Does a common virus suddenly cause liver failure in children?

Last October, a young girl with severe and unusual liver failure was admitted to a hospital in Birmingham, Alabama. His symptoms were typical: yellow skin and eyes with jaundice, markers of unusual liver damage. But she tested negative for all the usual suspects behind liver disease. His only positive test was, surprisingly, for adenovirus – a common virus best known for causing mild colds, pink eyes or stomach flu. In rare cases, it is linked to hepatitis or inflammation of the liver in immunocompromised patients. But this girl was healthy.

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

Buchfellner originally thought that everything that happened was local to Alabama. But this spring, investigators in the UK began to independently question their own mysterious rise in hepatitis in children. They have since identified more than 150 such cases in the UK. This prompted the CDC to expand its network, bringing the number of suspected cases in the United States to 109. Fifteen of the children required liver transplants and five died. Worldwide, probable cases now total 348 in 20 countries.

Early evidence continues to point to a link to adenovirus – an unexpected correlation that is too strong to discount and not strong enough to close the case. According to the World Health Organization, 70% of probable cases worldwide have tested positive for the adenovirus. But although biopsies were performed in a small fraction of these cases, they failed to find adenovirus in the children’s livers. At the same time, we know for sure that a different virus has recently infected large numbers of children: SARS-CoV-2, of course. Yet the correlation here is even less clear; only 18% 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 has altered adenovirus immunity patterns, allowing for more severe immunity or simply After 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 entirely mysterious. No identifiable cause is ever found in nearly half of children with liver failure so severe they might need a transplant. Ultimately, understanding the recent pattern of unexplained cases of liver failure in children may shed light on previously mysterious cases that were once too infrequent to attract much attention.

But why is there an increase right now? The only culprit that can be definitively ruled out is COVID vaccines, as children under 5, who make up the bulk of hepatitis cases, cannot yet be vaccinated. In the coming weeks, experts will examine three key pieces of data to analyze the remaining hypotheses.

The first set of data to collect, and perhaps the most obvious, is: have these children ever had COVID? The overwhelming majority of children with hepatitis have tested negative for coronavirus, but investigators 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,” Buchfellner says, but perhaps a COVID infection could have predisposed a child to liver failure once something else, such as an infection. to adenovirus, appeared. And although multisystem inflammatory syndrome, or MIS-C, following coronavirus infection can affect the liver, patients with hepatitis did not show the other hallmark signs of this disease, such as elevated inflammatory markers. and heart damage.

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

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

The exact number of children testing positive for adenovirus looks like a simple statistic, but it can get messy at first, when investigators are mostly dealing with retrospective data. Different doctors in different hospitals might think about ordering different tests. UAB has occasionally tested for adenovirus, but it’s so low on the list of hepatitis culprits that testing isn’t necessarily routine. And how the tests are done can affect whether they come back positive, says Benjamin Lee, a pediatric infectious disease physician at the University of Vermont. “Is the virus detectable in the blood when the patient presents for care? Are there other sites that should be tested? ” he asks. What about the nose and throat? Or stool? And indeed, British investigators had to make sense of a mix of blood, stool and respiratory tract samples, with varying positivity rates.

A third part of the investigation will focus on the adenoviruses found in these samples. Sequencing their genomes can determine if the viruses have recently acquired new mutations that may explain the link with liver failure. Adenovirus variants have appeared before, and this type of virus is particularly adept at re-engineering its genome. Whole genome sequencing is underway, although UK scientists have struggled to extract 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. Thus, initial progress may be slow.

Partial viral genome sequencing, however, has already identified a particular type of adenovirus that predominates in cases of hepatitis: adenovirus 41, also known as 41F. (There are over 100 types of adenoviruses. F refers to the species; the number reflects the order in which the types were discovered.) Adenovirus 41 infects the gastrointestinal tract. Platts-Mills 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 United States it does not cause enough problems 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 cases 41. The invisible surge, if there is one, could be due either to new viral mutations or to many young children being infected at the same time, as COVID restrictions are relaxed.

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 is not adenovirus 41 but types 1, 2, 3, 5, and 7. Additionally, these cases almost always occur in patients whose the immune system is weakened. “In these immunocompromised children, you could see it in the liver. When we were doing slides, you could see the virus particles,” says Kurt Schaberg, a pathologist at UC Davis who has studied adenovirus hepatitis. The dark centers of infected liver cells become large and swollen. It’s all pretty obvious. Biopsies found no such patterns in the livers of nonimmunocompromised children. If adenovirus plays a role, it is probably more indirect. Maybe it somehow triggers the immune system to start attacking the liver, either by itself or in combination with another virus, toxin, or environmental factor. And it could continue even after the virus itself is cleared, so adenovirus tests could come back negative.

All of this means that finding the answer to these cases of hepatitis in children will not be straightforward. “If we found a virus in the liver, we would be done,” says Buchfellner, in Alabama. “The fact that we can’t find that means it’s much harder to prove.” Instead of a single direct cause, investigators are likely looking for one or more indirect causes. In the coming weeks, determining three key questions — whether these children were also infected with COVID, whether their adenovirus infections were accidental, and whether their viruses mutated — will at least narrow the list of plausible hypotheses.

Meanwhile, all nine Alabama children are recovering. Whatever the cause, the doctors pointed out to me, the risk of severe hepatitis for healthy children is still very, very low.

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