Abstract
BACKGROUND: The anti-inflammatory cytokine interleukin-4 (IL4) has been recognised as a protective factor in various cardiovascular events, yet its prognostic value in patients with pulmonary hypertension (PH) remains unclear. The study aimed to measure the levels of plasma IL4 in patients with PH and to explore their potential association with disease risk and outcomes. METHODS: In this observational study, we analysed the levels of plasma IL4 in 766 PH patients and 191 healthy controls in Shanghai Pulmonary Hospital from October 2009 to January 2024. To establish the correlations between plasma IL4 levels and the risk and outcomes of PH, all patients were followed up from June 2013 to June 2024. The Spearman correlation test was employed to evaluate the relationships between IL4 and right heart catheterisation parameters among patients with PH. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic performance of IL4 for PH. The Cox proportional hazards models and Kaplan-Meier survival curves were used to assess the prognostic value of IL4 levels. Logistic regression analysis was performed to predict PH incidence. A nomogram was constructed to predict mortality, and its clinical utility was validated using decision curve analysis (DCA). RESULTS: Plasma IL4 levels were significantly decreased in patients with PH compared with controls (p < 0.001), as well as in different PH groups (p < 0.05 for all). The logistic regression analyses indicated that the lower IL4 levels were associated with the high risk of PH (OR = 0.79, 95% CI: 0.716-0.872; p < 0.001). IL4 levels correlated inversely with NT-proBNP (r = -0.10, p < 0.05) and mPAP (r = -0.01, p < 0.05), and positively with CI (r = 0.12, p < 0.05) and PaSaO2 (r = 0.11, p < 0.05), indicating an association with disease severity. Kaplan-Meier analysis revealed that patients with IL4 ≥ 2.8774 pg/mL had a 3-year cumulative survival rate of 91.28%, compared with 82.83% for those with IL4 < 2.8774 pg/mL (log-rank p = 0.007). Cox regression confirmed IL4 as an independent predictor of survival (HR = 0.810, 95% CI: 0.660-0.993; p = 0.043). A diagnostic model combining IL4, 6MWD and NT-proBNP demonstrated good prognostic value (AUC = 0.692, p < 0.0001). CONCLUSIONS: Plasma IL4 levels were significantly decreased in patients with PH, exhibiting a negative correlation with disease severity; furthermore, lower IL4 levels may serve as a prognostic indicator of poor outcomes in patients with PH.