{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:45:53Z","timestamp":1788306353090,"version":"build-2803163510"},"reference-count":34,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T00:00:00Z","timestamp":1619740800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"South African Government through the Technology Innovation Agency (TIA)"},{"name":"South African Research Chairs Initiative (SARChi) in TB Biomarkers","award":["86535"],"award-info":[{"award-number":["86535"]}]},{"name":"International Collaborations in Infectious Disease Research","award":["5U01IA115619"],"award-info":[{"award-number":["5U01IA115619"]}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"crossref","award":["109437"],"award-info":[{"award-number":["109437"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001713","name":"European and Developing Countries Clinical Trials Partnership","doi-asserted-by":"publisher","award":["TMA2018SF-2470-TBMBIOMARKERS"],"award-info":[{"award-number":["TMA2018SF-2470-TBMBIOMARKERS"]}],"id":[{"id":"10.13039\/501100001713","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","award":["57020"],"award-info":[{"award-number":["57020"]}],"id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>Stroke is a common complication in children with tuberculous meningitis (TBM). Host proteins may give us insight into the mechanisms of stroke in TBM and serve as biomarkers for detection of stroke, however, they have not been widely explored. In this study, we compared the concentrations of cerebrospinal fluid (CSF) and serum proteins between children who had TBM-related stroke and children with TBM without stroke.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We collected CSF and serum from 47 children consecutively admitted to the Tygerberg Academic Hospital in Cape Town, South Africa between November 2016, and November 2017, on suspicion of having TBM. A multiplex platform was used to measure the concentrations of 69 host proteins in CSF and serum from all study participants.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>After classification of study participants, 23 (48.9%) out of the 47 study participants were diagnosed with TBM, of which 14 (60.9%) demonstrated radiological arterial ischemic infarction. The levels of lipocalin-2, sRAGE, IP-10\/ CXCL10, sVCAM-1, MMP-1, and PDGF-AA in CSF samples and the levels of D-dimer, ADAMTS13, SAA, ferritin, MCP-1\/ CCL2, GDF-15 and IL-13 in serum samples were statistically different between children who had TBM-related stroke and children with TBM without stroke. After correcting for multiple testing, only the levels of sVCAM-1, MMP-1, sRAGE, and IP-10\/ CXCL10 in CSF were statistically different between the two groups. CSF and serum protein biosignatures indicated stroke in children diagnosed with TBM with up to 100% sensitivity and 88.9% specificity.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Serum and CSF proteins may serve as biomarkers for identifying individuals with stroke amongst children diagnosed with TBM at admission and may guide us to understand the biology of stroke in TBM. This was a pilot study, and thus further investigations in larger studies are needed.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0250944","type":"journal-article","created":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T17:37:09Z","timestamp":1619804229000},"page":"e0250944","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Serum and cerebrospinal fluid host proteins indicate stroke in children with tuberculous meningitis"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9343-9378","authenticated-orcid":true,"given":"Charles M.","family":"Manyelo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8690-1699","authenticated-orcid":true,"given":"Novel N.","family":"Chegou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2296-2302","authenticated-orcid":true,"given":"James A.","family":"Seddon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candice I.","family":"Snyders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6605-6275","authenticated-orcid":true,"given":"Hygon","family":"Mutavhatsindi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Portia M.","family":"Manngo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Walzl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Stanley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regan S.","family":"Solomons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,4,30]]},"reference":[{"key":"pone.0250944.ref001","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1128\/CMR.00042-07","article-title":"Central Nervous System Tuberculosis: Pathogenesis and Clinical Aspects.","volume":"21","author":"RB Rock","year":"2008","journal-title":"Clinical Microbiology Reviews"},{"key":"pone.0250944.ref002","doi-asserted-by":"crossref","first-page":"167","DOI":"10.12688\/wellcomeopenres.15535.1","article-title":"Tuberculous Meningitis International Research Consortium. The current global