Appendix 2: Overall Characteristics of included studies.
The population in question was adults in five studies16,17,28,36,38, children in eleven14,23-25,31-35,37,39, and both in eight15,18,21,22,26,27,29,30. Two studies were addressed to the caregivers of children19,20.
Two studies, including a RDBPC, investigated the effect of one-year pollen subcutaneous immunotherapy on hazelnut and walnut allergy17,28 in a total of 26 adults. Both studies assessed tree nut allergy by food challenges at baseline. The RDBPC trial used histamine injections as the placebo, while for the prospective cohort, the baseline assessment was used as a comparator. The primary outcome in both studies was the changes in Eliciting Dose (ED) during the exit food challenge. One study assessed immunological changes. No study assessed sustained unresponsiveness, cross-desensitization, or changes in the quality of life.
Three studies investigated sublingual immunotherapy16,26,36. One RDBPC and a follow-up trial were conducted by the same team and investigated sublingual immunotherapy with hazelnut extracts, standardized in unit masses of the major allergens Cor a 1 and Cor a 816,36, in 12 and 7 adults, after 8-12 weeks, and 11 months, respectively. All participants had a positive double-blinded, placebo-control food challenge (DBPCFC) at baseline. The primary outcome in both studies was the changes in Eliciting Dose (ED) during the exit food challenge. The third study26 investigated the effect of Pru p 3 SLIT in 29 children and adults with a history of an allergic reaction within the previous year to several fruits with/without symptoms with vegetables, and/or peanuts or nuts compared to 13 participants who followed the standard of care/avoidance. The primary aim was to assess the effectiveness of 1-year Pru p 3 SLIT by open oral food challenges (OFCs) to unpeeled peach and nuts. Two studies16,36 assessed immunological changes, and none assessed sustained unresponsiveness, cross-desensitization, or changes in the quality of life
Seven reports, by five published studies24,27,34,35,39and two conference abstracts23,25, have investigated oral immunotherapy (OIT) to a single tree nut. The implicated tree nut was walnut in three studies24,25,39, hazelnut in two34,35, cashew in one27, and one conference abstract reported peanut and/or tree nut OIT without further information23. All studies included children. In total, 66 children received walnut OIT, 170 children received hazelnut OIT, 50 children received cashew OIT27, and 37 children reported in an abstract23 received peanut/ tree OIT, with no further information provided. Inclusion required a positive oral food challenge, open or double-blinded, in three studies23,34,39, and a positive OFC or a history of a recent reaction in three 24,27,35. In one study, children with no history of reaction, but a strong immunological suggestion of tree nut allergy, were also included35. In one abstract25, inclusion criteria were not reported. In three studies, the control group received standard of care (avoidance)23,24,27, and four studies used baseline assessment as a comparator25,34,35,39. The primary outcome was desensitization in five studies23,24,27,34,35, sustained unresponsiveness in one39, and both in one25. The oral immunotherapy protocol, the maintenance dose, and the time of intervention varied between studies. One study used antihistamine premedication until the maintenance dose was reached39. Three studies assessed cross-desensitization to another nut24,25,27, two studies assessed changes in quality of life23,24, and one study assessed the acceptance of children and their caregivers of the OIT protocol35.
Multiple oral Immunotherapy (multi-OIT), including tree nuts, was reported in nine studies14,15,19-22,29,30,33. Most studies were generated from the same group14,15,19-22,29,30. Two studies included children14,33, five children and adults15,21,22,29,30, and two caregivers of children19,20. In total, 194 participants included cashew in their OIT, pistachio, 156 walnut, 121 pecan, 58 hazelnut, and 47 almond. With one exception33, the studies required food challenges prior to intervention. Two studies used baseline assessment as a comparator20,21, and two used patients on standard care or on a waiting list for multi-OIT. One study compared multi OIT to single peanut OIT22, one study compared multi OIT with and without omalizumab with the standard of care14, and three compared different maintenance doses15,29,30. Safety was the main outcome in three studies21,22,33, efficacy in two 14,15, and both in two 29,30. In two studies, the change in the quality of life reported by caregivers was the main outcome19,20. No other study assessed quality of life. The oral immunotherapy protocol, the maintenance dose, and the time of intervention varied. One study used antihistamines as adjuvant22, and five used omalizumab14,15,19,21,29. One study assessed sustained unresponsiveness15, and three assessed cross-desensitization 14,15,29.
The remaining studies investigated the effectiveness of other interventions in multi-food allergic patients, including patients with a tree nut allergy. Two studies used omalizumab as the intervention in children, including two children allergic to cashew, one to pistachio, four to walnut, six to hazelnut, and three to almond31,32. In a case report, dupilumab was used in an adult with pistachio and corn allergy and sensitization to cashew, walnut, hazelnut, and almond38. Traditional Chinese Medicine37 and Chinese Herbal Medicine (Food Allergy Herbal Formula-2)18 were used in multi allergic subjects in the remaining studies. Three studies performed OFCs prior to intervention18,32,38; one required a recent history of allergic reaction37 and one a positive OFC and/ or convincing history31. One study assessed sustained unresponsiveness18, and three assessed changes in the quality of life31,32,37 through different questionnaires.