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A reappraisal of corticosteroids use for COVID-19

Published:August 15, 2022DOI:https://doi.org/10.1016/j.ejim.2022.08.019
      Dear Editor,
      The current evidence suggests that the rapid clinical progression of the Coronavirus Disease 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is closely related to the hyperinflammatory syndrome resulting from a dysregulated host innate immune response [
      • Gustine J.N.
      • Jones D.
      Immunopathology of Hyperinflammation in COVID-19.
      ]. Not surprisingly, aside from active antiretroviral therapy, this has prompted the development of anti-inflammatory therapies for the treatment of patients with COVID-19, and among them the use of corticosteroids in hospitalized patients has been object of numerous clinical investigations, with inconsistent results [
      • Russell C.D.
      • Millar J.E.
      • Baillie J.K.
      Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.
      ,
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • Linsell L.
      RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with Covid-19—Preliminary report.
      ,
      • Jeronimo C.M.P.
      • Farias M.E.L.
      • Val F.F.A.
      • Sampaio V.S.
      • Alexandre M.A.A.
      • Melo G.C.
      Metcovid Team
      Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus disease 2019 (COVID-19; Metcovid): a randomized, double-blind, Phase IIb, placebo-controlled trial.
      ,
      The Writing Committee for the REMAP-CAP Investigators
      Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 Corticosteroid Domain randomized clinical trial.
      ,
      • Tomazini B.M.
      • Maia I.S.
      • Cavalcanti A.B.
      • Silva M.V.A.O.
      • Baldassare F.P.
      • Costa E.L.V.
      • et al.
      Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial.
      ]. At the beginning of the SARS-CoV-2 pandemic, the World Health Organization (WHO) advised against systematic use of corticosteroids in COVID-19 patients [
      • Russell C.D.
      • Millar J.E.
      • Baillie J.K.
      Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.
      ]. However, after the publication of RECOVERY trial [
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • Linsell L.
      RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with Covid-19—Preliminary report.
      ], the WHO changed its original suggestion and recommended the use of corticosteroids in patients with severe COVID-19 [

      Corticosteroids for COVID-19: living guidance, 2 September 2020. Available at: https://apps.who.int/iris/handle/10665/334125 (last visited July, 11, 2022).

      ]. Since then, a huge number of controlled clinical trials have been conducted in order to evaluate the efficacy and safety of corticosteroids for COVID-19 patients, and others are underway or in development. Because of the great amount of clinical data available, several systematic reviews (SRs) and meta-analysis have been published in the last years. Their conclusions are, however, quite inconsistent and reflect the wide heterogeneity between different studies in terms of design, conduct, and reporting. The current study is an overview of systematic reviews, also called umbrella review [
      • Aromataris E.
      • Fernandez R.
      • Godfrey C.M.
      • Holly C.
      • Khalil H.
      • Tungpunkom P.
      Summarizing systematic reviews: methodological development, conduct and reporting of an umbrella review approach.
      ], and is aimed to reappraise the validity of the conclusions of the SRs and meta-analyses related to corticosteroids use for the treatment of COVID-19.
      We considered for inclusion in this umbrella review SRs that included randomized controlled trials (RCTs) and non-RCTs (i.e., prospective, retrospective, cross-sectional, cohort studies and case series) evaluating the safety and efficacy of corticosteroids in COVID-19 patients. We considered SRs on COVID-19 at any stage of disease severity, from asymptomatic/pauci-symptomatic to life-threatening cases, and in any setting (outpatients and hospitalized patients). Treatment with corticosteroids at any dose, timing and frequency was compared to standard of care or placebo. We included the following outcomes: overall mortality, viral clearance, clinical progression, length of hospital stay, adverse reactions. Where available, we reported also results of subgroup analyses based on the severity of COVID-19 and on the design of the studies included in the SRs. Relevant studies in four bibliographic databases (Embase, PubMed, Web of Science, and Cochrane) were searched as of June 2022, using Medical Subjects Heading: (“COVID-19″ OR “SARS-CoV-2″) AND (“systematic review” OR “meta-analysis”).
      For the quantitative synthesis, we reported the effect size (odds ratio [OR], risk ratio [RR], risk difference [RD], Hazard ratio [HR] or risk difference [RD] with the 95% confidence intervals (CI), as reported in individual reviews, and the main conclusions of each systematic review/meta-analysis. The quality of evidence was appraised following the GRADE approach (Grades of Recommendation, Assessment, Development, and Evaluation), applied in its five domains (risk of bias, indirectness, imprecision, inconsistency, and publication bias) [

      Schünemann H., Brożek J., Guyatt G., Oxman A., ed. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach (updated October 2013). GRADE Working Group, 2013. Available from gdt.guidelinedevelopment.org/app/handbook/handbook.html 2013.

