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Study finds possible link between long COVID and mystery hepatitis in kids

A small study on children with hepatitis points to prior COVID-19 infection as a possible cause, but experts say it's still too soon to tell.

A small, new study from Israel describes a potential link between liver injury in children and long COVID. But it also highlights how much we still don't know about the ongoing mystery hepatitis outbreak in kids.

The lead study author and experts agree that it's too soon to tell whether prior infection with COVID-19 is behind the recent rise in cases of hepatitis in kids with no known cause.

Mysterious Hepatitis Cases: What we know so far

Since April 2022, health officials around the world have been monitoring a mysterious outbreak of acute hepatitis among children. There are at least 290 cases under investigation in the U.S., according to the most recent data from the Centers for Disease Control and Prevention. Globally, at least 700 cases are under investigation in 34 countries, according to the World Health Organization.

What makes these pediatric hepatitis cases so mysterious is that there is no known cause. Hepatitis, or inflammation of the liver, is often caused by viral infections, and the most common causes are hepatitis viruses A, B, C, D and E. However, none of these are behind the recent outbreak of hepatitis among children worldwide, which has left scientists puzzled.

While cases of unexplained pediatric hepatitis pop up every year, the number of cases detected since fall 2021 has caused concern among health officials and parents alike. The CDC recently published an analysis that found, between October 2021 and March 2022, there was no increase in hepatitis or adenovirus versus pre-pandemic levels. But this was limited to data from the U.S., and WHO has previously said that other countries have seen higher-than-usual rates of pediatric hepatitis with an unknown cause.

Of the 700 pediatric hepatitis cases reported worldwide, at least 38 children have required liver transplants and 10 have died, according to the most recent data from WHO.

Researchers have studied possible links between the current hepatitis outbreak and SARS-CoV-2, the virus that causes COVID-19, as well as adenovirus, a group of very common viruses that cause cold- and flu-like symptoms. Adenovirus has been identified in a number of these pediatric hepatitis cases, but it usually doesn't cause hepatitis in healthy children, according to the CDC.

Researchers in Israel published findings from a small study, which suggests that prior infection with COVID-19, and its impact on the immune system, could play a role in the outbreak. The study, titled “Long COVID-19 Liver Manifestation in Children,” was published in the Journal of Pediatric Gastroenterology and Nutrition last week.

What did this new study find?

The study describes five children in Israel who recovered from COVID-19 and later presented with liver injury. It was a retrospective case series, meaning it looked back at existing data from patients.

"Basically, this was an observation we made in the last year or two, describing a liver injury type that is likely caused by a post-COVID phenomenon," Dr. Orith Waisbourd-Zinman, pediatric gastroenterologist at Schneider Children’s Medical Center of Israel and lead investigator of the study, told TODAY. Post-COVID liver injury has been well-documented among adults, the scientists note in the study, but the data from children are sparse.

All five patients, who were between 3 months and 13 years old, presented with liver injury after recovering from a case of mild or asymptomatic COVID-19. Two patients, both infants, had liver failure. They all had elevated liver enzymes, suggesting inflammation or damage, and the most common symptoms were jaundice, abdominal pain, nausea and weakness.

All of the subjects were previously healthy and tested negative for the usual culprits of liver injury during extensive blood workups, said Waisbourd-Zinman, which is what prompted researchers to test for antibodies to SARS-CoV-2 and look into long COVID.

The study describes a type of liver injury that was "not caused by the virus itself, but rather the immune response after the virus disappears ... which is similar to other long COVID phenomena," said Waisbourd-Zinman. These include prolonged fatigue, brain fog, gastrointestinal symptoms and more.

The scientists posited that after recovering from COVID-19, the immune system may be primed to react differently to infection, leading to liver injury.

Although adenovirus has been a leading theory, Waisbourd-Zinman said it’s a “weak link.” Only one of the patients in this study had a positive test for adenovirus. “But when we stained the liver for the presence of adenovirus, it was negative," she added. Adenovirus was not found in the livers of any other patients in the study, either.

Multi-system inflammatory syndrome in children (MIS-C), a condition in which organs and other parts of the body become inflamed, has also been reported in children with a previous COVID infection and can cause liver injury. But the patients in the study didn't meet the diagnostic criteria for MIS-C.

Three of the patients in the study recovered from hepatitis with treatment involving steroids, except for the two young infants with liver failure, who required transplants. Waisbourd-Zinman said that none of the patients had been vaccinated against COVID-19.

The scientists concluded that the likely causes of the acute hepatitis were "either a post-infectious immune reaction similar to MIS-C" or the immune system becoming dysregulated after a COVID-19 infection, "priming the immune system to other infectious agents like adenovirus."

Long-COVID may or may not be the answer

Overall, the jury is still out on whether long COVID can trigger an immune response that leads to acute severe hepatitis in kids.

Not all experts are convinced by the study, which had a number of limitations. First, the sample size was very small, and the study was observational. It did not investigate the mechanisms of liver injury on a molecular level, so it may be too soon to rule out other factors. Also, the cases occurred between December 2020 and September 2021, prior to the current outbreak.

"Any viral infection can prime your immune system to have an odd or aberrant reaction. ... This is not unique to COVID-19," Dr. Rima Fawaz, pediatric gastroenterologist at Yale Medicine, who wasn't involved in the study, told TODAY.

The liver is a very resilient organ, so when it comes to liver injury, especially in healthy children, “often there’s a predisposing factor,” Dr. Michael Wilsey, vice chair of the Division of Gastroenterology at Johns Hopkins All Children’s Hospital in Florida, who wasn't involved in the study, told TODAY. Is that factor prior COVID-19 infection, adenovirus, a genetic component or some combination of these? We simply do not know.

It's worth noting that one of the patients in the study was diagnosed with hemophagocytic lymphohistiocytosis (HLH), a systemic inflammatory syndrome, which Fawaz said can prime you to have a dysregulated immune reaction and cause a prolonged, even fatal inflammatory response.

Although the common thread among these patients was prior COVID infection, there could be another common cause that researchers are not yet able to identify through existing tests.

“These may be patients who are at risk for reasons we don’t fully understand to developing post-COVID liver injury," said Wilsey. "We test for everything we know to test for."

The experts and study authors agree that more data and research is needed to fully understand these mysterious pediatric hepatitis cases and the potential link to long COVID.

The bottom line: Do not panic

Another thing the experts agreed on was that there is no need to panic. Acute hepatitis is still relatively rare. "I would reassure parents that they shouldn’t be stressed,” Waisbourd-Zinman said.

If your child has had COVID-19, that does not mean they will develop hepatitis. Parents do not need proactively look for liver problems or ask the doctor for liver tests after their kid recovers, Waisbourd-Zinman said.

But it is important to know how to recognize the symptoms of hepatitis. These include jaundice or yellowing of the skin and eyes, abdominal pain, dark-colored urine, light-colored stools, nausea, joint pain, fever and fatigue.

While this study may leave us with more questions than answers, it is certainly a step in the right direction. "Basically this is what we were hoping for: to gather more information so we can further study the mechanisms and understand this disease," said Waisbourd-Zinman.