Bronchodilator reversibility in asthma and COPD: findings from three large population studies

Christer Janson; Andrei Malinovschi; Andre F.S. Amaral; Simone Accordini; Jean Bousquet; A. Sonia Buist; Giorgio Walter Canonica; Barbro Dahlén; Judith Garcia-Aymerich; Louisa Gnatiuc; Marek L Kowalski; Jaymini Patel; Wan Tan; Kjell Torén; Torsten Zuberbier; Peter Burney; Deborah Jarvis

doi:10.1183/13993003.00561-2019

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FIGURE 1
Study design. ECRHS: European Community Respiratory Health Survey; GA²LEN: Global Asthma and Allergy European Network; BOLD: Burden of Obstructive Lung Disease study; COPD: chronic obstructive pulmonary disease.
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FIGURE 2
Association between bronchodilator responsiveness and asthma and chronic obstructive pulmonary disease (COPD) with participants without airway disease as the reference group. The association is expressed as OR (95% CI) adjusted for pre-bronchodilator forced expiratory volume in 1 s (FEV₁). FVC: forced vital capacity.

TABLE 1

Characteristics and prevalence of bronchodilator reversibility

	No airway disease (controls)	Current asthma	*p-value versus* controls**	COPD	*p-value versus* controls**	*p-value asthma versus* COPD**
Subjects n	31 649	2833		1146
Characteristics
Female	53.0	63.1	<0.0001	26.4	<0.0001	<0.0001
Age years	54±11	53±12	<0.0001	60±11	<0.0001	<0.0001
Smoking history			<0.0001		<0.0001	<0.0001
Never-smoker	61.2	54.6		0
Ex-smoker	21.8	30.4		40.9
Current smoker	17.0	15.1		59.1
BMI kg·m⁻²			<0.0001		<0.0001	<0.0001
<20	8.3	5.3		14.8
20–25	33.6	29.6		37.4
>25–30	35.3	32.2		32.8
>30	22.8	32.9		15.0
Pre-bronchodilator FEV₁ % pred	87±18	78±21	<0.0001	65±20	<0.0001	<0.0001
Pre-bronchodilator FVC % pred	90±18	88±18	<0.0001	87±20	<0.0001	0.58
Pre-bronchodilator FEV₁/FVC %	77±7	69±13	<0.0001	57±10	<0.0001	<0.0001
Post-bronchodilator FEV₁ % pred	89±18	82±21	<0.0001	69±20	<0.0001	<0.0001
Post-bronchodilator FVC % pred	90±18	90±18	>0.99	92±20	0.001	0.001
Post-bronchodilator FEV₁/FVC %	79±7	73±12	<0.0001	58±9	<0.0001	<0.0001
Flow response
ΔFEV₁ ≥12% from baseline	5.9	20.2	<0.0001	24.5	<0.0001	<0.0001
ΔFEV₁ ≥10% pred	8.9	25.8	<0.0001	29.8	<0.0001	0.10
ΔFEV₁ ≥12% and 200 mL from baseline	5.1	17.3	<0.0001	18.4	<0.0001	0.39
Volume response
ΔFVC ≥10.5% from baseline	5.3	15.8	<0.0001	25.2	<0.0001	<0.0001
ΔFVC ≥9.2% pred	10.7	22.8	<0.0001	31.6	<0.0001	<0.0001
ΔFVC ≥10.5% and 320 mL from baseline	3.6	11.8	<0.0001	21.6	<0.0001	<0.0001

Data are presented as % or mean±sd, unless otherwise stated. COPD: chronic obstructive pulmonary disease; BMI: body mass index; FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity.

