1.2. Oral immunotherapy (OIT) (Table 2)
Single tree nut
Five studies23,24,30,31,33 investigated OIT to a single tree nut in children. 58 children received walnut OIT in two studies24,33, 170 received hazelnut OIT in two studies30,31, and 50 children received cashew OIT in one23. Inclusion required a low dose positive oral food challenge in a case report of three children undergoing low dose walnut OIT33, a positive DBPCFC in 70 children receiving hazelnut OIT30, and a positive OFC or a history of a recent reaction in the rest of the studies23,24,31. In one hazelnut-OIT study, 4 children with no history of reaction, but a strong immunological suggestion of tree nut allergy, were also included31. One walnut and the cashew OIT-studies included a control group receiving standard of care (avoidance)23,24, and the rests used baseline assessment as a comparator30,31,33. The primary outcome was desensitization in four studies23,24,30,31and sustained unresponsiveness in the case report study33. The oral immunotherapy protocol included an initial escalation phase in four studies23,24,33. All included a build-up phase until maintenance dose, which varied from 75mg33 to 1200mg23,24 of nut protein, while the case report study used antihistamine premedication until the maintenance33. The time of intervention varied from 6 to 12 months. Overall, according to each study’s primary outcome, OIT succeeded in 41% of treated patients for hazelnut, 88% for cashew and to 89% for walnut, and induced favorable immunological changes (Table 2 and Supplementary text). During OIT most participants reported at least one allergic adverse event. Epinephrine administration varied from 0 to 20% of participants, depending on the protocol. Studies with lower maintenance dose30,33 report no epinephrine use. Eosinophilic esophagitis was reported in 2 out of 278 patients, while 4 patients developed symptoms compatible with oral immunotherapy-induced gastrointestinal and eosinophilic responses (OITGER), which subsided with temporary dose reduction.
Multiple food (multi-OIT)
Multi-OIT including tree nuts, was reported in six studies17,18,20,21,25,26, all generated from the same group, addressed in children17 or children and adults18,20,21,25,26. All studies required DBPCFC prior to intervention and included an initial escalation, followed by a build-up phase. The maintenance dose varied from 30018to 4000mg21 of nut protein and the time of intervention from 9 to 72 months. Two studies used antihistamines as adjuvant20,21, and four used omalizumab17,18,25,26. One study used baseline assessment as a comparator21, one study compared multi OIT to single peanut OIT21, one compared multi OIT with and without omalizumab with the standard of care17, and three compared the efficacy of different maintenance doses (2000 or 1000 and 300mg) to sustain desensitization after reaching the initially maintenance dose18,20,25. Safety was the main outcome in two studies21,26, efficacy in two17,18, and both in two20,25. One study assessed sustained unresponsiveness18 and three assessed cross-desensitization17,18,25. In total, 128 participants included cashew in their OIT and 91 of them were co-treated with omalizumab, 104 included walnut of which 39 with omalizumab, 57 hazelnut (44 with omalizumab), 33 almond (22 with omalizumab), and 30 pecan (15 with omalizumab). Collectively, desensitization achieved in 88% of treated nuts, 89% in omalizumab multi-OIT and 86% in multi-OIT alone, and tolerogenic immunological changes were noted. Hazelnut-OIT had the lowest (70%) and pecan-OIT the highest (100%) efficacy, regardless of omalizumab use. The use of omalizumab helped to accelerate the procedures26. Compared to single OIT, multi-OIT required more time to reach maintenance21. Of interest, all but one of the 104 patients who reduced the maintenance dose to 300mg of tree nut protein, retained their tolerance to a 2000mg challenge, regardless of the implicated tree nut or the use of omalizumab18,20,25.
Regarding safety, multi- and single-OIT performed similarly when tested in the same protocol and population21, with two reported uses of epinephrine in each group, while omalizumab reduced the frequency of adverse reactions during the initial phases of OIT17. Comparing all OIT studies, patients in single-OIT without omalizumab experienced more frequent and more severe adverse reactions than patients treated with multi-OIT, with or without omalizumab, but different protocols and different populations must be considered. The occurrence of allergic reactions tended to decrease over time in the long term follow up studies20,25.
Other interventions
The remaining studies investigated the effectiveness of other interventions in multi-food allergic patients, including patients with tree nut allergy27,29,32. Two studies performed OFCs prior to intervention29,32 and one required a recent history of allergic reaction27. All assessed changes in the quality of life through different questionnaires.
Two studies assessed omalizumab in food allergic children, including two children allergic to cashew, one to pistachio, four to walnut, six to hazelnut, and three to almond27,29. Administration of omalizumab for 4-6 months resulted in increasing ED27or tolerance29 in approximately 60% of tree nuts reported, but reactivity or tolerance were not always tested with OFCs before treatment.
In a case report, a three-month treatment with dupilumab for atopic dermatitis in an adult with pistachio and corn allergy and sensitization to cashew, walnut, hazelnut, and almond, resulted in pistachio tolerance32.
Sustained Unresponsiveness (SU)
Two studies, the case report of low walnut-OIT33 and the RDBPC multi-OIT with omalizumab study18, assessed the maintenance of tolerance after discontinuation of the intervention. In the walnut study the time on maintenance was 1 year on 75 mg of walnut protein and the discontinuation period was two weeks. All three participants retained SU to 450mg of walnut protein. The multi-OIT study assessed 6 weeks SU after 2.5 years on maintenance with 2000-4000mg of treenut protein. 53% of tree nuts OFC were successful at a cumulative dose of 2000 mg of nut protein, with walnut performing the highest (82%) and cashew the lowest (18%) SU. Of note, SU was not assessed in 26% of tested tree nuts.
Cross-desensitization
Five studies assessed cross-desensitization to another nut, one regarding walnut-OIT24, one cashew-OIT23, and three multi-OIT17,18,25. Walnut-OIT desensitized 8 out of 15 (53%) hazelnut allergic patients24, 5 of 19 cashew (26%) allergic patients24 , and 71 of 79 (90%) pecan allergic patients17,18,24. Additionally, in one omalizumab multi-OIT study25, of the 8 participants with pecan in their OIT and 10 with walnut, 7 were desensitized to both foods. Cashew-OIT desensitized 4 of 11 (36%) walnut allergic patients23 and 61 of 68 (90%) pistachio allergic patients17,18,23. Higher success rates were noted between nuts with similar phylogenetic origin (cashew and pistachio, and walnut and pecan).
Quality of life assessment
Changes in quality of life were assessed by three studies24,27,29, of which, one concerned walnut-OIT24, and two omalizumab only27,29. The questionnaires used were the age-appropriate “Food Allergy Quality of Life Questionnaire” (FAQLQ) in the walnut-OIT study24, the FAQLQ-Parental Form (PF)27, and the “Pediatric Quality of Life Inventory” (PedsQL) 4.0 questionnaire in the omalizumab studies29.
Walnut-OIT resulted in a clinical meaningful improvement only in participants desensitized to all nuts they were allergic to.
Omalizumab’s effect on food allergy collectively resulted in a significant improvement in the health status, reduced stress associated with the allergy, and a significant decrease in the limitations of activities in daily life27. The PedsQL questionnaire scores were significantly increased by the treatment in both parents and patients, with greater improvement in the physical health summary score and the psychosocial health summary score29.
Additionally, a hazelnut-OIT study31 used a non-validated Likert questionnaire, addressed to children and their caregivers, to assess children’s acceptance of hazelnut-OIT. The questionnaire was completed at a median of 47.5 months after the initial consultation. Children considered OIT effective and would recommend it to another child, but daily consumption was considered as a strain and as a medication.