Why a harmless pathogen caused a serious hepatitis epidemic in children

Quiz solved? In the spring and summer of 2020, an unusually large number of children in Europe and North America fell ill with jaundice of unknown cause – none of the common pathogens were found in them. Now three research teams have discovered the possible cause: the adeno-associated virus AAV2 has been detected in almost all sick children. This virus is harmless on its own, but in combination with other viruses and the children’s immune systems, which have been weakened by the lockdowns, could have triggered the severe liver inflammation.

Hepatitis is one of the most common infectious diseases worldwide. It can cause jaundice – an acute inflammation of the liver, which in the worst case can lead to liver destruction and even death. Common causes of hepatitis are usually the five previously known types of hepatitis viruses, but bacteria can also cause the disease. However, acute jaundice or chronic hepatitis are rare in children.

Wave of disease in Europe and America: 22 children die of hepatitis

It was therefore all the more alarming that in spring and summer 2020 in Europe and North America an unusually large number of children aged up to ten years an suffering from liver inflammation. Since then there have been around 1,000 cases in 35 countries. The affected children were often seriously ill and had to be treated in hospital or even in the intensive care unit. 55 of the little patients could only be helped by a liver transplant, 22 children died of their hepatitis.

The strange thing about it: the children suffering from this hepatitis did not carry any of the known hepatitis viruses. According to initial analyses, herpes viruses and the SARS-CoV-2 coronavirus only occurred in isolated cases. To clarify the cause of this puzzling outbreak of liver inflammation, three research teams, two in the UK and one in the US, took a closer look at the cases.

They subjected the blood and liver tissue samples taken from the children to a whole series of genetic and virological analyses. Samples were also taken from some of the children.

Infection with an actually harmless virus

It turned out that the sick children were conspicuously often infected with a virus that had previously been considered rather harmless, the adeno-associated virus (AAV2). They belong to a group of viruses that need the help of a second type of virus to reproduce. In this specific case, adenoviruses supply AAV2 with the proteins it needs to multiply in our liver cells. However, AAV2 is not considered pathogenic: around 30 to 80 percent of the general population are infected with this virus without showing any symptoms.

In the two British studies, the researchers detected this adeno-associated virus in high concentrations in 81 and 96 percent of cases. In the US, AAV2 was detectable in 93 percent of small patients. In the children of the healthy control groups, on the other hand, an AAV2 infection was the exception.

“We were surprised that the mysterious infections were not caused by an unknown, newly emerged virus, but apparently by pathogens commonly found in children,” says Charles Chiu from the University of California in San Francisco, first author of the US study.

Multiple infections and the end of the lockdown make for difficult courses

This raises the question of why these actually harmless viruses caused such severe liver inflammation in children. The researchers suspect that the acute cases of jaundice were caused by an unfortunate coincidence of several infections and a weakened immune system. Because almost all children suffering from hepatitis were infected in addition to AAV2 with various adenoviruses and sometimes also with herpes viruses or the Epstein-Barr virus, as the scientists report. In the US study, the proportion of such triple infections was almost 86 percent.

In addition, most of the infections occurred immediately after the end of the first major corona lockdown. The children had therefore sometimes spent weeks or months without contact with other children and largely protected from any type of infection. “It is likely that this has greatly reduced the children’s immunity to adenoviruses and AAV2,” explain Sofia Morfopoulou from University College London and her colleagues. This could have allowed the virus to multiply abnormally in the liver cells, causing hepatitis.

The hepatologist Frank Tacke from the Charité – Universitätsmedizin Berlin, who was not involved in the studies, also considers this explanation to be plausible: “The timing of the hepatitis outbreaks is striking: the wave of hepatitis cases coincided with the relaxation of the corona measures worldwide and increased then off relatively quickly,” writes Tacke in an accompanying “Nature” comment. Although the cellular mechanisms behind this childhood jaundice epidemic are not fully understood, it suggests that the particular immunological circumstances during the pandemic played a role. (Nature, 2023; doi: 10.1038/s41586-023-05948-2; doi: 10.1038/s41586-023-06003-w; doi: 10.1038/s41586-023-05949-1)

Quelle: Nature, University of California – San Francisco

This article was written by Nadja Podbregar