IL-33 associates with type 2 burden and lung function in paediatric asthma, alongside exploratory IL-33–linked lipid changes

BACKGROUND: Interleukin-33 (IL-33) is an epithelial alarmin positioned upstream of type 2 (T2) inflammation, yet its clinical correlates and systemic molecular context in paediatric asthma remain incompletely defined. We investigated whether circulating IL-33 is associated with objective disease-burden measures and whether IL-33 elevation co-occurs with exploratory plasma lipid differences. METHODS: In a paediatric case-control cohort (August 2023-June 2025; asthma n = 60, controls n = 60), plasma IL-33 was quantified by ELISA and related to spirometry (FEV1, FEV1/FVC, PEF) and T2 markers (blood eosinophils, total IgE, FeNO). Associations were assessed using correlation analyses and multivariable linear regression treating IL-33 as a continuous exposure (mean-centred ln[IL-33]) with adjustment for age, sex, BMI, and group, plus an Age × IL-33 interaction. ROC analyses were used to describe case-control discrimination within the cohort. Untargeted plasma lipidomics was performed in an exploratory discovery subset (asthma n = 8, controls n = 8) to define differential lipids, IL-33-anchored lipid patterns, and an exploratory six-lipid IL-33-linked score; score-trait associations were evaluated as exploratory analyses with group residualization. RESULTS: Compared with controls, children with asthma showed worse lung function and higher T2 burden (all P < 0.001), alongside higher IL-33 (107.1 ± 38.5 vs. 52.4 ± 21.6 pg/mL; P < 0.001). Across the cohort, IL-33 correlated inversely with lung function (FEV1 r = - 0.652; FEV1/FVC r = - 0.585; PEF r = - 0.683; all P < 0.001) and positively with T2 markers (eosinophils r = 0.534; IgE r = 0.583; FeNO r = 0.622; all P < 0.001). In multivariable models, ln(IL-33) remained significantly associated with each outcome after adjustment for age, sex, BMI, and group status, whereas the Age × IL-33 interaction was not significant (all P > 0.05). IL-33 showed case-control discrimination within the cohort (AUC 0.92; cut-off 75.4 pg/mL). In the exploratory lipidomics subset, PCA suggested group separation, although this should be interpreted cautiously given the small sample size. Differential lipids were dominated by glycerophospholipids (66.67%), followed by sphingolipids (18.1%). Exploratory IL-33-anchored analyses identified provisional glycerophospholipid/cardiolipin-positive and sphingomyelin-negative lipid patterns. The exploratory IL-33-linked lipid score showed high apparent discrimination within the discovery subset (AUC 0.96; LOOCV AUC 0.97) and, after group residualization, remained directionally associated with lung function and T2 markers. CONCLUSION: In this paediatric case-control cohort, circulating IL-33 was elevated in children with asthma and was significantly associated with objective airflow limitation and systemic type 2 inflammatory burden. Higher IL-33 levels also co-occurred with exploratory plasma lipid differences. These findings should be interpreted as adjusted associations observed within a cross-sectional case-control design and require longitudinal and external validation before any broader biomarker or clinical application can be considered.