Intravenous anakinra for cytokine storm syndromes

In their Viewpoint on cytokine storm syndromes, Puja Mehta and colleagues¹ stated that “there is a critical need and growing call for unified nomenclature (such as cytokine storm syndromes)”. Although we agree that a multidisciplinary effort is needed to analyse and classify these conditions, we have concerns about unifying them all under a single umbrella. Indeed, cytokine storm syndromes currently encompass several different conditions with extremely varied causes, pathophysiological processes, or prominant cytokines. Although they manifest with similar symptoms, they might have only one truly common feature: hypercytokinaemia.

For instance, haemophagocytic lymphohistiocytosis might be the consequence of deficient cytotoxic cells (primary and some virally-induced haemophagocytic lymphohistiocytosis),² hyperactivation of the inflammasome pathway (NLRC4-associated macrophage activation syndrome),³ or a yet-to-be-defined combination of these factors (eg, Still's disease spectrum). All of these conditions are characterised by elevated plasma concentrations of IL-1 family cytokines (IL-1β and IL-18) and tissue haemophagocytosis. Alternatively, cytokine release syndrome secondary to chimeric antigen receptor T-cell therapy has been linked to high IFN-γ release, whereas the involvement of the IL-1 family cytokines seemed less prominent.⁴ Lastly, it is noteworthy that cytokine storm has attracted great interest, as a result of its description as a major determinant of COVID-19 outcomes. Yet, despite there being no definitive understanding of its immunopathology, a hallmark of COVID-19-associated cytokine storms seems to be prominent IL-6 elevation, with only 25% of patients showing evidence for IL-1-driven macrophage activation or haemophagocytosis.⁵ In the remaining 75% of patients, the disease has been compared with complex immune dysregulation seen in patients with sepsis (ie, prominent role for IL-6, low HLA-DR expression, and lymphopenia).

These considerations are important because the clinicians' armamentarium is now large enough to offer the best targeted therapies in these different contexts (ie, inhibitors of IL-1, IFN-γ, or IL-6). Defining criteria for choosing one treatment over the other, or instead of a less-targeted therapy (eg, corticosteroids or Janus kinase inhibitors) will certainly be one of the challenges of clinical trials in the near future.

Overall, we suggest that if an international, multidisciplinary effort is mounted to unify cytokine storm syndromes within one spectrum, this nomenclature will have to be subdivided on the basis of the cause, the supposed pathophysiology, and the pivotal cytokines involved. In daily practice, the availability of rapid immune monitoring tests (eg, cytokine multiplex assays) would therefore be of utmost interest.