Cytokine biomarkers associated with acute flaccid myelitis

Original publication: William C. Weldon, Kun Zhao, Heather A. Jost, Kimbell Hetzler, Jessica Ciomperlik-Patton, Jennifer L. Konopka-Anstadt, M. Steven Oberste. Cytokine biomarkers associated with clinical cases of acute flaccid myelitis. Journal of Clinical Virology 131 (2020) 104591.

Acute Flaccid Myelitis (AFM) is a neurological condition characterized by a rapid onset of flaccid muscle weakness, with associated abnormalities on imaging of the spinal cord (MRI). This disease predominantly affects the gray matter of the spinal cord in children and is usually preceded by a febrile illness which has been linked to an infectious disease produced by a respiratory virus, enterovirus D-68. Weldon and his colleagues recently published in the Journal of Clinical Virology, an analysis of the expression of immune proteins called cytokines and chemokines in patients affected by AFM. Cytokine and chemokines are mediators of inflammation as they regulate the function and trafficking of immune cells in the body and are particularly important during stages of inflammation or response to infections. They are particularly important for the understanding of AFM as they may play a role in the process of inflammation that targets the spinal cord.

The investigators tested paired samples of cerebrospinal fluid (CSF) and serum obtained from 70 confirmed AFM patients as defined by the CDC criteria and 47 non-AFM control subjects with other diseases. The goal of the study was to determine if there are any specific signals that distinguish the cytokine and chemokine response observed in patients with AFM as compared with controls, responses which may provide clues about the pathogenesis of AFM. All cases of AFM were defined as ’confirmed’ when magnetic resonance imaging (MRI) showed predominantly gray matter lesions spanning at least one or more segments of the spinal cord –, and

The study analyzed the levels of these cytokines and chemokines in confirmed AFM and non-AFM patients, and also compared between limb weakness vs. no limb weakness and those who were positive for enterovirus and not. The study found several cytokines that were observed to be increased in the CSF of AFM-positive patients compared to non-AFM cases which were unique to those samples positive for enterovirus and limb weakness.  Two pro-inflammatory cytokines/chemokines called IP- 10 and IL-6 were significantly elevated in AFM patients compared to non-AFM patients.

In the central nervous system, IP-10 has been associated with other illnesses induced by viral infections, and elevated IL-6 is expressed in neuroimmune conditions such as neuromyelitis optica spectrum disorder and also has been shown to be high in viral infections of the CNS such as Zika virus. The findings of the study by Weldon and collaborators add further evidence of the active and aggressive inflammatory damage the spinal cord suffers in patients affected by AFM. While there were limitations in the study sampling and unmatched controls were used, the results of the study reveal the need for further examination of the pathogenic mechanisms leading to the extensive damage of motor neurons that affect AFM patients. Future prospective natural history studies of AFM may need to confirm these preliminary observations to determine if the modulation of these specific cytokines/chemokines may be of therapeutic value and also to investigate with more detail the role that cytokines and chemokines may play in the mechanisms that lead to spinal cord damage in AFM.

This summary of the peer-reviewed publication in Journal of Clinical Virology was reviewed by Dr. Carlos A. Pardo, Professor of Neurology at Johns Hopkins University and Director of the Johns Hopkins Myelitis and Myelopathy Center and includes his views on the importance of this study.