Long‐term outcomes of low‐dose followed by conventional oral immunotherapy for egg allergy

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Egg allergy is a leading cause of pediatric food allergies. While many children outgrow it by school age, those with persistent allergies, especially with a history of anaphylaxis and high egg-specific immunoglobulin E (sIgE) levels, have low tolerance rates.1 Oral immunotherapy (OIT) induces desensitization; low-dose OIT may enhance safety and feasibility by lowering maintenance doses; however long-term outcomes are not well understood.2, 3 This study investigated 8-year follow-up data on patients who initially received low-dose OIT for low-threshold egg allergy, followed by conventional OIT. This prospective, single-center study was conducted at Sagamihara National Hospital from September 2013 to August 2022 (UMIN: 000011202). Eligibility criteria included children aged ≥5 years with objective symptoms to ≤194 mg egg protein during an oral food challenge (OFC) and who consented to OIT. The median age was 8.7 years, with 85.7% participants having a history of egg anaphylaxis. The median threshold dose was 194 mg; egg white- and ovomucoid-sIgE levels were 50 and 39 kUA/L, respectively (Table S1). The initial low-dose OIT protocol has been previously reported.4 We report outcomes from the second year onward, including addition of conventional OIT for 21 subjects who initially received low-dose OIT.4 In the second year, the upper limit for egg protein was 3100 mg. From the third year onward, it was increased to 6200 mg (equivalent to one heated egg). Participants ingested heated hen's eggs that were scrambled or baked. If adherence to these forms was difficult, processed foods (e.g., bread, processed meats, biscuits, and fish cakes) with equivalent egg protein were allowed. Daily consumption was required until short-term unresponsiveness (STU) to 3100 mg of egg protein was achieved; thereafter, intake was reduced to at least two to three times per week (Figure S1). An annual OFC after 2 weeks of egg avoidance was conducted to evaluate STU at 3100 or 6200 mg. Subjects passing a 3100 mg OFC and consuming this amount without symptoms were classified as “3100 mg STU”; those passing an OFC with one heated egg and consumed it without symptoms were classified as “6200 mg STU.” Subjects not achieving 3100 mg STU by the study's end were categorized as non-STU. Dropouts were defined as individuals discontinuing follow-up before achieving 3100 mg STU during the 8-year period. Egg white- and ovomucoid-sIgE levels were measured annually. Statistical analyses used Fisher's exact test and Wilcoxon's signed rank test, with significance set at p < .05. Ethical approval was obtained from the Sagamihara National Hospital Ethics Committee; all data were anonymized. During the 8-year study, five patients dropped out, three due to adverse reactions. The proportion of subjects achieving 3100 mg STU increased progressively: 5% (n = 1) in the first year, 29% (n = 6) in the second year, 48% (n = 10) in the third and fourth years, 67% (n = 14) in the fifth and sixth years, and 71% (n = 15) in the seventh and eighth years (Figure 1). Additionally, 10% (n = 2), 24% (n = 5), and 29% (n = 6) of subjects reached 6200 mg STU in the fourth, sixth, and eighth years. Adverse reactions occurred in 4.9% (1370 times) out of 28,099 doses taken at home, with moderate and severe symptoms in 0.4% (113 times) and 0.004% (one time), respectively. Anaphylaxis and adrenaline use occurred in 0.004% (one time) of all doses. Frequency of adverse reactions decreased significantly over time in the trend test (p = .006) (Table 1). During the evaluation period, 29% (n = 6) of patients continued consuming scrambled egg; other patients consumed baked egg and/or processed products. Egg white- and ovomucoid-sIgE levels decreased significantly over the 8-year follow-up (89% and 93% reductions, respectively; p < .001; Figure S2). No significant differences were observed in patient backgrounds between the 3100 mg STU group and non-STU group. However, the 3100 mg STU group tended to have lower baseline egg white- and ovomucoid-sIgE levels (39.1 and 36.8 kUA/L) than the non-STU group (79.9 and 81.0 kUA/L), with p-values of 0.235 and 0.066, respectively. This study is the first to report 8-year follow-up results of combination OIT with low-dose and conventional OIT. Here, the proportion achieving 3100 mg STU increased over time, reaching 71% after 8 years. Taniguchi et al. reported a 26.5% tolerance rate to half or whole heated egg by age 12 in patients with anaphylaxis