title: Microbial translocation is associated with extensive immune activation in dengue virus infected patients with severe disease.
abstract: BACKGROUND
  Severe dengue virus (DENV) disease is associated with extensive immune activation, characterized by a cytokine storm. Previously, elevated lipopolysaccharide (LPS) levels in dengue were found to correlate with clinical disease severity. In the present cross-sectional study we identified markers of microbial translocation and immune activation, which are associated with severe manifestations of DENV infection.
  
  
  METHODS
  Serum samples from DENV-infected patients were collected during the outbreak in 2010 in the State of São Paulo, Brazil. Levels of LPS, lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14) and IgM and IgG endotoxin core antibodies were determined by ELISA. Thirty cytokines were quantified using a multiplex luminex system. Patients were classified according to the 2009 WHO classification and the occurrence of plasma leakage/shock and hemorrhage. Moreover, a (non-supervised) cluster analysis based on the expression of the quantified cytokines was applied to identify groups of patients with similar cytokine profiles. Markers of microbial translocation were linked to groups with similar clinical disease severity and clusters with similar cytokine profiles.
  
  
  RESULTS
  Cluster analysis indicated that LPS levels were significantly increased in patients with a profound pro-inflammatory cytokine profile. LBP and sCD14 showed significantly increased levels in patients with severe disease in the clinical classification and in patients with severe inflammation in the cluster analysis. With both the clinical classification and the cluster analysis, levels of IL-6, IL-8, sIL-2R, MCP-1, RANTES, HGF, G-CSF and EGF were associated with severe disease.
  
  
  CONCLUSIONS
  The present study provides evidence that both microbial translocation and extensive immune activation occur during severe DENV infection and may play an important role in the pathogenesis.
authors.affiliation: Viroscience Lab, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Cornelia A M
authors.initials: CA
authors.lastname: van de Weg
authors.forename: Cláudio S
authors.initials: CS
authors.lastname: Pannuti
authors.forename: Evaldo S A
authors.initials: ES
authors.lastname: de Araújo
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: van den Ham
authors.forename: Arno C
authors.initials: AC
authors.lastname: Andeweg
authors.forename: Lucy S V
authors.initials: LS
authors.lastname: Boas
authors.forename: Alvina C
authors.initials: AC
authors.lastname: Felix
authors.forename: Karina I
authors.initials: KI
authors.lastname: Carvalho
authors.forename: Andreia M
authors.initials: AM
authors.lastname: de Matos
authors.forename: José E
authors.initials: JE
authors.lastname: Levi
authors.forename: Camila M
authors.initials: CM
authors.lastname: Romano
authors.forename: Cristiane C
authors.initials: CC
authors.lastname: Centrone
authors.forename: Celia L
authors.initials: CL
authors.lastname: de Lima Rodrigues
authors.forename: Expedito
authors.initials: E
authors.lastname: Luna
authors.forename: Eric C M
authors.initials: EC
authors.lastname: van Gorp
authors.forename: Albert D M E
authors.initials: AD
authors.lastname: Osterhaus
authors.forename: Byron E E
authors.initials: BE
authors.lastname: Martina
authors.forename: Esper G
authors.initials: EG
authors.lastname: Kallas
mesh_terms: D000293:Adolescent; D000328:Adult; D018988:Bacterial Translocation / Q000276:immunology*; D001938:Brazil / Q000453:epidemiology; D002648:Child; D016207:Cytokines / Q000097:blood*; D004196:Disease Outbreaks; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019595:Severe Dengue / Q000150:complications* / Q000276:immunology / Q000473:pathology*; D055815:Young Adult
chemical_list: D016207:Cytokines