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 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.
    PLoS ONE 06/2014; 9(6):e100514. DOI:10.1371/journal.pone.0100514 · 3.23 Impact Factor
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    • "Release of DNA into the circulation makes it a useful, albeit nonspecific marker of tissue injury. Increased levels of CFD have been detected in many pathological situations such as infection, inflammation, trauma, respiratory insufficiency, pulmonary embolism, autoimmune disease, sepsis, and cancer and have been found to be an adverse prognostic marker for morbidity and mortality [1–6]. "
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    ABSTRACT: Background. Despite great advances in the treatment of burn patients, useful prognostic markers are sparse. During the past years there has been increasing interest in circulating plasma cell free DNA as a potential marker for tissue injury. We have developed a rapid direct fluorescent assay for cell free DNA quantification that allows obtaining accurate, fast, and inexpensive measurements. Objective. To use this technique for measuring plasma cell free DNA levels in burn patients and to further explore the use of cell free DNA as a potential marker of patient outcome in burns. Methods. Cell free DNA levels obtained from 14 burn victims within 6 hours of injury and 14 healthy controls were quantified by a direct rapid fluorometric assay. Results. Patient admission cell free DNA levels were significantly elevated compared with that of controls (1797 ± 1523 ng/mL versus 374 ± 245 ng/mL, P = 0.004). There are statistically significant correlations between cell free DNA admission levels and burn degree (Spearman's correlation = 0.78, P = 0.001), total body surface area (Spearman's correlation = 0.61, P = 0.02), and total burn volume (Spearman's correlation = 0.64, P = 0.014). Conclusions. Admission cell free DNA levels can serve as a prognostic factor in burns and future routine use can be made possible by use of our direct rapid fluorometric assay.
    BioMed Research International 06/2014; 2014:306580. DOI:10.1155/2014/306580 · 2.71 Impact Factor
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    • "Both nuclear DNA (n-DNA) and mitochondrial DNA (mt-DNA) are released into the circulation from apoptotic and necrotic cells, although the exact mechanism is unclear [8,9]. Cell-free plasma n-DNA and mt-DNA are biomarkers with prognostic utility in a range of conditions associated with a high rate of cell death, including trauma [10], stroke [11], myocardial infarction [12], burns [13], sepsis, and critical conditions [14-16]. We and others reported that high concentrations of plasma n-DNA can predict treatment outcomes and mortality in conditions associated with global ischemia-reperfusion injury, such as acute mesenteric ischemia and cardiac arrest [17-19]. "
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    ABSTRACT: Introduction Cell-free plasma mitochondrial DNA (mt-DNA) and nuclear DNA (n-DNA) are biomarkers with prognostic utility in conditions associated with a high rate of cell death. This exploratory study aimed to determine the plasma levels of both nucleic acids in patients with massive and submassive pulmonary embolism (PE) and to compare them with other biomarkers, such as heart-type fatty acid-binding protein (H-FABP) and troponin I (Tn-I) Methods This was a prospective observational study of 37 consecutive patients with massive PE, 37 patients with submassive PE, and 37 healthy subjects. Quantifications of plasma mt-DNA and n-DNA with real-time quantitative polymerase chain reaction (PCR), and plasma H-FABP and Tn-I by commercial assays, were done on blood samples drawn within 4 hours after presentation at the emergency department. Results Plasma mt-DNA and n-DNA concentrations were much higher in patients with massive PE (median, 2,970 GE/ml; interquartile range (IQR), 1,050 to 5,485; and 3,325 GE/ml, IQR: 1,080 to 5,790, respectively) than in patients with submassive PE (870 GE/ml and 1,245 GE/ml, respectively; P < 0.01) or controls (185 GE/ml and 520 GE/ml, respectively). Eighteen patients with massive PE died of a PE-related cause by day 15 of observation. Plasma mt-DNA and n-DNA values were 2.3-fold and 1.9-fold higher in the subgroup of nonsurviving patients than in survivors. H-FABP and Tn-I values were also higher in patients with massive PE who died (7.3 ng/ml and 0.023 ng/ml, respectively) than in those who survived (6.4 ng/ml, and 0.016 ng/ml, respectively). By receiver operating curve (ROC) analysis, the best cutoff values for predicting 15-day mortality were 3,380 GE/ml for mt-DNA, 6.8 ng/ml for H-FABP, 3,625 GE/ml for n-DNA, and 0.020 ng/ml for Tn-I, based on the calculated areas under the curve (AUCs) of 0.89 (95% confidence interval (CI), 0.78 to 0.99), 0.76 (95% CI, 0.69 to 093), 0.73 (95% CI, 0.58 to 0.91), and 0.59 (95% CI, 0.41 to 0.79), respectively. By stepwise logistic regression, a plasma mt-DNA concentration greater than 3,380 GE/ml (adjusted odds ratio (OR), 8.22; 95% CI, 1.72 to 39.18; P < 0.001) and a plasma value of H-FBAP >6.8 ng/ml (OR, 5.36; 95% CI, 1.06 to 27.08; P < 0.01) were the only independent predictors of mortality. Conclusions mt-DNA and H-FBAP might be promising markers for predicting 15-day mortality in massive PE, with mt-DNA having better prognostic accuracy.
    Critical care (London, England) 05/2013; 17(3):R90. DOI:10.1186/cc12735 · 4.48 Impact Factor
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