Is a common virus suddenly causing liver failure in children?

Last October, a girl with unusual and severe liver failure was admitted to a hospital in Birmingham, Alabama. Her symptoms were typical: yellow skin and eyes with jaundice, markers of liver damage off the charts. But she tested negative for all the usual suspects behind liver disease. Surprisingly, her only positive test was for adenovirus, a common virus best known for causing minor colds, conjunctivitis, or gastroenteritis. In rare cases, it is related to hepatitis, or inflammation of the liver, in immunocompromised patients. But this girl had been healthy.

Then it happened again. A second child came in, about the same age, with the same symptoms and again positive for adenovirus. “A patient is a coincidence; two is a pattern,” says Markus Buchfellner, a pediatric infectious disease physician at the University of Alabama at Birmingham (UAB). Two quickly became three and then four. Alarmed, hospital doctors alerted local health authorities and the CDC, whose investigation ultimately found nine cases of this unusual type of hepatitis in Alabama children. Two liver transplants needed.

Buchfellner originally thought that what was happening was local to Alabama. But this spring, researchers in the UK independently began to puzzle over their own mysterious rise in hepatitis among children. Since then, they have identified more than 150 such cases in the UK. This prompted the CDC to cast a wider net, bringing the number of suspected cases in the US to 109. Fifteen of the children required liver transplants and five died. Worldwide, probable cases now number 348 spread across 20 countries.

Initial evidence continues to point to a link to adenovirus, an unexpected correlation that is too strong to rule out and not strong enough to close the case. Seventy percent of probable cases globally have tested positive for adenovirus, according to the World Health Organization. But although biopsies have been done in a small fraction of those cases, they have not been able to find adenovirus in the children’s livers. At the same time, we definitely know that a different virus infected a lot of children recently: SARS-CoV-2, of course. However, the correlation here is even less clear; only 18 percent of probable cases tested positive for COVID.

Adenovirus and coronavirus are not necessarily mutually exclusive explanations. Leading hypotheses now suggest an interaction between adenovirus and the pandemic, either because social distancing changed adenovirus immunity patterns, allowing for a more severe or simpler response. plus adenovirus infections, or because a previous infection or co-infection with the coronavirus triggers an unusual response to the adenovirus. Alternatively, has the adenovirus itself recently changed, evolving to more easily damage the liver?

Severe liver failure in children is very rare, says Helena Gutierrez, medical director of pediatric liver transplants at UAB and Children’s of Alabama. But when it does happen, a significant proportion of cases, even in normal times, remain completely mysterious. An identifiable cause is never found in nearly half of children with liver failure severe enough to require a transplant. Ultimately, understanding the recent pattern of unexplained liver failure cases in children may shed light on previously mysterious cases that were once too rare to attract much attention.

But why is there an increase at this time? The only culprit that can be conclusively ruled out is COVID vaccines, because children under the age of 5, who make up the bulk of hepatitis cases, cannot yet be vaccinated. In the coming weeks, the experts will analyze three key pieces of information to analyze the remaining hypotheses.

The first and perhaps most obvious set of data to collect is: Have these children had COVID before? The vast majority of children with hepatitis tested negative for the coronavirus, but researchers are now collecting antibody data to see if any of them had COVID in the past. “I don’t think it’s directly related to the virus itself,” says Buchfellner, but perhaps a COVID infection could have predisposed a child to liver failure once something else, say, an adenovirus infection, had come along. And while multisystem inflammatory syndrome, or MIS-C, after coronavirus infection can affect the liver, patients with hepatitis did not exhibit the other hallmarks of that condition, such as high inflammatory markers and heart damage.

When the COVID antibody data comes out, many of the children will be positive, simply because many children in general have recently had COVID. Experts will want to go a step further to determine if the coronavirus is really playing a role. If so, they would expect that children with hepatitis would be more likely to have COVID antibodies than a control group of children who did not have hepatitis.

