1. Do Intracerebral Cytokine Responses Explain the Harmful Effects of Dexamethasone in Human Immunodeficiency Virus-associated Cryptococcal Meningitis?
- Author
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Beardsley J, Hoang NLT, Kibengo FM, Tung NLN, Binh TQ, Hung LQ, Chierakul W, Thwaites GE, Chau NVV, Nguyen TTT, Geskus RB, and Day JN
- Subjects
- Adaptor Proteins, Signal Transducing cerebrospinal fluid, Adaptor Proteins, Signal Transducing genetics, Chemokine CCL2 cerebrospinal fluid, Chemokine CCL2 genetics, Cryptococcus drug effects, Cryptococcus growth & development, Cryptococcus pathogenicity, Epoxide Hydrolases cerebrospinal fluid, Genotype, Granulocyte-Macrophage Colony-Stimulating Factor cerebrospinal fluid, Granulocyte-Macrophage Colony-Stimulating Factor genetics, HIV growth & development, HIV pathogenicity, HIV Infections complications, HIV Infections immunology, HIV Infections mortality, Humans, Interferon-gamma cerebrospinal fluid, Interferon-gamma genetics, Interleukins cerebrospinal fluid, Interleukins genetics, Meningitis, Cryptococcal complications, Meningitis, Cryptococcal immunology, Meningitis, Cryptococcal mortality, Survival Analysis, Thailand, Treatment Outcome, Tumor Necrosis Factor-alpha cerebrospinal fluid, Tumor Necrosis Factor-alpha genetics, Uganda, Vietnam, Dexamethasone adverse effects, Epoxide Hydrolases genetics, Gene Expression drug effects, Glucocorticoids adverse effects, HIV Infections drug therapy, Meningitis, Cryptococcal drug therapy
- Abstract
Background: The CryptoDex trial showed that dexamethasone caused poorer clinical outcomes and slowed fungal clearance in human immunodeficiency virus-associated cryptococcal meningitis. We analyzed cerebrospinal fluid (CSF) cytokine concentrations from participants over the first week of treatment to investigate mechanisms of harm and test 2 hypotheses: (1) dexamethasone reduced proinflammatory cytokine concentrations, leading to poorer outcomes and (2) leukotriene A4 hydrolase (LTA4H) genotype influenced the clinical impact of dexamethasone, as observed in tuberculous meningitis., Methods: We included participants from Vietnam, Thailand, and Uganda. Using the Luminex system, we measured CSF concentrations of the following: interferon γ, tumor necrosis factor (TNF) α, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant 1, macrophage inflammatory protein 1α, and interleukin 6, 12p70, 8, 4, 10, and 17. We determined the LTA4H genotype based on the promoter region single-nucleotide polymorphism rs17525495. We assessed the impact of dexamethasone on cytokine concentration dynamics and the association between cytokine concentration dynamics and fungal clearance with mixed effect models. We measured the influence of LTA4H genotype on outcomes with Cox regression models., Results: Dexamethasone increased the rate TNF-α concentration's decline in (-0.13 log2pg/mL/d (95% confidence interval, -.22 to -.06 log2pg/mL/d; P = .03), which was associated with slower fungal clearance (correlation, -0.62; 95% confidence interval, -.83 to -.26). LTA4H genotype had no statistically significant impact on outcome or response to dexamethasone therapy. Better clinical outcomes were associated with higher baseline concentrations of interferon γ., Conclusions: Dexamethasone may slow fungal clearance and worsen outcomes by increasing TNF-α concentration's rate of decline., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)
- Published
- 2019
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