As scientists around the world rush to understand what triggered a spate of hitherto unexplained cases of childhood hepatitis – including some requiring liver transplants – two new British studies offer new clues.
Both papers implicate an unusual virus called adeno-associated virus-2 (AAV2) as one aspect of a complex mechanism that could cause rare and serious liver problems, 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 suffering from liver inflammation not caused by the obvious culprits, such as the usual family of hepatitis viruses, alongside healthy controls.
Researchers in both regions identified high levels of AAV2 in blood samples from young patients with unexplained hepatitis and indications of other viral infections.
The findings suggest that co-infection with two viruses at once — AAV2, plus an adenovirus or, in some cases, a herpes virus — could cause hepatitis in certain children. The Scottish team also noted that the majority of affected children had a specific gene, DRB1-0401.
“Eight out of nine children had this special gene…while in Scotland it is only present in the background in 15.6 percent,” said one of the authors of the Glasgow study, Antonia Ho, a clinical senior lecturer at the MRC. -University of Glasgow Center for Virus Research.
“So we’re wondering if maybe it’s co-infection with AAV2 and an adenovirus, in children who have this special gene, which makes them more susceptible to getting these viruses and having an abnormal immune response to them.”
Trio of possible factors
It is a complicated theory, which links three possible factors.
The early findings also do not confirm a root cause, Ho’s team acknowledged, and more global research was needed to pinpoint exactly what caused more than 1,000 possible cases of acute severe hepatitis of unknown origin in young children in 35 countries. according to the latest figures from the World Health Organization.
The total number of cases rose this year, including a rise that first caught the attention of British officials, then declined to include 22 deaths. No children have died in Canada this year from 24 cases of acute severe hepatitis reported nationwidealthough two children required liver transplants.
There has been an intense debate about what could be going on, with scientists around the world pointing the finger at viruses ranging from a common adenovirus known to cause stomach upset, to the widespread SARS-CoV-2, the virus behind COVID-19.
So far, no theory has been a slam dunk. Doctors have also raised questions about whether this is even a new phenomenon, as medical teams have long noted sporadic cases of serious liver problems in children that have no apparent cause – even before the flood of cases this year sent global health officials on high. alert.
While there are still more questions than answers, the latest UK research explores some intriguing possibilities, opening up more potential pieces to this puzzle.
Particularly fascinating — and unexpected — was its possible connection to AAV2, several scientists told UKTN News. It is what is known as a dependoparvovirus, which usually does not replicate itself in the human body.
“It’s basically a parasite. There must be another UKTN virus present to replicate its genome,” said Charlotte Houldcroft, a virologist in the University of Cambridge’s department of genetics who was not involved in any of the new studies.
A high percentage of the population is probably infected with AAV2, but may never realize it.
Usually, the virus isn’t thought to cause disease on its own, because it also requires a “helper virus,” Houldcroft said. However, some research suggests: infection with AAV2or are use as vector in gene therapy to treat certain diseases may be related to liver-related health problems.
Houldcroft noted that the specific gene identified in patients by the Scottish team may turn out to be another key factor, as it’s already been linked to certain autoimmune diseases.
“The genetic susceptibility would explain why this is rare,” she said.
“And then the fact that you might need two different infections, and we’ve had this big wave of adenovirus 41 in the UK from December 2021 to the spring of 2022 – that could explain why these rare cases came 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 that the articles contain points of interest, linking together data that could eventually explain the rare but worrisome cases emerging this year, and perhaps even some unexplained childhood hepatitis cases that preceded it.
But it’s important to validate the results outside of these two small studies, he stressed, given all the possible 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 – showed a great deal that they probably were. It’s not the whole story,” Feld said.
There are also major limitations in the articles, noted by both outside experts and the authors themselves, including small sample size and unclear cause and effect.
The role of COVID-19 also remains obscure.
Ho, of the Glasgow team, said her team found no clear links to SARS-CoV-2, and said more cases of childhood hepatitis should have been seen during previous waves of the pandemic if that virus was the cause.
Meanwhile, the authors of the UK paper stressed that their data alone is not sufficient to rule out an effect of the Omicron variant, “the appearance of which preceded the outbreak of unexplained hepatitis,” with more results needed from large groups. , case-controlled studies.
Feld stressed that whatever causes the unexplained hepatitis in children remains an incredibly rare phenomenon, even as more medical professionals are paying close attention to cases.
Parents may look for telltale symptoms, including jaundice — yellowing of a child’s eyes and skin — dark urine, pale stools, abdominal pain, and vomiting.
“There is certainly no rampant epidemic of severe acute hepatitis,” Feld said. “So I’d say take a deep breath first. Most kids will be fine.”