Bronchodilator response of advanced lung function parameters depending on COPD severity

Figures & data

Table 1 Patient characteristics, daily medication and baseline lung function

	All	Group 1 (FEV1% <65)	Group 2 (FEV1% >65)
Demographics
N	81	27	54
Age (range), years	67 (65–68)	65 (61–67)	67 (66–69)**
Current/former smoker, n	19/62	4/23	15/39
Pack-years (range)	30 (23–40)	38 (28–50)	27 (21–37)**
Sex, females/males	39/42	13/14	26/28
COPD, n	40	27	13
BMI (range), kg/m^2	26 (24–29)	25 (23–29)	27 (24–29)
ICS, n	22	17	5
SABA, n	13	11	2
LAMA, n	24	18	6
LABA, n	21	17	4
CCQ score (range)	6 (2–14)	14 (8–21)	4 (2–7)***
Body plethysmography
FEV1 (range), L	2.1 (1.6–2.9)	1.1 (1.0–1.8)	2.6 (2.1–3.2)***
FEV1 (range), %p	82 (50–94)	42 (33–50)	91 (80–98)***
FVC (range), L	3.4 (2.7–4.2)	2.8 (2.2–3.2)	3.8 (3.0–4.3)***
FVC (range), %p	90 (78–101)	74 (63–82)	97 (88–104)***
FEV1/FVC (range)	0.67 (0.51–0.74)	0.44 (0.37–0.51)	0.73 (0.67–0.76)***
RV (range), %p	122 (105–152)	171 (141–190)	117 (96–126)***
TLC (range), %p	109 (100–116)	115 (107–129)	108 (100–113)**
Impulse oscillometry
R5 (range), %p	105 (83–127)	150 (124–199)	94 (75–108)***
R20 (range), %p	88 (71–107)	100 (84–145)	83 (67–94)***
R5–R20 (range), %p	183 (100–342)	400 (284–681)	133 (83–233)***
X5 (range), %p	306 (178–566)	587 (966–314)	226 (144–366)***
Helium diffusion carbon monoxide diffusion
DL,CO (range), %p	67 (51–77)	46 (34–53)	71 (65–80)***
VA (range), %p	87 (80–96)	79 (71–87)	90 (86–97)***
DL,CO/VA (range), %p	77 (61–91)	59 (51–66)	82 (72–93)***

Notes:

** P<0.01 and

*** P<0.001, compared to Group 1.

Abbreviations: FEV₁%p, forced expiratory volume in 1 second percent predicted; BMI, body mass index; SABA, short-acting β2 agonist; LAMA, long-acting muscarinic antagonist; LABA, long-acting β2 agonist; CCQ, Clinical COPD Questionnaire; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity; VA, alveolar volume; ICS, inhaled corticosteroids.

Figure 1 Flowchart of the study design.

Figure 2 FVC%p at (A) baseline and (B) after inhalation of SABA and additional SAMA in COPD patients and controls.

Notes: The solid line to left and the hatched line to right of the BP are the segmented linear fits that join at the BP, estimated in the top of the figure (circles with the associated 95% confidence intervals). An ordinary LR line (hatched gray) and the reference and a nonparametric fit by the loess (local regression) method (gray line) are also displayed. Dots show the values of each subject. (C) The first two (A and B) linear/segmented linear curves plotted into one graph to illustrate bronchodilator response.

Abbreviations: FVC, forced vital capacity; %p, percent predicted; SABA, short-acting β2 agonist; SAMA, short-acting muscarinic antagonist; BP, break point; LR, linear regression.

Figure 3 Lungfunction, before and after bronchodilators.

Notes: (A) FEV₁/FVC, (B) IC%p, (C) R_ex and (D) FEV₁%p at baseline and after inhalation of SABA and additional SAMA in COPD patients and controls. Graphs show linear regression lines or segmented regression lines (if segmentation was significant).

