Association between respiratory impedance measured by forced oscillation technique and exacerbations in patients with COPD

Figures & data

Figure 1 Flow chart of patient enrolment.

Table 1 Characteristics of the 119 patients with COPD and comparison of characteristics between exacerbators and nonexacerbators

Characteristics	All (n=119)	Exacerbators (n=37)	Nonexacerbators (n=82)	P-value
Male, n (%)	106 (89)	33 (89)	73 (89)	0.979
Age, years	73.0 (67.0, 79.0)	76.0 (71.0, 82.0)	72.5 (66.0, 79.0)	0.029*
Smoking, pack per year	54.0 (30.0, 86.0)	55.0 (36.9, 106.5)	51.3 (29.3, 82.5)	0.178
Smoking, never/former/current, n	4/83/32	1/30/6	3/53/26	0.189
BMI, kg/m^2	22.3 (20.1, 24.7)	22.4 (20.1, 25.1)	22.3 (20.1, 25.1)	0.774
WBC count,/μL	6,300.1 (5,400.1, 7,300.1)	6,900.0 (5,700.0, 8,800.0)	6,150.0 (5,100.0, 7,000.0)	0.013*
Eosinophil count,/μL	207.3 (131.3, 324.8)	188.4 (131.9, 281.1)	217.7 (131.3, 331.0)	0.618
% eosinophil, %	3.3 (1.9, 5.2)	3.0 (1.7, 4.6)	3.6 (2.5, 6.5)	0.231
Types of inhaled medication, n (%)
LABA	62 (52)	24 (65)	38 (46)	0.061
LAMA	95 (80)	32 (86)	63 (77)	0.224
ICS	27 (23)	11 (30)	16 (20)	0.218
Number of medications, n (%)
1	58 (49)	13 (35)	45 (55)	0.046*
2	31 (26)	12 (32)	19 (23)	0.287
3	20 (17)	10 (27)	10 (12)	0.045*
Details of medications (%)
LABA	11 (9)	3 (8)	8 (10)	0.774
LAMA	47 (39)	10 (27)	37 (45)	0.062
ICS	0 (0)	0 (0)	0 (0)	–
LABA/ICS	5 (4)	0 (0)	5 (6)	0.125
LAMA/ICS	2 (2)	1 (3)	1 (1)	0.560
LABA/LAMA	26 (22)	11 (30)	15 (18)	0.162
LABA/LAMA/ICS	20 (17)	10 (27)	10 (12)	0.045*
No inhaled drug	8 (7)	2 (5)	6 (7)	0.700

Notes: All values are median (interquartile range) unless otherwise stated. Exacerbator group consisted of patients experiencing one or more exacerbations within 2 years. Nonexacerbator group consisted of patients who had never experienced exacerbation within 2 years. P-values represent statistical analyses between Exacerbator and Nonexacerbator groups.

* P<0.05.

Abbreviations: BMI, body mass index; ICS, inhaled corticosteroids; LABA, long-acting beta-agonists; LAMA, long-acting muscarinic antagonist; WBC, white blood cell.

Table 2 Comparisons of characteristics between exacerbators and nonexacerbators by Global Initiative for Chronic Obstructive Lung Disease stage

