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Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone

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dc.contributor.authorWhitworth, Laura J.
dc.contributor.authorTroll, Rajan
dc.contributor.authorPagán, Antonio J.
dc.contributor.authorRoca Soler, Francisco José
dc.contributor.authorEdelstein, Paul H.
dc.contributor.authorTroll, Mark
dc.contributor.authorTobin, David M.
dc.contributor.authorPhu, Nguyen Hoan
dc.contributor.authorBang, Nguyen Duc
dc.contributor.authorThwaites, Guy E.
dc.contributor.authorThuong, Nguyen Thuy Thuong
dc.contributor.authorSewell. Roger F.
dc.contributor.authorRamakrishnan, Lalita
dc.contributor.departmentBioquímica y Biología Molecular B e Inmunología
dc.date.accessioned2026-02-25T16:10:41Z
dc.date.available2026-02-25T16:10:41Z
dc.date.copyright© 2021 the Author(s)
dc.date.issued2021-03-03
dc.description.abstractAdjunctive treatment with antiinflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in Leukotriene A4 Hydrolase (LTA4H), which regulates expression of the proinflammatory mediator leukotriene B4 (LTB4). TT homozygotes, with increased expression of LTA4H, have the highest survival when treated with dexamethasone and the lowest survival without. While the T allele is present in only a minority of the world’s population, corticosteroids confer modest survival benefit worldwide. Using Bayesian methods, we examined how pretreatment levels of cerebrospinal fluid proinflammatory cytokines affect survival in dexamethasone-treated tuberculous meningitis. LTA4H TT homozygosity was associated with global cytokine increases, including tumor necrosis factor. Association between higher cytokine levels and survival extended to non-TT patients, suggesting that other genetic variants may also induce dexamethasone-responsive pathological inflammation. These findings warrant studies that tailor dexamethasone therapy to pretreatment cerebrospinal fluid cytokine concentrations, while searching for additional genetic loci shaping the inflammatory milieu.
dc.formatapplication/pdf
dc.format.extent8
dc.identifier.citationPNAS 2021 Vol. 118 No. 10 e2024852118
dc.identifier.doihttps://doi.org/10.1073/pnas.2024852118
dc.identifier.eissn1091-6490
dc.identifier.issn0027-8424
dc.identifier.urihttp://hdl.handle.net/10201/213561
dc.languageeng
dc.publisherNational Academy of Sciences
dc.relationThis work was supported by Wellcome Trust core-funding support to the Wellcome Sanger Institute (award number 206194) (GR, MB) and NIH MERIT award (R37 AI054503) and a Wellcome Trust Principal Research Fellowship (LR).
dc.rightsAttribution 4.0 International*
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectTuberculous meningitis
dc.subjectCytokines
dc.subjectInflammation
dc.subjectCorticosteroids
dc.subjectBayesian analysis
dc.subject.odsObjetivo 3: Salud
dc.titleElevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication7f46a88a-1ff4-4f80-948e-7d636b80e75d
relation.isAuthorOfPublication.latestForDiscovery7f46a88a-1ff4-4f80-948e-7d636b80e75d
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