Small Airways Response to Bronchodilators in Adults with Asthma or COPD: A Systematic Review

Figures & data

Table 1 The PICO (Population, Intervention, Comparator, Outcome) and Study Design for the Systematic Review

PICO	Inclusion Criteria	Exclusion Criteria
Population	- Adult patients aged at least 18 years with a clinical diagnosis of COPD or Asthma	- Other chronic lung diseases such as cystic fibrosis.
		- Patients younger than 18 years old
Intervention	Small airways function (IOS, FOT, MMEF, FEF50, MBW, SBW) response to BDR using short acting beta2 agonist (SABA) via various aerosol delivery devices.
Comparator	BDR in conventional lung function (FEV1)
Outcome	Change in small airways function after administrating the bronchodilator therapy.
Study design	Randomised Control Trials (RCT), Cohort, Cross-sectional, Longitudinal, Case-series >10 patients, Systematic reviews	Reviews, Editorials, Case series of <10 Patients, Case reports

Note: The Systematic review included the following inclusion and exclusion criteria, as described above.

Abbreviations: COPD, chronic obstructive pulmonary disease; IOS, impulse oscillometry; FOT, forced oscillometry; FEV₁, forced expiratory volume in 1 second; MMEF, mean mid-maximal expiratory flow; FEF₅₀, forced expiratory flow at 50% of FVC.

Figure 1 PRISMA flow chart showing the studies identification process from EMBASE and Medline databases.

Notes: Adapted from: Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.⁶² Creative Commons.

