Serum CCL-18 level is a risk factor for COPD exacerbations requiring hospitalization

Figures & data

Table 1 Characteristic features of the study groups

	NSp	COPD	P-value
Subjects, n	20	60
Males, n (%)	10 (50)	56 (93.3)	<0.0001
Age, years	59.9±12.6	63.1±8.8	0.25
Smoking status
Ex-smoker	4 (20)	51 (85)	<0.0001
Current smoker	16 (80)	9 (15)
Smoking, pack-years	22.3±17.2	49.5±24.9	<0.0001
Postbronchodilator FEV1, %predicted	84.4±21.9	45.7±15.2	<0.0001
Postbronchodilator FEV1/FVC, %	76.8±10.5	62.1±11.4	<0.0001
BMI, kg/m^2	27.8±5.3	28.1±6.8	0.87
CCI	0.43±0.8	3.4±1.5	<0.0001
COPD severity, GOLD
Mild (I)	–	1 (1.8)
Moderate (II)		26 (45.6)
Severe (III)		20 (35.1)
Very severe (IV)		10 (17.5)

Notes: Data are presented as mean ± SD or numbers (%). Statistical significance was determined by the two-sample t-test for normally distributed continuous variables and the Mann–Whitney U-test for the comparison of continuous non-normal data between the groups. A chi-square test was used to compare proportions between two groups.

Abbreviations: n, number of subjects; NSp, normal spirometry participants; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory flow volume in 1 s; FVC, forced vital capacity; BMI, body mass index; CCI, Charlson Comorbidity Index; GOLD, Global Initiative for Chronic Obstructive Lung Disease; SD, standard deviation.

Table 2 Clinical and functional characteristics of the infrequent versus frequent exacerbator COPD patients

	COPD group		P-value
	IE-COPD (n=33)	FE-COPD (n=27)
Sex, M/F, n	29/4	27/0	0.06
Age, years	66.0±10.0	67.0±8.3	0.69
BMI, kg/m^2	29.8±5.6	26.2±7.6	0.06
Smoking, pack-years	42.6±21.3	56.6±26.7	0.036
Postbronchodilator FEV1, %predicted	50.5±13	40.5±15.6	0.012
Postbronchodilator	65.4±8.7	58.5±13.1	0.026
FEV1/FVC, %
mMRC	1.4±1.1	2.9±0.8	<0.0001
BODE	2.0±1.2	5.4±2.5	<0.0001
CAT	11.6±7.4	25.4±5.7	<0.0001
6MWD, m	380±68	235±114	<0.0001
CCI	3.6±1.7	3.2±1.2	0.042
CCL-18, ng/mL	167.9±76.5	195.9±72.6	0.09
CRP, mg/dL	1.0±1.0	1.1±1.2	0.52
Number of exacerbations/year	1 (0–1)	3 (2–5)	<0.0001
Patients with exacerbations requiring hospitalization, n (%)	7 (28)	18 (72)	<0.0001

Notes: Data are mean ± standard deviation or median (IQR 25–75), as appropriate. Statistical significance was determined by the two-sample t-test for normally distributed continuous variables and the Mann–Whitney U-test for comparison of continuous non-normal data between groups. Chi-square test was used to compare proportions between the two groups. BMI, post-bronchodilator FEV₁ %predicted, mMRC score, and the 6MWD were integrated to calculate the 10-point BODE index as described previously.²²

Abbreviations: COPD, chronic obstructive pulmonary disease; IE-COPD, infrequent exacerbator chronic obstructive pulmonary disease patients; FE-COPD, frequent exacerbator chronic obstructive pulmonary disease patients; M, males; F, females; BMI, body mass index; FEV₁, forced expiratory flow volume in 1 s; FVC, forced vital capacity; mMRC, modified Medical Research Council Dyspnea Scale; BODE index, body mass index, airflow obstruction, dyspnea, exercise capacity index; CAT, COPD Assessment Test; 6MWD, 6-min walking distance; CCI, Charlson Comorbidity Index; CCL-18, chemokine (C-C motif) ligand 18; CRP, C-reactive protein.

Table 3 Clinical and functional characteristics of the COPD patients with and without exacerbations requiring hospitalization

	COPD group		P-value
	Hospitalized exacerbations
	0 (n=35)	≥1 (n=25)
Sex, M/F, n	33/2	23/2	0.73
Age, years	64.3±9.5	69.7±7.8	0.026
BMI, kg/m^2	28.3±5.8	27.8±8.1	0.77
Smoking, pack-years	44.6±21.3	56.2±28.3	0.11
Postbronchodilator FEV1, %predicted	50.4±14.8	38.8±13.3	0.004
Postbronchodilator FEV1/FVC, %	66.3±9.2	56.1±11.8	0.001
mMRC	1.7±1.1	2.7±1.2	0.002
BODE	2.7±2.2	4.9±2.6	0.003
CAT	15.4±9.5	21.6±8.7	0.016
6MWD, m	344±99	268±129	0.005
CCI	3.4±1.7	3.5±1.1	0.77
CCL-18, ng/mL	136.7±41.0	239.4±71.6	<0.0001
CRP, mg/dL	0.8±0.8	1.2±1.3	0.29
Number of exacerbations/year	1.6±2.1	1.2±1.4	0.001

Notes: Data are mean ± standard deviation or median (IQR 25–75), as appropriate. Statistical significance was determined by the two-sample t-test for normally distributed continuous variables and the Mann–Whitney U-test for the comparison of continuous non-normal data between groups. Chi-square test was used to compare proportions between the two groups.

