Discordant diagnostic criteria for pneumonia in COPD trials: a review

Robert A. Wise; Mona Bafadhel; Courtney Crim; Gerard J. Criner; Nicola C. Day; David M.G. Halpin; MeiLan K. Han; Peter Lange; David A. Lipson; Fernando J. Martinez; Diego J. Maselli; Dawn Midwinter; Dave Singh; Maeva Zysman; Mark T. Dransfield; Richard E.K. Russell

doi:10.1183/16000617.0124-2021

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FIGURE 1
Flowchart describing study selection. ICS: inhaled corticosteroid.
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FIGURE 2
COPD trials by pneumonia capture methodology. Some trials included multiple pneumonia capture methodologies.

TABLE 1

Pneumonia incidence in identified COPD clinical trials, ordered by treatment comparison and pneumonia capture

Citation	Study and study length	Study population	Pneumonia capture method^#	Pneumonia incidence, % (n/N)^¶		*Increased incidence of pneumonia versus* comparator arm**
Citation	Study and study length	Study population	Pneumonia capture method^#	ICS arm	Comparator arm	Comparison	Fold increase in risk⁺
Studies comparing ICS/LAMA/LABA triple therapy with non-ICS-containing treatment
Pneumonia capture: investigator reporting confirmed by radiographic imaging and independent adjudication
Rabe, 2020 [14]	ETHOS (52 weeks)	Post-bronchodilator FEV₁ 25–50% pred and ≥1 moderate/severe exacerbation or post-bronchodilator FEV₁ 50–65% pred and ≥2 moderate or ≥1 severe exacerbation in the year prior to screening CAT total score ≥10	Investigator reported, adjudicated by a clinical end-point independent committee Radiographic imaging compatible with the diagnosis of pneumonia, ≥2 of a list of clinical signs, symptoms or laboratory findings, and treatment with antibiotics and/or antiviral and/or antifungal agents were also required to support the adjudication	BUD/GLY/FOR 320/18/9.6 µg twice daily: 4.2% (90/2144) BUD/GLY/FOR 160/18/9.6 µg twice daily: 3.5% (75/2124) BUD/FOR 320/9.6 µg twice daily: 4.5% (96/2136)	GLY/FOR 18/9.6 µg twice daily: 2.3% (48/2125)	BUD/GLY/FOR 320/18/9.6 µg versus GLY/FOR	1.9
						BUD/GLY/FOR 160/18/9.6 µg versus GLY/FOR	1.6
						BUD/FOR versus GLY/FOR	2.0
Ferguson, 2018 [26]	KRONOS (24 weeks)	Post-bronchodilator FEV₁ ≥25% and <80% pred CAT total score ≥10	Investigator reported, adjudicated by an independent committee Radiographic imaging compatible with the diagnosis of pneumonia, ≥2 of a list of clinical signs, symptoms or laboratory findings, and treatment with antibiotics and/or antiviral and/or antifungal agents were also required	BUD/GLY/FOR 320/18/9.6 μg twice daily via MDI: 1.9% (12/639) BUD/FOR 320/9.6 μg twice daily via MDI: 1.9% (6/314) BUD/FOR 400/12 µg twice daily via DPI: 1.3% (4/318)	GLY/FOR 18/9.6 μg twice daily via MDI: 1.6% (10/625)	BUD/GLY/FOR versus GLY/FOR	1.2
						BUD/FOR 320/9.6 µg via MDI versus GLY/FOR	1.2
						BUD/FOR 400/12 µg via DPI versus GLY/FOR	0.8
Pneumonia capture: investigator reporting confirmed by radiographic imaging
Chapman, 2018 [27]	SUNSET (26 weeks)	Post-bronchodilator FEV₁ ≥40% and <80% pred ≤1 moderate/severe exacerbation in the year prior to screening	Investigator reported Radiographic imaging was required to confirm the diagnosis of pneumonia	TIO 18 µg once daily plus SAL/FP 50/500 µg twice daily: 1.7% (9/526)	IND/GLY 110/50 µg once daily: 1.1% (6/527)	TIO+SAL/FP versus IND/GLY	1.5
