As health officials continue to investigate unexplained cases of liver inflammation in children, what is known is still not.
According to health agencies in Europe and the United States, there have been at least 500 cases of hepatitis of unknown cause in children in nearly 30 countries. As of May 18, 180 cases are being reviewed in 36 US states and territories.
Many 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.
This disease is mainly seen in children below five years of age. So far, health agencies have ruled out common causes of hepatitis, while reporting that some children have tested positive for adenovirus. That pathogen—the one that infects basically everyone, usually without serious issues—is not known to be the primary cause of liver damage. For some children who are positive, officials have identified a particular adenovirus: type 41.
But there are several reasons why pinning an adenovirus as the sole hepatitis culprit doesn’t add up completely, the researchers say. Nor is it clear whether the recent cases indicate an increase in hepatitis diseases, or simply indicate greater attention. Although cases have come from nowhere, “we’ve seen this kind of rare serious liver disease 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 occurrence,” Peters says. “Parents shouldn’t panic.”
hepatitis in children
Hepatitis is an inflammation of the liver that can interfere with many of the organ’s functions, including filtering the blood and controlling 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 faecal material gets into the mouth. Children can get B and C when transmitted from a pregnant person to an infant. Vaccines are available for A and B but not C. Excessive doses of acetaminophen can also cause hepatitis in children.
Symptoms of hepatitis may include nausea, fatigue, a yellowish discoloration of the skin and eyes, darker urine than usual, and light-colored stools. Hepatitis that develops quickly is usually cured, while some cases progress more slowly and lead to liver damage over time.
It is rare for a child to develop sudden liver failure. According to the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, an estimated 500 to 600 cases occur each year in the United States, and about 30 percent of them are “indeterminate,” meaning no cause has been found.
The uncertain category of sudden liver failure has been known for some time, Peters says, and the subset of cases under investigation have similarities to hepatitis. Peters says there has yet to be any data on whether the recent cases represent an increase over what has been seen in previous years. “Maybe it’s an increased recognition of something that is going on.”
Adenovirus as a suspect
Not all children with hepatitis are positive for adenovirus, nor have all of them been tested. The European Center for Disease Prevention and Control, or ECDC, has reported that 90 of the 151 cases tested were positive, or 60 percent. The UK’s Health Protection Agency’s last dispatch from early May noted that 126 of the 163 samples tested were positive, of which 91, or 72 per cent, were positive. Further analysis of 18 cases identified adenovirus type 41.
Adenoviruses commonly infect people, usually causing colds, bronchitis, or other respiratory illnesses. Two types, adenovirus 40 and 41, target the intestines, causing gastrointestinal symptoms such as vomiting and diarrhea.
“These types are consistently detected everywhere, including this prime suspect, type 41,” says virologist Adriana Cajon of the Lovelace Biomedical Research Institute in Albuquerque. “They all exist and have been consistently reported for decades.”
People usually recover from adenovirus infection. The exceptions are those whose immune system is not working properly – again, an infection can be serious. Cases of hepatitis from adenovirus have been reported in immunocompromised children, but the children being examined are not immunocompromised.
There are several curious details about adenovirus findings. For example, children who tested positive for the virus had low levels in their blood. In cases of hepatitis from adenovirus, “the virus level is very, very high,” Peters says.
Nor has adenovirus 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 the liver tissue of six children. The virus had no symptoms in the liver, researchers reported on May 6. Morbidity and Mortality Weekly Report,
“It’s very hard to trap a virus that you can’t find in a crime scene,” Cajon said May 3 at a symposium for Clinical Virology in West Palm Beach, Fla.
Another oddity: There doesn’t seem to be a route for viral spread from one place to another. This is in contrast to SARS-CoV-2, the virus that causes COVID-19, “where it originally spread fairly clearly from some epicenter,” says virologist and physician Andrew Tai of the University of Michigan Medical School in Ann Arbor. who treat patients with liver disease.
An adenovirus culprit isn’t outside the realm of possibility, but “virus associations with diseases are always hard to really nail and prove,” says virologist Katherine Spindler of the University of Michigan Medical School. “We’re going to be hard pressed to say that this is due to adenovirus 41, let alone adenovirus.”
Keeping in view the COVID-19
Hovering all this is the possibility that a much larger infectious disease outbreak, COVID-19, could be a part of it all.
Researchers have found that SARS-CoV-2 affects the liver in mild and more severe cases of COVID-19. There is evidence that the liver becomes inflamed during infection in children and adults. Liver failure can occur with severe outbreaks of COVID-19. And children who develop multisystem inflammatory syndrome, or MIS-C, after COVID-19 may have hepatitis as part of that syndrome.
Peters and his colleagues have suggested another way SARS-CoV-2 can endanger the liver. The team reported the case of a young female patient from the fall of 2020 who had sudden liver failure about three weeks after SARS-CoV-2 infection. He 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 reported in May. Journal of Pediatric Gastroenterology and Nutrition Report, The patient recovered after treatment with anti-inflammatory drugs.
Some children with hepatitis have tested positive for SARS-CoV-2, but more have not. The ECDC has reported that 20 of the 173 cases tested were positive for SARS-CoV-2, while the UK’s Health Protection Agency detected the virus in 24 of the 132 samples tested.
However, little data has been reported about whether children have antibodies to SARS-CoV-2, which would be evidence of previous infection. (Vaccination is not available for most of these young children.) The ECDC found that 14 of the 19 cases tested were positive for antibodies to the virus.
One theory is that earlier SARS-CoV-2 infection set the stage for an unexpected response to an adenovirus or other infection. With people now minimizing contact, the spread of adenovirus and other respiratory viruses is returning to pre-pandemic levels.
“We are probably seeing a return of these forgotten pathogens, so to speak, exacerbating the disease or relapsing severe inflammation as a result of some sort of preexisting condition,” Cajon said on May 3, which may be associated with COVID-19. Could be -19.
“I can’t think of anything else that has had a worldwide impact that could explain the cases of hepatitis in places as far away as the UK and Argentina,” Cajon says.
With SARS-CoV-2, researchers have a good understanding of how it causes disease during an active infection, Peters says. But as for the long-term effects, “everyone is still sorting things out.”