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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

Oliver Kumpf1*, Evangelos J Giamarellos-Bourboulis23, Alexander Koch4, Lutz Hamann5, Maria Mouktaroudi23, Djin-Ye Oh56, Eicke Latz78, Eva Lorenz9, David A Schwartz10, Bart Ferwerda2, Christina Routsi11, Chryssanthi Skalioti3, Bart-Jan Kullberg2, Jos WM van der Meer2, Peter M Schlag12, Mihai G Netea2, Kai Zacharowski4 and Ralf R Schumann5

Author Affiliations

1 Department of Anesthesiology, Intensive Care Medicine and Pain Management, Hanse-Klinikum Stralsund, Große Parower Strasse 47-53, Stralsund 18435, Germany

2 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

3 4th Department of Internal Medicine University of Athens, Medical School, 1 Rimini, Athens 12462, Greece

4 Clinic of Anesthesiology, Intensive Care Medicine and Pain Management, J.W.-Goethe-University Hospital, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany

5 Institute for Microbiology and Hygiene, Charite-University Medical Center Berlin, Dorotheenstrasse 96, Berlin 10117, Germany

6 The Floating Hospital of Children, Tufts University, 755 Washington Street, Boston, MA 02111, USA

7 Department of Medicine, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01605, USA

8 Institute of Innate Immunity, University of Bonn, Sigmund-Freud-Strasse 25, Bonn 53127, Germany

9 Thurston Arthritis Research Center, University of North Carolina, 3330 Thurston Building, Chapel Hill, NC 27599, USA

10 Center for Genes, Environment, and Health, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA

11 1st Department of Critical Care, University of Athens, Medical School, 45-47 Ipsilantou Street, Athens 10676, Greece

12 Charite Comprehensive Cancer Center, Charite-University Medical Center Berlin, Invalidenstrasse 80, Berlin 10115, Germany

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Critical Care 2010, 14:R103  doi:10.1186/cc9047

Published: 3 June 2010



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.


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.


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.


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.