Lipson, 2018 [13]	IMPACT (52 weeks)	Post-bronchodilator FEV₁ <50% pred with ≥1 moderate/severe exacerbation in the year prior to screening, or post-bronchodilator FEV₁ 50–80% pred and ≥2 moderate or ≥1 severe exacerbation in the year prior to screening CAT total score ≥10	Investigator reported Radiographic imaging was required to confirm the diagnosis of pneumonia	FF/UMEC/VI 100/62.5/25 µg once daily: 7.6% (317/4151) FF/VI 100/25 µg once daily: 7.1% (292/4134)	UMEC/VI 62.5/25 µg once daily: 4.7% (97/2070)	FF/UMEC/VI versus UMEC/VI	1.6
Lipson, 2018 [13]	IMPACT (52 weeks)				UMEC/VI 62.5/25 µg once daily: 4.7% (97/2070)	FF/VI versus UMEC/VI	1.5
Magnussen, 2014 [28]	WISDOM (52 weeks)	Post-bronchodilator FEV₁ <50% pred ≥1 exacerbation in the year prior to screening	Investigator reported Radiographic imaging was requested when pneumonia was suspected	FP/SAL/TIO (500 µg twice daily/50 µg twice daily/18 µg once daily): 5.8% (72/1243)	SAL/TIO (50 µg twice daily/18 µg once daily): 5.5% (68/1242)	FP/SAL/TIO versus SAL/TIO	1.1
Pneumonia capture: investigator reporting
Papi, 2018 [12]	TRIBUTE (52 weeks)	Post-bronchodilator FEV₁ <50% pred ≥1 moderate/severe exacerbation in the year prior to screening CAT total score ≥10	Investigator reported	BDP/FOR/GLY 87/5/9 µg twice daily: 3.7% (28/764)	IND/GLY 85/43 µg: 3.6% (27/768)	BDP/FOR/GLY versus IND/GLY	1.0
Vestbo, 2017 [29]	TRINITY (52 weeks)	Post-bronchodilator FEV₁ <50% pred ≥1 moderate/severe exacerbation in the year prior to screening CAT total score ≥10	Investigator reported	BDP/FOR/GLY 100/6/12.5 µg (2 actuations twice daily): 2.6% (28/1077) BDP/FOR 100/6 µg (2 actuations twice daily)+TIO 18 µg (1 actuation once daily): 2.2% (12/537)	TIO 18 µg once daily: 1.8% (19/1076)	BDP/FOR/GLY versus TIO	1.5
Vestbo, 2017 [29]	TRINITY (52 weeks)		Investigator reported		TIO 18 µg once daily: 1.8% (19/1076)	BDP/FOR+TIO versus TIO	1.3
Jung, 2012 [30]	(24 weeks)	Post-bronchodilator FEV₁ <65% pred	Investigator reported	TIO 18 µg once daily+FP/SAL 250/50 µg twice daily: 0.9% (2/223)	TIO 18 µg once daily: 0.9% (2/232)	TIO+FP/SAL versus TIO	1.0
Studies comparing ICS/LABA dual therapy with non-ICS-containing treatment
Pneumonia capture: investigator reporting and independent adjudication with/without confirmation by radiographic imaging
Hanania, 2020 [31]	SOPHOS (52 weeks)	Post-bronchodilator FEV₁ ≥25% and <80% pred ≥1 moderate/severe exacerbation in the year prior to screening CAT total score ≥10	Investigator reported, adjudicated by an independent committee	BUD/FOR 320/10 µg twice daily: 1.6% (10/619) BUD/FOR 160/10 µg twice daily: 2.4% (15/617)	FOR 10 µg twice daily: 2.3% (14/607)	BUD/FOR 320/10 µg versus FOR BUD/FOR 160/10 µg versus FOR	0.7 1.1
Ferguson, 2018 [32]	TELOS (24 weeks)	Post-bronchodilator FEV₁ <80% pred CAT total score ≥10	Investigator reported, adjudicated by an independent committee Radiographic imaging compatible with the diagnosis of pneumonia, ≥2 of a list of clinical signs, symptoms or laboratory findings, and treatment with antibiotics and/or antiviral and/or antifungal agents were also required	BUD/FOR 320/10 μg twice daily via MDI: 0.8% (5/655) BUD/FOR 160/10 μg twice daily via MDI: 1.1% (7/637) BUD 320 µg twice daily via MDI: 0.5% (1/206) BUD/FOR 400/12 µg twice daily via DPI: 1.4% (3/219)	FOR 10 µg twice daily via MDI: 1.4% (9/644)	BUD/FOR 320/10 μg versus FOR	0.5
