Paediatric hepatitis outbreak solved?

A series of 3 studies may have the answers we've been waiting for

In spring 2022, attention turned to a mysterious outbreak of liver inflammation (hepatitis) impacting children in the UK. Whilst relatively rare, the cases were severe. A significant number needed liver transplantation. The usual culprits for causing hepatitis were ruled out, leaving people scratching their heads as to the cause. Unfortunately this left room for a some commentators to confidently declare the cause was obviously Covid-19, or bizarrely the Covid vaccines.

The journal Nature has now published a series of 3 studies which bring a pretty compelling case forward for the cause.

Spoiler alert: it’s not Covid-19 or the vaccines.

What are the studies?

The series includes 2 studies from the UK and one from the USA. Each is a truly phenomenal piece of work, and a credit to the contributing teams and the collaboration between many different streams of science and public health.

The first study from the UK detects high levels of a virus called Adenovirus Associated Virus 2 (AAV2) in the blood and liver of 26/32 affected children, compared to low levels of AAV2 in only 5/74 in a control group (made up of healthy children, children with Adenovirus infection but no hepatitis, and children with other diseases or hepatitis of other causes). On inspection of the liver, they found AAV2 within different parts of liver cells (called hepatocytes) and cells lining the small blood vessels within the liver (arterioles) which were also not present in control samples. Fascinatingly, in genetic analysis of the affected children they also detected 93% had at least one copy of the allele DRB1*04:01 which was only present in 16% of controls. This gene is associated with a number of autoimmune conditions.

In regards to Covid-19, the SARS-CoV-2 virus was only found in 10% cases on nasal swabs (one of which tested positive after getting hepatitis), and in none of the samples from blood or liver. In regards to Covid antibodies, the seropositivity rate was 52% in the cases which is lower than in the general population at the time (59%).

Authors conclude it looks highly likely AAV2 is causative, and no role of SARS-CoV-2.

The second study from the UK, high levels of AAV2 were also found in 27/28 cases (alongside Adenovirus in 23/31 and Herpesvirus 6B in 16/23 cases tested) compared to very low levels of AAV2 in controls of children with Adenovirus, including with severe immunosuppression. Examination of liver samples suggested that high levels of AAV2, aided by Adenovirus and Herpesvirus 6B triggered immune mediated liver disease. SARS-CoV-2 was not detected on any metagenomics performed.

Regarding both studies, the outbreak occurred well before almost any children in the UK were even eligible for the Covid-19 vaccine, which can immediately be written off as a potential cause.

The third study from the US detects AAV2 in 13/14 cases compared with only 4/113 controls, with all 14 cases also testing positive for Adenovirus. Interestingly, of the 13 children positive for AAV2 they also found a third virus, of either Epstein-Barr virus (EBV) or HHV-6.

SARS-CoV-2 was not detected in blood or liver from any patient.

What does this all mean?

AAV2 has been known about for a while. It has its name as it is unable to cause infection by itself, and requires the presence of another virus (such as Adenovirus). It was previously not thought to cause disease in humans. That is probably now about to change.

The findings in these incredibly rigorous studies make a comprehensive case for AAV2 causing severe hepatitis in children - most likely in the presence of a genetic predisposition - through an immune mediated mechanism (rather than the virus directly injuring the liver itself). There remains no evidence of any involvement of SARS-CoV-2, even indirectly.

It has been well recognised for quite some time that a substantial number of cases of severe, acute hepatitis in children have no clear cause (around 40%). This too may be about to change. New awareness of AAV2 as a potential culprit may lead to the net being cast wider in future, and we will likely learn more things progress.

What is still unclear is precisely how novel, and where, this particular outbreak of severe hepatitis in children really was. The reason it was first detected was because of a huge increase in the number of cases being clinically managed in the UK. This led to active surveillance of any cases of severe hepatitis in children without a clear cause by the EUCDC and WHO. We have no idea how many cases is normal (we don’t routinely count them) so it is still unclear which other countries actually saw more cases of these than usual, and how many countries were just reporting the normal number of cases they might experience.

It is clear that the UK at least experienced a significant outbreak. Why did this happen? The leading hypothesis is that reduced exposure to Adenovirus and AAV2 during the pandemic (when many infectious diseases reduced circulating) led to a reduction in population immunity (lots of children who had never been infected before). When AAV2 and Adenovirus began circulating again, lots of children became infected for the first time, and these infections spread widely. This led to more children getting infected with Adenovirus and more children getting infected with AAV2, hence more children with this genetic predisposition getting infected, and more cases of severe hepatitis.

Whilst we may never know the answer for certain, this is certainly the most compelling case.

Summary

The outbreak of severe hepatitis in children in 2022 was likely caused by infection with AAV2 in children with a genetic susceptibility leading to immune mediated liver damage. This may have occurred due to reduced immunity to adenovirus and AAV2 in the UK following measures to reduce the spread of COVID-19. Further evidence is needed to establish the exact mechanism, and whether this may be the cause of more cases of hepatitis in children than we previously recognised.

There is no evidence of any involvement of SARS-CoV-2 or Covid vaccines, and beware any commentators who confidently blame anything and everything on either these two factors.