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.
BACKGROUND
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.
Department of Anesthesiology, Intensive Care Medicine and Pain Management, Hanse-Klinikum Stralsund, Grosse Parower Strasse 47-53, Stralsund 18435, Germany. oliver.kumpf@klinikum-hst.de
Oliver
O
Kumpf
Evangelos J
EJ
Giamarellos-Bourboulis
Alexander
A
Koch
Lutz
L
Hamann
Maria
M
Mouktaroudi
Djin-Ye
DY
Oh
Eicke
E
Latz
Eva
E
Lorenz
David A
DA
Schwartz
Bart
B
Ferwerda
Christina
C
Routsi
Chryssanthi
C
Skalioti
Bart-Jan
BJ
Kullberg
Jos W M
JW
van der Meer
Peter M
PM
Schlag
Mihai G
MG
Netea
Kai
K
Zacharowski
Ralf R
RR
Schumann
D000368:Aged; D015331:Cohort Studies; D003428:Cross Infection / Q000235:genetics / Q000503:physiopathology; D016207:Cytokines / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005858:Germany; D006115:Greece; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated / Q000235:genetics* / Q000503:physiopathology; D011110:Polymorphism, Genetic; D011184:Postoperative Period; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000502:physiology; D018570:Risk Assessment; D018805:Sepsis / Q000235:genetics* / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000235:genetics*
D016207:Cytokines; D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4