A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis
Tuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticos...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
eLife Sciences Publications
2021
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| _version_ | 1826309675501486080 |
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| author | Whitworth, L Coxon, J van Laarhoven, A Thuong, NTT Dian, S Alisjahbana, B Ganiem, AR van Crevel, R Thwaites, GE Troll, M Edelstein, PH Sewell, R Ramakrishnan, L |
| author_facet | Whitworth, L Coxon, J van Laarhoven, A Thuong, NTT Dian, S Alisjahbana, B Ganiem, AR van Crevel, R Thwaites, GE Troll, M Edelstein, PH Sewell, R Ramakrishnan, L |
| author_sort | Whitworth, L |
| collection | OXFORD |
| description | Tuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in the leukotriene A4 hydrolase (LTA4H) gene encoding an enzyme that regulates inflammatory eicosanoids. LTA4H TT patients with increased expression had increased survival, consistent with corticosteroids benefiting individuals with hyper-inflammatory responses. However, an Indonesia study did not find an LTA4H TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that LTA4H TT genotype confers survival benefit that begins early and continues long-term in both populations. This benefit is nullified in the most severe cases with high early mortality. LTA4H genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it. |
| first_indexed | 2024-03-07T07:39:17Z |
| format | Journal article |
| id | oxford-uuid:5eccdcac-c9a4-4b31-a499-da85bd81f77a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:39:17Z |
| publishDate | 2021 |
| publisher | eLife Sciences Publications |
| record_format | dspace |
| spelling | oxford-uuid:5eccdcac-c9a4-4b31-a499-da85bd81f77a2023-04-13T11:33:44ZA Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5eccdcac-c9a4-4b31-a499-da85bd81f77aEnglishSymplectic ElementseLife Sciences Publications2021Whitworth, LCoxon, Jvan Laarhoven, AThuong, NTTDian, SAlisjahbana, BGaniem, ARvan Crevel, RThwaites, GETroll, MEdelstein, PHSewell, RRamakrishnan, LTuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in the leukotriene A4 hydrolase (LTA4H) gene encoding an enzyme that regulates inflammatory eicosanoids. LTA4H TT patients with increased expression had increased survival, consistent with corticosteroids benefiting individuals with hyper-inflammatory responses. However, an Indonesia study did not find an LTA4H TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that LTA4H TT genotype confers survival benefit that begins early and continues long-term in both populations. This benefit is nullified in the most severe cases with high early mortality. LTA4H genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it. |
| spellingShingle | Whitworth, L Coxon, J van Laarhoven, A Thuong, NTT Dian, S Alisjahbana, B Ganiem, AR van Crevel, R Thwaites, GE Troll, M Edelstein, PH Sewell, R Ramakrishnan, L A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis |
| title | A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis |
| title_full | A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis |
| title_fullStr | A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis |
| title_full_unstemmed | A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis |
| title_short | A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis |
| title_sort | bayesian analysis of the association between leukotriene a4 hydrolase genotype and survival in tuberculous meningitis |
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