Scientists in the UK say they have found “strong circumstantial evidence” linking an obscure type of associated virus called adeno-associated virus to unexplained cases of liver damage in children around the world.
Research also suggests that affected children may share a genetic susceptibility, although what role this plays is unclear.
Since October, more than 1,000 children worldwide, including more than 350 in the United States, have been diagnosed with hepatitis, or liver swelling, with no known cause. Most of the children are young – under the age of 5. Many were healthy before suddenly falling ill. In the United States, at least 20 people have needed liver transplants and 11 have died, according to the latest CDC updates.
About half tested positive for adenovirus 41, a stomach bug that often causes vomiting, diarrhea and flu-like symptoms in children, but has never been known to cause hepatitis.
Most of the children who tested positive had low levels of adenovirus in the blood and no adenovirus infection in the liver, leading many doctors to suspect another cause like Covid-19, or a complicating factor like genes or environmental exposure.
In two new studies, scientists say they may have found compelling evidence in adeno-associated virus 2, which is different from advenovirus 41.
Adeno-associated virus 2 was present in high amounts in liver tissue and blood in almost all children with unexplained hepatitis in the studies. And it was only rarely found in healthy children, those who only had adenovirus infections but no liver damage, or those who had liver damage with a clear cause.
A STRONG LINK BETWEEN CASES
Adeno-associated viruses are tiny pieces of DNA that they cannot copy to themselves until they are in the presence of another virus, usually an adenovirus or herpes. They belong to a family of viruses called dependoparvovirus.
Virologists say they look a bit like remoras, the fish that attach themselves to sharks and eat the leftovers from their meals.
“A remora isn’t the best analogy, but it’s a bit like that. It has to have a host virus,” said Alex Greninger, associate director of the University of Washington Clinical Virology Laboratory.
Gary Ketner, a molecular microbiologist at Johns Hopkins University who specializes in the study of adenoviruses, describes them as “very small viruses that contain DNA. They only have two genes. And by themselves, when they infect cells, they are unable to grow”. because they don’t encode all the functions required for replication. They therefore depend on the fact that a cell is infected at the same time by a helper virus, and the helper is generally an adenovirus.
Because they are believed to be mostly inert on their own, adeno-associated viruses are being studied as vehicles for gene therapy.
Beyond that, scientists say, not much is known about them. The researchers say this discovery has them scratching their heads.
“These are viruses that deserve about a line in very small print in the biggest textbooks, so I’ve never come across them as a cause of disease,” said Will Irving, a virologist at the University of Nottingham.
DETAILED INVESTIGATIONS DISCOVER INDICATORS
In the first study, led by researchers at University College London, scientists performed deep genome sequencing on liver tissue samples from five children who needed transplants due to unexplained hepatitis. . They did the same for blood samples from other children with unexplained hepatitis who never got so sick they needed a transplant.
The investigators then compared these results to tests on blood and liver samples from various control groups: healthy children, those who were hospitalized for unrelated reasons, children who had good immune function and poor immune function with and without adenovirus infections, and those with Covid-19 infections and hepatitis caused by other things. In total, there were 23 cases of unexplained hepatitis in the study, compared with 136 controls.
Without exception, researchers have found elevated levels of adeno-associated virus 2 in children’s liver tissue who required liver transplantation due to sudden, unexplained hepatitis. But it was only present in the liver tissue of one child in the control group.
In blood, adeno-associated virus 2 was present in 94% of samples from children with unexplained hepatitis and was found at high levels in 91% of samples.
In contrast, the researchers found adeno-associated viruses in only 6% of children with normal immune function who were hospitalized for unrelated reasons and 31% of immunocompromised controls.
In the second study, conducted by researchers at the Glasgow Center for Virus Research, Adeno-associated virus was detected in blood and liver samples from all children with unexplained hepatitis, but none of the samples from healthy children, those with adenovirus infections without hepatitis, or those with had hepatitis of known cause.
When adeno-associated viruses were present, herpes and adenoviruses – which are necessary for adeno-associated viruses to reproduce – were also frequently found.
In further analysis, the researchers looked at changes in the genes that make up the human leukocyte antigen complex, or HLA. HLA genes code for cell surface markers that help regulate immune function.
Almost 90% of children with unexplained hepatitis had the same form of change in their HLA genes, suggesting a genetic vulnerability affecting the functioning of their immune system. In comparison, this same change is only found in around 15.6% of Scottish blood donors.
The new studies were published online as preprints, before being reviewed by external experts and published in medical journals.
OTHER STUDIES IN PROGRESS
The researchers say their studies cannot prove cause and effect. They are not sure that adeno-associated viruses directly damage the liver. They could be a marker for something else going on. At best, they write, it is “strong circumstantial evidence.”
They note that many hepatitis cases followed the Omicron wave, which hit many countries in winter and spring. Although some of the children tested positive for Covid-19 before or during their admission for hepatitis, the researchers found no evidence of active coronavirus infection in the blood or livers of the infected children. Instead, they say, the pandemic may have indirectly contributed to these cases, affecting children’s immunity when people started to mix again after periods of relative isolation.
A larger study by the UK Health Security Agency is underway, and the researchers say its results should help clarify the significance of the new findings.
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