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; IC, inspiratory capacity; %p, percent predicted; SABA, short-acting β2 agonist; SAMA, short-acting muscarinic antagonist.

Figure 4 Bronchodilator response.

Notes: (A) ΔFVC%, (B) ΔFEV₁/FVC, (C) ΔIC%p and (D) ΔR_ex in COPD patients and controls. The solid line to the left and the hatched line to the right of the BP are the segmented linear fits that join at the BP, estimated in the top of the figure (circles with the associated 95% confidence intervals). An ordinary LR line (hatched gray) and the reference and a nonparametric fit by the loess (local regression) method (gray line) are also displayed. Dots show the values of each subject.
Abbreviations: FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 second; IC, inspiratory capacity; %p, percent predicted; BP, break point; LR, linear regression, SABA, short-acting β2 agonist (salbutamol); SAMA, short-acting muscarinic antagonist (ipratropium).

Table 2 LR and SLR for lung function response to SABA and additional SAMA

Parameters	LR or SLRa (BP)b	P-value for BP	Slope (left/right)c	P-value for slope (left/right)d	Intercepte	P-value for interceptf
ΔFVC%p	SLR (58)	<0.001	−0.68/−0.05	<0.001/0.150	41.69	<0.001
ΔFEV1/FVC	SLR (52)	<0.001	0.00/0.00	<0.001/0.670	−0.19	<0.001
ΔIC%p	SLR (57)	0.044	−0.58/0.05	0.036/0.516	35.22	0.004
ΔRex	SLR (44)	0.004	0.72/0.02	0.001/0.533	−33.59	0.001
ΔRin	LR	ns	0.02	<0.001	−2.10	<0.001
ΔRtot%p	LR	ns	1.05	<0.001	−116.26	<0.001
ΔAX	LR	ns	0.01	<0.001	−1.23	<0.001
ΔRV%p	LR	ns	0.37	0.001	−37.47	<0.001
ΔR5–R20%p	LR	ns	1.41	0.004	−169.50	<0.001
ΔFRC%p	LR	ns	0.14	0.026	−16.67	0.001
ΔDL,CO %p	LR	ns	−0.06	0.029	4.92	0.040
ΔR5%p	LR	ns	0.20	0.046	−31.91	<0.001
ΔFEV1 %p	LR	ns	−0.03	0.144	7.04	<0.001
ΔX5%p	LR	ns	5.20	0.056	600.25	0.008
ΔDL,CO/VA%p	LR	ns	−0.06	0.061	5.58	0.029
ΔR20%p	LR	ns	0.02	0.746	−11.33	0.062
ΔTLC%p	LR	ns	0.03	0.384	−3.37	0.243
ΔVA%p	LR	ns	−0.03	0.096	1.71	0.306

Notes: Bold numbers indicate significance (P<0.05). Δ indicates absolute response.

a Parameter is labeled SLR if there is a significant SLR (defined from P-value in the next column: “P-value for BP”), otherwise it is labeled LR.

b The subsequent BP from the SLR is shown in parentheses.

c Slope (left/right) is the slope of the linear regression line or the slope of the two regression lines if there is a significant segmented linear regression (then the slopes of the regression lines [left and right] of the BP are shown within parentheses).

d P-value for slope (left/right) indicates if the slope is significant (ie, if there is a slope that is different from a horizontal line).

e Intercept indicates where the regression line crosses the Y-axis.

f P-value for intercept indicates a significant response (ie, the response lines are significantly different from a horizontal line at y =0).

Abbreviations: LR, linear regression; SLR, segmented linear regression; SABA, short-acting β2 agonist (salbutamol); SAMA, short-acting muscarinic antagonist (ipratropium); BP, break point; FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 second; %p, percent predicted; IC, inspiratory capacity; AX, reactance area; RV, residual volume; FRC, functional residual capacity; VA, alveolar volume; TLC, total lung capacity.