TABLE 2

Comparison between participants with asthma with or without bronchodilator reversibility

	ΔFEV₁			ΔFVC
	<12%	≥12%	p-value	<10.5%	≥10.5%	p-value
Subjects n	2261	572		2280	429
Wheeze	72.8	81.5	<0.0001	72.9	81.8	<0.0001
Wheeze and breathlessness	55.1	63.9	<0.0001	55.8	62.7	0.008
Wheeze when no cold	44.4	47.5	0.18	44.8	49.0	0.12
Nocturnal chest tightness^#	41.2	51.0	0.10	40.4	57.0	<0.0001
Breathlessness at rest^#	26.0	33.8	0.02	26.2	36.0	0.02
Breathless after effort^#	54.2	61.4	0.06	53.6	64.4	0.02
Nocturnal breathlessness^#	26.6	36.2	0.006	26.6	36.3	0.02
Nocturnal cough^#	55.5	51.0	0.24	55.8	47.1	0.052
Habitual cough	49.0	47.0	0.39	47.7	50.4	0.31
Chronic bronchitis	23.9	29.6	0.006	22.4	34.5	<0.0001
Asthma attacks in past 3 months^#			0.99			0.96
0	61.9	62.0		62.0	61.6
1	17.1	17.2		17.2	16.5
≥2	21.0	20.8		20.8	21.8
Nasal allergy^#	65.7	62.2	0.35	66.9	56.3	0.01
IgE sensitisation^¶
Pets	51.0	58.0	0.09	52.7	50.4	0.63
Mite	33.9	42.4	0.03	35.3	35.8	0.91
Pollen	54.6	56.0	0.74	56.0	50.4	0.24
Any	70.1	75.1	0.18	72.3	67.0	0.22
Total IgE^¶	64 (59–71)	108 (90–131)	<0.0001	68 (62–74)	80 (59–108)	0.28
F_eNO⁺	20 (19–21)	25 (22–29)	0.001	20 (19–21)	24 (20–28)	0.04

Data are presented as % or geometric mean (95% CI), unless otherwise stated. FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; F_eNO: exhaled nitric oxide fraction. ^#: n=1321; ^¶: n=1215; ⁺: n=878.

