Anakinra for patients with COVID-19

In The Lancet Rheumatology, Giulio Cavalli and colleagues¹ report potential beneficial effects of the IL-1 receptor antagonist anakinra in patients with COVID-19, acute respiratory distress syndrome (ARDS), and hyperinflammation. In the study protocol, anakinra was given in combination with a 4-aminoquinoline and, although promising, we suggest that this combination cannot be fully synergistic in the presence of cytokine release syndrome.

4-aminoquinolines impair the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells by inhibiting lysosomal acidification. However, by blocking autophagosome fusion and degradation, 4-aminoquinoline also blocks autophagy, which is not desirable in the presence of hyperinflammation. Autophagy plays a pivotal role in a number of fundamental biological processes, including ageing, immunity, clearance of viral particles and inflammation, by influencing the survival of inflammatory cells and the secretion of cytokines.² More importantly, autophagy modulates transcription, processing, and secretion of IL-1β, and might control inflammation in part through the degradation of IL-1β³. By contrast, IL-1α and IL-1β have both been shown to induce autophagy, serving as a negative feedback mechanism. Blocking autophagy in patients with the most severe forms of COVID-19 with cytokine release syndrome is probably ineffective, and it could potentially be harmful. Furthermore, recent publications have linked 4-aminoquinolines to an increase in the secretion of IL-1β in some viral infections, in which autophagy serves as a cell-intrinsic mechanism to restrict secretion of IL-1β⁴; nevertheless, this aspect has not been studied in COVID-19 patients.

Notably, induction of autophagy with rapamycin and other stimulators inhibits the secretion of IL-1β via the NLRP3 inflammasome, and thereby decreases inflammation-induced tissue damage. Interestingly, in the context of other coronaviruses, NLRP3 activation has been shown to trigger cytokine storms.⁵ This observation suggests that there is an interplay between SARS-CoV2, autophagy, and cytokine release, and we propose that in future trials, combining anakinra with autophagy inhibitors should be avoided in patients with COVID-19 and evidence of hyperinflammation. It is also reasonable to hypothesise that a combination of anakinra and an autophagy activator should be explored. Although the mechanism needs to be studied further, enhancing autophagy might help to decrease IL-1β production and limit inflammatory cell influx and production of other cytokines, thereby working synergistically with immunomodulatory agents in attenuating the cytokine storm.