In this phase 1 study, we have shown that participants allergic to multiple foods can be safely desensitized to up to five foods simultaneously using a modified OIT protocol. Despite the increasing interest in food OIT in recent years, the safety or efficacy of using multiple food flour/powder allergens in parallel has, to our knowledge, not been published. These findings are particularly relevant considering the already high and likely growing number of food allergic participants who are allergic to more than one food allergen [22–25].
The multi OIT study was designed as a proof of concept, phase 1 study; therefore, safety measurements were the primary endpoint. The rate of reactions observed in the multi-allergen OIT group was within the acceptable range for an OIT study and was similar to a reference cohort of peanut mono-allergic participants undergoing the same protocol to peanut only. This supports the view that it is not the diversity or multiplicity of the food allergen binding surface IgE but rather the total dose of allergen administered that determines OIT reactions. However, this data should be viewed as proof of concept data until randomized, controlled, double-blinded phase 2 studies with larger sample sizes are performed.
In previous single OIT studies, overall reaction rates tended to vary, possibly due to differences in escalation protocols, allergens, selection of participants or use of anti-histamine pre-medication [7–9, 13–15, 19]. However, severe reactions needing epinephrine injections have been consistently shown to be an occurrence, albeit rare, when performing OIT. In our study, 2 participants from each group required epinephrine during the study period. Although the number of allergens did not seem to increase the risk of severe reactions, a state of continual vigilance is needed to perform OIT. As most reactions occurred at home (including those severe reactions requiring injectable epinephrine), participants and families carry reaction medications at all times and are educated on the proper use of injectable epinephrine and on the recognition of severe reactions that warrant its use. It is also important that the food doses be from a verifiable and reproducible source, that they be carefully measured and cross-checked by clinical staff and stored and dispensed from an appropriate facility.
We chose to proceed with a single dose of each food in an equal protein stoichiometric ratio. In some smaller children that are slow eaters, the process of eating their dose could take up to 1 hour with a mix of 5 nuts at full dose. In such cases, it would not have been feasible to wait in between foods for the occurrence of a reaction. Our final maintenance dose was 4000 mg per allergen. The optimal long term maintenance dose for food OIT has not been identified yet and may need to be individualized. More studies are needed to determine this parameter of OIT which may have an impact on subject compliance with ingestion.
Except for one participant who was excluded due to eczema flares and two drop-outs, all participants reached a 10 fold increase in their reaction threshold during the study period. The median time at which participants on single allergen OIT reached this dose was 14 weeks earlier than for those on the multi-allergen therapy. Participants undergoing multi-allergen OIT also took more time reaching the 300 mg, 1000 mg and 4000 mg doses. This delay is to be expected since there were up to 5 food allergens given simultaneously and the dose for each individual food allergen was divided evenly. Importantly, this phase 1 study demonstrates that it is possible and feasible to test the effect of multi food allergen therapy simultaneously, rather than performing single immunotherapy in sequence for patients, a process that could take many years for patients who are multi-sensitized to food allergens.
Although no SCORAD was calculated, it is worth noting that the participant that failed the initial dose escalation had significantly more severe eczema than other participants, for which he reported a history of systemic treatment and a clear relation with ingestion of food allergens. The eczema was active at enrolment despite topical treatment.
Despite showing proper dose progression, our study did not prove treatment efficacy. To measure true clinical tolerance, participants would have to stop their maintenance dose and demonstrate sustained unresponsiveness on a challenge after weeks to months of avoidance, which was beyond the scope of this study .
Serological analysis did show an increase in peanut-specific IgG4 similar to the monotherapy group. Peanut-specific IgE were stable after one year but this was not unexpected, as previous reports have shown that food specific IgE may start decreasing below baseline levels only after the first year of therapy [8, 13, 16, 32].
One limitation to this study was the absence of randomization. This said, this is not a requirement for phase 1 studies. The single and multiple allergic participant were part of the same protocol. We cannot rule out that the molecular sensitization profile could be different in multi-allergic participants that exhibit cross-reactivity with other nuts as it was not tested fully. Regardless, these proof of concept results show that OIT to multiple foods might be as safe as peanut OIT in single-allergic participants.
In conclusion, using a modified OIT protocol we have shown that simultaneous desensitization to multiple foods is feasible and worthy of further study. The reaction profile compared to that of peanut single-allergic participants undergoing monotherapy and participants showed comparable changes on serological examination. At this time, OIT should be considered an experimental treatment and should be conducted by trained research personnel in a hospital setting. Randomized, placebo-controlled phase 2 multicenter trials are needed to continue to determine safety and efficacy parameters of multi OIT in multi-allergic participants.