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J Infect Dis. 2015 Sep 1;212(5):769-78. doi: 10.1093/infdis/jiv067. Epub 2015 Feb 4.

Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial.

Author information

1
Infectious 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.
2
Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis Infectious Disease Institute, Makerere University, Kampala, Uganda.
3
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis.
4
Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis.
5
Mbarara University of Science and Technology.
6
Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis Infectious Disease Institute, Makerere University, Kampala, Uganda Department of Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
7
Infectious 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 Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Department of Medicine, Imperial College London, United Kingdom.

Abstract

INTRODUCTION:

Earlier antiretroviral therapy (ART) initiation in cryptococcal meningitis resulted in higher mortality compared with deferred ART initiation (1-2 weeks vs 5 weeks postmeningitis diagnosis). We hypothesized this was due to ART-associated immune pathology, without clinically recognized immune reconstitution inflammatory syndrome.

METHODS:

Three macrophage activation markers and 19 cytokines/chemokines were measured from cryopreserved cerebrospinal fluid (CSF) and serum during the Cryptococcal Optimal ART Timing (COAT) trial. Comparisons were made between trial arms (early vs deferred) at 1, 8, 14, and 21 days following meningitis diagnosis.

RESULTS:

More participants with early ART initiation had CSF white cell count (WCC) ≥5/µL at day 14 (58% vs 40%; P = .047), after a median of 6-days ART. Differences were mainly driven by participants with CSF WCC <5/µL at meningitis diagnosis: 28% (10/36) of such persons in the early ART group had CSF WCC ≥5/µL by day 14, compared with 0% (0/27) in the deferred arm (P = .002). Furthermore, Kampala participants (the largest site) receiving early ART had higher day-14 CSF levels of interleukin-13 (P = .04), sCD14 (P = .04), sCD163 (P = .02), and CCL3/MIP-1α (P = .02), suggesting increased macrophage/microglial activation.

CONCLUSIONS:

Early ART initiation in cryptococcal meningitis increased CSF cellular infiltrate, macrophage/microglial activation, and T helper 2 responses within the central nervous system. This suggests that increased mortality from early ART in the COAT trial was immunologically mediated.

KEYWORDS:

AIDS; HIV; IRIS; cryptococcal meningitis; immunology; macrophage; randomized controlled trial; sCD14; sCD163

PMID:
25651842
PMCID:
PMC4527410
DOI:
10.1093/infdis/jiv067
[Indexed for MEDLINE]
Free PMC Article

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