Behind the scenes of the pediatric acute hepatitis outbreak investigation
Today I’m sharing an interview with CDC epidemiologists Dr. Julia Baker and Dr. Jordan Cates on an outbreak of pediatric acute hepatitis of unknown cause (unexplained liver disease in children, to put it more plainly) that was in the news this time last year. I wanted to follow up with the CDC team for the latest developments in this epidemiological mystery. I’ll be back in your inbox later in the week with an update on what’s going around.
Caitlin: How did the pediatric acute hepatitis outbreak come to your attention?
Dr. Julia Baker: Back in October-November of 2021 a handful of astute clinicians at a single Alabama hospital identified five children with hepatitis of unknown cause.
Taking a step back for a moment: hepatitis is inflammation of the liver, and generally severe hepatitis is pretty rare in children, notably. There are not a lot of potential causes of hepatitis, but it’s not unusual for the cause to be unknown; this occurs in about 30-50% of cases. But for the children in Alabama, the more common causes of hepatitis had been ruled out, and they caught the attention of clinicians because of a couple of things. One was the timing: all five of these cases occurred within a couple of months. Next was the status of the children: all of them had been previously healthy and didn't have any significant underlying medical conditions. And then, lastly, all five of these children tested positive for adenovirus in blood specimens.
Adenovirus is a very common virus that typically causes cold- or flu-like respiratory illness, or sometimes gastrointestinal illness, but it wasn’t really known to cause hepatitis in healthy children. So, over the next couple of months the clinicians really did monitoring and reviewing of hospital records to identify anyone else who may show up with those same symptoms. And essentially, they found four additional patients over the next couple of months. Again, all of these children had hepatitis and adenovirus infection.
So then, by February of 2022 the Alabama Department of Public Health put out a statewide call to find additional potential cases in the state, but none had been identified. And then, just a couple of months later, in April of 2022, the UK Health Security Agency reported an increase in cases of hepatitis of unknown cause among children there, and this additional information from the UK basically gave us momentum for the investigation here in the U.S. Within a couple of weeks, CDC issued a nationwide notice, requesting that clinicians report any potential cases to the State and Local Health Departments. And this call for cases went back to October when those first Alabama cases had been identified.
Since then, CDC’s been collaborating really closely with jurisdictional health departments across the US to compile information on these children.
Caitlin Rivers: So, you have concerning news first from astute clinicians, and then from the Alabama Department of Health that something is amiss. What did that set in motion?
Julia Baker: One of the first things we wanted to do was really put these cases into context. So, we wanted to know, are we seeing an increase in pediatric hepatitis of unknown cause? To evaluate this, we looked at a couple of different things. So, first we examined trends in acute hepatitis of unspecified etiology [this means unknown cause] in children and we did this using ED visits and hospitalizations with hepatitis-associated diagnoses, and then we also looked at liver transplants. We compared recent data, which at the time was October 2021 through March 2022 to pre-Covid pandemic baseline levels. And essentially, we did not see an increase in pediatric hepatitis cases. So, that was reassuring.
But given the association we had identified in the Alabama cases with adenovirus, our next several questions were around adenovirus, of course. So, one of the first things we wanted to evaluate was whether or not we are seeing more adenovirus infections from children than usual. So, again we looked at trend data. We looked at adenovirus 40 and 41, which is an enteric adenovirus and that we had seen in a few of these Alabama cases. So, we looked at testing and positivity trends, and again didn’t see an increase above these pre-Covid-19 pandemic baseline levels. So, then we wondered, well, maybe there’s something unique about [the] adenovirus that’s circulating right now. Could this be an unusual strain? And so, working with some collaborators, we did some additional lab testing on a subset of children basically looking at the genetic sequencing of a key part of the viral structure to see if it had changed in some way. And essentially what we found is that the adenovirus that these children were infected with was not new. It wasn’t different than those that that had been circulating or causing infection for many years. So, this suggested to us that this was not an outbreak driven by a single novel strain.
