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British researchers have developed a working hypothesis to explain the recent cases of acute unexplained hepatitis that have hit young children.

Two preprint studies of affected children have detected near-consistent presence of adeno-associated virus 2 (AAV2), a virus that wasn't previously recognized as pathogenic, and that relies on a "helper" virus to replicate.

Coinfection with adenovirus (often type 41, as identified in previous reports) or a herpesvirus (typically HHV6) was frequent in these cases, researchers reported.

In addition, most of the cases had a specific mutation in a class II HLA gene, which is involved in immune response, that may have rendered them more susceptible to infection, the researchers stated.

And there is another factor at play: The lifting of pandemic restrictions likely led to a surge in cases of these viruses in previously unexposed kids. Indeed, a large wave of adenovirus cases preceded the first cluster of mystery hepatitis cases in Scotland, the researchers reported.

The papers also concluded that it was unlikely that SARS-CoV-2 infection is to blame, since patients' antibody levels were similar to the general population. One study pointed out that cases occurred well after the COVID peak in Scotland, but shortly after the adenovirus infection spike.

"While we still have some unanswered questions about exactly what led to this spike in acute hepatitis, we hope these results can reassure parents concerned about COVID-19 as neither teams have found any direct link with SARS-CoV-2," Judith Breuer, MD, of University College London, said in a statement.

While the online research community acknowledged the solid nature of the early results, authors did express caution around causality, particularly regarding AAV2. "Call me overly cautious, but I'm more 'innocent bystander/proxy marker' for #AAV2 with [adenovirus] being the villain. I'd like to see more evidence for AAV being pathogenic," , of University Hospital of Wales in Cardiff, who was involved in one of the reports.

AAV2 is a DNA virus that relies on coinfection with a helper virus for replication, most commonly adenovirus or a herpesvirus. It may be familiar to the research community because it's been used as a vector in gene therapy, and in some early trials, researchers saw some instances of hepatitis associated with an immune-mediated response against AAV2.

More than 1,000 cases of mystery acute hepatitis from 35 countries have been reported to the , as researchers zero in on an explanation. In the U.S., are under investigation across 42 states and jurisdictions.

Scottish Study

Emma Thomson, PhD, of the University of Glasgow Center for Virus Research, and colleagues, studied nine early cases of acute hepatitis of unknown etiology in Scotland and compared them with 58 controls.

Using genetic sampling, they reported in that they found AAV2 in the plasma samples of all nine patients, and in all four patients for whom liver samples were available. AAV2 was not detected in samples from any of the controls.

Since AAV2 needs a helper virus to replicate, the researchers looked for coinfection and discovered adenovirus in six of nine cases and human herpesvirus 6B (HHV6B) in three cases.

They also found that eight of the nine cases were positive for a specific HLA allele, DRB1*0401, which was found in just 15.6% of Scottish blood donors serving as a control population, suggesting an increased genetic immune susceptibility in cases.

As for the role of SARS-CoV-2, 67% of cases had evidence of prior exposure to the virus, which was comparable to the seroprevalence in Scottish kids, ages 5-11, between mid-March and early April when the cases were first detected, the researchers reported.

They also noted a spike in adenovirus infections in Scotland, predominantly affecting children under 5 years, directly before the outbreak of unexplained hepatitis.

Thomson and colleagues concluded that AAV2 may be directly implicated in the pathology of mystery hepatitis following a coinfection with adenovirus or herpesvirus, and class II HLA type may contribute to disease susceptibility, but larger case-control studies are needed to better understand how these various factors may cause disease.

University College London Study

Breuer and colleagues conducted on samples from 28 cases, five of whom had liver transplantation, and compared them with 136 controls.

They reported in medRxiv that in the five cases who'd had a liver transplant, they detected high levels of AAV2 in the explanted livers. They also found high levels of AAV2 in blood samples from 10 of 11 non-transplanted cases.

Among controls, AAV2 was only detected at very low levels in six of 100 samples from immunocompetent controls.

They also found low levels of adenovirus and HHV6B in the five explanted livers, and in the majority of blood samples from 23 non-transplanted cases.

In addition, four of the five liver transplant cases carried the DRB1*0401 allele in the class II HLA gene, providing further support that this unexplained hepatitis is immune-mediated, occurring in children who are genetically predisposed, the researchers wrote.

As in the Glasgow study, Breuer and colleagues noted that the findings likely reflect the impact of the pandemic in "child mixing and infection patterns," with children not previously exposed to adenovirus or AAV2 being exposed in large numbers after pandemic restrictions lifted.

"The contemporaneous development of unexplained hepatitis with an outbreak of [adenovirus type 41] and the finding of [adenovirus type 41] in many cases, suggests that the two are linked," they wrote.

They cautioned that the study was limited by its small size and that causality could not be determined; their theory needs further testing in properly controlled studies.

'Everything Seems to Fit'

In the medical Twittersphere, researchers hailed the quality of the data, even if the numbers are small and don't establish causality.

"The fact that this AAV2 virus was found in all cases and no controls is highly suggestive," , of University College London, who was not involved in the study. "They [study authors] acknowledge more research is urgent but this is [very] useful data!"

"Everything seems to fit," , of University Hospital Southampton in England. "Will be interesting to see if further examination can confirm this as the cause -- hopefully putting to bed some of the debates."

Munro noted that some clinicians who had suspected SARS-CoV-2 to be the culprit in unexplained hepatitis had called for treatment with steroids, which "could have caused significant harm" if AAV2 or adenovirus are confirmed to be the culprit.

"Generating high-quality evidence *first* is what patients need, and deserve from us," .

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