Q&A: Understanding pediatric hepatitis cases linked to adenovirus

The CDC on Friday announced that it was investigating 109 cases of severe, acute hepatitis with an unknown cause among children in 25 states. The cases have resulted in five deaths.

Adenovirus infection has been implicated — but not proven — as the cause of the unexplained illnesses, which have also been reported in Europe.

We spoke with Kevin Messacar, MD, PhD, a pediatric infectious disease physician and researcher at Children's Hospital Colorado and the University of Colorado School of Medicine, about the cases and other uncommon pediatric illnesses caused by infections, including acute flaccid myelitis (AFM).

Kevin Messacar

Healio: Like with AFM, a virus — in this case, adenovirus — has been implicated as a possible cause of the unusual hepatitis cases in children. How would an adenovirus cause hepatitis in a child?

Messacar: That's something still under investigation. The new observation of an unusual number of cases of unexplained hepatitis in children was first noted in the U.S. in Alabama, as well as in Europe and elsewhere. That initiated an investigation to confirm that an unusual increase was occurring and what were potential causes. They noted in Alabama that they were able to detect adenovirus DNA in the blood of several cases, which became the initial hypothesis, potentially associated with the increase in hepatitis cases. There still are many questions that are being investigated regarding the particular adenovirus implicated, adenovirus 41, that has been around and that we've known about as a cause of gastroenteritis for a long time, but that has not been previously associated with hepatitis. So, they're trying to understand better the association between that virus and the how it could lead to liver inflammation in the new hepatitis cases that have been reported.

Healio: As a pediatric infectious disease specialist, do these cases surprise you?

Messacar: Any time we see an increase in a particular disease associated with an infectious agent it merits further investigation as to what's occurring and why. This was very similar to what we saw back in 2014 with the cases of AFM that were associated with a circulating enterovirus at the time, enterovirus D68 (EV-D68). Although from the beginning we noted an association of the cases of paralysis that were occurring with the circulation of EV-D68, there were a lot of steps that we needed to take to carefully investigate the relationship between the pathogen and the disease. That process took time, and I think you're seeing that same process play out in real time with these cases of hepatitis. It requires careful collaboration between the clinicians who recognize the unusual new disease or increase in cases with epidemiologists and public health experts who help to create case definitions, get the word out to create awareness and conduct ongoing surveillance. Researchers can help investigate the pathophysiology of how the infectious agent potentially could be leading to new or increased disease presentations. So, any time we see an unusual signal, it spurs further investigation and collaboration between many different disciplines, which need to be done carefully and take time.

Healio: Is there enough evidence yet to say that the EV-D68 has been the cause of AFM cases in the U.S.?

Messacar: Over the past 8 years, the investigations into that association have built up enough data to suggest that the relationship is likely to be a causal one. There are a series of criteria, called the Bradford Hill criteria, that can be used to evaluate the strength of association between cause and effect, such as between EV-D68 and AFM, and we've previously published on the strong case to be made for a causal association there. This is based on everything from laboratory data and animal models to epidemiologic data from case-control studies and surveillance over time showing that during periods when EV-D68 was circulating AFM cases were peaking.

Healio: How does EV-D68 cause AFM in a child?

Messacar: The best data we have on pathogenesis come from the laboratory and animal models. We now know that EV-D68 can infect neurons in vitro in the laboratory. There are also animal models that show that EV-D68 can lead to AFM-like paralysis in neonatal mice. With these models, we can then investigate pathophysiology to see how the virus is affecting the nervous system by examining the brain and spinal cord. What researchers find in these mice is that the virus infects the spinal cord motor neurons that control limb movement, and that those neurons often go on to die after they're infected. So, the leading theory is that after infection with EV-D68, patients who go on to have the rare complication of paralysis have effects both from the virus infecting neurons in their spinal cord leading to those neurons dying, as well as inflammation from the immune response in that area. There's still ongoing research into the role of the direct viral effect itself vs. the inflammation due to the immune response to the virus being there. Those are the type of investigations that over time can help us to better understand the relationship between pathogen and disease and inform the development of therapeutics to try to prevent or stop that disease process.

