Budesonide in the treatment of COVID-19 in an outpatient setting? What we know so far and the role nebulisers can play

According to a pivotal Lancet study (dubbed the STOIC study), the glucocorticoid budesonide could save patients treated in an outpatient setting from severe COVID-19 progression [1]. This report has generated a great deal of interest, as budesonide is widely available, cost-effective and long-established as an asthma medication. Since its publication, the study design of the STOIC study has come under criticism from the medical world. In fact, the interim evaluation of another large study (dubbed the PRINCIPLE study) has delivered less groundbreaking results, but is currently being used to underpin differentiated recommendations in the United Kingdom. The question now arises: Under which circumstances can budesonide treatment be beneficial and when is its use as a nebuliser solution an option?
 

Current study data on budesonide in the treatment of COVID-19: Preliminary data show a positive trend

The STOIC study from Oxford University has generated the following hypothesis: In adults, relatively early administration of inhaled budesonide at the first symptoms of COVID-19 reduced the likelihood of needing intensive or urgent medical care and reduced hospitalisation rates. The study also found that administration of budesonide reduced time to recovery. In the budesonide group, fewer patients were still struggling with persistent symptoms of COVID-19 after 14 and 28 days. [1]

Another study (the PRINCIPLE study) with a larger number of patients, reached the interim conclusion that inhaled budesonide could reduce time to recovery by 3 days. Hospitalisation rates also fell by just under 2 percentage points from 10.3 to 8.5% [2], which would, however, only indicate incremental progress. This study also included more elderly and high-risk patients than the STOIC study. This study barely registered in the media because its outcomes were less spectacular, but it now underpins the first differentiated recommendation in the UK.

The study position can be summarised as follows: The hypothesis now needs to be confirmed in larger studies. Given the intense pressure on healthcare facilities during the COVID-19 pandemic, the question arises whether it may be beneficial to recommended inhaled budesonide now for individual cases, and if so, under which circumstances.
 

Initial statements from professional societies: The UK has a clear recommendation; Germany is still cautious

Budesonide is currently the subject of intense debate in professional circles. According to the president of the DEGAM (Martin Scherer), a low (Grade C) recommendation could be issued for the use of budesonide in COVID-19. He added that the risk-benefit profile should be considered for each individual patient [3]. Other professional societies are still reserved to skeptical on the subject [4].

In the United Kingdom, a consortium including the National Health Service (NHS) issued an interim position statement recommending the use of budesonide - based on the PRINCIPLE study - for patients who meet all of the following criteria:

• Patients with onset of symptoms of COVID-19 within the past 14 days, and symptoms are ongoing.
• COVID-19 confirmed by PCR test within the past 14 days.
• 65 years and over OR 50-64 years with a comorbidity consistent with a long-term health condition from the Flu List [5]

Budesonide is considered safe and cost-effective and is widely available. According to the DEGAM president Prof. Scherer, the decision should be made by the attending physician on a case-by-case basis after carefully considering the risks and benefits. [3]

Some doctors are already making case-by-case decisions, including Dr Thomas Voshaar (Head Physician at the Bethanien Hospital in Moers) in interview with Focus Online. “When the study preview came out a few weeks ago we immediately expanded our standards for treating COVID-19 in an outpatient setting”, Dr Voshaar explained. “Patients who only present with a mild pulmonary infection, who don’t have a high fever, respiratory distress or elevated blood levels and therefore do not need to be hospitalised are given the blood thinner heparin and an antibiotic and now also budesonide for treatment at home” [6] he continues.

Dr Voshaar also suggests there is an initial positive development: “Since we have been using the asthma spray only one of our outpatients has had to be admitted because their condition deteriorated – it used to be more than that.” [6] But he does point out that it is not yet clear if this can actually be attributed to inhalation with budesonide. More studies are required to explore this.
 

Budesonide inhalation also available as a nebuliser solution

In the NDR Corona Update, Prof. Sandra Ciesek points out that budesonide should certainly not be given prophylactically (without the presence of a confirmed COVID diagnosis). She highlights that this would risk a fungal infection in the throat as a known side effect. [7] Dr Thomas Grünewald from Chemnitz Hospital also points out the side effect when used incorrectly. It can also be expected that some patients will not use the medication correctly, as not everyone is able to use a dry powder inhaler (DPI) or an asthma spray (MDI) properly. [8]

For patients who cannot get on with a DPI or MDI, budesonide is also available as a nebuliser solution. Inhalation therapy with a nebuliser does not require the patient to learn any special inhalation techniques. For the drug to reach the lungs, all the patient has to do is calmly breathe in an out.

References

_{[1] Ramakrishnan S et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Medicine Published Online First: 2021. doi: 10.1016/s2213-2600(21)00160-0
[2] Ly-Mee et al. (2021): Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial
[3] https://www.aerztezeitung.de/Podcasts/Sollte-jeder-ambulante-COVID-19-Patient-jetzt-Budesonid-erhalten-418738.html}

[4] Idzko M. et al. (2021): Stellungnahme der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP), der Österreichischen Gesellschaft für Pneumologie (ÖGP) und der Deutschen Gesellschaft für Allergologie und Klinische Immunologie (DGAKI). pneumologie.de/fileadmin/user_upload/COVID-19/20210419_DGP_OEGP_DGAKI__C19_und_ICS__STOIC-Studie.pdf