Eosinophil Granule Proteins in Chronic Rhinosinusitis: A Systematic Review of Biomarker Utility for Disease Characterization and Outcomes

Background/Objectives: Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory condition increasingly understood through endotyping, with eosinophilic CRS (eCRS) representing a clinically distinct and often refractory phenotype. Eosinophils exert their pathogenic effects in part through the release of four highly cationic granule proteins—major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPX), and eosinophil-derived neurotoxin (EDN)—each with distinct biological activities and measurable tissue and systemic expression profiles. Despite growing interest in precision medicine approaches to CRS management, the clinical utility of these granule proteins as biomarkers has not been systematically characterized. This systematic review evaluates the diagnostic and prognostic utility of eosinophil granule proteins as biomarkers in CRS. Methods: This systematic review was conducted per PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) 2020 guidelines and prospectively registered in PROSPERO (CRD420261399189). PubMed, Embase, Web of Science, and Cochrane Library were searched for studies measuring MBP, ECP, EPX, or EDN in tissue, serum/plasma, nasal secretions, lavage fluid, or nasal swabs in adults with CRS, reporting a predefined clinical outcome (endotype/phenotype discrimination, disease severity, recurrence, or postoperative outcomes). Reported statistics were deemed significant if p < 0.05. Meta-analysis was not conducted due to substantial methodological heterogeneity and incomplete outcome reporting across the included studies. Results: Of 708 identified references, 71 studies met inclusion criteria. Of the included studies, 73% were cross-sectional studies, and 24% were cohort studies (prospective or retrospective), with 1% classified as case–control and 1% as a randomized controlled trial. ECP was the most extensively evaluated biomarker, evaluated in 65% of the studies meeting inclusion criteria. Several studies evaluated this protein as a tool to discriminate eosinophilic from non-eosinophilic disease and chronic rhinosinusitis with nasal polyps (CRSwNP) from chronic rhinosinusitis without nasal polyps (CRSsNP), with promising results. EPX was less frequently studied but demonstrated a high diagnostic accuracy, including strong performance in minimally invasive nasal secretion and swab sampling. Several studies demonstrated that granule proteins correlated more consistently with objective radiographic or endoscopic severity than with patient-reported symptom scores. ECP showed reproducible prognostic value for postoperative recurrence and disease control. Conclusions: Eosinophil granule proteins are promising biomarkers for endotyping and prognostication in CRS. Further work is needed to compare the diagnostic accuracy of these proteins directly, to standardize specimen handling and quantification methods, and to establish threshold values suitable for clinical use. Ultimately, large-scale prospective studies will be required to determine whether these biomarkers can reliably prognosticate clinical outcomes and inform selection of candidates for biologic therapy.