As scientists around the world are racing to understand what caused a spate of so-far unexplained cases of hepatitis in children — including some who needed liver transplants — two new U.K. studies are offering fresh clues.

In both papers, an unusual virus called adeno-associated virus-2 (AAV2) is implicated as one aspect of a complex mechanism that might be sparking rare and serious liver issues, including two dozen cases this year among Canadian children.

The preprint studies are from research teams in London and Glasgow, and not yet formally published or peer-reviewed. The teams looked at small numbers of children who suffered from liver inflammation which wasn’t caused by the obvious culprits, such as the usual family of hepatitis viruses, alongside healthy control subjects.

Researchers in both regions identified high levels of AAV2 in blood samples taken from young patients with unexplained hepatitis and indications of other viral infections.

The findings suggest co-infection with two viruses at once — AAV2, plus an adenovirus or, in some cases, a herpes virus — could be triggering hepatitis in certain kids. The Scottish team also noted the majority of children impacted shared a specific gene, DRB1-0401.

“Eight of the nine kids had this special gene … whereas in the background in Scotland, it’s only present in 15.6 per cent,” said one of the Glasgow study’s authors, Antonia Ho, a clinical senior lecturer at MRC-University of Glasgow Centre for Virus Research.

“So we wonder whether, perhaps, it’s co-infection with AAV2 and an adenovirus, in kids that have this special gene, that makes them more susceptible to getting these viruses and having an abnormal immune response to them.”

Trio of possible factors

It’s a complicated theory, linking together a trio of possible factors. 

The early findings also don’t confirm a root cause, Ho’s team acknowledged, with more global research needed to drill into exactly what sparked more than 1,000 probable cases of acute severe hepatitis of unknown origin in young children across 35 countries, according to the latest figures from the World Health Organization.

The overall case count spiked this year, including a rise that first caught the attention of U.K. officials, then dropped off, and included 22 deaths. No children have died in Canada this year out of 24 cases of acute severe hepatitis reported across the country, though two children did require liver transplants.

There’s been intense debate over what could be at play, with scientists around the globe pointing the finger at viruses ranging from a common adenovirus that’s known for causing stomach upset, to the widely circulating SARS-CoV-2, the virus behind COVID-19.

So far, no theory has been a slam dunk. Clinicians have also raised questions over whether this is even a new phenomenon, since medical teams have long noticed sporadic instances of serious liver issues in children that don’t have any obvious cause — even before this year’s rash of cases put global health officials on high alert.

Though there are still more questions than answers, the latest U.K. research investigates some intriguing possibilities, offering more potential pieces to this puzzle. 

Particularly fascinating — and unexpected — was the possible connection to AAV2, several scientists told CBC News. It’s what’s known as a dependoparvovirus, which doesn’t usually replicate on its own inside the human body. 

WATCH | Cause of rare liver disease outbreak a mystery to experts: 

Cause of rare liver disease outbreak in kids a mystery to experts

Doctors aren’t sure what’s causing a mysterious liver disease outbreak that’s been seen in kids from a dozen countries around the world. While at least one child has died, experts insist most children will fully recover from the disease.

“It’s effectively a parasite. It has to have another DNA virus present in order to replicate its genome,” said Charlotte Houldcroft, a virologist in the department of genetics at the University of Cambridge who wasn’t involved with either of the new studies.

A high percentage of the population is likely infected with AAV2, but might never realize it. 

Typically, the virus is not thought to cause disease in its own right, since it requires a “helper virus” to be present as well, Houldcroft said. However, some studies do suggest infection with AAV2, or its use as a vector in gene therapy to treat certain diseases, may be linked to liver-related health issues.

Houldcroft noted the specific gene identified in patients by the Scottish team may prove to be another key factor, since it’s already associated with certain autoimmune conditions.

“The genetic susceptibility would explain why this is rare,” she said.

“And then the fact that perhaps you need two different infections, and we’ve had this big surge of adenovirus 41, in the United Kingdom from December 2021, through to spring 2022 — that might explain why these rare cases bunched together in time, and why we suddenly noticed this disease.”

More research, larger studies needed

Dr. Jordan Feld, a clinician-scientist at the Toronto Western Hospital Liver Clinic, agreed the papers present interesting points, linking together data which may, in time, explain the rare yet concerning cases emerging this year, and perhaps even some unexplained childhood hepatitis cases which came before.

But it’s important to validate the results beyond these two, small studies, he stressed, given all the potential factors at play.

“When people first proposed adenovirus, and first proposed SARS-CoV-2 as the cause of this, everyone around the world went back to their samples and looked carefully to see and — I would say — to a large degree showed that those probably weren’t the whole story,” Feld said.

There are also major limitations in the papers, both outside experts and the authors themselves noted, including small sample sizes and unclear cause-and-effect.

The role of COVID-19 remains murky as well.

Ho, from the Glasgow team, said her team didn’t find clear links to SARS-CoV-2, and said more instances of childhood hepatitis should have been seen during earlier waves of the pandemic if that virus was the cause. 

Meanwhile the authors of the U.K. paper stressed that their data alone are not sufficient to rule out an impact from the Omicron variant, “the appearance of which preceded the outbreak of unexplained hepatitis,” with more results needed from large, case-controlled studies.

Feld stressed that, whatever is causing unexplained hepatitis in children, it remains an incredibly rare phenomenon, even as more medical professionals are watching closely for cases.

Parents can look for telltale symptoms, including jaundice — yellowing of a child’s eyes and skin — dark urine, pale stool, abdominal pain, and vomiting.

“There’s certainly not a rampant epidemic of severe acute hepatitis,” Feld said. “So I would say, first thing is take a deep breath. Most kids are going to be completely fine.”