In the spring of 2022, a strange hepatitis outbreak started to emerge in several countries. Children — mostly healthy, many under the age of 10 — were arriving with signs of severe liver inflammation. Some became critically ill, and a few needed liver transplants. At least 19 children died.

Doctors were not sure what to make of this. The usual viruses that cause hepatitis — A through E — weren’t showing up. Early reports suggested a possible link to a common virus called adenovirus. Others floated theories ranging from environmental toxins to rare co-infections. But no clear answer emerged.

Now, some two years later, researchers believe they’ve found the culprit behind at least some of those cases: it was COVID all along.

Disease forensics

Back in 2022, the hepatitis outbreak appeared unexpectedly. By April, over 200 cases of acute hepatitis of unknown origin (AHUO) had been reported in children across Europe, the United States, and parts of Asia. The UK had the highest concentration but by the time it was all said and done, several countries had over 100 cases, including Japan, Brazil, and the US.

What made the outbreak so disturbing was how sudden and severe it seemed. While isolated pediatric hepatitis cases do occur, specialists noticed something different. Centers that might typically see one or two severe hepatitis cases per month were now seeing dozens. In some places, children needed liver transplants at unprecedented rates. This was a trend, not a bunch of isolated cases.

The cause was never really understood. Adenovirus 41, a strain usually associated with stomach bugs in children, was found in many of the UK patients. That led researchers to suspect a coinfection or immune complication involving a second, less detectable virus. Others speculated that the lifting of COVID-era hygiene restrictions had allowed common viruses to spread more freely, exposing children’s undertrained immune systems.

Now, a new study led by researchers across Europe — including Austria, Germany, and Portugal — offers new evidence. The team analyzed liver biopsies from 12 children who developed severe unexplained hepatitis during the 2022 outbreak.

Long COVID

Eleven out of twelve children had SARS-CoV-2 proteins — specifically, parts of the virus’s spike and nucleocapsid structures — still present in their liver tissue. These were not signs of active infection. PCR and RNA tests were negative. But leftover fragments of the virus — likely remnants from past infections — were embedded in liver cells, particularly in areas where the tissue was most damaged.

The inflamed areas were full of CD8+ T cells, a type of immune cell that normally hunts down virus-infected cells. These T cells weren’t acting alone. They were found interacting with two other cell types: liver endothelial cells and myeloid immune cells. The researchers described this as a “pathogenic cellular triad,” a trio of immune and liver cells locked in a destructive cycle.

Simply put, the children’s immune systems were reacting to those remnants — and attacking their own livers in the process. Essentially, the immune system was behaving as though the liver was still infected, even though no active virus was present. Instead, the immune cells were responding to viral leftovers. They were fighting tiny fragments of SARS-CoV-2 protein that had persisted long after the respiratory symptoms were gone.

Notably, most of the children in the study had mild or even asymptomatic COVID infections in the months before their liver problems began. Some had detectable antibodies. A few had only a history of household exposure. Many had never tested positive on a nasal swab at all.

Not all cases are explained

It’s important to note that the new study doesn’t claim to explain every case from the 2022 outbreak. In the UK, a separate line of investigation found a different suspect: adeno-associated virus 2 (AAV2), which may have partnered with adenovirus in vulnerable children. That study suggested the outbreak was multifactorial — driven by new virus combinations and weakened immunity after lockdowns.

But the discovery shows that there’s still much we don’t understand about long COVID.

In adults, we’ve seen persistent brain fog, fatigue, and cardiovascular problems long after recovery. In children, too, post-COVID complications are emerging — often in organs we don’t associate with respiratory illness.

The liver may now be part of that picture. And this hepatitis outbreak may have been one of the first red flags.

The study was published in BMJ.