TABLE 3

Determinants of bronchodilator reversibility in subjects with asthma

	ΔFEV₁		ΔFVC
	≥12%	≥12% + 200 mL	≥10.5%	≥10.5% + 320 mL
Age per 10 years	0.90 (0.82–0.99)	0.82 (0.75–0.91)	1.23 (1.11–1.37)	1.08 (0.96–1.22)
Female	1.19 (0.95–1.50)	0.99 (0.79–1.25)	1.19 (0.91–1.54)	0.72 (0.55–0.95)
Smoking history
Never-smoker	1	1	1	1
Ex-smoker	0.96 (0.74–1.24)	1.01 (0.78–1.31)	1.05 (0.79–1.41)	1.15 (0.84–1.57)
Current smoker	0.75 (0.55–1.01)	0.78 (0.57–1.06)	1.06 (0.76–1.06)	1.08 (0.75–1.06)
BMI kg·m⁻²
<20	0.60 (0.37–0.97)	0.51 (0.31–0.85)	0.61 (0.36–1.06)	0.60 (0.33–1.06)
20–25	1	1	1	1
>25–30	0.98 (0.75–1.29)	1.06 (0.81–1.40)	1.10 (0.80–1.52)	1.06 (0.76–1.48)
>30	1.06 (0.81–1.38)	1.06 (0.81–1.40)	1.31 (0.96–1.79)	1.17 (0.84–1.64)
Wheeze	1.33 (1.02–1.73)	1.36 (1.04–1.79)	1.42 (1.04–1.92)	1.19 (0.86–1.64)
Wheeze and breathlessness	1.17 (0.94–1.46)	1.16 (0.93–1.45)	1.10 (0.85–1.42)	1.02 (0.78–1.33)
Wheeze not having a cold	1.05 (0.84–1.31)	1.10 (0.88–1.38)	1.16 (0.90–1.49)	1.08 (0.82–1.42)
Nocturnal chest tightness	1.32 (0.93–1.86)	1.35 (0.6–1.91)	2.31 (1.50–3.55)	2.25 (1.44–3.52)
Breathless at rest	1.28 (0.89–1.86)	1.28 (0.88–1.86)	1.48 (0.95–2.31)	1.65 (1.04–2.60)
Breathless after effort	0.92 (0.64–1.31)	0.87 (0.61–1.24)	1.08 (0.70–1.68)	1.32 (0.83–2.10)
Nocturnal breathlessness	1.14 (0.79–1.66)	1.12 (0.77–1.63)	1.19 (0.76–1.88)	1.25 (0.78–1.99)
Nocturnal cough	0.84 (0.59–1.20)	0.82 (0.58–1.17)	0.64 (0.42–0.98)	0.59 (0.38–0.93)
Chronic cough	0.74 (0.59–0.92)	0.71 (0.57–0.88)	0.86 (0.67–1.10)	0.96 (0.74–1.25)
Chronic bronchitis	0.85 (0.67–1.09)	0.90 (0.76–0.92)	1.15 (0.88–1.50)	1.12 (0.84–1.50)
Asthma attacks in past 3 months
0	1	1	1	1
1	1.13 (0.70–1.82)	1.15 (0.72–1.86)	1.42 (0.80–2.52)	1.38 (0.75–2.53)
≥2	0.92 (0.59–1.44)	0.85 (0.54–1.33)	1.03 (0.60–1.75)	1.13 (0.66–1.96)
Nasal allergy	1.15 (0.79–1.66)	1.12 (0.77–1.62)	0.84 (0.54–1.29)	0.79 (0.50–1.25)
IgE sensitisation
Pollen	1.80 (1.22–2.67)	1.54 (1.03–2.31)	1.44 (0.90–2.29)	1.57 (0.94–2.60)
Mite	1.91 (1.30–2.81)	2.00 (1.36–2.93)	1.58 (0.99–2.53)	1.69 (1.04–2.76)
Pets	1.56 (1.04–2.34)	1.82 (1.23–2.69)	1.60 (0.98–2.59)	1.29 (0.80–2.11)
Any	2.19 (1.37–3.51)	1.36 (1.04–1.79)	1.57 (0.93–2.64)	1.42 (0.82–2.45)
Total IgE per log unit	1.50 (1.12–2.03)	1.53 (1.13–2.06)	0.94 (0.65–1.36)	1.01 (0.68–1.49)
F_eNO per log unit	5.27 (2.47–11.3)	5.02 (2.36–10.7)	3.61 (1.48–8.82)	3.80 (1.49–9.64)
Pre-bronchodilator FEV₁ % pred	0.94 (0.93–0.95)	0.95 (0.95–0.96)	0.94 (0.94–0.95)	0.97 (0.96–0.98)
Pre-bronchodilator FVC % pred	0.96 (0.95–0.97)	0.97 (0.96–0.98)	0.94 (0.93–0.95)	0.96 (0.96–0.97)

Data are presented as OR (95% CI), adjusted by sex, age, body mass index (BMI), smoking, pre-bronchodilator forced expiratory volume in 1 s (FEV₁) and study. Statistically significant associations are presented in bold. FVC: forced vital capacity; F_eNO: exhaled nitric oxide fraction.

TABLE 4

Comparison between participants with chronic obstructive pulmonary disease with or without bronchodilator reversibility

	ΔFEV₁			ΔFVC
	<12%	≥12%	p-value	<10.5%	≥10.5%	p-value
Subjects n	865	281		833	280
Wheeze	37.3	52.0	<0.0001	40.2	45.0	0.16
Wheeze and breathlessness	15.3	30.6	<0.0001	17.2	25.7	0.002
Wheeze when no cold	17.2	28.8	<0.0001	18.8	24.3	0.047
Habitual coughing	39.3	47.0	0.02	40.6	44.3	0.28
Chronic bronchitis	18.7	26.2	0.007	18.8	26.3	0.008
Exacerbations			0.008			0.13
0	94.9	89.6		94.3	91.0
1	1.4	2.3		1.3	2.8
≥2	3.7	8.1		4.5	6.3
mMRC score			<0.0001			0.001
0	60.4	43.5		58.9	46.2
1	24.6	31.3		25.8	29.4
2	4.3	4.9		4.4	5.5
3 or 4	10.6	20.3		10.9	18.9
SF-12^#
MCS-12	50.5±10.2	49.2±11.0	0.12	50.5±10.0	49.6±11.3	0.32
PCS-12	45.1±10.2	42.2±11.0	0.0006	45.0±10.2	42.6±11.1	0.005

Data are presented as % or mean±sd, unless otherwise stated. FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; mMRC: modified Medical Research Council; SF-12: 12-item short form questionnaire; MCS: mental health component score; PCS: physical component score. ^#: n=839.