						BUD/FOR 160/10 μg versus FOR	0.8
						BUD versus FOR	0.3
						BUD/FOR 400/12 µg via DPI versus FOR	1.0
Pneumonia capture: investigator reporting confirmed by radiographic imaging
Ferguson, 2017 [33]	RISE (26 weeks)	Post-bronchodilator FEV₁ ≤70% pred ≥1 moderate/severe exacerbation in the year prior to screening mMRC dyspnoea score ≥2	Investigator reported Radiographic imaging compatible with the diagnosis of pneumonia and ≥2 of a list of clinical signs, symptoms or laboratory findings were also required	BUD/FOR 320/9 µg twice daily: 0.5% (3/605)	FOR DPI 9 µg twice daily: 1.0% (6/613)	BUD/FOR versus FOR	0.5
Papi, 2017 [24]	EFFECT (52 weeks)	Post-bronchodilator FEV₁ ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening	Investigator reported Radiologically and/or clinically confirmed per British Thoracic Society criteria	FP/FOR 500/20 μg twice daily: 2.9% (17/587) FP/FOR 250/10 μg twice daily: 3.9% (23/588)	FOR 12 µg twice daily: 1.9% (11/590)	FP/FOR 500/20 μg versus FOR	1.6
Papi, 2017 [24]	EFFECT (52 weeks)				FOR 12 µg twice daily: 1.9% (11/590)	FP/FOR 250/10 μg versus FOR	2.1
Wedzicha, 2016 [34]	FLAME (52 weeks)	Post-bronchodilator FEV₁ ≥25 to <60% pred ≥1 moderate/severe exacerbation in the year prior to screening mMRC dyspnoea score ≥2	Investigator reported Radiographic imaging was required	FP/SAL 500/50 µg twice daily: 4.8% (80/1680)	IND/GLY 110/50 µg once daily: 3.2% (53/1678)	FP/SAL versus IND/GLY	1.5
Ohar, 2014 [35]	NCT01110200 (26 weeks)	Post-bronchodilator FEV₁ <70% pred Recent exacerbation (≤14 days)	Investigator reported Radiographic imaging was required	FP/SAL 250/50 µg twice daily: 4.1% (13/314)	SAL 50 µg twice daily: 3.1% (10/325)	FP/SAL versus SAL	1.3
Vogelmeier, 2013 [36]	ILLUMINATE (26 weeks)	Post-bronchodilator FEV₁ 40–80% pred 0 moderate/severe exacerbations in the year prior to screening	Investigator reported Radiographic imaging was required	FP/SAL 500/50 µg twice daily: 1.5% (4/264)	IND/GLY 110/50 µg once daily: 0 (0/258)
Anzueto, 2009 [10]	NCT00115492 (52 weeks)	Post-bronchodilator FEV₁ ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening	Investigator reported Radiographic imaging was required	FP/SAL 250/50 µg twice daily: 6.6% (26/394)	SAL 50 µg twice daily: 2.5% (10/403)	FP/SAL versus SAL	2.7
Pneumonia capture: investigator reporting
Suissa, 2018 [37]	Up to 1-year follow-up	Cohort of patients aged ≥55 years with COPD initiating treatment with a LAMA or ICS/LABA during 2002–2015 from the UK's Clinical Practice Research Datalink	Hospital admissions due to severe pneumonia (according to diagnostic codes)	ICS/LABA: 3.1% (380/12 366)	LAMA: 2.3% (279/12 366) of patients	ICS/LABA versus LAMA	1.4
Vestbo, 2016 [38], Crim, 2017 [39]	SUMMIT (event driven, common end date of 3 years)	Post-bronchodilator FEV₁ ≥50% and ≤70% pred History or increased risk of cardiovascular disease mMRC dyspnoea score ≥2	Investigator reported	FF/VI 100/25 µg once daily: 5.7% (237/4140) FF 100 µg once daily: 5.5% (228/4157)	VI 25 µg once daily: 3.9% (163/4140) Placebo: 5.2% (214/4131)	FF/VI versus VI	1.5
Vestbo, 2016 [38], Crim, 2017 [39]	SUMMIT (event driven, common end date of 3 years)		Investigator reported			FF versus placebo	1.1
