ABSTRACT
Background: Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening hyperinflammatory syndrome that occurs after primary SARS-CoV-2 infection. The pathogenesis of MIS-C remains undefined, and whether specific inflammatory biomarker patterns can distinguish MIS-C from other hyperinflammatory syndromes including Kawasaki disease (KD) and macrophage activation syndrome (MAS) is unknown.Methods: We studied a prospective cohort of nineteen MIS-C and nine KD patients and an established cohort of eleven new onset SJIA and nine MAS associated SJIA patients. Clinical and laboratory features as well as S100A8/A9, S100A12, IL-18, CXCL9 and IL-6 levels were compared between disease groups.Findings: KD and MIS-C patients have similar S100 proteins and IL-18 profiles but are distinguished by significantly higher levels of the IFN-γ-induced chemokine CXCL9 in MIS-C. Stratifying MIS-C patients by CXCL9 levels revealed differential severity of clinical and laboratory presentation. MIS-C with high CXCL9 levels was associated with acute kidney injury, altered mental status, a higher frequency of shock (40 vs 90%), myocardial dysfunction (20 vs 50%), and more severe systemic inflammatory markers, cytopenia, and coagulopathy. The low CXCL9 MIS-C group in contrast resembled KD patients including the frequency of coronary involvement. We also found that elevated S100A8/A9, S100A12 and IL-18 were useful in distinguishing SJIA from KD with high sensitivity and specificity.Interpretation: Our findings show MIS-C is distinguished from KD primarily by elevated CXCL9. The stratification of CXCL9 levels of MIS-C patients provides support for MAS pathophysiology in patients with severe MIS-C, suggesting new approaches for diagnosis and management.Funding: This work was supported by an Academic Research Clinical (ARC) award to AG and GS from the Cincinnati Children’s Research Foundation. GS was supported by NIAMS/NIH K08-AR072075, AG by P30-AR070549, and JRS and GC by T32-AR069512. EV was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG/448863690).Declaration of Interests: AG has served as a consultant and received research support from Novartis, Sobi, NovImmune and AB2Bio. GS consulting fees from Novartis and SOBI. All other authors report no disclosures.Ethics Approval Statement: The study was approved by the Institutional Review Board (CCHMC IRB2018-2408).