Analysis of Airway Thickening and Serum Cytokines in COPD Patients with Frequent Exacerbations: A Heart of the Matter

Figures & data

Figure 1 Study diagram showing the flowchart of subject recruitment.

Table 1 Baseline Characteristics of Frequent and Nonfrequent Exacerbators

	Total	Nonfrequent Exacerbators (n=106)	Frequent Exacerbators (n=106)	P-value
Age (yrs)	66.18±7.50	67.07±7.54	65.30±7.39	0.085
Male, n (%)	135(63.7)	65(30.7)	70(33.0)
Female, n (%)	77(36.3)	41(19.3)	36(17.0)
Height (cm)	160.27±8.63	160.23±8.72	160.31±8.58	0.953
Weight (kg)	63.77±11.45	62.77±11.22	64.77±11.64	0.205
BMI (kg/m^2)	24.69±3.15	24.32±3.09	25.06±3.18	0.087
6MWT (m)	337.17±116.64	353.54±112.23	320.80±119.17	0.041
Exacerbation frequency	1.50 (0–2.75)	0 (0–0)	2.50 (2–3)	0.001
Smoking condition				0.039
Smoker, n (%)	144(68)	79(37.3)	65(30.7)
Nonsmoker, n (%)	68(32)	27(12.7)	41(19.3)
Smoking index	51±25	47±22	55±27	0.001
CAT score,	18 (12–24)	15 (9–20)	22 (16–27)	0.001
mMRC score,	3 (1–3)	2 (1–3)	3 (2–4)	0.004
SGRQ score,	44.72 (27.96–57.51)	38.74 (16.94–50.59)	51.07 (37.56–63.98)	0.001
GOLD stage, n (%)
1	15(7.1)	8(3.8)	7(3.3)
2	72(34)	38(18)	34(16)
3	80(37.7)	34(16)	46(21.7)
4	45 (21.2)	26 (12.2)	19 (9)
Inhaled long medicine
LAMA	20(9.4)	12(5.7)	8(3.8)
LAMA+ICS	5(2.4)	3(1.4)	2(0.9)
LAMA+LABA	7(3.3)	3(1.4)	4(1.9)
LAMA+LABA+ICS	5(2.5)	2(0.9)	3(1.4)
Spirometry
FEV1 (L)	1.30±0.55	1.31±0.56	1.30±0.54	0.979
FEV1 (% predicted)	47.17±19.97	47.26±21.02	47.09±18.97	0.952
FVC (L)	2.73±0.74	2.71±0.72	2.75±0.77	0.680
FVC (% predicted)	73.50±17.28	72.64±16.88	74.35±17.72	0.472
FEV1/FVC (%)	47.35±13.06	47.36±13.43	47.34±12.74	0.992

Notes: Values are given as the mean ± SD, number (%), or median (interquartile range).

Abbreviations: BMI, body mass index; 6MWT, 6-min walk test; CAT, COPD assessment test; mMRC, modified Medical Research Council; SGRQ, St George’s Respiratory Questionnaire; LAMA, long-acting antimuscarinic; LABA, long-acting beta2-agonist; ICS, inhaled corticosteroids; FEV1, forced expiratory volume in one second; FEV1%pred, predicted percentage of FEV1; FVC, forced vital capacity; FVC%pred, predicted percentage of FVC.

Table 2 Quantitative CT Parameters and Inflammatory Index Between Frequent and Nonfrequent Exacerbators

	Total	Nonfrequent Exacerbators (n=106)	Frequent Exacerbators (n=106)	P-value
Emphysema index (%)	11.54 (3.39–25.42)	12.07 (3.45–30.88)	9.30 (3.42–22.56)	0.369
Emphysema grading (%)				0.222
Emphysema index <5%	66(31.1)	30(14.2)	36(17)
5%≤emphysema index <25%	92(43.4)	44(20.8)	48(22.6)
25%≤emphysema index <50%	51(24.1)	29(13.7)	22(10.4)
50%≤emphysema index <75%	3(1.4)	3(1.4)	0(0)
Air trapping (%)	44.17 (25.11–62.33)	42.44 (22.91–62.81)	45.83 (26.19–59.63)	0.916
Airway thickness
Pi10	2.71±0.54	2.54±0.54	2.89±0.48	0.001
WA%	54.80±7.90	51.93±8.23	57.75±6.36	0.001
Inflammatory cells
Leukocyte (,10^9/L)	7.63±2.59	7.30±2.36	7.97±2.76	0.057
Neutrophil (×10^9/L)	4.82±2.16	4.52±1.84	5.12±2.41	0.041
Neutrophil % (%)	61.54±11.12	60.64±10.51	62.43±11.68	0.242
Leukomonocyte (×10^9/L)	1.95±0.87	1.92±0.91	2.00±0.83	0.547
Leukomonocyte % (%)	26.75±9.73	27.26±9.43	26.24±10.05	0.443
Monocyte (×10^9/L)	0.61±0.23	0.61±0.24	0.60±0.23	0.883
Monocyte % (%)	8.26±2.69	8.59±2.64	7.93±2.72	0.070
Eosinophils (×10^9/L)	0.20±0.18	0.21±0.19	0.20±0.160	0.919
Eosinophils % (%)	2.76±2.11	2.82±2.20	2.70±2.02	0.673
Basophil (×10^9/L)	0.02(0–0.06)	0.03(0–0.06)	0.02(0–0.06)	0.372
Basophil % (%)	1.00(0–1.00)	1.00(0–1.00)	1.00(0–1.00)	0.062
Cytokines
IL-1β (pg/mL)	1.96(1.34–2.57)	1.46(1.13–1.99)	2.33(1.95–2.80)	0.001
IL-4 (pg/mL)	4.08(3.31–4.77)	3.69(3.01–4.37)	4.49(3.65–5.11)	0.001
IL-5 (pg/mL)	6.75(5.06–9.43)	6.94(5.04–9.48)	6.58(5.23–8.67)	0.602
IL-6 (pg/mL)	8.11(5.60–11.21)	6.83(4.90–13.40)	8.79(6.60–10.69)	0.037
IL-13 (pg/mL)	28.1(26.3–34.9)	27.02(20.37–35.60)	25.18(19.41–34.55)	0.329
IL-17 (pg/mL)	62.1(58.6–71.6)	58.43(44.13–73.49)	58.58(43.19–69.92)	0.996
IFN-γ (pg/mL)	93.9(80.3–96.4)	83.73(66.04–102.71)	78.5(58.72–95.40)	0.157

