Abstract
IntroductionActivation of inflammation and coagulation are closely related and mutually interdependent in sepsis. The acute-phase protein, plasminogen activator inhibitor-1 (PAI-1) is a key element in the inhibition of fibrinolysis. Elevated levels of PAI-1 have been related to worse outcome in pneumonia. We aimed to evaluate the effect of functionally relevant 4G/5G polymorphism of PAI-1 gene in pneumonia induced sepsis.MethodsWe enrolled 208 Caucasian patients with severe sepsis due to pneumonia admitted to an intensive care unit (ICU). Patients were followed up until ICU discharge or death. Clinical data were collected prospectively and the PAI-1 4G/5G polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism technique. Patients were stratified according to the occurrence of multiple organ dysfunction syndrome, septic shock or death.ResultsWe found that carriers of the PAI-1 4G/4G and 4G/5G genotypes have a 2.74-fold higher risk for multiple organ dysfunction syndrome (odds ratio [OR] 95% confidence interval [CI] = 1.335 - 5.604; p = 0.006) and a 2.57-fold higher risk for septic shock (OR 95%CI = 1.180 - 5.615; p = 0.018) than 5G/5G carriers. The multivariate logistic regression analysis adjusted for independent predictors, such as age, nosocomial pneumonia and positive microbiological culture also supported that carriers of the 4G allele have a higher prevalence of multiple organ dysfunction syndrome (adjusted odds ratio [aOR] = 2.957; 95%CI = 1.306 -6.698; p = 0.009) and septic shock (aOR = 2.603; 95%CI = 1.137 - 5.959; p = 0.024). However, genotype and allele analyses have not shown any significant difference regarding mortality in models non-adjusted or adjusted for acute physiology and chronic health evaluation (APACHE) II. Patients bearing the 4G allele had higher disseminated intravascular coagulation (DIC) score at admission (p = 0.007) than 5G/5G carriers. Moreover, in 4G allele carriers the length of ICU stay of non-survivors was longer (p = 0.091), fewer ventilation-free days (p = 0.008) and days without septic shock (p = 0.095) were observed during the first 28 days.ConclusionsIn Caucasian patients with severe sepsis due to pneumonia carriers of the 4G allele of PAI-1 polymorphism have higher risk for multiple organ dysfunction syndrome and septic shock and in agreement they showed more fulminant disease progression based on continuous clinical variables.
Highlights
Activation of inflammation and coagulation are closely related and mutually interdependent in sepsis
We found that carriers of the plasminogen activator inhibitor-1 (PAI-1) 4G/4G and 4G/5G genotypes have a 2.74-fold higher risk for multiple organ dysfunction syndrome and a 2.57-fold higher risk for septic shock than 5G/5G carriers
The multivariate logistic regression analysis adjusted for independent predictors, such as age, nosocomial pneumonia and positive microbiological culture supported that carriers of the 4G allele have a higher prevalence of multiple organ dysfunction syndrome and septic shock
Summary
Activation of inflammation and coagulation are closely related and mutually interdependent in sepsis. Sepsis is a complex clinical syndrome that results from an infection-triggered systemic inflammatory response. Patients with apparently similar general condition and severity of infection may present profoundly different survival rates. Patient, as recognized by the PIRO (predisposition, infection, response, organ dysfunction) concept [2]. Single nucleotide polymorphisms (SNPs) in genes involved in the inflammatory response that influence sepsis susceptibility or severity may explain the clinical variability observed during the course of similar infections. It is already known that activation of inflammation and coagulation are closely related and mutually interdependent in sepsis [3]. The imbalance between fibrin generation and dissolution contributes to disseminated intravascular coagulation and multiple organ dysfunction syndrome (MODS) [4]
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