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

Publication ,  Journal Article
Whitworth, LJ; Troll, R; Pagán, AJ; Roca, FJ; Edelstein, PH; Troll, M; Tobin, DM; Phu, NH; Bang, ND; Thwaites, GE; Thuong, NTT; Sewell, RF ...
Published in: Proc Natl Acad Sci U S A
March 9, 2021

Adjunctive 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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 9, 2021

Volume

118

Issue

10

Location

United States

Related Subject Headings

  • Tuberculosis, Meningeal
  • Survival Rate
  • Predictive Value of Tests
  • Middle Aged
  • Male
  • Humans
  • Genetic Variation
  • Female
  • Epoxide Hydrolases
  • Disease-Free Survival
 

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Whitworth, L. J., Troll, R., Pagán, A. J., Roca, F. J., Edelstein, P. H., Troll, M., … Ramakrishnan, L. (2021). Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone. Proc Natl Acad Sci U S A, 118(10). https://doi.org/10.1073/pnas.2024852118
Whitworth, Laura J., Rajan Troll, Antonio J. Pagán, Francisco J. Roca, Paul H. Edelstein, Mark Troll, David M. Tobin, et al. “Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone.Proc Natl Acad Sci U S A 118, no. 10 (March 9, 2021). https://doi.org/10.1073/pnas.2024852118.
Whitworth LJ, Troll R, Pagán AJ, Roca FJ, Edelstein PH, Troll M, et al. Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone. Proc Natl Acad Sci U S A. 2021 Mar 9;118(10).
Whitworth, Laura J., et al. “Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone.Proc Natl Acad Sci U S A, vol. 118, no. 10, Mar. 2021. Pubmed, doi:10.1073/pnas.2024852118.
Whitworth LJ, Troll R, Pagán AJ, Roca FJ, Edelstein PH, Troll M, Tobin DM, Phu NH, Bang ND, Thwaites GE, Thuong NTT, Sewell RF, Ramakrishnan L. Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone. Proc Natl Acad Sci U S A. 2021 Mar 9;118(10).
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 9, 2021

Volume

118

Issue

10

Location

United States

Related Subject Headings

  • Tuberculosis, Meningeal
  • Survival Rate
  • Predictive Value of Tests
  • Middle Aged
  • Male
  • Humans
  • Genetic Variation
  • Female
  • Epoxide Hydrolases
  • Disease-Free Survival