Background: There are sparse and limited studies on small sample size reporting the application of next-generation sequencing (NGS) in the detection of central nervous system (CNS) viral infections. We assessed the diagnostic performance of NGS of cerebrospinal fluid (CSF) for predicting viral infections of the CNS caused by the neurotropic herpes viruses in a pilot population. Materials and Methods: We prospectively collected CSF samples from 24 patients with CNS viral infection from April 2017 to October 2018. Of the 24 patients, 19 patients were infected with herpes simplex virus 1 (HSV-1), 1 patient with HSV-2, and 4 patients with varicella-zoster virus (VZV). All CSF samples were screened for viral DNA using NGS technologies to detect viral CNS infections. Results: Of the 24 patients with confirmed viral CNS infection caused by the neurotropic herpes viruses, 10 (10/24, 41.67%) patients exhibited positive NGS results. With the help of NGS, HSV-1 DNA was detected in the CSF of 6 patients (6/19; 31.58%). HSV-2 DNA was detected in 1 patient (1/1; 100%) and VZV DNA was detected in 3 patients (3/4; 75%). The positive rate of virus detected by NGS decreased with time. The positive rates of NGS of CSF in the first, second, and third weeks were 54.5% (6/11), 44.4% (4/9), and 0% (0/4), respectively. Conclusions: NGS method is a promising pathogen detection tool for identifying viral CNS infections. It should be recommended to sequence viral DNA of CSF in the early stage of CNS viral infections.

Keywords:
Etiology, Herpes simplex viruses, Herpes zoster viruses , Meningitis, Meningoencephalitis, Next-generation sequencing
1.
Glaser CA, Honarmand S, Anderson LJ, Schnurr DP, Forghani B, Cossen CK, et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis.
Clin Infect Dis
. 2006 Dec; 43(12): 1565–77.
2.
Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL, Morgan D, et al.; UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study.
Lancet Infect Dis
. 2010 Dec; 10(12): 835–44.
3.
Tyler KL. Acute Viral Encephalitis.
N Engl J Med
. 2018 Aug; 379(6): 557–66.
4.
Vora NM, Holman RC, Mehal JM, Steiner CA, Blanton J, Sejvar J. Burden of encephalitis-associated hospitalizations in the United States, 1998-2010.
Neurology
. 2014 Feb; 82(5): 443–51.
5.
Wilson MR, Naccache SN, Samayoa E, Biagtan M, Bashir H, Yu G, et al. Actionable diagnosis of neuroleptospirosis by next-generation sequencing.
N Engl J Med
. 2014 Jun; 370(25): 2408–17.
6.
Brown JR, Morfopoulou S, Hubb J, Emmett WA, Ip W, Shah D, et al. Astrovirus VA1/HMO-C: an increasingly recognized neurotropic pathogen in immunocompromised patients.
Clin Infect Dis
. 2015 Mar; 60(6): 881–8.
7.
Guan H, Shen A, Lv X, Yang X, Ren H, Zhao Y, et al. Detection of virus in CSF from the cases with meningoencephalitis by next-generation sequencing.
J Neurovirol
. 2016 Apr; 22(2): 240–5.
8.
Jeffery KJ, Read SJ, Peto TE, Mayon-White RT, Bangham CR. Diagnosis of viral infections of the central nervous system: clinical interpretation of PCR results.
Lancet
. 1997 Feb; 349(9048): 313–7.
9.
Steiner I, Budka H, Chaudhuri A, Koskiniemi M, Sainio K, Salonen O, et al. Viral meningoencephalitis: a review of diagnostic methods and guidelines for management.
Eur J Neurol
. 2010 Aug; 17(8): 999–e57.
10.
Jeon YJ, Zhou Y, Li Y, Guo Q, Chen J, Quan S, et al. The feasibility study of non-invasive fetal trisomy 18 and 21 detection with semiconductor sequencing platform.
PLoS One
. 2014 Oct; 9(10):e110240.
11.
Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform.
Bioinformatics
. 2010 Mar; 26(5): 589–95.
12.
Steiner I, Kennedy PG, Pachner AR. The neurotropic herpes viruses: herpes simplex and varicella-zoster.
Lancet Neurol
. 2007 Nov; 6(11): 1015–28.
13.
Whitley RJ. Herpes simplex virus infections of the central nervous system. Encephalitis and neonatal herpes.
Drugs
. 1991 Sep; 42(3): 406–27.
14.
Baldwin KJ, Cummings CL. Herpesvirus Infections of the Nervous System.
Continuum (Minneap Minn)
. 2018 Oct; 24 5, Neuroinfectious Disease: 1349–69.
15.
Nahmias AJ, Lee FK, Beckman-Nahmias S. Sero-epidemiological and -sociological patterns of herpes simplex virus infection in the world.
Scand J Infect Dis Suppl
. 1990; 69: 19–36.
16.
Opstelten W, Neven AK, Eekhof J. Treatment and prevention of herpes labialis.
Can Fam Physician
. 2008 Dec; 54(12): 1683–7.
17.
Skripuletz T, Pars K, Schulte A, Schwenkenbecher P, Yildiz Ö, Ganzenmueller T, et al. Varicella zoster virus infections in neurological patients: a clinical study.
BMC Infect Dis
. 2018 May; 18(1): 238.
18.
Hughes PS, Jackson AC. Delays in initiation of acyclovir therapy in herpes simplex encephalitis.
Can J Neurol Sci
. 2012 Sep; 39(5): 644–8.
19.
Erdem H, Cag Y, Ozturk-Engin D, Defres S, Kaya S, Larsen L, et al. Results of a multinational study suggest the need for rapid diagnosis and early antiviral treatment at the onset of herpetic meningoencephalitis.
Antimicrob Agents Chemother
. 2015; 59(6): 3084–9.
20.
Brown JR, Bharucha T, Breuer J. Encephalitis diagnosis using metagenomics: application of next generation sequencing for undiagnosed cases.
J Infect
. 2018 Mar; 76(3): 225–40.
21.
Davies NW, Brown LJ, Gonde J, Irish D, Robinson RO, Swan AV, et al. Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections.
J Neurol Neurosurg Psychiatry
. 2005 Jan; 76(1): 82–7.
22.
Koyuncu OO, Hogue IB, Enquist LW. Virus infections in the nervous system.
Cell Host Microbe
. 2013 Apr; 13(4): 379–93.
23.
Woźniakowski G, Samorek-Salamonowicz E. Animal herpesviruses and their zoonotic potential for cross-species infection.
Ann Agric Environ Med
. 2015; 22(2): 191–4.
24.
Ai JW, Weng SS, Cheng Q, Cui P, Li YJ, Wu HL, et al. Human Endophthalmitis Caused By Pseudorabies Virus Infection, China, 2017.
Emerg Infect Dis
. 2018 Jun; 24(6): 1087–90.
25.
Kennedy PG, Quan PL, Lipkin WI. Viral Encephalitis of Unknown Cause: Current Perspective and Recent Advances.
Viruses
. 2017 Jun; 9(6): 138.
26.
Simner PJ, Miller S, Carroll KC. Understanding the Promises and Hurdles of Metagenomic Next-Generation Sequencing as a Diagnostic Tool for Infectious Diseases.
Clin Infect Dis
. 2018 Feb; 66(5): 778–88.
© 2019 S. Karger AG, Basel
2019
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.