How much did coronavirus lockdown contribute to rising hepatitis cases among young children?

Lockdown restrictions imposed to tackle coronavirus have been partly blamed for causing a mysterious outbreak of severe liver disease in young children.

Scientists working on two new studies believe the measures prevented children from developing immunity to two common viruses – adenovirus and adeno-associated virus two (AAV2).

In some rare cases, scientists believe that the coinfection of an adenovirus or herpes virus with AAV2 triggered the serious complication of hepatitis, explaining a recent spate in the illness.

Adenovirus normally causes colds and stomach upsets, while AAV2 usually causes no illness and requires a “helper” virus – such as adenovirus – to replicate, which could explain why some youngsters went on to develop liver complications.

Many youngsters with the condition were in hospital for several days, with 11 children in England and one in Scotland requiring a liver transplant.

Scientists have partly attributed the spike in hepatitis cases to the fact children had lower immunity levels from staying indoors and were not coming into contact with the normal range of viruses.

Professor Judith Breuer, one of the investigators and an expert in virology at University College London and Great Ormond Street Hospital, said: “During the lockdown period when children were not mixing, they were not transmitting viruses to each other.

“They were not building up immunity to the common infections they would normally encounter.

“When the restrictions were lifted, children began to mix, viruses began to circulate freely – and they suddenly were exposed with this lack of prior immunity to a whole battery of new infections.”

What were these studies looking at?

In two independent research papers, scientists concluded that the rise in hepatitis cases is actually connected to the common adeno-associated virus two, or AAV2.

AAV2 is not known to normally cause disease on its own and often accompanies infection with adenoviruses – these can cause cold or flu-like illness.

Experts said they could not completely exclude the chance that affected children had somehow developed increased susceptibility to getting sick, but they said this was extremely unlikely to be caused by the Covid-19 virus itself.

The studies, which have yet to be peer-reviewed, were published by the University of Glasgow and Great Ormond Street Hospital (GOSH) in London.

What did scientists discover?

They found that AAV2, which cannot replicate without a “helper” virus such as an adenovirus, was present in all nine cases in the Glasgow study and 94% (16 of 17) of cases in the GOSH study.

The 94% is significantly higher than the 16% normally found in the general population.

The scientists, therefore, believe that dual infection infection with AAV2 and an adenovirus, or possibly a herpes virus HHV6, may offer the best explanation for the onset of severe liver disease in affected children.

How many children are affected?

In the UK, most of the 268 children affected by sudden-onset hepatitis have been aged under five, with nearly 40% of children taken to hospital needing intensive care.

In total, at least 1,000 cases have been reported worldwide.

What did the Scottish study look at?

The Scottish study also looked at the genetics of the children to identify whether any of them had underlying susceptibility to acute hepatitis.

Using detailed genomic testing of the patients, researchers were able to identify differences in the Human Leukocyte Antigen gene, that were not commonly found in the control groups of healthy children, or in the genes of children with other forms of hepatitis.

The team believe these genetic sequences may offer another part of the answer as to why some children have become seriously unwell.

What are the scientists saying?

Dr Antonio Ho, clinical senior lecturer at the MRC-University of Glasgow Centre for Virus Research (MRC CVR), explained to STV News the origins of the hepatitis outbreak in Glasgow.

“A Glasgow clinician noticed a cluster of children presenting with severe hepatitis, who didn’t test positive for all the kind of normal causes that we would expect,” she said.

“This led to Public Health Scotland developing a public health response in association with the UK Health and Security Agency and with academic partners.

“We recruited all these patients into a research study – it included nine of the early cases that presented between mid-March and early April. We did metagenomic sequencing and we found two key viruses – firstly we found adenovirus in six out of the nine cases, and we unexpectedly also found a second virus called adeno-associated virus in all nine cases.

“We don’t know the sequence with which these occur but the majority of patients presented with gastroenteritis symptoms such as vomiting, diarrhoea, abdominal pain.”

How worried should we be?

Dr Ho explains that common adeno-associated virus two is not new and has been around for some time.

“It was first discovered in 1965. Most of us – I would say 85-90% of us have been exposed to it,” she said.

“Secondly, the case numbers seem to be trending down and that seems to mirror the trends in adenovirus infection, so it’s a virus that has been around for a long time.

“Why is this causing this outbreak of hepatitis now? We’re wondering if it’s because we’ve seen a massive uptick in adenovirus cases that hasn’t been seen in previous years.

“It may have caused this in a small number of cases that would have been under the radar – we’ve never looked for this virus.

“But because there’s been this huge surge in adenovirus cases we’ve picked up this cluster and we’ve done active case finding along with public health agencies. I personally wouldn’t be worried because it’s happening to a very small number of children.”

Professor Emma Thomson, senior author of the Scottish study and an expert in infectious diseases, said: “There are many unanswered questions and larger studies are urgently needed to investigate the role of AAV2 in paediatric hepatitis cases.

“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 susceptible young children.”