DISCUSSION
Overall, although all included studies required food challenges or a
recent convincing history of reaction for recruitment and an exit oral
food challenge assessing outcomes, they were highly heterogenous
regarding the population, interventions used, primary outcomes, and
preferred methods of reporting results. While some studies aimed to
recruit both children and adults, most of the included participants are
children.
Besides that, one of the major drawbacks of all but three
studies22,25,37 is the lack of component resolved
characterization of tree nut allergy. Some studies addressed this issue
by requiring a low eliciting dose at the baseline food challenge, which
is unlikely to occur when the allergy is due to panallergens.
Immunotherapy with pollen extracts15,26 might benefit
patients with secondary nut allergy due to cross-reactivity with PR-10
or profilin panallergens, which are usually labile and are responsible
for mild reactions, limited to mouth and oropharynx38.
This approach is unlikely to be beneficial in patients with primary tree
nut allergy to seed storage proteins, which are the cause of severe,
life-threatening reactions.
Sublingual immunotherapy has been investigated only for hazelnut
allergy, with moderate efficacy but a favorable safety
profile14,34. Nevertheless, the sample size was small,
and the extract used was standardized for Cor a 1 (PR-10) and Cor a 8
(LTP) allergens, and not for Cor a 9 (legumin) or Cor a 14 (2S albumin),
which better predict severe hazelnut allergy39,40. LTP
allergy has an extremely variable clinical
presentation41, which could explain the loss of
protection described in one patient in the follow-up study after he had
tolerated the highest dose in the original study.
The same might account for the trials using omalizumab or dupilumab
without OIT in multi-allergic patients, in which tree nut allergy seems
to be a manifestation of the LTP-syndrome29,30,36.
OIT trials varied substantially regarding the escalation protocol, the
maintenance dose, the definition of desensitization, and the method used
to report adverse reactions. In general, the efficacy and the safety of
tree nut OIT were found to be similar to that demonstrated by peanut OIT
trials42, regardless of whether the intervention is
single tree nut-, multi-food-, or omalizumab-facilitated-OIT. Omalizumab
appears to allow for faster desensitization with fewer adverse
reactions, especially during the build-up phase. Maintenance doses,
between 30013 and 4000mg19, seem to
be effective in achieving desensitization to the full range of tree nuts
(a full portion), while a maintenance dose as low as 75mg protein per
day may confer protection from accidental
ingestions37.
As expected, sustained unresponsiveness depended on the length of
avoidance, with fewer participants maintaining their desensitization
over time13,23,37. The current knowledge of immune
modulation during OIT43 does not support the
acquisition of a permanent tolerance phenotype. The frequency and the
dose required to maintain desensitization are probably dependent on
individual biomarkers, still not fully elucidated.
Cross-desensitization between cashew and pistachio, or walnut and
cashew, was described in multi-OIT and single-OIT
studies12,13,22,27, attributed to the close
phylogenetic affinity of respective nuts38.
Interestingly, cross-desensitization to distant phylogenetic nuts
through walnut and cashew OIT was also documented in three
studies22,23,25, although details about the
implicating nuts lack in one of them23. Linear and
structural homologies of vicilin, legumin, and 2S albumin epitopes of
tree nuts belonging to different botanical families have been
demonstrated38. These homologies could contribute to
the observed cross-desensitization, which straightly affects the
management options for multi-nut allergic patients.
Managing tree nut allergy seems to have a positive effect on the quality
of life of patients and families, irrespectively of the intervention
used. The effect is pronounced when desensitization to more nuts is
achieved.
The heterogeneity of the studies included in this review prevented
pooling and meta-analysis. Only a small number of studies assessed
interventions specifically for tree nut allergy, while the majority
referred to multi-food allergic individuals, including subgroups with a
co-existing tree nut allergy. To overcome this obstacle, we had to
extrapolate the participants and the outcomes in interest, although they
were not fully characterized. Caution should also be taken when
reviewing the numbers of patients treated with multi-OIT, with or
without omalizumab, as most studies are originated by the same team,
thus the population might have been recycled.
Although there are recent reviews on the management and diagnosis of
tree nut allergy44-48, this is the first systematic
review thoroughly investigating the available information on therapeutic
options for the desensitization of patients with IgE-mediated tree nut
allergy, other than peanut.
Even though strict avoidance remains the only approved care for patients
with tree nut allergy, alternative approaches have been tested in
clinical trials and real-life studies. Among them, oral immunotherapy
seems to be the most effective option, although not without the risk of
allergic reactions. The possibility to simultaneously achieve
desensitization to multiple nuts with only one nut in OIT is of great
interest for multi-nut allergic individuals and requires further
investigation.