A UC San
Francisco-led research team has detected the immunological remnants of a common
seasonal virus in spinal fluid from dozens of patients diagnosed with acute
flaccid myelitis (AFM)—a polio-like illness that causes permanent, sometimes
life-threatening paralysis in young children. The findings provide the clearest
evidence to date that AFM is caused by an enterovirus (EV) that invades and
impairs the central nervous system.
The study
was published October 21, 2019 in Nature Medicine.
AFM, which
begins with cold-like symptoms and progresses to limb weakness and paralysis in
a matter of days, was first documented in 2012. Since then, AFM outbreaks have
occurred every other year, with more than 500 confirmed cases recorded so far.
But because scientists have had trouble pinpointing a cause, AFM has been the
subject of contentious debate within the medical community.
Mounting
evidence implicated EVs as the likely culprit—specifically the so-called D68
and A71 strains of the virus. EV outbreaks are common and normally cause
nothing more severe than cold-like symptoms or the rash-producing hand, foot
and mouth disease.
Scientists
started to notice, however, that EV outbreaks coincided with spikes in AFM.
They also found that respiratory samples from children diagnosed with AFM often
tested positive for EVs. Plus, laboratory studies found that these strains
caused paralysis in mice.
But many
experts remained skeptical of the enterovirus hypothesis, instead proposing
that AFM is an autoimmune disorder or is caused by some other,
as-yet-undiscovered virus. These EV skeptics argued that that the evidence
linking the virus to AFM was circumstantial, because the virus could not be
found in 98 percent of AFM patients who had their spinal fluid tested. They
maintained that until there was ample evidence of the virus invading the human
nervous system, the link between EVs and AFM remained unproven.
"People
were hung up on the fact that enteroviruses were rarely detected in the
cerebrospinal fluid of AFM patients. They wanted to know how someone could get
neurologic symptoms with no virus detectable in their central nervous
system," said Michael Wilson, MD, associate professor of neurology, member
of the UCSF Weill Institute for Neurosciences, and senior author of the new
study. "If we could detect something specific to a virus in in the spinal
fluid of AFM patients, we would feel more secure claiming that the neurologic
symptoms of the disease are virally mediated."
The group
first searched for the virus directly in spinal fluid using advanced deep
sequencing technologies, but this sort of direct detection of the virus failed,
as it had previously. Therefore, to find evidence of the missing virus, Wilson
and his collaborators—researchers at the Chan Zuckerberg Biohub, the Centers
for Disease Control and Prevention, the California Department of Public Health,
the University of Colorado, Boston Children's Hospital and the University of
Ottawa—used an enhanced version of a virus-hunting tool called VirScan, first
developed at Harvard Medical School in the laboratory of Stephen J. Elledge,
Ph.D.
VirScan,
which is a customized version of a Nobel Prize-winning technique called phage
(rhymes with "beige") display, allowed Wilson's team to probe the
spinal fluid of AFM patients for signs of an immune response against
enterovirus and thousands of other viruses simultaneously.
"When
there's an infection in the spinal cord, antibody-making immune cells travel
there and make more antibodies. We think finding antibodies against enterovirus
in the spinal fluid of AFM patients means the virus really does go to the
spinal cord. This helps us lay the blame on these viruses," said Ryan
Schubert, MD, a clinical fellow in UCSF's Department of Neurology, a member of
Wilson's Lab, and lead author of the new study.
The
researchers created molecular libraries consisting of nearly 500,000 small
chunks of every protein found in the over 3,000 viruses known to infect
vertebrates (including humans), as well as those that infect mosquitoes and
ticks (an effort to rule out disease transmission through their bites). They
then exposed these molecular libraries to spinal fluid obtained from 42
children with AFM and, as a control, 58 who were diagnosed with other
neurological diseases. Any chunks of viral protein cross-reacting with any
antibodies present in the spinal fluid would provide evidence for a viral
infection in the central nervous system.
Antibodies
against enterovirus were found in the spinal fluid of nearly 70 percent of AFM
patients; less than 7 percent of non-AFM patients tested positive for these
antibodies. Furthermore, because spinal fluid from AFM patients did not contain
antibodies against any other virus, every other known virus could be eliminated
as a possible culprit. These results were confirmed using more conventional lab
techniques.
"The
strength of this study is not just what was found, but also what was not
found," said Joe DeRisi, Ph.D., professor of biochemistry and biophysics
at UCSF, co-president of the Chan Zuckerberg Biohub, and co-author of the new
study. "Enterovirus antibodies were the only ones enriched in AFM
patients. No other viral family showed elevated antibody levels."
Though the
study provides the most robust evidence so far that enteroviruses cause AFM,
many questions around AFM and these viruses remain unanswered. For example,
though the AFM-causing enterovirus strains—EV-D68 and EV-A71—were identified
decades ago, they only recently seemed to have gained the ability to cause
paralysis, with the D68 strain in particular responsible for the most severe
cases of AFM.
"Presumably
there are changes that are causing the virus to be more neurovirulent, but no
one knows for sure what they are," Schubert said. "Because the virus
is found in such low amounts, if at all, it's hard to zero in on the
differences between an A71 virus that causes routine hand, foot, and mouth
disease and one that causes AFM."
Also,
because enteroviruses are extremely common, scientists are still trying to
figure out why fewer than 1 percent of infected children get AFM, and they're
also trying to understand why children are the only ones affected. "We
don't know for sure why children get paralysis and adults don't," Schubert
said. "The thinking is that young children have low immunity to the virus
that increases as they get older, so we see the most severe effects in children
around the age of two. But more work needs to be done to understand AFM."
For study
co-author Riley Bove, MD, answering these unresolved questions is a deeply
personal mission. Bove, an assistant professor of neurology and member of the
UCSF Weill Institute for Neurosciences, is the mother of a child who was
diagnosed with AFM.
In the
summer of 2014, Bove's entire family came down with what seemed to be a severe
cold. Everyone recovered except Bove's then four-year-old son. Just days after
the onset of the cold-like symptoms, he started experiencing difficulty
breathing. Soon, he was paralyzed from head to toe and had trouble breathing on
his own.
Today,
Bove's son is a thriving nine-year-old, but she says the physical and emotional
effects of AFM will be with him the rest of his life. "For every family
with a child diagnosed with AFM, the long-term consequences of the disease
remain the top issue," she said.
Bove hopes
that the new study will lead to a scientific consensus around enterovirus as
the cause of AFM, since this a key step on the road to improved diagnostics and
the development of a vaccine for the illness.
"Public
health education is important, but it's not enough to prevent AFM," Bove
said. "The virus is too common to avoid. A vaccine is the only way to
meaningfully prevent the disease."
For now,
there's no way to prevent or treat AFM. But if it follows the biennial pattern
first established after the 2012 outbreak, AFM cases may spike again next year.
"We're all holding our breath for 2020," Schubert said.
Source: https://medicalxpress.com/news/2019-10-virus-dozens-children-paralyzed-polio-like.html
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