Cashew Reaction Thresholds, Its Predictors, and Very Low Validated Safe Doses, in a Large Allergic Population (Nut <scp>CRACKER</scp> Study)

BACKGROUND: Cashew is a widespread food allergen with a high rate of severe, and near-fatal reactions. Understanding cashew reaction thresholds and its predictors might improve patients' management and precautionary allergen labeling. METHODS: A prospective cohort study with post hoc analysis of cashew oral food challenges (OFCs) performed at Shamir (Assaf-Harofeh) Medical Center between July-2014 and May-2023. OFCs were performed according to either a diagnostic protocol in patients with suspected cashew allergy or an oral immunotherapy (OIT) protocol, intended to identify individual single highest tolerated dose (SHTD) at the beginning of OIT. No observed adverse effect levels and lowest observed adverse effect levels (NOAEL and LOAEL, respectively) of each OFC were identified. OFCs with extended dosing intervals were performed to determine individual validated SHTD (safe dose). RESULTS: Overall, 293 positive cashew OFCs (155 diagnostic-OFCs and 138 OIT-OFCs) were analyzed. The ED01 and ED05 for all patients were 0.2 mg (range 0.1-4.1) and 0.9 mg (range 0.2-14.8) for discrete, and 0.2 mg (range 0.1-11.7) and 1.2 mg (range 0.3-47.1) for cumulative doses, respectively. Pistachio co-allergy (p < 0.0001), higher sIgE to cashew (p = 0.004), Ana-o-3 (p < 0.001) and pistachio (p = 0.02), and an OIT-OFC protocol (p < 0.001) were associated with lower cashew thresholds. Cashew safe doses for 90% and 75% of the population were only 0.1 and 1 mg protein, respectively compared to 1 and 7.5-10 mg protein for sesame, walnut and peanut. CONCLUSIONS: The population cashew ED05 is within the range of other nuts and seeds, but safe doses are lower. Pistachio co-allergy and higher cashew and pistachio sensitization are risk factors for low reaction thresholds.