Hepatitis in children is on the rise globally, researchers race to solve the puzzle of these mysterious cases

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

One of his first tasks has been to try to find out if these cases of sudden and often severe liver damage in children represent a real increase in recent 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 cares for children with liver disease in three national hospitals.

“The care of these children is highly centralized,” Diedre Kelly, a professor of pediatric hepatology at the University of Birmingham in the United Kingdom, said at a press call for reporters on Thursday, which was organized by the independent Science Media Center without profit.

In an average year, Kelly says they would see about 20 children who suddenly develop hepatitis with no obvious cause for the liver inflammation. This year, they have seen 176 such cases, a nearly 8-fold increase.

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

Kelly says that they are still trying to figure out what that means. “Either Europe is behind us and has yet to catch up, or it is a phenomenon that is not happening 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 being investigated here represent an increase in what doctors typically see.

In a CDC call for physicians Thursday, Amanda Ingram, an epidemiologist with the Alabama Department of Public Health, said state researchers had seen an increase in emergency department visits statewide for children presenting with hepatitis, jaundice and liver failure for about a year. month between November 21 and December 25, 2021. Alabama was the first state to flag a cluster of 9 unexplained cases of hepatitis in children.

What parents need to know about the rise in unexplained hepatitis in children

Investigators don’t have a smoking gun. But they have been able to reduce some of the things that they are seeing.

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

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

“We have looked very carefully at the case control data and also those with severe disease and those without severe disease and there is no difference between these children with respect to contacts with dogs,” Semple said.

Although covid-19 has not been completely ruled out, it seems less and less likely that it will play a role.

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

However, that is not to say that the pandemic, with its social distancing, masks, and other behavioral changes, has nothing to do with all of this. It is quite possible that after nearly two years of minimal exposure to infections, our immune systems are behaving differently.

Researchers in the UK are looking at T-cell responses in affected children to see if there is any unusual activation of these immune defenders in these run-of-the-mill infections.

Around 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 difficult to ignore.

But the researchers aren’t sure if they tested children of the same age and sex who didn’t have hepatitis, they would find as many with adenoviruses 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 the data could be coming soon.

“Adenovirus is the main contender here, but we need more data to be convinced, at least by me,” Irving said.

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

“It’s very hard to know if this is the cause, which we would instinctively feel like it wasn’t, or if 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, suggesting a dose response, something researchers are looking for when trying to understand whether two things that are associated are linked because one has caused the other or by sheer coincidence.

Interestingly though, although many of the children test positive for adenovirus in their blood, samples of their destroyed liver tissue usually do not find any virus.

CDC investigates more than 100 cases of unexplained hepatitis in children, including 5 deaths

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

“Liver cells are absolutely teeming with new adenovirus particles. So there’s no question that the virus itself is infecting hepatocytes and killing them. We don’t have that link yet,” Irving said.

So there are a couple of factors to consider, Irving said. Perhaps the virus is not acting alone. Or it may be triggering a harmful immune reaction.

In Alabama, 75% of cases (nine out of 12 children currently identified with sudden and 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 of coronavirus OC43, human metapneumovirus, and rotavirus. , which usually causes diarrhea. None tested positive for a current Covid-19 infection.

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

Almost all had been vomiting, more than half had diarrhea and fever. Nearly 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 appear to be no geographical or social links between the cases, meaning the children do not know each other or live in the same areas. “It really is sporadic,” says Kelly.

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

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

“Which then begs the question, what’s so special about these little kids?” 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 the genetic traits of affected children and their parents to see if they had any unrecognized risk factors for your liver problems.

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

“We must not forget that there are 170 families [in the UK] who are very distressed about this mysterious disease that is causing so much trouble for their children, and getting a liver transplant is a life-changing event for them,” Semple said.

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