Highways to hell: Mechanism-based management of cytokine storm syndromes

Since the first textbook devoted to cytokine storm syndromes (CSSs) was published in 2019, the world has changed dramatically and the term's visibility has broadened. Herein, we define CSSs broadly to include life/organ-threatening systemic inflammation and immunopathology regardless of the context in which it occurs, recognizing that the indistinct borders of such a definition limit its utility. Nevertheless, we are focused on the pathomechanisms leading to CSSs, including impairment of granule-mediated cytotoxicity, specific viral infections, excess IL-18, and chimeric antigen receptor T-cell therapy. These mechanisms are often reflected in distinct clinical features, functional tests, and/or biomarker assessments. Moreover, these mechanisms often indicate specific, definitive treatments. This mechanism-focused organization is vital to both advancing the field and understanding the complexities in individual patients. However, increasing evidence suggests that these mechanisms interact and overlap. Likewise, the utility of a broad term such as "cytokine storm" is that it reflects a convergence on a systemic inflammatory phenotype that, regardless of cause or context, may be amenable to "inflammo-stabilization." CSS research must improve our appreciation of its various mechanisms and their interactions and treatments, but it must also identify the signs and interventions that may broadly prevent CSS-induced immunopathology.