Cell-Free Plasma DNA as a Predictor of Outcome in Severe Sepsis and Septic Shock

Departments of Medicine and Emergency Care, Helsinki University Central Hospital, Helsinki, Finland.
Clinical Chemistry (Impact Factor: 7.91). 06/2008; 54(6):1000-7. DOI: 10.1373/clinchem.2007.101030
Source: PubMed


Increased concentrations of cell-free DNA have been found in plasma of septic and critically ill patients. We investigated the value of plasma DNA for the prediction of intensive care unit (ICU) and hospital mortality and its association with the degree of organ dysfunction and disease severity in patients with severe sepsis.
We studied 255 patients with severe sepsis or septic shock. We obtained blood samples on the day of study inclusion and 72 h later and measured cell-free plasma DNA by real-time quantitative PCR assay for the beta-globin gene.
Cell-free plasma DNA concentrations were higher at admission in ICU nonsurvivors than in survivors (median 15 904 vs 7522 genome equivalents [GE]/mL, P < 0.001) and 72 h later (median 15 176 GE/mL vs 6758 GE/mL, P = 0.004). Plasma DNA values were also higher in hospital nonsurvivors than in survivors (P = 0.008 to 0.009). By ROC analysis, plasma DNA concentrations had moderate discriminative power for ICU mortality (AUC 0.70-0.71). In multiple regression analysis, first-day plasma DNA was an independent predictor for ICU mortality (P = 0.005) but not for hospital mortality. Maximum lactate value and Sequential Organ Failure Assessment score correlated independently with the first-day plasma DNA in linear regression analysis.
Cell-free plasma DNA concentrations were significantly higher in ICU and hospital nonsurvivors than in survivors and showed a moderate discriminative power regarding ICU mortality. Plasma DNA concentration was an independent predictor for ICU mortality, but not for hospital mortality, a finding that decreases its clinical value in severe sepsis and septic shock.

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Available from: Ville Pettilä, Jan 20, 2014
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    • "Circulating DNA has a short half-life (10 to 15 min) and the liver is the major organ for removal of circulating nucleosomes (DNA and histones complexes)[14,15]. Elevated levels of cfDNA have been found in various pathologic conditions including sepsis, trauma, stroke, myocardial infarction, cancer, and autoimmune diseases[13,161718192021222324. The accumulation of cfDNA in the circulation is presumed to result from increased cell death and/or activation, impaired clearance of cfDNA, or both. "
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    ABSTRACT: Disseminated intravascular coagulation (DIC) is a heterogeneous group of disorders, which manifest as a spectrum of haemorrhage and thrombosis complicating many primary conditions including sepsis, trauma and malignancies. The pathophysiology of this condition is complex. In the recent years there is growing evidence that damage associated molecular patterns (DAMPs) play a crucial role in the pathogenesis of DIC. Upon cell-death and/or cell activation of hematopoietic and parenchymal cells extracellular cell-free DNA as well as DNA binding proteins (e.g. histones and high mobility group box 1 protein [HMGB1]) are released into circulation. This release is a highly regulated process mediated among others by serine proteases, such as factor VII-activating protease (FSAP) and DNase1. Circulating cell-free DNA has been demonstrated to influence primary and secondary hemostasis by inducing platelet aggregation, promoting coagulation activation, inhibition of fibrinolysis and directly interfering with clot stability. In this respect cell-free DNA in tissue as well as released into the circulation after neutrophil activation in the form of neutrophil extracellular traps (NETs) has been shown to be cytotoxic and highly procoagulant. DNA-binding proteins such as histones and HMGB1 are also strongly procoagulant and are involved in the pathogenesis of DIC. The present review gives an overview on how extracellular DNA is released into circulation and the structure of circulating DNA. In addition it summarizes the effect of extracellular DNA and DNA-binding proteins on platelet activation, plasmatic coagulation as well as fibrinolysis.
    Preview · Article · Dec 2015 · Blood reviews
    • "It is also well understood that placental hypoxia favours necrotic rather than apoptotic shedding of syncytial fragments into the maternal circulation [18]. In addition, cell free DNA has been accepted an indicator of hypoperfusion, tissue hypoxia and cell death [20] [21]. Thus it is suggested that the increased amounts of cell free fetal DNA is liberated from necrotic or apoptotic areas in the placenta [10]. "

    No preview · Article · Jan 2015 · Clinical and experimental obstetrics & gynecology
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    • "Circulating cell-free DNA (CFD), a product of cell necrosis, apoptosis and active secretion, is being investigated as a new reliable marker for assessing prognosis in various pathologies, including cancer, trauma and chronic renal failure (CRF) treated by hemodialysis [5], [6], [7], [8]. Several studies evaluated the prognostic accuracy of CFD for ICU general-patients and septic-patients for death prediction and found good correlation with other outcome predicting scores and markers, such as APACHE, SOFA and CRP level [9], [10], [11], [12], [13], [14]. In a recent publication, Dwivedi et al. found that their CFD assay had a sensitivity of 87.9% and specificity of 93.5% for predicting ICU mortality in patients with severe sepsis- better than multiple organ dysfunction (MOD) and APACHE II scores [14]. "
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    ABSTRACT: Aim The aim of the current study is to assess the mortality prediction accuracy of circulating cell-free DNA (CFD) level at admission measured by a new simplified method. Materials and Methods CFD levels were measured by a direct fluorescence assay in severe sepsis patients on intensive care unit (ICU) admission. In-hospital and/or twenty eight day all-cause mortality was the primary outcome. Results Out of 108 patients with median APACHE II of 20, 32.4% have died in hospital/or at 28-day. CFD levels were higher in decedents: median 3469.0 vs. 1659 ng/ml, p<0.001. In multivariable model APACHE II score and CFD (quartiles) were significantly associated with the mortality: odds ratio of 1.05, p = 0.049 and 2.57, p<0.001 per quartile respectively. C-statistics for the models was 0.79 for CFD and 0.68 for APACHE II. Integrated discrimination improvement (IDI) analyses showed that CFD and CFD+APACHE II score models had better discriminatory ability than APACHE II score alone. Conclusions CFD level assessed by a new, simple fluorometric-assay is an accurate predictor of acute mortality among ICU patients with severe sepsis. Comparison of CFD to APACHE II score and Procalcitonin (PCT), suggests that CFD has the potential to improve clinical decision making.
    Full-text · Article · Jun 2014 · PLoS ONE
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