Expert panel consensus recommendations on the utilization of nebulized budesonide for managing asthma and COPD in both stable and exacerbation stages in Thailand

Figures & data

Figure 1. PRISMA diagrams summarizing the literature search process for asthma (A) and COPD (B) studies. DPI: dry powder inhaler; pMDI: pressurized metered dose inhaler; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1. Clinical studies assessing the efficacy and/or safety of nebulized budesonide in adults with asthma.

Publication	Country	Design	Patients, n	Age, years	Population	Treatment group(s)	Key outcomes
Nematollahi et al. (88)	Iran	RCT	228	Mean, 36.79 ± 0.727	Post-rain asthma with dyspnea	Salbutamol (5 mg × 3 in 20 min) plus budesonide 0.5 mg × 3 in 20 min) vs salbutamol alone	There was greater improvement in PEFR at 40 and 60 min in the budesonide plus salbutamol group compared with the salbutamol group (p < 0.001). However, there were no significant differences in FEV1 at 0, 20, 40, 60 min between the groups.
Marghli et al. (2022) (44)	Tunisia	Randomized, placebo-controlled, double-blind trial	50	18–50	Acute exacerbation	100 mg IV hydrocortisone plus 0.5 mg budesonide four times daily vs 100 mg IV hydrocortisone alone	There was no significant difference in PEF, respiratory rate, heart rate, and rate of hospitalization between the two treatment groups
Ito et al. (2020) (43)	Japan	Retrospective cohort study	98	22–92	Severe exacerbation	SCS plus LABA vs SCS plus LABA plus 0.25 mg budesonide four times daily	The use of budesonide was associated with a shortened length of hospital stay, reduced symptoms, and reduced medical costs
Sheikh-Motahar-Vahedi et al. (2019) (42)	Iran	RCT	41	Mean, 55.7 (budesonide); 60.3 (placebo)	Moderate-to-severe exacerbation	Budesonide vs placebo	Heart rate, respiratory rate and O2 saturation were improved significantly in the budesonide group vs placebo (p < 0.05)
Vogelmeier et al. (2015) (41)	Germany	Randomized, placebo-controlled, double-blind trial; open-label budesonide arm	199	18–65	Severe persistent, OCS-dependent asthma	0.5 or 1 mg budesonide twice daily administered with AKITA as add-on therapy to standard care	Budesonide applied with AKITA resulted in a significant reduction in daily OCS dose, significant improvement in FEV1, with fewer patients experiencing asthma exacerbations compared with placebo
Chian et al. (2011) (40)	Taiwan	Retrospective cohort study	28	Mean, 25.8 ± 12.0	Severe exacerbation	2 × 2 mg budesonide twice daily vs 2 × 15 mg oral prednisolone twice daily	Improvements in PEF, FEV1 and daytime symptom scores were similar in both treatment groups
Murphy et al. (2007) (39)	USA	Randomized, active-controlled study	758	12 to <17; 17 to <65; ≥65 years	Moderate-to-severe persistent asthma; previously received inhaled corticosteroids via a pMDI or DPI	Budesonide 0.5 mg once daily, 1 mg once daily, 1 mg twice daily, 2 mg twice daily; 400 µg twice daily via DPI (active control)	There was no significant difference in mean change from baseline in FEV1 between budesonide 0.5 mg once daily and 2 mg twice daily groups (0.02 vs 0.01 L, respectively). All budesonide dosage groups experienced similar responses for variables associated with asthma control including FVC, asthma symptom scores, rescue medication use, PEF, percentages of symptom-free and rescue medication-free periods
Shah et al. (2006) (38)	USA	Randomized, placebo-controlled, single blind study	13	21–72	Outpatient asthma	0.25 or 0.5 mg budesonide once daily vs SCS	Treatment with nebulized budesonide had no significant effect on mucociliary clearance or FEV1
Ediger et al. (2006) (37)	Turkey	RCT	30	Mean, 47.1 +/- 2.1	Acute exacerbation	4 mg/day budesonide vs 1 mg/kg/day methylprednisolone vs budesonide plus methylprednisolone	Nebulized budesonide successfully improved airway obstruction and symptoms in patients hospitalized with acute asthma exacerbations as early as day 1 or 2 of treatment
Otulana et al. (1992) (36)	UK	Open-label trial	18	19–62	Steroid-dependent asthma	4–8 mg/day budesonide	Budesonide treatment resulted in increased mean FEV1 (1.9 +/- 0.9 to 2.2 +/- 0.9 L), and mean PEFR (238 +/- 119 to 286 +/- 130 L/min) and significantly decreased number of hospital admissions for acute severe asthma (1.5 +/- 1.8 to 0.9 +/- 1.1 per year)

