Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis

Nguyen T.T. Thuong, Dorothee Heemskerk, Trinh T.B. Tram, Le T.P. Thao, Lalita Ramakrishnan, Vu T.N. Ha, Nguyen D. Bang, Tran T.H. Chau, Nguyen H. Lan, Maxine Caws, Sarah J. Dunstan, Nguyen V.V. Chau, Marcel Wolbers, Nguyen T.H. Mai, Guy E. Thwaites

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Abstract

Background. Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. Methods. We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations. Results. LTA4H genotype predicted survival of human immunodeficiency virus (HIV)-uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype. Conclusions. LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.

Original languageEnglish
Pages (from-to)1020-1028
Number of pages9
JournalJournal of Infectious Diseases
Volume215
Issue number7
DOIs
Publication statusPublished - 1 Jan 2017
Externally publishedYes

Keywords

  • Cytokines
  • Inflammatory response
  • Leukotriene A4 hydrolase genotype
  • Survival
  • Tuberculous meningitis

Cite this

Thuong, Nguyen T.T. ; Heemskerk, Dorothee ; Tram, Trinh T.B. ; Thao, Le T.P. ; Ramakrishnan, Lalita ; Ha, Vu T.N. ; Bang, Nguyen D. ; Chau, Tran T.H. ; Lan, Nguyen H. ; Caws, Maxine ; Dunstan, Sarah J. ; Chau, Nguyen V.V. ; Wolbers, Marcel ; Mai, Nguyen T.H. ; Thwaites, Guy E. / Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis. In: Journal of Infectious Diseases. 2017 ; Vol. 215, No. 7. pp. 1020-1028.
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title = "Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis",
abstract = "Background. Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. Methods. We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations. Results. LTA4H genotype predicted survival of human immunodeficiency virus (HIV)-uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95{\%} confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype. Conclusions. LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.",
keywords = "Cytokines, Inflammatory response, Leukotriene A4 hydrolase genotype, Survival, Tuberculous meningitis",
author = "Thuong, {Nguyen T.T.} and Dorothee Heemskerk and Tram, {Trinh T.B.} and Thao, {Le T.P.} and Lalita Ramakrishnan and Ha, {Vu T.N.} and Bang, {Nguyen D.} and Chau, {Tran T.H.} and Lan, {Nguyen H.} and Maxine Caws and Dunstan, {Sarah J.} and Chau, {Nguyen V.V.} and Marcel Wolbers and Mai, {Nguyen T.H.} and Thwaites, {Guy E.}",
year = "2017",
month = "1",
day = "1",
doi = "10.1093/infdis/jix050",
language = "English",
volume = "215",
pages = "1020--1028",
journal = "Journal of Infectious Diseases",
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Thuong, NTT, Heemskerk, D, Tram, TTB, Thao, LTP, Ramakrishnan, L, Ha, VTN, Bang, ND, Chau, TTH, Lan, NH, Caws, M, Dunstan, SJ, Chau, NVV, Wolbers, M, Mai, NTH & Thwaites, GE 2017, 'Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis', Journal of Infectious Diseases, vol. 215, no. 7, pp. 1020-1028. https://doi.org/10.1093/infdis/jix050

Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis. / Thuong, Nguyen T.T.; Heemskerk, Dorothee; Tram, Trinh T.B.; Thao, Le T.P.; Ramakrishnan, Lalita; Ha, Vu T.N.; Bang, Nguyen D.; Chau, Tran T.H.; Lan, Nguyen H.; Caws, Maxine; Dunstan, Sarah J.; Chau, Nguyen V.V.; Wolbers, Marcel; Mai, Nguyen T.H.; Thwaites, Guy E.

In: Journal of Infectious Diseases, Vol. 215, No. 7, 01.01.2017, p. 1020-1028.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Leukotriene A4 hydrolase genotype and HIV infection influence intracerebral inflammation and survival from tuberculous meningitis

AU - Thuong, Nguyen T.T.

AU - Heemskerk, Dorothee

AU - Tram, Trinh T.B.

AU - Thao, Le T.P.

AU - Ramakrishnan, Lalita

AU - Ha, Vu T.N.

AU - Bang, Nguyen D.

AU - Chau, Tran T.H.

AU - Lan, Nguyen H.

AU - Caws, Maxine

AU - Dunstan, Sarah J.

AU - Chau, Nguyen V.V.

AU - Wolbers, Marcel

AU - Mai, Nguyen T.H.

AU - Thwaites, Guy E.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background. Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. Methods. We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations. Results. LTA4H genotype predicted survival of human immunodeficiency virus (HIV)-uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype. Conclusions. LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.

AB - Background. Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. Methods. We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations. Results. LTA4H genotype predicted survival of human immunodeficiency virus (HIV)-uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype. Conclusions. LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.

KW - Cytokines

KW - Inflammatory response

KW - Leukotriene A4 hydrolase genotype

KW - Survival

KW - Tuberculous meningitis

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U2 - 10.1093/infdis/jix050

DO - 10.1093/infdis/jix050

M3 - Article

VL - 215

SP - 1020

EP - 1028

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

SN - 0022-1899

IS - 7

ER -