Viral infections and gene variants are associated with cases of hepatitis in children

A complex combination of factors could be responsible for the pediatric hepatitis cases that have baffled doctors for the past few months, according to two small, new studies.

The studies are based on only a few dozen cases and have not yet been peer-reviewed or published in scientific journals. Still, they suggest that the children who developed severe, unexplained cases of liver inflammation may have been infected with two different viruses at the same time, including one known as adeno-associated virus 2 (AAV2), a typically benign virus that which needs a second “helper” virus to replicate.

Adenoviruses, previously found in many of the children with the mysterious hepatitis reported last year, are common helper viruses for AAV2.

Many of the children studied also had a relatively unusual version of a gene that plays an important role in immune response, the scientists found.

Taken together, the results suggest a possible explanation for the hepatitis cases: A small subset of children with this particular gene variant are co-infected with AAV2. and a helper virus, often an adenovirus, trigger an abnormal immune response that damages the liver.

However, the researchers acknowledged that the studies were based on a small number of children in just one region of the world (the UK) and that a causal link had not been established.

“There’s a lot we still don’t know,” said Dr. Antonia Ho, Senior Clinical Lecturer at Glasgow MRC University’s Center for Viral Research and author of one of the new studies.

But she added: “We felt – because there are very few answers as to what causes it – that we needed to publish these results so that other people can start looking for AAV2.” and examine this further.”

The results are intriguing, but preliminary, said Dr. Saul Karpen, a pediatric hepatologist at Emory University and Children’s Healthcare of Atlanta, who was not involved in the research. “This is not a definitive study,” he said. “It can certainly make sense thematically, but there isn’t full support for it.”

Pediatric hepatitis cases are extremely rare but can be serious. As of July 8, 1,010 probable cases have been reported from 35 countries, according to the World Health Organization. Five percent of these children required liver transplants and two percent died.

Several early studies found that many of the children were infected with an adenovirus, one of a group of common viruses that typically cause cold- or flu-like symptoms. The new studies suggest that if adenoviruses are involved in hepatitis cases, they may be only part of the story.

In one of the new studies, scientists compared nine Scottish children with unexplained hepatitis with 58 children in control groups. The researchers used genome sequencing to identify all of the viruses present in the children’s blood, liver and other samples.

The scientists found adeno-associated virus 2 in the blood of all nine affected children and in liver samples from all four children from whom such samples were available. They also found an adenovirus in six of the children and a common herpes virus in three.

However, the researchers were unable to detect AAV2 in healthy children, in children with adenovirus infections but normal liver function, or in children with hepatitis of known causes.

These results are consistent with those of a second study, led by researchers in London, which examined samples from 28 children with unexplained hepatitis from across the UK. This scientific team also found high levels of AAV2 in the blood and liver of many children. Many also had low levels of an adenovirus or herpesvirus in their samples.

The Scottish researchers also found that eight of the nine affected children, or 89 per cent, shared a relatively unusual variant of a gene that codes for a crucial protein in the body’s immune response. This particular variant is present in only 16 per cent of Scottish blood donors.

The London team found the same gene variant in four of the five transplant recipients studied.

“Both studies independently produced remarkably similar results,” Sofia Morfopoulou, a computational statistician at the Great Ormond Street Institute of Child Health at University College London and author of the second article, said in an email.

Although the idea remains tentative, it’s possible that a recent resurgence of adenovirus after a decline in circulation during the coronavirus pandemic explains why doctors have noticed a sudden spike in these rare cases, the scientists said.

“Perhaps some of these infections that may have been spread out over a few years are coming on at once,” said Dr. Emma Thomson, MD at the Center for Virology Research and senior author of the Scottish study.

Additional, larger studies are still needed, specifically focusing on children in other countries, the researchers said.

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