Just days after the World Health Organization (WHO) announced that 650 total cases – and another 99 suspected cases – of mysterious acute hepatitis have been discovered in 33 countries worldwide, a top virologist has told Health Policy Watch that doctors and scientists may fail to ever find the root cause of the illness.

“There are a number of investigations that are ongoing and a number of hypotheses,” William Irving, a professor of virology at the University of Nottingham said. “I cannot guarantee that we are going to find a cause in a week, a month or even a year. We are looking, but thus far, we have not found exactly what is going on… I think we might not find out the cause at all.”

Hepatitis is an inflammation of the liver, and acute hepatitis is a sudden onset of hepatitis. The inflammation is usually caused by viral hepatitis infections A, B, C or E. The disease usually passes without the need for special treatment. However, according to WHO, in rare cases, it can result in severe liver failure or even death.

As the number of children, mostly young children under the age of 5, suffering from acute hepatitis has grown in recent weeks, WHO on Friday labelled the risk at the global level as “moderate.”

The 650 cases were found between 5 April and 26 May, and WHO said that the cause of the cases is under investigation. However, Irving stressed that finding the root “could be difficult” because there are not too many cases and the cases appear to be declining – at least in the United Kingdom, where Irving lives and where the highest number of children have been reported.

“The problem researchers are going to have will be declining cases,” Irving explained. “Some of the studies will need relatively large numbers to have statistical significance.”

Moreover, there are so many potential and overlapping causes for these cases of acute hepatitis that “it is like you are in a dark room and you are trying to find a needle, but you have no idea where you are going,” said Prof Cyrille Cohen, head of the Immunotherapy Lab at Bar-Ilan University in Israel.

Majority of cases discovered in European region

WHO broke down the origins of the cases, with the majority (58%) emanating from 22 countries in the WHO European region, with 34% of cases from the United Kingdom and Northern Ireland alone. The next largest group (216 cases) was reported in the United States, followed by the South-East Asia region and Eastern Mediterranean region.

In Europe, three-quarters (75.4%) of the cases were individuals under the age of five. Some 156 were reportedly hospitalised due to hepatitis and 12% of patients received a liver transplant. Out of the 650 patients, only 6% required transplants.

Overall, said WHO, 110 (61%) of the 180 children in the European region tested for adenovirus had it. Another 12% of 188 cases tested for COVID-19 were infected at the time they developed hepatitis, and 73% of the 26 individuals who underwent serological tests showed they had been infected with SARS-CoV-2 in the past. The majority (53 out of 63 cases with data) were unvaccinated.

Nine deaths out of the collective 650 infected children have been reported to WHO.

“Laboratory testing has excluded hepatitis A-E viruses in these children,” WHO said. “Further detailed epidemiological, clinical, laboratory, histopathological and toxicological investigations of the possible cause(s) of these cases are underway by several national authorities, research networks and across different working groups in WHO and with partners. Additional investigations are also planned to ascertain whether and where the detected cases are above-expected baseline levels.”

WHO: ‘Hypotheses related to side effects from COVID-19 vaccines are currently not supported’

But while those tests are ongoing, scientists have developed a number of hypotheses for the inflammation. At the forefront is infection with Type 41 adenovirus.

Irving said that doctors have known about Type 41 adenovirus for decades and “it is a good lead,” but cannot explain the recent phenomenon on its own because “this strain of adenovirus has not previously been linked to such a clinical presentation in otherwise healthy children.”

He said that either the virus has mutated, though he believes this to be unlikely, or the host has changed.

“It could be that these children were infected recently with SARS-CoV2, and the combination of SARS and adenovirus in some way is resulting in liver damage,” Irving hypothesised. “But if so, there is not going to be any way to prove that because probably most children under five had had a SARS infection.”

Alternatively, he said, it is possible that lockdown and lifestyle changes that were implemented during the height of the pandemic have made children more susceptible to acute infection. Many countries, for example, saw a decline in influenza and respiratory syncytial virus (RSV) when public health measures were in place and then a rapid and unseasonal spike in those viruses when the public returned to routine.

If this is the case, the effect will gradually decrease over time “because we are now mixing and children are getting all the normal coughs and colds that children normally get,” Irving said.

The WHO also suggested that it could be the result of a super antigen-mediated immune cell activation caused by COVID-19 but stressed that “hypotheses related to side effects from COVID-19 vaccines are currently not supported as most of the affected children did not receive these vaccines.”

WHO asked that doctors take whole blood, serum, urine, stool, respiratory and liver biopsy samples for all cases meeting the case definition to help the agency develop interim guidance and to aid researchers in figuring out a cause.

Expert advises parents to keep threat in perspective

But even as these cases of hepatitis continue to cause concern, Irving reminded parents to keep the situation in perspective. In the UK, for example, there are five million children under the age of five and only 180 cases of mysterious hepatitis.

“Although it is much more common than it usually is, it is still very rare,” he said. “It is a significant event if you are a child or parent of a child that is affected. But the risk to the general population is extremely small.”

Additionally, only about 10% of cases require any serious intervention, and in the UK, no one has died. Most children experience vomiting, diarrhoea, abdominal pain, jaundice and pale stools as a result of hepatitis.

WHO offered a handful of ways to help keep children safe while cases continue to spread. These include practising good hygiene, avoiding crowded spaces, ensuring good ventilation, using safe water for drinking, following safe food handling practices and regularly cleaning surfaces you often touch with your hands.

“There are a lot of questions,” Cohen concluded. “Right now, we just don’t have enough information.”

Meanwhile, the US Food and Drug Administration (FDA) are investigating the link between a hepatitis outbreak in 17 children in the US and Canada and organic strawberries sold under the FreshKampo and HEB brands.

Image Credits: National Institutes of Health , World Health Organization, Maccabi Health Services, PIXNIO.