Discrimination of COVID‐19 From Inflammation‐Induced Cytokine Storm Syndromes Using Disease‐Related Blood Biomarkers

Abstract Objectives Infection with the novel coronavirus SARS‐CoV‐2 triggers severe illness with high mortality in a subgroup of patients. Such critical course of coronavirus disease (COVID)‐19 is thought to associate with cytokine storm as in macrophage activation syndrome (MAS) or secondary hemophagocytic lymphohistiocytosis (sHLH), although these specific data are still lacking. In this study we aimed to directly address the question, whether immune activation in COVID‐19 does indeed mimic conditions as in these classical cytokine storm syndromes. Methods We quantified levels of 22 biomarkers in serum samples of COVID‐19 (n=30, n=83 longitudinal samples in total), sHLH/MAS patients (n=50) as well as healthy controls (n=9) using bead array assay as well as single‐marker ELISA and correlated results with disease outcome. Results In sHLH/MAS we observed dramatic activation of the interleukin(IL)‐18‐interferon (IFN)‐γ axis, while increased serum levels of IL‐1 receptor antagonist (IL‐1Ra), intracellular adhesion molecule 1 (ICAM‐1) and IL‐8, as well as strongly reduced levels of soluble Fas ligand (sFasL) in course of SARS‐CoV‐2 infection discriminate immune dysregulation in critical COVID‐19 from the investigated well‐recognized cytokine storm conditions. Conclusions Serum biomarker profiles clearly separate COVID‐19 from MAS or sHLH, which questions the significance of systemic hyperinflammation following SARS‐CoV‐2 infection as well as the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID‐19.