Public health officials in the United States, Europe, and Canada are issuing warnings about acute hepatitis outbreaks affecting children, which have already resulted in one death and liver transplants in 17 others.

On Saturday, the World Health Organization said that it had received reports of the illness in 169 children across the United States, the United Kingdom, and Northern Ireland. The affected children range in age from one month old to 16 years old. The WHO said that the adenovirus—a virus that can cause the common cold— had been detected in 74 of the children affected and SARS-CoV-2 was detected in 20 cases. In 19 of the 20 cases, both viruses were detected.

“The WHO is being cautious and saying they don’t know if it’s really an increase in cases or just increased awareness,” William Schaffner, an infectious disease specialist at Vanderbilt University School of Medicine tells Inverse. “The notion that in 17 of these cases the children have received liver transplants is striking to me. Something is going on.”

George Rutherford, a professor of epidemiology and biostatistics at UCSF agrees. “If there are 169 confirmed cases and 17 have needed liver transplants, that’s 10 percent. That’s huge.”

Here’s the background — Hepatitis occurs when there’s inflammation in the liver, and viruses are often the cause. There are five main types of viral hepatitis: A, B, C, D, and E. A and E are caused by ingestion of contaminated food or water; B, C, and D are transmitted through certain bodily fluids.

Rutherford says it’s extremely rare for kids to have such extreme outcomes with hepatitis. “The one exception is Hepatitis E, but that’s very rare here. But with the other types, it’s extremely rare for kids to need a liver transplant from hepatitis.”

In the United States, Schaffner adds, most kids are required to be vaccinated against Hepatitis A and B to go to daycare or school. “We’ve been doing that for 15 years now. And as a result, Hepatitis B in children has been almost eliminated in the United States.”

What’s behind these unusual outbreaks in kids? — The recent outbreaks in children aren’t the result of any of the five most common types of Hepatitis, the WHO says.

Schaffner says other viruses can cause hepatitis. For example, “Yellow Fever” got its name because the virus can go to the liver and cause jaundice, he says.

Given that adenovirus has been detected in 74 of the kids afflicted, the WHO is zeroing in on that as a possible culprit.

It could also be what’s called a recombinant virus, which can occur when two strains of a virus combine, or when two viruses infect the same cell.

“That’s something we’ve seen with Covid,” Rutherford says.

While public health officials are looking at viral exposure, hepatitis can also be caused by contaminated products like medication, food, or water, as well as exposure to other toxins.

“When you start an investigation, you don’t close your mind to anything,” Schaffner says.

How epidemiologists solve disease mysteries

When trying to figure out the source of an outbreak or unusual disease occurrence, three investigations happen simultaneously. The first investigation happens at the bedside of the patient: doctors doing clinical investigations.

“Here, the doctors are trying to define the illness in as many different ways as possible,” Schaffner says. “How does it present? What organ systems are affected? How quickly does the illness progress?”

The second investigative prong happens in the lab. Doctors treating the patient will send all kinds of specimens to the lab like throat swabs, stool samples, and liver cells.

“The laboratorians look for a whole array of things that might tell them something about what caused the disease and how it’s affecting the body,” Schaffner says.

Genotyping cell cultures from the liver are likely how doctors ruled out the five main types of hepatitis, Rutherford says.

The third prong of the investigation is up to public health officials, and likely what the WHO and CDC are involved in: finding the source of infection.

“This is where disease detectives are out there trying to find something in common,” Schaffner says. “And not just viruses but also exposure to toxins.”

Initially, this investigation is “basically an open-ended kind of hypothesis-generating exercise,” Rutherford says. “From there, you hope you can find more evidence and narrow it down to a common factor.”

Finding that common factor will be a tricky task, Schaffner explains. “It quickly became evident—at least in the U.S.— that the affected kids did not have personal contact with each other. They didn’t go to the same church or summer camp or anything.”

Given that the kids didn’t have contact with each other, researchers will turn to dietary history, and personal environment, asking questions like “What toys did these kids play with? What games did they play?”

If disease detectives have a good hypothesis for a common factor, researchers do a case-control study, which attempts to determine if the common factor is significantly associated with the disease.

“If you can prove that, you then try to control whatever it is,” Rutherford says.