Characteristics	Stage I (n=35)			Stage II (n=47)			Stage III + IV (n=37)
	Exacerbators (n=5)	Nonexacerbators (n=30)	P-value	Exacerbators (n=17)	Nonexacerbators (n=30)	P-value	Exacerbators (n=15)	Nonexacerbators (n=22)	P-value
Male, n (%)	4 (80)	27 (90)	0.515	14 (82)	28 (93)	0.241	15 (100)	18 (82)	0.080
Age, years	78.0 (67.5, 82.5)	70.0 (65.5, 79.0)	0.333	79.0 (71.0, 84.0)	72.5 (65.8, 77.3)	0.019*	74.0 (68.0, 81.0)	73.0 (72.0, 80.8)	0.864
Smoking, pack per year	82.5 (22.5, 109.0)	45.5 (20.0, 66.4)	0.099	52.0 (17.4, 82.0)	60.8 (27.6, 91.0)	0.150	80.0 (50.0, 129.0)	53.0 (36.8, 84.8)	0.013*
Smoking, never/former/current, n	1/3/1	1/23/6	0.326	0/15/2	1/17/12	0.080	0/12/3	1/13/8	0.357
BMI, kg/m^2	21.5 (19.5, 22.7)	23.0 (20.5, 25.1)	0.089	24.1 (21.9, 25.2)	22.9 (21.1, 25.3)	0.628	20.4 (16.8, 23.5)	21.4 (18.1, 22.7)	0.205
WBC count,/μL	7,000.0 (5,850.0, 10,000.0)	6,000.0 (4,900.0, 7,100.0)	0.024*	6,350.0 (5,400.0, 7,525.0)	6,000.0 (5,100.0, 6,900.0)	0.131	7,400.0 (6,150.0, 9,200.0)	6,300.0 (5,675.0, 7,100.0)	0.423
Eosinophil count,/μL	130.2 (69.6, 315.3)	222.0 (131.6, 327.6)	0.568	197.1 (131.7, 339.6)	260.4 (115.1, 339.4)	0.674	170.1 (140.8, 276.0)	194.2 (122.8, 360.3)	0.443
% eosinophil, %	2.1 (0.7, 5.2)	3.7 (2.3, 5.7)	0.091	3.5 (2.2, 5.7)	3.9 (1.9, 5.6)	0.921	2.6 (1.6, 3.8)	3.0 (2.1, 5.7)	0.333
Types of medication, n (%)
LABA	3 (60)	12 (40)	0.403	11 (65)	19 (63)	0.104	10 (67)	14 (64)	0.850
LAMA	4 (80)	20 (67)	0.552	15 (88)	22 (73)	0.230	13 (87)	21 (95)	0.336
ICS	1 (20)	3 (10)	0.515	6 (35)	3 (10)	0.034*	4 (27)	10 (45)	0.247
Numbers of medication, n (%)
1	3 (60)	18 (60)	1.000	5 (24)	19 (63)	0.025*	5 (33)	8 (36)	0.850
2	1 (20)	5 (17)	0.855	6 (35)	9 (30)	0.708	5 (33)	5 (23)	0.476
3	1 (20)	1 (3)	0.137	5 (29)	0 (0)	0.002*	4 (27)	9 (41)	0.373
Details of medication, n (%)
LABA	1 (20)	4 (13)	0.693	1 (6)	4 (13)	0.426	1 (7)	0 (0)	0.220
LAMA	2 (40)	14 (47)	0.782	4 (24)	15 (50)	0.076	4 (27)	8 (36)	0.536
ICS	0 (0)	0 (0)	–	0 (0)	0 (0)	–	0 (0)	0 (0)	–
LABA/ICS	0 (0)	2 (7)	0.552	0 (0)	2 (7)	0.277	0 (0)	1 (5)	0.403
LAMA/ICS	0 (0)	0 (0)	–	1 (6)	1 (3)	0.677	0 (0)	0 (0)	–
LABA/LAMA	1 (20)	5 (17)	0.855	5 (29)	6 (20)	0.464	5 (33)	4 (18)	0.292
LABA/LAMA/ICS	1 (20)	1 (3)	0.137	5 (29)	0 (0)	0.002*	4 (27)	9 (41)	0.373
No medication	0 (0)	4 (13)	0.386	1 (6)	2 (7)	0.916	1 (7)	0 (0)	0.220

Notes: All values are median (interquartile range) unless otherwise stated. Exacerbator group consisted of patients experiencing one or more exacerbations within 2 years. Nonexacerbator group consisted of patients who had never experienced exacerbation within 2 years. P-values represent statistical analyses between Exacerbator and Nonexacerbator groups.

* P<0.05.