AKITA: novel computer-controlled: compressor-driven inhalation system; DPI: dry powder inhaler; FEV₁: forced expiratory volume in 1 s; IV: intravenous; LABA: long-acting: ß₂-agonist; OCS: oral corticosteroid; PEFR: peak expiratory flow rate; pMDI: pressurized metered-dose inhaler; RCT: randomized controlled trial; SCS: systemic corticosteroid; UK: United Kingdom; USA: United States of America.

Table 2. Clinical studies assessing the efficacy and/or safety of nebulized budesonide in adults with COPD.

Publication	Country	Design	Patients, n	Age, years	Population	Treatment group(s)	Key outcomes
Hashemian et al. (2018) (53)	Iran	RCT	55	Mean, 55.7 ± 14.7 (budesonide); 57.3 ± 18.4 (control)	COPD stage 4, difficult-to-wean from mechanical ventilation	0.5 mg budesonide/day vs placebo	Budesonide significantly reduced the number of days on mechanical ventilation vs placebo (p = 0.014), and reduced BAL CXCL-8 and IL-6 levels vs placebo (p < 0.05). Dynamic compliance was significantly improved in the budesonide group (day 3, p = 0.018; day 5, p = 0.011)
Gu et al. (2022) (59)	China	Cost effectiveness analysis	291	45–80	AECOPD	0.5 mg budesonide three times/day vs 40 mg IV methylprednisolone once daily	Clinical efficacy rates were similar in the budesonide and methylprednisolone groups
Nguyen et al. (2021) (58)	USA	Retrospective cohort study	128	41–85	AECOPD	SCS plus budesonide vs SCS monotherapy	Daily corticosteroid dose increases, progression in ventilatory support, in-hospital mortality, and COPD 30-day readmissions were similar in the two groups. However, patients in the combination therapy arm had longer lengths of hospital stay (p = 0.04).
Aghili et al. (2020) (57)	Iran	RCT	84	>18	AECOPD	0.5 mg budesonide three times/day vs 50 mg oral prednisolone	A significant increase in PEFR was observed in the budesonide and prednisolone groups (p = 0.032 and 0.008, respectively). The upward trend of PEFR in the budesonide group was significantly better than that of the prednisolone group during 24 h of treatment (p = 0.005).
Chen et al. (2020) (56)	China	Post hoc analysis of retrospective cohort study [Zhang et al. (2018)]	3646	≥40	AECOPD	Budesonide vs SCS vs budesonide plus SCS	Following propensity score matching, budesonide plus SCS was associated with greater length of hospital stay and greater hospitalization costs than the other two treatments in patients without respiratory failure (p < 0.001)
Zhang et al. (2020) (55)	China	RCT	321	>50	AECOPD	4 mg budesonide/day (1 mg every 6 h) vs 8 mg budesonide/day (2 mg every 6 h) vs 8 mg budesonide/day (4 mg every 12 h)	High dose budesonide (8 mg/day) improved pulmonary function and symptoms more effectively than the conventional dose of budesonide (4 mg/day) in the early treatment of AECOPD, especially when given as 4 mg twice daily. No differences were observed between the groups in rates of adverse effects, hospital stay length, and frequency of exacerbations within 3 months of discharge.
Zheng et al. (2019) (54)	China	Post hoc analysis of Zhang et al. 2018 (89)	3121	>40	AECOPD	Budesonide vs SCS	Initial budesonide or SCS treatment resulted in similar outcomes in terms of improvements in FEV1, PaO2, SaO2, and PaCO2. When the groups were stratified according to whether the initial treatment was subsequently intensified or reduced, the budesonide maintenance/reduction group showed the lowest mortality rate
Jiang et al. (2017) (52)	China	RCT	86	45–78	AECOPD	250 µg ipratropium bromide plus 1 mg budesonide twice daily (observation group) vs saline (control group)	Serum TNF-α, IL-6, and CRP levels in the observation group were significantly lower than those of the control group. FVC, FEV1, PaO2, SaO2 and respiratory failure index were significantly higher than those in the control group, while PaCO2 levels were lower. The clinical efficacy (clinical curative effect) of the observation group was significantly better than that of the control group (p < 0.05); ventilation time and total treatment time was significantly shorter (p < 0.05)
