title: Decreased cytokine production by mononuclear cells after severe gram-negative infections: early clinical signs and association with final outcome.
abstract: Failure of circulating monocytes for adequate cytokine production is a trait of sepsis-induced immunosuppression; however, its duration and association with final outcome are poorly understood.
  
  
  
  We conducted a substudy of a large randomised clinical trial. Peripheral blood mononuclear cells (PBMCs) were isolated within the first 24 h from the onset of systemic inflammatory response syndrome in 95 patients with microbiologically confirmed or clinically suspected gram-negative infections. Isolation was repeated on days 3, 7 and 10. PBMCs were stimulated for cytokine production. The study endpoints were the differences between survivors and non-survivors, the persistence of immunosuppression, and determination of admission clinical signs that can lead to early identification of the likelihood of immunosuppression.
  
  
  
  PBMCs of survivors produced significantly greater concentrations of tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, IL-10, interferon-γ and granulocyte-macrophage colony-stimulating factor after day 3. Using ROC analysis, we found that TNF-α production less than 250 pg/ml after lipopolysaccharide stimulation on day 3 could discriminate patients from healthy control subjects; this was associated with a 5.18 OR of having an unfavourable outcome (p = 0.046). This trait persisted as long as day 10. Logistic regression analysis showed that cardiovascular failure on admission was the only independent predictor of defective TNF-α production on day 3.
  
  
  
  Defective TNF-α production is a major trait of sepsis-induced immunosuppression. It is associated with significant risk for unfavourable outcome and persists until day 10. Cardiovascular failure on admission is predictive of defective TNF-α production during follow-up.
  
  
  
  ClinicalTrials.gov identifier: NCT01223690 . Registered on 18 October 2010.
authors.affiliation: 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Antonakos
authors.affiliation: 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tsaganos
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.|Centre for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Oberle
authors.affiliation: 2nd Department of Critical Care Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Iraklis
authors.initials: I
authors.lastname: Tsangaris
authors.affiliation: 2nd Department of Internal Medicine, Sismanogleion Athens General Hospital, Athens, Greece.
authors.forename: Malvina
authors.initials: M
authors.lastname: Lada
authors.affiliation: 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Pistiki
authors.affiliation: 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Machairas
authors.affiliation: 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Souli
authors.affiliation: Centre for Sepsis Control and Care, Jena University Hospital, Jena, Germany.|Department of Anaesthesiology and Intensive Care, Jena University Hospital, Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.affiliation: 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece. egiamarel@med.uoa.gr.|Centre for Sepsis Control and Care, Jena University Hospital, Jena, Germany. egiamarel@med.uoa.gr.
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017291:Clarithromycin / Q000494:pharmacology / Q000627:therapeutic use; D003661:Decision Support Techniques; D005260:Female; D006090:Gram-Negative Bacteria / Q000378:metabolism* / Q000472:pathogenicity; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000097:blood; D006115:Greece; D006801:Humans; D007239:Infections / Q000097:blood / Q000150:complications*; D007371:Interferon-gamma / Q000032:analysis / Q000097:blood; D016753:Interleukin-10 / Q000032:analysis / Q000097:blood; D015850:Interleukin-6 / Q000032:analysis / Q000097:blood; D016209:Interleukin-8 / Q000032:analysis / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000145:classification* / Q000473:pathology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011446:Prospective Studies; D012372:ROC Curve; D011994:Recombinant Proteins / Q000032:analysis / Q000097:blood; D018709:Statistics, Nonparametric; D017741:Survivors / Q000706:statistics & numerical data; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000097:blood
chemical_list: C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D010919:Placebos; D011994:Recombinant Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C101659:granulocyte-macrophage colony-stimulating factor, Arg(21)-; D016753:Interleukin-10; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017291:Clarithromycin
keywords: Immunosuppression; Prediction; Sepsis; Survival