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. 2011;6(7):e21700.
doi: 10.1371/journal.pone.0021700. Epub 2011 Jul 1.

Fatal outcome in bacteremia is characterized by high plasma cell free DNA concentration and apoptotic DNA fragmentation: a prospective cohort study

Reetta Huttunen  1 , Taru Kuparinen, Juulia Jylhävä, Janne Aittoniemi, Risto Vuento, Heini Huhtala, Janne Laine, Jaana Syrjänen, Mikko Hurme
Affiliations

Fatal outcome in bacteremia is characterized by high plasma cell free DNA concentration and apoptotic DNA fragmentation: a prospective cohort study

Reetta Huttunen et al. PLoS One. 2011.

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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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. cf-DNA line plot diagram.
A Line plot diagram showing cell free DNA (cf-DNA) concentration detected on days 1–4, 5 to 17 days and >25 days after blood culture in nonsurvivors (black plots) and in survivors (open plots).
Figure 2
Figure 2. cf-DNA ROC curve.
Receiver operating characteristic (ROC) curve for maximal plasma cell free DNA (cf-DNA) concentration detected on days 1–4 after positive blood culture in relation to case fatality in bacteremia patients.
Figure 3
Figure 3. cf-DNA and survival curve.
Cumulative 30-d survival in bacteremia patients with maximum plasma cell free DNA (cf-DNA) >1.52 ug/ml compared to those with cf-DNA ≤1.52 ug/ml. The cut off value of 1.52 ug/ml was chosen using ROC curve. The survival curve was calculated using the Kaplan-Meier method, and survival differences between groups were compared by log-rank test.
Figure 4
Figure 4. Qualitive cf-DNA analysis.
Qualitative analysis of plasma cf-DNA in 8 bacteremia survivors (panel A) and 8 non-survivors (panel B) after NucleoSpin® Plasma XS kit extraction. Analyses were performed with Agilent's High Sensitivity Lab-on-a-chip DNA assay. Green lines indicate the low-weight (35 bp) DNA marker and purple lines the high- weight (10 380 bp) DNA marker. TP 1 = time point 1 (1 to 4 days after blood culture), TP 2 =  time point 2 (5 to 17 days after blood culture), TP 3 = time point 3 (recovery, >25 days after blood culture). The intensity of the low-molecular-weight cf-DNA band was graded as follows: 1 = no visible cf-DNA or weak intensity, 2 = intermediate intensity, 3 = strong intensity. Abbreviations; bp =  base pairs, TP = time point.
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