Vestbo, 2016 [40]	Salford Lung Study (52 weeks)	≥1 COPD exacerbations in the previous 3 years	Investigator reported pneumonia SAEs	FF/VI 100/25 µg once daily: 6.7% (94/1396)	Usual care: 5.9% (83/1403)	FF/VI 100/25 µg versus usual care	1.1
Vogelmeier, 2016 [41]	AFFIRM (24 weeks)	Post-bronchodilator FEV₁ <80% pred CAT total score ≥10	Investigator reported	FP/SAL 500/50 µg twice daily: 1.9% (9/466)	ACL/FOR 400/12 µg twice daily: 0.6% (3/467)	FP/SAL versus ACL/FOR	3.2
Zheng, 2015 [42]	NCT01376245 (24 weeks)	Asian patients Post-bronchodilator FEV₁ ≤70% pred mMRC dyspnoea score ≥2	Investigator reported	FF/VI 50/25 µg: 1.3% (2/160) FF/VI 100/25 µg: 0.6% (1/161) FF/VI 200/25 µg: 3.1% (5/160)	Placebo: 2.5% (4/162)	FF/VI 50/25 µg versus placebo	0.5
						FF/VI 100/25 µg versus placebo	0.3
						FF/VI 200/25 µg versus placebo	1.3
Zhong, 2015 [43]	LANTERN (26 weeks)	Post-bronchodilator FEV₁ ≥30% and <80% pred ≤1 moderate/severe exacerbation in the year prior to screening mMRC dyspnoea score ≥2	Investigator reported	FP/SAL 500/50 µg: 2.7% (10/369)	IND/GLY 110/50 µg: 0.8% (3/372)	FP/SAL versus IND/GLY	3.4
Rossi, 2014 [44]	INSTEAD (26 weeks)	GOLD stage II 0 moderate/severe exacerbation in the year prior to screening	Investigator-reported pneumonia SAEs	FP/SAL 500/50 µg twice daily: 0.7% (2/288)	IND 150 µg once daily: 0 (0/293)	FP/SAL versus IND
Wedzicha, 2014 [45]	FORWARD (48 weeks)	Post-bronchodilator FEV₁ ≥30% and <50% pred ≥1 moderate/severe exacerbation in the year prior to screening	Investigator reported	BDP/FOR 200/12 µg twice daily: 3.8% (23/601)	FOR 12 µg twice daily: 1.8% (11/596)	BDP/FOR versus FOR	2.1
Dransfield, 2013 [46], Crim, 2015 [47]	NCT01009463, NCT01017952 (52 weeks)	Post-bronchodilator FEV₁ <70% pred ≥1 moderate/severe exacerbation in the year prior to screening	Investigator reported	FF/VI 200/25 µg once daily: 6.8% (55/811) FF/VI 100/25 µg once daily: 6.3% (51/806) FF/VI 50/25 µg once daily: 5.9% (48/820)	VI 25 µg once daily: 3.3% (27/818)	FF/VI 50/25 µg versus VI	1.8
						FF/VI 100/25 µg versus VI	1.9
						FF/VI 200/25 µg versus VI	2.1
Kerwin, 2013 [48]	NCT01053988 (24 weeks)	Post-bronchodilator FEV₁ ≤70% pred mMRC dyspnoea score ≥2	Investigator reported	FF/VI 100/25 µg once daily: 2.4% (5/206) FF/VI 50/25 µg once daily: 1.5% (3/206) FF 100 µg once daily: 1.9% (4/206)	VI 25 µg once daily: 2.4% (5/205) Placebo: 1.4% (3/207)	FF/VI 100/25 µg versus VI	1.0
						FF/VI 50/25 µg versus VI	0.6
						FF versus placebo	1.3
Martinez, 2013 [49]	NCT01054885 (24 weeks)	Post-bronchodilator FEV₁ ≤70% pred mMRC dyspnoea score ≥2	Investigator reported	FF/VI 200/25 µg once daily: 2.0% (4/205) FF/VI 100/25 µg once daily: 0.5% (1/204) FF 200 µg once daily: 1.5% (3/203) FF 100 µg once daily: 1.0% (2/204)	VI 25 µg once daily: 1.0% (2/203) Placebo: 0 (0/205)	FF/VI 200/25 µg versus VI	2.0
						FF/VI 100/25 µg versus VI	0.5
						FF 200 µg versus VI	1.5
						FF 100 µg versus VI	1.0
Doherty, 2012 [50]	(52 weeks)	Post-bronchodilator FEV₁ 25–60% pred Symptoms of COPD for ≥24 months prior to enrolment	Investigator reported	MF/FOR 400/10 µg twice daily: 3.1% (7/225) MF/FOR 200/10 µg twice daily: 1.7% (4/239) MF 400 µg twice daily: 2.0% (5/253)	FOR 10 µg twice daily: 1.6% (4/243) Placebo: 0.8% (2/236)	MF/FOR 400/10 µg versus FOR	1.9
						MF/FOR 200/10 µg versus FOR	1.0
						MF versus placebo	2.3