situation for tuberculous meningitis: epidemiology, diagnostics, treatment and outcomes","volume":"4","author":"JA Seddon","year":"2019","journal-title":"Wellcome Open Research"},{"key":"pone.0250944.ref003","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nrneurol.2017.120","article-title":"Tuberculous meningitis","volume":"13","author":"RJ Wilkinson","year":"2017","journal-title":"Nat Rev Neurol"},{"key":"pone.0250944.ref004","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/S1473-3099(14)70852-7","article-title":"Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis","volume":"14","author":"SS Chiang","year":"2014","journal-title":"The Lancet Infectious Diseases"},{"key":"pone.0250944.ref005","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/S1474-4422(13)70168-6","article-title":"Tuberculous meningitis: more questions, still too few answers","volume":"12","author":"GE Thwaites","year":"2013","journal-title":"The Lancet Neurology"},{"key":"pone.0250944.ref006","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jns.2010.12.015","article-title":"Stroke in tuberculous meningitis","volume":"303","author":"UK Misra","year":"2011","journal-title":"J Neurol Sci"},{"key":"pone.0250944.ref007","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.ejpn.2008.07.004","article-title":"Cerebral infarction and neurodevelopmental outcome in childhood tuberculous meningitis","volume":"13","author":"P Springer","year":"2009","journal-title":"European Journal of Paediatric Neurology"},{"key":"pone.0250944.ref008","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1093\/cid\/cix540","article-title":"Biomarkers of Cerebral Injury and Inflammation in Pediatric Tuberculous Meningitis","volume":"65","author":"UK Rohlwink","year":"2017","journal-title":"Clin Infect Dis"},{"key":"pone.0250944.ref009","doi-asserted-by":"crossref","first-page":"e33478","DOI":"10.7554\/eLife.33478","article-title":"A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults","volume":"7","author":"NT Mai","year":"2018","journal-title":"eLife"},{"key":"pone.0250944.ref010","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.neulet.2008.02.060","article-title":"Proinflammatory cytokine levels in the serum and cerebrospinal fluid of tuberculous meningitis patients","volume":"436","author":"G Nagesh Babu","year":"2008","journal-title":"Neuroscience Letters"},{"key":"pone.0250944.ref011","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.neulet.2010.07.029","article-title":"A study of cytokines in tuberculous meningitis: Clinical and MRI correlation","volume":"483","author":"UK Misra","year":"2010","journal-title":"Neuroscience Letters"},{"key":"pone.0250944.ref012","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/BF02734223","article-title":"Interleukin-8 levels in children with bacterial, tuberculous and aseptic meningitis","volume":"69","author":"E Yilmaz","year":"2002","journal-title":"Indian J Pediatr"},{"key":"pone.0250944.ref013","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/S1473-3099(10)70138-9","article-title":"Tuberculous meningitis: a uniform case definition for use in clinical research","volume":"10","author":"S Marais","year":"2010","journal-title":"The Lancet Infectious Diseases"},{"key":"pone.0250944.ref014","doi-asserted-by":"crossref","first-page":"5657","DOI":"10.1073\/pnas.96.10.5657","article-title":"Tumor necrosis factor is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system","volume":"96","author":"L Tsenova","year":"1999","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"pone.0250944.ref015","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jns.2017.06.001","article-title":"Cytokines do play a role in pathogenesis of tuberculous meningitis: A prospective study from a tertiary care center in India","volume":"379","author":"S Sharma","year":"2017","journal-title":"Journal of the Neurological Sciences"},{"key":"pone.0250944.ref016","doi-asserted-by":"crossref","first-page":"376","DOI":"10.3389\/fped.2019.00376","article-title":"Potential of Host Serum Protein Biomarkers in the Diagnosis of Tuberculous Meningitis in Children.","volume":"7","author":"CM Manyelo","year":"2019","journal-title":"Front Pediatr."},{"key":"pone.0250944.ref017","doi-asserted-by":"crossref","first-page":"7582948","DOI":"10.1155\/2019\/7582948","article-title":"Application of Cerebrospinal Fluid Host Protein Biosignatures in the Diagnosis of Tuberculous Meningitis in Children from a High Burden Setting. Giovarelli M, editor","volume":"2019","author":"CM Manyelo","year":"2019","journal-title":"Mediators of Inflammation"},{"key":"pone.0250944.ref018","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/S1473-3099(10)70138-9","article-title":"Tuberculous meningitis: a uniform case definition for use in clinical research","volume":"10","author":"S Marais","year":"2010","journal-title":"The Lancet Infectious Diseases"},{"key":"pone.0250944.ref019","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1093\/cid\/ciu781","article-title":"Host