Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia

  1. Francesco Salton
  2. Paola Confalonieri
  3. G Umberto Meduri
  4. Pierachille Santus
  5. Sergio Harari
  6. Raffaele Scala
  7. Simone Lanini
  8. Valentina Vertui
  9. Tiberio Oggionni
  10. Antonella Caminati
  11. Vincenzo Patruno
  12. Mario Tamburrini
  13. Alessandro Scartabellati
  14. Mara Parati
  15. Massimiliano Villani
  16. Dejan Radovanovic
  17. Sara Tomassetti
  18. Claudia Ravaglia
  19. Venerino Poletti
  20. Andrea Vianello
  21. Anna Talia Gaccione
  22. Luca Guidelli
  23. Rita Raccanelli
  24. Paolo Lucernoni
  25. Donato Lacedonia
  26. Maria Pia Foschino Barbaro
  27. Stefano Centanni
  28. Michele Mondoni
  29. Matteo Davì
  30. Alberto Fantin
  31. Xueyuan Cao
  32. Lucio Torelli
  33. Antonella Zucchetto
  34. Marcella Montico
  35. Annalisa Casarin
  36. Micaela Romagnoli
  37. Stefano Gasparini
  38. Martina Bonifazi
  39. Pierlanfranco D’Agaro
  40. Alessandro Marcello
  41. Danilo Licastro
  42. Barbara Ruaro
  43. Maria Concetta Volpe
  44. Reba Umberger
  45. Marco Confalonieri

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Abstract

Background

In hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism. We hypothesize that early prolonged methylprednisolone (MP) treatment could accelerate disease resolution, decreasing the need for intensive care unit (ICU) admission and mortality.

Methods

We conducted a multicenter observational study to explore the association between exposure to prolonged, low-dose MP treatment and need for ICU referral, intubation, or death within 28 days (composite primary end point) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels.

Results

Findings are reported as MP (n = 83) vs control (n = 90). The composite primary end point was met by 19 vs 40 (adjusted hazard ratio [aHR], 0.41; 95% CI, 0.24–0.72). Transfer to ICU and invasive MV were necessary in 15 vs 27 (P = .07) and 14 vs 26 (P = .10), respectively. By day 28, the MP group had fewer deaths (6 vs 21; aHR, 0.29; 95% CI, 0.12–0.73) and more days off invasive MV (24.0 ± 9.0 vs 17.5 ± 12.8; P = .001). Study treatment was associated with rapid improvement in PaO2:FiO2 and CRP levels. The complication rate was similar for the 2 groups (P = .84).

Conclusion

In patients with severe COVID-19 pneumonia, early administration of prolonged, low dose MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Treatment was safe and did not impact viral clearance. A large randomized controlled trial (RECOVERY trial) has been performed that validates these findings.

Clinical trial registration. ClinicalTrials.gov NCT04323592.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.06.17.20134031: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: It was registered on Clinicaltrials.gov (NCT043235929) after approval by the referral Ethics Committee for the Coordinating Centre (University Hospital of Trieste, #CEUR-2020-Os-052).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Exposure to methylprednisolone (non-patented drug, ATC code H02AB04) complied with the following protocol: a loading dose of 80 mg iv at study entry (baseline), followed by an infusion of 80 mg/day in 240 mL normal saline at 10 mL/h for at least eight days, until achieving either a PaO2:FiO2 > 350 mmHg or a CRP < 20 mg/L.
    ATC
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    After matching the expression changes induced by SARS-CoV2 in human lung tissue tissues and A549 lung cell line against the expression changes triggered by 5,694 FDA-approved drugs, methylprednisolone was found to be the drug with the greatest potential to revert the changes induced by COVID-19.[22] The safety profile reported in our study is consistent with the findings of multiple RCTs investigating prolonged corticosteroid treatment in thousands of patients with severe sepsis, septic shock and ARDS.[17] In these RCTs, hyperglycemia was transient in response to the initial loading bolus and did not impact negatively on outcome.[17] Viral shedding in both groups of our study was in agreement with international literature.[23, 24] Moreover, there is no evidence linking delayed viral clearance to worsened outcome in critically ill COVID-19 patients, and it is unlikely that it would have a greater negative impact than the host’s own cytokine storm.[25] The observational design of our study implies some obvious limitations, namely a possible restricted control over data collection and potential inclusion biases. However, internal validity was achieved by (1) the comparability of concurrent groups at baseline, (2). accounting for potential confounders into the multivariable Cox regression analyses, and (3) conducting sensitivity analysis to assess for potential bias in outcome ascertainment potentially influenced by medical decision making. Our study’s strengths include a prospec...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04323592CompletedMethylprednisolone for Patients With COVID-19 Severe Acute R…
    NCT043235929Trial number did not resolve on clinicaltrials.gov. Is the number correct?NA

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1093/ofid/ofaa421
  3. Version published to 10.1101/2020.06.17.20134031v2 on medRxiv
  4. ScreenIT

    SciScore for 10.1101/2020.06.17.20134031: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIt was registered on Clinicaltrials . gov ( NCT043235929 ) after approval by the referral Ethics Committee for the Coordinating Centre ( University Hospital of Trieste , #CEUR-2020-Os-052) .Randomizationnot detected.BlindingLimitations of the study is that we did not control for center effects and site investigators were not blinded to treatment as with any observational study.Power Analysisnot detected.Sex as a biological variablenot detected.Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    After matching the expression changes induced by SARS-CoV2 in human lung tissue tissues and A549 lung cell line against the expression changes triggered by 5,694 FDA-approved drugs, methylprednisolone was found to be the drug with the greatest potential to revert the changes induced by COVID-19.22 The safety profile reported in our study is consistent with the findings of multiple RCTs investigating prolonged corticosteroid treatment in thousands of patients with severe sepsis, septic shock and ARDS.
    A549
    suggested: None
    Software and Algorithms
    SentencesResources
    Exposure to methylprednisolone ( non-patented drug , ATC code H02AB04 ) complied with the following protocol: a loading dose of 80 mg/kg iv at study entry ( baseline) , followed by an infusion of 80 mg/day in 240 mL normal saline at 10 mL/h for at least eight days , until achieving either a PaO2:FiO2 > 350 mmHg or a CRP < 20 mg/L .
    ATC
    suggested: None

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

    • The observational design of our study implies some obvious limitations, namely a possible restricted control over data collection and potential inclusion biases.
    • However, internal validity was achieved by (1) the comparability of concurrent groups at baseline,
    • Limitations of the study is that we did not control for center effects and site investigators were not blinded to treatment as with any observational study.
    • Despite these limitations, we believe that our findings represent valid and generalizable conclusions, and evidence will be further strengthened with a RCT.

    Results from OddPub: We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  5. Version published to 10.1101/2020.06.17.20134031v1 on medRxiv