To the Editor:
Meta-analyses have the advantage of providing a summary effect estimate when there are a number of methodologically homogenous studies that examine the same intervention in the same study populations. Forty-five days after the publication of the Recovery trial,1 a meta-analysis of eight randomized trials (7,184 participants) was published,2 and a corresponding WHO guideline panel subsequently recommended systemic corticosteroids in patients with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence).3
In contrast, the systematic review and metanalysis published in CHEST (March 2021) by Cano et al4 includes only one randomized controlled trial1 and 72 observational studies, analyzed together, with a search end date of July 22, 2020. Of the observational studies, only four reported outcomes of propensity score-matched populations. Even with adjustment or propensity-matching, observational studies are subjected to residual cofounding (imbalances in baseline characteristics and post-baseline time-dependent patient differences that influence the decision to prescribe corticosteroids) and other sources of bias. Given this, the Cochrane handbook specifically discourages meta-analysts from pooling randomized controlled trials and observational studies together given, the method heterogeneity. Based on their analysis, the authors of this review concluded that “the potential role for corticosteroids as an immunomodulatory agent in COVID-19 needs to be explored further in clinical trials.”
The authors also combined studies without a predefined treatment protocol with preregistered trials that used an established and explicit corticosteroid protocol. Unsurprisingly, Cano et al4 were unable to generate conclusions around optimal dosing, indication, and timing of corticosteroids across studies.
Nevertheless, despite the limitations in their analysis, we agree with Cano et al4 that there is a need for further studies that will examine corticosteroids in COVID-19. Specifically, more data are needed that evaluate the impact of type of corticosteroid, timing of initiation, dose, mode of administration, duration, and dose tapering on patient-important outcomes.5 Further exploration of laboratory parameters of oxygenation and inflammation and how they may be incorporated into corticosteroid treatment protocols would also be important. The MEDEAS trial (Methylprednisolone vs. Dexamethasone in COVID-19 Pneumonia trial, ClinicalTrials.gov Identifier: NCT04636671) will address this issue by comparing the RECOVERY randomized controlled trial protocol to a protocol similar to the one investigated in an Italian prospective observational study.6
Footnotes
FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.
Editor's Note: Authors are invited to respond to Correspondence that cites their previously published work. Those responses appear after the related letter. In cases where there is no response, the author of the original article declined to respond or did not reply to our invitation.
References
- 1.RECOVERY Collaborative Group. Horby P., Lim W.S. Dexamethasone in hospitalized patients with Covid-19: preliminary report. N Engl J Med. 2021;384(8):693–704. doi: 10.1056/NEJMoa2021436. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Sterne J.A.C., The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: A meta-analysis. JAMA. 2020;324(13):1330–1341. doi: 10.1001/jama.2020.17023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Rochwerg B., Siemieniuk R.A., Agoritsas T. A living WHO guideline on drugs for covid-19. BMJ. 2020;370:m3379. doi: 10.1136/bmj.m3379. [DOI] [PubMed] [Google Scholar]
- 4.Cano E.J., Fonseca Fuentes X., Corsini Campioli C. Impact of corticosteroids in coronavirus disease 2019 outcomes: systematic review and meta-analysis. Chest. 2021;159(3):1019–1040. doi: 10.1016/j.chest.2020.10.054. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Meduri G.U., Annane D., Confalonieri M. Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS. Intensive Care Med. 2020 doi: 10.1007/s00134-020-06289-8. In press. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Salton F., Confalonieri P., Meduri G.U. Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia. Open Forum Infect Dis. 2020;7(10):ofaa421. doi: 10.1093/ofid/ofaa421. [DOI] [PMC free article] [PubMed] [Google Scholar]