Table 2 Characteristics of Included Studies

Study ID	Study Design	Population	n= (M/F)	Age	SABA /Dose	Aerosol Device	BDR Time	SAF test	SAF Change	FEV1 Change
Ohwada et al 2011^a	Observational	Asthma	45 (12/33)	36.8±10.2	Salbutamol/ 200 mcg	pMDI + Spacer	15 min	MMEF(%)	6.7%±10.5	5.5%±8.1
								FEF50(%)	33.3%±48.9
Schecker et al 1993^b	Randomized Controlled Trial	Asthma	20(16/4)	44±18	Pirbuterol/ 0.4 mg	pMDI	60 min	MMEF(%)	44.6%±8.6	31.1%±4.8
						Autohaler		MMEF(%)	45.6%±7	32%±5.8
Fakharian et al 2008^a	Observational	Asthma	40(15/25)	43.1±12.99	Salbutamol/ 400 mcg	Asmyar (spacer)	10 min	MMEF(%)	16.3%±12.1	7.7%±5.1
								FEF50 (%)	13.5%±11.8
			40(15/25)	43.1±12.99		Damyar (spacer)	10 min	MMEF(%)	16.1%±13.1	7.1%±5.9
								FEF50 (%)	14.4%±11.4
Mariotta et al 2005^a	Observational	Asthma (Intermittent)	108(68/40)	29.4±5.22	Salbutamol/ 200 mcg	pMDI	20 min	MMEF(%)	19.3%±17.9	5.03%±4.6
								FEF50 (%)	18.65%±16.2
		Asthma (Persistent)	183(88/95)	31.07±10.48				MMEF(%)	28.9%±23.1	8.65%±5.9
								FEF50 (%)	27.1%±20.9
		Control	38(24/14)	30.9±9.36				MMEF(%)	18.26%±9.3	3.4%±2.8
								FEF50 (%)	15.2%±8.9
Rajkumar et al 2002^d	Observational	Asthma	15(7/8)	31.8	Salbutamol/ 200 mcg	pMDI (Market Spacer)	NR	MMEF(%)	37.0%	19.0%
						pMDI (Homemade Spacer)		MMEF(%)	47.0%	22.7%
Castro et al 2015^a	Observational	Asthma (-reversibility)	50(18/32)	61.2±11.9	Salbutamol/ 400 mcg	pMDI + Spacer	10 min	MMEF(%)	5.3%±10.9	3.9%±5.1
		Asthma (+reversibility)	50(28/22)	56.1±15.6				MMEF(%)	39.4%±62.6	18.5%±11.8
El-Khatib et al 2014^a	Observational	Asthma (Group 1)	44(21/23)	51±14	Salbutamol/ 2.5 mg	SVN	15–30 min	MMEF(L/s)	0.5±0.6	0.2L±0.3
								FEF50 (L/s)	0.7±0.9
		Asthma (Group 2)	44(22/22)	52±13				MMEF(L/s)	0.2±0.4	0.2L±0.3
								FEF50 (L/s)	0.3±0.7
		Asthma (Group 3)	44(23/21)	53±8				MMEF(L/s)	0.1±0.1	0.2L±0.2
								FEF50 (L/s)	0.1±0.2
Lipworth et al 1997^c,e	Observational	Asthma mild	10	31.7±8.7	Salbutamol/ 40mcg/kg	SVN	30 min	MMEF(L/s)	0.7 (0.0 to 0.1)	0.4L (−0.4 to 0.4)
		Asthma severe	10	52.9±15.2					0.3	0.4
		Control	10	20.6±1					0.7 (0.1 to 0.9)	0. 2 (−0.2 to 0.6)
Yaegashi et al 2006^a	Observational	Asthma	126(30/96)	45.1±13.9	Pirbuterol/ 0.8mg/	pMDI	30 min	R5(kPa/L/s)	−0.2±0.2	0.2L
								R5-R20(kPa/L/s)	−0.1±0.1
								R20(kPa/L/s)	−0.1±0.1
Nair et al 2011^c	Observational	Asthma	82(28/54)	48.7±16.51	Salbutamol/ 400mcg	Accuhaler DPI	15 min	R5(%)	−33.0% (−42.6 to −25.0)	6.3% (5.0 to 7.6)
								R20(%)	−20.1% (−27.8 to −12.4)
								X5(%)	−72.9% (−249.6 to 103.8)
		Control	61(27/34)	28.2±10.13				R5(%)	−14.9% (−19.9 to −9.9)	2.25% (1.6 to 2.9)
								R20(%)	−15.7% (−21.0 to −10.4)
								X5(%)	40.1% (−91.4 to 171.7)
Park et al 2019^b	Observational	COPD	40(36/4)	74.35±4.7	Salbutamol/ 200 mcg	pMDI	15 min	Fres(Hz)	−9.6%±2.1	6.3%±1.0
								R5(kPa/L/s)	−9.3%±1.8
								R20(kPa/L/s)	−6.8%±1.6
								R5-20(kPa/L/s)	−8.5%±1.6
								X5(kPa/L/s)	−13.5%±3.2
								AX(kPa/L/s)	−22.7%±4.5
								MMEF(%)	8.3%±3.0
		Asthma	30 (23/7)	74.70±4.84				Fres(Hz)	−15.3%±2.6	9.2%±1.9
								R5(kPa/L/s)	−12.7%±2.7
								R20(kPa/L/s)	−6.4%±2.6
								R5-20 (kPa/L/s)	−10.3%±2.6
								X5(kPa/L/s)	−5.9%±7.3
								AX(kPa/L/s)	−22.9%±7.3
								MMEF(%)	NR
Borrill et al 2004^c	Observational	COPD	24 (16/8)	63.6±7.1	Salbutamol/ 20 mcg	Dosimeter	15 min	R5(kPa/L/s)	− 9.0%(−14 to −4)	2.8%(0.8 to 4.9)
								R20(kPa/L/s)	−2.7%(−7 to −1.7)
								X5(kPa/L/s)	−18.5%(−27.2 to −9.8)
								Fres(Hz)	−11.1%(−15 to −7.2)
								MMEF(L/s)	3.6%(−1.8 to 8.9)
					Salbutamol/ 50 mcg			R5(kPa/L/s)	−16.7%(−22.5 to −10.8)	8%(5.2 to 10.4)
								R20(kPa/L/s)	−5.8%(−10.4 to - 2.2)
								X5(kPa/L/s)	−32.0%(−47 to −16.9)
								Fres(Hz)	−19.4%(−25 to −13.7)
								MMEF(L/s)	12.9%(4.2 to 21.4)
					Salbutamol/ 100 mcg			R5(kPa/L/s)	−16%(−23.3 to −8.6)	10.2%(7.4 to 12.9)
								R20(kPa/L/s)	−4.6%(−11.6 to 2.3)
								X5(kPa/L/s)	−26.7%(−42.7 to −10.7)
								Fres(Hz)	−17.9%(−23.3 to −12.4)
								MMEF(L/s)	13.6%(5.2 to 22.1)
					Salbutamol/ 200 mcg			R5(kPa/L/s)	−17.9%(−25.5 to −10.3)	11.9%(8.6 to 15.1)
								R20(kPa/L/s)	−6.2%(−13 to 0.6)
								X5(kPa/L/s)	−28.6%(−45.9 to −11.3)
								Fres(Hz)	−20.7%(−25.8 to - 12.4)
								MMEF(L/s)	21.3%(11.1 to 31.6)
					Salbutamol/ 400 mcg			R5(kPa/L/s)	−20%(−28.3 to −11.6)	13.7%(10.2 to 17.2)
								R20(kPa/L/s)	−7.4%(−13.9 to −0.9)
								X5(kPa/L/s)	−32.8%(−48.8 to −16.8)
								Fres(Hz)	−22.7%(−29.1 to −16.3)
								MMEF(L/s)	19.3%(7.9 to 30.7)
					Salbutamol/ 800 mcg			R5(kPa/L/s)	−22.4%(−29.3 to −15.4)	16.3%(12.2 to 20.4)
								R20(kPa/L/s)	−11.0%(−17.4 to −4.6)
								X5(kPa/L/s)	−36.2%(−49.6 to −22.8)
								Fres(Hz)	−23.3%(−29.0 to −17.5)
								MMEF(L/s)	25.0%(11.8 to 38.2)
								AX(cmH2O)	−0.10±0.3
								R15(cmH2O)	−0.008±0.1

