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      Fatal Outcome in Bacteremia is Characterized by High Plasma Cell Free DNA Concentration and Apoptotic DNA Fragmentation: A Prospective Cohort Study

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          Abstract

          Introduction

          Recent studies have shown that apoptosis plays a critical role in the pathogenesis of sepsis. High plasma cell free DNA (cf-DNA) concentrations have been shown to be associated with sepsis outcome. The origin of cf-DNA is unclear.

          Methods

          Total plasma cf-DNA was quantified directly in plasma and the amplifiable cf-DNA assessed using quantitative PCR in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, ß-hemolytic streptococcae or Escherichia coli. The quality of cf-DNA was analyzed with a DNA Chip assay performed on 8 survivors and 8 nonsurvivors. Values were measured on days 1–4 after positive blood culture, on day 5–17 and on recovery.

          Results

          The maximum cf-DNA values on days 1–4 (n = 132) were markedly higher in nonsurvivors compared to survivors (2.03 vs 1.26 ug/ml, p<0.001) and the AUCROC in the prediction of case fatality was 0.81 (95% CI 0.69–0.94). cf-DNA at a cut-off level of 1.52 ug/ml showed 83% sensitivity and 79% specificity for fatal disease. High cf-DNA (>1.52 ug/ml) remained an independent risk factor for case fatality in a logistic regression model. Qualitative analysis of cf-DNA showed that cf-DNA displayed a predominating low-molecular-weight cf-DNA band (150–200 bp) in nonsurvivors, corresponding to the size of the apoptotic nucleosomal DNA. cf-DNA concentration showed a significant positive correlation with visually graded apoptotic band intensity (R = 0.822, p<0.001).

          Conclusions

          Plasma cf-DNA concentration proved to be a specific independent prognostic biomarker in bacteremia. cf-DNA displayed a predominating low-molecular-weight cf-DNA band in nonsurvivors corresponding to the size of apoptotic nucleosomal DNA.

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          Most cited references16

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          IDO expression by dendritic cells: tolerance and tryptophan catabolism.

          Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan. The concept that cells expressing IDO can suppress T-cell responses and promote tolerance is a relatively new paradigm in immunology. Considerable evidence now supports this hypothesis, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases. In this review, we summarize key recent developments and propose a unifying model for the role of IDO in tolerance induction.
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            Cell-free plasma DNA as a predictor of outcome in severe sepsis and septic shock.

            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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              Plasma DNA concentration as a predictor of mortality and sepsis in critically ill patients.

              Risk stratification of severely ill patients remains problematic, resulting in increased interest in potential circulating markers, such as cytokines, procalcitonin and brain natriuretic peptide. Recent reports have indicated the usefulness of plasma DNA as a prognostic marker in various disease states such as trauma, myocardial infarction and stroke. The present study assesses the significance of raised levels of plasma DNA on admission to the intensive care unit (ICU) in terms of its ability to predict disease severity or prognosis. Fifty-two consecutive patients were studied in a general ICU. Blood samples were taken on admission and were stored for further analysis. Plasma DNA levels were estimated by a PCR method using primers for the human beta-haemoglobin gene. Sixteen of the 52 patients investigated died within 3 months of sampling. Nineteen of the 52 patients developed either severe sepsis or septic shock. Plasma DNA was higher in ICU patients than in healthy controls and was also higher in patients who developed sepsis (192 (65-362) ng/ml versus 74 (46-156) ng/ml, P = 0.03) or who subsequently died either in the ICU (321 (185-430) ng/ml versus 71 (46-113) ng/ml, P < 0.001) or in hospital (260 (151-380) ng/ml versus 68 (47-103) ng/ml, P < 0.001). Plasma DNA concentrations were found to be significantly higher in patients who died in the ICU. Multiple logistic regression analysis determined plasma DNA to be an independent predictor of mortality (odds ratio, 1.002 (95% confidence interval, 1.0-1.004), P = 0.05). Plasma DNA had a sensitivity of 92% and a specificity of 80% when a concentration higher than 127 ng/ml was taken as a predictor for death on the ICU. Plasma DNA may be a useful prognostic marker of mortality and sepsis in intensive care patients.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                1 July 2011
                : 6
                : 7
                : e21700
                Affiliations
                [1 ]Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
                [2 ]University of Tampere Medical School, Tampere, Finland
                [3 ]Department of Microbiology and Immunology, University of Tampere Medical School, Tampere, Finland
                [4 ]Centre for Laboratory Medicine, Pirkanmaa Hospital District, Tampere, Finland
                [5 ]School of Health Sciences, University of Tampere, Tampere, Finland
                Institut de Pharmacologie et de Biologie Structurale, France
                Author notes

                Conceived and designed the experiments: RH RV JS MH JL. Performed the experiments: JJ TK JA RV MH. Analyzed the data: JA JS RV RH HH. Contributed reagents/materials/analysis tools: JJ MH TK. Wrote the paper: RH JA.

                Article
                PONE-D-11-05126
                10.1371/journal.pone.0021700
                3128600
                21747948
                a69baed3-b16c-4e86-b736-64164c78595c
                Huttunen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 9 March 2011
                : 5 June 2011
                Page count
                Pages: 8
                Categories
                Research Article
                Biology
                Biochemistry
                Nucleic Acids
                DNA
                Forms of DNA
                Molecular Cell Biology
                Cell Death
                Medicine
                Critical Care and Emergency Medicine
                Sepsis
                Diagnostic Medicine
                Pathology
                General Pathology
                Biomarkers
                Infectious Diseases
                Bacterial Diseases
                Bacteremia

                Uncategorized
                Uncategorized

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