A systemic epithelial-immune-neural framework for pediatric atopic dermatitis-allergic rhinitis comorbidity

Atopic dermatitis (AD) and allergic rhinitis (AR) commonly coexist in childhood and are associated with an important clinical burden. Their frequent coexistence and substantial mechanistic overlap suggest that pediatric AD-AR comorbidity may involve patterns more complex than simple co-occurrence. However, existing models do not provide an operational approach for determining whether reproducible coupling between AD and AR disease activity extends beyond shared susceptibility and disease-specific responses occurring in parallel. In this Hypothesis and Theory article, we propose the systemic epithelial-immune-neural framework as an operational and falsifiable model for investigating pediatric AD-AR comorbidity. The framework integrates four interacting proposed mechanistic domains-epithelial barrier and alarmin signaling, type 2 immune activation, neuroimmune signaling, and microbiome regulation-and distinguishes established organ-specific mechanisms from candidate cross-organ coupling. It also separates core mechanisms from external inputs, contextual modifiers, and observable outcomes, and translates the proposed relationships into directed edges, feedback loops, testable predictions, and falsification criteria. Current evidence supports the biological plausibility of the framework and demonstrates substantial mechanistic overlap between AD and AR, but direct pediatric evidence for reproducible cross-organ coupling between AD and AR disease activity remains limited. The framework should therefore be regarded as a research model rather than a new diagnostic classification, composite network score, or separate treatment pathway. Clinical assessment and management should remain grounded in validated, guideline-based approaches for AD and AR. By organizing shared mechanisms and clinical observations into explicit and testable claims, the framework provides a structured basis for investigating the existence, potential mechanisms, heterogeneity, and clinical relevance of cross-organ coupling in pediatric AD-AR comorbidity.