Do intra-cerebral cytokine responses explain the harmful effects of dexamethasone in HIV-associated cryptococcal meningitis?
The CryptoDex trial showed dexamethasone was associated with poorer clinical outcomes and slower fungal clearance in HIV-associated cryptococcal meningitis. We analysed CSF cytokine concentrations from CrytpoDex participants over the first week of treatment to investigate potential mechanisms of harm and test two hypotheses: dexamethasone reduced pro-inflammatory cytokine concentrations leading to poorer outcomes; and leukotriene A4 hydrolase (LTA4H) genotype (previously associated with dexamethasone responsiveness in tuberculous meningitis) influenced dexamethasone's clinical impact.
We included participants from Vietnam, Thailand, and Uganda. We measured CSF concentrations of IFN-γ, TNF-α, GM-CSF, IL-6, IL-12p70, IL-8, MCP-1, MIP-1α, IL-4, IL-10, and IL-17 from days 1 to 7 of treatment using the Luminex system. We determined LTA4H genotype using a TaqMan genotyping assay of the promoter region SNP 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 measure the influence of LTA4H genotype on outcomes with Cox regression models.
Dexamethasone increased the rate of TNF-α concentration decline (-0.13 pg/ml/day (95%CI -0.22 to -0.06) p=0.03), which was associated with slower fungal clearance (correlation -0.62 (-0.83 to -0.26)). LTA4H genotype had no statistically significant impact on outcome or response to dexamethasone therapy. Better clinical outcomes were associated with higher baseline concentrations of IFN-γ.
Dexamethasone may slow fungal clearance and worsen outcomes by increasing the rate of decline of TNF-α concentration.