title: A Glucuronoxylomannan-Associated Immune Signature, Characterized by Monocyte Deactivation and an Increased Interleukin 10 Level, Is a Predictor of Death in Cryptococcal Meningitis.
abstract: Cryptococcal meningitis remains a significant cause of death among human immunodeficiency virus type 1 (HIV)-infected persons in Africa. We aimed to better understand the pathogenesis and identify immune correlates of mortality, particularly the role of monocyte activation.
  
  
  
  A prospective cohort study was conducted in Cape Town, South Africa. Patients with a first episode of cryptococcal meningitis were enrolled, and their immune responses were assessed in unstimulated and stimulated blood specimens, using flow cytometry and cytokine analysis.
  
  
  
  Sixty participants were enrolled (median CD4(+) T-cell count, 34 cells/µL). Mortality was 23% (14 of 60 participants) at 14 days and 39% (22 of 57) at 12 weeks. Nonsurvivors were more likely to have an altered consciousness and higher cerebrospinal fluid fungal burden at presentation. Principal component analysis identified an immune signature associated with early mortality, characterized by monocyte deactivation (reduced HLA-DR expression and tumor necrosis factor α response to lipopolysaccharide); increased serum interleukin 6, CXCL10, and interleukin 10 levels; increased neutrophil counts; and decreased T-helper cell type 1 responses. This immune signature remained an independent predictor of early mortality after adjustment for consciousness level and fungal burden and was associated with higher serum titers of cryptococcal glucuronoxylomannan.
  
  
  
  Cryptococcal-related mortality is associated with monocyte deactivation and an antiinflammatory blood immune signature, possibly due to Cryptococcus modulation of the host immune response. Validation in other cohorts is required.
authors.affiliation: Liverpool School of Tropical Medicine Wellcome Trust Liverpool Glasgow Centre for Global Health Research, Liverpool Clinical Infectious Diseases Research Initiative Department of Medicine, University of Cape Town and Groote Schuur Hospital, South Africa.
authors.forename: James E
authors.initials: JE
authors.lastname: Scriven
authors.affiliation: Clinical Infectious Diseases Research Initiative.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Graham
authors.affiliation: Clinical Infectious Diseases Research Initiative Department of Medicine, University of Cape Town and Groote Schuur Hospital, South Africa.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Schutz
authors.affiliation: South African TB Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine Department of Paediatrics and Child Health, University of Cape Town.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
authors.affiliation: Clinical Infectious Diseases Research Initiative.
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
authors.affiliation: Department of Medicine, Imperial College London Mill Hill Laboratory, Francis Crick Institute, London, United Kingdom Clinical Infectious Diseases Research Initiative.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis.
authors.forename: David R
authors.initials: DR
authors.lastname: Boulware
authors.affiliation: Liverpool School of Tropical Medicine.
authors.forename: Britta C
authors.initials: BC
authors.lastname: Urban
authors.affiliation: Liverpool School of Tropical Medicine Wellcome Trust Liverpool Glasgow Centre for Global Health Research, Liverpool.
authors.forename: David G
authors.initials: DG
authors.lastname: Lalloo
authors.affiliation: Department of Medicine, Imperial College London Clinical Infectious Diseases Research Initiative Department of Medicine, University of Cape Town and Groote Schuur Hospital, South Africa.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000276:immunology / Q000401:mortality*; D000328:Adult; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D016753:Interleukin-10 / Q000097:blood*; D008297:Male; D016919:Meningitis, Cryptococcal / Q000097:blood / Q000276:immunology / Q000401:mortality*; D009000:Monocytes / Q000276:immunology*; D011134:Polysaccharides / Q000276:immunology*; D011446:Prospective Studies; D013019:South Africa; D016019:Survival Analysis
chemical_list: D016207:Cytokines; C508609:IL10 protein, human; D011134:Polysaccharides; D016753:Interleukin-10; C027478:glucuronoxylomannan
keywords: Cryptococcus neoformans; HIV; HLA-DR; IL-10; TNF-alpha; cryptococcal meningitis; flow cytometry; monocytes; mortality; principal component analysis