Abbreviations: BMI, body mass index; ICS, inhaled corticosteroids; LABA, long-acting beta-agonists; LAMA, long-acting muscarinic antagonist; WBC, white blood cell.

Table 3 Comparisons of parameters measured by spirometry and FOT between exacerbators and nonexacerbators

Parameters	All (n=119)	Exacerbators (n=37)	Nonexacerbators (n=82)	P-value
Spirometry
% predicted FVC	95.5 (81.7, 109.0)	85.8 (73.8, 97.1)	99.2 (86.8, 109.7)	0.049*
% predicted FEV1	64.5 (44.6, 80.8)	58.1 (37.3, 70.0)	67.7 (48.2, 87.6)	0.008*
FEV1/FVC, %	55.0 (41.7, 66.5)	44.9 (37.6, 62.2)	56.3 (42.0, 69.5)	0.006*
FOT/resistance (R)
R5, kPa·L^−1·s^−1	3.48 (2.77, 4.44)	3.96 (3.00, 4.79)	3.41 (2.59, 4.16)	0.349
R20, kPa·L^−1·s^−1	2.58 (2.02, 3.17)	2.88 (2.33, 3.50)	2.39 (1.95, 3.02)	0.028*
R5–R20, kPa·L^−1·s^−1	0.90 (0.49, 1.30)	1.16 (0.51, 1.57)	0.77 (0.49, 1.25)	0.821
FOT/reactance (X)
X5, kPa·L^−1·s^−1	−0.96 (−2.58, −0.37)	−2.18 (−3.21, −0.94)	−0.69 (−2.12, −0.30)	0.024*
Fres, Hz	11.2 (7.61, 17.0)	15.60 (10.72, 18.96)	9.50 (6.82, 15.59)	0.004*
ALX, kPa·L^−1	4.72 (1.41, 20.18)	15.99 (4.20, 27.83)	3.58 (1.19, 16.61)	0.008*
ΔX5, kPa·L^−1·s^−1	−0.34 (−1.71, 0.16)	−1.08 (−2.12, 0.11)	−0.06 (−1.10, −0.17)	0.520

Notes: All values are median (interquartile range). Exacerbator group consisted of patients experiencing one or more exacerbations within 2 years. Nonexacerbator group consisted of patients who had never experienced exacerbation within 2 years. P-values represent statistical analyses between Exacerbator and Nonexacerbator groups. The analyses of FOT parameters are adjusted for age, gender, height, and smoking status.

* P<0.05.

Abbreviations: FOT, forced oscillation technique; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; R5, resistance at 5 Hz; R20, resistance at 20 Hz; R5–R20, difference between R5 and R20; X5, reactance at 5 Hz; Fres, resonant frequency; ALX, reactance area; ΔX5, difference between inspiratory and expiratory respiratory system reactance.

Table 4 Comparisons of parameters measured by spirometry and FOT between exacerbators and nonexacerbators by Global Initiative for Chronic Obstructive Lung Disease stage

