Virus World

Finding a probable culprit can sometimes happen fairly quickly when something new pops up in the infectious diseases sphere. But that doesn't mean the end of the mystery. I n 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.  “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.

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.)

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.....

Carter Roberts’ motorized wheelchair didn’t arrive until the day he died. It had been a long time coming and his parents had fought hard to get it. The chair cost more than $32,000 and the insurance companies wouldn’t cover it, so the family went to court. One insurer eventually agreed to pay for some components of the chair but not the whole thing. And then none of it mattered anyway. On Sept. 22, 2018, the Roberts’ doorbell rang and the chair was delivered. Also on Sept. 22, 2018, Carter died, just three months shy of his sixth birthday. He had been largely paralyzed for the final two years of his life. The family is only now beginning to pick their way through the horror of what happened. “Our eight-year-old daughter believes she can speak to him,” says Carter’s mother Robin. “She was playing video games the other day and she’s looking up and going, ‘Carter are you seeing this? I need your help.’”

By any measure, the Roberts family of Richmond, Va. was spectacularly unlucky. They lost their son to a disease that science first recognized only in 2012. It’s new enough that it didn’t even have a formally accepted name until 2014. When it got one, it was one of those names that is more or less just a clinical description of what the disease is: acute flaccid myelitis (AFM), a sudden inflammation of spinal tissue resulting in flaccid paralysis of the muscles of the limbs, neck, face and often diaphragm. It’s a lot like polio but it’s not polio; it’s a little like meningitis and Guillain-Barré syndrome but it’s not them either. Indeed, no one knows exactly what it is. For the moment it remains rare: In the U.S., where AFM is closely tracked, the disease attacks fewer than one in a million people even in peak years, and it very rarely kills. But in the past seven years, it’s been striking more and killing more, and there is a tick-tock certainty to when it will hit next. As with polio, AFM is seasonal—though unlike polio, it arrives in late summer and early to mid fall, rather than in the spring and summer. Also unlike polio, it runs in an every-other-year cycle, peaking in even-numbered years.

While spotty outbreaks of AFM have been retrospectively diagnosed in the U.S. from 2005 to 2012, it was in 2014 that the disease established its current pattern. That year, there were 120 confirmed cases scattered around the country; in 2015, the total fell to 22 cases; it climbed again in 2016 to 149 cases; fell again in 2017 to 35 cases and jumped back up last year to 201 cases. So far in 2019, there have been 20 cases of AFM in nine states. Now, as an even-numbered year inevitably approaches, there is a growing feeling of looming menace. When 2020 arrives—and then 2022 and 2024 and on into the future—more and more children are destined to be claimed, unless science gets a handle on the disease fast. “This is our generation’s polio,” Carter’s mother, Robin Roberts says flatly.

That’s not just the opinion of a grieving mother; doctors admit to feeling daunted too. “I can’t think of a single disease that had this pattern that we’re seeing, with modern laboratory diagnostics not figuring it out,” says Dr. Nancy Messonnier, director of the CDC’s National Center for Immunization and Respiratory Diseases.....