Virus Identified For Disease That Paralyses Children And Warning That Next Seasonal Attack Could Be Severe

Medical researchers from University of California, have finally identified the culprits behind a mysterious disease called acute flaccid myelitis that has been on the increase over the last seven years and affects predominantly children with flu-like symptoms which later causes paralysis in them. Cases have been reported globally the last few years with more cases identified in the US due to better diagnosis whereas in countries like Myanmar and Cambodia, where doctors are not even aware of the diseases, despite having numerous cases, patients have been diagnosed wrongly have been paralysed permanently or have died as a result. Scientists are also warning that as the virus mutates and becomes more virulent, a more severe attack if forecasted during the next seasonal attack.
A team of medical researchers lead by University of 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 in Nature Medicine journal.

Acute flaccid myelitis 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 800 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.

Supporting 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 acute flaccid myelitis. 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.

Dr Michael Wilson, associate professor of neurology, member of the UCSF Weill Institute for Neuroscience and senior author of the new study commented in an interview with Thailand Medical News, "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. 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 team 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 Colorad o, 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 display, allowed Wilson's team to probe the spinal fluid of acute flaccid myelitis patients for signs of an immune response against enterovirus and thousands of other viruses simultaneously.

Dr Ryan Schubert, a clinical fellow in UCSF's Department of Neurology and lead author of the new study also commented in an interview with Thailand Medical News, "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."

The medical 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-acute flaccid myelitis 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.

Dr 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 also commented to Thailand Medical News "The strength of this study is not just what was found, but also what was not found. Enterovirus antibodies were the only ones enriched in AFM patients. No other viral family showed elevated antibody levels."

Although the study provides the most concrete 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 acute flaccid myelitis.

"Presumably there are changes that are causing the virus to be more neurovirulent, but no one knows for sure what they are. 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." Dr Schubert said.

As 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. 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." added Dr Schubert

Public health education is important, but it's not enough to prevent acute flaccid myelitis. 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.

Many medical researchers are warning that the next seasonal spike could be extremely severe with more children being infected due to the possible mutation of the virus which is making it more virulent. Furthermore unpredictable climate changes could make the next seasonal attack even earlier.

Reference:
 Pan-viral serology implicates enteroviruses in acute flaccid myelitis, Nature Medicine (2019). DOI: 10.1038/s41591-019-0613-1 , https://nature.com/articles/s41591-019-0613-1