Tashkin, 2012 [51]	NCT00383435 (52 weeks)	Post-bronchodilator FEV₁ ≥25% and ≤60% pred Symptoms of COPD for ≥24 months	Investigator reported	MF/FOR 400/10 µg twice daily: 1.8% (4/217) MF/FOR 200/10 µg twice daily: 0.5% (1/207) MF 400 µg twice daily: 1.0% (2/210)	FOR 10 µg twice daily: 1.9% (4/209)	MF/FOR 400/10 µg versus FOR	1.0
						MF/FOR 200/10 µg versus FOR	0.3
						MF versus FOR	0.5
Sharafkhaneh, 2012 [52]	NCT00419744 (52 weeks)	Pre-bronchodilator FEV₁ ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening	Investigator reported	BUD/FOR 320/9 µg twice daily: 6.4% (26/407) BUD/FOR 160/9 µg: 4.7% (19/408)	FOR 9 µg twice daily: 2.7% (11/403)	BUD/FOR 320/9 µg versus FOR	2.3
Sharafkhaneh, 2012 [52]	NCT00419744 (52 weeks)		Investigator reported		FOR 9 µg twice daily: 2.7% (11/403)	BUD/FOR 160/9 µg versus FOR	1.7
Calverley, 2010 [53]	NCT00476099 (48 weeks)	Post-bronchodilator FEV₁ 30–50% pred ≥1 moderate/severe exacerbation in the year prior to screening	Investigator reported	BDP/FOR 200/12 µg twice daily: 2.2% (5/232) BUD/FOR 400/12 µg twice daily: 2.9% (7/238)	FOR 12 µg twice daily: 0.4% (1/233)	BDP/FOR versus FOR	5.0
Calverley, 2010 [53]	NCT00476099 (48 weeks)		Investigator reported		FOR 12 µg twice daily: 0.4% (1/233)	BUD/FOR versus FOR	6.9
Rennard, 2009 [54]	NCT00206167 (52 weeks)	Post-bronchodilator FEV₁ ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening mMRC dyspnoea score ≥2	Investigator reported	BUD/FOR 320/9 µg twice daily: 4.0% (20/494) BUD/FOR 160/9 µg twice daily: 3.4% (17/494)	FOR 9 µg twice daily: 3.4% (17/495) Placebo: 5.0% (24/481)	BUD/FOR 320/9 µg versus FOR	1.2
Rennard, 2009 [54]	NCT00206167 (52 weeks)		Investigator reported		FOR 9 µg twice daily: 3.4% (17/495) Placebo: 5.0% (24/481)	BUD/FOR 160/9 µg versus FOR	1.0
Ferguson, 2008 [11]	NCT00144911 (52 weeks)	Post-bronchodilator FEV₁ ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening	Investigator reported	FP/SAL 250/50 µg twice daily: 7.4% (29/394)	SAL 50 µg twice daily: 3.9% (15/388)	FP/SAL versus SAL	1.9
Tashkin, 2008 [55]	NCT00206154 (26 weeks)	Pre-bronchodilator FEV₁ ≤50% pred ≥1 moderate/severe exacerbation in the year prior to screening mMRC dyspnoea score ≥2	Investigator reported	BUD/FOR 320/9 µg twice daily: 0.4% (1/277) BUD/FOR 160/9 µg twice daily: 0.7% (2/281) BUD 320 µg twice daily+FOR 9 µg twice daily: 0.7% (2/287) BUD 320 µg twice daily: 1.1% (3/275)	FOR 9 µg twice daily: 0.4% (1/284) Placebo: 0.3% (1/300)	BUD/FOR 320/9 µg versus FOR	1.0
						BUD/FOR 160/9 µg versus FOR	2.0
						BUD 320 µg+FOR 9 µg versus FOR	2.0
						BUD versus placebo	3.3
Wedzicha, 2008 [56], Calverley, 2011 [57]	INSPIRE (2 years)	Post-bronchodilator FEV₁ <50% pred, mMRC dyspnoea score ≥2, clinical history of exacerbations	Investigator reported	FP/SAL 500/50 µg twice daily: 7.6% (50/658)	TIO 18 µg once daily: 3.6% (24/665)	FP/SAL versus TIO	2.1
Calverley, 2007 [58], Crim, 2009 [59]	TORCH (3 years) (pneumonia incidences from a post hoc analysis focusing on pneumonia are reported here)	Pre-bronchodilator FEV₁ <60% pred	Investigator reported	FP 500 µg twice daily: 14.4% (224/1552) FP/SAL 500/50 µg twice daily: 16.0% (248/1546)	SAL 50 µg twice daily: 10.5% (162/1542) Placebo: 9.0% (139/1544)	FP/SAL versus SAL	1.5
Calverley, 2007 [58], Crim, 2009 [59]		Pre-bronchodilator FEV₁ <60% pred	Investigator reported			FP versus placebo	1.6

