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
Analytics

Downloadable Content

Download PDF
Request Version for Screen Reader
Creator
  • Kumpf, Oliver
    • Other Affiliation: Hanse-Klinikum Stralsund
  • Giamarellos-Bourboulis, Evangelos J
    • Other Affiliation: Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i)
  • Koch, Alexander
    • Other Affiliation: J.W.-Goethe-University Hospital
  • Hamann, Lutz
    • Other Affiliation: Charite-University Medical Center Berlin
  • Mouktaroudi, Maria
    • Other Affiliation: Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i)
  • Oh, Djin-Ye
    • Other Affiliation: Charite-University Medical Center Berlin
  • Latz, Eicke
    • Other Affiliation: University of Massachusetts Medical School
  • Lorenz, Eva
    • Affiliation: School of Medicine, Thurston Arthritis Research Center
  • Schwartz, David A
    • Other Affiliation: National Jewish Health
  • Ferwerda, Bart
    • Other Affiliation: Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i)
  • Routsi, Christina
    • Other Affiliation: University of Athens
  • Skalioti, Chryssanthi
    • Other Affiliation: 4th Department of Internal Medicine University of Athens, Medical School
  • Kullberg, Bart-Jan
    • Other Affiliation: Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i)
  • van der Meer, Jos WM
    • Other Affiliation: Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i)
  • Schlag, Peter M
    • Other Affiliation: Charite-University Medical Center Berlin
  • Netea, Mihai G
    • Other Affiliation: Radboud University Nijmegen Medical Center and Nijmegen Institute for Infection, Inflammation and Immunity (N4i)
  • Zacharowski, Kai
    • Other Affiliation: J.W.-Goethe-University Hospital
  • Schumann, Ralf R
    • Other Affiliation: Charite-University Medical Center Berlin
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
DOI
Identifier
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
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • August 23, 2012

Relations

Parents:

This work has no parents.

Items

Thumbnail Title Date Uploaded Visibility Actions
file details cc9047.pdf 2019-05-07 Public Download
file details cc9047.xml 2019-05-07 Public Download
file details Supplementary Tables S1 to S5. The supplementary tables contain detailed information about the studied cohorts. 2019-05-07 Public Download