Puzzling pediatric hepatitis cases echo an earlier mysterious illness

In early April, when word began to circulate that hospitals in the United Kingdom were seeing unexplained hepatitis cases in very young children, some physicians and researchers on this side of the Atlantic experienced a moment of déjà vu.

Kevin Messacar and colleagues at Children’s Hospital Colorado found themselves remarking on how reminiscent the unfolding investigation was of a medical mystery they’ve been enmeshed in for the past eight years — acute flaccid myelitis, or AFM, a polio-like condition in children.

Meanwhile, Carlos Pardo, the co-principal investigator of a National Institutes of Health study into the natural history of AFM, started fielding queries from hepatologists at Johns Hopkins Medicine, where he teaches, about what kinds of samples they should be collecting from suspected hepatitis cases.

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“There are many parallels between this initial investigation of these cases of hepatitis of unknown origin and our initial investigations of AFM cases,” Messacar, a pediatric infectious disease physician and an associate professor at the University of Colorado, told STAT.

As public health agencies race to figure out what is behind the unusual hepatitis cases, Messacar, Pardo, and others believe there are lessons to be learned from the ongoing efforts to solve the mysteries of AFM.

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Chief among them is that getting to satisfactory answers is likely going to take time. There may be an answer to the fundamental question of what is causing these illnesses. But the whys and the how — Why now? Why only some children? Why these children? How is the damage being done? — may take considerably longer to resolve.

“I think it could be a very difficult nut to crack,” said Michael Osterholm, director of the University of Minnesota’s Center for Infectious Diseases Research and Policy.

Finding a probable culprit can sometimes happen fairly quickly when something new pops up in the infectious diseases sphere, said Thomas Clark, deputy director of the division of viral diseases at the Centers for Disease Control and Prevention. Clark was the CDC’s incident manager for the AFM investigation in 2018-2019.

Such was the case when scientists started investigating AFM, which first pinged on the medical world’s radar in 2012, after California reported a few cases of unexplained paralysis among children. Suspicion soon focused on EV-D68, a member of the enterovirus family that is now generally assumed to be the primary cause of AFM. (Another enterovirus, A71, is also thought to trigger the condition in some cases.)

AFM cases occur in very low numbers year round, but have been seen to cluster in every-other-year surges that occurred in 2014, 2016, and 2018. Where in an odd year there may be two or three dozen cases, there were 153 cases and 239 cases in 2016 and 2018, respectively. (Like many other viral illnesses, AFM has been driven to very low levels during the first two years of the Covid-19 pandemic, with an expected spike of cases failing to materialize in 2020.)

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Settling on a suspect seems to have happened even faster with the unexplained cases of pediatric hepatitis, with many researchers hypothesizing that an adenovirus might be to blame.

In the cases, previously healthy children, many under the age of 5, develop severe liver inflammation. Some — about 14% of the cases reported so far in the United States and 10% of those reported in the U.K. — have required liver transplants and a few children have died.

The first observed cases occurred last October in Alabama, where five of the state’s eventual nine cases tested positive for an adenovirus. Like enteroviruses, the adenovirus family is large, encompassing about 50 types that infect people. Most cause cold-like illnesses, but a couple are known to infect the gastrointestinal tract. The one spotted by the Alabama physicians was one of the latter, type 41.

A substantial portion — though not all — of the roughly 450 cases reported worldwide at this point have tested positive for adenovirus, and in the U.K., more in-depth testing has revealed at least some of those were adenovirus type 41.

It remains unclear if this is an incidental finding unrelated to the hepatitis, or if the virus is causing the condition. Investigators are also exploring the question of whether there is some other contributing factor, such as the possibility that two years of pandemic-induced masking and social distancing may have left children’s immune systems inexperienced in fighting off an infection like this one. Another theory is that current or prior Covid-19 infection is amplifying the illness induced by adenovirus infection.

As of yet, testing of liver biopsies taken from a number of the suspected cases and from failed livers that were removed from the children who needed transplants has not shown signs of adenovirus infection.

Fingering a culprit, though, is only the first step in getting to the bottom of why a small but unusual number of very young children are ending up in hospital with their livers under attack.

“It is often true, I guess, that the most commonly implicated virus or the one that’s putatively identified ends up explaining the illness,” said the CDC’s Clark. “But the mechanisms and the why are the challenge to figure out.”

Scientists are still working to explain why EV-D68 causes paralysis as well as why it only does so in a tiny fraction of the children it infects.

