As health officials continue their investigation of unexplained cases of liver inflammation in children, what is known is still trumped by what is not.
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 severe, with more than two dozen children needing liver transplants. At least a dozen children have died, including five in the United States.
The diseases were mainly observed in children under five years of age. So far, health agencies have ruled out common causes of hepatitis, while reporting that some of the children have tested positive for adenovirus. This pathogen – which infects basically everyone, usually without serious problems – is not known to be the main cause of liver damage. For some children who are positive, authorities have identified the specific adenovirus: type 41.
But there are several reasons why identifying an adenovirus as the sole culprit of hepatitis doesn’t quite fit, the researchers say. It is also unclear whether the recent cases indicate an increase in hepatitis disease, or just more attention. While the cases seem to have come out of nowhere, “we’ve seen severe liver disease 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 shouldn’t panic.”
Hepatitis in children
Hepatitis is an inflammation of the liver that can interfere with many organ functions, including filtering blood and regulating clotting. Three hepatitis viruses, called hepatitis A, B, and C, are common causes of illness in the United States. Hepatitis A is spread when infected fecal material reaches the mouth. Children can get B and C when they are passed from a pregnant person to a baby. There are vaccines available for A and B, but not for C. An overdose of acetaminophen can also cause hepatitis in children.
Signs of hepatitis can include nausea, fatigue, yellowing of the skin and eyes, darker than normal urine, and pale stools, among other symptoms. Hepatitis that comes on quickly 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% of them are “undetermined,” meaning that a cause has not been found, according to the American Society of Gastroenterology, Hepatology, and Pediatric Nutrition.
The undetermined category of sudden liver failure has been known for some time, says Peters, and this subset of cases has similarities to the hepatitis under investigation. There is still no data reported on whether the recent cases represent an increase from what has been seen in previous years, says Peters. “Maybe this is just a greater recognition of something that is happening.”
Adenovirus as a suspect
Not all children with hepatitis were positive for adenovirus, nor were they tested. The European Center for Disease Prevention and Control, or ECDC, reported that of 151 cases tested, 90 were positive, or 60%. The latest dispatch from the UK Health Safety Agency, from early May, noted that 126 samples out of 163 had been tested, with 91, or 72%, positive. Additional analyzes of 18 cases identified adenovirus type 41.
Adenoviruses commonly infect people, often causing colds, bronchitis, or other respiratory illnesses. Two types, adenovirus 40 and 41, target the intestines, leading to gastrointestinal symptoms such as vomiting and diarrhea.
“All these types, including the prime suspect type 41, have been detected everywhere continuously,” says virologist Adriana Kajon of the Lovelace Biomedical Research Institute in Albuquerque. “They all existed and were reported on continuously for decades.”
People usually recover from an adenovirus infection. The exception is those whose immune systems are not working properly – so an infection can be serious. There have been cases of adenovirus hepatitis in immunocompromised children, but the children under investigation are not immunocompromised.
There are several curious details about the adenovirus findings. For example, children who tested positive for the virus had low blood levels. In cases of adenovirus hepatitis, “the virus levels are very, very high,” says Peters.
Nor was adenovirus 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 report May 6 in Weekly Morbidity and Mortality Report.
“It’s very difficult to implicate a virus that you can’t find at the scene of the crime,” Kajon said May 3 at a clinical virology symposium in West Palm Beach, Florida.
Another oddity: there doesn’t seem to be a viral propagation path from one location to another. This is different from SARS-CoV-2, the virus that causes COVID-19, “where there was clearly a spread from some epicenter originally,” says virologist and clinician Andrew Tai of the University of Michigan School of Medicine in Ann Arbor. , which treats patients. with liver disease.
A culprit adenovirus is not out of the realm of possibility, but “virus associations with disease are always difficult to identify and prove,” says virologist Katherine Spindler, also at the University of Michigan School of Medicine. “We’ll be hard-pressed to say this is due to adenovirus 41, let alone adenovirus.”
Hovering over all of this is the possibility that an infectious disease outbreak of many magnitudes greater, COVID-19, could play a part.
Researchers have found that SARS-CoV-2 affects the liver in both 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 outbreak 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 his colleagues described yet another way that SARS-CoV-2 could put the liver at risk. The team reported the case of a young patient from the fall of 2020 who had sudden liver failure about three weeks after a SARS-CoV-2 infection. She didn’t have MIS-C. A liver biopsy showed signs of autoimmune hepatitis, a type in which the body attacks its own liver, Peters and colleagues report in May. Journal of Pediatric Gastroenterology and Nutrition Reports. The patient recovered after treatment with anti-inflammatory medication.
Some of the children with hepatitis tested positive for SARS-CoV-2, but others did not. The ECDC reported that 20 of 173 cases tested were positive for SARS-CoV-2, while the UK Health Safety Agency detected the virus in 24 of 132 samples tested.
However, there is very little data reported on whether children have antibodies to SARS-CoV-2, which would be evidence of a past infection. (Vaccination is not available for most of these children.) The ECDC found that of 19 cases tested, 14 were positive for antibodies to the virus.
One theory is that a previous SARS-CoV-2 infection 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.
“Possibly, we are seeing the return of these forgotten pathogens, so to speak, exacerbating disease or causing severe inflammation resulting from some sort of preexisting condition,” which could be COVID-19, Kajon said May 3.
“I can’t think of anything else that has a worldwide impact that could explain cases of hepatitis as far away as the UK and Argentina,” says Kajon.
With SARS-CoV-2, researchers have a good sense of how it causes illness during an active infection, says Peters. But for long-term effects, “everybody is still working things out.”