Significances of spirometry and impulse oscillometry for detecting small airway disorders assessed with endobronchial optical coherence tomography in COPD

Figures & data

Table 1 Baseline characteristics

Parameters	Never-smokers	Heavy-smokers	COPD patients
			Stage I	Stage II	Stage III–IV
Gender (male/female)	13/8	25/1a	16/1a	17/1a	23/1a
Age (years)	50.5±12.4	52.8±9.4	56.1±9.1	55.9±4.8	56.2±6.4
Height (cm)	163.9±8.1	165.4±7.3	166.0±5.4	167.2±7.8	164.6±6.3
Weight (kg)	62.2±11.5	63.9±10.6	64.8±8.2	65.2±4.6	60.4±8.1
BSA (m^2)	1.7±0.2	1.7±0.2	1.7±0.1	1.7±0.1	1.7±0.1
Smoking pack-yearsb	0	34.0±22.2	30.5±20.9	33.4±17.3	38.9±22.9
TLAA%c	2.3±4.4	5.0±7.1	11.4±12.4	12.0±11.6a	25.8±19.2a,d
FEV1 % predicted	98.6±9.4	94.1±9.1	88.3±8.3a	64.7±9.1a,d,e	34.5±8.8a,d,f
FEV1 /FVC%	79.2±5.3	76.9±4.3	65.4±3.1a,d	55.9±9.4a,d,e	39.1±10.0a,d,f
MMEF% predicted	68.8±15.5	62.2±13.0	38.9±6.6a,d	23.1±7.4a,d,e	8.9±3.6a,d,f

Notes: Continuous data were expressed as mean (SD). Comparisons between different groups were made by one-way analysis-of-variance or Kruskal-Wallis test, with subjected to Bonferroni correction.

a Compared with never-smokers, P<0.05;

b Comparison among heavy-smokers, stage I, stage II and stages III–IV COPD;

c 17/21 never-smokers, 22/26 heavy-smokers, 16/17 stage I COPD, 17/18 stage II COPD and 24/24 stages III–IV COPD patients received CT examination;

d Compared with heavy-smokers, P<0.05;

e Compared with stage I COPD, P<0.05;

f Compared with stage II COPD, P<0.05.

Abbreviations: BSA, body surface area; TLAA, total low-attenuation area; MMEF, maximal mid-expiratory flow.

Figure 1 Comparisons of endobronchial optical coherence tomography (EB-OCT) parameters of the seventh to ninth generation of bronchi among never-smokers, heavy-smokers and patients with stages I–IV COPD.

Notes: The comparisons of airway inner area (A), and airway wall area percentage (B), average value (C), average value (D), from 7 to 9 generation of bronchi among five groups. Multiple-group comparisons were made by using one-way ANOVA. ^✫Indicates a significant difference (P<0.05) between heavy-smokers and never-smokers. *Compared with never-smokers, P<0.05; ^※Compared with heavy-smokers, P<0.05; ^§compared with stage I COPD, P<0.05; ^#compared with stage II COPD, P<0.05. Abbreviations: Gen 7–9, from the seventh to ninth generation bronchi; Ai, airway internal area; Aw, airway wall area; Aw%, airway wall area percentage, calculated with the formula of [Aw/(Aw + Ai)×100%]; BSA, body surface area; NS, never-smokers; SNL, heavy-smokers with normal lung function.

Figure 2 Cross-sectional endobronchial optical coherence tomography (EB-OCT) images of the seventh, eighth, and ninth generation of bronchi.

Notes: Compared with never-smokers (A1–A3), patients with COPD are characterized by significant small-airway wall thickening and luminal narrowing (panel C–E). Despite the abnormality to a lesser extent, heavy-smokers also displayed small-airway wall thickening and luminal narrowing compared with never-smokers (B1–B3).

Figure 3 Comparison of impulse oscillometry (IOS) parameters in never-smokers, heavy-smokers and patients with stages I–IV COPD.

