Physiological Impairments on Respiratory Oscillometry and Future Exacerbations in Chronic Obstructive Pulmonary Disease Patients without a History of Frequent Exacerbations

Figures & data

Table 1. Patients’ characteristics.

Characteristics	Overall (N = 134)	Group A (N = 48)	Group B (N = 71)	Group CD (N = 15)
Age (years)	73 (66, 78)	70 (64, 76)	74 (68, 78)	75 (69, 80)
Male (%)	100	100	100	100
BMI (kg/m^2)	22.3 (3.1)	22.7 (2.7)	22.0 (3.4)	22.0 (2.6)
Smoking pack years	54 (42, 76)	58 (45, 75)	48 (37, 68)	64 (50, 84)
mMRC score	1 (0, 2)	0 (0, 0)	1 (1, 2)	1 (1, 2)
CAT score	10 (5, 18)	4 (2, 6)	15 (11, 22)	10 (7, 17)
FVC (L)	3.05 (0.73)	3.30 (0.83)	2.96 (0.64)	2.72 (0.65)
FEV1 (L)	1.62 (0.62)	1.91 (0.67)	1.54 (0.52)	1.05 (0.37)
FEV1/FVC (%)	52 (14)	57 (11)	52 (14)	39 (11)
FEV1 (% predicted)	59 (20)	68 (20)	58 (18)	42 (14)
%FEV1 <50%, n (%)	47 (35.1%)	10 (20.8%)	26 (36.6%)	11 (73.3%)
A history of exacerbation in the previous year (%)	30	21	21	100
LAV% on CT (%)	30 (9)	27 (8)	31 (10)	32 (8)
Follow-up period (years)	4.18 (1.48)	4.19 (1.47)	4.06 (1.59)	4.70 (0.77)
No. exacerbations (/year)	0.37	0.14	0.45	0.67

Data are expressed as means (SD) or medians (IQR) or number (percentage). BMI = body mass index. mMRC = modified Medical Research Council dyspnea scale. CAT = COPD assessment test. FVC = forced vital capacity. FEV₁ = forced expiratory volume in 1 s. %FEV₁ = FEV₁ (% predicted). GOLD = Global initiative for chronic obstructive lung disease. LAV% = the percentage of low attenuation regions less than -950 HU to the total lung regions.

Table 2. Patients’ respiratory oscillometry characteristics.

	Overall (N = 134)	Group A (N = 48)	Group B (N = 71)	Group CD (N = 15)
R5-ins (kPa/L/s)	0.19 (0.14, 0.25)	0.17 (0.13, 0.23)	0.20 (0.14, 0.25)	0.24 (0.18, 0.3)
R5-ins (% predicted)	64 (51, 85)	58 (48, 76)	68 (54, 86)	70 (64, 104)
R5-exp (kPa/L/s)	0.25 (0.19, 0.34)	0.22 (0.17, 0.3)	0.27 (0.2, 0.36)	0.33 (0.27, 0.34)
R5-exp (% predicted)	89 (68, 117)	77 (57, 101)	91 (72, 119)	98 (86, 125)
R20-ins (kPa/L/s)	0.19 (0.16, 0.23)	0.17 (0.15, 0.24)	0.2 (0.17, 0.23)	0.2 (0.16, 0.25)
R20-ins (% predicted)	66 (56, 82)	61 (55, 84)	69 (58, 80)	65 (56, 79)
R20-exp (kPa/L/s)	0.21 (0.17, 0.26)	0.19 (0.16, 0.26)	0.22 (0.18, 0.26)	0.23 (0.2, 0.24)
R20-exp (% predicted)	73 (61, 91)	68 (56, 90)	76 (63, 92)	73 (66, 80)
X5-ins (kPa/L/s)	−0.06 (-0.1, 0.04)	−0.06 (-0.09, −0.04)	−0.07 (-0.1, −0.05)	−0.11 (-0.16, −0.08)
X5-ins (% predicted)	69 (43, 103)	60 (33, 81)	69 (44, 102)	113 (73, 142)
X5-exp (kPa/L/s)	−0.08 (-0.15, −0.03)	−0.05 (-0.1, −0.03)	−0.09 (-0.14, −0.03)	−0.19 (-0.26, −0.12)
X5-exp (% predicted)	72 (37, 152)	51 (26, 98)	86 (40, 150)	201 (105, 278)
Fres-ins (Hz)	10.41 (8.31, 13.69)	8.82 (7.56, 11.93)	10.97 (8.66, 13.66)	14.75 (11.52, 18.4)
Fres-ins (% predicted)	105 (86, 146)	90 (80, 119)	113 (87, 147)	142 (117, 190)
Fres-exp (Hz)	12.97 (8.32, 19.1)	9.48 (7.3, 14.95)	14.36 (8.54, 19.21)	21.04 (17.2, 23.0)
Fres-exp (% predicted)	133 (86, 196)	97 (75, 154)	141 (89, 196)	223 (167, 249)
ALX-ins (Hz*kPa/L/s)	0.29 (0.17, 0.52)	0.21 (0.13, 0.39)	0.32 (0.19, 0.52)	0.73 (0.36, 1.31)
ALX-ins (% predicted)	167 (96, 303)	134 (67, 219)	181 (104, 325)	345 (203, 740)
ALX-exp (Hz*kPa/L/s)	0.41 (0.13, 1.11)	0.21 (0.1, 0.56)	0.58 (0.14, 1.02)	1.51 (0.86, 2.53)
ALX-exp (% predicted)	230 (85, 635)	120 (47, 313)	296 (93, 629)	1009 (351, 1495)

