Severe acute hepatitis in children still does not have a definitive cause

Clusters of unexplained acute hepatitis among children have declined from their peak in early summer, but a small number of cases are still being reported, and a singular definitive cause still has not been identified, according to a presentation this month at the AASLD Liver Meeting.

As previously reported, the cluster was first detected in the United Kingdom in the spring. By 21 April, at least 169 cases of acute hepatitis of unknown origin had been reported to the World Health Organization (WHO). Once health officials and clinicians knew what to look for, more cases were identified. By the time case numbers began to decline in July, more than 1010 probable cases had been reported in 35 countries, dating back to October 2021, according to WHO’s last update on the outbreak.

Multiple possible causes were proposed and dismissed, including well-known hepatitis viruses (the children tested negative for hepatitis A, B, C, D and E), current SARS-CoV-2 infection (most tested negative), COVID-19 vaccines (most were too young to be eligible) and exposure to dogs.

Other potential causes remained in play. Some suggested that previous SARS-CoV-2 infection might lead to residual liver damage, inflammation and impaired immune function even in children who no longer test positive. Some early evidence pointed to an adenovirus (in particular, adenovirus type 41). In July, research teams in England and in Scotland independently reported that a different virus, adeno-associated virus type 2 (AAV2), might be the cause, but it requires the help of another virus, which could be adenovirus 41 or something else.

In an attempt to learn more, researchers from around the world joined an international collaborative effort to characterise the clinical characteristics and outcomes of paediatric acute hepatitis cases.

As Dr Rohit Kohli of Children’s Hospital Los Angeles and colleagues reported, the Severe Hepatitis in Pediatric Patients international registry was created in July. Paediatric gastroenterologists around the world were invited to contribute and 25 sites responded, mostly in North America. Data were included to 28 October.

The registry included children under age 18 with an ALT level above 500 and no known chronic liver disease or ingestion of paracetamol, which can cause acute liver damage.

A total of 151 cases had been reported to the registry at the time of Kohli’s presentation. Cases peaked at around 20 in May and June, with 10 or fewer cases reported in July, August and September.

Most children were very young, with a median age of 41 months. Just over half were boys and 40% were Hispanic. At presentation, 80% reported gastrointestinal symptoms, followed by fever (27%) and respiratory symptoms (23%). Some 15% were taking medications for chronic conditions, including nearly 3% on immunosuppressant drugs. Fifteen children (10%) had SARS-CoV-2 infection during the past year, and 20 (13%) had received COVID-19 vaccines.

Diagnostic testing revealed a range of viruses, but none were present in a majority of the children. Just over 40% tested positive on a respiratory infection panel, with common cold viruses being most frequent. Furthermore, 22% tested positive for adenovirus, 13% for Epstein-Barr virus and 4% for cytomegalovirus. Kohli noted that there was “a lot of overlap with multiple positive viruses in many patients.”

Laboratory values, including ALT, AST and bilirubin, were elevated. Thirty-six children (24%) had evidence of autoimmune markers.

Sixty-three children (42%) received liver biopsies. Pathology descriptions emphasised portal and lobular inflammation with infiltration of CD8 T cells, according to Kohli. Three patients developed hemophagocytic lymphohistiocytosis, a build-up of white blood cells that can be triggered by viral infections. However, none of the biopsy samples showed a definitive viral cause of hepatitis.

More than a quarter of the children (27%) required treatment in an intensive care unit. Eight (5%) underwent liver transplantation. About a third (32%) received steroids, and this group was more likely to require transplantation. Kohli acknowledged that some other centres, such as King’s College Hospital in London, have reported a higher proportion of transplants, but they may be more likely to have severe cases referred to them.

Three of the children died. The good news, Kohli said, is that more than 90% survived with their original liver intact. Most of the recovered children at his centre returned to normal liver function, he noted, but the registry does not include long-term follow-up data.

In this large international dataset of paediatric patients, “the majority did not have a singular definitive etiology,” Kohli concluded. He added that continued community surveillance and close co-operation through the registry are critical to further investigate the indeterminate causes of hepatitis in children. “This is a call to arms to all of us,” he said.

These findings raise the question of how best to prevent and treat acute paediatric hepatitis. In response to an audience question about adenovirus vaccination, Kohli replied that this would be premature. “I’m not sure we can blame one virus at this point,” he said.

Nonetheless, some clinicians have attempted to treat adenovirus infection in children with acute hepatitis. In another presentation, Dr Sunitha Vimalesvaran of King's College Hospital reported on the safety and efficacy of cidofovir for this indication.

Among the 258 children with acute hepatitis tested for adenovirus in the UK, two thirds tested positive for adenovirus – much higher than the rate in the SHIPP registry.

Although there are no approved treatments for adenovirus infection, several drugs have been tried, including cidofovir, a broad-spectrum nucleotide analogue antiviral that is used to treat cytomegalovirus retinitis in people with AIDS. It was found to be active against all known types of human adenovirus in laboratory studies.

Nine children received cidofovir for acute hepatitis. The median age was approximately 3 years. They all tested positive for adenovirus. Most had evidence of prior SARS-CoV-2 infection, including two within six weeks prior to hepatitis presentation. Six received liver transplants

All patients were treated using the standard 5mg/kg dose of cidofovir once weekly for two weeks and then every two weeks. Four children experienced complete adenovirus clearance and four others had significant viral load reduction, Vimalesvaran reported. None of the liver transplants recipients experienced a recurrence of adenovirus-associated hepatitis in the new liver, despite immunosuppression.

The major side effect of cidofovir is kidney toxicity, and the patients also received probenecid, a medication that protects the kidneys, and other therapies to reduce adverse events. The liver transplant recipients received tacrolimus, which also causes kidney toxicity. Although all children had normal kidney function at presentation, five required kidney dialysis as part of acute liver failure management. Four children developed kidney dysfunction after the first or second dose of cidofovir, but all except one had normalised liver function at the time of hospital discharge.

“Whilst we continue to understand the precise aetiology and pathophysiology of this condition, interim use of cidofovir in children with acute liver failure and adenoviraemia appears to be safe, well-tolerated and effective in reducing adenoviraemia,” the researchers concluded.