A second key fact is about the adenovirus itself. Adenoviruses are very common, so could all the positive tests just reflect incidental infections unrelated to liver failure? Here, too, the researchers will want to see if children hospitalized with hepatitis are more likely to test positive for adenovirus than those hospitalized for other reasons. If they are, the link to the adenovirus becomes stronger. The UK is currently analyzing this exact data and is expected to have results next week.

Exactly how many children test positive for adenovirus seems like a simple statistic, but it can be tricky at first, when researchers deal primarily with retrospective data. Different doctors at different hospitals might think about ordering different tests. UAB went on to test for adenovirus, but it’s so far down the hepatitis culprit list that testing isn’t necessarily routine. And how tests are done can affect whether they come back positive, says Benjamin Lee, a pediatric infectious disease physician at the University of Vermont. “Can the virus be detected in the blood at the time the patient presents for care? Are there other sites that need to be tested? he asks. What about the nose and throat? or stool? And indeed, UK researchers have had to make sense of a mix of blood, stool and respiratory samples, with varying rates of positivity.

A third aspect of the investigation will focus on the adenoviruses found in these samples. Sequencing their genomes can determine whether the viruses have recently acquired new mutations that may explain the link to liver failure. Adenovirus variants have appeared before, and this type of virus is particularly adept at rearranging its genome. Whole genome sequencing is in the works, though UK scientists originally had trouble getting enough virus from early samples. And scientists don’t have a large database of old adenovirus samples of this type to compare with new ones. “We take that for granted with SARS-CoV-2,” says James Platts-Mills, an infectious disease physician at the University of Virginia. So initial progress can be slow.

However, partial sequencing of the viral genome has already identified a particular type of adenovirus that predominates in hepatitis cases: adenovirus 41, also known as 41F. (There are more than 100 types of adenoviruses. F refers to the species; the number reflects the order in which the types were discovered). Adenovirus 41 infects the GI tract. Platts-Mills has studied adenovirus 41 in developing countries, where it is a leading cause of hospitalizations for diarrhea in children. It also circulates in rich countries, but in the US it doesn’t cause enough trouble to warrant active surveillance. Potentially, says Platts-Mills, the hepatitis cases are just the “tip of the iceberg” of a large number of undocumented mild adenovirus 41 cases. The unseen increase, if any, could be due to new viral mutations or many young children becoming infected at once, with the relaxation of COVID restrictions.

Still, it’s surprising to see adenovirus 41 specifically as a suspect in these hepatitis cases, adenovirus experts told me. Although adenovirus has been linked to severe liver failure, it has not been adenovirus 41 but types 1, 2, 3, 5, and 7. Furthermore, these cases almost always occur in patients with weakened immune systems. “In those immunocompromised children, you could see it in the liver. When we did slides, you could see the viral particles,” says Kurt Schaberg, a UC Davis pathologist who has studied adenovirus hepatitis. The dark centers of infected liver cells become enlarged and swollen. It’s all pretty obvious. The biopsies found none of these patterns in the livers of the non-immunocompromised children. If adenovirus plays a role, it’s probably more indirect. Perhaps it somehow causes the immune system to start attacking the liver, either alone or in combination with another virus, toxin, or environmental factor. And this could continue even after the virus is cleared, so adenovirus tests could come back negative.

All this means that discovering the answer to these cases of hepatitis in children will not be easy. “If we found viruses in the liver, we would be finished,” says Buchfellner, in Alabama. “The fact that we can’t find that means it’s much harder to test.” Rather than a single direct cause, researchers are likely looking for an indirect one or multiple indirect ones. In the coming weeks, pinning down three key questions — whether these children have also been infected with COVID, whether their adenovirus infections are incidental, and whether their viruses have mutated — will at least narrow down the list of plausible hypotheses.

Meanwhile, the nine Alabama children are on the mend. Whatever the cause, the doctors stressed to me, the risk of severe hepatitis to healthy children remains very, very small.

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