Data are expressed as means (SD) or medians (IQR), % = percentage of predicted values. R5 = resistance at 5 Hz. R20 = resistance at 20 Hz. X5 = reactance at 5 Hz. Fres = resonant frequency. ALX = low-frequency reactance area. ins = inspiration. exp = expiration.

Table 3. The coefficient of variation of multiple respiratory oscillometry measurements within a day.

Variables	Coefficient of variation (%)
R5-exp (kPa/L/s)	5.96 (3.01, 12.48)
R5-ins (kPa/L/s)	6.55 (3.27, 14.03)
R20-exp (kPa/L/s)	5.73 (2.56, 10.57)
R20-ins (kPa/L/s)	6.22 (2.81, 12.46)
Fres-exp (Hz)	6.20 (3.47, 11.69)
Fres-ins (Hz)	4.88 (2.60, 7.65)
ALX-exp (Hz*kPa/L/s)	23.52 (11.92, 41.38)
ALX-ins (Hz*kPa/L/s)	15.25 (9.67, 25.24)

Data are expressed as medians (IQR). R5 = resistance at 5 Hz. R20 = resistance at 20 Hz. Fres = resonant frequency. ALX = low-frequency reactance area. Ins = inspiration. Exp = expiration.

Table 4. Univariable cox proportional hazard models to explore an association of physiological indices with a risk of future exacerbations.

Variables	All patients				GOLD A and B groups
	HR	95%CI	P value	FDR	HR	95%CI	P value	FDR
%FEV1	1.36	1.21-1.53	<.001	<.001	1.33	1.18-1.50	<.001	<.001
%FVC	1.16	1.04-1.30	<.01	0.07	1.16	1.03-1.31	0.01	0.03
%R5-ins	1.12	1.01-1.24	0.03	0.04	1.10	0.99-1.23	0.07	0.12
%R5-exp	1.08	0.98-1.18	0.11	0.16	1.08	0.97-1.19	0.17	0.24
%R20-ins	1.02	0.91-1.14	0.78	0.99	1.00	0.89-1.13	0.99	0.99
%R20-exp	1.01	0.91-1.13	0.82	0.96	1.00	0.89-1.12	0.96	1.00
%X5-ins	1.19	1.08-1.32	<.001	<.01	1.16	1.04-1.29	<.01	0.02
%X5-exp	1.13	1.04-1.23	<.01	0.02	1.10	1.01-1.21	0.04	0.08
%Fres-ins	1.18	1.08-1.29	<.001	<.001	1.19	1.08-1.31	<.001	<.01
%Fres-exp	1.20	1.10-1.32	<.001	<.001	1.19	1.08-1.32	<.001	<.01
%ALX-ins	1.18	1.08-1.29	<.001	<.001	1.15	1.04-1.26	<.01	0.01
%ALX-exp	1.11	1.02-1.20	0.02	0.03	1.08	0.99-1.18	0.08	0.12

HR = hazard ratio. CI = confidence interval. % = percentage of predicted values. FEV₁ = forced expiratory volume in 1 s. FVC = forced vital capacity. R5 = resistance at 5 Hz. R20 = resistance at 20 Hz. X5 = reactance at 5 Hz. Fres = resonant frequency. ALX = low-frequency reactance area. ins = inspiration. exp = expiration. Each variable was normalized by dividing by the half standard deviation.

