A glucuronoxylomannan-associated immune signature, characterized by monocyte deactivation and an increased interleukin 10 level, is a predictor of death in cryptococcal meningitis

James E. Scriven, Lisa M. Graham, Charlotte Schutz, Thomas J. Scriba, Katalin A. Wilkinson, Robert J. Wilkinson, David R. Boulware, Britta C. Urban, David G. Lalloo, Graeme Meintjes

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Background. 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. Methods. 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. Results. 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. Conclusions. 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.

Original languageEnglish (US)
Pages (from-to)1725-1734
Number of pages10
JournalJournal of Infectious Diseases
Volume213
Issue number11
DOIs
StatePublished - Jun 1 2016

Bibliographical note

Publisher Copyright:
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Keywords

  • Cryptococcal meningitis
  • Cryptococcus neoformans
  • HIV
  • HLA-DR
  • IL-10
  • Monocytes
  • Mortality
  • TNF-alpha
  • flow cytometry
  • principal component analysis

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