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Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis
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 A(4) hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426373/ https://www.ncbi.nlm.nih.gov/pubmed/28419368 http://dx.doi.org/10.1093/infdis/jix050 |
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author | 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. |
author_facet | 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. |
author_sort | Thuong, Nguyen T. T. |
collection | PubMed |
description | 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 A(4) 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. |
format | Online Article Text |
id | pubmed-5426373 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54263732017-05-16 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. J Infect Dis Major Article 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 A(4) 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. Oxford University Press 2017-04-01 2017-04-17 /pmc/articles/PMC5426373/ /pubmed/28419368 http://dx.doi.org/10.1093/infdis/jix050 Text en © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Major Article 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 |
title | Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis |
title_full | Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis |
title_fullStr | Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis |
title_full_unstemmed | Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis |
title_short | Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis |
title_sort | leukotriene a4 hydrolase genotype and hiv infection influence intracerebral inflammation and survival from tuberculous meningitis |
topic | Major Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426373/ https://www.ncbi.nlm.nih.gov/pubmed/28419368 http://dx.doi.org/10.1093/infdis/jix050 |
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