In the JournalsPerspective

New findings provide additional evidence of AFM, enterovirus link

Testing of 14 patients with acute flaccid myelitis, or AFM, showed they had antibodies against enteroviruses, especially EV-D68, in their cerebrospinal fluid at a significantly higher rate than controls, supporting “the plausibility of a link” between enterovirus infection and AFM, researchers reported in mBio.

“Physicians and scientists have long suspected that enteroviruses — a family of viruses responsible for polio, another paralyzing disease — are behind AFM, but there has been little evidence to support this idea," Nischay Mishra, PhD, assistant professor of epidemiology at the Columbia University Mailman School of Public Health’s Center for Infection and Immunity, said in a news release. "Further work is needed with larger, prospective studies. Nonetheless, these results take us one step closer to understanding the cause of AFM, and one step closer to developing diagnostic tools and treatments.”

According to Mishra and colleagues, AFM has caused more than 560 cases of motor paralysis in the United States in the last 5 years.

To explore the possible relationship between AFM and enteroviruses, the researchers used a viral-capture high-throughput sequencing system to analyze CSF collected from 14 people with AFM and five people with other central nervous system diseases. They then tested CSF and serum samples from patients and controls for antibodies to enteroviruses using peptide microarrays.

They identified enterovirus RNA in CSF from only one adult with AFM and one non-AFM case. However, most patients with AFM (n = 11; 79%) had antibodies to enterovirus peptides in their spinal fluid, according to Mishra and colleagues. This prevalence was significantly higher than the prevalence identified among non-AFM patients (n = 1 of 5; 20%), adults with other non-AFM central nervous system diseases (n = 2 of 11; 18%) and children with Kawasaki disease (n = 0 of 10), they reported.

According to the study, peptides to EV-D68 — an enterovirus that has been suspected to cause AFM among children — were commonly identified among patients with AFM (CSF: n = 6 of 14 [43%]; serum samples: n = 8 of 11 [73%]). Furthermore, the researchers identified no immunoreactivity against EV-D68 in three control groups through their CSF (group 1: n = 0 of 5; P = .008; group 2: n = 0 of 10; P = .0003; group 3: n = 0 of 11; P = .035) or serum (n = 0 of 2; P = .139; group 2: n = 0 of 8; P = .002; group 3: n = 0 of 5; P = .009).

“Pathogen discovery has historically focused on direct detection of infectious agents. The introduction of new methods that allow us to also test for footprints of exposure will lead to new insights into infectious diseases,” W. Ian Lipkin, MD, director of Center for Infection and Immunity, said in the release. – by Katherine Bortz

Disclosures: The authors report no relevant financial disclosures.

Testing of 14 patients with acute flaccid myelitis, or AFM, showed they had antibodies against enteroviruses, especially EV-D68, in their cerebrospinal fluid at a significantly higher rate than controls, supporting “the plausibility of a link” between enterovirus infection and AFM, researchers reported in mBio.

“Physicians and scientists have long suspected that enteroviruses — a family of viruses responsible for polio, another paralyzing disease — are behind AFM, but there has been little evidence to support this idea," Nischay Mishra, PhD, assistant professor of epidemiology at the Columbia University Mailman School of Public Health’s Center for Infection and Immunity, said in a news release. "Further work is needed with larger, prospective studies. Nonetheless, these results take us one step closer to understanding the cause of AFM, and one step closer to developing diagnostic tools and treatments.”

According to Mishra and colleagues, AFM has caused more than 560 cases of motor paralysis in the United States in the last 5 years.

To explore the possible relationship between AFM and enteroviruses, the researchers used a viral-capture high-throughput sequencing system to analyze CSF collected from 14 people with AFM and five people with other central nervous system diseases. They then tested CSF and serum samples from patients and controls for antibodies to enteroviruses using peptide microarrays.

They identified enterovirus RNA in CSF from only one adult with AFM and one non-AFM case. However, most patients with AFM (n = 11; 79%) had antibodies to enterovirus peptides in their spinal fluid, according to Mishra and colleagues. This prevalence was significantly higher than the prevalence identified among non-AFM patients (n = 1 of 5; 20%), adults with other non-AFM central nervous system diseases (n = 2 of 11; 18%) and children with Kawasaki disease (n = 0 of 10), they reported.

According to the study, peptides to EV-D68 — an enterovirus that has been suspected to cause AFM among children — were commonly identified among patients with AFM (CSF: n = 6 of 14 [43%]; serum samples: n = 8 of 11 [73%]). Furthermore, the researchers identified no immunoreactivity against EV-D68 in three control groups through their CSF (group 1: n = 0 of 5; P = .008; group 2: n = 0 of 10; P = .0003; group 3: n = 0 of 11; P = .035) or serum (n = 0 of 2; P = .139; group 2: n = 0 of 8; P = .002; group 3: n = 0 of 5; P = .009).

“Pathogen discovery has historically focused on direct detection of infectious agents. The introduction of new methods that allow us to also test for footprints of exposure will lead to new insights into infectious diseases,” W. Ian Lipkin, MD, director of Center for Infection and Immunity, said in the release. – by Katherine Bortz

Disclosures: The authors report no relevant financial disclosures.

    Perspective
    Anthony S. Fauci

    Anthony S. Fauci

    Enteroviruses have been strongly implicated as a causative agent of AFM. However, their genetic material has rarely been recovered in CSF specimens from patients with AFM and causation has not been established.

    Lipkin and colleagues analyzed CSF and serum samples from 14 patients with AFM collected in 2018, as well as from control patients with non-AFM central nervous system diseases and Kawasaki disease. Using a novel peptide microarray platform, they found antibodies against enterovirus peptides in the CSF of AFM cases at a higher rate than in controls. When they looked for antibodies against a peptide specific to EV-D68, it was found in 43% of CSF and 73% of serum from AFM cases and not in the CSF or serum of the controls.

    Identifying the cause of AFM is critical to develop the most effective treatments, vaccines and diagnostic assays. This work is an important step in that direction. These important findings warrant further investigation regarding the association between EV-D68 and other enteroviruses with AFM. 

    • Anthony S. Fauci, MD
    • Director
      National Institute of Allergy and Infectious Diseases

    Disclosures: Fauci reports no relevant financial disclosures.

    Perspective
    Amesh A. Adalja

    Amesh A. Adalja

    As the mysteries of AFM are unraveled, there is a growing amount of converging evidence that points to an enteroviral infection as being the trigger for this syndrome. That antibodies were found to enterovirus peptides in the CSF of patients with AFM is another piece of a puzzle.

    As a consensus emerges around enterovirus infections as the etiologic agent, it is hoped that it will spur research efforts to understand the risk factors and the pathophysiology for this complication as well as efforts to further develop enterovirus vaccines.

    • Amesh A. Adalja, MD
    • Senior scholar
      Johns Hopkins Center for Health Security

    Disclosures: Adalja reports no relevant financial disclosures.