Notes: The magnitude of Fres (A), R₅ (B), R₂₀ (C), R₅–R₂₀ (D), X₅ (E), AX (F) and Z₅ (G) in five groups. Multiple-group comparisons were made by using one-way ANOVA. *Compared with never-smokers (NS), P<0.05; ^※compared with heavy-smokers, P<0.05; ^§compared with stage I COPD, P<0.05; ^#compared with stage II COPD, P<0.05.
Abbreviations: Fres, resonance frequency; R₅, airway resistance at 5 Hz; R₂₀, airway resistance at 20 Hz; R₅–R₂₀, the difference between airway resistance at 5 Hz and 20 Hz; X₅, pulmonary reactance at 5 Hz; AX, reactance area; Z, impedance; NS, never-smokers; SNL, smokers with normal lung function.

Figure 4 The diagnostic value of spirometric and impulse oscillometry (IOS) parameters in discriminating the presence from the absence of small-airway disorders in never-smokers, heavy-smokers, and patients with stage I COPD.

Notes: The cut-off value was 51.0% for Aw% 7–9, according to our previous study.¹⁵ *Compared with FEV₁% predicted, P<0.05; ^#compared with MMEF% predicted, P<0.05. The diagnostic value of spirometric and IOS was compared for discriminating the presence from the absence of small-airway disorders in never-smokers and heavy-smokers (A), and discriminating the presence from the absence of small-airway disorders in heavy-smokers and patients with stage I COPD (B), respectively.
Abbreviations: MMEF, maximal mid-expiratory flow; Fres, resonant frequency; R₅–R₂₀, peripheral airway resistance; AUC, area under the curve; COMB, Combination of Fres, R₅–R₂₀, FEV₁% and MMEF% predicted.

Figure 5 Correlation among FEV₁% predicted, MMEF% predicted, Aw% 7–9, Fres and R₅–R₂₀ in COPD patients and heavy-smokers.

Notes: The correlations between FEV₁% predicted and Aw%7–9 (A), MMEF% predicted and Aw%7–9 (B), Fres and Aw%7–9 (C), R5–R20 and Aw%7–9 (D). All r values denoted the Spearman’s correlation coefficient of each parameter in both patients with COPD and heavy-smokers. The dashed line was not shown in Figure B–D for the measurements of MMEF% predicted, Fres and R₅–R₂₀ were overlapped in COPD staging based on the conventional classification with the reduction in FEV₁. The different colors indicated the five individual groups, including heavy-smokers (yellow circles), patients with stage I COPD (green rectangles), patients with stage II COPD (dark blue triangles), and patients with stages III–IV COPD (gray inverse triangles).
Abbreviations: MMEF, maximal mid-expiratory flow; Fres, resonant frequency; R₅–R₂₀, peripheral airway resistance; Aw%, airway wall area percentage.

Figure S1 Bland-Altman analysis for endobronchial optical coherence tomography (EB-OCT) measurements by observer A and observer B (n=106).

Note: Bland-Altman analysis for D7–9 (A), Ai7–9 (B) and Aw7–9 (C) as measured by observer A and observer B.

Abbreviations: D7–9, mean diameter from 7th to 9th generation of bronchi; Ai7–9, airway internal area from 7th to 9th generation of bronchi; Aw7–9, airway wall area from 7th to 9th generation of bronchi.

Figure S2 Receiver operating characteristic (ROC) curve analysis of endobronchial optical coherence tomography (EB-OCT) parameter for discriminating never-smokers from patients with COPD.

Notes: The diagnostic value of Aw% 7–9 for discriminating the presence from the absence of small-airway disorders in never-smokers and COPD patients (never-smokers, n=17; COPD patients, n=48) (Figure A. Data from the previous study¹). The diagnostic value of Aw% 7–9 for discriminating the presence from the absence of small-airway disorders in never-smokers and COPD patients (never-smokers, n=21; COPD patients, n=59) (Figure B. Data from the current study).

Abbreviations: 7–9, from 7th to 9th generation of bronchi; Aw%, airway wall area percentage.

Figure S3 Incidences of small airway disorders (SADs) in never-smokers, heavy-smokers and patients with different stages of COPD.