Ding et al. (2016) (51)	China	RCT	410	60–80	AECOPD	2 mg budesonide three times/day vs 40 mg IV methylprednisolone once daily	There were no significant differences in improvements in symptoms, pulmonary function and arterial blood gas analysis between the two groups. However, the incidence of adverse events in the budesonide group was lower (p < 0.05). Patients treated with methylprednisolone showed a higher degree of PaO2 level improvement.
Sun et al. (2015) (50)	China	RCT	30	>50	AECOPD	3 mg budesonide twice daily vs 40 mg IV methylprednisolone once daily for three days and oral methylprednisolone 8 mg twice daily	There were no significant differences in improvements in symptoms, pulmonary function and blood gas analysis between the two groups. There were no significant differences of IL-8, TNF-α and hs-CRP levels between the two groups. The incidence of adverse events (heart rate, blood pressure, hyperglycemia, sleep condition, gastrointestinal symptoms) was lower in the budesonide group than the methylprednisolone group (p < 0.05)
Ucar et al. (2014) (49)	Turkey	RCT	86	>40	AECOPD	SCS vs 4 mg budesonide/day vs 8 mg budesonide/day	There were no significant differences between the groups for any of the parameters evaluated (PaO2, PaCO2, SaO2, FVC, FEV1, including the incidence of adverse events. This was true at all post-baseline timepoints (24 h, 48 h, discharge).
Gunen et al. (2007) (48)	Turkey	RCT	159	Mean, 63.5 ± 10.1 (group 1); 64.9 ± 7.1 (group 2); 63.9 ± 9.7 (group 3)	AECOPD	Standard bronchodilator treatment (group 1) vs 40 mg prednisolone/day (group 2) vs 1.5 mg budesonide four times/day (group 3)	Arterial blood gases and spirograms recovered faster in groups 2 and 3 than group 1. Blood glucose exhibited an upward trend only in group 2.
Mirici et al. (2007) (47)	Turkey	Randomized, placebo-controlled, double-blind trial	40	Mean, 63.06 (budesonide); 64.8 (prednisolone)	AECOPD	8mg budesonide/day vs IV prednisolone 40 mg/day	There were no significant differences between groups for all parameters (PEFR, PaO2, PaCO2, SaO2, pH) at all timepoints. No adverse events were recorded in either group.
Maltais et al. (2002) (46)	Canada	Randomized, placebo-controlled, double-blind trial	199	Mean, 69.1 ± 8.7 (budesonide) ;70.4 ± 7.7 (prednisolone); 70.4 ± 8.9 (placebo)	AECOPD	2 mg budesonide every 6 h vs 30 mg oral prednisolone every 12 h vs placebo	Improvements in FEV1 and airflow were similar in the budesonide and prednisolone groups. The occurrence of serious adverse events was also similar except that there was a higher incidence of hyperglycemia in the prednisolone group.
Morice et al. (1996) (45)	UK	RCT	19	Mean, 50	AECOPD	2 mg budesonide twice daily vs 30 mg oral prednisolone once daily	Improvement in mean FEV1 over the 5-day study was similar in both groups (budesonide: 1.9 to 2.0 L; prednisolone: 1.8 to 2.1 L). Biochemical markers associated with SCS-induced osteoporosis (serum osteocalcin, urinary calcium to creatinine ratio) were significantly lower in patients treated with budesonide than in those who received prednisolone.

AECOPD: acute COPD exacerbation; BAL: bronchoalveolar lavage; CRP: C-reactive protein; IL: interleukin; IV: intravenous; LABA: long-acting ß₂-agonist; PaCO₂: partial pressure of arterial carbon dioxide; PaO₂: partial pressure of arterial oxygen; PEFR: peak expiratory flow rate; FVC: forced vital capacity; RCT: randomized controlled trial; SaO₂: arterial oxygen saturation; SCS: systemic corticosteroid; TNF: tumor necrosis factor UK: United Kingdom; USA: United States of America.

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Data availability statement

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.