Hepatitis: The mysterious rise in cases among children has been linked to a virus that was considered to be harmless

Two studies have linked the mysterious rise in unexplained hepatitis cases among children to the adeno-associated virus 2, which infects nearly everyone early in childhood

By Michael Le Page

Two independent studies of children in the UK who developed unexplained liver damage, or hepatitis, have found a virus called adeno-associated virus 2 in nearly all of them, but not in other similar children. Almost all the children with hepatitis also have a gene variant that affects their immune response.

Adeno-associated virus 2, or AAV2, is a common virus that infects nearly everyone early in childhood but wasn’t previously thought to cause any disease. The virus can integrate its DNA into the genome of infected cells and thus remain in the body indefinitely.

However, AAV2 is rather unusual in that it can only replicate in the presence of other viruses such as an adenovirus or herpes virus. So it remains unclear if AAV2 is the cause of the hepatitis or just an indicator of infection by an adenovirus, says Emma Thomson at the University of Glasgow, UK.

What the findings do suggest is that AAV2 or another virus could be triggering liver damage via an as-yet-unknown immune mechanism in children with a genetic predisposition.

“There may be an immune-mediated cause of the hepatitis triggered by viruses, though a lot more work is needed to validate that hypothesis,” says Thomson.

She suspects that small numbers of these cases have been going unrecognised for many years. In Scotland, there were lower than usual numbers of adenovirus infections due to covid-19 restrictions, followed by a big peak in adenovirus infections once measures were relaxed, which may have led to lots of hepatitis cases occurring at the same time.

“We don’t think the lockdown precipitated this, we are just seeing everything at once,” says Thomson.

It was in April this year that doctors in Scotland reported a cluster of cases of young children developing liver damage that wasn’t due to the hepatitis viruses usually responsible. The children initially had gastrointestinal symptoms such as diarrhoea, says Antonia Ho, also at the University of Glasgow, and developed hepatitis in the following weeks.

Globally, more than 1000 cases of hepatitis of unknown cause in children have now been reported. Most have recovered, but 22 children have died so far.

The true numbers could be larger than this, says Ho. Many countries don’t test for the hepatitis viruses and thus cannot identify cases that aren’t caused by them.

To try and pinpoint the cause, Ho, Thomson and their colleagues sequenced all the DNA and RNA in blood samples from nine children with hepatitis, 12 healthy children of the same age and 13 children with adenovirus infections but no liver damage. AAV2 was found in all nine of the children with hepatitis but not in any of the others. For four of the nine children, liver samples were available and AAV2 was present in all four.

The team also found that eight of the nine children have a gene variant called HLA-DRB1*04:01 that can affect the immune response to infections. This variant is found in only 16 per cent of people in Scotland.

A separate team led by Judith Breuer at the UCL Great Ormond Street Institute of Child Health in London did a similar study, comparing 28 children with hepatitis with another 136 children. The findings were almost identical, with AAV2 found in the blood of 27 of the 28 children and not in the other children, or only at very low levels.

Breuer’s team also discovered AAV2 RNA in five liver samples, but couldn’t find viral proteins or see viral particles with an electron microscope. “This suggests to us that there’s an indirect viral mechanism,” says Breuer.

Thomson thinks it is “extremely unlikely” that the SARS-CoV-2 coronavirus plays any role in the development of these hepatitis cases. Affected children were no more likely than the others to have had covid-19 in the past, for instance.

In the UK, hepatitis case numbers in children are now declining. International cooperation will be required to do larger studies to confirm the findings and try to work out the underlying mechanism, says Breuer.

Until more is known, it is too early to talk about treatments, says Thomson.