Table 3 Absolute response of lung function parameters after SABA with additional SAMA

Parameters	Group 1 (FEV1% <65)	Group 2 (FEV1% >65)	Significancea
Body plethysmography
ΔFEV1 (L)	0.21 (0.10 to 0.25)	0.10 (0.04 to 0.19)	ns
ΔFEV1%p	6.0 (3.1 to 8.9)	3.3 (1.5 to 6.5)	*
ΔFVC (L)	0.35 (0.10 to 0.52)	0.01 (−0.07 to 0.12)	***
ΔFVC%p	9.6 (3.3 to 15.6)	0.5 (−1.5 to 2.8)	***
ΔFEV1/FVC	0.01 (−0.02 to 0.03)	0.03 (0.01 to 0.05)	*
ΔRV (L)	−0.46 (−0.82 to −0.06)	−0.04 (−0.26 to 0.14)	***
ΔRV%p	−20.9 (−39.7 to −2.2)	−2.2 (−12.0 to 5.9)	**
ΔFRC%p	−11.9 (−16.6 to −3.9)	−4.2 (−11.2 to 2.2)	**
ΔIC%p	7.8 (2.4 to 13.7)	1.4 (−2.1 to 7.2)	ns
ΔRex (kPa·s/L)	−2.29 (−6.14 to −0.76)	−0.60 (−1.03 to −0.16)	**
ΔRin (kPa·s/L)	−1.23 (−2.30 to −0.51)	−0.45 (−0.63 to −0.14)	***
ΔRtot%p	−55.5 (−95.6 to −21.3)	−15.2 (−26.8 to −4.5)	***
Impulse oscillometry
ΔR5%p	−27.1 (−45.9 to −11.7)	−13.9 (−20.8 to −4.5)	**
ΔR20%p	−11.9 (−22.2 to −1.3)	−9.0 (−17.5 to −2.5)	ns
ΔR5–R20%p	−117.0 (−250.0 to −25.0)	−33.0 (−75.0 to 0.0)	**
ΔFres (Hz)	−1.84 (−3.51 to −0.47)	−1.54 (−4.12 to −0.03)	ns
ΔX5%p	−102.9 (−226.2 to −21.7)	−47.6 (−94.9 to −22.1)	*
ΔAX (kPa/L)	−0.54 (−1.39 to −0.11)	−0.08 (−0.37 to −0.01)	**
Single-breath helium dilution carbon monoxide diffusion
ΔDL,CO%p	2.0 (−2.5 to 3.5)	0.0 (−4.0 to 3.0)	ns

Notes: Data show median response (and IQR) within each group. Bold numbers indicate significant bronchodilator response compared to baseline.

a Significant difference between Group 1 and Group 2 in response (*P<0.05, **P<0.01 and ***P<0.001). ns, no significant difference. Δ indicates absolute response.

Abbreviations: SABA, short-acting β2 agonist (salbutamol); SAMA, short-acting muscarinic antagonist (ipratropium); FEV₁, forced expiratory volume in 1 second; %p, percent predicted; FVC, forced vital capacity; RV, residual volume; FRC, functional residual capacity; IC, inspiratory capacity; AX, reactance area; IQR, interquartile range.

Table 4 Correlation between absolute response in lung function parameters (in Δ values) after inhalation of SABA+SAMA

	ΔFEV1%p	ΔFVC%p	ΔRtot%p	ΔRV%p	ΔR5−R20%p
Group 1 (FEV1% <65)
ΔFVC%p	0.44*
ΔRtot%p	−0.34	−0.71***
ΔRV%p	−0.29	−0.61***	−0.06
ΔR5–R20%p	−0.14	−0.18	0.29	0.44*
ΔAX	−0.32	−0.41*	0.46*	0.40*	0.87***
Group 2 (FEV1% >65)
ΔFVC%p	0.56***
ΔRtot%p	−0.09	−0.21
ΔRV%p	−0.13	−0.27	0.22
ΔR5–R20%p	−0.36**	−0.11	−0.12	0.17
ΔAX	−0.36**	−0.23	0.04	0.14	0.80***

Notes: Δ indicates the absolute response in each parameter after inhaling SABA+SAMA.

