April 4, 2023 – Researchers have found that co-infection by multiple common viruses may have caused a mysterious hepatitis outbreak in kids worldwide.
Since October 2021, these hepatitis cases in young children affected more than 1,000 kids in 35 countries. Although most children survived, of about 350 patients identified in the United States until May 2022, 22 required a liver transplant and 13 died.
Most of these children were under 6 years old.
Not only are these hepatitis cases acute and severe, but what’s causing them is a mystery. They don’t fit into the common categories of liver inflammation, known as hepatitis A through E.
Now, researchers have zeroed in on a possible culprit. They identified a strain of virus, called adeno-associated virus type 2 (AAV2), as the central player in the outbreak. And if they are correct, AAV2 is not acting alone.
In fact, this virus is not strong enough to cause these severe cases without help. Instead, affected children must have at least one other “helper" virus at the same time, such as a human adenovirus (which can cause symptoms similar to the common cold or flu, according to the CDC), Epstein-Barr virus, and/or human herpesvirus 6.
The new study was published online March 30 in the journal Nature.
Pointing to the Pandemic
The researchers say there is no evidence linking the illnesses to the virus that causes COVID-19, but the pandemic may still be a factor in these infections. Because many children were not exposed to the viruses linked to the hepatitis cases during lockdowns and social isolation, as they normally would be, they did not build up immunity to them.
“So it is possible once restrictions were lifted, they were suddenly exposed over a short period of time to multiple viruses,” said senior study author Charles Chiu, MD, PhD, a laboratory medicine and infectious disease specialist at the University of California San Francisco School of Medicine.
This setup and lack of a strong immune system to deal with these specific viruses “would have increased their risk of developing severe disease.”
William Balistreri, MD, a pediatric hepatitis specialist who was not affiliated with the study, agreed this was possible.
This has been a popular theory, especially in view of the timing of the bulk of cases, peaking during the height of the COVID-19 pandemic and associated isolation procedures," said Balistreri, who is also a professor of pediatrics and director emeritus of the Pediatric Liver Care Center at Cincinnati Children’s Hospital Medical Center.
What to Watch for in Kids
As for his take-home message for parents and health care providers, “the keys are awareness and reassurance,” Balistreri said.
Vigilance also is warranted, he said, if a child has symptoms that often come right before hepatitis, including respiratory symptoms, nausea, vomiting, diarrhea, and belly pain. Also, If jaundice or yellowing of the eyes from jaundice, called scleral icterus, develops, then hepatitis should be suspected.
“Reassurance is based on the good news that most children with acute hepatitis get better. If a case arises, it is good practice to keep the child well-hydrated, offer a normal diet, and avoid medications that may be cleared by the liver,” Balistreri said, noting that COVID vaccination is "strongly suggested.”
Working to Solve the Mystery
Chiu and colleagues were not completely in the dark at first. They knew from previous research that adenoviruses might be involved. So they used genomic sequencing and other advanced technologies to look for the virus in 27 blood, stool, and other samples from 16 children with this severe hepatitis. They also wanted to know what other viruses might be present.
And for comparison, they searched for the same viruses in a group of 113 children without this severe hepatitis of unknown origin.
Strengthening their findings were two other studies that were done at different institutions and published in the same journal at the same time. One was a genomic study confirming the presence of AAV2 and other suspected viruses, and the other was a genomic and laboratory study further supporting the results.
Of the 16 affected children studied by Chiu and colleagues, the average age was 3. About half were boys. These children were diagnosed with severe hepatitis starting when it was first detected on Oct. 1, 2021, until May 22, 2022.
Of the three studies published in Nature, using different diagnostic tools, there was a consistent presence of the adeno-associated virus type 2 in all or almost all of children, while the "helper" viruses of varying types were also discovered.
Also striking in the studies: what was not found. Of 113 children in one comparison group, among those with diagnoses other than the mystery ailments -- including stomach flu, hepatitis of known origin, and those admitted to a hospital for liver failure -- AAV2 was much less common.
There was also hardly any evidence of the "helper" viruses.
“I am quite confident that we have identified the key viruses" because they used comprehensive genetic sequencing "to look for potential infections from any virus or non-viral pathogen,” Chu said.
The next steps in the research could go beyond identifying presence of these viruses and figuring out which one – or ones – are adding the most to the acute pediatric hepatitis.
There was also a study in the United Kingdom that identified a specific genetic factor linked to the condition, and Chiu and colleagues might look into that further.
They also said they might study other things linked to the COVID pandemic, including if and how long COVID fits into this and resurgence of other viruses, such as respiratory syncytial virus (RSV) and the flu.