Intravenous methylprednisolone pulse therapy and the risk of in-hospital mortality among acute COVID-19 patients: Nationwide clinical cohort study

Steroids are widely used to modulate the inflammatory reactions associated with coronavirus disease 2019 (COVID-19); however, the optimal upper limit dose of steroid use for acute COVID-19 care remains unclear and currently available data may suffer from a time-dependent bias of no effectiveness or reversed causation given the desperate situation of treatment during this pandemic. Accordingly, the aim of this study was to elucidate the impact of intravenous pulse therapy with methylprednisolone (500 mg or greater per day) on the risk of in-hospital mortality among patients with COVID-19 by controlling for time-dependent bias.We performed a prospective cohort study with 67,348 hospitalised acute COVID-19 patients at 438 hospitals during 2020-2021 in Japan. The impact of intravenous methylprednisolone pulse therapy on the risk of in-hospital mortality was examined based on hazard ratios (HRs) and 95% confidence intervals (95% CIs), with stratification according to the status of invasive mechanical ventilation (iMV). Time-dependent bias was controlled for in a marginal structural model analysis, with reference to patients without methylprednisolone therapy.During the study period, 2400 patients died. In-hospital mortality rates of iMV-free patients without or with methylprednisolone pulse therapy were 2.3% and 19.5%, and the corresponding values for iMV-receiving patients were 24.7% and 28.6%, respectively. The marginal structural model analysis showed that intravenous pulse therapy with methylprednisolone was associated with a lower risk of in-hospital mortality among patients receiving-iMV (HR 0.59; 95% CI 0.52-0.68). In contrast, pulse therapy with methylprednisolone increased the risk of in-hospital mortality among iMV-free patients (HR 3.38; 95% CI 3.02-3.79). The benefits of pulse therapy for iMV-receiving patients were greater than in those treated with intermediate/higher doses (40-250 mg intravenously) of methylprednisolone (HR 0.80; 95% CI 0.71-0.89).The results of our study suggest that intravenous methylprednisolone showed dose-response efficiencies, and pulse therapy may benefit critically ill patients with acute COVID-19, such as those requiring iMV.