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

Justin Beardsley,Freddie M Kibengo,Nhat L T Hoang,Ronald B Geskus,Le Q Hung,Nguyen V V Chau,Thuong T T Nguyen,Nguyen L N Tung,Tran Q Binh,Jeremy N Day,Wirongrong Chierakul,Guy E Thwaites

doi:10.1093/cid/ciy725

Abstract

BackgroundThe 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.MethodsWe 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.ResultsDexamethasone 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.ConclusionsDexamethasone may slow fungal clearance and worsen outcomes by increasing TNF-α concentration’s rate of decline.

Highlights

The CryptoDex trial showed that dexamethasone caused poorer clinical outcomes and slowed fungal clearance in human immunodeficiency virus–associated cryptococcal meningitis
Dexamethasone increased the rate tumor necrosis factor (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
The rationale for the trial, described in the protocol [7], was that cryptococcal meningitis (CM) is often associated with inflammatory complications which can include increased intracranial pressure, cerebral edema, and vasculitis [8,9,10,11]

Summary

Introduction

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

Results

Conclusion