(CNN) The US Centers for Disease Control and Prevention said Friday that it's investigating 109 cases of severe and unexplained hepatitis in children in 25 states and territories that may be linked to a worldwide outbreak.
Among them, 14% needed transplants, and five children have died.
Nearly all the children -- more than 90% -- needed to be hospitalized.
Dr. Jay Butler, the CDC's deputy director of infectious diseases, stressed that the investigation -- a partnership between the CDC and state health departments -- is an evolving situation. Not all the hepatitis cases they are studying now may ultimately be caused by the same thing.
"It's important to note that this is an evolving situation, and we are casting a wide net to help broaden our understanding," Butler said.
Hepatitis, or swelling of the liver, can be caused by infections, autoimmune diseases, drugs and toxins. A family of viruses well known for attacking the liver causes hepatitis A, hepatitis B and hepatitis C.
It's not clear what's driving these cases in young children. Butler said some of the common causes of viral hepatitis have been considered but were not found in any of the cases.
Adenovirus has been detected in more than 50% of cases, although its role isn't clear.
On April 21, the CDC alerted doctors to a cluster of unusual cases of hepatitis in nine children in Alabama.
It asked doctors and public health officials to notify the agency if they had similar cases of children under the age of 10 with elevated liver enzymes and no apparent explanation for their hepatitis going back to October.
Since then, health departments have been working with pediatric specialists in their states to identify possible cases. The numbers shared at Friday's news briefing are the first national look at cases.
Cases are under investigation in Alabama, Arizona, California, Colorado, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Louisiana, Michigan, Minnesota, Missouri, North Carolina, North Dakota, Nebraska, New York, Ohio, Pennsylvania, Puerto Rico, Tennessee, Texas, Washington and Wisconsin.
The CDC's alert followed reports of children from England, Wales, Scotland, and Northern Ireland going to hospitals with unexplained hepatitis.
As of May 1, there are 228 probable cases linked to the outbreak in 20 countries, with more than 50 cases under investigation, Dr. Philippa Easterbrook, a senior scientist in the World Health Organization's Global Hepatitis Program, said in a briefing Wednesday. Among these cases, one child has died, and about 18 have needed liver transplants, she said.
Most of the children were healthy when they developed symptoms that included fatigue, loss of appetite, vomiting, diarrhea, belly pain, dark urine, light-colored stools and yellowing of their skin and eyes -- a sign called jaundice.
Pediatric gastroenterologist Dr. Heli Bhatt of M Health Fairview Masonic Children's Center in Minneapolis has treated two children who are part of the CDC's investigation. One, a 2-year-old from South Dakota, had a liver transplant this week.
Bhatt says liver failure in kids is "super rare." And even before scientists started tracking this outbreak, half of cases were never explained.
Doctors who have treated these children say their cases stood out.
"Even during the first case, I thought it was weird," says Dr. Markus Buchfellner, a pediatric infectious disease specialist at the University of Alabama at Birmingham, where staffers started seeing cases in October.
"And then when the second one came in, that's when I said, 'OK, we need to talk to someone about this.' " He reached out to senior physicians in his department, who contacted the state health department and the CDC.
Buchfellner says the cases stood out because the liver inflammation was so severe.
Sometimes, common viruses like Epstein-Barr or even SARS-CoV-2 will raise a child's liver enzymes a little, indicating what Buchfellner calls "small bits of hepatitis," but the kids typically recover as their bodies fight off the infection.
"But it's very odd to see a child who's healthy come in with the amount of liver injury that these kids had," he said.
Initially, UAB saw nine kids with unexplained hepatitis, and all nine tested positive for adenovirus in their blood. None of them tested positive for Covid-19 during their hospitalization or had a documented history of Covid-19, Butler said at the news briefing.
Since those cases were reported, two more children in Alabama have been identified. Their cases are under investigation, bringing the state's total to 11, said Dr. Wes Stubblefield, medical officer for Alabama's Northern and Northeastern Districts.
There are about 100 kinds of adenoviruses. About 50 of them are known to infect humans, so experts needed a closer look at the virus to try to figure out if all the children had the same one.
