Physicians have been treating acute hepatitis in young children since January 2022, some of whom have required liver transplants, and some of whom have died. The cause of the outbreak has remained unanswered.
Problems with a single cause are typically easier to resolve in any aspect of life. However, solutions to problems with multiple possible factors can be intimidating, as has been the case with these hepatitis patients.
Two separate but complementary research suggest that the unexplained hepatitis cases in children are likely to be the result of one or two interfering viruses and perhaps a gene mutation.
Both studies were conducted at the University of Glasgow in Scotland, and the other at the UCL Great Ormond Street Institute of Child Health in London.
Adeno-associated virus 2, or AAV2, was found to be present in almost all affected children, although not in healthy children used as controls. AAV2 is quite common, infecting nearly everyone in childhood, and may remain in the body at low levels for life.
AAV2 is thought to be harmless and is untested, thus adding to the mystery.
Because AAV2 can only operate in the presence of other adenoviruses or herpes viruses, its existence may suggest that one of them is involved in these unidentified hepatitis instances.
The Scottish researchers did discover traces of the likely adenoviruses HAdV (species C and F) and human herpes virus 6B (HHV6B) in six out of nine affected children.
HLA-DRB1*04:01 was found in only 15.6% of Scottish blood donors.
Dr. Paul Spearman, the director of the Cincinnati Children's Hospital's infectious diseases division, who was not involved in either study, said the findings were interesting but that they need to be further investigated.
These are intriguing investigations that suggest that AAV2, in combination with adenovirus, may be to blame for the high rate of hepatitis in children. The numbers are small, and the conclusions can't be guaranteed. This will require further research. Dr. Paul Spearman
However, larger investigations may also investigate AAV2 and try to reinforce this finding. So, the importance here is that this is a possible clue to the cause, and now we have to take this observation and apply it more broadly to see if the link remains.
The hepatitis mystery has been solved.
The corresponding author of the Scottish research, Professor Emma Thompson, told MNT The first step is for others to test for AAV2 and the HLA association in their cohorts around the world.
We already have two independent studies that stated the same thing, but it'll be important to see if this is also the case in other countries, according to the author.
Dr. Spearman noted that physicians and researchers shouldn't have much difficulty testing for the gene mutation: This is a fairly straightforward test. Most hospitals or reference laboratories can perform this test.
Second, said Prof. Thompson, we need some more mechanistic research. One such avenue is to investigate IgM antibody responses (which rise in primary infection) to see if the children were recently infected.
Prof. Thompson recommends examining the immune response antibody and T cell to proteins from AAV2 [and] HAdV. She also mentioned HHV6, herpes, as a possible candidate, although she suspects it is much less likely to be involved.
Prof. Thompson said all of these investigations are being planned at the moment.
A direct connection
AAV2 levels were detected in blood and tissue samples taken from children with unidentified hepatitis who were suspected to have been infected during a recent AdV-F41 outbreak, according to a UCL study.
According to them, we were unable to discover any evidence by electron microscopy, immunohistochemistry, or proteomics of [H]AdV or AAV2 viral particles or proteins in explanted livers, thus hepatic pathology is not due to direct lytic infection by either virus.
These findings suggest that there is an indirect viral mechanism, according to Professor Judith Breuer, the corresponding author of the UCL paper.
Prof. Thompson stated that there are two possible solutions, and he explained them to MNT:
It's possible that the methods we're using aren't sufficiently efficient to detect protein, so additional antibody testing is required to be sure. If there truly is a lack of protein, then I believe that the mechanism would be most likely to be immune-directed, perhaps as a cross-reactive response from antibodies or T cells to liver cells.
Prof. Thompson believes that AAV2's genetic footprint is still very clear, but that the immune response has already cleared the protein by the time the children go to hospital. We need to do a lot more to investigate these mechanistic issues.
Why should there be only children?
Prof. Thompson explains why it might be that these unexplained hepatitis infections may only be happening to children.
I suspect that this may be a multi-hit phenomenon, that children may have the underlying susceptibility and have been exposed to both HAdV and AAV2 for the first time, while most adults will already have been exposed to these viruses (possibly one at a time).
Dr. Spearman suggested that you can speculate that if AAV2 is causing liver inflammation, it might only happen during the initial infection in children with the adenovirus and not with reactivation in older individuals.
Prof. Thompson cautions that we need to do a lot more research to investigate that. This may have meant that we may have overlooked occasional instances in the past in young people. We need to understand what the seasonal patterns of AAV2 exposure are like.
There are still many, many questions to be answered, according to her.