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.