T/NK-cell remodeling and IFN-responsive myeloid activation delineate immunometabolic risk profiles in chronic active Epstein-Barr virus disease

Background Chronic active Epstein-Barr virus disease (CAEBV) is a rare EBV-associated T/NK-cell lymphoproliferative disorder characterized by persistent viral infection, systemic inflammation, and highly variable clinical courses. Patients may develop HLH-like hyperinflammation, severe organ involvement, lymphoma transformation, or death, yet current assessment does not fully explain why patients with similar viral burden follow divergent trajectories. Methods We integrated PBMC single-cell RNA-sequencing profiles from healthy controls and CAEBV samples with a retrospective cohort of 130 independent CAEBV patients to connect cellular immune remodeling with clinically measurable features. Results Single-cell analysis identified T/NK remodeling toward cytotoxic, exhaustion-associated, senescence-associated, and metabolically altered states, accompanied by IFN-responsive, antigen-presenting myeloid programs. Ligand-receptor and receiver-side analyses prioritized candidate IFNγ-associated T/NK-to-myeloid communication within this IFN-responsive program, linking NK and CD8+ T-cell states with myeloid inflammatory activation. Guided by these findings, we mapped inflammatory, metabolic, coagulation, and lymphocyte-subset variables into a biology-informed clinical immunometabolic index reflecting inflammatory cytokine activation, metabolic stress, and adaptive immune contraction. Internally defined index strata were associated with increasing CAEBV+HLH, death, and severe-disease burden. Unsupervised clinical mapping further identified three exploratory but interpretable immunometabolic patterns, including immune-metabolically preserved, intermediate immune-contraction, and IFNγ-high immunometabolic high-risk, with distinct immune-cell, inflammatory, metabolic, and outcome profiles. Conclusions Together, these findings organize CAEBV heterogeneity around linked T/NK remodeling, myeloid activation, and systemic immunometabolic stress. This single-cell-informed clinical-pattern map complements EBV-DNA and organ-size assessment and supports prospective validation of clinically measurable, mechanism-guided monitoring and intervention strategies.