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Three Part Question

In [adults with COVID-19] is [inhaled budesonide given in the community] useful for [reducing future emergency department or urgent care visits and hospitalization]?

Clinical Scenario

You are discharging a 52-year-old man who tested positive for COVID-19 recently from the emergency department. He lives in a remote area and asks you if there’s anything else you can give him to help “stay away from the hospital”. You vaguely remember some reports on inhaled budesonide and wonder whether prescribing an inhaler would help.

Search Strategy

Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations and Daily <1946 to January 20, 2023>
1 budesonide.mp. or exp Budesonide/ 7057
2 (corticosteroid or corticosteroids).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 119569
3 (corticoid or corticoids).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 6162
4 adrenal cortex hormone.mp. or exp Adrenal Cortex Hormones/ 420956
5 glucocorticoid.mp. or exp Glucocorticoids/ 236131
6 (COVID-19 or SARS-CoV-2).mp. 317798
7 (2019-nCoV Infection or 2019 nCoV Infection or 2019-nCoV Infections).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 194

8 (2019-nCoV or 2019 nCoV or 2019-nCoV).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 2756
9 emergency department.mp. or exp Emergency Service, Hospital/ 157700
10 (emergency room or ER or ED).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 223597
11 (accident and emergency).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 11584
12 (AE or A&E).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 30092
13 hospitalization.mp. or exp Hospitalization/ 393035
14 (admission or admit).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 251820
15 inhaled.mp. 50831
16 (inhaler or inhalation).mp. [mp=title, book title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 141407
17 nebulizer.mp. or exp "Nebulizers and Vaporizers"/ 14843
18 1 or 2 or 3 or 4 or 5 505283
19 16 or 17 or 18 171444
20 6 or 7 or 8 326345
21 9 or 10 or 11 or 12 or 13 or 14 878713
22 18 and 19 and 20 and 21 105

Search Outcome

A total of 105 papers were found in the initial search. Using two independent reviewers, two papers were deemed relevant to the research question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Ramakrishnan et al. 2021 United Kingdom	A total of 146 community members (adults >18 years old with both symptoms of and confirmed COVID-19 within the past 7 days) were randomized to usual care [symptomatic treatment with Tylenol, non-steroidal anti-inflammatory drugs (NSAIDs), and honey] (n=73) or inhaled budesonide (400 ug per actuation, 2 puffs twice daily) (n=73).	Open-label Randomized Control Trial (RCT)	COVID-19-related urgent care visits, including emergency department (ED) assessment or hospitalization	From intention to treat analysis (ITT), ED visits or hospitalization occurred less often in the budesonide group vs. the usual care group. (3% vs 15% respectively, difference in proportions 0.12, 95% CI 0.03 to 0.21; p=0.009). The number needed to treat (NNT) with inhaled budesonide to reduce COVID-19 ED-related visits was 8. From per-protocol analysis, ED visits or hospitalization occurred less often in the budesonide group vs. the usual care group. (1% to 14%, 95% CI 0.04-0·22; p=0.004), representing a relative risk reduction of 91% for budesonide.	- small sample size and study stopped early due to pandemic control measures, limiting recruitment from outside the local region. - outcome based on ED or hospitalization “related to SARS-CoV-2 infection”. No mention of how this distinction is made in paper or appendix, or if researchers or decision makers were blinded to treatment arms - pandemic measures in the UK stated that community members were to contact a government telephone advice line before attending ED, with COVID-19 specific general practice hubs also available. This may have contributed to already low ED/urgent care visits. - risk of differential misclassification bias across intervention groups due to lack of blinding, leading to co-intervention, compliance, and/or contamination. - unclear how many patients were fully vaccinated to COVID-19; stratified analysis based on vaccine status with a larger population would have helped guide treatment recommendations. - multiple authors received funding/grants/personal fees from AstraZeneca, main manufacturer for Pulmicort
Yu, M.L., et al. 2021 United Kingdom	A total of 4700 patients were randomly assigned to either budesonide (400 ug per actuation, 2 puffs twice daily, n=1073); usual care alone (symptom management with antipyretics, n=1988); or other treatments (n=1639).	Open-label, multi-arm, prospective RCT	COVID-19-related hospital admission within 28 days	Hospital admission rate was 6.8% (95% Bayesian Credible Interval (BCI) 4.0- 10.2) in the budesonide group versus 8.8% (95% BCI 5.5-12.7) in the usual care group (estimated absolute difference 2.0% [95% BCI 0.2- 4.5]; odds ratio 0.75 [95% BCI 0.55-1.03])	- outcome based on “hospital admission or death due to possible SARS-CoV-2 infection”. No mention of how this distinction is made in paper or appendix, or if researchers or decision makers were blinded to treatment arms - predominantly Caucasian (>90%) study population, limiting generalizability. - exclusion criteria only entailed patients with previous inhaled or systemic steroid use or allergies, no mention of previous COVID-19 infections, biologics, or anti-viral usage. - budesonide group did not meet the pre-specified superiority threshold for the COVID-19-related hospital admission or death outcome (0.975)

Comment(s)

Budesonide is an accessible outpatient adjunct with a good safety profile. However, the research was completed prior to widespread vaccination, and the perceived benefit of inhaled budesonide within a vaccinated population is unknown. Furthermore, the trials had many potential sources of bias, which could have overestimated results.

Clinical Bottom Line

Inhaled budesonide (800 mcg INH BID for 14 days) is a safe but expensive option to consider at a community level with limited evidence at reducing ED or urgent care visits among adults suffering from suspected or confirmed COVID-19 infections.

References

1. Ramakrishnan, S, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial The Lancet Respiratory Medicine 2021 Jul;9(7):763-772
2. Yu, M.L., et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial The Lancet 2021 Sept; P843-855