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 Public Deposited

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Creator
  • Latz, Eicke
    • Other Affiliation: Department of Medicine, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01605, USA; Institute of Innate Immunity, University of Bonn, Sigmund-Freud- Strasse 25, Bonn 53127, Germany
  • Hamann, Lutz
    • Other Affiliation: Institute for Microbiology and Hygiene, Charite-University Medical Center Berlin, Dorotheenstrasse 96, Berlin 10117, Germany
  • van der Meer, Jos WM
    • Other Affiliation: Department of Medicine, Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Geert Grooteplein 8, Nijmegen 6525 GA, The Netherlands
  • Ferwerda, Bart
    • Other Affiliation: Department of Medicine, Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Geert Grooteplein 8, Nijmegen 6525 GA, The Netherlands
  • Netea, Mihai G
    • Other Affiliation: Department of Medicine, Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Geert Grooteplein 8, Nijmegen 6525 GA, The Netherlands
  • Schwartz, David A
    • Other Affiliation: Center for Genes, Environment, and Health, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA
  • Skalioti, Chryssanthi
    • Other Affiliation: 4th Department of Internal Medicine University of Athens, Medical School, 1 Rimini, Athens 12462, Greece
  • Schumann, Ralf R
    • Other Affiliation: Institute for Microbiology and Hygiene, Charite-University Medical Center Berlin, Dorotheenstrasse 96, Berlin 10117, Germany
  • Mouktaroudi, Maria
    • Other Affiliation: Department of Medicine, Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Geert Grooteplein 8, Nijmegen 6525 GA, The Netherlands; 4th Department of Internal Medicine University of Athens, Medical School, 1 Rimini, Athens 12462, Greece
  • Giamarellos-Bourboulis, Evangelos J
    • Other Affiliation: Department of Medicine, Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Geert Grooteplein 8, Nijmegen 6525 GA, The Netherlands; 4th Department of Internal Medicine University of Athens, Medical School, 1 Rimini, Athens 12462, Greece
  • Koch, Alexander
    • Other Affiliation: Clinic of Anesthesiology, Intensive Care Medicine and Pain Management, J.W.-Goethe-University Hospital, Theodor- Stern-Kai 7, Frankfurt am Main 60590, Germany
  • Lorenz, Eva
    • Affiliation: School of Medicine, Thurston Arthritis Research Center
  • Oh, Djin-Ye
    • Other Affiliation: Institute for Microbiology and Hygiene, Charite-University Medical Center Berlin, Dorotheenstrasse 96, Berlin 10117, Germany; The Floating Hospital of Children, Tufts University, 755 Washington Street, Boston, MA 02111, USA
  • Kumpf, Oliver
    • Other Affiliation: Department of Anesthesiology, Intensive Care Medicine and Pain Management, Hanse-Klinikum Stralsund, Große Parower Strasse 47-53, Stralsund 18435, Germany
  • Schlag, Peter M
    • Other Affiliation: Charite Comprehensive Cancer Center, Charite-University Medical Center Berlin, Invalidenstrasse 80, Berlin 10115, Germany
  • Kullberg, Bart-Jan
    • Other Affiliation: Department of Medicine, Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Geert Grooteplein 8, Nijmegen 6525 GA, The Netherlands
  • Zacharowski, Kai
    • Other Affiliation: Clinic of Anesthesiology, Intensive Care Medicine and Pain Management, J.W.-Goethe-University Hospital, Theodor- Stern-Kai 7, Frankfurt am Main 60590, Germany
  • Routsi, Christina
    • Other Affiliation: 1st Department of Critical Care, University of Athens, Medical School, 45-47 Ipsilantou Street, Athens 10676, Greece
Abstract
  • Abstract 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.
Date of publication
Identifier
  • 20525286
  • doi:10.1186/cc9047
Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Oliver Kumpf et al.; licensee BioMed Central Ltd.
License
Journal title
  • Critical Care
Journal volume
  • 14
Journal issue
  • 3
Page start
  • R103
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1364-8535
Bibliographic citation
  • Critical Care. 2010 Jun 03;14(3):R103
Access
  • Open Access
Publisher
  • BioMed Central Ltd
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