With rare conditions, it’s often not clear why one child is infected without harm while another battles severe disease. Despite decades of research into polio, it’s not known why the viruses that cause it spare 199 children they infect on average, but cripple one. Scientists have been studying AFM for eight or so years and can’t answer the why question either. As for pediatric hepatitis cases, Clark said flatly: “We might never know why.”

A particularly perplexing part of the puzzle is the fact that, as was true with EV-D68, adenovirus type 41 is a known pathogen that is acting in a previously unobserved way, assuming it’s the culprit. EV-D68 and adenovirus 41 are not new bugs, but this behavior is — or at least it is happening at a scale not seen hitherto.

With adenovirus 41, research efforts are underway to try to determine if the virus has changed genetically in ways that might make it more virulent. British scientists have managed to genetically sequence copies of the virus and are studying them for clues.

Another similarity between the outbreaks — and a lesson the hepatitis investigation should learn from the one into AFM — is the need to establish which biological samples should be collected from suspected cases and how and when those samples should be taken.

“Anytime you are dealing with viruses, you need to think about what samples you are taking, what conditions, and what is the timing,” said Pardo, who is a professor of neurology and pathology at Johns Hopkins.

Already, it’s clear that discrepancies in the samples taken from the various pediatric hepatitis cases may be preventing the picture from coming into clear focus.

In a report on the investigation published earlier this month, the U.K. Health Security Agency noted that it isn’t possible to conclude that suspected cases who tested negative for adenovirus were true negatives, because testing was not done using whole blood samples, the best way to detect the viruses. “It is therefore not possible to definitively rule out adenovirus in these cases,” the report said.

An update on the situation issued on Friday by the European Centre for Disease Prevention and Control and the World Health Organization’s European office shows how hard it is to gauge what’s going on when different places are collecting different bits of information and running a raft of different tests.

The agencies said that as of May 13, European countries had reported 232 possible cases. But only 151 of them had been tested for adenoviruses and some of the testing was done on fecal, plasma, or serum samples, not whole blood.

Marion Koopmans, head of the department of viroscience at Erasmus Medical Center in Rotterdam, the Netherlands, expressed frustration at the state of the available data.

“It’s the same story all over again. It is!” Koopmans said. “With an unexplained disease syndrome, what you would want is a protocol that people could use. If you see this type of disease profile, this is what I always collect — in terms of clinical data, and samples — and this is what I can always rule out. Because it is indeed so patchy and non-standardized, it is very difficult to know what is even part of the syndrome.”

Collecting the right samples, at the right time, is critical. It’s like looking for a robber at the scene of a crime. If the police arrive promptly, the culprit may be caught in the act. If they’re delayed, they’ll find the aftermath of the break-in — or the damage wrought by the infection — but the perpetrator will be gone.

“If you wait too long, you are losing that opportunity,” Pardo said, adding that to find adenovirus, testing needs to be done in the first week of symptoms. The same is true for the timing of sample collection in AFM case investigations. “If you wait one week and you take a nasal swab, you are losing the opportunity already.”

Something that has complicated the study of AFM may do the same for the efforts to solve the mysteries of these unusual pediatric hepatitis cases. Viruses typically circulate at specific times of the year, with peaks of transmission in the winter for influenza, say, and the late summer and early fall for EV-D68. But the patterns of viruses that aren’t thought to pose much of a threat to human health — viruses like adenovirus 41 — are often not well-tracked.

And virus circulation can be cyclical, with low levels some years and more transmission in other years, after there has been a buildup of susceptible children. Before measles vaccination become commonplace, there were epidemics — explosions of cases — every two to three years, with fewer infections in between. From 2012 to 2018, it appeared AFM worked on a two-year cycle. It may turn out that adenovirus 41 is responsible for these unusual hepatitis cases, but it remains to be seen if it will do so annually, biennially, or sporadically.

Messacar said his group in Colorado saw one of the first clusters of AFM cases in 2014 and continued to study the phenomenon, even when it appeared to have gone away in 2015. It will be critical to do the same with pediatric hepatitis of unknown origin, he said.

“It’s really important to continue to follow these initial outbreaks or leads, because you never know what pattern it’s going to take or when it’s going to come back,” he said.

It’s also important not to jump to premature conclusions, Messacar said.

“You have to follow the data wherever it leads. And for us, that’s been an eight-plus-year story of getting to the bottom of AFM,” he said. “You can do everything you can to prepare to collect the best data you can, to do the best analysis you can, to develop the best tools you can to combat the diseases that we study. But science takes time. And I think you’re seeing that with the hepatitis outbreak. I think you saw that with AFM.”

Source: STAT