And then, lastly, we sort of wondered what the potential etiologic role could be for adenovirus, if it is indeed causing these illnesses. And so again, in a subset of children, we had liver tissue specimens collected during their clinical care, and those were ultimately submitted to CDC for some further evaluation. And findings from these evaluations were generally non-specific, so we didn’t see the typical features of classic adenoviral hepatitis that we might expect if the adenovirus was directly impacting the liver. So, while a lot of a number of these children have tested positive for adenovirus over the course of the investigation, we don’t yet know if it’s really the positive agent here.
And we’re continuing to evaluate this, as we collect more information. We also have a number of questions that go beyond adenovirus, of course, and thinking about what other factors might be contributing here – potentially other pathogens or co-infections.
Dr. Jordan Cates: This investigation had many different parts to it; it was quite complex. One of the big parts was doing medical chart abstraction: looking at the medical reports from the children and gathering data on their clinical illness. This was led by the Health Departments in really close collaboration with the clinicians that were helping treat the children and also obtaining a lot of laboratory data. So, the health alert [issued by the CDC] recommended testing for adenovirus, but these children also were potentially tested for other different pathogens based on the clinicians’ discretion on the clinical course and the illness of the child. So, we really wanted to get all of that really rich clinical data to better inform what was going on.
But then another key component was that Health Departments also led interviews, conducting interviews with the parents. It was really important to have that personal contact with the parents to get better context about what exposures the child may have had to various products, medications, asking about whether there were environmental factors, or also asking about history of other illnesses that may not have been appropriately captured in the medical records. For example, when a child has COVID-19 illness they may not always have medical care, and it may not always be in the medical record, so it’s really beneficial to have those interviews with the parents.
So, we’ve been looking at all of that data over the past year plus, and from the interviews we have found that there’s no kind of common epidemiologic links, no common exposures. We looked at history of COVID-19 illness, and there are some reports of COVID-19 history of illness, but no major signals there.
Caitlin: There’s dozens of serotypes of adenovirus and we don’t routinely test for them. So, I’m wondering if you felt like you had the surveillance data to do the kind of comparison that you might want?
Julia Baker: Adenovirus is not reportable [to public health authorities] and so some of the existing data was definitely limited. But some of the evidence from the cases that we did get sort of early on in the investigation suggested that adenovirus 41 might be a player here, so that’s one that we ended up focusing on. But I would say that we have been doing typing of adenovirus specimens that have been sent to CDC to see what types of adenovirus are more common.
Jordan Cates: We were able to look at trends of adenovirus in the last year compared to pre-pandemic baselines and that was because of key collaborations with laboratory partners that do collect laboratory testing of adenovirus. And in particular, we were able to look at enteric adenoviruses, so that type 41 that Julie was mentioning that we had some preliminary insight that it might be a key player here. That was a great resource that we were able to capitalize on, even if it wasn’t kind of the traditional surveillance that you might expect for a pathogen.
Caitlin Rivers: And what's the current status of the outbreak?
Jordan Cates: It’s still an ongoing investigation. We continue to have cases reported by clinicians to the Health Departments, and then to CDC. So, we’re continuing to look into better understanding what maybe one of the driving factors of the hepatitis of unknown cause in these children. As Julia mentioned earlier, adenovirus has been the most commonly detected pathogen, but some of the liver pathology findings in general suggest that we’re not seeing the direct effect of the pathogen on the liver. So, still a lot to be explored and understood about the role of adenovirus, either alone or in conjunction potentially with other co-infections or co-factors.
Caitlin Rivers: Lastly, can you address any myths that this could be related to the COVID-19 vaccine?
Julia Baker: This is something that we paid close attention to, especially given the timing of this outbreak with the COVID-19 pandemic. Most of the children were around 2 years of age at the time of their illness, so most of them were not age-eligible to receive the COVID-19 vaccine when they became ill. Given that, we are quite confident that COVID-19 vaccination is not the cause of illness here.