As global cases rise, researchers race to solve puzzle of mysterious hepatitis cases in children

Brenda Goodman

The global toll of sudden and unexplained hepatitis in children has risen to 621 cases from 34 countries, the European Centre for Disease Prevention and Control said in an update on Thursday.

About half of those cases come from just two countries—the United States and the UK. On Thursday, investigators from both those countries said they were working diligently to get answers.

One of their first tasks has been to try to figure out whether these cases of sudden and often severe liver damage in kids represent a true increase over past years. The answer is that it depends on where you look.

The UK has better data on its hepatitis cases than many other countries because it only sees children with liver disease at three national hospitals.

“The care of these children is highly centralized,” said Diedre Kelly, a professor of pediatric hepatology at the University of Birmingham, in the UK, in a press call for reporters on Thursday, which was hosted by the independent nonprofit Science Media Centre.

In an average year, Kelly says they would see about 20 children who suddenly develop hepatitis without an obvious cause for their liver inflammation. This year, they’ve seen 176 such cases, a nearly 8-fold increase.

That’s in contrast to European countries. Kelly said she was recently part of a study that counted children’s hepatitis cases at liver specialty centers across Europe, and “they saw absolutely no increase in the numbers of acute, severe hepatitis” or in liver transplants compared to previous years.

Kelly says they’re still trying to figure out what that means. “Either Europe is behind us and has still got to catch up, or it’s a phenomenon that’s not occurring in Europe,” she said.

In the United States, unexplained cases of hepatitis are not routinely reported to public health authorities, making it difficult to know whether the 180 cases under investigation here are an increase over what doctors normally see.

On a CDC call for clinicians on Thursday, Amanda Ingram, an epidemiologist with the Alabama Department of Public Health said state investigators there had seen an increase in emergency department visits across the state for children presenting with hepatitis, jaundice, and liver failure for roughly a month between November 21 and December 25, 2021. Alabama was the first state to flag a cluster of 9 unexplained hepatitis cases in children.

Investigators don’t have a smoking gun. But they have been able to narrow some of the things they’re looking at.

So far, they say, based on questionnaires collected from cases they’ve been able to rule out contact with dogs as a potential contributor to the illnesses, said Dr. Calum Semple, a pediatrician and professor of child health and outbreak medicine at the University of Liverpool.

Many of the children under study had pet dogs or reported recent contact with dogs, so that possibility was initially on the list, but after further study, researchers say it’s been ruled out as a factor.

“We’ve looked very carefully at case control data and also those with severe disease and those without severe disease and there’s no difference at all between these children regarding dog contacts,” Semple said

Though Covid-19 has not been fully ruled out, it seems less and less likely to be playing a role.

“I don’t think we’re ruling out Covid completely,” Semple said, “I’m saying I think Covid is moving down that list” of possibilities under consideration, “and adenovirus and adeno-associated viruses and other viruses like it are moving up the list,” he said.

That’s not to say, however, that the pandemic, with its social distancing, masks and other behavioral changes, may not have a hand in all this. It could very well be that after nearly two years of minimal exposure to infections, our immune systems are behaving differently.

Investigators in the UK are looking at the T-cell responses in affected children to see if there’s some unusual activation of these immune defenders in these otherwise run-of-the-mill infections.

About 70% of children in the UK and more than half of children in the US have tested positive for adenovirus 41F in their blood, making the association hard to ignore.

But researchers aren’t sure, if they tested children the same age and same sex that didn’t have hepatitis, if they would find just as many with adenovirus in their blood. That’s called a case-control study, and Will Irving, a professor of virology at the University of Nottingham, in the UK, said that data may be coming shortly.

“Adenovirus is the leading contender here, but we do need more data to be convinced, at least I do,” said Irving.

Scientists are skeptical because adenovirus 41 isn’t usually a big player when it comes to viral infections. It isn’t even among the top 10 in terms of adenoviruses that make people sick every year, Ingram said.

“It’s very difficult to know whether this is the cause, which instinctively we would feel it wasn’t, or whether it was a trigger in the child who was susceptible for some other reason,” Kelly said.

In the Alabama cases, the sickest children—those who eventually needed liver transplants—had the highest levels of adenovirus in their blood, which suggests a dose response—something researchers look for when trying to understand whether two things that are associated are linked because one has caused the other or because of pure coincidence.

Curiously, though, while many of the children test positive for adenovirus in their blood, samples of their destroyed liver tissue aren’t usually finding any virus.

Researchers say they don’t know what that means, but say it is unusual. When adenovirus 5 attacks the liver, for example, and you look at liver cells under a microscope.

“The liver cells are absolutely stuffed full with new adenovirus particles. So there’s no question that the virus itself is infecting the hepatocytes and killing them. We do not have that link yet,” Irving said.

So there are a couple of factors to consider, then, Irving said. Maybe the virus isn’t acting alone. Or may it’s triggering a damaging immune reaction.

In Alabama, 75% of cases—nine out of 12 children currently identified as having sudden, unexplained hepatitis–had more than one virus detected at the time of their illness.

In addition to adenovirus 41, the children tested positive for viruses known to cause upper respiratory infections including rhinovirus, enterovirus, respiratory syncytial virus (RSV), a type coronavirus OC43, human metapneumovirus, and rotavirus—which typically causes diarrhea. None were positive for a current Covid-19 infection.

What’s clear from the detailed study of the children in Alabama is that the kids were very sick.

Nearly all of them had been throwing up, more than half had diarrhea and fever. Almost all had yellow in the whites of their eyes or a yellowish orange tint to their skin, a symptom called jaundice.-

Reassuringly, at least in the UK, there don’t seem to be any geographical or social links between the cases, meaning the children don’t know each other or live in the same areas. “It’s sporadic really,” Kelly says.

If the hepatitis is being caused by an infection, or infections, but there it’s not happening to children in the same area, what does that mean?

Irving, the virologist, said he thinks that could mean that many, many children and maybe adults too are being infected, but for most, those infections aren’t resulting in serious liver problems.

“Which then begs the question, what is special about these young children?” who are being diagnosed with liver problems, Irving said.

For that, researchers are turning to genetics to try to unravel the mystery behind these cases, with several projects already underway to study genetic traits of the affected children and their parents to see if they had any unrecognized risk factors for their liver problems.

While the puzzle of these cases is fascinating, the researchers say they’re trying to keep the affected families at the center of their work.

“We mustn’t forget that there’s 170 families [in the UK] who are highly distressed about this mystery disease that is causing such problems with their kids, and to get a liver transplant is a life changing event,” Semple said.

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