What we know about cases of unexplained hepatitis in children

As health officials continue to investigate unexplained cases of liver inflammation in children, what is known continues to be outnumbered by what is not known.

At least 500 cases of hepatitis of unknown cause have been reported in children in about 30 countries, according to health agencies in Europe and the United States. As of May 18, 180 cases are under review in 36 US states and territories.

Many of the children have recovered. But some cases have been serious, with more than two dozen children needing liver transplants. At least a dozen children have died, including five in the United States.

The illnesses have been seen mainly in children under the age of five. So far, health agencies have ruled out common causes of hepatitis, while reporting that some of the children have tested positive for adenoviruses. That pathogen, which infects basically everyone, usually without serious problems, is not known to be the main cause of liver damage. For some children who test positive, officials have identified the particular adenovirus: type 41.

But there are several reasons why pinpointing an adenovirus as the sole culprit in hepatitis doesn’t quite add up, the researchers say. It’s also unclear if the recent cases indicate an increase in hepatitis illnesses or simply more attention. Although the cases seem to have come out of the blue, “we have seen rare serious liver diseases similar to this in children,” says Anna Peters, a pediatric transplant hepatologist at Cincinnati Children’s Hospital Medical Center.

Above all, it’s important for parents to remember that the cases described so far “are a rare phenomenon,” says Peters. “Parents should not panic.”

hepatitis in children

Hepatitis is an inflammation of the liver that can interfere with many functions of the organ, including blood filtration and coagulation regulation. Three hepatitis viruses, called hepatitis A, B, and C, are common causes of the disease in the United States. Hepatitis A is spread when infected fecal matter gets into the mouth. Children can get B and C when it is passed from a pregnant woman to a baby. Vaccines are available for A and B but not for C. An excessive dose of acetaminophen can also cause hepatitis in children.

Signs of hepatitis can include nausea, fatigue, a yellow tint to the skin and eyes, urine that is darker than usual, and light-colored stools, among other symptoms. Hepatitis that develops rapidly usually resolves, while some cases progress more slowly and lead to liver damage over time.

It is rare for a child to develop sudden liver failure. An estimated 500 to 600 cases occur each year in the United States, and about 30 percent of them are “undetermined,” meaning no cause is found, according to the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition .

The indeterminate category of sudden liver failure has been known about for some time, says Peters, and that subset of cases has similarities to the hepatitis under investigation. Data has not yet been reported on whether the recent cases represent an increase over what has been seen in previous years, says Peters. “Maybe this is just more recognition of something that has been going on.”

Adenovirus as a suspect

Not all children with hepatitis have tested positive for adenovirus, nor have all been tested. The European Center for Disease Prevention and Control, or ECDC, reported that of 151 cases tested, 90 were positive, or 60 percent. The latest dispatch from the UK Health Security Agency, from early May, noted that 126 samples out of 163 had been tested, with 91, or 72 percent, positive. Further analysis of 18 cases identified adenovirus type 41.

Adenoviruses commonly infect people and usually cause colds, bronchitis, or other respiratory illnesses. Two types, adenovirus 40 and 41, target the intestines and cause gastrointestinal symptoms such as vomiting and diarrhea.

“All of these types, including this prime suspect type 41, have been detected everywhere continuously,” says virologist Adriana Kajon of the Lovelace Biomedical Research Institute in Albuquerque. “All of them have been around and have been continuously reported for decades.”

People usually recover from an adenovirus infection. The exception is those whose immune system is not working properly; then an infection can be serious. There have been cases of adenovirus hepatitis in immunosuppressed children, but the children under investigation are not immunosuppressed.

There are several curious details about the adenovirus findings. For example, children who tested positive for the virus had low levels in their blood. In cases of adenovirus hepatitis, “the virus levels are very, very high,” says Peters.

Adenovirus has also not been found in the liver. In a study of nine children with hepatitis in Alabama who tested positive for adenovirus in blood samples, researchers studied liver tissue from six of the children. There was no sign of the virus in the liver, the researchers reported May 6 in Weekly Morbidity and Mortality Report.

“It’s very difficult to implicate a virus that you can’t find at a crime scene,” Kajon said May 3 at a clinical virology symposium in West Palm Beach, Florida.

Another oddity: There doesn’t seem to be a viral spread path from one place to another. That’s unlike SARS-CoV-2, the virus that causes COVID-19, “where there was clearly spread from some epicenter originally,” says virologist and physician Andrew Tai of the University of Michigan Medical School in Ann. Arbor, which treats patients. with liver disease.

An adenovirus culprit isn’t out of the realm of possibility, but “virus-disease associations are always difficult to determine and prove,” says virologist Katherine Spindler, also of the University of Michigan Medical School. “We’re going to have a hard time saying this is due to adenovirus 41, let alone adenovirus.”

Considering COVID-19

Hovering over all of this is the possibility that an outbreak of an infectious disease many magnitudes larger, COVID-19, may have something to do with it.

Researchers have found that SARS-CoV-2 affects the liver in milder and more severe cases of COVID-19. There is evidence that the liver becomes inflamed in children and adults during an infection. Liver failure can occur with a severe attack of COVID-19. And children who develop multisystem inflammatory syndrome in children, or MIS-C, after COVID-19 may have hepatitis as part of that syndrome.

Peters and colleagues have described another way that SARS-CoV-2 could put the liver at risk. The team reported the case of a young female patient from the fall of 2020, who had sudden liver failure about three weeks after a SARS-CoV-2 infection. She did not have MIS-C. A liver biopsy showed signs of autoimmune hepatitis, a type in which the body attacks its own liver, Peters and her colleagues report in the May issue. Journal of Pediatric Gastroenterology and Nutrition Reports. The patient recovered after treatment with anti-inflammatory drugs.

Some of the children with hepatitis tested positive for SARS-CoV-2, but most did not. The ECDC has reported that 20 of the 173 cases tested were positive for SARS-CoV-2, while the UK Health Security Agency detected the virus in 24 of the 132 samples tested.

However, very little data has been reported on whether children have antibodies to SARS-CoV-2, which would be evidence of past infection. (Vaccination has not been available for most of these young children.) The ECDC found that out of 19 cases tested, 14 tested positive for antibodies to the virus.

One theory is that a previous SARS-CoV-2 infection has set the stage for an unexpected response to an adenovirus or other infection. With people no longer minimizing contact, the spread of adenoviruses and other respiratory viruses is returning to pre-pandemic levels.

“We are possibly seeing the return of these forgotten pathogens, so to speak, that aggravate disease or cause severe inflammation as a result of some kind of pre-existing condition,” which could be COVID-19, Kajon said on May 3.

“I can’t think of anything else that has had a global impact that could explain hepatitis cases in places as far apart as the UK and Argentina,” says Kajon.

With SARS-CoV-2, researchers have a good idea of ​​how it causes disease during an active infection, says Peters. But for long-term effects, “everyone is still figuring things out.”

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