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

J Allergy Clin Immunol. 2021 Feb;147(2):561-566.e4. doi: 10.1016/j.jaci.2020.11.006. Epub 2020 Nov 19.


Background: Immunomodulants have been proposed to mitigate severe acute respiratory syndrome coronavirus 2-induced cytokine storm, which drives acute respiratory distress syndrome in coronavirus disease 2019 (COVID-19).

Objective: We sought to determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation.

Methods: A secondary analysis of prospective observational cohort studies was carried out at an Italian tertiary health care facility. COVID-19 patients consecutively hospitalized (February 25, 2020, to March 30, 2020) with hyperinflammation (ferritin ≥1000 ng/mL and/or C-reactive protein >10 mg/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: A total of 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 = .005). Unadjusted and adjusted risk of death was significantly lower for treated patients compared with controls (hazard ratio, 0.33, 95% CI, 0.15-0.74, P = .007, and HR, 0.18, 95% CI, 0.07-0.50, P = .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 the use of either agent alone are needed to confirm these results.

Keywords: COVID-19; SARS-CoV-2; anakinra; anti–IL-1; corticosteroids; hyperinflammation; immunomodulation; mechanical ventilation; methylprednisolone; respiratory failure.

Publication types

  • Observational Study

MeSH terms

  • Aged
  • Anti-Inflammatory Agents / therapeutic use*
  • COVID-19 / complications
  • COVID-19 / mortality
  • COVID-19 / therapy
  • COVID-19 Drug Treatment*
  • Cohort Studies
  • Drug Therapy, Combination
  • Female
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use*
  • Male
  • Methylprednisolone / therapeutic use*
  • Middle Aged
  • Pneumonia / drug therapy*
  • Pneumonia / etiology
  • Pneumonia / mortality
  • Pneumonia / therapy
  • Receptors, Interleukin-1 / antagonists & inhibitors*
  • Respiration, Artificial
  • Respiratory Insufficiency / drug therapy*
  • Respiratory Insufficiency / etiology
  • Respiratory Insufficiency / mortality
  • Respiratory Insufficiency / therapy
  • SARS-CoV-2*


  • Anti-Inflammatory Agents
  • Interleukin 1 Receptor Antagonist Protein
  • Receptors, Interleukin-1
  • Methylprednisolone