Concomitant IVIG and intermediate-dose methylprednisolone in critically ill patients with severe COVID-19: a retrospective cohort study

Aims: Severe COVID-19 pneumonia with acute respiratory distress syndrome (ARDS) continues to carry high mortality in critically ill patients. During the pre-dexamethasone era, various immunomodulatory strategies were explored. We investigated whether early concomitant intravenous immunoglobulin (IVIG) and intermediate-dose methylprednisolone improved outcomes in ICU patients with severe COVID-19. Methods: Single-centre retrospective cohort study (30 March-14 November 2020) of 178 critically ill adults with laboratory-confirmed severe COVID-19. Eighty-eight patients received IVIG (400 mg/kg/day ×5 days) plus intermediate-dose methylprednisolone (250 mg/day ×5 days) within 7 days of ICU admission in addition to early-pandemic background therapy; 90 patients received background therapy alone. Combination therapy was modelled as a time-dependent covariate in an extended Cox model (primary analysis) with 7-day landmark sensitivity analysis. The primary outcome was in-hospital mortality. Results: Combination therapy was initiated at a median of 4 (IQR 3-6) days after ICU admission. In-hospital mortality was 30.7% in the combination group versus 81.1% in the control group. After multivariable adjustment, combination therapy was independently associated with substantially lower mortality (time-dependent adjusted HR 0.39, 95% CI 0.22-0.68; p<0.001; landmark adjusted HR 0.42, 95% CI 0.23-0.76; p=0.004). No excess nosocomial infections, venous thromboembolism, or renal replacement therapy was observed. Conclusion: In this pre-dexamethasone era ICU cohort, early concomitant IVIG and intermediate-dose methylprednisolone was independently associated with a >60% relative reduction in mortality without evidence of harm. Prospective randomised trials are warranted.