Immune Response to Tuberculous Meningitis","volume":"60","author":"DH Visser","year":"2015","journal-title":"Clinical Infectious Diseases"},{"key":"pone.0250944.ref020","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1136\/thoraxjnl-2015-207999","article-title":"Diagnostic performance of a seven-marker serum protein biosignature for the diagnosis of active TB disease in African primary healthcare clinic attendees with signs and symptoms suggestive of TB","volume":"71","author":"NN Chegou","year":"2016","journal-title":"Thorax"},{"key":"pone.0250944.ref021","article-title":"Diagnostic Potential of Novel Salivary Host Biomarkers as Candidates for the Immunological Diagnosis of Tuberculosis Disease and Monitoring of Tuberculosis Treatment Response.","volume":"13","author":"R Jacobs","year":"2016","journal-title":"PLOS ONE"},{"key":"pone.0250944.ref022","doi-asserted-by":"crossref","first-page":"57581","DOI":"10.18632\/oncotarget.11420","article-title":"Identification of novel host biomarkers in plasma as candidates for the immunodiagnosis of tuberculosis disease and monitoring of tuberculosis treatment response","volume":"7","author":"R Jacobs","year":"2016","journal-title":"Oncotarget"},{"key":"pone.0250944.ref023","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1002\/bimj.200410135","article-title":"Estimation of the Youden Index and its Associated Cutoff Point","volume":"47","author":"R Fluss","year":"2005","journal-title":"Biom J"},{"key":"pone.0250944.ref024","doi-asserted-by":"crossref","first-page":"772","DOI":"10.3389\/fneur.2019.00772","article-title":"ADAMTS13: An Emerging Target in Stroke Therapy.","volume":"10","author":"X Chen","year":"2019","journal-title":"Front Neurol"},{"key":"pone.0250944.ref025","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1055\/s-0032-1326782","article-title":"D-Dimer Assays in Diagnosis and Management of Thrombotic and Bleeding Disorders","volume":"38","author":"S Bates","year":"2012","journal-title":"Seminars in Thrombosis and Hemostasis"},{"key":"pone.0250944.ref026","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s12974-019-1556-7","article-title":"Lipocalin-2 may produce damaging effect after cerebral ischemia by inducing astrocytes classical activation","volume":"16","author":"N Zhao","year":"2019","journal-title":"J Neuroinflammation."},{"key":"pone.0250944.ref027","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/1742-2094-11-79","article-title":"Accumulation of natural killer cells in ischemic brain tissues and the chemotactic effect of IP-10","volume":"11","author":"Y Zhang","year":"2014","journal-title":"J Neuroinflammation"},{"key":"pone.0250944.ref028","doi-asserted-by":"crossref","first-page":"3191","DOI":"10.1021\/pr801012x","article-title":"Vascular MMP-9\/TIMP-2 and Neuronal MMP-10 Up-Regulation in Human Brain after Stroke: A Combined Laser Microdissection and Protein Array Study","volume":"8","author":"E Cuadrado","year":"2009","journal-title":"Journal of Proteome Research"},{"key":"pone.0250944.ref029","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1155\/2009\/490867","article-title":"Temporal Patterns of Soluble Adhesion Molecules in Cerebrospinal Fluid and Plasma in Patients with the Acute Brain Infraction","volume":"26","author":"V Selakovic","year":"2009","journal-title":"Dis Markers"},{"key":"pone.0250944.ref030","article-title":"A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults.","volume":"7","author":"NT Mai","journal-title":"eLife."},{"key":"pone.0250944.ref031","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.1182\/blood-2009-03-213264","article-title":"von Willebrand factor\u2013cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke","volume":"114","author":"B-Q Zhao","year":"2009","journal-title":"Blood"},{"key":"pone.0250944.ref032","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1182\/blood-2016-10-747089","article-title":"ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery","volume":"130","author":"H Xu","year":"2017","journal-title":"Blood"},{"key":"pone.0250944.ref033","first-page":"599","article-title":"Stroke, angiogenesis and phytochemicals","volume":"4","author":"Y-C Chen","year":"2012","journal-title":"Front Biosci (Schol Ed)."},{"key":"pone.0250944.ref034","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1007\/s00381-008-0785-3","article-title":"MRI to demonstrate diagnostic features and complications of TBM not seen with CT","volume":"25","author":"M Pienaar","year":"2009","journal-title":"Childs Nerv Syst"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0250944","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T17:37:47Z","timestamp":1619804267000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0250944"}},"subtitle":[],"editor":[{"given":"Katalin Andrea","family":"Wilkinson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,4,30]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0250944","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,30]]}}}