When researchers tried to read the genes of the adenovirus in infected kids, only five had enough genetic material to get a full sequence. In all five, the virus was a particular kind called adenovirus 41. It typically causes diarrhea and vomiting in kids, sometimes with congestion or a cough, but has never before been associated with liver failure in otherwise healthy children.
Butler said Friday that adenovirus 40 and 41 have been linked to hepatitis but almost exclusively in immunocompromised children.
Also Friday, researchers with the UK Health Security Agency posted a new technical briefing with an update on its hepatitis investigation. Of 163 cases, 126 patients have been tested for adenovirus, and 91, or 72%, were positive for that pathogen.
Investigators have tried to sequence the entire genome of an adenovirus from one of the patients but have not been able to get a sample with enough of the virus to do that. There were 18 cases in which where they were able to partially sequence the genome, and all of them have been adenovirus 41F, the same one found in the US cases.
Many have wondered whether the cases may somehow be related to SARS-CoV-2, the virus that causes Covid-19.
UK investigators say they're still looking at that possibility, but only 24 out of 132 patients tested -- 18% -- had SARS-CoV-2 detected.
The report says they are not ruling out some role for a Covid-19 infection in these cases. Perhaps a prior Covid-19 infection somehow primed the immune system to make these children unusually susceptible, or maybe a co-infection of the two viruses together overwhelms the liver.
Researchers also want to know if the hepatitis is part of some kind of syndrome that strikes kids after a SARS-CoV-2 infection, like the rare complication called multisystem inflammtory syndrome in children, or MIS-C.
Another working theory from UK investigators is that there's some kind of outsized or irregular immune response in these children, perhaps because they were sheltered more than usual during the pandemic.
Yet another theory is that the adenovirus may have always caused liver failure in a tiny percentage of children who were infected, and these rare cases are coming to light only because it is causing an exceptionally large wave of infections.
And investigators in the UK say they are still testing for drugs, toxins or perhaps an environmental exposure, even though some kind of infection is probably more likely to be the cause.
Another thing that's puzzled doctors, Buchfellner says, is that they found adenovirus in blood samples but not in samples of liver tissue taken during biopsies of the patients in Alabama.
"All nine of them have liver biopsies that were showing lots of inflammation and hepatitis. But we did not find the virus in the liver. We only found the virus in the blood," he said.
Bhatt's case, a child from South Dakota, was also positive for adenovirus in her blood but not in her liver.
If adenovirus 41 is somehow responsible in these cases -- and that's still a big if -- Buchfellner says he doesn't know why it would only show up in the blood but not in heavily damaged liver tissue. But he has some theories.
"Maybe the liver is clearing the virus before it's been cleared in the blood," he said. "And so by the time that the damage has been done to the liver and we do the biopsy, the immune system has already cleared the virus from the liver. And what's left over is just inflammation."
His second theory is that it's not the virus itself that's responsible for the liver damage, but perhaps the immune system overreacts when trying to fight off the virus and ends up damaging the liver.
Adenovirus infections are common, so maybe finding the virus in some of these patients is just a coincidence. "We are not 100% sure that this is just that adenovirus. There's still a lot to be known," Bhatt said.
In an April 29 statement on the cases, the CDC wrote, "we believe adenovirus may be the cause for these reported cases, but other potential environmental and situational factors are still being investigated."
Butler said Friday that experts are considering a range of possibilities, including exposure to animals.
"We really are casting a broad net and keeping an open mind in terms of whether the adenovirus data may reflect an innocent bystander or whether there may be cofactors that are making the adenovirus infections manifest in a way that's not been commonly seen before," he said.
Investigators say they know that this news may worry parents.
Butler says investigators still believe these cases are very rare. They have not seen an increase, for example, in children coming to emergency rooms with hepatitis.
"We are still telling at least our families here in Alabama -- and I would encourage other families the same way -- not to be too concerned about this just yet." Buchfellner said. "I mean, at the end of the day, this is still a pretty rare phenomenon."
Buchfellner says adenoviruses are commonly passed around day cares and schools. They typically cause nothing worse than something that feels like stomach flu for a few days.
"it's been around for a long time, and it's gonna continue to go around. And in total, we only have around 200 cases that have been reported across the globe. So this isn't a Covid pandemic-like situation where everybody needs to be really concerned about this," he said.