title: Mortality in Severe Human Immunodeficiency Virus-Tuberculosis Associates With Innate Immune Activation and Dysfunction of Monocytes.
abstract: Case fatality rates among hospitalized patients diagnosed with human immunodeficiency virus (HIV)-associated tuberculosis remain high, and tuberculosis mycobacteremia is common. Our aim was to define the nature of innate immune responses associated with 12-week mortality in this population.
  
  
  
  This prospective cohort study was conducted at Khayelitsha Hospital, Cape Town, South Africa. Hospitalized HIV-infected tuberculosis patients with CD4 counts <350 cells/µL were included; tuberculosis blood cultures were performed in all. Ambulatory HIV-infected patients without active tuberculosis were recruited as controls. Whole blood was stimulated with Escherichia coli derived lipopolysaccharide, heat-killed Streptococcus pneumoniae, and Mycobacterium tuberculosis. Biomarkers of inflammation and sepsis, intracellular (flow cytometry) and secreted cytokines (Luminex), were assessed for associations with 12-week mortality using Cox proportional hazard models. Second, we investigated associations of these immune markers with tuberculosis mycobacteremia.
  
  
  
  Sixty patients were included (median CD4 count 53 cells/µL (interquartile range [IQR], 22-132); 16 (27%) died after a median of 12 (IQR, 0-24) days. Thirty-one (52%) grew M. tuberculosis on blood culture. Mortality was associated with higher concentrations of procalcitonin, activation of the innate immune system (% CD16+CD14+ monocytes, interleukin-6, tumour necrosis factor-ɑ and colony-stimulating factor 3), and antiinflammatory markers (increased interleukin-1 receptor antagonist and lower monocyte and neutrophil responses to bacterial stimuli). Tuberculosis mycobacteremia was not associated with mortality, nor with biomarkers of sepsis.
  
  
  
  Twelve-week mortality was associated with greater pro- and antiinflammatory alterations of the innate immune system, similar to those reported in severe bacterial sepsis.
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.|Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.|Center for Experimental and Molecular Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Janssen
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.|Department of Medicine, Groote Schuur Hospital.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Schutz
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.
authors.forename: Amy
authors.initials: A
authors.lastname: Ward
authors.affiliation: South African Tuberculosis Vaccine Initiative, University of Cape Town, South Africa.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nemes
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.|Francis Crick Institute Mill Hill Laboratory, London.
authors.forename: Katalin A
authors.initials: KA
authors.lastname: Wilkinson
authors.affiliation: 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.forename: James
authors.initials: J
authors.lastname: Scriven
authors.affiliation: Center for Experimental and Molecular Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Mischa A
authors.initials: MA
authors.lastname: Huson
authors.affiliation: Computational Cancer Biology, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam.
authors.forename: Nanne
authors.initials: N
authors.lastname: Aben
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town.
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
authors.affiliation: Department of Medicine, Groote Schuur Hospital.|Khayelitsha Hospital, Cape Town, South Africa.
authors.forename: Rosie
authors.initials: R
authors.lastname: Burton
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.|Department of Medicine, Groote Schuur Hospital.|Francis Crick Institute Mill Hill Laboratory, London.|Division of Medicine, Imperial College London, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.affiliation: Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Grobusch
authors.affiliation: Center for Experimental and Molecular Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Van der Poll
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.|Department of Medicine, Groote Schuur Hospital.|Khayelitsha Hospital, Cape Town, South Africa.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
mesh_terms: D000328:Adult; D018791:CD4 Lymphocyte Count; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000453:epidemiology / Q000276:immunology* / Q000401:mortality*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D011446:Prospective Studies; D013019:South Africa / Q000453:epidemiology; D014376:Tuberculosis / Q000150:complications / Q000453:epidemiology / Q000276:immunology* / Q000401:mortality*
keywords: HIV; innate immunity; mortality; mycobacteremia; tuberculosis