At least 180 cases of severe hepatitis in children reported from 36 states and territories are under investigation to see whether they are connected with the outbreak of recent months, the Centers for Disease Control and Prevention (CDC) has said.

This number, last updated on May 18, is up significantly from May 5, when 109 cases were reported, but part of the rise is because the CDC is also looking at older cases of liver damage in children as it investigates the possible link to adenovirus 41.

"Since CDC’s investigation looks at patients reported back to October of 2021, most of these numbers involve patients that are just now being reported, rather than new cases of hepatitis," the CDC said in a statement. "So not all are recent, and some may ultimately wind up not being linked to this current investigation."

The number of child patients with severe liver damage requiring liver transplants has gone down since their last update on May 5, from 15 percent to 9 percent, while the total number of deaths attributed to the condition remains at six.

The CDC is continuing to test for potential causes of the liver inflammation, including hepatitis viruses A, B, C, D, and E. However, as with other investigations taking place around the world, adenovirus 41 is considered a "strong lead". 

"Further laboratory tests are being conducted to look more closely at the virus genome and other potential pathogens, such as SARS-CoV-2," the CDC added. They are not the first to suspect a possible link with COVID-19, with experts writing in The Lancet of a possible link between the virus and the liver damage seen in recent months.

In April, a likely culprit emerged: adenovirus type 41, which was found in 75 percent of children tested, according to one study. Sixteen percent also tested positive for COVID-19, though the UK Health Security Agency stressed that COVID-19 was prevalent during the time of admission, so this was not unexpected.

However, as Professor Will Irving of the University of Nottingham explained in April, this still leaves the puzzle as to why the adenovirus could be causing liver damage when it hadn't done previously.

 "The link with adenovirus infection remains tantalising – a definite possibility but not yet proven," Irving said. "There are very few case reports in the global literature of adenovirus infection being associated with hepatitis in immunocompetent children (or adults) – so if it transpires that adenoviral infection is involved in causing this disease outbreak, there will be a need to explain why the natural history of adenovirus infection has changed so dramatically in 2022."

The correspondence piece published in The Lancet suggested a possible answer: previous COVID-19 infection, lurking in the intestines. "SARS-CoV-2 viral persistence in the gastrointestinal tract can lead to repeated release of viral proteins across the intestinal epithelium, giving rise to immune activation," the team wrote.

They explain that when the immune system is also met with adenovirus infection, this could trigger an over-reaction to the infection, releasing large amounts of inflammatory proteins and inflaming the liver.

"We hypothesise that the recently reported cases of severe acute hepatitis in children could be a consequence of adenovirus infection with intestinal trophism in children previously infected by SARS-CoV-2 and carrying viral reservoirs," they posit.

"We suggest that children with acute hepatitis be investigated for SARS-CoV-2 persistence in stool, T-cell receptor skewing, and IFN-γ upregulation, because this could provide evidence of a SARS-CoV-2 superantigen mechanism in an adenovirus-41F-sensitised host."

The CDC stress that severe hepatitis in children remains rare, but encourages parents and carers to be aware of the signs of the disease, especially jaundice (the yellowing of the skin and eyes).