RT Journal Article
SR Electronic
T1 Serological and metagenomic interrogation of cerebrospinal fluid implicates enteroviruses in pediatric acute flaccid myelitis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 666230
DO 10.1101/666230
A1 Ryan D. Schubert
A1 Isobel Hawes
A1 Prashanth S. Ramachandran
A1 Akshaya Ramesh
A1 Emily D. Crawford
A1 John E. Pak
A1 Wesley Wu
A1 Carly K. Cheung
A1 Brian D. O’Donovan
A1 Cristina M. Tato
A1 Amy Lyden
A1 Michelle Tan
A1 Rene Sit
A1 Gavin Sowa
A1 Hannah A. Sample
A1 Kelsey C. Zorn
A1 Debarko Banerji
A1 Lillian M. Khan
A1 Riley Bove
A1 Stephen L. Hauser
A1 Amy A. Gelfand
A1 Bethany Johnson-Kerner
A1 Kendall Nash
A1 Kalpathy S. Krishnamoorthy
A1 Tanuja Chitnis
A1 Joy Z. Ding
A1 Hugh J. McMillan
A1 Charles Y. Chiu
A1 Benjamin Briggs
A1 Carol A. Glaser
A1 Cynthia Yen
A1 Victoria Chu
A1 Debra A. Wadford
A1 Samuel R. Dominguez
A1 Terry Fei Fan Ng
A1 Rachel L. Marine
A1 Adriana S. Lopez
A1 W. Allan Nix
A1 Ariane Soldatos
A1 Mark P. Gorman
A1 Leslie Benson
A1 Kevin Messacar
A1 Jennifer L. Konopka-Anstadt
A1 M. Steven Oberste
A1 Joseph L. DeRisi
A1 Michael R. Wilson
YR 2019
UL http://biorxiv.org/content/early/2019/06/18/666230.abstract
AB Background Since 2014, the United States has experienced a biennial spike in pediatric acute flaccid myelitis (AFM). Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF) and only inconsistently identified from the respiratory tract, serum, or stool.Methods We interrogated CSF from children with AFM (n=42) and pediatric controls with other neurologic diseases (OND) (n=58). Samples were incubated with T7 bacteriophage expressing 481,966 sixty-two amino acid peptides with a fourteen amino acid overlap tiled across all known vertebrate virus and arbovirus genomes, an adaption of the VirScan method. Antibody-bound phage were deep sequenced to quantify enriched peptides with normalized counts expressed as reads per hundred thousand (rpK). EV antibody findings were confirmed with ELISA using whole viral protein 1 (VP1) from contemporary enterovirus (EV) A71 and D68 strains. Separately, metagenomic next-generation sequencing (mNGS) of CSF RNA, both unbiased and with targeted enrichment for EVs, was performed.Results The most significantly enriched viral family by VirScan of CSF in AFM versus OND controls was Picornaviridae (mean rpK 11,266 versus mean rpK 950, p-adjusted < 0.001, Wilcoxon signed-rank test with Bonferroni adjustment). Enriched Picornaviridae peptides belonged almost entirely to the genus Enterovirus. The mean EV VP1 ELISA signal in AFM (mean OD 0.51) was significantly higher than OND controls (mean OD 0.08, p-value < 0.001, Mann-Whitney test). mNGS did not detect additional enterovirus RNA in CSF.Conclusion Despite the rare detection of EV RNA in the CNS of patients with AFM, a pan-viral serologic assay identified high levels of CSF EV antibodies in AFM CSF compared to CSF from OND controls. These results provide further evidence for a causal role of non-polio enteroviruses in AFM.