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.