Extracorporeal cytokine adsorption as an alternative to pharmacological inhibition of IL-6 in COVID-19.

With great interest we read the article by Convertino et al. discussing potential treatment targets for pharmacological immunomodulation in coronavirus disease 2019 (COVID-19) with acute respiratory distress syndrome (ARDS) [1]. We would like to add to the debate some thoughts about cytokine adsorption, which was mentioned only in passing in this discussion.

Following initial reports describing Interleukin-6 (IL-6) as a predictive factor for a negative outcome, extracorporeal cytokine adsorption was discussed as a possible treatment option for severe COVID-19 cases. Initial experience at our center using the CytoSorb® device (CytoSorbents Europe, Berlin, Germany) in combination with veno-venous extracorporeal membrane oxygenation (V-V ECMO) in severe COVID-19 yielded promising results; cytokine adsorption resulted in a more pronounced decrease of IL-6 after initiation of V-V ECMO as compared to patients treated without cytokine adsorption [2].

The use of the term “cytokine storm” in the context of COVID-19 has been challenged, though. While elevated levels of IL-6 are associated with poor outcome, absolute levels in these cases are rather moderately elevated in comparison to other forms of ARDS with extensive IL-6 increases [3]. Inflammatory dysregulation in severe cases is probably more complex and does not only go along with an upregulation of interleukins or TNF-α but also with an impaired interferon response [4].

A major advantage of extracorporeal cytokine adsorption over the other therapeutic approaches discussed in this debate is that it does not selectively block a specific receptor or signal transduction cascade, but it rather reduces particularly elevated concentrations of various inflammatory mediators such as interleukins, TNF-α, and also interferons; these factors have both pro- and anti-inflammatory functions. Only mildly elevated, physiological, or even decreased concentrations are not relevantly altered; thus, over-suppression of the immune response may be prevented [5]. Furthermore, cytokine adsorption can be better controlled than the other mentioned treatment options—it can be terminated at any time without any specific after-effect. These two aspects may be particularly relevant, e.g., in the case of bacterial superinfection in severe COVID-19 when an adequate immune response is required.

In conclusion, we recommend a cautious approach to intervention or “modulation” in the immune response in COVID-19 patients as long as the pathophysiological background remains to be unveiled. All interventions discussed in this debate should be considered experimental and therefore applied and evaluated within clinical trials.