Interferon-gamma and C-X-C motif chemokine ligand 9, which is better for haemophagocytic lymphohistiocytosis diagnosis and monitoring?

Interferon-gamma (IFN-γ) and C-X-C motif chemokine ligand 9 (CXCL9) have been implicated as potential biomarkers for haemophagocytic lymphohistiocytosis (HLH); however, which of the two cytokines is better for the diagnosis and monitoring of HLH has not been clarified. We systematically evaluated both markers in HLH and control cohorts. While both IFN-γ and CXCL9 showed marked elevation in HLH patients, a subset (17.0%, 9/53) exhibited normal IFN-γ levels, whereas CXCL9 demonstrated near-universal positivity (98.1%, 52/53) across HLH subtypes. In the differential diagnosis of HLH versus non-Epstein-Barr virus (EBV) infection, both biomarkers showed strong discriminatory capacity with comparable area under curve (AUC) values (IFN-γ: 0.928 vs. CXCL9: 0.948; p = 0.599). However, IFN-γ demonstrated superior diagnostic precision in distinguishing EBV-HLH from infectious mononucleosis (AUC 0.926 vs. CXCL9 0.568; p < 0.001). IFN-γ levels declined to normal levels within 7 days in 85% of treated cases versus only 35% for CXCL9. Persistent CXCL9 elevation demonstrated a robust correlation with disease reactivation. These findings advocate a complementary dual-biomarker strategy-utilizing IFN-γ and CXCL9 for diagnostic confirmation and CXCL9 for therapeutic monitoring-to optimize risk-stratified management of HLH.