Notes: By using cut-off value of 51% for Aw% 7–9, SADs were detected in 1/21 (4.8%) never-smokers, 17/26 (65.4%) heavy-smokers, 15/17 (88.2%) stage I, 17/18 (94.4%) stage II and 24/24 (100%) stages III–IV COPD patients.

Abbreviations: NS, never-smokers; SNL, heavy-smokers with normal lung function.

Figure S4 Partial correlation among spirometric, impulse oscillometry (IOS) and endobronchial optical coherence tomography (EB-OCT) parameters in heavy-smokers (A) and COPD patients (B).

Notes: Partial correlation analysis were performed with controlling for age and height. The color of individual boxes indicated the partial correlation coefficient of two parameters (red fillings indicated significantly positive correlation, whereas blue fillings indicated significantly negative correlation).

Abbreviations: MMEF, maximal mid-expiratory flow; 7–9, from 7th to 9th generation of bronchi; Ai, airway internal area; Aw, airway wall area; Aw%, airway wall area percentage; D, mean diameter; Fres, resonance frequency; R₅, airway resistance at 5 Hz; R₂₀, airway resistance at 20 Hz; R₅–R₂₀, the difference between airway resistance at 5 Hz and 20 Hz; X₅, pulmonary reactance at 5 Hz; AX, reactance area; Z, impedance.

Table S1 Symptoms, treatment and comorbidities in patients with COPD

	Stage I COPD	Stage II COPD	Stage III–IV COPD
Smoking status
Current smoker	11 (64.7%)	11 (61.1%)	19 (79.2%)
Ex-smoker	4 (23.5%)	5 (27.8%)	3 (12.5%)
Non-smoker	2 (11.8%)	2 (11.1%)	2 (8.3%)
Symptoms
Cough	10 (58.8%)	12 (66.7%)	18 (75%)
Sputum	8 (47.1%)	10 (55.6%)	17 (70.8%)
Shortness of breath	6 (35.3%)	7 (38.9%)	12 (50%)
Treatment
ICS+LABA	8 (47.1%)	11 (61.1%)	17 (70.8%)
LAMA	3 (17.6%)	4 (22.2%)	19 (79.2%)
Comorbidities*
Hypertension and/or Diabetes	3 (17.6%)	6 (33.3%)	10 (41.7%)

Note:

* Patients with pulmonary heart disease, pulmonary arterial hypertension, bronchiectasis, pulmonary fibrosis and pneumonia were excluded from this study.

Abbreviations: ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting anticholinergic.

Table S2 Receiver operating characteristic curve of spirometric and IOS parameters in discriminating the presence or absence of small-airway disorders in never-smokers and heavy-smokers

Parameters	AUC	95% CI		Cut-off	Sensitivity (%)	Specificity (%)	PPV	NPV
		Lower limit	Upper limit
FEV1 % pred	0.570	0.417	0.713	89.7	36.8	85.7	0.64	0.69
MMEF% pred	0.558	0.406	0.703	50.65	26.3	92.9	0.71	0.68
Z5	0.644	0.491	0.778	0.37	57.9	67.9	0.50	0.70
Fres	0.771a	0.625	0.881	8.86	89.5	53.6	0.53	0.88
R5	0.621	0.468	0.759	0.39	31.6	89.3	0.56	0.66
R20	0.529	0.378	0.676	0.26	84.2	28.6	0.42	0.73
R5 –R20	0.753	0.605	0.867	0.04	63.2	89.3	0.73	0.78
X5	0.638	0.485	0.773	−0.1	57.9	71.4	0.58	0.75
AX	0.696	0.549	0.822	0.12	89.5	42.9	0.48	0.86
COMB	0.825a,b	0.687	0.920	0.25	94.7	60.7	0.59	0.94

Notes: The cut-off value was 51.0% for Aw% 7–9, according to our previous study.¹

a Compared with R₅–R₂₀, P<0.05.

b Compared with Fres, P<0.05.

