Current evidence on the use of anakinra in COVID-19

Abstract

Despite the progressing knowledge in COVID-19 management, remdesivir is the only agent that got approval to inhibit viral replication. However, there are limited data about effective immunomodulatory agents to prevent cytokine release in COVID-19. Cytokine release syndrome in COVID-19 resembles secondary hemophagocytic lymphohistiocytosis, in which interleukin-1 (IL-1) plays a key role. Anakinra is the first recombinant IL-1 receptor antagonist studied for off-label use in COVID-19 treatment. This study reviews the current clinical evidence on the role of interleukin-1 in COVID-19-related cytokine storm, therapeutic effects, significant clinical concerns, and pros and cons of anakinra administration in the management of COVID-19 patients. In this review, four items are shown to be important for achieving the optimal therapeutic effects of anakinra in COVID-19 patients. These items include duration of treatment ≥ 10 days, doses ≥ 100 mg, intravenous administration, and early initiation of therapy. Also, anakinra might be more beneficial in the early stages of the disease when higher levels of cytokines are yet to be observed, which could prevent progression to severe illness and mechanical ventilation. Further studies are required to address the SARS-CoV-2 induced cytokine release syndrome and the role of anakinra in identifying ideal treatment approaches for COVID-19 patients based on their clinical status.

Keywords: Acute respiratory distress syndrome; Anakinra; COVID-19; Cytokine release syndrome; Interleukin-1; Multiple organ failure.

Fig. 1

The effects and blockade of interleukin-1 (IL-1) signaling by anakinra. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the epithelial cells of the lungs and destruction of cells leads to IL-1α release, which in turn recruits neutrophils and monocytes and promotes IL-1β release from monocytes/macrophages. Furthermore, SARS-CoV-2 directly leads to IL-1β release from monocytes/macrophages and neutrophils. Both IL-1α and IL-1β bind to IL-1 receptors. Accordingly, MyD88, IL-1 receptor-associated kinase 4 (IRAK4), and nuclear factor kappa B (NFκB) are phosphorylated. NFκB stimulates the transcription of pro-inflammatory genes. Anakinra blocks IL-1 receptors and inhibits the binding of IL-1α and IL-1β, thus preventing the signaling pathway. DIC, disseminated intravascular coagulation; MOF, multiple organ failure.