Anakinra combined with methylprednisolone in patients with severe COVID-19 pneumonia and hyperinflammation: an observational cohort study

Background Immunomodulants have been proposed to mitigate SARS-Cov-2-induced cytokine storm, which drives acute respiratory distress syndrome in COVID-19. Objective To determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation. Methods Secondary analysis of prospective observational cohort studies at an Italian tertiary health-care facility. COVID-19 patients consecutively hospitalized (02/25/2020 to 03/30/2020), with hyperinflammation (ferritin ≥1000ng/mL and/or C-reactive protein >10mg/dL) and respiratory failure (oxygen therapy from 0.4 FiO2 Venturi mask to invasive mechanical ventilation) were evaluated to investigate the effect of high-dose anakinra plus methylprednisolone on survival. Patients were followed from study inclusion to day 28 or death. Crude and adjusted (sex, age, baseline PaO2:FiO2 ratio, Charlson Index, baseline mechanical ventilation, hospitalization to inclusion lapse) risks were calculated (Cox proportional regression model). Results 120 COVID-19 patients with hyperinflammation (median age 62 years, 80.0% males, median PaO2:FiO2 ratio 151, 32.5% on mechanical ventilation) were evaluated. Of these, 65 were treated with anakinra and methylprednisolone and 55 were untreated historical controls. At 28 days, mortality was 13.9% in treated patients and 35.6% in controls (Kaplan-Meier plots, p=0.005). Unadjusted and adjusted risk of death was significantly lower for treated patients compared to controls (HR 0.33 (95%CI 0.15-0.74), p=0.007 and HR 0.18 (95%CI 0.07-0.50), p=0.001, respectively). No significant differences in bloodstream infections or laboratory alterations were registered. Conclusions Treatment with anakinra plus methylprednisolone may be a valid therapeutic option in COVID-19 patients with hyperinflammation and respiratory failure, also on mechanical ventilation. Randomized, controlled trials including use of either agent alone are needed to confirm these results.