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.