Biomarkers of Treatment-Escalation Risk by Obesity Status in Pediatric Asthma: A Development and External Validation Cohort Study

Background/Objectives: Obesity may alter the prognostic value of biomarkers in childhood asthma. We examined whether transforming growth factor beta 1 (TGF-β1), soluble suppression of tumorigenicity 2 (sST2), C-X-C motif chemokine ligand 8 (CXCL8), and insulin-like growth factor 1 (IGF-1) were associated with sustained treatment escalation and whether associations differed by obesity status. Methods: The development cohort included 292 children: 90 non-atopic controls, 108 with normal-weight asthma, and 94 with obese asthma; longitudinal analyses included 202 with asthma. Biomarkers were modeled continuously in prespecified Cox models with biomarker-by-obesity interactions, internally validated with 1000 bootstrap resamples, and applied without refitting or recalibration to an independent Van cohort of 180 children with asthma. Results: Seventy-five children experienced sustained treatment escalation. TGF-β1 was associated with escalation in obese asthma (hazard ratio [HR] per 500 pg/mL, 2.12; 95% confidence interval [CI], 1.66–2.70; interaction q < 0.001), whereas CXCL8 was associated with escalation in normal-weight asthma (HR per 10 pg/mL, 2.06; 95% CI, 1.67–2.54; interaction q < 0.001). Adding TGF-β1 or CXCL8 increased 12-month time-dependent area under the curve (AUC) from 0.623 to 0.732 and 0.746. In Van, AUCs were 0.751 and 0.744, and interactions remained significant after adjustment (q = 0.036). sST2 showed a weaker obesity-related signal, whereas IGF-1 added little prognostic information. Conclusions: Prognostic biomarker associations differed by obesity status. TGF-β1 was associated with escalation in obese asthma, whereas CXCL8 was associated with escalation in normal-weight asthma. Further validation is needed before clinical use.