| Bias | Author's judgement | Support for judgement |
| Confounding |
Moderate |
Comment: The following review confounders (Age, Gender, Severity-SOFA score ; PaO2 :FiO2, CRP levels) were controlled for in the regression model. Review confounders co-morbidities were not adjusted for however from Table 1 the proportion per arm seems to be balanced. Other confounders less relevant to this study’s context were not controlled for : ethnicity, socio-economic status. |
| Selection of participants into the study |
Serious |
Quote: "28 patients who reached the primary endpoint before admission to RHDU or within 24 hours from admission to RHDU were excluded from the analysis; 20 out of these 28 patients did not start MP treatment." The statistical methods used to adjust for confounding was Multi-variable logistic regression. This is insufficient to account for selection bias introduced. Comment: Study baseline/Time zero is the same for all included patients: admission to RHDU and meeting inclusion criteria into the study. Once admitted/included, if MP was administered it was done so soon after admission according to a prescription protocol. |
| Intervention classification |
Low |
Quote : "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 PA02 : Fi02 > 350mmHg or a CRP < 20mg/L. After which mg/L. After which, oral administration at 16 mg or 20 mg iv twice daily until CRP reached < 20% of % on room air). The MP protocol was developed by the coordinating Center in accordance with the “recommendation for COVID-19 clinical management” by the National Institute for the Infectious Diseases “L. Spallanzani”, Rome. The decision to apply the protocol to COVID-19 was left to the discretion of the treating team for each individual patient. Unexposed patients (controls) were selected from concurrent consecutive COVID-19 patients with the same inclusion and exclusion criteria. Quote : "Data was manually extracted from electronic medical records or charts and anonymously coded onto in a standardized data collection form. Three independent physicians checked the data and two researchers adjudicated any difference in interpretation between the primary reviewers." |
| Deviation from intended intervention |
Serious |
Comment: Table S1 provides data related to the administered co-interventions for each center. Antivirals and HCQ are unbalanced in administration in favor for the control arm. Both are experimental treatments that could influence outcomes. Quote: "Patients in both study groups received standard of care, comprising noninvasive respiratory support, antibiotics, antivirals, vasopressors, and renal replacement therapy as deemed suitable by the healthcare team" |
| Missing data |
Low |
Quote: "There were no missing data with regard neither to the composite primary endpoint and the adjustment factors included in the final Cox models, nor to MV- free days. Available case analysis was performed for time variation of C-reactive protein (CRP) and PaO2:FiO2 levels." Risk assessed to be low for the outcome: Time to death |
| Measurements of outcomes |
Low |
Comment : Outcome assessors were likely aware of the intervention received however the outcomes were objectively measured. Risk assessed to be low for the outcome: Time to death |
| Selection of the reported results |
Low |
Comment: The outcomes and analyses are clearly defined in the Methods section. Both registered protocol and statistical analysis plan are available. |