Prognostic utility of admission cell-free DNA levels in patients with chronic obstructive pulmonary disease exacerbations

Figures & data

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.

Table 1 Cell-free DNA divided into tertiles

Parameter	Lowest tertile (n=21)	Intermediate (n=20)	Highest tertile (n=21)	P-value
DNA level (IQR)	972 ng/mL (880–1,034)	1,634 (1,461–1,751)	2,804 (2,311–3,636)	<0.0001a
Age, years (±SD)	68±9	61±8	66±11	0.053
Male sex	14 (67%)	15 (75%)	17 (81%)	0.57
Pulmonary function tests
FEV1/FVC	56±8	53±12	55±10	0.71
FEV1 (%), (n=58)	39±10	40±15	34±13	0.34
Blood gases
pH	7.38±0.04	7.37±0.05	7.33±0.06	0.009b
PaCO2 (mmHg)	43±9	50±15	59±18	0.008c
PaO2 (mmHg), median (IQR)	89 (60–93)	86 (71–95)	75 (69–84)	0.29
Hospital length of stay, median days (IQR)	4 (3–7)	4 (3–6)	4 (3–6)	0.51
Noninvasive ventilation during hospital	3 (14%)	4 (20%)	4 (19%)	0.88

Notes: Data presented as median (IQR), mean ± SD, or n (%).

a All tertiles P<0.05, post-hoc Bonferroni comparison between tertiles:

b (lowest and intermediate) vs highest, P<0.05;

c lowest vs highest only, P<0.05.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; IQR, interquartile range; PaCO₂, partial arterial pressure of carbon dioxide; PaO₂, partial arterial pressure of oxygen; SD, standard deviation.

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.

Table 2 Mortality risk of clinical characteristics and cfDNA levels

Parameter	Unadjusted HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value
cfDNA (high ≥1,924 ng/mL vs low levels)	2.01 (1.04–3.89)	0.035	1.92 (0.93–3.95)	0.08
Age (every 10 years)	1.74 (1.19–2.47)	0.003	2.15 (1.37–3.37)	0.0009
Male sex	1.55 (0.74–3.86)	0.21	0.79 (0.34–2.37)	0.83
FEV1%, n=58 (every 10% increase)	0.69 (0.52–0.94)	0.02	0.60 (0.43–0.86)	0.005

Abbreviations: cfDNA, cell-free DNA; CI, confidence interval; FEV₁, forced expiratory volume in 1 second; HR, hazard ratio.

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.