(CNN) — UK scientists say they have found “strong circumstantial evidence” linking a type of secondary virus called adeno-associated virus to cases of liver damage of unknown origin in children around the world.
Research also suggests that affected children may share a genetic susceptibility, although it is not clear what role this plays.
Since October, more than 1,000 children from all over the world, more than 350 of them in the United States have been diagnosed with hepatitis, or inflammation of the liver, with no known cause. Most of the children are young, under 5 years old. Many were healthy before suddenly falling ill. In the United States, at least 20 have needed liver transplants and 11 have lost their lives, according to the latest updates from the US Centers for Disease Control and Prevention (CDC).
About half have tested positive for adenovirus 41, a stomach virus 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 their blood and no adenovirus infection in the liver, leading many doctors to suspect another cause, such as COVID-19, or a complicating factor. such as genes or environmental exposure.
In two new studies, scientists say they may have found a clue in adeno-associated virus 2, which is different from advenovirus 41.
Adeno-associated virus 2 was present in large amounts in the liver tissue and blood of almost all children with hepatitis of unknown origin 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.
Strong relationship between cases
Adeno-associated viruses are small pieces of DNA that cannot copy themselves until they are in the presence of another virus, usually adenoviruses or herpes. They belong to a family of viruses called dependoparvoviruses.
Virologists say they are like remoras, the fish that attach themselves to sharks and eat their leftover meals.
“A remora isn’t the best analogy, but it’s something like that. It has to have a host virus,” said Alex Greninger, deputy director of the clinical virology laboratory at the University of Washington.
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 do not encode all the functions necessary for replication. So they depend on the cells being infected at the same time with a helper virus, and the helper is usually the adenovirus.”
Because they are believed to be nearly 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 finding has them baffled.
“These are viruses that deserve a line in very small print in the larger textbooks, so I’ve never come across them as a cause of disease,” said Will Irving, a virologist at the University of Nottingham.
Uncover clues in detailed investigations
In the first study, led by researchers at University College London, scientists performed deep genome sequencing on liver tissue samples from five children who required a transplant due to hepatitis of unknown origin. They did the same with blood samples from other children with hepatitis who never got sick enough to need a transplant.
The researchers then compared those results with tests done on blood and liver samples from various control groups: healthy children, children hospitalized for unrelated reasons, children with good 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 hepatitis of unknown origin in the study, compared to 136 controls.
The researchers found, without exception, elevated levels of adeno-associated virus 2 in the liver tissue of children who required liver transplantation due to sudden and unknown hepatitis. However, it was only present in the liver tissue of one child in the control group.
In the blood, adeno-associated virus 2 was present in 94% of samples from children with hepatitis of unknown origin and was found at high levels in 91% of samples.
In contrast, the researchers found adeno-associated virus in only 6% of children with normal immune function who were hospitalized for unrelated reasons and in 31% of immunosuppressed controls.
In the second studyled by researchers at the Glasgow Virus Research Center, adeno-associated viruses were detected in blood and liver samples from all children with hepatitis of unknown origin, but in none of the samples from healthy children, of those who had infections due to adenovirus without hepatitis or those with hepatitis from a known cause.
When adeno-associated viruses were present, herpes and adenoviruses, necessary for adeno-associated viruses to replicate, were also frequently found.
In a further analysis, the researchers looked at changes in the genes that make up the human leukocyte antigen complex, or HLA. HLA genes encode markers on the surface of cells that help regulate immune function.
Almost 90% of the children with hepatitis of unknown origin had the same form of change in their HLA genes, suggesting a genetic vulnerability that affects the functioning of their immune system. By comparison, this same change is only found in 15.6% of Scottish blood donors.
The new studies were published online in preprint status, before being peer-reviewed and published in medical journals.
More studies are underway
The researchers say their studies cannot prove a cause-and-effect relationship. They are not sure that adeno-associated viruses directly damage the liver. It could be that they were a marker of something else going on. At best, they write, this is “strong circumstantial evidence.”
The researchers note that many of the hepatitis cases occurred after the omicron wave, which affected many countries in winter and spring. Although some of the children tested positive for COVID-19 before or during their admissions for hepatitis, the researchers were unable to find any evidence of active coronavirus infection in the blood or liver of the infected children. Instead, they say, the pandemic may have contributed to these cases indirectly, affecting children’s immunity as people began to gather again after periods of relative isolation.
A larger study is underway by the UK’s health safety agency, and the researchers say their results should help clarify the significance of the new findings.