title: Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial.
abstract: BACKGROUND
  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.
authors: 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.
authors: James E
authors: JE
authors: Scriven
authors: Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis Infectious Disease Institute, Makerere University, Kampala, Uganda.
authors: Joshua
authors: J
authors: Rhein
authors: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis.
authors: Katherine Huppler
authors: KH
authors: Hullsiek
authors: Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis.
authors: Maximilian
authors: M
authors: von Hohenberg
authors: Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis.
authors: Grace
authors: G
authors: Linder
authors: Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis.
authors: Melissa A
authors: MA
authors: Rolfes
authors: Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis Infectious Disease Institute, Makerere University, Kampala, Uganda.
authors: Darlisha A
authors: DA
authors: Williams
authors: Mbarara University of Science and Technology.
authors: Kabanda
authors: K
authors: Taseera
authors: 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.
authors: David B
authors: DB
authors: Meya
authors: 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.
authors: Graeme
authors: G
authors: Meintjes
authors: Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis.
authors: David R
authors: DR
authors: Boulware
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects / Q000379:methods*; D002555:Cerebrospinal Fluid / Q000166:cytology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D007964:Leukocytosis / Q000139:chemically induced*; D008262:Macrophage Activation; D008297:Male; D016919:Meningitis, Cryptococcal / Q000175:diagnosis*; D055502:Secondary Prevention; D016019:Survival Analysis
chemical_list: D016207:Cytokines
keywords: AIDS; HIV; IRIS; cryptococcal meningitis; immunology; macrophage; randomized controlled trial; sCD14; sCD163
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