The Conversation on Oral Immunotherapy for Preschool Children Must Continue

There is an ongoing impetus for oral immunotherapy (OIT) for the treatment of food allergies even prior to the US Food and Drug Administration approval of a peanut OIT product (Palforzia) for the treatment of peanut allergy [1]. Almost contemporaneously, there is a shift trending towards commencing OIT in earlier age groups. Even so, debates continue among experts regarding the measurement of treatment outcomes, including effectiveness, safety and tolerability together with patient-reported outcomes such as health-related quality of life. Through the Core Outcome Measures for Food Allergy (COMFA) initiative, ‘allergic symptoms’ and ‘quality of life’ (QoL) were identified as the two core outcomes recommended to be measured in all food allergy trials in addition to mandatory reporting of adverse events [2]. Interestingly, while the clinical outcomes of desensitisation or remission did not meet the pre-defined inclusion criteria by the COMFA consortium, these were also considered important to some of the stakeholder groups [2].

In this issue, Soller and colleagues propose a case for OIT as a key role in the management of food allergy for pre-schoolers, where there may be a window of opportunity for OIT in early life. This proposition adds an element of urgency to both research and clinical practice in this area. Hence, it is imperative that the evidence is continuously evaluated for OIT in this younger age group as compared to older children. Using the lens of the core outcomes, there is a lack of randomised controlled trial (RCT) information on the effects of OIT in infants or toddlers on QoL, and as such Level I or II evidence is lacking in addressing a core outcome. Although there have been separate RCTs for peanut OIT conducted at different ages and populations with much heterogeneity in regimen and definition of clinical outcomes, harmonisation and consensus have not been possible even if real-world studies are included. The closest arguably, if separate RCTs using Palforzia were compared for their primary efficacy outcome, the desensitisation rates did not show a dramatic difference for tolerating ≥ 600 mg peanut protein at the exit challenge (73.5% active vs. 6.3% placebo in children age 1 to < 4 compared to 67.2% active vs. 4% placebo in children 4–17 years, respectively) whereas the secondary outcome of tolerating ≥ 1000 mg may infer a difference (68.4% active vs. 4.2% placebo (age 1 to < 4 years) compared to 50.3% active vs. 2.4% placebo (age 4–17 years)) [3, 4]. This suggests that the relative impact of age on OIT outcome may vary according to outcome definitions. Furthermore, looking descriptively at the probiotic peanut OIT (PPOIT-003) study where a priori stratification into 1–5 years vs. 6–10 years may imply a higher desensitisation and remission rates for the younger age groups (desensitisation and remission rates for both active arms combined of 83% and 58% for age 1–5 years vs. 67% and 37% for age 6–10 years respectively) but this was not the primary aim of the study [5]. However, the placebo rate in PPOIT-003 was 10% in ages 1–5 years vs. 0% in ages 6–10 years [5] and hence interpretation of efficacy in younger children needs to be considered in light of higher natural resolution rates in this age group. Furthermore, no QoL studies solely for children younger than 5 years were reported in any of the published RCTs or real-world studies. As such, it may be that an RCT with QoL as its main focus in pre-school children undergoing OIT vs. placebo or avoidance is needed to provide comprehensive QoL evidence for this age group.

Furthermore, there is contrasting evidence on whether or not early age is the key factor for OIT success, but rather the levels of specific IgE, i.e. for example, peanut sIgE measured prior to peanut OIT commencement, may be more important [6]. Although the theoretical concept of immune plasticity, where earlier age has been recognised to have a greater potential effect for immune modulation by OIT, it may be that the presence of biomarkers such as lower levels of sIgE are more malleable instead, irrespective of age. Regardless of which factor is the greater driver for OIT success, it has not been determined how long OIT is required to continue modifying the immunological plasticity, if present, in the earlier age group or if the effects are long-lasting or the optimal therapeutic window of this plasticity. There are still many unknowns, including whether or not the cessation of OIT prematurely may have a more detrimental effect in the long term or what is the rate of OIT relapse or recurrence if the ideal treatment duration is not achieved or when OIT daily dosing should cease or be extended until the beneficial effects of less regular ingestion are sustained. Follow-up studies such as PALISADE-ARC004 suggest that non-daily dosing leads to lower desensitisation rates [7] or consuming a lower maintenance dose after a high maintenance dose for 2 years does not retain the desensitisation benefits of the higher dose, as shown in the POISED study [8]. Thus, while the pre-school period might appear to be an attractive period for the initiation of OIT, the child's potential long-term dependence on continued, regular ingestion needs to be considered and formal QoL outcomes from these types of interventions are needed in order to support evidence-based practice.

With this in mind, we need to recognise that starting OIT at an earlier age requires a long follow-up period and therefore a long road ahead. There are very few long-term follow-up studies following OIT, and evidence on the durability of OIT post-treatment is lacking. The hypothetical scenario of OIT starting in early childhood by the parent but ceased in the teenage or adolescent years by the adolescent themselves remains a possibility, where any benefits of OIT if it is not sustained, are then lost and may not be regained. Depending on the clinical outcomes that were achieved, whether it is desensitisation or remission, the long-term factors influencing the success of maintaining these outcomes are unknown. However, the difficulty of maintaining daily ingestion with more frequent and greater reaction severity has been shown in patients who are desensitised compared to those who have achieved remission [9]. Allergic reactions in the absence of co-factors can occur during daily ingestion even after long periods of maintenance. It is not known if the OIT recurrence rate is similar to the recurrence of food allergies in those who may have passed a diagnostic oral food challenge to prove tolerance, or it could possibly be higher as neither desensitisation nor remission is the same as true tolerance. The appropriate time for recommending cessation of carriage of an adrenaline injector is unknown, but is unlikely to occur in a patient in a state of perpetual desensitisation. Treatment of the pre-schooler invariably changes the dynamics in the family, including siblings. As consent is provided by the parent, and while the whole course of treatment is targeted to the child, it primarily relies on the parent to manage this and hence is not dissimilar to many other chronic conditions that occur in early life. It is still unknown if the drivers for OIT demand are more pronounced from families of younger children despite the paradox of knowing that OIT causes frequent reactions.

To this end, the overwhelming enthusiasm for OIT in pre-schoolers should be tempered by ongoing vigilance and realism in this vulnerable population where growth and development of the child are still occurring. The long lead time to reach adulthood from a therapy starting early in life needs to be monitored throughout the life of the child, where decisions are made on behalf of the child. High quality evidence needs to be generated with harmonised, patient-centred core outcomes (such as from COMFA) while being cognisant that OIT for younger age groups is likely here to stay. Despite the current knowledge gaps in this age group, we can remain optimistic while balanced by respectful discussion that there are still many unknowns—lest we ‘regret’ the advice given after many decades down the track. Learnings from previous examples such as hydrolysed formula for the prevention of allergic disease in high risk infants and delaying allergenic foods for food allergy prevention where this advice was once part of international guidelines but is no longer recommended due to either conflicting or updated evidence gives us a measure to reflect. As clinicians who ultimately administer this treatment to patients and families, it is imperative that the highest quality evidence is presented, notwithstanding the nuances that come with clinical practice, that the best intention is for the individual patient in front of us, and that is through empowering both parties with the knowledge that is impartial and balanced.

The author reports consultant fees from SPRIM Consulting and an institutional grant from Siolta Therapeutics outside the submitted work.