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While public health authorities are scrambling to figure out what is causing a rise in mystery hepatitis cases among children worldwide, scientists are already finding possible holes in their top theory.
Around 460 cases of the unexplained liver inflammation have been identified among children aged 16 and younger. Eleven children have died and a small percentage of cases have needed a liver transplant, according to the latest information from the European Center for Disease Prevention and Control.
Here, we unpick what we know so far and explain why the top theory is making some experts scratch their heads.
How many cases have been identified?
The World Health Organization was first notified on April 5 of 10 children in Scotland with unusual, severe hepatitis.
To date, the total number of cases reported worldwide is approximately 460, including 176 in the UK as of May 10, and up to 106 in EU/EEA countries as of May 11. Italy and Spain have seen the most cases in the bloc, with 35 and 22 infections respectively.
Outside of the EU/EEA, 181 cases have so far been reported, including 109 identified in the US, according to a press briefing by the US Centers for Disease Control and Prevention on May 6. Cases have also been found in Indonesia, Argentina, Brazil, Canada, Costa Rica, Israel, Japan, Panama, the territories, Serbia, Singapore and South Korea.
From these, there have been 11 deaths, five in Indonesia, one in the Palestinian territories and five in the United States, according to an ECDC statement on Wednesday.
Eleven children have received a liver transplant in the UK
Why are these cases baffling doctors?
Hepatitis is an inflammation of the liver. It is most commonly caused by viruses but it can also result from exposure to toxic substances and autoimmune diseases, for example.
What’s unusual about these cases is what has not been found: None of the common viruses that cause acute viral hepatitis (hepatitis viruses A, B, C, D, E) has been detected in any of the children.
What’s the leading hypothesis?
A common virus that normally causes mild, cold-like symptoms — and in some cases gastroenteritis — is the top suspect.
Adenovirus has been identified in 72 percent of the 126 children so far tested for it in the UK In the US half of the cases have so far confirmed adenovirus infections.
With such high numbers, “it’s very difficult to ignore that,” pointed out Will Irving, professor of virology at the University of Nottingham.
World Health Organization scientist Philippa Easterbrook on Tuesday also confirmed the theory: “At present the leading hypotheses remain those which involve adenovirus,” she said.
There are a range of possible hypotheses involving the virus, according to the UK Health Security Agency’s most recent report. These include an abnormal reaction to an adenovirus infection due to lack of exposure during the pandemic, or an exceptionally large wave of infections causing rare symptoms to present more frequently.
Adenovirus infections in the UK are higher than normal for this time of the year, the UKHSA report shows.
The agency is also looking into a potentially abnormal response to adenovirus following a coronavirus or other viral infection, as well as the possibility this may be a new variant of adenovirus.
Is everyone on board with this theory?
no. Some experts have highlighted a number of flaws in this hypothesis.
Farid Jalali, an adult gastroenterologist and hepatologist based in California, pointed out that adenovirus type 41, which has been identified as the most commonly found virus among the children, typically causes gastroenteritis, not hepatitis. Other types of adenovirus can cause hepatitis, but only usually in immunocompromised people, as opposed to healthy children.
In addition, “a core diagnostic criteria” of adenovirus hepatitis is “seeing the virus on the liver biopsy,” he told POLITICO. That has not been the case in any of the children who have undergone analysis of their liver tissue according to the US and UK reports so far, Jalali said.
Virologist Isabella Eckerle, of the Geneva Center for Emerging Viral Diseases, raised similar concerns.
“Normally viruses causing hepatitis are massively found in the blood,” she tweeted. But the UKHSA reports that viral loads were very low, she added.
With low levels of virus detected in blood samples, UKHSA has also been unable to carry out a full genome sequence to find out if this is a new variant.
Erika Duffell, principal expert in hepatitis at the ECDC and the technical lead for the outbreak, said that, while an adenovirus infection continues to be the leading hypothesis, it was by no means settled.
“We’d hoped that we would have solved it by now,” the ECDC expert said.
She pointed to the detection of adenovirus type 41 in cases in both the US and UK as an interesting piece of evidence. Many children also presented with gastrointestinal symptoms commonly associated with that type. The lack of the virus in tissue samples was puzzling, but on the other hand, adenovirus infections don’t usually make children with regular immune systems so sick, so it’s not clear what should be expected, Duffel explained.
In some cases analysis has also revealed the presence of an adeno-associated virus, which can only multiply with the help of another virus, most commonly an adenovirus. Putting the pieces together, it could be the case that the combination of viruses is causing the unusually severe symptoms. But, Duffel cautioned, this was one theory among others.
The adenovirus “could be a red herring,” the hepatitis expert warned.
Could it be coronavirus?
Virologist Irving underlined that while no one yet knows the true cause of the condition, he thinks it’s “more than a coincidence that we’re seeing this unusual event two years after a pandemic.”
“If I was a betting person, I would say I think two things are probably related, but quite in what way the pandemic has rendered these children susceptible to getting severe hepatitis, that again is unknown,” he said.
The UKHSA is continuing to investigate “the potential role” of COVID-19, including a new variant, a post-infection syndrome including an Omicron-restricted effect, and co-infection with adenovirus.
At the WHO, Easterbrook said that COVID-19 as a co-infection or a past infection is still an “important consideration.”
When will we know more?
Health authorities are carrying out many tests to narrow down their hypothesis, including generating case control data to establish if it’s normal to find high levels of adenovirus among children at the moment.
“What we don’t know … is if you took 100 children who don’t have severe hepatitis today and tested them, in how many would you find this virus?” said Irving. “There’s no case control data at the moment.”
This data from the UK should be landing within the next week, said Easterbrook at WHO. It will then allow authorities to compare the detectable rate of adenovirus in children with liver disease to the rates in other hospitalized children.
This should help decipher whether the adenovirus infections were incidental or causal, she said.
In addition, further data on whether these children have had a past COVID infection is still lacking from public reports.
What are doctors doing to treat infected children?
One thing clinicians are keen to learn is how best to treat these patients.
Data sharing on effective treatment is vital, argued Eckerle, since these children’s condition can decline very quickly. She out that antiviral treatments are pointed only effective if the virus is replicating in the body, while treatments that suppress the system, like steroids, could be suitable for immune reactions triggered by a previous (unknown) infection.
In the meantime, what should parents look out for?
While cases are extremely rare, the UKHSA said the children’s most common symptom was a yellowing of the skin, called jaundice, followed by vomiting.
The children also had other symptoms including diarrhea, nausea, abdominal pain and pale stools.
“We know that this may be a concerning time for parents of young children,” said Meera Chand, director of clinical and emerging infections at the agency. She underlined that the likelihood of a child developing hepatitis, however, is “extremely low.”
Parents should be alert to the signs of hepatitis, particularly jaundice, she said, and contact their doctor if concerned. She advised good hygiene measures including washing hands.
This article has been updated with latest figures for the number of cases and comment from Erika Duffel.
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