Mysterious childhood hepatitis continues to vex researchers

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An increase in cases of pediatric hepatitis could be linked to reduced exposure to a common virus.Credit: Peter Byrne/PA via Alamy

In the months since British doctors sounded the alarm over mysterious cases of hepatitis that appeared to strike young children, researchers have been scrambling to pinpoint the cause – and a possible link to the pandemic of coronavirus has been one of the main hypotheses.

But on June 17, researchers from the US Centers for Disease Control and Prevention (CDC) released data suggesting that – in the US, at least – rates of hepatitis, or inflammation of the liver, of unknown cause had not changed since 2017 in children. 11 years old or younger1. If true, the discovery could confound the pandemic link theory.

However, not everyone is convinced by the data and it is unclear whether the same conclusion will emerge from other countries. “I can tell you that having worked in this country for 30 years as a liver doctor, we had a large number of cases in 2022,” says Deirdre Kelly, a pediatric hepatologist at the University of Birmingham, UK. United. “And I think the case-checking in the UK is extremely good.”

Despite the US results, the CDC continues to explore possible links to the pandemic. An analysis published on June 24 showed that 26% of 123 children with unexplained hepatitis in the United States had a history of testing positive for COVID-19 before their liver disease.2. The CDC is now working to collect the samples it needs to test for antibodies against SARS-CoV-2, to find out if other children with hepatitis have had previous infections that have not been detected, says David Sugerman, a physician in the Division of Viral Diseases at the CDC’s National Center for Immunization and Respiratory Diseases. “We are still looking closely at SARS-CoV-2,” he says.

Known and unknown causes

Hepatitis in children has a number of known causes, including infection with viruses such as hepatitis A and exposure to certain drugs, such as paracetamol. But every year, a few cases of unexplained pediatric hepatitis occur.

In early April, the UK Health Safety Agency (UKHSA) informed the public of an apparent increase in the number of young children with severe liver inflammation. At the time, the agency reported 60 possible cases in children under 10 in 2022. Doctors typically see around 20 such cases a year in the UK, Kelly says.

So far this year, more than 250 British children have had hepatitis – and as of May 26 a total of around 650 cases in 33 countries had been reported to the World Health Organisation. Twelve of the British children needed a liver transplant; none died. In the United States, 11 of 296 children suspected of having the disease have died.

Adenovirus infections

In the UK and US, many children with mysterious liver inflammation have also been infected with a member of a family of common viruses called adenoviruses. This has led to speculation that hepatitis is caused by an adenovirus. But although this is the main hypothesis of the UKHSA, it is not very popular. The researchers pointed to the lack of statistical controls: Adenovirus infections often peak in winter and spring, and it is unclear what the rate of infection was in children who did not develop hepatitis.

There is also a lack of precedent: Adenoviruses are not known to cause hepatitis in children with healthy immune systems. And the levels of virus found in most children with liver inflammation are low. “I don’t think it’s an adenovirus,” says pediatric hepatologist Orit Waisbourd-Zinman of Schneider Children’s Medical Center in Petah Tikva, Israel.

On June 10, Waisbourd-Zinman published a case series of five children with unexplained hepatitis3. Only one of them, she says, tested positive for adenovirus. Microbiologist Sumit Rawat of Bundelkhand Medical College in Sagar, India tested samples from 17 children with unexplained hepatitis and found adenovirus in only 3 of them.

But Waisbourd-Zinman and Rawat both say that all of the children they saw had either tested positive for SARS-CoV-2 before or had family members who had. The UKHSA has also consistently listed COVID-19 as a possible explanation. However, only 15% of UK children with hepatitis were actively infected with SARS-CoV-2 at the time of their diagnosis, and the agency has not published data on the number of antibodies against the virus, which which would have suggested a previous infection.

COVID Connection

Although neither hypothesis is a clear winner yet, the timing of the apparent hepatitis outbreak strongly suggests a link to the pandemic, says virologist William Irving of the University of Nottingham, UK. The rise in cases could be a consequence of direct damage from prior SARS-CoV-2 infection, reduced exposure to viruses during the lockdown, or aberrant immune responses triggered by the coronavirus. “It’s just out of hand,” he says. “But I feel like the COVID pandemic must be critical.”

One thing is clear, and that is that the disease is not linked to vaccination against COVID-19: only a handful of children in the UK who developed hepatitis had been vaccinated.

The CDC study, covering the period 2017-2022, challenges any explanation involving the pandemic. The team selected data from health care records, organ transplant records, and laboratory testing of stool samples for adenovirus. Ultimately, the researchers found no recent increases in the number of pediatric hepatitis cases, transplants, or adenovirus-positive stool samples.1.

Hidden diagnostics

But Waisbourd-Zinman says a simple scan of electronic health records might not reveal the true rates of unexplained hepatitis in children. She attempted a similar study in Israel, she says, but soon discovered she had to manually dig through health records to find buried diagnoses. For example, one case of hepatitis was found to be the result of drugs used in a kidney transplant; another was infection with a virus known to cause hepatitis. These causes were not coded as such in health records and a cursory review would have grouped them with unexplained cases of liver inflammation.

This noise makes it difficult to detect truly unexplained cases, she says. “It’s just impossible to see an increase,” she says. “It’s so heterogeneous.”

In April, researchers also determined that rates of unexplained hepatitis among children in continental Europe were no higher than the baseline for that region.4. But Kelly, who consulted on that analysis, notes it was also limited: Like in the United States, healthcare data in Europe is fragmented, she says, and the European survey only included hospitals. specialized.

Some countries, including Israel and the UK, have now asked doctors to report cases of pediatric hepatitis that are not explained by known causes to public health authorities, to help track the disease. This, along with the variety of research studies that have been launched to find the cause of the disease, could shed light on the handful of mysterious cases of pediatric liver inflammation that appear each year – whether or not they are related to COVID-19 – says Kelly.

“I think there might be something special about these kids that makes them sensitive,” she says. “Maybe one of the positive aspects of that is that we could find out what it is.”

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