{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T18:23:12Z","timestamp":1780510992410,"version":"3.54.1"},"reference-count":28,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,1,15]],"date-time":"2019-01-15T00:00:00Z","timestamp":1547510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009318","name":"Helmholtz Association","doi-asserted-by":"publisher","award":["iMed Initiative on Personalized Medicine"],"award-info":[{"award-number":["iMed Initiative on Personalized Medicine"]}],"id":[{"id":"10.13039\/501100009318","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Cluster of Excelence RESIST"],"award-info":[{"award-number":["Cluster of Excelence RESIST"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005624","name":"Medizinischen Hochschule Hannover","doi-asserted-by":"publisher","award":["Junge Akademie"],"award-info":[{"award-number":["Junge Akademie"]}],"id":[{"id":"10.13039\/501100005624","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Enteroviruses are among the most common causes of viral meningitis. Enteroviral meningitis continues to represent diagnostic challenges, as cerebrospinal fluid (CSF) cell numbers (a well validated diagnostic screening tool) may be normal in up to 15% of patients. We aimed to identify potential CSF biomarkers for enteroviral meningitis, particularly for cases with normal CSF cell count. Using targeted liquid chromatography-mass spectrometry, we determined metabolite profiles from patients with enteroviral meningitis (n = 10), and subdivided them into those with elevated (n = 5) and normal (n = 5) CSF leukocyte counts. Non-inflamed CSF samples from patients with Bell\u2019s palsy and normal pressure hydrocephalus (n = 19) were used as controls. Analysis of 91 metabolites revealed considerable metabolic reprogramming in the meningitis samples. It identified phosphatidylcholine PC.ae.C36.3, asparagine, and glycine as an accurate (AUC, 0.92) combined classifier for enterovirus meningitis overall, and kynurenine as a perfect biomarker for enteroviral meningitis with an increased CSF cell count (AUC, 1.0). Remarkably, PC.ae.C36.3 alone emerged as a single accurate (AUC, 0.87) biomarker for enteroviral meningitis with normal cell count, and a combined classifier comprising PC.ae.C36.3, PC.ae.C36.5, and PC.ae.C38.5 achieved nearly perfect classification (AUC, 0.99). Taken together, this analysis reveals the potential of CSF metabolites as additional diagnostic tools for enteroviral meningitis, and likely other central nervous system (CNS) infections.<\/jats:p>","DOI":"10.3390\/ijms20020337","type":"journal-article","created":{"date-parts":[[2019,1,16]],"date-time":"2019-01-16T03:09:13Z","timestamp":1547608153000},"page":"337","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Identification of Cerebrospinal Fluid Metabolites as Biomarkers for Enterovirus Meningitis"],"prefix":"10.3390","volume":"20","author":[{"given":"Dominica","family":"Ratuszny","sequence":"first","affiliation":[{"name":"Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8077-481X","authenticated-orcid":false,"given":"Kurt-Wolfram","family":"S\u00fchs","sequence":"additional","affiliation":[{"name":"Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany"},{"name":"Centre for Individualised Infection Medicine, Feodor-Lynen-Str. 15, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Novoselova","sequence":"additional","affiliation":[{"name":"Institute for Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany"},{"name":"United Institute of Informatics Problems, the National Academy of Sciences of Belarus, Surganova 6, 220012 Minsk, Belarus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Institute for Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany"},{"name":"Research Group Biomarkers for Infectious Diseases, Helmholtz-Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volkhard","family":"Kaever","sequence":"additional","affiliation":[{"name":"Research Core Unit Metabolomics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Skripuletz","sequence":"additional","affiliation":[{"name":"Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2504-5398","authenticated-orcid":false,"given":"Frank","family":"Pessler","sequence":"additional","affiliation":[{"name":"Centre for Individualised Infection Medicine, Feodor-Lynen-Str. 15, 30625 Hannover, Germany"},{"name":"Institute for Experimental Infection Research, TWINCORE Centre for Experimental and Clinical Infection Research GmbH, Feodor-Lynen-Str. 7, 30625 Hannover, Germany"},{"name":"Research Group Biomarkers for Infectious Diseases, Helmholtz-Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2504-5398","authenticated-orcid":false,"given":"Martin","family":"Stangel","sequence":"additional","affiliation":[{"name":"Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany"},{"name":"Centre for Individualised Infection Medicine, Feodor-Lynen-Str. 15, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,1,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/1756285609337975","article-title":"Pathophysiology and treatment of bacterial meningitis","volume":"2","author":"Hoffman","year":"2009","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_2","first-page":"1255","article-title":"Acute bacterial and viral meningitis","volume":"18","author":"Bartt","year":"2012","journal-title":"Continuum"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1002\/jmv.23470","article-title":"Viral infections of the central nervous system in Spain: A prospective study","volume":"85","author":"Avellon","year":"2013","journal-title":"J. Med. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/jcla.20129","article-title":"Enterovirus meningitis in Greece from 2003\u20132005: Diagnosis, CSF laboratory findings, and clinical manifestations","volume":"20","author":"Dumaidi","year":"2006","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s12245-009-0128-5","article-title":"Lumbar punctures: Use and diagnostic efficiency in emergency medical departments","volume":"2","author":"Majed","year":"2009","journal-title":"Int. J. Emerg. