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Update (April 25):  The WHO announced on Saturday that one child has died as a result of severe hepatitis of unknown origin. In a press release, the organization writes that 169 cases of the mysterious liver disease have now been reported in 12 countries, including the UK, the US, Spain, Israel, Denmark, Ireland, the Netherlands, Italy, France, Norway, Romania, and Belgium.

Update (April 22): In response to nine cases of severe hepatitis found in children in Alabama, the US Centers for Disease Control released a nationwide health alert yesterday urging doctors to look out for and report similar cases to the agency. The alert encourages doctors to test children with hepatitis of unknown origin for adenovirus infection.

Scientists and public health officials in the UK, US, and Spain are investigating the cause of a number of cases of severe hepatitis in children younger than 10. 

On April 5, public health officials in Scotland notified the World Health Organization of 10 cases of severe hepatitis—liver inflammation—in children under the age of 10 years old, according to a WHO press release. Within three days, 74 cases had been identified throughout the United Kingdom. All of the children were admitted to and diagnosed in the hospital. As of April 12, none of the children had died, but some were severely ill. Seven have had to receive liver transplants.

“This is a severe phenomenon,” Deirdre Kelly, a pediatric hepatologist at Birmingham Children’s Hospital in England, tells Science. “These [were] perfectly healthy children . . . up to a week ago. Most of [the children] recover on their own,” Kelly notes. According to New Scientist, doctors in the UK have been advised to watch out for children age under age 16 who have symptoms of hepatitis, which include jaundice (a yellowish tinge to the skin), discoloration of the urine or feces, itchy skin, fever, nausea, and abdominal pain.

On April 14, the Centers for Disease Control (CDC) reported that nine cases of hepatitis have been identified in children ages one to six in Alabama since last fall. Two of the nine needed liver transplants, Science reports. In a statement issued to STAT, the CDC says it’s working with the Alabama Department of Public Health and other state departments to investigate the cause of the outbreak. STAT reports that the Alabama public health department issued an alert to doctors in early February that mentioned a case in another state, but the alert did not give details.

Meanwhile, in Spain, the government of the Madrid region announced on April 13 that three regions—Madrid, Aragón, and Castilla-La Mancha—have each reported one case of severe hepatitis of indeterminate origin in young children, according to Science, and one of those children has received a liver transplant.

Hepatitis is typically caused by pathogens, most commonly the hepatitis C virus. That virus, along with the hepatitis A, B, and E viruses, was not present in any of the UK or Spanish cases, according to Science. According to STAT, hepatitis viruses have also been ruled out as a potential cause of the outbreak in Alabama. Severe cases of hepatitis are rarely found in children who are not immunocompromised, and the cause of the current outbreak is still unknown. 

“Seeing children with severe [hepatitis] in the absence of severe underlying health problems is very rare,” pediatrician Karen Landers, a district medical officer for the Alabama Department of Public Health, tells STAT in an interview. “That’s what really stood out to us in the state of Alabama.”

Experts tell Science that an adenovirus, a virus that typically causes colds, may be the culprit. Adenoviruses typically attack the respiratory tract but have occasionally been linked to hepatitis. 

Researchers in Scotland published a study on April 14 detailing cases of children with hepatitis in five children ages three to five this year, writing that an adenovirus infection is “the leading hypothesis.” According to Science, as many as half of the affected children in Spain and the UK tested positive for an adenovirus upon entering the hospital. Five of the nine children in Alabama also tested positive for an adenovirus. 

There are a number of adenoviruses that can infect people. In Alabama, genetic testing is underway to determine whether there is a link between the type of adenovirus infecting children there, known as type 41, and liver disease. Such data is not yet available in the UK and Spain.

“CDC is working with state health departments to see if there are additional U.S. cases, and what may be causing these cases. At this time adenovirus may be the cause for these, but investigators are still learning more—including ruling out the more common causes of hepatitis,” Kirstin Norlund, a spokeswoman for the CDC, tells STAT. 

Researchers speculate that isolation during the COVID-19 pandemic could have left the children immunologically vulnerable and more prone to severe illness from viral infection, Science reports. Alternatively, a previous COVID-19 infection may have left children vulnerable to infection or illness, or the illness may also be a long-term complication of COVID-19 itself, New Scientist reports. A handful of the children had tested positive for SARS-CoV-2 prior to or upon hospital admission.