Hunt begins for the cause of acute hepatitis cases

Usual causes of sudden onset hepatitis have not been found and several studies are underway to understand its potential causes. Nayanah Siva reports.

As of April 21, 2022, 169 children have been reported to have severe acute hepatitis of unknown aetiology worldwide, most of whom are in the UK as well as in the EU, the USA, Israel, Japan, Canada, Indonesia, and Singapore. As of April 25, the UK Health Security Agency (UKHSA) has recorded 145 cases in the UK; ten children have received a liver transplant and none have died. There are reports that three children have died in Indonesia and there is one suspected death, still being investigated, in Wisconsin, USA.

The UKHSA is leading several studies into the cause. Testing has excluded viral hepatitis types A, B, C, D, and E, as well as other known causes of acute hepatitis. “We do see children with severe hepatitis [non A–E hepatitis], for which we find no cause every year”, Deirdre Kelly, Professor of Paediatric Hepatology, University of Birmingham (UK), told The Lancet. “And there’s often a peak in the spring, which we are in now…But obviously there’s a far greater number [now] than we normally see…It’s a real phenomenon.”

Detailed epidemiological and laboratory investigations are under way, but recent reports found that the most commonly found pathogen was adenovirus. In one report, UKHSA found that 40 of 53 cases were positive for adenovirus. Preliminary typing has been consistent with one subtype: 41F.

Adenoviruses are very common and not usually dangerous, explains David Matthews, Professor of Virology, University of Bristol. There have been a few cases of severe viral hepatitis in immunocompromised children; however, in all recently reported cases, children were otherwise healthy and not immunocompromised. “If you’d have asked me two weeks ago to write a list of viruses causing hepatitis, I wouldn’t have put adenoviruses on the list”, said Will Irving, Professor of Virology, University of Nottingham.

“So, if the adenovirus finding is important, there has to be some explanation. Something else has changed. Either the virus has changed, or something has happened to the individual patients that meant their response to the virus has all of a sudden become focused on the liver”, said Irving.

One possibility is that young children did not have the usual exposure to these viruses during the COVID-19 pandemic and so could now be showing severe immune responses. “Lockdown was a very dramatic and huge change in societal behaviour”, said Irving. “And we know from laboratory reports that this winter we have seen increases in a whole range of viruses, including adenoviruses.”

Another hypothesis is that COVID-19 itself could be a factor. The UKHSA study reported that ten children tested positive for SARS-CoV-2 either in recent weeks or on hospital admission (of 61 children with available data). But the general prevalence of SARS-CoV-2 is very high and, at present, there is no evidence of a new variant.

“So perhaps, prior infection with SARS-CoV-2 is doing something to the immune system, such that when it meets what would otherwise be a perfectly normal, trivial virus infection, it is triggering a damaging response to the liver”, said Irving. Kelly points out that this has happened before; after the first wave of COVID-19, there were reports of a severe and new paediatric inflammatory multisystem syndrome in some children 6–8 weeks after having COVID-19. In addition, because none of the children in the UK had been vaccinated, the UKHSA has ruled out any association with the COVID-19 vaccine. There have been suggestions that the hepatitis cases could be associated with the omicron (B.1.1.529) variant of COVID-19, first detected in South Africa in November, 2021. However, after reviewing hospital records at a hospital in Alabama, USA, a recent Centers for Disease Control and Prevention report found that nine patients with severe acute hepatitis of unknown cause were admitted to hospital as early as October, 2021. Concomitant adenovirus infection was detected in all children.

The idea of a toxin from the environment or food is not being ruled out. The UKHSA is conducting epidemiological studies that involve retrospectively assessing the children’s environment, demographics, and food intake. “It is possible that some food stuff has been contaminated with something, but as yet there is no evidence for that”, said Irving. With some adenoviruses frequently detected in water bodies, the UKHSA is also conducting a study to retrospectively analyse wastewater where cases are reported. In addition, the UKHSA is undertaking whole-genome sequencing of several samples to allow for further categorisation of any adenoviruses that are involved.

So, why does the UK have such high case numbers? Experts believe the UK has a good surveillance system. “If you’ve got a joined-up system for surveillance of infectious disease that is effective and works well, you will probably always be the first to find lots of cases”, says Matthews. And Kelly points out that milder cases may be being missed. “If children have a tummy ache, vomiting, and diarrhoea, which lots of children have for lots of reasons, they may not be noticed until they get jaundiced and then suddenly the penny drops, this could be the liver.”