Abbreviations: COPD, chronic obstructive pulmonary disease; M, males; F, females; BMI, body mass index; FEV₁, forced expiratory flow volume in 1 s; FVC, forced vital capacity; mMRC, modified Medical Research Council Dyspnea Scale; BODE index, body mass index, airflow obstruction, dyspnea, exercise capacity index; CAT, COPD Assessment Test; 6MWD, 6-min walking distance; CCI, Charlson Comorbidity Index; CCL-18, chemokine (C-C motif) ligand 18; CRP, C-reactive protein.

Table 4 Univariable and multivariable analysis of possible risk factors for exacerbation requiring hospitalization in the previous year

Variables	Univariable regression analysis				Multivariable regression anlaysis
	B ± SE	OR	95% CI	P-value	B ± SE	OR	95% CI	P-value
Age, years	0.04±0.03	1.04	0.97–1.11	0.218	–	–	–	–
Sex	−0.36±1.04	0.70	0.09–5.31	0.728	–	–	–	–
Smoking, pack-years	0.02±0.01	1.02	0.99–1.04	0.136	–	–	–	–
BODE index	0.38±0.15	1.46	1.08–1.98	0.013	0.44±0.29	1.55	0.84–2.76	0.133
CCL-18, ng/mL	0.04±0.01	1.04	1.02–1.06	<0.0001	0.05±0.02	1.05	1.01–1.09	0.014
Number of exacerbations	0.35±0.16	1.42	1.04–1.93	0.026	0.92±0.56	2.52	0.83–7.60	0.101

Note: Bold indicates significant values.

Abbreviations: BODE index, body mass index, airflow obstruction, dyspnea, exercise capacity index; SE, standard error; OR, odds ratio; CI, confidence intervals; CCL-18, chemokine (C-C motif) ligand 18.

Table 5 Univariate correlations (r) between serum CCL-18 level and frequency of exacerbations, frequency of exacerbations requiring hospitalization, airflow limitation, dyspnea perception, total symptom scores, 6-min walking distance, BODE index, and comorbidities in the COPD group (n=60)

	CCL-18, ng/mL
	r	P-value
Smoking exposure (pack-years)	0.45	<0.0001
Number of exacerbations per year	0.30	0.026
Number of exacerbations requiring hospitalization per year	0.68	<0.0001
Post-bronchodilator FEV1 %predicted	−0.39	0.001
Post-bronchodilator FEV1/FVC, %	−0.34	0.004
mMRC	0.46	<0.0001
CAT	0.41	<0.0001
6-min walking distance (m)	−0.27	0.037
BODE	0.58	<0.0001
SpO2 (resting), %	−0.45	<0.0001
CCI	0.41	<0.0001

Note: Spearman correlation coefficients are presented.

Abbreviations: FEV₁, forced expiratory flow volume in 1 s; FVC, forced vital capacity; mMRC, modified Medical Research Council Dyspnea Scale; BODE index, body mass index, airflow obstruction, dyspnea, exercise capacity index; CAT, COPD Assessment Test; CCI, Charlson Comorbidity Index; CCL-18, Chemokine (C-C motif) ligand 18; SpO₂, oxygen saturation.

Figure 1 Comparison of serum CCL-18 concentration of infrequent exacerbator COPD patients with frequent exacerbator COPD patients. The central horizontal line on each box represents the median, the ends of the boxes are 25 and 75 percentiles and the error bars 5% and 95%. P-values derived from the Mann–Whitney U-test.

Abbreviations: COPD, chronic obstructive pulmonary disease; IE-COPD, infrequent exacerbator chronic obstructive pulmonary disease patients; FE-COPD, frequent exacerbator chronic obstructive pulmonary disease patients.

Figure 2 Comparison of serum CCL-18 concentration in COPD patients with ≥1 hospitalized exacerbations and those who were not hospitalized. The central horizontal line on each box represents the median, the ends of the boxes are 25 and 75 percentiles and the error bars 5% and 95%. P-values derived from the Mann–Whitney U-test.

Abbreviations: CCL-18, chemokine (C-C motif) ligand 18; COPD, chronic obstructive pulmonary disease.

Figure 3 Receiver operator characteristic curve distinguishing COPD patients and smokers with normal spirometry AUC: 0.86 (95% CI: 0.77–0.94). The cutoff that maximizes the sum of sensitivity (83.1%) and specificity (73.7%) was >105.76 ng/mL.

Abbreviations: ROC, receiver operating characteristics curve anlaysis; CCL-18, chemokine (C-C motif) ligand 18; AUC, area under curve; CI, confidence intervals.

Figure 4 Receiver operator characteristic curve distinguishing COPD patients with hospitalized exacerbations from those who were not hospitalized, AUC: 0.92 (95% CI: 0.85–0.99). The cutoff that maximizes the sum of sensitivity (88%) and specificity (88.2%) was >108.71 ng/mL.

Abbreviations: ROC, receiver operating characteristics curve anlaysis; CCL-18, chemokine (C-C motif) ligand 18; AUC, area under curve; CI, confidence intervals.

Figure 5 Scatterplot graph of serum CCL-18 concentration with number of exacerbations requiring hospitalization in COPD group.

Abbreviations: CCL-18, chemokine (C-C motif) ligand 18; COPD, chronic obstructive pulmonary disease.

CelliBRCoteCGMarinJMThe body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary diseaseN Engl J Med2004350101005101214999112

 PubMed Web of Science ®Google Scholar