To the Editor,
Wheat allergy is one of the most common forms of food allergy in the pediatric population. 1 , 2
Oral immunotherapy (OIT) is the main disease‐modifying approach under investigation for food allergy, 3 but adverse reactions, especially during the build‐up phase, remain a key barrier to adherence. 4 , 5 Patient heterogeneity and variation in OIT protocols (e.g., food forms and escalation schedules) contribute to inconsistent outcomes; therefore, patient‐tailored desensitization strategies are clinically relevant.
We hypothesized that a constant increment dosing schedule based on the BACH (Building‐An‐Augmentation‐Curve‐Harmoniously) principle could improve safety and efficacy. 6
This pilot/feasibility study evaluated three constant‐increment wheat OIT protocols with individualized starting doses based on baseline OFC thresholds; outcomes were desensitization and immunologic changes (not powered for between‐protocol comparisons). Nineteen children were screened; one was excluded at screening due to a predefined exclusion criterion (pre‐existing eosinophilic esophagitis). Eighteen were enrolled; three (two OIT and one control) did not complete follow‐up, thus fifteen children completed the study: 10 (9 boys; mean age 7.7 years) underwent a 1‐year home OIT regimen (OIT‐group) and 5 (4 boys; mean age 7.2 years), whose parents declined OIT served as untreated controls. All controls had documented recent (<1 month) reactions to wheat (two anaphylaxis, three urticaria) and were followed for one‐year. Inclusion criteria were age 2–16 years; IgE‐mediated wheat allergy with a physician documented reaction within 1 year; positive wheat SPT (>3 mm), and/or wheat specific IgE f4 >0.35 kUa/L; positive baseline OFC, unless exempted in participants with a physician‐documented IgE‐mediated reaction to wheat within 3 months prior to enrolment [no OIT participant met this OFC‐exemption criterion (n = 0), therefore all enrolled OIT participants underwent baseline OFC]; and written informed consent from a parent or legal guardian. Exclusion criteria included uncontrolled asthma or significant pulmonary disease; severe anaphylactic reaction to wheat requiring Intensive Care Unit (ICU) admission within the past 12 months; current immunotherapy, subcutaneous/sublingual (SCIT/SLIT), biologics or other immunomodulatory treatment; wheat‐dependent exercise induced anaphylaxis; celiac disease or other non‐IgE‐mediated wheat‐related disorders; eosinophilic gastrointestinal diseases; presence of cardiovascular disease or other significant systemic diseases; and/or severe anaphylactic reaction to very low wheat doses (<0.024 gr of wheat protein during baseline OFC).
Following initial evaluation, a baseline OFC was performed within 7–30 days to determine each patient's reactivity threshold and starting dose. Patients were instructed to consume wheat daily, with weekly dose escalations. Wheat pasta (Misko No 6, 12% protein), free from cross‐contamination was used for both OFCs and OIT dosing. Upon reaching the predefined maintenance dose (23 gr of boiled wheat pasta/2.76 gr of wheat protein) a clinical reassessment was conducted. Patients then continued daily intake of the maintenance dose (or equivalent) for additional 6 months, followed by a final reassessment, including repeat testing and a second OFC. The baseline OFC consisted of sequential doses (0.09–0.9–2.7–9.6–27–75 gr), while the second OFC included higher doses (3–42 gr), administered at 30‐min intervals. In case of second OFC failure, patients continued maintenance dosing for an additional 3 months before reevaluation. Caregivers received standardized training in symptom recognition and epinephrine use, with 24/7 physician access. Adverse reactions were prospectively recorded from caregiver real‐time reports and clinic contacts; events were graded using Sampson's severity criteria.
Allergy evaluation included SPTs, total and component—resolved wheat specific IgEs (f4, f79, f98, f416, f433) (ImmunoCAP, Thermo Fisher Scientific, Uppsala, Sweden), Basophil Activation Test (BAT) 7 and celiac serology at baseline and study completion. Ethical approval was obtained from the institutional review board of “P. & A. Kyriakou Children's Hospital”. Written informed consent was obtained from all participants' guardians. The study was registered (NCT03352193), and analyses were conducted using SPSS 26.0. As a pilot/feasibility study, no formal sample size calculation was performed; analyses are descriptive and exploratory.
