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Three Part Question

[In adult patients with confirmed COVID-19 infection] does [inhaled budesonide] lead to [reduced mortality and/or reduced time to recovery]?

Clinical Scenario

A 70-year-old woman presented to the Emergency Department with hypoxia and confusion. Her chest X-ray findings are consistent with severe COVID-19 pneumonia. COVID-19 infection was confirmed with RT-PCR testing. A colleague mentions inhaled budesonide as a possible treatment. You wonder if inhaled budesonide would reduce mortality or time to recovery. You also wonder if it is associated with increased adverse events.

Search Strategy

Medline using OVID interface
EMBASE using OVID interface
Medline using PubMed
Cochrane Library
Further Google Scholar search to ensure no missing relevant material

PubMed:
("inhaled budesonide"[All Fields]) AND ("Covid-19"[All Fields] OR "coronavirus"[All Fields] OR "Severe acute respiratory syndrome coronavirus 2"[All Fields] OR "SARS-CoV-2"[All Fields] OR "2019 novel coronavirus"[All Fields] OR "2019-nCoV"[All Fields] OR "coronavirus disease 2019"[All Fields]) AND (hasabstract[text] AND ("2019/12/01"[PDAT] : "3000/12/31"[PDAT]) AND English[lang])

OVID:
(exp * inhaled budesonide/ or inhaled budesonide.mp.) and ((Covid-19 or coronavirus or Severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 or 2019 novel coronavirus or 2019-nCoV or coronavirus disease 2019).mp. LIMIT to (english language and yr="2019 -Current")


Cochrane:
inhaled budesonide AND COVID-19

Google Search:
(inhaled budesonide) AND (Covid-19 OR coronavirus OR Severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2 OR 2019 novel coronavirus OR 2019-nCoV OR coronavirus disease 2019) LIMIT to English AND Human

Search Outcome

Pubmed: 19 results of which 2 relevant
Medline: 22 papers no new relevant research found
EMBASE: 177 papers no new relevant research found
Cochrane: 9845 trials found but no new published research
Google Scholar: no new relevant papers found

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Ramakrishan et al April 9, 2021 United Kingdom	146 adults aged older than 18 years with symptoms of COVID-19 (new onset cough and fever or insomnia, or both) within 7 days	RCT, 'Open-label' Trial	COVID-19-related urgent care visit, including emergency department assessment or hospitalization	1% of participants (vs. 14%; p=0.004).	Open-label study. Trial stopped early. No placebo-controlled group. Exclusion of older population with more comorbidities.
			Self-reported clinical recovery (symptom resolution)	Time to recovery 7 days (vs. 8 days; p=0.007).
			Viral symptoms measured using the Common Cold Questionnaire (CCQ) and the InFLUenza Patient Reported Outcome Questionnaire (FLUPro)	Mean total score change was better (p=0.044).
			Blood oxygen saturations.	No significant difference.
			SARS-CoV-2 viral load	No significant difference.
Yu et al August 10, 2021 United Kingdom	4700 adults aged at least 65 years or at least 50 years with comorbidities and had ongoing symptoms from PCR-confirmed or suspected COVID-19, which had started within the previous 14 days	RCT, 'Open-label' Trial, multicenter study	Time to first self-reported recovery.	Benefit of 2.94 days (vs. 11.8 days; p <0.01).	Open-label study. No blinding. Budesonide group did not meet superiority threshold for the hospitalization or death outcome. Small proportion of the study population had received a SARS-CoV-2 vaccine, which might underpower the analysis.
			Hospital admission or death related to COVID-19, within 28 days.	Estimated rate of hospital admission or death was 6.8% (vs. 8.8%; p=0.037)

Comment(s)

Inhaled budesonide is an inhaled glucocorticoid often used in the treatment of asthma and chronic obstructive pulmonary disease. Initial investigation of inhaled budesonide as a treatment for COVID-19 by Ramakrishnan et al.1 found that early administration in the COVID-19 disease course can significantly reduce the likelihood of a patient needing urgent medical care (1 (1%) of 69 participants in the budesonide group; p=0.004) and significantly reduce time to recovery (1 day shorter in budesonide group; p=0.007). Follow-up investigation by Yu et al.2 also concluded that administration of inhaled budesonide significantly reduced time to recovery in patients who received treatment (2.94 days shorter; p <0.01). They were unable to conclude with significance if treatment with inhaled budesonide would decrease the rate of hospitalization or death in COVID-19 patients. The study by Ramakrishnan et al.1 was limited by being an open-label study that was stopped early and lacked a placebo control. The study by Yu et al.2 was limited by being an open-label study that lacked blinding. Both studies showed strong safety with a limited number of adverse events in the treatment groups. Ramakrishnan et al.1 reported 5 adverse events and Yu et al.2 reported 2 adverse events.

Clinical Bottom Line

Current evidence suggests that inhaled budesonide could be a safe and effective treatment for reducing COVID-19 positive patients’ time to recovery and their possible need for emergency medical care. More evidence is needed to conclude if budesonide is an effective treatment for reducing mortality in this patient population.

References

1. Ramakrishan et al Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial
2. Yu 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