Novel Respiratory Impedance-Based Phenotypes Reflect Different Pathophysiologies in Chronic Obstructive Pulmonary Disease Patients

Figures & data

Figure 1 Definition of the four novel FOT-based phenotypes in COPD patients. The vertical and horizontal dashed lines show the 3rd quartile value for R5 = 0.214 and X5 = −0.057, respectively, in the non-COPD smokers. Using these cut-off values, 164 COPD patients were divided into four phenotypes.

Abbreviations: NL, normal group; RD, resistance-dominant group; XD, reactance-dominant group; MIX, mixed group; FOT, forced oscillation technique; R5, respiratory system resistance at 5 Hz; X5, respiratory system reactance at 5 Hz.

Table 1 Characteristics of the Study Subjects

	COPD (n = 164)	Non-COPD (n = 22)	p-Value
Age (years)	72.2 ± 8.1	70.6 ± 9.3	N.S.
Sex (male/female)	152/12	21/1
BMI (kg/m^2)	23.2 ± 3.2	22.6 ± 2.3	N.S.
Smoking history
Current/former/never^†	33/129/2	4/18/0
Pack-years	59.6 ± 30.1	58.3 ± 38.6	N.S.
mMRC score	1.2 ± 1.1	0.9 ± 1.0	N.S.
Total CAT score	10.5 ± 7.3	10.0 ± 8.0	N.S.
Pulmonary function tests
VC (L)^¶	3.5 ± 0.8	3.3 ± 0.7	N.S.
FEV1 (L)^¶	1.9 ± 0.7	2.4 ± 0.5	0.0003
FEV1/FVC (%)^¶	54.2 ± 12.4	74.3 ± 3.2	<0.0001
FEV1%predicted (%)^¶	70.5 ± 21.6	88.1 ± 15.0	0.0002
DLCO/VA (mmol/min/kPa/L)^§	0.9 ± 0.4	1.1 ± 0.4	N.S.
GOLD airflow limitation severity
1/2/3/4	56/80/21/7	-

Notes: Data are presented as the mean ± standard deviation unless otherwise stated and were analyzed by Wilcoxon’s rank-sum test. ^†inhalation biomass; ^¶n = 163; ^§n = 158.

Abbreviations: BMI, body mass index; CAT, COPD assessment test; COPD, chronic obstructive lung disease; DL_CO/VA, carbon monoxide diffusing capacity of the lung for carbon monoxide and alveolar volume ratio; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; mMRC, modified Medical Research Council dyspnea scale; N.S., not significant (p > 0.05); VC, vital capacity.

Table 2 Comparison of FOT Indices Between COPD Patients and Non-COPD Smokers

	COPD (n = 164)	Non-COPD (n = 22)	p-Value
R5 (kPa/L/s)	0.23 ± 0.09	0.18 ± 0.05	<0.05
R20 (kPa/L/s)	0.18 ± 0.06	0.15 ± 0.04	<0.01
R5-R20 (kPa/L/s)	0.05 ± 0.04	0.03 ± 0.02	N.S.
X5 (kPa/L/s)	−0.08 ± 0.09	−0.05 ± 0.05	N.S.
Fres (Hz)	11.37 ± 5.57	9.01 ± 3.32	N.S.
ALX (kPa/L/s·Hz)	0.54 ± 0.90	0.23 ± 0.41	N.S.

Notes: Data are presented as the mean ± standard deviation and were analyzed by Wilcoxon’s rank-sum test. Each oscillatory index was expressed as the mean value of five entire respiratory cycles.

Abbreviations: ALX, low-frequency reactance area; Fres, resonant frequency; N.S., not significant (p > 0.05); R5, Rrs at 5 Hz; R20, Rrs at 20 Hz; R5-R20, difference from R5 to R20; X5, Xrs at 5 Hz.