and a positive 194 mg egg protein OFC at age six.1 Our subjects had comparable or more severe allergies, suggesting effectiveness even in high-risk cases. In our study, 29% participants achieved 6200 mg STU after 8 years. Jones et al. reported that 50% of patients on OIT for 4 years achieved sustained unresponsiveness to one egg,5 with 5% experiencing adverse reactions and 1.6% requiring treatment after the third year.5 Despite the severity of allergies and longer evaluation in our study, adverse reactions and treatment rates were lower. Sugiura et al. showed that 34.7% of egg-allergic patients achieved desensitization to 10 times the initial threshold with slow low-dose OIT over a year, without needing adrenaline or emergency care, supporting safety.6 Prior OIT protocols indicates that conventional OIT is faster for desensitization and sustained unresponsiveness.7 Our study balances low-dose safety with the efficacy of conventional OIT. In our study, adverse reactions significantly decreased over time, with most being mild. Severe symptoms, anaphylaxis, and adrenaline use were reported in a single case. Similarly, Nagakura et al. reported fewer adverse reactions during long-term wheat OIT, with no anaphylaxis after the second year.2 These findings suggest that OIT becomes safer over time, with a reduced risk of severe reactions, including anaphylaxis. Additionally, increasing the maintenance dose with conventional OIT after the second year does not increase adverse reactions. In our study, egg white- and ovomucoid-sIgE levels decreased by 69% and 74% at 3 years, and by 89% and 93% over 8 years. Perezábad et al. reported an 80% reduction in both markers after 1 year of higher dose OIT.8 Sasamoto et al. observed 62% and 72% reductions in egg white- and ovomucoid-sIgE after 3 years with a 1/6 egg maintenance dose.9 These findings suggest that starting with low-dose OIT and avoiding rapid escalation may gradually reduce sIgE levels. However, combining low-dose with conventional OIT may achieve reductions comparable to or exceeding those reported by Sasamoto et al., with sustained long-term improvement. The present study has several limitations. First, our study has a non-randomized design; we observed a higher STU rate than previous natural history studies, supporting strong efficacy. Second, the 2-week elimination before the confirmatory OFC was relatively short for assessing sustained unresponsiveness. Third, the sample size was small, and dropout rate was 24%. However, a prior high-dose OIT study reported a 37.5% dropout rate,5 suggesting that starting with low doses may be advantageous for achieving higher adherence. Finally, we did not routinely evaluate sustained unresponsiveness to unheated egg, because it is not common in Japanese school meals due to infection risk. Combination OIT with low-dose and conventional OIT enabled over 70% of severe egg allergy patients to ingest half a heated egg over 8 years, with rare severe symptoms and significant immunological changes. This study supports real-world allergy management and provides evidence that prolonged treatment improves outcomes, advocating for long-term OIT. Kento Takahashi: Writing – original draft; conceptualization; data curation; formal analysis; investigation. Ken-ichi Nagakura: Supervision; conceptualization; writing – review and editing. Yoko Miura: Conceptualization; supervision. Sakura Sato: Conceptualization; supervision; methodology. Motohiro Ebisawa: Conceptualization; supervision; project administration; resources. Noriyuki Yanagida: Supervision; conceptualization; methodology. We thank the participating children, parents, and Sagamihara National Hospital staff. We also express our gratitude to Editage (www.editage.com) for their English language editing support. This research was supported by the Practical Research Project for Allergic Disease and Immunology from the Japan Agency for Medical Research and Development (AMED, 17ek0410019h0003). Motohiro Ebisawa received consulting fees from Novartis, Sanofi, and ARS Pharmaceuticals, and honoraria from Viatris. The other authors report no conflicts of interest. Ethical approval for this study was obtained from the Institutional Review Board at Sagamihara National Hospital, and all procedures were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants or their legal guardians. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) and the registration number is 000011202. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Figure S1. Figure S2. Table S1. Figure Legend. 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