Study confirms pathogenesis of EV-D68 virus, which causes polio-like disease in children

A report published in New England Medical Journal provides evidence that D68 enterovirus directly affects neurons in the spinal cord and that there is a correspondingly reliable immune response – a direct cause of polio-like paralysis, acute flaccid myelitis (AFM). Matthew Vogt, MD, PhD, Associate Professor of Pediatrics, Microbiology and Immunology at UNC School of Medicine, is the lead author of the study.

Acute flaccid myelitis (ARI) has emerged in recent years with large outbreaks observed in 2014, 2016 and 2018. AFM is a serious neurological disease that causes muscle weakness that sometimes leads to permanent paralysis, such as polio. The disease is rare and it affects the nervous system, particularly the spinal cord, causing muscles and reflexes in the body to become weak. This can often lead to skeletal muscle paralysis, and in severe cases can affect the muscles of swallowing and breathing. The majority of AFM cases (over 90%) were in children. Recovery after AFM may vary, but rarely involves a full recovery of all strength. Mortality is low, with only two reported deaths out of 682 confirmed AFM cases since 2014 in the United States.

Increasing evidence shows a causal link between D68 enterovirus infection (EV-D68), one of more than 100 polio-free enteroviruses, and AFM. EV-D68 can cause mild and severe respiratory illnesses such as runny nose, wheezing, cough, body and muscle aches. But after that AFM can develop and cause rapid progression of symptoms. For example, it usually takes 48 to 72 hours for weakness to reach its worst.

“Enterovirus D68 is very similar to rhinovirus, where it usually starts with the symptoms of the common cold,” said Vogt, an associate professor of pediatric infectious diseases and a member of the UNC Children’s Research Institute. “Right when these symptoms start to improve, within five days or so, then weakness will start to appear. It is very variable. Weakness can range from minor to paralysis of every muscle in the body,” he said.

EV-D68 is often detected in respiratory samples of patients with AFM, but is rarely detected in their cerebrospinal fluid. Several autopsies have investigated the pathogenesis of human AFM, so most understanding of pathogenesis occurs through mouse models of infection. It was learned that the EV-D68 was associated with AFM, but there was no direct evidence causal relationship. The study began in 2019, when Dr. Vogt was a staff member of pediatric infectious diseases in the laboratory of James Crow, MD, at Vanderbilt University Medical Center. At the time, his research included studying the types of antibodies produced by humans in response to EV-D68 infection.

“Antibody and B-cell research is now very effective because the techniques used identify the mechanisms of immunity and at the same time can be used to isolate therapeutic molecules,” Blood said.

“Over time, scientists have conducted quite a few experiments in the lab and found a lot of evidence to suggest that the EV-D68 is probably the main cause of AFM,” Vogt said. “Researchers have been able to use mouse models to document severe symptoms and observe how the virus infects motor neurons in the spinal cord.” These are the very neurons that control movement in the limbs that are now paralyzed. “

Twelve years after a five-year-old boy died of AFM in 2008, Vogt and researchers returned to the patient’s autopsies to deeply investigate the pathology and immune response of the virus, especially now that EV-D68 is linked to outbreaks. it was clear further. The pathogenesis was confirmed when a study showed that EV-D68 directly infects spinal cord neurons. The area of ​​infected neurons was clinically consistent with upper limb weakness, and a strong immune response was present.

“The central nervous system, of which the spinal cord is a part, is what we often call the immune privileged place, which means that the immune system does not tend to work the same in the spinal cord and brain as it does. tends to work in the rest of the body, “Vogt said.” Sometimes, when an immune response to an infection occurs, it can cause prolonged damage to infected tissues, even affecting surrounding cells that are not infected. By design, cytolytic CD8 + T cells help destroy infected cells, which is a normal part of cleansing viruses in most tissues. But when it happens in the central nervous system, we don’t think neurons are regenerating. In the study, we found many of these CD8 + T cells right where these neurons were infected. ”

These findings further support the plausibility of the role of immunopathogenesis, which promotes AFM, the last part that links the causal relationship of EV-D68 to acute flaccid myelitis. Thus, optimal acute treatment of AFM is likely to require a multifaceted approach focused on antiviral and anti-inflammatory strategies.

“There must be a balance,” Vogt said. “Antiviral drugs or antibody drugs in combination with anti-inflammatory drugs can be useful for treatment. Currently, patients with AFM are usually given immunomodulatory drugs in an attempt to limit this immune-mediated damage, like what cytolytic T cells can do.” that if you take away the whole immune response, you can stop this viral infection, causing the virus to get out of control.My hypothesis after I saw the data is that the patient needs to be treated for both options if they Unfortunately, we do not currently have antiviral drugs and drugs to treat EV-D68 in humans. “

Dr. Vogt and his colleagues used monoclonal antibodies, as well as that used to treat SARS-CoV-2, to neutralize EV-D68. Evidence has shown that when antibodies are given to infected mice during the onset of paralysis, this treatment helps to improve outcomes – meaning it will improve overall paralysis. Since this evidence in the study leaves no doubt that EV-D68 causes AFM, the information derived from this case report can provide information on approaches to treatment and further referral of laboratory studies.

This study also confirms the high value of autopsies and tissue biobanking for cases of poorly explained infectious syndromes.

“I think this case actually shows that the family of this five-year-old boy who decided to have the autopsy made an incredibly important observation in science that happened more than ten years after their child died,” Vogt said. . “Their child’s legacy lives on in the understanding of this disease, which unfortunately took his life. Their decision, in turn, could be a lifeline for future children diagnosed with AFM. If we can understand how this disease works, then we can work to understand how to prevent this from happening. ”