Definition and validation of serum biomarkers for optimal differentiation of hyperferritinaemic cytokine storm conditions in children: a retrospective cohort study

BackgroundCytokine storm syndromes are life-threatening complications that can occur in children with rheumatic conditions (macrophage activation syndrome [MAS]), inherited cytotoxicity defects (ie, primary haemophagocytic lymphohistiocytosis [HLH]), or as a result of infection malignancies secondary HLH). To adequately steer treatment, an early and clear discrimination these entities is essential. We aimed to define validate serum biomarker profiles differentiate between HLH, HLH (predominantly infection-associated), MAS associated systemic juvenile idiopathic arthritis (systemic JIA-MAS).MethodsIn this multicentre, retrospective, cohort study, samples from patients (0–18 years) clinical diagnosis JIA-MAS were analysed by immunoassays for 55 cytokines chemokines. Serum collected treated at seven centres Europe North America. 15 biomarkers validated using independent commercial assay, the diagnostic accuracy best performing was tested validation cohort.FindingsSerum Dec 7, 2010, Jan 26, 2018. In discovery 43 (24 girls 19 boys) multi-marker analyses revealed distinct versus JIA-MAS. Ten identified differentially elevated either distinguished entities, six which 79 (34 45 boys). concentrations S100A12 interleukin-18, well ratios both IL-18 chemokine (C-X-C motif) ligand (CXCL)9 CXCL10 most promising candidates differential diagnostics.InterpretationAt initial presentation, when it unclear whether patient excessive hyperferritinaemic inflammation has infection-associated MAS, high indicate JIA-MAS, thus helping guide subsequent treatment decisions. therefore suggest inclusion investigations syndromes; however, definition introduction universially applicable cutoff values still required.FundingGerman Research Foundation, Center Interdisciplinary Clinical University Hospital Muenster, EU's Horizon 2020 research innovation programme, Deutsche Kinderkrebsstiftung. Cytokine JIA-MAS). cohort. diagnostics. At required.