Beyond the Storm: CXCL9 and the New Era of Precision Hemophagocytic Lymphohistiocytosis Diagnostics

Hemophagocytic lymphohistiocytosis (HLH) is associated with high mortality, underscoring the importance of rapid diagnosis and treatment. However, accurate and timely diagnosis is challenging due to its similarities with other acute inflammatory conditions. Traditional diagnostic frameworks rely on fever, lymphadenopathy, cytopenias, hyperferritinemia, hypofibrinogenemia, and related laboratory abnormalities, many of which may reflect either HLH or the underlying condition that triggered or mimics it. Newer diagnostics have emerged that are based on the underlying disease biology, particularly interferon-gamma (IFN-γ)-driven immune activation. C-X-C motif chemokine ligand 9 (CXCL9), a downstream marker of IFN-γ activity, has emerged as a promising adjunctive biomarker for HLH diagnosis, risk stratification, monitoring treatment response, and detection of disease reactivation. This narrative review examines the current evidence surrounding CXCL9 and its role in HLH.