title: Prognostic utility of admission cell-free DNA levels in patients with chronic obstructive pulmonary disease exacerbations.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease exacerbations (COPDEs) are associated with increased morbidity and mortality. Cell-free DNA (cfDNA) is a novel biomarker associated with clinical outcomes in several disease states but has not been studied in COPD. The objectives of this study were to assess cfDNA levels during a COPDE, to evaluate the association of cfDNA with clinical parameters and to explore the prognostic implications of cfDNA levels on long-term survival.
  
  
  METHODS
  This was an observational study that assessed cfDNA levels in patients admitted to hospital for a COPDE. Plasma cfDNA levels of COPDE patients were compared to those of matched stable COPD patients and healthy controls. Multivariable and Cox regression analyses were used to assess the association of cfDNA levels with blood gas parameters and long-term survival.
  
  
  RESULTS
  A total of 62 patients (46 males, forced expiratory volume in 1 second [FEV1] 38%±13%) were included. The median cfDNA levels on admission for COPDE patients was 1,634 ng/mL (interquartile range [IQR] 1,016-2,319) compared to 781 ng/mL (IQR 523-855) for stable COPD patients, matched for age and disease severity, and 352 ng/mL (IQR 209-636) for healthy controls (P<0.0001, for both comparisons). cfDNA was correlated with partial arterial pressure of carbon dioxide (PaCO2,r=0.35) and pH (r=-0.35),P=0.01 for both comparisons. In a multivariable analysis, PaCO2was the only independent predictor of cfDNA. Using a cfDNA level of 1,924 ng/mL (threshold for abnormal PaCO2), those with high levels had a trend for increased 5-year mortality risk adjusted for age, sex and FEV1% (hazard ratio 1.92, 95% confidence interval 0.93-3.95,P=0.08).
  
  
  CONCLUSIONS
  Plasma cfDNA might offer a novel technique to identify COPD patients at increased risk of poor outcomes, but the prognostic utility of this measurement requires further study.
authors.affiliation: Department of Medicine, Pulmonology Institute, Soroka Medical Center, Ben-Gurion University, Beer-Sheva, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Avriel
authors.affiliation: Division of Respirology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Rozenberg
authors.affiliation: Department of Medicine, Pulmonology Institute, Soroka Medical Center, Ben-Gurion University, Beer-Sheva, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Raviv
authors.affiliation: Department of Medicine, Pulmonology Institute, Soroka Medical Center, Ben-Gurion University, Beer-Sheva, Israel.
authors.forename: Dov
authors.initials: D
authors.lastname: Heimer
authors.affiliation: Department of Medicine, Pulmonology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv.
authors.forename: Amir
authors.initials: A
authors.lastname: Bar-Shai
authors.affiliation: Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Gavish
authors.affiliation: Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA; Department of Clinical Biochemistry, Faculty of Health Sciences, Soroka Medical Center, Ben-Gurion University, Beer-Sheva, Israel.
authors.forename: Jony
authors.initials: J
authors.lastname: Sheynin
authors.affiliation: Department of Clinical Biochemistry, Faculty of Health Sciences, Soroka Medical Center, Ben-Gurion University, Beer-Sheva, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Douvdevani
mesh_terms: D000368:Aged; D019540:Area Under Curve; D001784:Blood Gas Analysis; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004247:DNA / Q000097:blood* / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005541:Forced Expiratory Volume; D005819:Genetic Markers; D006801:Humans; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010343:Patient Admission; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000503:physiopathology; D012372:ROC Curve; D012307:Risk Factors; D012720:Severity of Illness Index; D017741:Survivors; D013997:Time Factors; D014797:Vital Capacity
chemical_list: D005819:Genetic Markers; D004247:DNA
keywords: biomarker; cell-free DNA; chronic obstructive pulmonary disease; exacerbation; prognosis