Possible culprits identified in outbreaks of severe liver damage cases in children

An onslaught of common childhood viruses may have been behind the mysterious outbreak of cases of severe liver damage in children that began popping up in late 2021, as lockdowns were relaxed and schools reopened.

Severe acute hepatitis and liver failure are extremely rare in otherwise healthy children, and the cases puzzle experts. In the United States, the Centers for Disease Control and Prevention has investigated 390 cases in 46 states since the fall of 2021. Twenty-two children needed a liver transplant, and 13 have died. Worldwide, there have been about 1,000 cases, according to the World Health Organization.

Research published Thursday in the journal Nature homes in on a possible culprit: adeno-associated virus 2, or AAV2, a virus not previously known to cause illness. In 93% of the cases investigated, the researchers detected AAV2.

But importantly, the researchers found that AAV2 didn’t appear to be acting alone. It needed “helper” viruses — other infections — to get into liver cells.

The study focused on 16 US children with severe hepatitis, analyzing samples of blood, stool and liver biopsies. In a majority of cases, patients were infected with three or four common viruses at the same time.

Multiple co-infections “was an unexpected finding,” said senior study author Dr. Charles Chiu, director of the University of California-San Francisco’s Clinical Microbiology Laboratory.

In 75% of the cases, researchers found evidence of infection with at least three viruses at the same time. In about a third of the cases, there was evidence of four viruses.

A range of viruses was detected. One was adenovirus type 41, which had previously been identified as a potential suspected in the illnesses. That virus usually causes an upset stomach. Researchers also found a herpes virus, an enterovirus and Epstein-Barr virus, which can cause mononucleosis.

The findings do not prove that co-infections directly caused severe hepatitis, but give important clues.

The results were compared to 113 pediatric patients who were either healthy or had liver problems in which the cause was known. There was no evidence of multiple viruses in this control group.

Two other studies first released as preprints last summer also detected AAV2 in severe pediatric hepatitis cases in the United Kingdom.

“Similar findings by three independent studies give strong credibility to the results,” Thomas Baumert, head of the Inserm Research Institute for Viral and Liver Diseases and the University of Strasbourg in France said in a statement to the media. Baumert was not part of the new research.

It is not uncommon to see children with several viruses at the same time, usually without serious outcomes, said Dr. Ibukun Kalu, a pediatric infectious diseases physician at Duke University Hospital in Durham, North Carolina. “You might have a toddler that has a sniffly nose for a month, even though we would expect a standard viral infection to last about two weeks.”

What concerns Kalu, however, is the potential that “historically nonpathogenic viruses are now becoming pathogenic when they combine with or are present with some other viruses.”

What about Covid?

There was no indication that Covid or the Covid vaccines were related to these clusters of cases. But the cases are likely a consequence of the pandemic, Chiu said.

When schools were closed, children were not exposed to the common viruses that usually circulate. Once restrictions began to lift, kids were suddenly exposed to multiple viruses at once.

Globally, cases have been in young children, ages 10 or younger. “This is precisely the time period in which immune systems are being formed,” Chiu said. “What I suspect has happened is that for this certain population of children at this critical age, their immune development was simply disrupted over two years.”

“One of the unintended consequences of the Covid pandemic may have been that we now have a population of children who have altered immunity,” Chiu said. “We need to be alert for the possibility that we may be seeing unusual disease manifestations such as hepatitis in the future.”

While cases linked to the recent outbreaks appear to be waning, Dr. Amy Feldman, the pediatric liver transplant medical director at Children’s Hospital Colorado in Colorado Springs, said she sees about a “handful” of unexplained cases of liver failure each year.

Her team has now added adenovirus screening for her pediatric patients with liver inflammation. Understanding the potential causes of such cases can help doctors “understand better how to prevent and how to treat them,” Feldman said.

“Stopping the spread of germs is important,” Feldman said. “The more that you can wash your hands, the better.”

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