Figure 1. Association between forced expiratory volume in 1 sec and inspiratory resonant frequency in patients with COPD and colored 3-Dimensional visualization of respiratory changes in reactance in GOLD group B patients.

(A) % of predicted forced expiratory volume in 1s (%FEV₁) was associated with % predicted of resonant frequency at inspiration (%Fres-ins). The linear regression showed that 50% in %FEV₁ corresponded to 135% in % Fres-ins. (B) Colored 3-Dimensional visualization of respiratory changes in reactance in GOLD group B patients with low inspiratory resonant frequency (Fres-ins, 70%, left) and high Fres (253%, right).

Table 5. Clinical and physiological comparisons between patients with high and low inspiratory resonant frequency.

Characteristics	Group A with low %Fres-ins (N = 39)	Group A with high %Fres-ins (N = 9)	Group B with low %Fres-ins (N = 46)	Group B with high %Fres-ins (N = 25)
Age (years)	70 (63, 75)	71 (67, 77)	75 (69, 77)	73 (67, 79)
Male (%)	100	100	100	100
BMI (kg/m^2)	23.0 (2.4)	21.2 (3.5)*	22.9 (3.6)	20.4 (2.4)**
Smoking pack years	59 (45, 76)	50 (45, 60)	50 (36, 71)	48 (38, 64)
mMRC score	0 (0, 0)	0 (0, 1)	1 (1, 2)	1 (1, 2)
CAT score	4 (2, 6)	5 (3, 8)	15 (10, 20)	16 (12, 23)
FEV1 (% predicted)	74 (16)	42 (10)**	66 (16)	42 (11)**
A history of exacerbation in the previous year (%)	17.9	33.3	19.6	24
LAV% on CT	26 (7)	31 (11)	28 (9)	37 (8)**

Data are expressed as means (SD) or medians (IQR) or number (percentage). %Fres-ins = % predicted of resonant frequency at inspiration. BMI = body mass index. mMRC = modified Medical Research Council dyspnea scale. CAT = COPD assessment test. FEV₁ = forced expiratory volume in 1 s. LAV% = the percentage of low attenuation regions less than -950 HU to the total lung regions. * p < 0.05 compared with patients with the same GOLD group. ** p < 0.001 compared with patients with the same GOLD group.

Figure 2. Further categorization of the GOLD A and B groups using FEV₁ and resonant frequency to compare the time to the first future exacerbation over 5 years.

(A) Based on a cutoff of 50% for % of predicted forced expiratory volume in 1 s (%FEV₁), the GOLD A and B groups were further divided into Group A with high FEV₁, Group A with low FEV₁, Group B with high FEV₁ and Group B with low FEV₁. A Group C D indicates a combined group from the GOLD C and D groups. (B) Based on a cutoff for % predicted of resonant frequency at inspiration (%Fres-ins = 135%), the GOLD A and B groups were further divided into Group A with high Fres, Group A with low Fres, Group B with high Fres, and Group B with low Fres.

Table 6. Multivariable Cox proportional hazard models to explore relative contributions of baseline physiological impairments to future exacerbations.

	Model 1	Model 2
Age	1.03 (0.90-1.18)	1.02 (0.90-1.17)
Smoking pack-years	1.11 (0.98-1.26)	1.12 (0.99-1.27)
BMI	1.02 (0.89-1.18)	1.05 (0.91-1.22)
LAV% on CT	1.08 (0.93-1.25)	1.12 (0.98-1.28)
GOLD A group	1 (reference)	1 (reference)
GOLD B group	2.42 (1.41-4.14)*	2.26 (1.32-3.85)*
%FEV1 > 50 %	1 (reference)	–
%FEV1 ≤ 50 %	1.81 (1.01-3.25)*	–
%Fres-ins ≤ 135%	–	1 (reference)
%Fres-ins > 135%	–	1.76 (1.01-3.08)*

Data are expressed as HR (95% CI). HR = hazard ratio. CI = confidence interval. BMI = body mass index. LAV% = low attenuation volume percentage. GOLD = Global initiative for chronic obstructive lung disease. %FEV₁ = % of predicted forced expiratory volume in 1 s. %Fres-ins = % predicted of resonant frequency at inspiration. Each continuous variable was normalized by dividing by the half standard deviation. * p < 0.05.