* P<0.05,

** P<0.01, and

*** P<0.001 show significance of the correlation (significant correlations are bolded for clarification). Numbers presented as correlation coefficients.

Abbreviations: SABA, short-acting β2 agonist; SAMA, short-acting muscarinic antagonist; FEV₁, forced expiratory volume in 1 second; %p, percent predicted; FVC, forced vital capacity; RV, residual volume; AX, reactance area.

Figure 5 Relationship between ΔFEV₁%p and ΔRV%p.

Notes: To visualize the flow versus volume response in each patient. Dotted lines are median of ΔFEV₁%p and ΔRV%p.
Abbreviations: FEV₁, forced expiratory volume in 1 second; %p, percent predicted; RV, residual volume.

Table S1 Continuous analysis of SABA

Parameters	LR or SLR (BP%)	P-value for BP	Slope (left/right)	P-value for slope (left/right of BP)	Intercept	P-value for intercept
ΔFVC%p	SLR (86)	0.028	−0.21/0.06	<0.001/0.206	17	<0.001
ΔFEV1/FVC	LR	ns	0	0.091	−0.015	0.277
ΔIC%p	SLR (61)	0.033	−595/0.07	0.10/0.451	36	0.001
ΔRex	SLR (47)	<0.001	0.53/0.008	0.012/0.691	−26	0.001
ΔRin	LR	ns	0.02	<0.001	−2.0	<0.001
ΔRtot%p	LR	ns	0.94	<0.001	−99	<0.001
ΔAX	LR	ns	0.01	0.003	−0.87	<0.001
ΔRV%p	LR	ns	0.29	0.001	−28	<0.001
ΔR5–R20%p	LR	ns	1.01	0.036	−116	0.004
ΔFRC%p	LR	ns	0.12	0.027	−13	0.003
ΔDL,CO%p	LR	ns	−0.04	0.093	4.2	0.033
ΔR5%p	LR	ns	0.12	0.184	−21	0.006
ΔFEV1%p	LR	ns	−0.03	0.128	4.8	0.004
ΔX5%p	LR	ns	4.86	0.076	−534	0.018
ΔDL,CO/VA%p	LR	ns	−0.04	0.123	5.4	0.018
ΔR20%p	LR	ns	1.01	0.036	−116	0.004
ΔTLC%p	LR	ns	0.02	0.457	−2.2	0.362
ΔVA%p	LR	ns	−0.02	0.164	1.1	0.326

Notes: Bold numbers indicate significance (P<0.05). Δ indicates absolute response.

Abbreviations: SABA, short-acting β2 agonist (salbutamol); LR, linear regression; SLR, segmented linear regression; BP, break point; FVC, forced vital capacity; %p, percent predicted; FEV₁, forced expiratory volume in 1 second; IC, inspiratory capacity; AX, reactance area; RV, residual volume; FRC, functional residual capacity; D_L,CO, diffusion capacity of the lung for carbon monoxide; TLC, total lung capacity; VA, alveolar volume; ns, no significant difference.

