Adenoviruses are common in children, causing infections such as mild colds and pinkeye.
Adenoviruses are common in children, causing infections such as mild colds and pinkeye.

Between April and July of this year, 1,010 cases of severe hepatitis without any explainable cause were reported in children in more than 35 countries. Nearly half of these cases were in Europe, including over a quarter in the UK.

Usually, childhood hepatitis is caused by an infection from one of the hepatitis viruses (such as hepatitis A or hepatitis C). But although children were presenting with elevated levels of hepatitis markers in their blood, no traces of hepatitis viruses were detected in these children, nor in any of the related cases since.

Initial investigations found a potential link between adenovirus infection and these cases of hepatitis. Adenoviruses are very common viral infections, especially in children. They typically cause infections such as mild colds, pink eye (conjunctivitis) or stomach problems. However, if they get to the liver they can on rare occasion cause hepatitis.

However, given how common adenoviruses are in children – and because they rarely cause hepatitis in healthy people – it was difficult to say this was the probable cause.

A new study suggests that the spate of severe hepatitis cases seen in children may be the result of three factors working together: adenovirus, adeno-associated virus 2 (AAV2) and an underlying genetic predisposition to the disease.

A potential cause emerges

In a pre-print study (which means it has not yet been reviewed by other scientists), a team of researchers looked at nine of the original hepatitis cases in April and conducted a large range of tests, seeking to find new or previously undetected viruses or genetic factors that may have caused hepatitis in the children.

The team found that all nine children had been infected with adeno-associated virus 2. They then compared their findings with 13 healthy children and 12 children who'd had adenovirus infections but no hepatitis. Adeno-associated virus 2 was not detected in any of these children. This was a strong indicator that AAV2 was a cause of these mystery hepatitis cases.

Adeno-associated virus 2 belongs to a group of viruses called Dependoparvovirus which infects both humans and some primates. But what's particularly interesting about AAV2 is that in order to infect the host, it requires another virus to also be infecting the host at the same time. It uses this helper virus in order to replicate inside human cells. The most common helper viruses of AAV2 are adenovirus and herpesvirus.

AAV2 needs a helper virus – such as an adenovirus – to infect someone.
AAV2 needs a helper virus – such as an adenovirus – to infect someone.

The researchers found that six out of the nine patients they looked at had an adenovirus, while three had signs of a herpes virus. This makes it's likely these hepatitis infections were caused by a combination of AAV2 and one of these helper viruses.

Immune systems and infections

But both AAV2 and infections such as adenovirus and herpes virus are quite common in children, and most children infected with these don't go on to develop hepatitis. This means there must be an additional factor at play here, perhaps even at the genetic level.

The team of researchers then analysed the children's genomes to look for specific immune system markers, called human leucocyte antigens. Immune system cells use human leucocyte antigens to detect other viruses and pathogens, and engulf them.

This then sends a signal to other immune cells which come along and destroy the pathogen. There are many different types of human leucocyte antigens, and depending on why type a person has can determine which infections they may be more susceptible to.

The researchers found that eight out of the nine children had a higher genetic prevalence of a certain type of human leucocyte antigen, which may have increased their likelihood of getting hepatitis symptoms from these viral infections. This type is also more common in people of European descent, which may further explain why these hepatitis cases were mainly seen in Europe.

Although it appears from this study that a combination of factors may explain the sudden, severe hepatitis cases spotted in children, the study itself was small and only conducted on participants in Scotland. A much larger, peer-reviewed study will need to be done in order to fully figure out the exact link and how best to protect children going forward.

Another factor that might have played into this were COVID-19 restrictions, which meant many children weren't being exposed to these viruses and developing immunity at the ages they normally would have. This meant that when restrictions were lifted, children were exposed to these viruses all at once, which would overwhelm their immune system which is not prepared to deal with it.

However, research will need to be done in order to investigate whether or not this really played a role in the severe hepatitis cases. But if it is shown to be a cause, then it's likely we will see fewer and fewer cases of hepatitis in children as the months pass since the last lockdown.

Conor Meehan does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.