Based on baseline OFC thresholds, participants were assigned to one of three desensitization protocols (Table 1), designed according to clinical experience and the BACH principle to achieve the same maintenance dose over 27 weeks. Protocol allocation was pragmatic (no predefined eliciting dose/ED cutoffs) and based on baseline ED, reaction severity, clinical history, and family preference after discussion with parents. Protocols differed in starting doses and applied constant weekly escalation rates (Protocol 1: 20%, Protocol 2: 15%, Protocol 3: 10%). Clinical efficacy in the OIT group was assessed by change in OFC reactivity threshold [baseline ED and exit OFC tolerated dose/cumulative tolerated dose]. Controls did not undergo OFC; therefore ED change could not be assessed in controls.
TABLE 1.
Wheat spaghetti desensitization protocols used in the study.
| Weeks | Protocol 1—Grams of spaghetti (before boiling) | Protocol 2—Grams of spaghetti (before boiling) | Protocol 3—Grams of spaghetti (before boiling) |
|---|---|---|---|
| 1 | 0.2 | 0.6 | 2 |
| 2 | 0.24 | 0.7 | 2.2 |
| 3 | 0.29 | 0.8 | 2.4 |
| 4 | 0.34 | 0.9 | 2.6 |
| 5 | 0.41 | 1 | 2.9 |
| 6 | 0.5 | 1.2 | 3.2 |
| 7 | 0.6 | 1.4 | 3.5 |
| 8 | 0.7 | 1.6 | 3.9 |
| 9 | 0.85 | 1.8 | 4.3 |
| 10 | 1 | 2.1 | 4.7 |
| 11 | 1.25 | 2.4 | 5.2 |
| 12 | 1.5 | 2.8 | 5.7 |
| 13 | 1.8 | 3.2 | 6.3 |
| 14 | 2.1 | 3.7 | 6.9 |
| 15 | 2.6 | 4.2 | 7.6 |
| 16 | 3 | 4.9 | 8.4 |
| 17 | 3.7 | 5.6 | 9.2 |
| 18 | 4.4 | 6.4 | 10 |
| 19 | 5.3 | 7.4 | 11 |
| 20 | 6.4 | 8.5 | 12 |
| 21 | 7.6 | 9.8 | 13.5 |
| 22 | 9.2 | 11.3 | 15 |
| 23 | 11 | 13 | 16 |
| 24 | 13.25 | 15 | 18 |
| 25 | 16 | 17.2 | 19.5 |
| 26 | 19 | 19.8 | 21.5 |
| 27 | 23 | 23 | 23 |
No OIT participant met the protocol criteria for OFC exemption (physician‐documented IgE‐mediated reaction to wheat within 3 months prior to enrolment); therefore, all enrolled OIT participants underwent baseline OFC and completed the protocol without serious adverse events. Mild transient reactions occurred in three participants during updosing, resolving with minimal intervention; temporary dose reduction was implemented before resuming escalation (Supplementary Table S1). All children successfully completed the final OFC without symptoms. Baseline characteristics did not differ significantly between groups (Table 2), while allergy diagnosis measurements are depicted in Table 3. Six months post intervention, mean SPT wheal diameter was significantly lower in the ΟΙΤ group compared to controls (p = .009), with a within‐group trend toward significance (p = .074).
TABLE 2.
Clinical characteristics of participants (cases and controls).
| Variable | Cases | Controls | p value | ||
|---|---|---|---|---|---|
| n | Value | N | Value | ||
| Mean age [SD] (years) | 10 | 7.7 [3.56] | 5 | 7.2 [3.85] | 0.807 |
| Males, n (%) | 9 (90%) | 4 (80%) | 0.591 | ||
| Comorbidities | |||||
| Active atopic dermatitis, n (%) | 5 (50%) | 3 (60%) | 0.714 | ||
| Other IgE‐mediated food allergy, n (%) | 8 (80%) | 5 (100%) | 0.283 | ||
| Asthma, n (%) | 4 (40%) | 2 (40%) | 1.0 | ||
| Allergic rhinitis, n (%) | 3 (30%) | 2 (40%) | 0.699 | ||
| Mean ED during baseline OFC [SD] (gr of wheat protein) | 10 | 0.19 [0.19] | — | — | |
| Symptoms severity during baseline OFC based on Sampson's grading | |||||
| 1, n (%) | 5 (50) | ||||
| 2, n (%) | 0 (0) | ||||
| 3, n (%) | 1 (10) | ||||
| 4, n (%) | 4 (40) | ||||
| OIT initial dose | |||||
| 0.2 gr of wheat pasta, n (%) | 5 (50) | ||||
| 0.6 gr of wheat pasta, n (%) | 3 (30) | ||||
| 2 gr of wheat pasta, n (%) | 2 (20) | ||||
| Mean time to reach maintenance [Μin, Max] (months) | |||||
| 0.2 gr of wheat pasta group | 32 [27, 41] | ||||
| 0.6 gr of wheat pasta group | 28 [28, 28] | ||||
| 2 gr of wheat pasta group | 28 [27, 29] | ||||
Abbreviations: ED, eliciting dose, OFC, oral food challenge, OIT, oral immunotherapy, SD, standard deviation.
