Until recently, the prevailing theory about severe cases of hepatitis in children was that adenovirus was the culprit.
Since April, many young children with dangerous inflammation of the liver have tested positive for adenovirus 41, which usually causes a cold-like illness or stomach ache. But two studies released this month shed light on another theory: Some children may be infected with adeno-associated virus, which uses a second helper virus to replicate.
Researchers from Scotland and England have identified a specific adeno-associated virus called AAV2 in the blood and livers of UK children with severe hepatitis. The researchers suggest that some children may have been infected with other viruses, such as AAV2 and adenovirus 41, which may cause liver failure. Research has also identified a genetic marker that may put children at higher risk of this outcome.
But doctors do not know that these events themselves are new. Even until this year, many cases of pediatric hepatitis were a mystery — according to the Centers for Disease Control and Prevention, 30% to 50% of such cases have unknown causes.
“Liver failure always sounds scary and should never happen, but it does happen, and it happens without us even knowing it’s in kids,” said Saul Karpen, M.D., professor of gastroenterology at Emory University School of Medicine. “We conduct all research properly. We can’t understand it.”
According to Karpen, about half of the cases of acute hepatitis come to Children’s Healthcare of Atlanta. About 10% of these cases progress to severe liver failure and may require a transplant, he estimates. In a recent editorial in the New England Journal of Medicine, Karpen called for more data to determine whether the latest cases are truly unusual.
In a report published earlier this month, the European CDC said it was not clear whether the cases detected since April were “part of a real increase compared to the baseline”.
New insight into the possible causes of this disease may help solve a long-standing medical mystery.
Are recent cases of hepatitis abnormal?
In April, the World Health Organization identified more than 1,000 possible cases in 35 countries, including 22 deaths, as a large number of cases of pediatric hepatitis in the UK raised concern.
By the end of June, 473 cases had been reported in Europe, mostly in children under the age of 5. About half of the patients recovered, but 80 remained in medical care and 20 in liver transplantation. A child died of the disease in Ireland in May, and another in Greece this month.
As of Wednesday, health officials in the US were investigating more than 350 suspected cases of acute hepatitis in children under the age of 10, all since October 2021.
But last month, the CDC said there was no indication that the number of children hospitalized with hepatitis is increasing compared to pre-Covid pandemic rates. Between October 2021 and March 2022, there were an average of 22 hepatitis-related hospitalizations every month among children under 4 years of age and 12 among children 5 to 11 years of age in the United States. The country made similar average indicators in 2019.
Some experts believe that cases of hepatitis may have temporarily increased after the Covid restrictions, because young children are later exposed to viruses that their bodies have not seen before.
“Imagine that everyone who has received it in the last three years will only receive it this year,” said David Thomas, a professor of medicine at Johns Hopkins University.
If that’s true, he continued, the last moments could be “an ancient thing that we couldn’t explain before.”
According to Karpen, the recent surge in the UK may just be part of a “natural history of chaos that has not been seen with this kind of scrutiny before”.
The most powerful theory
A new theory of pediatric hepatitis related to hepatitis in a small sample: 37 patients in two preliminary studies. But disease experts say the idea is intriguing.
Lishan Su, who heads the Department of Virology, Pathogenesis and Cancer at the Institute of Human Virology at the University of Maryland, said that the combination of the two viruses and a unique genetic marker lead to liver inflammation.
Both studies found AAV2 adeno-associated virus in nearly all blood and liver samples from children with cryptic hepatitis. A Scottish study did not detect AAV2 in blood samples from healthy children or those hospitalized with hepatitis.
The association with AAV2 “seems really strong based on this small number of patients,” Su said.
Research has also revealed Low levels of adenovirus 41 and herpes virus in many liver and blood samples, suggesting that one of these viruses may be assisting AAV2 replication. This may explain why other studies have found adenovirus 41 in some pediatric patients.
The CDC reports that between October 2021 and June 2022, 45% of children with cryptic hepatitis had symptoms of adenovirus, with adenovirus 41 being the most common subtype. A recent UK study tested 90% of pediatric cases of adenovirus.
A genetic marker identified in the Scottish study helps determine the body’s immune response to viruses, so it may be an important part of the story, Su said. The marker was found in eight of the nine cases of cryptic hepatitis studied by the researchers. In comparison, it was only 16% of Scottish blood donors. A second study also identified the marker in four of five cases requiring liver transplantation.
But this new study also leaves unanswered questions. For example, no preprint study found evidence of current virus in the liver tissue of infected children. It is the immune response, not the virus itself, that can cause liver damage. But there is no evidence of this yet, Karpen said.
Thomas said the full explanation is that children can become sick and confused for a variety of reasons.
“This is a story that is still being told,” he said. “We’ve just got another chapter – a good chapter – but it’s not the end of the book.”
Still, understanding some aspects of acute hepatitis in children would be a major advance, Thomas added.
“These children are suffering. Families are suffering, he said. “If we could prevent half of it, that would be amazing.”