Identification of Serum Prognostic Biomarkers for 5-Year CVIDc Disease Progression

Background Noninfectious complications in CVID (CVIDc) are highly heterogeneous, characterized by variable end-organ involvement, immune phenotypes, and disease progression among patients. This complexity challenges the feasibility and efficiency of CVIDc clinical trial design and is further compounded by the absence of prognostic biomarkers and surrogate endpoints to predict disease trajectories and assess therapeutic responses. Objectives We sought to determine the relationship between baseline serum biomarkers and 5-year CVIDc disease progression. Methods Serum cytokine levels were measured by ELISA in 83 CVID participants at enrollment. Elevated cytokine levels were defined as values exceeding 2 standard deviations above the mean of healthy controls. Subsequent disease progression was defined as the onset of a CVIDc complication and/or worsening end-organ dysfunction. The association between baseline cytokine markers and CVIDc progression-free intervals was analyzed. Results Of the 83 CVID participants, 65% (n = 54) had CVIDc complications at enrollment. Elevated baseline IFN-ɣ was the strongest predictor of 5-year CVIDc progression (hazard ratio [HR] 6.9, 95% CI 3.9–12.4, P < 0.0001). Elevated baseline BAFF (HR 2.4, 95% CI 1.3–4.4, P < 0.04), TNF-α (HR 2.0, 95% CI 1.04–3.7, P < 0.04), and IL-6 (HR 2.1, 95% CI 1.1–3.9, P < 0.03) were also associated with disease progression, though less strongly. Among participants without baseline CVIDc phenotypes but elevated IFN-γ, 75% (6/8) subsequently developed a complication (lymphoproliferative disease, cancer, or autoimmunity, n = 2 each) within 5 years. CVID lung diseases were previously associated with increased mortality. When lung-specific disease progression was examined, elevated baseline IFN-γ (HR 11.4, 95% CI 3.8-33.7, P = 0.003) and BAFF (HR 8.5, 95% CI 2.9-24.8, P = 0.01) were the strongest predictors, whereas TNF-α showed no significant association despite elevation in many CVIDc participants. Conclusion Elevated baseline IFN-γ is a robust prognostic biomarker for overall CVIDc progression, while both high IFN-γ and BAFF are strongly associated with lung disease progression. These findings suggest their biological relevance in poor CVIDc trajectory and potential as candidate surrogate endpoints for CVIDc clinical trials. Figure 1.