TABLE 3.
Allergy diagnostic testing of participants (cases and controls).
| Variable | Cases | Controls | p value | ||
|---|---|---|---|---|---|
| n | Value | N | Value | ||
| Mean wheat SPT wheal diameter [SD] (cm) | |||||
| Pre OIT | 10 | 0.72 [0.32] | 5 | 0.84 [0.71] | 0.802 |
| Post OIT | 10 | 0.49 [0.28] | 5 | 1.08 [0.37] | 0.009 |
| Pairwise pre‐post comparison p value | 0.074 | 0.461 | |||
| Mean baseline total IgE [SD] (kUA/L) | 10 | 1210.21 [1291.99] | 5 | 920.06 [950.84] | 0.54 |
| Mean wheat specific F4 [SD] (kUA/L) | |||||
| Pre OIT | 10 | 55.1 [40.6] | 5 | 75.58 [43.14] | 0.519 |
| Post OIT | 10 | 48.92 [40.3] | 5 | 71.26 [43.4] | 0.282 |
| Pairwise pre‐post comparison p value | 0.095 | 0.655 | |||
| Mean F79 [SD] (kUA/L) | |||||
| Pre OIT | 10 | 56.92 [39.03] | 5 | 64.46 [49.26] | 0.751 |
| Post OIT | 9 | 45.66 [36.54] | 5 | 62.16 [51.84] | 0.733 |
| Pairwise Pre‐post comparison p value | 0.01 | 0.655 | |||
| Mean F98 [SD] (kUA/L) | |||||
| Pre OIT | 8 | 40.49 [43.99] | 5 | 60.77 [53.71] | 0.454 |
| Post OIT | 9 | 31.84 [35.6] | 5 | 54.88 [50.03] | 0.384 |
| Pairwise Pre‐post comparison p value | 0.012 | 0.109 | |||
| Mean F416 [SD] (kUA/L) | |||||
| Pre OIT | 10 | 2.97 [4.17] | 5 | 23.66 [42.91] | 0.854 |
| Post OIT | 10 | 0.71 [1.35] | 5 | 22.72 [43.33] | 0.58 |
| Pairwise pre‐post comparison p value | 0.594 | 0.144 | |||
| Mean F433 [SD] (kUA/L) | |||||
| Pre OIT | 8 | 6.23 [12.71] | 5 | 41.58 [46.48] | 0.164 |
| Post OIT | 10 | 4.01 [8.51] | 5 | 23.03 [26.91] | 0.221 |
| Pairwise pre‐post comparison p value | 0.195 | 0.137 | |||
| Mean basophil activation test rate [SD] (%) | |||||
| Pre OIT | 8 | 56.56 [34.83] | 5 | 69.6 [24.91] | 0.884 |
| Post OIT | 9 | 45.22 [31.81] | 5 | 66.12 [13.59] | 0.192 |
| Pairwise pre‐post comparison p value | 0.089 | 0.672 | |||
Note: Bold indicates statistical significance.
Abbreviations: ED, eliciting dose; OIT, oral immunotherapy; Post OIT, 6 months after reaching maintenance dose; SD, standard deviation; SPT, skin prick test.
No significant between‐group differences were observed for F79 and F98 changes; however, both markers decreased significantly within the OIT group. For F4, BAT, and F416, decreases were greater in the OIT group but did not reach statistical significance.
Our constant‐incremental approach differs from conventional protocols that employ larger early doses, which may contribute to higher reaction rates. Compared with studies using faster escalation (often >100%) and reporting epinephrine use, particularly in early phases, 4 , 8 our constant‐increment protocol achieved 100% desensitization with no epinephrine use in this cohort. Desensitization rates in prior studies ranged from 50% to 88.9%, compared to 100% in our cohort. 4 , 8
Moreover, most studies apply uniform protocols despite substantial variability in patient sensitivity and thresholds. We align with Sugiura et al. 9 in advocating for severity‐stratified starting doses based on OFC results, as this may enhance safety.
