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Do Intracerebral Cytokine Responses Explain the Harmful Effects of Dexamethasone in Human Immunodeficiency

Justin Beardsley1,2,3, Nhat L T Hoang1, Freddie M Kibengo4

  • 1Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
|September 1, 2018
PubMed
Abstract

Insights

Dexamethasone worsened outcomes in HIV-associated cryptococcal meningitis by increasing tumor necrosis factor-alpha (TNF-α) decline, slowing fungal clearance. Leukotriene A4 hydrolase (LTA4H) genotype did not impact outcomes.

Area of Science:

  • Infectious Diseases
  • Immunology
  • Pharmacology

Background:

  • Dexamethasone treatment for HIV-associated cryptococcal meningitis led to poorer clinical outcomes and delayed fungal clearance.
  • Cerebrospinal fluid (CSF) cytokine concentrations were analyzed to understand the mechanisms behind dexamethasone's harmful effects.
  • Two hypotheses were tested: dexamethasone's impact on proinflammatory cytokines and the influence of leukotriene A4 hydrolase (LTA4H) genotype.

Purpose of the Study:

  • Investigate the mechanisms by which dexamethasone harms patients with HIV-associated cryptococcal meningitis.
  • Determine if dexamethasone alters CSF cytokine concentrations and if these changes correlate with clinical outcomes.
  • Assess whether LTA4H genotype modifies the clinical impact of dexamethasone.

Main Methods:

  • CSF samples from participants in Vietnam, Thailand, and Uganda were analyzed using the Luminex system for various cytokine concentrations.
  • LTA4H genotype was determined using the single-nucleotide polymorphism rs17525495.
  • Mixed-effects models assessed dexamethasone's impact on cytokine dynamics and their association with fungal clearance; Cox regression models evaluated LTA4H genotype's influence on outcomes.

Main Results:

  • Dexamethasone increased the decline rate of tumor necrosis factor-alpha (TNF-α) concentrations (P = .03), which correlated with slower fungal clearance (correlation, -0.62).
  • No statistically significant impact of LTA4H genotype on clinical outcomes or response to dexamethasone was observed.
  • Higher baseline concentrations of interferon-gamma were associated with better clinical outcomes.

Conclusions:

  • Dexamethasone may impair clinical outcomes and slow fungal clearance in HIV-associated cryptococcal meningitis by accelerating TNF-α decline.
  • The LTA4H genotype does not appear to influence the clinical effects of dexamethasone in this context.
  • Interferon-gamma levels may serve as a potential biomarker for predicting treatment response.
Keywords:
LTA4Hcorticosteroidscryptococcalcytokinesdexamethasone

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