Parameters	Stage I (n=35)			Stage II (n=47)			Stage III + IV (n=37)
	Exacerbators (n=5)	Nonexacerbators (n=30)	P-value	Exacerbators (n=17)	Nonexacerbators (n=30)	P-value	Exacerbators (n=15)	Nonexacerbators (n=22)	P-value
Spirometry
% predicted FVC	111.5 (82.0, 118.4)	110.0 (99.1, 114.6)	0.370	89.9 (85.2, 96.4)	97.7 (86.4, 109.0)	0.965	73.8 (66.8, 87.4)	82.1 (62.2, 96.5)	0.734
% predicted FEV1	81.1 (80.5, 93.6)	89.5 (85.9, 95.5)	0.187	65.1 (58.4, 69.9)	65.1 (57.6, 71.6)	0.947	35.1 (26.2, 42.2)	41.2 (31.8, 44.9)	0.210
FEV1/FVC, %	65.6 (62.2, 70.3)	69.7 (62.6, 75.9)	0.814	55.3 (44.2, 66.0)	54.9 (51.6, 62.4)	0.157	36.5 (31.1, 42.0)	36.7 (32.3, 42.3)	0.567
FOT/resistance (R)
R5, kPa·L^−1·s^−1	2.96 (2.18, 3.40)	2.84 (1.98, 3.84)	0.417	3.77 (2.73, 5.31)	3.32 (2.64, 3.76)	0.356	4.19 (3.96, 4.75)	4.27 (3.34, 5.16)	0.794
R20, kPa·L^−1·s^−1	2.42 (1.41, 2.80)	2.00 (1.57, 2.53)	0.743	2.78 (2.08, 4.02)	2.51 (2.08, 2.85)	0.390	3.08 (2.70, 3.50)	3.25 (2.25, 3.97)	0.926
R5–R20, kPa·L^−1·s^−1	0.48 (0.40, 1.01)	0.57 (0.35, 1.11)	0.346	1.16 (0.51, 1.57)	0.66 (0.48, 1.07)	0.964	1.27 (0.91, 1.69)	1.10 (0.81, 1.33)	0.740
FOT/reactance (X)
X5, kPa·L^−1·s^−1	−0.40 (−1.33, −0.06)	−0.36 (−0.67, −0.15)	0.938	−1.33 (−3.21, −0.76)	−0.73 (−1.30, −0.35)	0.017*	−3.00 (−3.77, −2.33)	−2.61 (−4.65, −1.06)	0.831
Fres, Hz	7.21 (5.37, 13.07)	7.18 (5.81, 9.64)	0.732	13.59 (9.83, 16.76)	9.44 (6.82, 12.02)	0.042*	19.77 (16.12, 22.23)	18.78 (12.24, 21.31)	0.594
ALX, kPa·L^−1	2.89 (0.84, 8.97)	1.25 (0.61, 4.72)	0.939	7.29 (3.36, 22.66)	2.94 (1.21, 6.87)	0.021*	21.48 (16.50, 28.99)	22.93 (0.32, 40.28)	0.418
ΔX5, kPa·L^−1·s^−1	0.17 (−0.34, 0.40)	0.06 (−0.38, 0.23)	0.359	−0.88 (−3.50, 0.20)	0.01 (−0.45, 0.19)	0.064	−1.71 (−2.22, −1.16)	−2.13 (−5.88, −0.29)	0.304

Notes: All values are median (interquartile range) unless otherwise stated. Exacerbator group: consisted of patients experiencing one or more exacerbations within 2 years. Nonexacerbator group: consisted of patients who had never experienced exacerbation within 2 years. P-values represent statistical analyses between Exacerbator and Nonexacerbator groups. The analyses of FOT parameters are adjusted for age, gender, height, and smoking status.

* P<0.05.

Abbreviations: FOT, forced oscillation technique; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; R5, resistance at 5 Hz; R20, resistance at 20 Hz; R5–R20, difference between R5 and R20; X5, reactance at 5 Hz; Fres, resonant frequency; ALX, reactance area; ΔX5, difference between inspiratory and expiratory respiratory system reactance.

Table 5 Accuracy of parameters measured by spirometry and FOT for identification of the risk of exacerbations in 119 patients with COPD

Parameters	Cutoff value (kPa·L^−1·s^−1)	AUC	Sensitivity (%)	Specificity (%)
Spirometry
% predicted FVC	94.7	0.66	75.7	63.4
% predicted FEV1	81.1	0.65	94.6	30.5
FEV1/FVC, %	50.5	0.61	59.5	68.3
FOT/resistance (R)
R5, kPa·L^−1·s^−1	3.52	0.63	67.6	58.5
R20, kPa·L^−1·s^−1	2.42	0.64	72.9	51.2
R5–R20, kPa·L^−1·s^−1	1.11	0.59	56.8	68.9
FOT/reactance (X)
X5, kPa·L^−1·s^−1	−0.875	0.70	81.1	59.8
Fres, Hz	13.585	0.69	67.6	74.4
ALX, kPa·L^−1	4.03	0.68	83.3	55.8
ΔX5, kPa·L^−1·s^−1	−0.55	0.61	67.6	69.5

Abbreviations: AUC, area under the curve; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; FOT, forced oscillation technique; R5, resistance at 5 Hz; R20, resistance at 20 Hz; R5–R20, difference between R5 and R20; X5, reactance at 5 Hz; Fres, resonant frequency; ALX, reactance area; ΔX5, difference between inspiratory and expiratory respiratory system reactance.

