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, PaCO₂ was 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).

Conclusion: 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.

Keywords: biomarker; cell-free DNA; chronic obstructive pulmonary disease; exacerbation; prognosis.

Figure 1

Flowchart of patients who met inclusion/exclusion criteria for the study population. Abbreviations: ED, emergency department; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

Figure 2

Cell-free DNA (cfDNA) levels of COPD exacerbation group vs COPD stable control and healthy controls. Notes: COPD exacerbation (n=62), 1,634 ng/mL (IQR 1,016–2,319) vs COPD controls (n=16), 781 ng/mL (IQR 523–855) vs Healthy controls (n=10), 352 ng/mL (IQR 209–636). *COPD exacerbation vs COPD controls and COPD exacerbation vs healthy controls, P<0.0001 for both comparisons; **COPD controls vs Healthy controls, P=0.014. Abbreviation: IQR, interquartile range.

Figure 3

(A) ROC curve for blood gas PaCO₂; (B) ROC curve for blood gas pH. Notes: (A) Area under curve for PaCO₂ >45 mmHg was 0.68 (95% CI 0.53–0.82, P=0.02). (B) Area under curve for pH <7.36 was 0.7 (95% CI 0.56–0.84, P=0.0l). Arterial blood gases were drawn simultaneously with the cfDNA levels. Abbreviations: PaCO₂, partial arterial pressure of carbon dioxide; ROC, receiver operating characteristic.

Figure 4

(A) Cell-free DNA levels at admission and 48 hours. (B) Cell-free DNA levels at admission and clinic (1-month post). Notes: (A) COPD acute DNA levels (2,853 ng/mL (IQR 1,249–3,636) vs 48 hours (1,918 ng/mL (IQR 1,686–2,547), P=0.11 (paired t-test) in 12 patients. (B) COPD acute DNA levels (2,305 ng/mL (IQR 1,249–3,636) vs 1 month (1,015 ng/mL (IQR 665–1,309), P=0.0003 (paired t-test) in 7 patients. Abbreviation: IQR, interquartile range.

Figure 5

Survival curve based on cfDNA levels. Note: Low cfDNA (<1,924 ng/mL) vs normal cfDNA levels (≥1,924 ng/mL), P=0.035. Abbreviation: cfDNA, cell-free DNA.