Table 3 Characteristics, Pulmonary Functions, and CT Imaging Biomarkers Among FOT-Based Phenotypes

	NL (n = 69)	RD (n = 22)	XD (n = 12)	MIX (n = 61)
Age	69.8 ± 8.1	69.7 ± 8.8	78.3 ± 5.4 *,**	74.7 ± 6.8*,**
Sex (male/female)	67/2	20/2	10/2	55/6
BMI (kg/m^2)	22.5 ± 2.9	24.0 ± 3.2	23.8 ± 3.7	23.6 ± 3.4*
pack-years^†	56.7 ± 26.8	49.3 ± 23.7	52.6 ± 29.8	64.9 ± 37.1
mMRC score^¶	0.9 ± 1.0	0.7 ± 0.6	1.6 ± 1.0*,**	1.6 ± 1.1*,**
Total CAT score^§	8.4 ± 6.5	10.1 ± 7.4	13.5 ± 8.6*	12.4 ± 7.4*
Pulmonary function tests	NL (n = 68)	RD (n = 22)	XD (n = 12)	MIX (n = 61)
FEV1 (L)	2.3 ± 0.5	2.0 ± 0.6*	1.5 ± 0.5*,**	1.4 ± 0.5*,**
FEV1/FVC (%)	60.3 ± 8.1	57.5 ± 9.5	49.8 ± 13.6*	46.7 ± 13.2*,**
FEV1%predicted (%)	82.0 ± 16.6	76.0 ± 16.1	60.1 ± 20.3*,**	57.0 ± 20.5*,**
VC (L)	3.9 ± 0.7	3.7 ± 0.7	3.1 ± 0.7*,**	3.1 ± 0.7*,**
DLCO/VA (mmol/min/kPa/L)^‡	0.9 ± 0.4	1.0 ± 0.3	0.9 ± 0.5	0.8 ± 0.4**
CT imaging biomarkers	NL (n = 55)	RD (n = 19)	XD (n = 9)	MIX (n = 49)
LAV% (%)	11.3 ± 9.9	7.9 ± 7.9	14.8 ± 14.5	15.7 ± 12.6**
√Aaw at Pi10 (mm)	3.69 ± 0.06	3.74 ± 0.06*	3.76 ± 0.08*	3.77 ± 0.06*,**

Notes: Data are presented as the mean ± standard deviation and were analyzed by Wilcoxon’s rank-sum test. ^†n = 67 (NL), 22 (RD), 12 (XD), and 61 (MIX); ^¶n = 69 (NL), 21 (RD), 12 (XD), and 60 (MIX); ^§n = 68 (NL), 21 (RD), 12 (XD), and 61 (MIX); ^‡n = 67 (NL), 22 (RD), 12 (XD), and 57 (MIX). *P < 0.05 vs NL; **P < 0.05 vs RD.

Abbreviations: √Aaw at Pi10, square root of the wall area of a hypothetical airway with an internal perimeter of 10 mm; BMI, body mass index; CAT, COPD assessment test; CT, computed tomography; DL_CO/VA, carbon monoxide diffusing capacity of the lung for carbon monoxide and alveolar volume ratio; FEV1, forced expiratory volume in 1 s; FOT, forced oscillation technique; FVC, forced vital capacity; LAV%, percentage of low attenuation volume; MIX, mixed group; mMRC, modified Medical Research Council dyspnea scale; NL, normal group; RD, resistance-dominant group; VC, vital capacity; XD, reactance-dominant group.

Figure 2 Distribution of the DPM parameters according to the FOT -based phenotypes. Bars show the data presented as the mean ± standard deviation of DPM_Normal (white), DPM_GasTrap (shaded), and DPM_Emph (black). The numbers of subjects are in 52, 21, 8, and 46 in the NL, RD, XD, and MIX groups, respectively. The Wilcoxon rank-sum test was used to compare DPM parameters among groups. *p < 0.05 compared with NL; **p < 0.05 compared with RD.

Abbreviations: DPM, disease probability measure; DPM_GasTrap, gas trapping lesion recognized by DPM; DPM_Emph, emphysematous lesion recognized by DPM; DPM_Normal, normal lesion recognized by DPM; FOT, forced oscillation technique; MIX, mixed group; NL, normal group; RD, resistance-dominant group; XD, reactance-dominant group.

Figure 3 Definition of the four novel FOT-based phenotypes by the GOLD classification of airflow limitation severity.

Abbreviations: FOT, forced oscillation technique; GOLD, Global Initiative for Chronic Obstructive Lung Disease; MIX, mixed group; NL, normal group; RD, resistance-dominant group; XD, reactance-dominant group.