Figure 2 ROC curve of spirometry and FOT parameters for identification of exacerbations in 119 patients with COPD.

Notes: ROC curve of % predicted FVC (A), % predicted FEV₁ (B), FEV₁/FVC (C), R5 (D), R20 (E), R5–R20 (F), X5 (G), Fres (H), and ALX (I) with the presence of exacerbation are shown. High AUC of all parameters of FOT to identify exacerbations were observed.
Abbreviations: ALX, reactance area; AUC, area under the curve; FEV₁, forced expiratory volume in 1 second; FOT, forced oscillation technique; Fres, resonant frequency; FVC, forced vital capacity; ROC, Receiver operating characteristic; R5, resistance at 5 Hz; R20, resistance at 20 Hz; R5–R20, differences between R5 and R20; ΔX5, difference between inspiratory and expiratory respiratory system reactance; X5, reactance at 5 Hz.

Table S1 Comparisons of parameters measured by spirometry and FOT between the Global Initiative for Chronic Obstructive Lung Disease stages

Parameters	Stage I (n=34)	Stage II (n=45)	Stage III + IV (n=31)	P-value
Spirometry
% predicted FVC	110.1 (98.9, 115.7)	93.0 (85.4, 107.5)	77.5 (66.7, 95.2)	<0.001*
% predicted FEV1	89.1 (84.3, 94.2)	65.1 (58.1, 70.7)	36.1 (27.9, 43.3)	<0.001*
FEV1/FVC, %	68.1 (62.7, 75.8)	54.9 (45.5, 64.6)	36.5 (31.4, 42.0)	<0.001*
FOT/resistance (R)
R5, kPa·L^−1·s^−1	2.86 (2.00, 3.64)	3.37 (2.68, 4.14)	4.19 (3.75, 4.86)	<0.001*
R20, kPa·L^−1·s^−1	2.02 (1.50, 2.48)	2.52 (2.08, 3.12)	3.17 (2.68, 3.75)	<0.001*
R5–R20, kPa·L^−1·s^−1	0.57 (0.36, 1.08)	0.75 (0.49, 1.30)	1.18 (0.85, 1.59)	0.003*
FOT/reactance (X)
X5, kPa·L^−1·s^−1	−0.37 (−0.71, −0.16)	−0.87 (−1.75, −0.40)	−2.74 (−4.43, −1.89)	<0.001*
Fres, Hz	7.21 (5.84, 10.58)	10.32 (7.66, 14.44)	19.71 (15.57, 21.39)	<0.001*
ALX, kPa·L^−1	1.28 (0.61, 4.72)	4.02 (1.48, 12.41)	22.32 (13.26, 35.20)	<0.001*
ΔX5, kPa·L^−1·s^−1	−0.07 (−0.34, 0.23)	−0.10 (−0.90, 0.18)	−1.92 (−4.04, −0.53)	<0.001*

Notes: All values are median (interquartile range) unless otherwise stated. P-values represent comparisons between three groups. The analyses of FOT parameters are adjusted for age, gender, height, and smoking status.

* P<0.05.

Abbreviations: FOT, forced oscillation technique; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; R5, resistance at 5 Hz; R20, resistance at 20 Hz; R5–R20, difference between R5 and R20; X5, reactance at 5 Hz; Fres, resonant frequency; ALX, reactance area; ΔX5, difference between inspiratory and expiratory respiratory system reactance.