Serum Biomarkers Help in the Differential Diagnosis of Hyperferritinemic Cytokine Storm Syndromes in Children

biomarker blood test
biomarker blood test
Researchers defined and validated serum biomarker profiles to differentiate between primary hemophagocytic lymphohistiocytosis (HLH), secondary HLH, and macrophage activation syndrome associated with systemic juvenile idiopathic arthritis.

High serum concentrations of S100A12 may suggest an initial differential diagnosis of systemic juvenile idiopathic arthritis (JIA) when it is unclear whether a pediatric patient with excessive hyperferritinemic inflammation has primary or secondary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS), according to research results published in the Lancet Rheumatology.

Researchers conducted a multicenter, retrospective, cohort study to define and validate the profiles of serum biomarkers that help in the differentiation of primary HLH, secondary HLH, and MAS linked with systemic JIA (JIA-MAS).

Serum samples were collected from 43 pediatric patients (0-18 years; 24 girls); 10 patients had active primary HLH, 12 patients had secondary HLH, 11 patients had systemic JIA-MAS, and 10 patients were healthy control participants. Immunoassays were used to analyze the serum samples for 55 cytokines and chemokines, and 15 serum biomarkers were validated using an independent commercial assay. In addition, an independent validation cohort of 79 patients (45 boys) was used to test the diagnostic accuracy of the best-performing biomarkers. 

Of the 10 biomarkers that were found to be differentially elevated in HLH or systemic JIA-MAS and differentiated between these conditions, 6 biomarkers were tested in the independent validation group. Researchers found that serum concentrations for S100A12, interleukin (IL)-18, and ratios of IL-18 to chemokine (C-X-C motif) ligand (CXCL) 9, IL-18 to CXCL10, S100A12 to CXCL9, and S100A12 to CXCL10 were the most promising biomarkers for differential diagnosis.

“Our data provide additional support for the ability of IL-18, CXCL9, and particularly S100A12 in distinguishing between different disease entities that are associated with a life-threatening cytokine storm,” the authors wrote. “These findings can support an early differential diagnosis between systemic JIA-MAS and HLH and thus can help to guide treatment decisions.”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Kessel C, Fall N, Grom A, et al. Definition and validation of serum biomarkers for optimal differentiation of hyperferritinaemic cytokine storm conditions in children: a retrospective cohort study. Lancet Rheumatol. Published online June 8, 2021. doi:10.1016/s2665-9913(21)00115-6