Healio: Did anti-COVID-19 measures affect the prevalence of AFM in 2020?

Messacar: That is the leading theory. There were clear epidemiologic patterns from 2014 to 2018, where we saw the circulation of EV-D68 and AFM peak during enterovirus season in the summer to fall of even years. So, we would have expected to see the next outbreak in 2020, which as we all know, was in the midst of the COVID-19 pandemic, at a time in which there were many public health measures in place. These measures to prevent the spread of COVID-19 would also be expected to prevent the spread of other respiratory pathogens, such as influenza, respiratory syncytial virus, and likely EV-D68. Along with the absence of significant EV-D68 circulation, we fortunately have not seen significant a major spike of AFM cases since 2018.

Healio: Are you expecting another even-numbered-year surge in 2022?

Messacar: The leading epidemiologic models for EV-D68 suggest that circulation patterns are driven by the growth of a susceptible population. There needs to be enough nonimmune children around who haven't yet seen the virus and are susceptible to infection for the virus to circulate again. So, that modeling theory suggests that since we haven't seen EV-D68 in a significant way since 2018, there are 4 years of potentially susceptible children who could lead to a potentially larger wave of EV-D68 and AFM the next time it circulates. But I think one thing that COVID-19 has taught us is that prediction of emerging infectious diseases is very difficult. It's potentially even more difficult when the epidemiologic patterns have been thrown off, like with a virus like EV-D68 that hasn't circulated in a significant way since 2018. So instead of trying and failing at prediction, I think we should be in the preparation business. We should be preparing at the public health level to make clinicians aware of the proper way to recognize, diagnose and report AFM cases and spread education about best practices to support, manage and treat those affected patients. Although we can't predict for certain what's going to happen in 2022 or beyond, we can prepare for the potential for another outbreak of EV-D68 and AFM.

Healio: Are there any other examples of common viruses that can cause uncommon and serious conditions in children?

Messacar: The paradigm of common infections leading to uncommon serious complications is actually more the rule than the exception with pediatric infectious diseases. Most infectious pathogens infect many more children with mild or no symptoms than have severe disease. For example, poliovirus, which is notorious for causing poliomyelitis, infects 200 to 500 people for every one that goes on to become paralyzed. Common viruses, like influenza, cause milder flu-like symptoms in some, but we also see children every year in our ICU with respiratory failure on ventilators or with neurologic disease, severe complications from what's often thought to be just the common flu. So, when we think about infectious diseases, particularly in children, many more are exposed and infected than go on to have severe disease. That to me is one of the most interesting — and for most diseases — one of the most unanswered questions: if so many people get infected with the same virus, why do those select few go on to have that severe presentation? Is it something about the host, their genetics or their immune response? Is it something about their environment or exposures? Is it something about the particular strain of that pathogen, the dose or route of infection? These are questions we still can’t answer for many common infectious diseases that have been around for a long time.

Healio: What lessons have you learned from your experience investigating EV-D68 and AFM that could inform the response to the hepatitis investigation?

With a new infectious disease outbreak investigation, the initial reaction tends to fall to two extremes: either a rush to try to push out answers prematurely or alternatively labeling it a mystery illness that we know nothing about. But there is an entire field of epidemiology dedicated to the methodic, systematic investigation of causality, which is how we ultimately get to the bottom of what is causing the new disease. There can be a leading theory or working hypothesis being actively pursued, while still remaining open minded and conducting open-ended investigations into alternative explanations or contributing factors. Sometimes new pathogens create new paradigms, and sometimes old pathogens break old paradigms by behaving in new ways or by emerging in different circumstances.  Ultimately, it is science, and the collaborative efforts of dedicated clinicians, researchers, epidemiologists and public health professionals working together in a deliberative manner that provides the answers that advance the field. Instead of jumping to conclusions or throwing our arms up with futility, we need to trust science, to trust the process and to trust the experts involved in investigating this outbreak.