Circulating Calprotectin and Other Neutrophil Activation Biomarkers in Sepsis: Mechanisms, Diagnostic and Prognostic Utility, and Translational Perspectives

Neutrophil activation biomarkers have attracted increasing interest as potential indicators of host-response activation, organ dysfunction, and prognosis in sepsis. This narrative review critically examines the biological mechanisms, diagnostic and prognostic evidence, analytical limitations, and translational potential of circulating calprotectin and other neutrophil activation biomarkers, including heparin-binding protein (HBP), neutrophil gelatinase-associated lipocalin (NGAL), other granule-derived proteins, neutrophil extracellular trap (NET)-associated markers, and cellular activation markers. Particular emphasis is placed on circulating calprotectin, an S100A8/S100A9 complex that can be rapidly released during myeloid activation and also participates in inflammatory signaling. Available studies suggest potential diagnostic and prognostic applications, but reported performance varies with clinical setting, sepsis definition, patient population, and analytical methodology. These biomarkers provide complementary information on degranulation, organ injury, and cellular phenotypes, although their clinical utility remains incompletely validated. No single biomarker in this group is currently sufficiently validated for routine standalone sepsis diagnosis or biomarker-guided treatment decisions. Future research should prioritize analytical standardization, prospective multicenter validation, and the demonstration of incremental clinical value beyond established diagnostic and prognostic approaches.