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Abstract

Background

Various pathogens, including bacteria, fungi, parasites, and viruses can lead to meningitis. Among viruses causing meningitis, Toscana virus (TOSV), a phlebovirus, is transmitted through sandfly bites. TOSV infection may be suspected if patients with enterovirus- and herpesvirus-negative aseptic (non-bacterial) meningitis recall recent insect bites. Other epidemiological factors (season, rural area) may be considered. The broad range of possible meningitis aetiologies poses considerable diagnosis challenges. Untargeted metagenomic next-generation sequencing (mNGS) can potentially identify pathogens, which are not considered or detected in routine diagnostic panels.

Aim

In this retrospective, single-centre observational study, we investigated mNGS usefulness to understand the cause of meningitis when conventional approaches fail.

Methods

Cerebrospinal fluid (CSF) samples from patients hospitalised in southern Spain in 2015–2019 with aseptic meningitis and no aetiology found by conventional testing, were subjected to mNGS. Patients’ demographic characteristics had been recorded and physicians had asked them about recent insect bites. Obtained viral genome sequences were phylogenetically analysed.

Results

Among 23 idiopathic cases, TOSV was identified in eight (all male; median age:  39 years, range: 15–78 years). Five cases lived in an urban setting, three occurred in autumn and only one recalled insect bites. Phylogenetic analysis of TOSV segment sequences supported one intra-genotype reassortment event.

Conclusions

Our study highlights the usefulness of mNGS for identifying viral pathogens directly in CSF. In southern Spain, TOSV should be considered regardless of recalling of insect bites or other epidemiological criteria. Detection of a disease-associated reassortant TOSV emphasises the importance of monitoring the spread and evolution of phleboviruses in Mediterranean countries.

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/content/10.2807/1560-7917.ES.2023.28.45.2200913
2023-11-09
2024-06-23
http://instance.metastore.ingenta.com/content/10.2807/1560-7917.ES.2023.28.45.2200913
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References

