Morphological changes in small pulmonary vessels are associated with severe acute exacerbation in chronic obstructive pulmonary disease

Figures & data

Table 1 Characteristics of COPD patients and non-COPD subjects

	COPD patients	Non-COPD subjects
Number of patients	81	28
Sex, male/female	79/2	19/9
Age, years	77.0 (55–89)	56.5 (26–73)
Smoking, pack-years	55.0 (10–212)	39.5 (6–136)
BMI, kg/m^2	20.8 (14.6–27.7)	23.8 (17.1–33.5)
Comorbidities
Bronchial asthma	8 (9.9)	1 (3.6)
Cardiovascular disease	32 (39.5)	0 (0)
Hypertension	25 (30.8)	8 (28.6)
Diabetes	9 (11.1)	4 (14.3)
Pulmonary function test
FVC, L	2.84 (1.29–4.68)	3.70 (1.81–5.54)
%FVC, %	87.9 (41.6–141.8)	105.6 (82.5–137.8)
FEV1/FVC, %	48.1 (21.1–69.9)	77.6 (71.9–96.4)
FEV1, L	1.27 (0.51–2.96)	2.96 (1.37–4.12)
%FEV1, %	60.2 (22.6–121.8)	103.4 (81.3–141.0)
GOLD I	22 (27.2)
GOLD II	32 (39.5)
GOLD III	23 (28.4)
GOLD IV	4 (4.9)
COPD managements
LAMA	60 (74.1)
LABA	57 (70.4)
ICS	42 (51.9)
LTOT	11 (13.8)
Incidence of severe	26 (32.1)
AE-COPD

Note: Variables are presented as median (range) and n (%).

Abbreviations: COPD, chronic obstructive pulmonary disease; BMI, body mass index; FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; LAMA, long-acting muscarinic antagonists; LABA, long-acting β agonists; ICS, inhaled corticosteroid; LTOT, long-term oxygen therapy; AE-COPD, acute exacerbation of COPD.

Figure 1 Correlations between the %CSA and an airflow limitation.

Notes: The %CSA_<5 (A) and %CSA_5–10 (B) were compared in patients with COPD and non-COPD subjects. The %CSA_<5 (C) and the %CSA_5–10 (D) in patients with COPD according to GOLD classification. The upper and lower portions of the boxes indicate the 25th and 75th percentiles, respectively, and horizontal lines within the boxes indicate the 50th percentiles (median). The horizontal lines above and below the boxes indicate the 1.5-interquartile ranges of the lower and upper quartiles, respectively. The P-values were determined using the Mann–Whitney U-test and the Kruskal–Wallis test followed by post hoc analyses.
Abbreviations: %CSA, percentage of cross-sectional area; GOLD, Global Initiative for Chronic Obstructive Lung Disease; COPD, chronic obstructive pulmonary disease.

Table 2 Predictive values for severe AE-COPD

Predictor	Valuea	Cutoff	AUC	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Likelihood ratio
%FEV1 (%)	60.2 (45.4–81.0)	50.0	0.830	69.2	83.6	66.7	85.2	4.23
%LAV (%)	27.8 (15.9–39.6)	30.0	0.782	76.9	69.1	54.1	86.4	2.49
%CSA<5 (%)	1.16 (0.88–1.50)	1.0	0.636	53.8	70.9	46.7	76.5	1.85

Note:

a Median (25–75th percentile).

Abbreviations: AE-COPD, acute exacerbation of chronic obstructive pulmonary disease; AUC, area under the curve; PPV, positive predictive value; NPV, negative predictive value; FEV₁, forced expiratory volume in 1 second; %LAV, percent low attenuation volume; %CSA, percentage of cross-sectional area.

Table 3 Prediction of severe AE-COPD: univariate analyses

Variable	HR	95% CI	P-value
Age, 10 years	1.701	0.882–3.281	0.110
Sex, male	0.414	0.027–6.280	0.530
BMI <20 kg/m^2	3.845	1.778–8.319	<0.001
Smoking, 10 pack-years	1.060	0.978–1.150	0.160
Bronchial asthma	0.951	0.205–4.392	0.950
Cardiovascular disease	1.956	0.903–4.234	0.089
GOLD, 1-Stage increase	2.426	1.600–3.679	<0.001
%LAV >30%	4.233	1.728–10.37	<0.001
%CSA<5 <1.0	2.668	1.263–5.636	0.010

Note: Fine–Gray’s proportional hazards model was used.

