Plasma calprotectin as a severity biomarker in pediatric invasive Streptococcus pyogenes infections: insights from a multicenter immune profiling study during an outbreak

PURPOSE: To characterize the immune signature of pediatric invasive Streptococcus pyogenes infections (iGAS) and identify host biomarkers associated with disease severity. METHODS: Plasma samples (n = 32) were collected during an iGAS outbreak from a multicentric Spanish pediatric cohort, including patients with iGAS (n = 19), S. pyogenes acute tonsillitis (n = 3), and healthy children/controls (n = 10). Patients were monitored and stratified based on the need of pediatric intensive-care unit (PICU). A panel of 56 soluble markers -including cytokines, chemokines, immune-checkpoints, antimicrobial peptides, growth factors, and vascular inflammation, myeloid and thrombosis markers- were quantified in plasma. RESULTS: Regardless of disease severity, children with S. pyogenes infection exhibited a systemic inflammatory profile characterized by an upregulation of vascular inflammation markers. Patients with iGAS requiring PICU admission were mostly infected by emm1 S. pyogenes harboring speA and speJ genes and exhibited an immune profile characterized by alterations in CXCL10, IL-6, IL-10, IL-17A, sCD14, sCD40L, calprotectin, angiopoietin 2 and HGF. Area under the ROC curve analysis revealed that calprotectin and IL-6 exhibited the best classificatory performance for PICU admission (p < 0.01; AUC = 0.90 and AUC = 0.91, respectively), with an optimal Youden cut-off for calprotectin of 2753 ng/mL. A logistic regression model integrating both biomarkers and routine clinical parameters revealed an independent association between calprotectin levels and PICU admission. CONCLUSION: Pediatric iGAS is characterized by a complex immune landscape involving a combination of vascular and immune response mediators. Plasma calprotectin levels emerge as a promising severity biomarker, potentially aiding in the early identification of high-risk patients.