Table S2 Response to SABA

Parameters	Group 1 (FEV1% <65)	Group 2 (FEV1% >65)	Significance
Body plethysmography
ΔFEV1, L	0.12 (0.03 to 0.21)	0.04 (−0.05 to 0.13)	**
ΔFEV1%p	4.0 (1.1 to 5.9)	1.4 (−1.5 to 4.4)	*
ΔFVC, L	0.28 (0.11 to 0.36)	0.01 (−0.08 to 0.07)	***
ΔFVC%p	6.8 (2.7 to 10.0)	−0.1 (−2.1 to 1.8)	***
ΔFEV1/FVC	0.01 (−0.02 to 0.03)	0.01 (−0.01 to 0.03)	ns
ΔRV, L	−0.44 (−0.74 to −0.16)	−0.02 (−0.19 to 0.11)	***
ΔRV%p	−17.8 (−31.5 to −6.4)	−1.1 (−9.0 to 4.3)	***
ΔFRC%p	−8.5 (−16.4 to −3.1)	−2.3 (−7.3 to 2.2)	***
ΔIC%p	6.8 (0.5 to 11.7)	−0.7 (−3.8 to 7.3)	ns
ΔRex, kPa·s/L	−1.86 (−3.51 to −0.70)	−0.37 (−0.97 to 0.13)	**
ΔRin, kPa·s/L	−1.13 (−1.86 to −0.32)	−0.31 (−0.63 to −0.01)	***
ΔRtot%p	−38.8 (−76.4 to −14.9)	−12.1 (−24.0 to 0.3)	***
Impulse oscillometry
ΔR5%p	−17.9 (−43.9 to −3.8)	−8.7 (−19.9 to −0.4)	*
ΔR20%p	−10.5 (−19.1 to 2.3)	−6.7 (−13.7 to −0.5)	ns
ΔR5–R20%p	−67.0 (−156.3 to 35.5)	−21.0 (−54.3 to 0.00)	ns
ΔFres, Hz	−1.57 (−3.07 to −0.35)	−0.99 (−3.73 to 0.08)	ns
ΔX5%p	−88.8 (−209.3 to −24.9)	−28.9 (−62.2 to −6.8)	**
ΔAX, kPa/L	−0.43 (−0.98 to −0.05)	−0.07 (−0.28 to −0.02)	**
Single-breath helium dilution carbon monoxide diffusion
ΔDL,CO%p	3.0 (1.0 to 3.8)	1.0 (−1.0 to 3.0)	*

Notes: Bold numbers indicate significant bronchodilator response. Significant difference (*P<0.05, **P<0.01 and ***P<0.001) between Group 1 and Group 2. ns, no significant difference. Δ indicates absolute response.

Abbreviations: SABA, short-acting β2 agonist (salbutamol); FEV₁, forced expiratory volume in 1 second; %p, percent predicted; FVC, forced vital capacity; RV, residual volume; FRC, functional residual capacity; IC, inspiratory capacity; AX, reactance area; D_L,CO, diffusion capacity of the lung for carbon monoxide.

Table S3 Correlation of lung Δ function parameters after inhalation of SABA

	ΔFEV1%p	ΔFVC%p	ΔRtot%p	ΔRV%p	ΔR5–R20%p	ΔAX
Correlations of Δ lung function parameters in FEV1%p <65
Group 1 (FEV1% <65)
ΔFVC%p	0.25
ΔRtot%p	−0.23	−0.64***
ΔRV%p	0.02	−0.46*	0.45*
ΔR5–R20%p	−0.39	−0.21	0.19	−0.03
ΔAX	−0.65***	−0.49*	0.36	0.03	0.79***
Correlations of Δ lung function parameters in FEV1%p >65
Group 2 (FEV1% >65)
ΔFVC%p	0.40**
ΔRtot%p	−0.28*	−0.26
ΔRV%p	0.08	−0.22	−0.10
ΔR5–R20%p	−0.27*	−0.07	0.25	0.01
ΔAX	−0.42***	−0.15	0.42**	−0.04	0.66***

Notes: Δ indicates the change in each parameter after inhaling salbutamol. Significant difference (*P<0.05, **P<0.01 and ***P<0.001) of the correlation. Bold numbers indicate significance. Numbers presented as correlation coefficients.

Abbreviations: SABA, short-acting β2 agonist (salbutamol); FEV₁, forced expiratory volume in 1 second; %p, percent predicted; FVC, forced vital capacity; RV, residual volume; AX, reactance area.