Notes: Values are given as the mean ± SD, number (%), or median (interquartile range). Emphysema index (EI), CT automatic calculation of the volume fraction of the lungs below 950 HU at full inspiration (%LAA-950), air trapping, CT automatic calculation of the volume fraction of the lungs below 856 HU at full inspiration (%LAA-856). Goddard score: 0=EI < 5%, 1=5%<EI<25%, 2=25%<EI<50%, 3=50%<EI<75%, 4=75%≤ EI.

Abbreviations: Pi10, inner perimeter wall thickness of a 10-mm diameter bronchiole airway; WA%, wall area percentage; IL-1β, interleukin-1β; IL-4, interleukin-4; IL-5, interleukin-5; IL-6, interleukin-6; IL-13, interleukin-13; IL-17, interleukin-17; IFN-γ, interferon-γ.

Table 3 Association Between the Frequent Exacerbator Phenotype in COPD and Airway Thickening or Systemic Inflammation

Independent variable	Model 1		Model 2
	OR (95% CI)	P-value	OR (95% CI)	P-value
Airway thickening
Pi10	3.85 (2.14–6.95)	0.001	4.01 (2.05–7.83)	0.001
WA %	1.11 (1.07–1.16)	0.001	1.12 (1.06–1.17)	0.001
Systemic inflammation
Neutrophil (×10^9/L)	1.15 (1.00–1.30)	0.044	1.14 (0.99–1.31)	0.07
IL-1β	3.12 (2.02–4.83)	0.001	2.94 (1.87–4.63)	0.001
IL-4	2.32 (1.67–3.21)	0.001	2.24 (1.60–3.15)	0.001
IL-6	1.00 (0.98–1.03)	0.789	1.00 (0.98–1.03)	0.833

Notes: Data are shown as least-square means (95% CI). Model 1: Univariate linear regression model. Model 2: Multivariable linear regression model adjusted for sex, age, BMI, smoking index and FEV1%pred.

Abbreviations: Pi10, inner perimeter wall thickness of a 10-mm diameter bronchiole airway; WA%, wall area percentage; IL-1β, interleukin-1β; IL-4, interleukin-4; IL-6, interleukin-6; OR, odds ratio.

Figure 2 Associations between quartiles of Pi10, WA%, IL-1β, or IL-4 and the frequent exacerbation phenotype. The linear association between the odds ratio (OR) and variables was assessed by P for trend using a logistic regression model. (A) OR for quartile of Pi10 associated with the frequent exacerbator phenotype (p for trend <0.001). (B) OR for quartile of WA% associated with the frequent exacerbator phenotype (p for trend <0.001). (C) OR for quartile of IL-1β associated with the frequent exacerbator phenotype (p for trend <0.001). (D) OR for quartile of IL-4 associated with the frequent exacerbator phenotype (p for trend <0.001).

Table 4 Association Between Pi10 and the Inflammatory Index

Inflammatory Index	Continuous Variable of Pi10 (β 95% CI)	Quartiles of Pi10 (β 95% CI)
		Q1≤2.32	2.33≤Q2≤2.63	2.64≤Q3≤3.08	3.09≤Q4	P for trend
		N=52	N=51	N=57	N=52
Neutrophil	0.1 (−0.49–0.69)	0 (ref)	0.22 (−0.61–1.06)	0.55 (−0.27–1.37)	0.27 (−0.62–1.16)	0.514
IL-1β	1.47 (1.11–1.84)^a	0 (ref)	0.406 (−0.13–0.94)	0.832 (0.30–1.35)^c	1.763 (1.19–2.34)^d	0.001
IL-4	0.41 (0.12–0.69)^b	0 (ref)	0.336 (−0.06–0.74)	0.298 (−0.09–0.69)	0.55 (0.12–0.98)^e	0.024

Notes: Data are shown as least-square means (95% CI). Q, quartile; Q1, ≤25th percentile, Q2, 25th percentile-50th percentile, Q3, 50th percentile-75th percentile, Q4, ≥75th percentile-100th percentile, ref, reference, β, regression coefficient. Generalized linear model adjusted for sex, age, BMI, smoking index and FEV1%pred. ^aP <0.001, ^bP <0.05 ^cP_Q1-Q3<0.05, ^dP _Q1-Q4<0.001. ^eP_Q1-Q4<0.05.

Figure 3 Receiver operating characteristic curve for identification of the frequent exacerbator phenotype. ROC analysis yielded areas under the curve (AUCs) of 0.722, 0.736, 0.807 and 0.706, respectively, for the identification of FE. The greatest sum of sensitivity and specificity occurred at Pi10 = 2.51 mm, WA%=54%, IL-1β=1.686 (pg/mL), and IL-4=4.316 (pg/mL).

Data Sharing Statement

All data generated or analysed during this study are included in this published article.