OWithin days, the boy went from having cold symptoms to being unable to walk. To Peter Wright, a pediatric infectious disease physician at Dartmouth Hitchcock Medical Center, it sounded like polio – a disease you no longer see in the United States. It had to be something else.
The case happened in 2008 and, tragically, the 5-year-old boy from New Hampshire died. But his family allowed the scientific team to carry out an autopsy, to help solve “the mystery surrounding the child’s death and illness”, Wright recalls. Researchers have found something unusual: evidence of a common pathogen called enteroviruses, but in the fluid that bathes the spinal cord.
“Enterovirus 68 has not been previously reported as a cause of neurological disease,” the team wrote in a case reportciting the specific enterovirus – D68 – that they encountered.
A decade later, another researcher by the name of Matthew Vogt was studying a syndrome that had only been classified in subsequent years, reverting to the name acute flaccid myelitis. At that time, researchers suspected that AFM, a puzzling disease that caused muscle weakness and left some children paralyzed, was a rare consequence of infection with enterovirus D68, known as EV- D68, which usually causes respiratory symptoms. Vogt, then a fellow at Vanderbilt University, wondered if there might be any autopsy records that might help explain what was going on in the central nervous system of these children.
Vogt contacted Wright: Were there still samples from that autopsy he had already talked about?
It turned out there was. And in a document published Wednesday in the New England Journal of Medicine, Vogt, Wright and their colleagues described how reanalysis of these samples – with techniques that were not used at the time of the original autopsy – revealed direct infection. by the virus in the motor neurons of the spinal cord. They also found evidence of an inflammatory immune response that, instead of being protective, could damage neurons.
The paper further substantiates that EV-D68 causes cases of AFM and provides insight into what this infection looks like. It also highlights the value of autopsies when people die of mysterious causes – a value that can continue to accrue years later.
Until now, “we’ve never had direct evidence of what the virus is doing in the spinal cord during AFM,” said Kevin Messacar, a pediatrician who specializes in infectious diseases at Children’s Hospital Colorado, who n did not participate in the new search. He called the endeavor “incredible medical detective work.”
Reading the original report today, it is clear that it describes a case of AFM before the term existed. A number of the boy’s classmates had had cold symptoms, and he initially had a low fever, sore throat and neck tenderness. Within days his arms weakened and eventually he could not walk. He died shortly afterwards.
It wasn’t until 2014 that health authorities began tracking MFA cases nationwide. There seemed to be bursts of cases starting around August every two years, following the patterns of EV-D68, with the highest number of cases – 238 – being identified in 2018. (The pattern was thrown by the coronavirus pandemic, which has significantly curbed the transmission of other respiratory pathogens.)
Since AFM began to be documented, scientists have established evidence that EV-D68 was a cause, from correlating the timing of AFM spikes to virus transmission, to demonstrating that the virus could induce paralysis in mice, looking for antibodies against enteroviruses in the cerebrospinal fluid of children with AFM. (Another enterovirus, A71, is also suspected of causing some cases of MFA.)
With supportive care, most children who develop AFM survive, and deaths usually occur later from complications after the infection has cleared.
All of this made the samples from the 2008 case even more valuable: the boy died early in his infection. And in the new study, the researchers reported finding both protein and RNA from the virus in motor neurons in a region of the spinal cord called the anterior horn, which helps control limb movement.
The updated autopsy results don’t answer many of the questions researchers still have about AFM, including what causes the paralysis. Is it the infection that damages the neurons, the ensuing inflammatory response, or a combination of the two? This could dictate how clinicians should treat the disease – with drugs that target the virus or those that can calm the immune response.
Researchers also still don’t know why a relatively common virus triggers such a devastating reaction in a handful of children. It’s a similar question that scientists around the world face as they try to solve the mystery of what causes a wave of unexplained cases of hepatitis in children, and what role a common pathogen – in this case, adenovirus 41 – may play.
Vogt, now a pediatric infectious disease physician at the University of North Carolina, warned that the science team was just describing an autopsy, from a disease point, so “you can only draw a number limited in conclusions”.
But more broadly, Vogt emphasized the value of autopsies for people who die in confusing circumstances. It can be a tricky decision, especially when it comes to a child. But the hope is that studying these deaths can inform scientists’ efforts to identify what may start as puzzles, but that research can turn into something treatable.
“The hope would be that no other specimen like this ever existed,” Vogt said.
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