgow University and a senior author of the study, said: "It's quite likely that there's been a trickle of cases before that we haven't [noticed], so we don't think that lockdown necessarily precipitated this but that the patterns may have changed so that we've seen the cases come all at once instead of a steady trickle."

READ MORE: The inside story of Scotland's child hepatitis outbreak 

Prof Thomson added that it is unclear whether AAV2 is the direct cause of disease or whether is simply a "useful biomarker" for recent adenovirus infection, which may be the real pathogen but which can be harder to detect.

She said: "There are many unanswered questions and larger studies are urgently needed to investigate the role of AAV2 in paediatric hepatitis cases."

Scientists also found that the youngsters affected were much more likely than the general population to be carrying a particular genetic mutation, which is more commonly found in northern Europe than other parts of the world.

A link with Covid is now considered "extremely unlikely", and none of the children - who had a median age of 3.9 - had received the Covid vaccine.

Scotland was the first country in the world to raise the alarm following a string of admissions to hospital in Glasgow for children suffering from severe liver inflammation which was not caused by any of the common hepatitis viruses or environmental toxins.

Worldwide, more than 1000 cases have since been identified in 35 countries - mostly in the US and Europe - with 22 deaths.

In the UK, 12 children - including one in Scotland - have required liver transplants.

The vast majority are under five.

A study led by the MRC-University of Glasgow Centre for Virus Research (CVR) and the Royal Hospital for Children in Glasgow compared nine of the hepatitis patients against aged-matched controls, including 13 healthy children, 12 youngsters with recent adenovirus infections but normal liver function, and 33 paediatric hepatitis patients with a known cause.

While AAV2 was detected in all nine of the mystery hepatitis patients, it was not found in any of the 58 control participants.

Adenovirus was identified in six of the nine unexplained hepatitis cases, with herpesvirus found in three of the nine.

Two thirds of the children were positive for Covid antibodies, but this was at expected levels.

Since April, 11 children in England and one in Scotland have required liver transplants as a result of severe and unexplained hepatitisThe spike in unexplained paediatric hepatitis cases overlapped with a spike in adenovirus infections

The scientists stressed that Covid had been widely circulating for the past two years prior to the hepatitis outbreak, whereas adenovirus had largely disappeared.

The outbreak of unexplained hepatitis began around two weeks after a large spike in adenovirus cases.

The analysis also found that eight of the nine children in the mystery hepatitis group (89 per cent) were carriers of a gene variant known as HLA-DRB1*04:01, which is associated with multiple sclerosis and Type 1 diabetes, as well as higher rates of asymptomatic Covid.

Among the general Scottish population, the variant is found in fewer than 16% of people.

The findings chime with a separate study led by experts at Great Ormond Street children's hospital in London which identified AAV2 in 16 out of 17 blood and liver samples from children treated for hepatitis of unknown cause.

In contrast, it was found in only six out of 100 healthy children without hepatitis, and at much lower levels - 11 out of 32 (34%) - even in samples from immuno-compromised children.

READ MORE: Scotland-led study could pave way to faster elimination of Hepatitis C worldwide 

Dr Antonia Ho, an expert in infectious diseases at the CVR, said: "All the measures we put in place to reduce transmission of SARS-CoV2 meant that there was much reduced circulation of seasonal viruses.

"Now that there are children back at school and mixing, inevitability there is an equilibrium that needs to be re-established, so lots of these seasonal viruses are transmitting and circulating outside of what we would normally expect. This large wave [of adenovirus] that we've seen is not typical for the time of year.

"It might be that this kind of hepatitis with AAV2 has been seen in low numbers but, because of the huge peak we've had, we're now seeing clusters that we wouldn't have recognised before in years when adenovirus levels were lower."