Adenovirus? COVID? Both? The disease seems to have come out of nowhere.

Late last week, the CDC released a Health Alert Network advisory regarding a cluster of 9 cases of acute hepatitis in children in Alabama over a 5 month period from October 2021 to February 2022 – a rate substantially higher than what would be expected given the relative rarity of hepatitis in children.

Standard workup was negative for the common causative agents – hepatitis A, B, and C – and no toxic exposures were identified. But there was one common thread among all these kids. They all tested positive for adenovirus.

And that is really strange.

There are about 100 circulating adenoviruses in the world that we know of, and around 50 of them infect humans. If you are an adult, it’s a virtual certainty that you have been infected with an adenovirus in the past. Most strains cause symptoms we would describe as the common cold – runny nose, sore throat. Some strains cause conjunctivitis – pink eye. Some cause gastrointestinal illness – stomach bugs that kids get.

It's the banality of adenovirus that makes this hepatitis finding so surprising.

The US is not alone in reporting this new hepatitis syndrome. As of April 21st, 169 cases have been reported across the world including 114 in the United Kingdom.

Of the 169 cases reported worldwide, 74 had evidence of adenovirus infection. On molecular testing, 18 of those were adenovirus 41.

What I wanted to do today was go through the various hypotheses for what could be going on with these hepatitis cases, one by one, and highlight the evidence supporting them. We won’t reach a conclusion, but hopefully by the end the path forward will be more clear.  OK, let’s get started. 

Hypothesis #1: Nothing is happening.

It’s worth noting that “clusters” of disease occur all the time, even when no relevant epidemiologic process has occurred. If there is some baseline rate of hepatitis, every once in a while, through bad luck alone, you’d see a group of cases all at once. This is known as the “clustering illusion”. And I’m quite confident to say this is not the case here.

For one, this phenomenon is worldwide as we know from the WHO report. In fact, the CDC didn’t provide the most detailed data about the 9 (now 12) cases in the US. This study, from Scotland, is the first to give a detailed accounting of cases, reporting on 13 cases of acute hepatitis of unknown cause in kids at a single hospital from January to April. Typically, the hospital sees less than 4 cases of hepatitis per year. Five of these 13 kids tested positive for adenovirus. So let’s take the clustering illusion off the list.

Hypothesis #2: It’s the adenovirus.

The major evidence supporting adenovirus as the causative agent here is that a lot of these kids had adenovirus, and adenovirus 41 – a gut-tropic strain – in particular. This is important, since stool testing might be necessary for diagnosis and lots of kids with this condition didn’t get that. In other words, we have hard evidence of adenovirus infection in about 40% of the cases so far, but the true number might be substantially higher.

That said, adenovirus is seasonal, and we are in adenovirus season. Granted, 40% seems quite a bit higher than the background infection rate, but we have to be careful not to assume correlation means causation.

The evidence against adenovirus, even adenovirus 41, is that this acute hepatitis syndrome is new, and adenovirus 41 is not. To be fair, we know adenoviruses can cause acute hepatitis, but the vast majority of reports are in immunocompromised individuals – organ transplant recipients and those with HIV. I was able to find just a handful of cases of immunocompetent kids developing hepatitis from adenovirus prior to this current outbreak.

The current outbreak would exceed the published literature by nearly two orders of magnitude. It feels like something else has to be going on.

Hypothesis #3: It’s the coronavirus.

SARS-CoV-2 is a strange virus, both in its acute presentation and its long term outcomes. It was clear early in the pandemic that some children infected by the coronavirus would develop MISC-C, multisystem inflammatory condition of children. MIS-C is associated with hepatitis – in about 10% of children according to this New England Journal cohort.

But the presentation of these kids is quite different from MIS-C – fever is rare for example. The WHO reports that of the 169 identified cases so far, 20 had active COVID infection. The Scotland cohort suggests that a similar proportion had past COVID infections. In other times, we might consider this a smoking gun, but at this point a history of COVID is not remarkable – after the Omicron wave it’s about as common to have a history of COVID as it is not to have a history of COVID.

A brief aside here. It’s not the vaccine. I’m not even labeling that one as a hypothesis, as all the kids in the initial UK report were unvaccinated.

Which brings us to

Hypothesis #4: It’s coronavirus AND adenovirus.

This is sort of intriguing and can work a few different ways, via a direct and indirect path.

In the direct path, we posit that COVID infection does something to kids’ immune systems – something we don’t yet understand, that limits their ability to fight off adenovirus. There is some support for this idea.  This study in Immunity found that COVID infection can functionally impair dendritic cells and T-cells, including natural killer cells. These cells are important components of our innate antiviral immunity.

There’s an indirect path as well. COVID has led to lockdowns, distancing, masking – stuff that prevents kids from being exposed to germs from other kids. Could a lack of exposure to adenovirus or other viruses due to distancing increase the risk of severe disease when restrictions are lifted? Also possible – the severity of RSV infections this year is substantially higher than what we’ve seen in the past for example.

And finally, hypothesis #5: This is something new.

We can’t ignore the possibility that this is simply a new disease-causing agent. Toxicology studies so far have been negative, and we wouldn’t expect hepatitis due to a chemical toxin to appear in multiple countries around the world – this is almost certainly a biological phenomenon. It is possible that this is a new strain of adenovirus 41, or that adenovirus is a red-herring altogether. Remember – we knew about “non-A / non-B viral hepatitis” for more than two decades before hepatitis C was discovered.

The pace of science is faster now, fortunately, and information is coming out quickly. As we learn more, we’ll share it with you right here.

A version of this commentary first appeared on Medscape.com.