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1093\/cid\/civ011","article-title":"Adult bacterial meningitis: Earlier treatment and improved outcome following guideline revision promoting prompt lumbar puncture","volume":"60","author":"Glimaker","year":"2015","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ostergaard, A.A., Sydenham, T.V., Nybo, M., and Andersen, A.B. (2017). Cerebrospinal fluid pleocytosis level as a diagnostic predictor? A cross-sectional study. BMC Clin. Pathol., 17.","DOI":"10.1186\/s12907-017-0053-0"},{"key":"ref_8","first-page":"94","article-title":"Cerebrospinal fluid features in adults with enteroviral nervous system infection","volume":"68","author":"Ahlbrecht","year":"2018","journal-title":"Int. J. Infect. Dis. IJID Off. Publ. Int. Soc. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1128\/CMR.17.4.903-925.2004","article-title":"Molecular methods for diagnosis of viral encephalitis","volume":"17","author":"Debiasi","year":"2004","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1086\/591129","article-title":"Clinical features of viral meningitis in adults: Significant differences in cerebrospinal fluid findings among herpes simplex virus, varicella zoster virus, and enterovirus infections","volume":"47","author":"Ihekwaba","year":"2008","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1155\/2012\/378432","article-title":"Clinical presentation of patients with aseptic meningitis, factors influencing treatment and hospitalization, and consequences of enterovirus cerebrospinal fluid polymerase chain reaction testing","volume":"23","author":"Patriquin","year":"2012","journal-title":"Can. J. Infect. Dis. Med Microbiol. J. Can. Des Mal. Infect. Et De La Microbiol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12974-017-1041-0","article-title":"Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation","volume":"15","author":"Kuhn","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hosmer, D.W., and Lemeshow, S. (2000). Applied Logistic Regression, John Wiley & Sons, Inc.. [2nd ed.].","DOI":"10.1002\/0471722146"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4196","DOI":"10.1002\/sim.5824","article-title":"Impact of correlation on predictive ability of biomarkers","volume":"32","author":"Demler","year":"2013","journal-title":"Stat. Med."},{"key":"ref_15","first-page":"E1064","article-title":"Positive-strand RNA viruses stimulate host phosphatidylcholine synthesis at viral replication sites","volume":"113","author":"Zhang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"40314","DOI":"10.1074\/jbc.M406517200","article-title":"The yeast phospholipid N-methyltransferases catalyzing the synthesis of phosphatidylcholine preferentially convert di-C16:1 substrates both in vivo and in vitro","volume":"279","author":"Boumann","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhang, W., Randell, E.W., Sun, G., Likhodii, S., Liu, M., Furey, A., and Zhai, G. (2017). Hyperglycemia-related advanced glycation end-products is associated with the altered phosphatidylcholine metabolism in osteoarthritis patients with diabetes. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184105"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9748","DOI":"10.1038\/s41598-017-09619-x","article-title":"Characterization of a metabolomic profile associated with responsiveness to therapy in the acute phase of septic shock","volume":"7","author":"Cambiaghi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8047","DOI":"10.3390\/ijms14048047","article-title":"Mass spectrometry-based quantitative metabolomics revealed a distinct lipid profile in breast cancer patients","volume":"14","author":"Qiu","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_20","first-page":"137","article-title":"Integration of targeted metabolomics and transcriptomics identifies deregulation of phosphatidylcholine metabolism in Huntington\u2019s disease peripheral blood samples","volume":"12","author":"Mastrokolias","year":"2016","journal-title":"Metab. Off. J. Metab. Soc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1039\/c3lc50169h","article-title":"Paper-based microfluidic point-of-care diagnostic devices","volume":"13","author":"Yetisen","year":"2013","journal-title":"Lab Chip"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1136\/jclinpath-2016-204104","article-title":"Evaluation of a rapid antigen test for detection of Streptococcus pneumoniae in cerebrospinal fluid","volume":"70","author":"Boulos","year":"2017","journal-title":"J. Clin. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11457","DOI":"10.1038\/ncomms11457","article-title":"Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor","volume":"7","author":"Krall","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_24","first-page":"15","article-title":"Beneficial Effects of the Amino Acid Glycine","volume":"17","year":"2017","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1080\/09687680010028762","article-title":"Glycine neurotransmitter transporters: An update","volume":"18","author":"Geerlings","year":"2001","journal-title":"Mol. Membr. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1178646917691938","DOI":"10.1177\/1178646917691938","article-title":"Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects","volume":"10","author":"Badawy","year":"2017","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1056\/NEJM196507152730301","article-title":"Symptomatic Occult Hydrocephalus with \u201cNormal\u201d Cerebrospinal-Fluid Pressure. A Treatable Syndrome","volume":"273","author":"Adams","year":"1965","journal-title":"N. Engl. J. Med."},{"key":"ref_28","unstructured":"Novoselova, N., Wang, J., Pessler, F., and Klawonn, F. (2018, October 01). Biocomb: Feature Selection and Classification with the Embedded Validation Procedures for Biomedical Data Analysis. R Package Version 0.4. Available online: https:\/\/CRAN.R-project.org\/package=Biocomb."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/2\/337\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:26:05Z","timestamp":1760185565000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/2\/337"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,15]]},"references-count":28,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,1]]}},"alternative-id":["ijms20020337"],"URL":"https:\/\/doi.org\/10.3390\/ijms20020337","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,15]]}}}