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Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation

James E Scriven1, Joshua Rhein2, Katherine Huppler Hullsiek3

  • 1Infectious Diseases Unit, GF Jooste Hospital, Cape Town Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa Liverpool School of Tropical Medicine, United Kingdom.

The Journal of Infectious Diseases
|February 6, 2015
PubMed
Abstract

Insights

Starting antiretroviral therapy (ART) earlier for cryptococcal meningitis increased immune responses in the central nervous system, potentially explaining higher mortality. Deferred ART initiation showed lower immune activation and mortality.

Area of Science:

  • Neuroscience
  • Immunology
  • Infectious Diseases

Background:

  • Earlier antiretroviral therapy (ART) initiation in cryptococcal meningitis was linked to increased mortality compared to deferred initiation.
  • This higher mortality was hypothesized to stem from ART-associated immune pathology, distinct from clinically apparent immune reconstitution inflammatory syndrome.

Purpose of the Study:

  • To investigate the immunological mechanisms underlying increased mortality associated with early ART in cryptococcal meningitis.
  • To compare immune activation markers in cerebrospinal fluid (CSF) and serum between early and deferred ART initiation groups.

Main Methods:

  • The study analyzed macrophage activation markers and cytokines/chemokines in CSF and serum from the Cryptococcal Optimal ART Timing (COAT) trial.
  • Measurements were taken at multiple time points (1, 8, 14, 21 days) post-meningitis diagnosis, comparing early versus deferred ART arms.

Main Results:

  • Early ART initiation led to a higher incidence of elevated CSF white cell count (WCC) by day 14, particularly in patients with initially low WCC.
  • Increased levels of interleukin-13, sCD14, sCD163, and CCL3/MIP-1α were observed in the CSF of patients receiving early ART, indicating heightened macrophage/microglial activation.
  • These immunological changes were more pronounced in participants from the Kampala site.

Conclusions:

  • Early ART initiation in cryptococcal meningitis promotes increased cellular infiltration and macrophage/microglial activation within the central nervous system.
  • The findings suggest that the increased mortality observed with early ART in the COAT trial is immunologically mediated, likely due to exacerbated inflammatory responses.
Keywords:
AIDSHIVIRIScryptococcal meningitisimmunologymacrophagerandomized controlled trialsCD14sCD163

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