Inhibition studies to direct oral immunotherapy in walnut‐hazelnut co‐allergic patients (nut CRACKER study)

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BACKGROUND: Walnut OIT has been observed to induce cross-desensitization to hazelnut, but predictors of this response remain unclear. We sought to identify molecular predictors of hazelnut cross-desensitization following walnut OIT, to help guide treatment decisions in these co-allergic patients. METHODS: Patients with confirmed IgE-mediated walnut and hazelnut allergy underwent walnut OIT. Patients achieving full walnut desensitization to 4 g of walnut protein were re-challenged to 4-grams hazelnut protein after 6 months. Baseline sera were obtained and competitive ELISA inhibition assays performed to evaluate serum IgE cross-recognition of total walnut, total hazelnut and hazelnut component-specific IgE. Results were compared between patients fully (4-grams protein) or clinically (≥30-fold ED increase or mild reaction at full dose) cross-desensitized to hazelnut and those who remained hazelnut allergic following walnut OIT. RESULTS: Overall, 12/22 (54.5%) patients were fully cross-desensitized and 14/22 (63.6%) patients were clinically cross-desensitized to hazelnut following walnut OIT. Among the latter, walnut inhibited total hazelnut-specific IgE binding by a median of 95%, compared to 55% in those who remained hazelnut allergic (p < .01). Similarly, walnut extract competed for IgE binding to hazelnut components Cor a 9 (p = .003) and Cor a 16 (p = .023) in the cross-desensitized group following walnut OIT, but not in the persistent hazelnut allergic group. A ≥70% inhibition threshold accurately predicted cross-desensitization in 93% of cases (p < .001). CONCLUSION: Walnut OIT can induce clinical cross-desensitization to hazelnut in >60% of co-allergic individuals. Competitive ELISA inhibition is a promising predictive tool, with potential to guide targeted and efficient OIT strategies in walnut-hazelnut co-allergic patients.