  1. James SL, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. , GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-858.  https://doi.org/10.1016/S0140-6736(18)32279-7  PMID: 30496104 
  2. John CC, Carabin H, Montano SM, Bangirana P, Zunt JR, Peterson PK. Global research priorities for infections that affect the nervous system. Nature. 2015;527(7578):S178-86.  https://doi.org/10.1038/nature16033  PMID: 26580325 
  3. McGill F, Griffiths MJ, Bonnett LJ, Geretti AM, Michael BD, Beeching NJ, et al. , UK Meningitis Study Investigators. Incidence, aetiology, and sequelae of viral meningitis in UK adults: a multicentre prospective observational cohort study. Lancet Infect Dis. 2018;18(9):992-1003.  https://doi.org/10.1016/S1473-3099(18)30245-7  PMID: 30153934 
  4. Shukla B, Aguilera EA, Salazar L, Wootton SH, Kaewpoowat Q, Hasbun R. Aseptic meningitis in adults and children: Diagnostic and management challenges. J Clin Virol. 2017;94:110-4.  https://doi.org/10.1016/j.jcv.2017.07.016  PMID: 28806629 
  5. Faria NR, Azevedo RDSDS, Kraemer MUG, Souza R, Cunha MS, Hill SC, et al. Zika virus in the Americas: Early epidemiological and genetic findings. Science. 2016;352(6283):345-9.  https://doi.org/10.1126/science.aaf5036  PMID: 27013429 
  6. Ramachandran PS, Wilson MR. Metagenomics for neurological infections - expanding our imagination. Nat Rev Neurol. 2020;16(10):547-56.  https://doi.org/10.1038/s41582-020-0374-y  PMID: 32661342 
  7. Instituto Nacional de Estadística (INE). Córdoba: Población por municipios y sexo. [Population by municipalities and sex]. Madrid: INE. Spanish. Available from: https://www.ine.es/jaxiT3/Datos.htm?t=2901
  8. Gámbaro F, Pérez AB, Agüera E, Prot M, Martínez-Martínez L, Cabrerizo M, et al. Genomic surveillance of enterovirus associated with aseptic meningitis cases in southern Spain, 2015-2018. Sci Rep. 2021;11(1):21523.  https://doi.org/10.1038/s41598-021-01053-4  PMID: 34728763 
  9. Kalantar KL, Carvalho T, de Bourcy CFA, Dimitrov B, Dingle G, Egger R, et al. IDseq-An open source cloud-based pipeline and analysis service for metagenomic pathogen detection and monitoring. Gigascience. 2020;9(10):giaa111.  https://doi.org/10.1093/gigascience/giaa111  PMID: 33057676 
  10. Pickett BE, Greer DS, Zhang Y, Stewart L, Zhou L, Sun G, et al. Virus pathogen database and analysis resource (ViPR): a comprehensive bioinformatics database and analysis resource for the coronavirus research community. Viruses. 2012;4(11):3209-26.  https://doi.org/10.3390/v4113209  PMID: 23202522 
  11. Benson DA, Cavanaugh M, Clark K, Karsch-Mizrachi I, Lipman DJ, Ostell J, et al. GenBank. Nucleic Acids Res. 2013;41(Database issue) D1;D36-42. PMID: 23193287 
  12. Katoh K, Standley DM. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol. 2013;30(4):772-80.  https://doi.org/10.1093/molbev/mst010  PMID: 23329690 
  13. Nguyen L-T, Schmidt HA, von Haeseler A, Minh BQ. IQ-TREE: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies. Mol Biol Evol. 2015;32(1):268-74.  https://doi.org/10.1093/molbev/msu300  PMID: 25371430 
  14. Kalyaanamoorthy S, Minh BQ, Wong TKF, von Haeseler A, Jermiin LS. ModelFinder: fast model selection for accurate phylogenetic estimates. Nat Methods. 2017;14(6):587-9.  https://doi.org/10.1038/nmeth.4285  PMID: 28481363 
  15. Hoang DT, Chernomor O, von Haeseler A, Minh BQ, Vinh LS. UFBoot2: Improving the Ultrafast Bootstrap Approximation. Mol Biol Evol. 2018;35(2):518-22.  https://doi.org/10.1093/molbev/msx281  PMID: 29077904 
  16. Martin DP, Murrell B, Golden M, Khoosal A, Muhire B. RDP4: Detection and analysis of recombination patterns in virus genomes. Virus Evol. 2015;1(1):vev003.  https://doi.org/10.1093/ve/vev003  PMID: 27774277 
  17. Lole KS, Bollinger RC, Paranjape RS, Gadkari D, Kulkarni SS, Novak NG, et al. Full-length human immunodeficiency virus type 1 genomes from subtype C-infected seroconverters in India, with evidence of intersubtype recombination. J Virol. 1999;73(1):152-60.  https://doi.org/10.1128/JVI.73.1.152-160.1999  PMID: 9847317 
  18. Uchida K, Shinohara M, Shimada S, Segawa Y, Doi R, Gotoh A, et al. Rapid and sensitive detection of mumps virus RNA directly from clinical samples by real-time PCR. J Med Virol. 2005;75(3):470-4.  https://doi.org/10.1002/jmv.20291  PMID: 15648065 
  19. Quick J, Grubaugh ND, Pullan ST, Claro IM, Smith AD, Gangavarapu K, et al. Multiplex PCR method for MinION and Illumina sequencing of Zika and other virus genomes directly from clinical samples. Nat Protoc. 2017;12(6):1261-76.  https://doi.org/10.1038/nprot.2017.066  PMID: 28538739 