Notes: For each study, the population, numbers of participants by gender, average age of participant, SABA used, device for BDR, time from delivery to measurement, small airway function test (SAF), change in that test and change in FEV1 is reported. Change in SAF and FEV1 is reported in percent predicted or in units as reported in the table ^aChanges reported in mean ± standard deviation (SD). ^bChanges reported in mean ± standard error of mean (SEM). ^cChanges reported in mean (95% CI). ^dMean was only reported for this study. ^eMeasure of variance was not reported for severe asthmatic group.

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; MMEF, mean mid-maximal expiratory flow; FEF₅₀, forced expiratory flow at 50% of FVC; Fres, resonant frequency; R5, resistance at 5 Hz; R20, resistance at 20 Hz; R5–20, resistance between 5 and 20 Hz; X5, reactance at 5 Hz; AX, area of reactance curve (between X5 and Fres).

Figure 2 The average percentage change and absolute change in MMEF, FEF₅₀, FEV₁ and FVC across asthma studies.

Notes: Left vertical axis is % of change in MMEF, FEF₅₀, FEV₁ and FVC in asthmatic patients. Right Vertical axis is absolute change in MMEF, FEF₅₀, FEV₁. Data presented are means ± standard deviation (SD). Included data has been taken and adapted from Fakhrian et al,³⁵ Castro et al,⁴³ Ohwada et al,⁴⁰ Mariotta et al,³⁸ Schecker et al,⁴² Rajkumar et al,⁴¹ Elkhatib et al,³⁶ and Lipworth et al.³⁷ Measure of variances is not displayed in the error bars for Rajkumar et al⁴¹ and severe asthmatic patients in Lipworth et al³⁷ because SD was not reported. *BDR is statistically significant. **BDR is clinically significant according to ATS/ERS criteria.

Abbreviations: MMEF, mean mid-maximal expiratory flow; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; FEF₅₀, forced expiratory flow at 50% of FVC.

Figure 3 The % of change in spirometry indices (MMEF, FEV₁, and FVC) and in oscillometry indices (X5, Fres, and R5) in COPD patients.

Notes: Vertical axis is % of change in spirometry indices and oscillometry indices across different doses of salbutamol Borrill et al.²⁶ Data presented in the figure are mean (95% CI) for Borrill et al²⁶ and mean and standard error for Park et al⁴⁵ *BDR is statistically significant. **BDR is clinically significant according to ATS/ERS criteria.

Abbreviations: MMEF, mean mid-maximal expiratory flow; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; mcg, microgram. X5, reactance at 5 hertz; Fres, resonant frequency; R5, resistance at 5 hertz; FEV₁, forced expiratory volume in 1 second.

Figure 4 The percentage change of IOS parameters and FEV₁ in Asthmatic patients following BDR.

Notes: Vertical axis is % of change in oscillometry parameters in comparison to FEV₁ in asthmatic patients. Data is adapted from Park et al.⁴⁵ Data presented in the figure are the mean % change (± standard error of mean (SEM)).

Abbreviations: X5, reactance at 5 hertz; Fres, resonant frequency; R5, resistance at 5 hertz; R20, resistance at 20Hertz; R5-20, the difference between R5 and R20; AX, area of reactance; FEV₁, forced expiratory volume in 1 second.

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