Should we pretreat before we go nuts? Anthistamines modestly reduce the side effects of peanut oral immunotherapy

To the Editor:

Oral immunotherapy (OIT) is increasingly adopted as a proactive approach to facilitate desensitization to food allergens. Shortcomings include high rates of allergic reactions, particularly during the escalation phase. The most common side effects of peanut OIT are abdominal pain, vomiting, oropharyngeal pruritis or discomfort, cough, and urticaria.¹ Although a majority of these symptoms are mild and transient, adverse effects may be severe and lasting. Indeed, the risk of anaphylaxis has been shown to be higher in subjects undergoing OIT compared to avoidance alone, and OIT-induced gastrointestinal symptoms include the development of eosinophilic esophagitis (EoE).^{2, 3}

Pretreatment with antihistamines reduces adverse effects associated with subcutaneous immunotherapy to aeroallergens and venoms. In this issue, Chu et al⁴ examine whether a similar approach can be applied to food OIT. The authors conducted a prospective, single-center, three-arm, parallel design, randomized, placebo-controlled trial to examine the effects of pre-treatment with H1 (desloratadine) and H2 (ranitidine) antistamines on OIT-induced adverse effects. Pediatric subjects were randomized to receive peanut OIT with anthistamines, peanut OIT and placebo for antihistamines, or double placebo. Individuals were up-dosed using an established peanut OIT protocol until reaching maintenance dose of 500 mg of peanut protein. Primary outcomes were the risk and incidence of adverse reactions over time. Health-related quality of life was assessed as a secondary endpoint. Desensitization outcomes were assessed using a double-blind, placebo-controlled food challenge after at least 4 weeks of maintenance therapy.

Consistent with prior studies², OIT increased the risk for adverse events (AEs). This was true with or without anthihistamines compared to the double-placebo group. Notably, the incident rate ratio for moderate to severe adverse events with antihistamine premedication was approximately half the incident rate ratio for the group that received OIT alone. When specific AEs were examined, this effect was primarily driven by a reduction in urticaria. Indeed, rates of urticaria for the pretreatment and the double-placebo group were almost the same. A similar decrease was observed for abdominal pain that did not reach statistical significance. Unfortunately, antihistamine use also increased the indicence of neuropsychiatric events (ie, dizziness and fatigue). Quality of life scores improved in all three treatment arms and the group receiving OIT and anthistamines had slightly lower scores than did the group receiving OIT alone. With regards to treatment efficacy, pretreatment did not significantly increase the eliciting dose after OIT desensitization. Dropout rates were similar between both groups receiving OIT.

Previous and ongoing attempts to enhance the safety of OIT use non-pharmacologic, pharmacologic, and biologic approaches. Non-pharmacologic approaches include early age at initiation, dose modification, avoidance of augmentation factors, and priobiotics. Generally, moderate to severe AEs are an indication to hold at the current dose, down-dose, or discontinue OIT. Goldberg et al.⁵ recently showed that dose modification or temporary cessation may facilitate desensitization in a subset of individuals with OIT-induced gastrointestinal symptoms and peripheral eosinophilia. Exercise and sleep deprivation are modifiable augmentation factors that may decrease the threshold for reactivity.⁶ Finally, probiotics (Lactobacillus rhamnosus ATCC 53103) combined with peanut OIT may reduce GI AEs in younger children (aged 1–5 years).⁷

In terms of pharmacologic approaches, antihistamines are inexpensive and widely available. As such, they are potentially important first-line agents for prophylaxis. Pretreatment with anthistamines is commonly employed by centers and practitioners offering food OIT, but until now, the evidence for this approach was based on data extrapolated from studies of other disease states. The only studies similar to the current one are a restrospective case series of 5 patients with intractable abdominal pain, who were able to achieve maintenance therapy after treatment with montelukast⁸ and a small randomized controlled trial (n=6) suggesting ketotifen may reduce gastrointestinal side effects.⁹

Among the currently available biologic agents, omalizumab (anti-IgE) is the most studied as an adjunct to OIT.¹⁰ Omalizumab has been used in combination with single and multi-food OIT and enables rapid dose escalation, but it does not reduce gastrointestinal side effects. Another drawback is that anaphylaxis may be more common after discontinuing omalizumab. As noted by the authors, the OUTMATCH study (NCT03881696) will provide more definitive evidence for the efficacy of omalizumab alone or in combination with OIT. Additional studies examining the efficacy of omalizumab, dupilumab (anti-IL-4rα) and tezepelumab (anti-TSLP) combined with peanut OIT are planned or under way.

The authors demonstrate that antihistamines can mitigate moderate to severe OIT-induced AEs, but a number of open questions remain. This study was too small to determine whether pretreatment can prevent rare and serious events such as anaphylaxis or EoE. Antihistamines are not an effective treatment for EoE and thus are unlikely to prevent OIT-induced EoE. In this study, antihistamines were used daily to prevent adverse reactions. However, chronic antihistamine therapy during OIT increased neuropsychiatric events. This leads us to question: Can patients be treated intermittently as needed to minimize drug-induced AEs? Other important questions include: (1) Can patients requiring pretreatment be identified prior to initiating OIT? (2) Because most reactions occur early in the escalation phase, can anthistamine therapy be limited to the first 6 months? and (3) Can we discern which subjects will need pretreatment with anthistamines versus adjunctive therapy with a more expensive biologic?

In summary, anthistamines modestly decrease OIT-induced AEs, but they can also cause their own side effects. This improvement in safety was not accompanied by increased quality of life. The authors are commended for examining an important question with a robust study design, which allowed for blinded comparisons among treatment groups. Additional studies are needed to identify those individuals who are most likely to benefit from pretreatment and how this approach should be refined.

Abbreviations:

AE

adverse event

EoE

eosinophilic esophagitis

OIT

oral immunotherapy