  20. Alten B, Maia C, Afonso MO, Campino L, Jiménez M, González E, et al. Seasonal Dynamics of Phlebotomine Sand Fly Species Proven Vectors of Mediterranean Leishmaniasis Caused by Leishmania infantum. PLoS Negl Trop Dis. 2016;10(2):e0004458.  https://doi.org/10.1371/journal.pntd.0004458  PMID: 26900688 
  21. Collao X, Palacios G, Sanbonmatsu-Gámez S, Pérez-Ruiz M, Negredo AI, Navarro-Marí JM, et al. Genetic diversity of Toscana virus. Emerg Infect Dis. 2009;15(4):574-7.  https://doi.org/10.3201/eid1504.081111  PMID: 19331735 
  22. Saha S, Ramesh A, Kalantar K, Malaker R, Hasanuzzaman M, Khan LM, et al. Unbiased Metagenomic Sequencing for Pediatric Meningitis in Bangladesh Reveals Neuroinvasive Chikungunya Virus Outbreak and Other Unrealized Pathogens. MBio. 2019;10(6):e02877-19.  https://doi.org/10.1128/mBio.02877-19  PMID: 31848287 
  23. Ministerio De Sanidad. Informe de situación y evaluación del riesgo de enfermedad por flebovirus trasmitidos por flebotomos en España. [Situation report and risk assessment of sandfly-borne phlebovirus disease in Spain]. Madrid: Centro de Coordinación de Alertas y Emergencias Sanitarias (CCAES); 2019. Spanish. Available from:  https://www.sanidad.gob.es/profesionales/saludPublica/ccayes/analisisituacion/doc/ER_Flebovirus.pdf.
  24. Piantadosi A, Mukerji SS, Ye S, Leone MJ, Freimark LM, Park D, et al. Enhanced Virus Detection and Metagenomic Sequencing in Patients with Meningitis and Encephalitis. MBio. 2021;12(4):e0114321.  https://doi.org/10.1128/mBio.01143-21  PMID: 34465023 
  25. Wilson MR, Sample HA, Zorn KC, Arevalo S, Yu G, Neuhaus J, et al. Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis. N Engl J Med. 2019;380(24):2327-40.  https://doi.org/10.1056/NEJMoa1803396  PMID: 31189036 
  26. Ayhan N, Charrel RN. An update on Toscana virus distribution, genetics, medical and diagnostic aspects. Clin Microbiol Infect. 2020;26(8):1017-23.  https://doi.org/10.1016/j.cmi.2019.12.015  PMID: 31904562 
  27. Gori Savellini G, Gandolfo C, Cusi MG. Epidemiology of Toscana virus in South Tuscany over the years 2011-2019. J Clin Virol. 2020;128:104452.  https://doi.org/10.1016/j.jcv.2020.104452  PMID: 32474372 
  28. Sanbonmatsu-Gámez S, Pedrosa-Corral I, Navarro-Marí JM, Pérez-Ruiz M. Update in Diagnostics of Toscana Virus Infection in a Hyperendemic Region (Southern Spain). Viruses. 2021;13(8):1438.  https://doi.org/10.3390/v13081438  PMID: 34452304 
  29. Informe Semanal. Sistema Vigilancia Epidemiologica de Andalucía (SVEA). Meningitis Vírica 2016–2017. [Viral meningitis in Andalusia 2016–2017]. Spanish. 2019;24(3):BES 0319. Available from: https://www.repositoriosalud.es/bitstream/10668/3049/1/SVEAIS_24_03_2019.pdf
  30. Laroche L, Jourdain F, Ayhan N, Bañuls AL, Charrel R, Prudhomme J. Incubation Period for Neuroinvasive Toscana Virus Infections. Emerg Infect Dis. 2021;27(12):3147-50.  https://doi.org/10.3201/eid2712.203172  PMID: 34808074 
  31. Alkan C, Bichaud L, de Lamballerie X, Alten B, Gould EA, Charrel RN. Sandfly-borne phleboviruses of Eurasia and Africa: epidemiology, genetic diversity, geographic range, control measures. Antiviral Res. 2013;100(1):54-74.  https://doi.org/10.1016/j.antiviral.2013.07.005  PMID: 23872312 
  32. Ayhan N, Charrel RN. An update on Toscana virus distribution, genetics, medical and diagnostic aspects. Clin Microbiol Infect. 2020;26(8):1017-23.  https://doi.org/10.1016/j.cmi.2019.12.015  PMID: 31904562 
  33. Dersch R, Sophocleous A, Cadar D, Emmerich P, Schmidt-Chanasit J, Rauer S. Toscana virus encephalitis in Southwest Germany: a retrospective study. BMC Neurol. 2021;21(1):495.  https://doi.org/10.1186/s12883-021-02528-7  PMID: 34937553 
  34. Briese T, Calisher CH, Higgs S. Viruses of the family Bunyaviridae: are all available isolates reassortants? Virology. 2013;446(1-2):207-16.  https://doi.org/10.1016/j.virol.2013.07.030  PMID: 24074583 
  35. Collao X, Palacios G, de Ory F, Sanbonmatsu S, Pérez-Ruiz M, Navarro JM, et al. Granada virus: a natural phlebovirus reassortant of the sandfly fever Naples serocomplex with low seroprevalence in humans. Am J Trop Med Hyg. 2010;83(4):760-5.  https://doi.org/10.4269/ajtmh.2010.09-0697  PMID: 20889862 
  36. Palacios G, Tesh R, Travassos da Rosa A, Savji N, Sze W, Jain K, et al. Characterization of the Candiru antigenic complex (Bunyaviridae: Phlebovirus), a highly diverse and reassorting group of viruses affecting humans in tropical America. J Virol. 2011;85(8):3811-20.  https://doi.org/10.1128/JVI.02275-10  PMID: 21289119 
  37. Hall RJ, Wang J, Todd AK, Bissielo AB, Yen S, Strydom H, et al. Evaluation of rapid and simple techniques for the enrichment of viruses prior to metagenomic virus discovery. J Virol Methods. 2014;195:194-204.  https://doi.org/10.1016/j.jviromet.2013.08.035  PMID: 24036074 
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