Hepatitis cases of unknown origin raise concerns

More than 11 countries around the world, including the US, UK, Spain, Israel, Denmark, Norway and France among other countries, have reported acute, severe hepatitis of unknown origin. The cases are aged 1 month to 16 years old, with 17 children (approximately 10%) requiring liver transplantation; and at least one death reported, according to the World Health Organisation (WHO).

“The clinical syndrome among identified cases is acute hepatitis (liver inflammation) with markedly elevated liver enzymes. Many cases reported gastrointestinal symptoms including abdominal pain, diarrhoea and vomiting preceding presentation with severe acute hepatitis, and increased levels of liver enzymes (aspartate transaminase (AST) or alanine aminotransaminase (ALT) greater the 500 IU/L) and jaundice,” said the WHO in a statement.

Co-infections

“Most cases did not have a fever. The common viruses that cause acute viral hepatitis (hepatitis viruses A, B, C, D and E) have not been detected in any of these cases. International travel or links to other countries based on the currently available information have not been identified as factors.

“Adenovirus has been detected in at least 74 cases, and of the number of cases with information on molecular testing, 18 have been identified as F type 41. SARS-CoV-2 was identified in 20 cases of those that were tested. Furthermore, 19 were detected with a SARS-CoV-2 and adenovirus co-infection.”

While adenovirus is currently one hypothesis as the underlying cause, it does not fully explain the severity of the clinical picture, said WHO in a statement.

“Infection with adenovirus type 41, the implicated adenovirus type, has not previously been linked to such a clinical presentation. Adenoviruses are common pathogens that usually cause self-limited infections. They spread from person-to-person and most commonly cause respiratory illness, but depending on the type, can also cause other illnesses such as gastroenteritis (inflammation of the stomach or intestines), conjunctivitis (pink eye), and cystitis (bladder infection).”

Adenovirus Type 41

“There are more than 50 types of immunologically distinct adenoviruses that can cause infections in humans. Adenovirus type 41 typically presents as diarrhea, vomiting, and fever, often accompanied by respiratory symptoms. While there have been case reports of hepatitis in immunocompromised children with adenovirus infection, adenovirus type 41 is not known to be a cause of hepatitis in otherwise healthy children.

“Factors such as increased susceptibility amongst young children following a lower level of circulation of adenovirus during the COVID-19 pandemic, the potential emergence of a novel adenovirus, as well as SARS-CoV-2 co-infection, need to be further investigated. Hypotheses related to side effects from the COVID-19 vaccines are currently not supported as the vast majority of affected children did not receive COVID-19 vaccination. Other infectious and non-infectious explanations need to be excluded to fully assess and manage the risk.”

Peter White, Professor in Microbiology and Molecular Biology at the University of New South Wales, said viruses such as herpes and even measles can cause hepatitis, but the five main human hepatitis viruses — A, B, C, D and E — are well known, and well characterised.

“So if we get a hepatitis-causing virus that is not one of those, then that’s something new that we haven’t seen for 30 years.

“The likely candidate — F41 type of adenovirus — is known for causing gastroenteritis in children,” White said. “It also causes eye infections for type B viruses. It causes about 10–15% of global respiratory infections which we would call the ‘common cold’, mainly in kids, and about 5% of gastroenteritis cases in Sydney.”

Genome sequencing

“It is a big DNA virus that is capable of causing both gastrointestinal and respiratory illnesses. There are about 113 different types of adenoviruses, but F41 and a few of the others are well known to cause gastro.

“Now, having said that, they are very clever DNA viruses and capable of infecting different organs. For example, if you get cold-like symptoms from an adenovirus you may also get gastro a few days later, or if you get gastro from F41 adenovirus you will sometimes also get respiratory symptoms. Because it has the weaponry to infect more than one organ.

“The liver is really like the helper of the gastrointestinal system, so if the virus is now capable of infecting the liver, that would not be a surprise to me or any other virologist.

“If this virus now infects liver cells, that would indicate a tropism change, and I would say this suggests something must have changed with the virus.

“In Australia, the F41 type causes around 70% of the adenovirus gastro that we see clinically, and it normally only results in a mild gastro in the kids.

“I’d be looking at sequencing the whole virus to get the full genome. That is probably what is rapidly taking place now, sequencing to look for recombination or mutation that enables this change to allow it to affect the liver cells.”

Professor Andrew Lloyd, infectious diseases physician and hepatitis researcher, at the Kirby Institute at the University of New South Wales, said, “It is not yet possible to confidently advise on protective measures, but adenovirus 41 is spread by what is called faecal-oral transmission and is controlled by handwashing after going to the toilet and use of disinfectants to clean surfaces.”

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