In a year it was supposed to flare, polio-like syndrome in kids doesn’t, adding to mystery

Physicians who treat children who develop a strange polio-like syndrome known as acute flaccid myelitis had been steeling themselves this fall for an onslaught of cases of the irreversible condition, which appears to be triggered by infection with an enterovirus known as EV-D68.

Like many respiratory viruses, circulation of EV-D68 appeared to be suppressed by Covid-19 control measures earlier in the pandemic. But in late August and September hospitals in various parts of the country started admitting little kids with telltale signs of EV-D68 infection, which in the respiratory phase looks like a bad asthma attack in a child who doesn’t have asthma. Doctors who study AFM were convinced a heartbreaking influx of paralyzed children and petrified parents would soon follow; the Centers for Disease Control and Prevention sent out an alert in early September warning medical practitioners to be on the lookout for cases.

And then … nothing happened. The feared spike of AFM cases didn’t materialize, leaving those who study it “grateful but flummoxed,” said Janell Routh, team lead for AFM and domestic polio at the CDC.

“We all thought the enterovirus D68 part was going to happen, and it did. And we then also all thought that the AFM part was going to happen, and it didn’t. And that part is just perplexing,” said Matthew Vogt, an assistant professor of pediatric infectious diseases at the University of North Carolina, Chapel Hill.

AFM cases can occur at any time of the year. But in the past decade, in the period before the Covid pandemic, they spiked at two-year intervals. In those years there was always a lag time between when kids started getting infected with EV-D68 and when a small number of those children developed neurological disease and symptoms of paralysis set in. Some children develop weakness in one or several limbs. In severe cases, children may need to be placed on a ventilator because they are unable to breathe on their own.

Experts who study AFM feel confident that enough time has elapsed since the virus started circulating in August that if this were going to be a big year for cases, we’d have seen it by now.

“I don’t think it’s completely over, but I do think we’re far enough into this to say that we are not going to see the huge spikes we saw in 2014, 2016, and 2018,” said Kevin Messacar, a pediatric infectious diseases physician at Children’s Hospital Colorado, which has treated a few such patients this fall. Messacar said testing done at his hospital suggests the wave of EV-D68 infections is petering out in his state.

The sense of relief is palpable among people like Messacar, Routh, and Vogt. But so is the confusion. Some of the circumstances around AFM cases triggered by the virus were just starting to come into focus, they thought. For instance, for years researchers looked for proof that EV-D68 was causing AFM, to no avail. But this May, Vogt and colleagues reported in the New England Journal of Medicine that they had found EV-D68 RNA and protein in the spinal cord of a child who died from AFM.

“I thought I was sort of getting to a point where I had some understanding of how this virus worked,” said Vogt. “And it just took a damn left turn.”

Now among the myriad mysteries facing people who study this befuddling disease is a new one: Given that seemingly all the conditions were in place for a peak year of AFM cases in 2022, why didn’t it happen?

“I think it just leaves us with a bunch of questions. Do we think it’s gone away? Do we need to worry about it potentially being worse in 2024? I’m not sure of the answers yet,” said Megan Culler-Freeman, a pediatric infectious diseases physician at the University of Pittsburgh Medical Center, which hasn’t seen any AFM cases this fall.

The AFM story is a complicated one. Sudden paralysis can be triggered by a number of infectious agents as well as by some environmental exposures. In years when D68 enteroviruses aren’t circulating, the CDC normally hears about a couple of dozen cases, spread out over the course of the year. In 2021 there were 28 confirmed cases in 15 states; in 2020 there were 33 confirmed cases in 18 states. Often an explanation for these paralysis cases is never found.

But starting in 2012, there seemed to be an uptick of AFM cases in the fall; that year, California reported three cases. The CDC asked states to look for and report such cases and in 2014 there were 120. In 2016, the number rose to 150; in 2018, it was 238. The pattern of two-year cycles was attributed to years in which EV-D68 circulated.