Abbreviations: IOS, impulse oscillometry; MMEF, maximal mid-expiratory flow; Fres, resonant frequency; R₅–R₂₀, peripheral airway resistance; AUC, area under curve; AX, area of reactance; COMB, combination of Fres, R₅–R₂₀, FEV₁% and MMEF% predicted; NPV, negative predictive value; PPV, positive predictive value; R₅, airway resistance at 5 Hz; R₂₀, airway resistance at 20 Hz; X₅, pulmonary reactance at 5 Hz; Z, impedance.

Table S3 Receiver operating characteristic curve of spirometric and IOS parameters in discriminating the presence or absence of small-airway disorders in heavy-smokers and patients with stage I COPD

Parameters	AUC	95% CI		Cut-off	Sensitivity (%)	Specificity (%)	PPV	NPV
		Lower limit	Upper limit
FEV1 % pred	0.548	0.389	0.700	96.06	32.3	91.7	0.69	0.09
MMEF% pred	0.567	0.407	0.717	50.65	61.3	75.0	0.91	0.43
Z5	0.668	0.508	0.804	0.31	77.4	58.3	0.86	0.50
Fres	0.726	0.569	0.851	8.87	83.9	58.3	0.87	0.58
R5	0.657	0.497	0.795	0.29	77.4	50.0	0.83	0.46
R20	0.645	0.485	0.785	0.27	71.0	58.3	0.81	0.38
R5–R20	0.633	0.472	0.775	0.03	64.5	66.7	0.88	0.42
X5	0.618	0.458	0.762	−0.11	38.7	83.3	0.86	0.31
AX	0.672	0.512	0.807	0.34	29.0	100.0	1.00	0.32
COMB	0.761	0.606	0.877	0.74	67.7	83.3	0.92	0.47

Notes: The cut-off value was 51.0% for Aw% 7–9, according to our previous study.¹

a Compared with Fres, P<0.05;

b Compared with R₅–R₂₀, P<0.05.

Abbreviations: IOS, impulse oscillometry; MMEF, maximal mid-expiratory flow; Fres, resonant frequency; AUC, area under curve; COMB, combination of Fres, R₅–R₂₀, FEV₁% and MMEF% predicted; NPV, negative predictive value; PPV, positive predictive value; R₅, airway resistance at 5 Hz; R₂₀, airway resistance at 20 Hz; X₅, pulmonary reactance at 5 Hz; Z, impedance.

Table S4 Correlation between EB-OCT parameters and IOS and spirometric indices in never-smokers, heavy-smokers and different stages of COPD

	Cases	FEV1 % predicted		MMEF% predicted		Fres		R5 –R20
		r	P-value	r	P-value	r	P-value	r	P-value
Aw% 7–9
Never-smokers	21	−0.34	0.130	0.14	0.548	−0.27	0.246	−0.21	0.357
Heavy-smokers	26	0.11	0.589	0.13	0.535	0.54	0.005	0.39	0.047
Stage I COPD	17	0.09	0.729	0.24	0.348	0.49	0.047	0.37	0.141
Stage II COPD	18	−0.37	0.130	−0.30	0.220	0.44	0.067	0.50	0.033
Stage III COPD	19	−0.66	0.002	−0.45	0.056	0.51	0.026	0.37	0.118
Stage IV COPD	5	−0.50	0.391	−0.20	0.747	0.90	0.037	0.30	0.624
All COPD	59	−0.90	<0.001	−0.86	<0.001	0.83	<0.001	0.81	<0.001

Notes: Data in boldface indicated the correlation with statistical significance. All r values denoted the Spearman’s correlation coefficients.

Abbreviations: EB-OCT, endobronchial optical coherence tomography; MMEF, maximal mid-expiratory flow; IOS, impulse oscillometry; Aw%, airway wall area percentage = [Aw/(Ai+Aw)]×100%; 7–9, from 7th to 9th generation of bronchi; Fres, resonance frequency; R₅–R₂₀, the difference between airway resistance at 5 Hz and 20 Hz; FEV₁, forced expiratory volume in the first second.

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