Unveiling regional patterns of IgE sensitization to peanut, hazelnut, and walnut in Italy: a nationwide bottom-up molecular survey

Background: Tree nut and peanut allergy is increasing in prevalence across Europe, yet the molecular sensitization patterns underlying these allergies remain incompletely defined in Southern Europe, particularly in Italy. Objective: To characterize regional profiles of IgE sensitization to allergenic components of peanut, hazelnut, and walnut across Italy using a bottom-up, molecule-based diagnostic approach. Methods: We retrospectively analyzed data from 1526 patients with suspected nut allergy evaluated in three Italian centers representative of the Northeast, Central, and Southern regions. Specific IgE reactivity to 15 allergenic molecules was assessed using the MADX-ALEX2 multiplex platform. Co-sensitization patterns and regional variations were explored through Euler-Venn analysis. Results: All patients were sensitized to at least one nut allergen, revealing distinct geographic trends. In Northeast Italy, PR-10 proteins predominated (up to 63 %), consistent with birch-related cross-reactivity. In contrast, nsLTP sensitization was highly prevalent in the South (up to 91 %), while Central Italy showed intermediate profiles. Co-sensitization to PR-10 and nsLTPs in the Northeast was not associated with milder reactions. Sensitization to seed storage proteins progressively decreased from North to South. Jug r 1 was the predominant walnut allergen in the Northeast, whereas Jug r 2 and Jug r 3 prevailed in the South. Sensitization to oleosins was rare (<2 %). Conclusion: Italy represents a microcosm of Europe in terms of molecular allergy endotypes, showing a clear North-South gradient in nut allergen sensitization. Multiplex molecular diagnostics unveil region-specific co-sensitizations with potential clinical relevance and support geographically tailored diagnostic and management strategies within a precision allergy framework.