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Caution When Comparing the Impact of Corticosteroids in COVID-19

      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,
      • Horby P.
      • Lim W.S.
      • et al.
      RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with Covid-19: preliminary report.
      a meta-analysis of eight randomized trials (7,184 participants) was published,
      • 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.
      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).
      • Rochwerg B.
      • Siemieniuk R.A.
      • Agoritsas T.
      • et al.
      A living WHO guideline on drugs for covid-19.
      In contrast, the systematic review and metanalysis published in CHEST (March 2021) by Cano et al
      • Cano E.J.
      • Fonseca Fuentes X.
      • Corsini Campioli C.
      • et al.
      Impact of corticosteroids in coronavirus disease 2019 outcomes: systematic review and meta-analysis.
      includes only one randomized controlled trial
      • Horby P.
      • Lim W.S.
      • et al.
      RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with Covid-19: preliminary report.
      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 al
      • Cano E.J.
      • Fonseca Fuentes X.
      • Corsini Campioli C.
      • et al.
      Impact of corticosteroids in coronavirus disease 2019 outcomes: systematic review and meta-analysis.
      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 al
      • Cano E.J.
      • Fonseca Fuentes X.
      • Corsini Campioli C.
      • et al.
      Impact of corticosteroids in coronavirus disease 2019 outcomes: systematic review and meta-analysis.
      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.
      • Meduri G.U.
      • Annane D.
      • Confalonieri M.
      • et al.
      Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS.
      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.
      • Salton F.
      • Confalonieri P.
      • Meduri G.U.
      • et al.
      Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia.

      References

        • Horby P.
        • Lim W.S.
        • et al.
        • RECOVERY Collaborative Group
        Dexamethasone in hospitalized patients with Covid-19: preliminary report.
        N Engl J Med. 2021; 384: 693-704
        • 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: 1330-1341
        • Rochwerg B.
        • Siemieniuk R.A.
        • Agoritsas T.
        • et al.
        A living WHO guideline on drugs for covid-19.
        BMJ. 2020; 370: m3379
        • Cano E.J.
        • Fonseca Fuentes X.
        • Corsini Campioli C.
        • et al.
        Impact of corticosteroids in coronavirus disease 2019 outcomes: systematic review and meta-analysis.
        Chest. 2021; 159: 1019-1040
        • Meduri G.U.
        • Annane D.
        • Confalonieri M.
        • et al.
        Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS.
        Intensive Care Med. 2020; (In press)
        • Salton F.
        • Confalonieri P.
        • Meduri G.U.
        • et al.
        Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia.
        Open Forum Infect Dis. 2020; 7: ofaa421

      Linked Article

      • Impact of Corticosteroids in Coronavirus Disease 2019 Outcomes: Systematic Review and Meta-analysis
        CHESTVol. 159Issue 3
        • Preview
          Our results showed evidence of mortality benefit in severely ill COVID-19 patients treated with corticosteroids. Corticosteroids are used widely in COVID-19 patients worldwide, and a rapidly developing global pandemic warrants further high-quality clinical trials to define the most beneficial timing and dosing for corticosteroids.
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      • Response
        CHESTVol. 160Issue 2
        • Preview
          We appreciate the interest in our article1 by Confalonieri et al. The authors emphasize caution when combining retrospective and prospective studies into a meta-analytic synthesis. We agree with the authors that confounders often hinder observational studies; however, we also have firsthand experience during this pandemic that high-quality evidence often lags the clinical demand to treat patients.
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