Abbreviations: AE-COPD, acute exacerbation of chronic obstructive pulmonary disease; HR, hazard ratio; CI, confidence interval; BMI, body mass index; GOLD, Global Initiative for Chronic Obstructive Lung Disease; %LAV, percent low attenuation volume; %CSA, percentage of cross-sectional area.

Figure 2 Cumulative incidence of severe acute AE-COPD according to the %CSA_<5.

Notes: The cumulative incidence of severe AE-COPD was determined using the Fine and Gray method. The red line represents the subgroup with %CSA_<5 less than 1.0% and the blue line represents %CSA_<5 more than 1.0%. The P-values were determined using Gray’s test.
Abbreviations: AE-COPD, acute exacerbation of chronic obstructive pulmonary disease; %CSA, percentage of cross-sectional area.

Figure S1 Extracting the pulmonary small vessels as the CSA.

Notes: (A) CT images of lung field segmented within the threshold values between −500 and −1,024 HU. (B) Binary images converted from segmented image (A) with a window level of −720 HU. Pulmonary vessels are displayed in black. (C) Mask image for particle analysis after setting vessel size parameters within 0–5 mm² and the range of circularity within 0.9–1.0.

Abbreviations: CSA, cross-sectional area; CT, computed tomography; HU, Hounsfield units.

Figure S2 The relationships between the %CSA_<5 and pulmonary functions.

Notes: The relationships between the %CSA_<5 and the %FVC (A), %FEV₁ (B), the FEV₁/FVC (C), and the %LAV (D). ρ represents Spearman’s correlation coefficient.

Abbreviations: %CSA, percentage of cross-sectional area; %FVC, percent forced vital capacity; %FEV₁, percent forced expiratory volume in 1 second; %LAV, percent low attenuation volume.

Figure S3 The relationships between the %CSA_5–10 and pulmonary function parameters.

Notes: The relationships between the %CSA_5–10 and the %FVC (A), %FEV₁ (B), the FEV₁/FVC (C), and the %LAV (D). ρ represents Spearman’s correlation coefficient.

Abbreviations: %CSA, percentage of cross-sectional area; %FVC, percent forced vital capacity; %FEV₁, percent forced expiratory volume in 1 second; %LAV, percent low attenuation volume.

Table S1 Correlations between %CSA and clinical parameters

Variables	%CSA<5		%CSA5–10
	Coefficient (ρ)	P-value	Coefficient (ρ)	P-value
Age, years	−0.374	<0.001	−0.273	0.004
Smoking, pack-years	−0.161	0.095	−0.181	0.059
BMI, kg/m^2	0.442	<0.001	0.202	0.035
FVC, %	0.240	0.012	0.148	0.125
%FVC, %	0.284	0.003	0.143	0.138
FEV1, %	0.478	<0.001	0.296	0.002
%FEV1, %	0.491	<0.001	0.291	0.002
%FEV1/FVC, %	0.590	<0.001	0.379	<0.001
%LAV, %	−0.761	<0.001	−0.421	<0.001

Notes: Spearman rank correlation analysis was used. ρ represents Spearman’s correlation coefficient.

Abbreviations: BMI, body mass index; %CSA, percentage of cross-sectional area; FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 second; %LAV, percent low attenuation volume.

Table S2 Subgroup analyses of %CSA_<5 and clinical determinants with severe AE-COPD

Variables	%CSA<5		HR	95% CI	P-value
	<1.0% (n)	>1.0% (n)
BMI
>20 kg/m^2	14	35	3.171	0.920–10.93	0.068
<20 kg/m^2	16	16	1.578	0.627–3.967	0.330
GOLD stage
Stages I, II	17	37	3.984	1.088–14.59	0.037
Stages III, IV	13	14	1.178	0.489–2.838	0.710
%LAV <30%
>30%	7	37	1.780	0.198–16.00	0.610
<30%	23	14	1.442	0.589–3.582	0.420

Notes: Fine–Gray’s proportional hazard model was used. ρ represents Spearman’s correlation coefficient.

Abbreviations: AE-COPD, acute exacerbation of chronic obstructive pulmonary disease; HR, hazard ratio; CI, confidence interval; BMI, body mass index; GOLD, Global Initiative for Chronic Obstructive Lung Disease; %LAV, percent low attenuation volume; %CSA, percentage of cross-sectional area.