Background: Tree nut allergy is usually life-long and potentially life-threatening. Standard of care consists of strict avoidance of the culprit nut and symptomatic treatment of accidental reactions. Objective: To evaluate the potential therapeutic options for desensitization of patients with IgE-mediated tree nut allergy, focusing on, but not limited to, immunotherapy. Methods: We systematically searched three bibliographic databases for studies published until July 2022 for active treatments of IgE-mediated allergy to tree nuts (walnut, hazelnut, pistachio, cashew, and almond) with allergen-specific immunotherapy (AIT) using oral (OIT), sublingual (SLIT), epicutaneous (EPIT) or subcutaneous (SCIT) delivery, or with other disease-modifying treatments. Results: We included 17 studies (three randomized, double-blinded, placebo-controlled, five quasi-experimental prospective cohorts, five prospective cohorts, two retrospective cohorts, and two case reports. Three studies investigated sublingual immunotherapy, five investigated oral immunotherapy to a single tree nut, and six used multi-food oral immunotherapy with (four) or without (two) omalizumab. The remaining studies investigated the effectiveness of monoclonal antibodies in multi-food allergic patients, including patients with a tree nut allergy. The heterogeneity of the studies prevented pooling and meta-analysis. Conclusion: Even though strict avoidance remains the standard of care for patients with tree nut allergy, alternative approaches have been tested in clinical trials and real-life studies. These new concepts require further investigation with more well-designed studies including well-characterized nut allergic patients before implementing them in daily clinical practice.

This systematic review evaluates the potential therapeutic options for desensitization of patients with IgE-mediated tree nut allergy, focusing, but not limited to, on immunotherapy. We searched three bibliographic databases for studies published until July 2022 for active treatments of IgE-mediated allergy to tree nuts (walnut, hazelnut, pistachio, cashew, and almond) with allergen-specific immunotherapy (AIT) using oral (OIT), sublingual (SLIT), epicutaneous (EPIT) or subcutaneous (SCIT) delivery, or with other disease-modifying treatments. We included 26 studies, but the heterogeneity of the studies prevented pooling and meta-analysis. Immunotherapy with hazel pollen extracts might benefit patients with a secondary nut allergy due to cross-reactivity with PR-10 or profilin panallergens but is unlikely to be beneficial in patients with a severe nut allergy caused by seed storage proteins. Sublingual immunotherapy has a moderate efficacy but a favorable safety profile. Oral immunotherapy (OIT), single, or multi-nut, with or without omalizumab, is the most studied approach. In general, tree nut OIT is effective in conferring protection from accidental exposures, with safety similar to that demonstrated by peanut OIT. The observed cross-desensitization between tree nuts straightly affects the management options for multi-nut allergic patients.