Cytokine and Metabolomic Signatures of Mepolizumab Response Across Upper and Lower Airway Compartments in Severe Eosinophilic Asthma: An Exploratory Analysis

Background: Mepolizumab improves asthma control in severe eosinophilic asthma (SEA). However, its multidimensional effects on airway and systemic biomarkers are still incompletely understood. Methods: In this prospective study, 15 SEA patients were evaluated at baseline (T0), 6 (T6), and 12 months (T12) after starting mepolizumab. Lung function, FeNO values, asthma control, blood eosinophil count (BEC), cytokines, and metabolomic profiles (1H-NMR) were evaluated in serum, nasal secretions, and exhaled breath condensate (EBC). Univariate and multivariate (PCA, OPLS-DA) analyses were performed. Results: Mepolizumab reduced exacerbations, from a median of 2 at T0 to 0 at both T6 (p = 0.001) and T12 (p = 0.003). ACT improved from 18.7 ± 4.7 at baseline to 23.0 ± 2.8 at T6 (p = 0.026) and 23.4 ± 3.3 at T12 (p = 0.032), while FEV1 increased by 270 mL at T6 (p = 0.032) and remained stable at T12. Median BEC decreased from 450.0 (350.0–560.0) to 65.0 (50.0–87.5) cells/μL at T6 and to 50.0 (35.0–160.0) at T12 (p < 0.001), while FeNO showed a non-significant downward trend. IL-13 significantly decreased in serum and nasal secretions at T6 and T12, while IL-5 increased in nasal secretions at both timepoints and remained unchanged in serum. IL-2 showed opposite trends in serum and nasal samples, whereas GM-CSF and IFN-γ increased in nasal secretions at T12. Metabolomic profiling suggested compartment-specific changes, with decreased short-chain alcohols in EBC, increased amino acids in nasal secretions and serum at T6, and elevated pyruvate in serum at T12, although none reached statistical significance in univariate analysis. Conclusions: Mepolizumab induced consistent clinical, immunologic, and metabolic changes across compartments, supporting the use of integrated cytokine and 1H-NMR metabolomic profiling as a complementary approach for response assessment in SEA.