ICS: inhaled corticosteroid; LAMA: long-acting muscarinic antagonist; LABA: long-acting β₂-agonist; FEV₁: forced expiratory volume in 1 s; CAT: COPD Assessment Test; BUD: budesonide; GLY: glycopyrronium; FOR: formoterol; MDI: metered-dose inhaler; DPI: dry powder inhaler; TIO: tiotropium; SAL: salmeterol; FP: fluticasone propionate; FF: fluticasone furoate; UMEC: umeclidinium; VI: vilanterol; BDP: beclomethasone dipropionate; mMRC: modified Medical Research Council; SAE: serious adverse event; ACL: aclidinium; IND: indacaterol; GOLD: Global Initiative for Chronic Obstructive Lung Disease; MF: mometasone furoate. ^#: when a study uses different sets of criteria to define pneumonia and reports different pneumonia incidences when using these different criteria, only the pneumonia incidence for the most stringent pneumonia capture method is reported. The corresponding method is summarised in the “pneumonia capture method” column; ^¶: N is the total number of patients in the subgroup of interest, n the number of patients with events; ⁺: fold increase calculated as (incidence in treatment arm of interest)/(incidence in comparator arm).

TABLE 2

Pneumonia incidence determined by clinical end-point committee

Study and treatment group	Patients, n	Pneumonia events submitted to clinical end-point committee, n (%)	Pneumonia events confirmed by clinical end-point committee, n (%)
ETHOS [14]
BUD/GLY/FOR (160/18/9.6 µg)	2124	100 (4.7)	75 (3.5)
BUD/GLY/FOR (320/18/9.6 µg)	2144	115 (5.4)	90 (4.2)
BUD/FOR (320/9.6 µg)	2136	118 (5.5)	96 (4.5)
GLY/FOR (18/9.6 µg)	2125	66 (3.1)	48 (2.3)
KRONOS [26]
BUD/GLY/FOR (320/18/9.6 µg; via MDI)	639	16 (2.5)	12 (1.9)
BUD/FOR (320/9.6 µg; via MDI)	314	7 (2.2)	6 (1.9)
BUD/FOR (400/12 µg; via DPI)	318	6 (1.9)	4 (1.3)
GLY/FOR (18/9.6 µg; via MDI)	625	11 (1.8)	10 (1.6)

BUD: budesonide; GLY: glycopyrronium; FOR: formoterol; MDI: metered dose inhaler; DPI: dry powder inhaler.

Supplementary Materials

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Supplementary material ERR-0124-2021.SUPPLEMENT