Do Intracerebral Cytokine Responses Explain the Harmful Effects of Dexamethasone in Human Immunodeficiency Virus-associated Cryptococcal Meningitis?

Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Justin BeardsleyJeremy N Day

Abstract

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. 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 o...Continue Reading

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Citations

Nov 20, 2019·Antimicrobial Agents and Chemotherapy·Liise-Anne Pirofski, Arturo Casadevall
Aug 7, 2019·Journal of Fungi·Justin BeardsleySharon C-A Chen
Jul 6, 2019·F1000Research·Timothée Boyer-ChammardOlivier Lortholary
Feb 6, 2020·Frontiers in Cellular and Infection Microbiology·Yun YangLing-Juan Li
Apr 20, 2021·The Lancet Infectious Diseases·Katharine Elizabeth StottWilliam Hope

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Methods Mentioned

BETA
Assay
genotyping

Software Mentioned

R package mice
R package lme4
CryptoDex
R
R package multcomp
R package lmec

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