More evidence against inhaled steroids in COVID

This is part of the ongoing series of articles updating the evidence on current COVID-19 therapies. The rest of the series can be found here, and there is probably more to come. This article will cover the evidence for inhaled steroids in COVID-19.

I already covered the evidence for budesonide in the initial post for this series. At the time, I had not seen any studies looking at other inhaled steroids, and the guidelines all referred to budesonide specifically. It turns out, there are a few studies looking at other inhaled steroids. Evidence from before COVID tells us that all steroids are essentially equivalent, so when thinking about COVID-19, we should probably assess all inhaled steroids as a class. Similarly, if you decide to prescribe inhaled steroids for COVID, I don’t think there is any reason to specifically use budesonide. Use whatever inhaled steroid you usually use. (However, after reading this evidence, I imagine you won’t be using any inhaled steroids at all.)

The Ontario Science Table recommendation

Budesonide is not recommended in moderate or critically ill patients (where we use systemic steroids)

Budesonide is not recommended in mildly ill patients with a low risk of deterioration.

Budesonide may be considered in mildly ill patients with moderate to high risk of deterioration (defined in the document), but base on a low certainty of evidence.

(Full guideline available here)

The evidence for inhaled steroids

To briefly review what was discussed in the budesonide post, there was early observational data that inhaled steroids were associated with an increased mortality from COVID, but that result was probably just from confounders. (Schultze 2020) The STOIC trial was an open-label RCT of 146 patients that demonstrated a decrease in ‘COVID-19 related urgent care visit, emergency department assessment, or hospitalization’. (Ramakrishnan 2021) However, the trial was stopped early without meeting pre-specified criteria, was unblinded, and used the inherently biased ‘COVID-related’ hospital visits as their outcome, and so the results were not persuasive. The PRINCIPLE trial is a large adaptive platform open-label RCT, that did not see a difference in the original primary outcome of COVID related hospitalizations or death. (Yu 2021) They did report a benefit in terms of time to recovery, but this was not an original primary outcome, and a subjective outcome in an unblinded trial is entirely unconvincing. (We would expect to see this benefit due to placebo effect.) Thus, my bottom line was that the evidence was very unconvincing, and I do not routinely prescribe budesonide for COVID-19. However there are a few other trials to discuss.

Clemency and colleagues performed a multi-center double blind RCT comparing 320 ug BID of ciclesonide to placebo in 400 outpatients over the age of 12 with symptomatic, confirmed COVID. (Clemency 2022) Their primary outcome was time to alleviation of symptoms, and was identical in both groups (19.0 vs 19.0 days). There were no deaths in either group. Hospital admission was not statistically different, but the trial may have been under-powered (1.5% vs 3.4%, p=0.26). There was a statistical difference in the composite of emergency department visits or hospitalizations “due to COVID” (1.0% vs 5.4%, p=0.03). However, this is probably a meaningless secondary outcome, not just because of the biased ‘due to COVID’ stipulation, but also because if there was no change in hospitalization, the extra ED visits were by definition among healthy individuals who were able to go home. Bottom line: Unlike the two budesonide trials, this is a properly blinded trial, and there is no difference in symptoms with use of inhaled ciclesonide. 

The CONTAIN trial was a phase 2 placebo controlled RCT that compared inhaled (600 ug BID) and intranasal (200 ug daily) ciclesonide to placebo. (Ezer 2021) They enrolled 215 outpatients with confirmed symptomatic COVID within 6 days of symptom onset. Their primary outcome was self-reported resolution of symptoms by day 7, and there was no difference between the groups (40% vs 35%). The proportion of patients with symptoms resolved at 14 days was also not statistically different (66% vs 58%). There were no deaths. Hospital admission was not statistically different, but were higher with ciclesonide (3% vs 6%), so it is less likely that the trial was just underpowered for this outcome. The trial was stopped early, without meeting a prespecificied end point. Part of the logic was reasonable (fewer enrollments due to dropping COVID case counts), but they also state that the results of the STOIC trial influenced their decision to stop, which seems inappropriate to me. Bottom line: In another blinded RCT, inhaled and intranasal ciclesonide did provide benefit. 

Other comments

Unlike the budesonide studies, both of these studies are blinded and they are clearly negative. I already wasn’t prescribing inhaled steroids before this data, but these studies make me far more confident in that decision.

I was very surprised that, in the introduction of one of the ciclesonide studies, they state that their reason for using ciclesonide is that it inhibits viral replication. In general, we do not consider steroids to be anti-virals. If inhaled steroids are going to have an effect, I would expect it to be the result of their anti-inflammatory action. However, if that is the case, it seems like they would only have an effect in the later stages of disease, and the design of these trials, which focused on early treatment, is misguided. 

I know people are desperately looking for anything to prescribe to patients with COVID. It is worth reading the philosophical interlude in the first post to understand why I think this is a very bad idea.

Bottom line

The best available evidence suggests there is no benefit from inhaled steroids in COVID-19. At this point, they should not be prescribed routintely.

Other FOAMed

Other First10EM COVID therapeutics updates can be found here

Ontario Science Table Recommendations

REBEL EM: The STOIC Trial: Inhaled Budesonide in the Treatment of Early COVID-19

REBEL Cast Ep103: Outpatient COVID-19 Therapy

References

Clemency BM, Varughese R, Gonzalez-Rojas Y, Morse CG, Phipatanakul W, Koster DJ, Blaiss MS. Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA Intern Med. 2022 Jan 1;182(1):42-49. doi: 10.1001/jamainternmed.2021.6759. PMID: 34807241

Ezer N, Belga S, Daneman N, Chan A, Smith BM, Daniels SA, Moran K, Besson C, Smyth LY, Bartlett SJ, Benedetti A, Martin JG, Lee TC, McDonald EG. Inhaled and intranasal ciclesonide for the treatment of covid-19 in adult outpatients: CONTAIN phase II randomised controlled trial. BMJ. 2021 Nov 2;375:e068060. doi: 10.1136/bmj-2021-068060. PMID: 34728476

Ramakrishnan S, Nicolau DV Jr, Langford B, Mahdi M, Jeffers H, Mwasuku C, Krassowska K, Fox R, Binnian I, Glover V, Bright S, Butler C, Cane JL, Halner A, Matthews PC, Donnelly LE, Simpson JL, Baker JR, Fadai NT, Peterson S, Bengtsson T, Barnes PJ, Russell REK, Bafadhel M. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021 Jul;9(7):763-772. doi: 10.1016/S2213-2600(21)00160-0. Epub 2021 Apr 9. Erratum in: Lancet Respir Med. 2021 Jun;9(6):e55. PMID: 33844996

Yu LM, Bafadhel M, Dorward J, Hayward G, Saville BR, Gbinigie O, Van Hecke O, Ogburn E, Evans PH, Thomas NPB, Patel MG, Richards D, Berry N, Detry MA, Saunders C, Fitzgerald M, Harris V, Shanyinde M, de Lusignan S, Andersson MI, Barnes PJ, Russell REK, Nicolau DV Jr, Ramakrishnan S, Hobbs FDR, Butler CC; PRINCIPLE Trial Collaborative Group. 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. Lancet. 2021 Sep 4;398(10303):843-855. doi: 10.1016/S0140-6736(21)01744-X. Epub 2021 Aug 10. Erratum in: Lancet. 2021 Aug 18;: PMID: 34388395

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