This study has limitations, including small sample size and absence of OFCs in controls, thus limiting statistical power with regards to safety and efficacy analyses. Absence of follow‐up OFC in controls prevents evaluation of spontaneous change in ED and precludes between‐group comparisons of clinical desensitization threshold; thus, conclusions are limited to within‐treated‐participant changes. The fact that protocol allocation was not based on predefined ED cutoffs but rather on physician judgment and family preference impairs the reproducibility of our results, while potentially introducing subjectivity into patient stratification. Moreover, since children with extremely high‐risk features were excluded for safety in a home‐based protocol, our results may not generalize to this highest‐risk subgroup. However, these are partially offset by the prospective design and inclusion of recently reactive controls. Our preliminary hypothesis‐generating data should be interpreted cautiously but may inform future larger studies.
In conclusion, severity‐stratified wheat OIT using low, constant escalation dosing demonstrated promising feasibility and safety signals in this small cohort, although larger controlled studies are needed to confirm its efficacy and safety.
AUTHOR CONTRIBUTIONS
Nikolaos A. Kitsioulis: Conceptualization; investigation; writing – original draft; methodology; data curation; software; formal analysis; project administration. Paraskevi Xepapadaki: Writing – original draft; writing – review and editing; supervision; investigation; validation; methodology; data curation. Emmanouil Manousakis: Conceptualization; investigation; methodology. Styliani Taka: Formal analysis; methodology; investigation; software. Nikolaos G. Papadopoulos: Conceptualization; writing – review and editing; supervision; validation; methodology.
FUNDING INFORMATION
The authors received no financial support for the research, authorship, and/or publication of this study (ClinicalTrials.gov identifier NCT03352193).
CONFLICT OF INTEREST STATEMENT
The authors have no relevant conflicts of interest to declare.
Supporting information
Table S1. Patients' adverse reactions during OIT.
ACKNOWLEDGMENT
The publication of this article in OA mode was financially supported by HEAL‐Link.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
REFERENCES
- 1. Spolidoro GCI, Ali MM, Amera YT, et al. Prevalence estimates of eight big food allergies in Europe: updated systematic review and meta‐analysis. Allergy. 2023;78(9):2361‐2417. [DOI] [PubMed] [Google Scholar]
- 2. Leung AS, Pacharn P, Tangvalelerd S, et al. Food allergy in a changing dietary landscape: a focus on the Asia Pacific region. Pediatr Allergy Immunol. 2024;35(8):e14211. [DOI] [PubMed] [Google Scholar]
- 3. Leeds S, Belmont A, Winfield H, Nowak‐Wegrzyn A. A practical focus on wheat oral immunotherapy. J Food Allergy. 2022;4(2):136‐143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Sato S, Utsunomiya T, Imai T, et al. Wheat oral immunotherapy for wheat‐induced anaphylaxis. J Allergy Clin Immunol. 2015;136(4):1131‐1133. [DOI] [PubMed] [Google Scholar]
- 5. Kulmala P, Pelkonen AS, Kuitunen M, et al. Wheat oral immunotherapy was moderately successful but was associated with very frequent adverse events in children aged 6–18 years. Acta Paediatr. 2018;107(5):861‐870. [DOI] [PubMed] [Google Scholar]
- 6. Meglio P. Oral food desensitization: the BACH proposal for the very gradual reintroduction of a food. Curr Opin Allergy Clin Immunol. 2013;13(3):306‐314. [DOI] [PubMed] [Google Scholar]
- 7. Gabler AM, Gebhard J, Eberlein B, Biedermann T, Scherf KA, Brockow K. The basophil activation test differentiates between patients with wheat‐dependent exercise‐induced anaphylaxis and control subjects using gluten and isolated gluten protein types. Clin Transl Allergy. 2021;11(6):e12050. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Nowak‐Węgrzyn A, Wood RA, Nadeau KC, et al. Multicenter, randomized, double‐blind, placebo‐controlled clinical trial of vital wheat gluten oral immunotherapy. J Allergy Clin Immunol. 2019;143(2):651‐661. [DOI] [PubMed] [Google Scholar]
- 9. Sugiura S, Kitamura K, Makino A, et al. Slow low‐dose oral immunotherapy: threshold and immunological change. Allergol Int. 2020;69(4):601‐609. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Patients' adverse reactions during OIT.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.