Genomic and serologic characterization of enterovirus A71 brainstem encephalitis.

Neurol Neuroimmunol Neuroinflamm

From the Medical Scientist Training Program (K.E.L.), University of California, San Francisco; Biomedical Sciences Graduate Program (K.E.L., I.A.H.), University of California, San Francisco; Weill Institute for Neurosciences (R.D.S., I.A.H., P.S.R., A.R., M.R.W.), University of California, San Francisco; Department of Neurology (R.D.S., I.A.H., P.S.R., A.R., M.R.W.), University of California, San Francisco; Institut de Recerca Pediàtrica Hospital Sant Joan de Déu (D.C.-A., C.L., A.V.-R., C.M.-A.), Barcelona, Spain; Chan Zuckerberg Biohub (J.E.P., W.W., C.K.C., E.D.C., J.L.D.), San Francisco; Department of Biochemistry and Biophysics (L.M.K., H.A.S., K.C.Z., J.L.D.), University of California, San Francisco; CIBER Epidemiología y Salud Pública (CIBERESP) (C.L., M.C., C.M.-A.), Health Institute Carlos III; Department of Pediatrics (C.L.), Universitat de Barcelona, Barcelona; Enterovirus Unit (M.C.), Spanish National Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain; Division of Infectious Diseases (C.L.), Department of Medicine, University of California, San Francisco; and Department of Medicine. Universitat Internacional de Catalunya (C.M.-A.), Barcelona, Spain.

Published: May 2020

In 2016, Catalonia faced an outbreak of pediatric brainstem encephalitis caused by enterovirus A71 (EV-A71), with conventional tests often failing to identify the virus in the cerebrospinal fluid (CSF).
Researchers used metagenomic next-generation sequencing (mNGS) and CSF pan-viral serology (VirScan) to improve viral detection in children affected by encephalitis.
The study showed that mNGS increased detection of EV from 42% to 57%, while VirScan further raised the detection rate to 92%, revealing a strong link between the outbreak strain of EV-A71 and a neurovirulent strain from Germany.

Objective: In 2016, Catalonia experienced a pediatric brainstem encephalitis outbreak caused by enterovirus A71 (EV-A71). Conventional testing identified EV in the periphery but rarely in CSF. Metagenomic next-generation sequencing (mNGS) and CSF pan-viral serology (VirScan) were deployed to enhance viral detection and characterization.

Methods: RNA was extracted from the CSF (n = 20), plasma (n = 9), stool (n = 15), and nasopharyngeal samples (n = 16) from 10 children with brainstem encephalitis and 10 children with meningitis or encephalitis. Pathogens were identified using mNGS. Available CSF from cases (n = 12) and pediatric other neurologic disease controls (n = 54) were analyzed with VirScan with a subset (n = 9 and n = 50) validated by ELISA.

Results: mNGS detected EV in all samples positive by quantitative reverse transcription polymerase chain reaction (qRT-PCR) (n = 25). In qRT-PCR-negative samples (n = 35), mNGS found virus in 23% (n = 8, 3 CSF samples). Overall, mNGS enhanced EV detection from 42% (25/60) to 57% (33/60) (-value = 0.013). VirScan and ELISA increased detection to 92% (11/12) compared with 46% (4/12) for CSF mNGS and qRT-PCR (-value = 0.023). Phylogenetic analysis confirmed the EV-A71 strain clustered with a neurovirulent German EV-A71. A single amino acid substitution (S241P) in the EVA71 VP1 protein was exclusive to the CNS in one subject.

Conclusion: mNGS with VirScan significantly increased the CNS detection of EVs relative to qRT-PCR, and the latter generated an antigenic profile of the acute EV-A71 immune response. Genomic analysis confirmed the close relation of the outbreak EV-A71 and neuroinvasive German EV-A71. A S241P substitution in VP1 was found exclusively in the CSF.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136061	PMC
http://dx.doi.org/10.1212/NXI.0000000000000703	DOI Listing

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