Before the pandemic, the expectation was that 2020 would be another big year. But with kids in masks and out of schools, that didn’t materialize. (There was barely any flu the first winter of the pandemic either.) There wasn’t a spike in 2021 either, leading to the fear that with four years’ worth of susceptible children and EV-D68 circulating, the 2022 AFM count could far exceed that of 2018.

Yet so far only 27 children in 16 states have been diagnosed with AFM in 2022, according to the CDC. Doctors have reported 63 suspected cases to the agency, but because there is no diagnostic test for the condition, a panel of neurological experts must go through each child’s medical record to adjudicate on each suspected case. Some of the 36 remaining suspected cases have already been ruled out while others are still under investigation, Routh said.

Even if this year’s tally grows a little, 2022 looks more like an off year than a peak year.

Vogt wonders if something known as viral interference could explain what’s happening. That’s a theory that posits that some non-specific immune system weaponry that kicks into gear when you have an infection can help you fend off other infectious agents in the short term. There have been lots of respiratory pathogens circulating this summer and fall, he noted. Maybe prior infections with one of them armed kids’ immune systems to deal with EV-D68 more effectively, preventing the virus from moving into the spinal cord? “I’m grasping at straws,” Vogt admitted.

Steve Oberste, chief of CDC’s polio and picornavirus laboratory branch, is skeptical of that idea. “Yeah, I don’t know,” he said, questioning how, mechanistically, that would work in this case.

Culler-Freeman wonders if the lack of circulation of EV-D68 for several years paradoxically protected children, rather than putting them at greater risk. Maybe it’s second or subsequent infections that are riskier with EV-D68, she said. In that sense, the condition might be akin to dengue virus infections; in a phenomenon known as antibody dependent enhancement, low levels of antibodies against one strain of dengue can make infection with another more dangerous.

There isn’t universal acceptance of the notion that antibody dependent enhancement exists, especially outside of the realm of dengue infection. And Vogt said he thought it was unlikely to play a role with AFM, saying antibodies against EV-D68 are protective against the condition. He pointed to the age breakdown of AFM cases, which almost exclusively occurs in young children. “Having antibodies in your bloodstream that neutralize this virus is almost a universal condition of adulthood,” he said. “And adults don’t get this disease.”

Kenneth Tyler, who studies EV-D68 pathogenesis, thinks something else is at play. Tyler, chair of the department of neurology at the University of Colorado School of Medicine, said work his laboratory has been doing in baby mice that are susceptible to developing AFM shows that some strains of EV-D68 are more likely to trigger neurological damage than others.

He hasn’t yet tested viruses from 2022 in his mouse model, but viruses from earlier years show some strains will cause paralysis, while others won’t. But Tyler doesn’t believe that differences in the strains tells the whole story. He thinks it’s probably multifactorial.

Genetic factors may be at play: In some cases in which siblings have contracted EV-D68, one child developed paralysis, while others only had colds, he said. Tyler also wonders about age-related risk, noting the baby mice don’t develop AFM if they are exposed to EV-D68 after they get to be a little bit older. “It’s very hard to generate this disease in an adult mouse,” he said.

Asked about whether the CDC is observing changes to the virus that could explain this fall’s unexpected behavior, Oberste pointed out that the same question was asked when EV-D68 was first linked to AFM after the 2014 spike in cases. “It was really kind of a puzzle,” he said, adding that there is a lot of genetic sequencing being done. “It’s possible it’s something very subtle.”

For its part, the CDC is still urging caution, noting that viruses that disappeared early in the pandemic are acting in unexpected ways as they make their return. Case in point: Hospitals around the country are swamped right now with children sickened by RSV — respiratory syncytial virus — which normally strikes in winter months.

“After the pandemic, almost all bets are off. And so we’re not quite sure if things would get back to the same kind of cadence that they were previously,” Oberste said. “We’re still keeping an eye out. We still track trends … and we’ll continue to do that, just in case something happens a little bit out of season.”