TABLE 5

Determinants of bronchodilator reversibility in subjects with chronic obstructive pulmonary disease

	ΔFEV₁		ΔFVC
	≥12%	≥12% + 200 mL	≥10.5%	≥10.5% + 320 mL
Female	1.30 (0.92–1.84)	0.88 (0.61–1.28)	1.21 (1.04–1.40)	1.15 (0.99–1.33)
Age	1.10 (0.94–1.28)	0.95 (0.81–1.11)	1.61 (1.16–2.23)	1.11 (0.79–1.56)
Current smoking	0.97 (0.69–1.35)	0.93 (0.66–1.31)	1.14 (0.82–1.58)	1.03 (0.74–1.43)
BMI kg·m⁻²
<20	0.65 (0.41–1.04)	0.53 (0.32–0.90)	0.82 (0.52–1.29)	0.75 (0.47–1.21)
20–25	1	1	1	1
>25–30	1.32 (0.90–1.92)	1.30 (0.89–1.90)	1.19 (0.83–1.71)	1.14 (0.79–1.64)
>30	1.30 (0.82–2.07)	1.27 (0.80–2.03)	1.46 (0.94–2.27)	1.42 (0.91–2.21)
Wheeze	1.23 (0.90–1.70)	1.21 (0.88–1.68)	0.89 (0.65–1.20)	0.98 (0.72–1.34)
Wheeze and breathlessness	1.41 (0.98–2.03)	1.31 (0.90–1.91)	1.06 (0.74–1.52)	1.16 (0.80–1.67)
Wheeze when no cold	1.43 (0.99–2.06)	1.56 (1.08–2.26)	1.10 (0.77–1.57)	1.17 (0.81–1.69)
Habitual coughing	1.06 (0.77–1.45)	0.97 (0.69–1.34)	0.92 (0.68–1.25)	0.94 (0.69–1.28)
Chronic bronchitis	1.01 (0.70–1.47)	0.95 (0.64–1.39)	1.20 (0.85–1.70)	1.29 (0.91–1.84)
Exacerbations
0	1	1	1	1
1	0.94 (0.30–2.90)	0.88 (0.26–2.96)	1.38 (0.49–3.91)	1.53 (0.53–4.37)
≥2	1.16 (0.58–2.30)	0.65 (0.30–1.39)	0.87 (0.44–1.73)	1.04 (0.52–4.37)
mMRC score
0	1	1	1	1
1	1.10 (0.75–1.63)	1.13 (0.76–1.67)	0.98 (0.67–1.42)	0.96 (0.65–1.42)
2	0.70 (0.31–1.56)	0.67 (0.29–1.57)	0.91 (0.43–1.93)	0.71 (0.32–1.60)
3 or 4	0.84 (0.51–1.39)	0.69 (0.40–1.17)	0.99 (0.61–1.61)	1.02 (0.62–1.67)
SF-12^#
MCS-12	0.99 (0.97–1.004)	0.99 (0.98–1.01)	1.00 (0.99–1.02)	0.99 (0.98–1.01)
PCS-12	1.01 (0.99–1.03)	1.01 (0.99–1.02)	0.99 (0.98–1.01)	1.01 (0.99–1.03)
Pre-bronchodilator FEV₁ % pred	0.94 (0.93–0.95)	0.96 (0.95–0.97)	0.96 (0.95–0.97)	0.97 (0.96–0.98)
Pre-bronchodilator FVC % pred	0.96 (0.95–0.97)	0.98 (0.97–0.98)	0.95 (0.94–0.96)	0.96 (0.96–0.97)

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