TY - JOUR
TI - Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: An observational study in three cohorts
AU - Kumpf, O.
AU - Giamarellos-Bourboulis, E.J.
AU - Koch, A.
AU - Hamann, L.
AU - Mouktaroudi, M.
AU - Oh, D.
AU - Latz, E.
AU - Lorenz, E.
AU - Schwartz, D.A.
AU - Ferwerda, B.
AU - Routsi, C.
AU - Skalioti, C.
AU - Kullberg, B.
AU - van der Meer, J.W.M.
AU - Schlag, P.M.
AU - Netea, M.G.
AU - Zacharowski, K.
AU - Schumann, R.R.
JO - Critical Care and Resuscitation
PY - 2010
VL - 14
TODO - 3
SP - null
PB - 
SN - null
TODO - 10.1186/cc9047
TODO - gamma interferon;  granulocyte macrophage colony stimulating factor;  interleukin 10;  interleukin 1beta;  interleukin 2;  interleukin 4;  interleukin 5;  interleukin 6;  interleukin 8;  myeloid differentiation factor 88 adaptor like;  toll interleukin 1 receptor associated protein;  toll like receptor 4;  transcription factor;  tumor necrosis factor alpha;  unclassified drug;  cytokine;  interleukin 1 receptor;  membrane protein;  TIRAP protein, human;  TLR4 protein, human;  toll like receptor 4, adult;  article;  cohort analysis;  controlled study;  cytokine production;  cytokine release;  disease course;  disease predisposition;  enzyme linked immunosorbent assay;  ex vivo study;  female;  gene mutation;  genetic polymorphism;  genetic variability;  genotype;  Germany;  Gram negative bacterium;  Greece;  heart surgery;  high risk patient;  homozygote;  human;  in vivo study;  infection risk;  intensive care unit;  major clinical study;  male;  monocyte;  observational study;  outcome assessment;  population;  postoperative period;  priority journal;  prospective study;  sepsis;  single nucleotide polymorphism;  surgical patient;  tertiary health care;  university hospital;  ventilator associated pneumonia;  aged;  blood;  cross infection;  genetic predisposition;  genetics;  metabolism;  middle aged;  pathophysiology;  physiology;  risk assessment;  sepsis;  ventilator associated pneumonia, Aged;  Cohort Studies;  Cross Infection;  Cytokines;  Disease Progression;  Female;  Genetic Predisposition to Disease;  Germany;  Greece;  Humans;  Intensive Care Units;  Male;  Membrane Glycoproteins;  Middle Aged;  Pneumonia, Ventilator-Associated;  Polymorphism, Genetic;  Postoperative Period;  Receptors, Interleukin-1;  Risk Assessment;  Sepsis;  Toll-Like Receptor 4
TODO - Introduction: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations.Methods: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course.Results: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes.Conclusions: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery. © 2010 Kumpf et al.; licensee BioMed Central Ltd.
ER -