      ].
      The electronic and manual search retrieved 4202 references After the full texts were scrutinized against the inclusion and exclusion criteria, 35 SRs were included in the umbrella review (references available upon request to corresponding author). The 35 SRs included 307 overlapping reports (98 RCTs and 209 non-RCTs), based on 121 individual primary studies. The primary studies included 25 RCTs, 84 controlled non-RCTs, and 12 uncontrolled studies (single arm studies, including case series and case reports). Thirty-four SRs focused on systemic steroids as treatment of COVID-19, while one review was focused on inhaled use of steroids.
      The main findings of this umbrella review can be summarized as follows: (1) In critically ill patients, including those requiring invasive mechanical ventilation and those with ARDS, the use of steroids therapy was found significantly more effective in reducing mortality compared to SOC in 80% of the SRs (12 out of 15 SRs) reporting this outcome, more often with moderate/high level of certainty (7/12). (2) When the comparison included patients with different severity of infection (from severe to critical), the results were more heterogeneous, and a decrease in mortality was reported in only 52% of the SRs. (3) In patients not requiring oxygen supplementation the use of steroids compared to controls increased the overall mortality in 4 out of 6 comparisons (66.6%). (4) Rate of clinical progression of diseases (defined as need for mechanical ventilation, intensive care unit admission, or as a clinical progression composite score) were significantly higher in patients receiving standard of care compared to steroids recipients in 64.2% of the SRs reporting this outcome; the available evidence was graded from very-low to moderate. (5) In more than 80% of the SRs the occurrence of adverse events (serious adverse events, any adverse events, gastrointestinal bleeding, secondary infections and hyperglicemia) was similar among steroids recipients and controls. However, these findings can be biased because adverse events were often not reported in the systematic reviews and, when reported, there was often inconsistency in describing type and severity of adverse events. As expected, the quality of the evidence was on average higher in SRs of RCTs only. Moreover, compared to SRs including RCTs+non-RCTs and non-RCTs, SRs including RCTs only reported more commonly a reduction of mortality in steroids recipients than in controls (Table 1).
      Table 1Effects of corticosteroids on mortality. Main characteristics and results of the 33 SRs reporting mortality included in the umbrella review.
      Footnotes. RCT, randomized clinical trial; SARS, severe acute respiratory syndrome; MERS, Middle East respiratory syndrome; pts, patients; OR, odds ratio; RR, risk ratio; RD, risk difference; HR, hazard ratio; ROB, Risk of bias; SOC, standard of care. ICU, intensive care unit; LOS, length of hospital stay. na, not available.
      *Green flag, the effect size favors steroids compared to controls in a significant way; Yellow flag, no significant differences between steroids recipients and control; Red flag, the effect size favors controls compared to steroids in a significant way.
      Umbrella reviews assemble together several systematic reviews on the same condition, and allow to consider for inclusion the highest level of evidence available, namely other systematic reviews and meta-analyses [
      • Ioannidis J.P.
      Integration of evidence from multiple meta-analyses: a primer on umbrella reviews, treatment networks and multiple treatments meta-analyses.
      ]. Overall, patients receiving corticosteroids with coronavirus diseases in the early phase of the epidemic were more likely to be critically ill; hence, there was a significant selection bias in non-RCTs included in the SRs. In this extremely uncertain and changing context, typical of emergency situations such as those of the COVID-19 pandemic, it is evident that even SRs and meta-analyses have produced heterogeneous results. For the outcome most commonly reported, overall mortality, it was possible to perform subgroup analysis of SRs according to study design and severity of COVID-19 at baseline. It was also clear that most of the included studies (both RCTs and non-RCTs) were at risk of bias and showed important clinical, methodological and statistical heterogeneity. Other outcomes (i.e., viral clearance, and length of hospital stay) were addressed by only a minority of SRs with a high level of uncertainty, so that no definitive conclusions can be drawn. Likewise, some of the SRs addressed the issue of the optimal dose (e.g., pulse-dose, high and low-dose steroids) and type of steroids (e.g., dexamethasone, methylprednisolone, hydrocortisone) to be used for the treatment of COVID-19. In this respect the data available from primary studies and SRs are heterogeneous and sparse, so no firm conclusion can be drawn, but the interest in this area of research is timely and relevant, and several clinical trials evaluating the use of corticosteroids for the treatment of COVID-19 are underway or in development.
      In conclusion, there is moderate certainty of evidence that corticosteroids reduce mortality and progression of disease in critically ill COVID-19 patients compared to standard of care.

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