Sublingual immunotherapy reduces reaction threshold in three patients with wheat‐dependent exercise‐induced anaphylaxis
Authors: Dirk Tomsitz, Tilo Biedermann, Knut Brockow
Journal: Allergy (2021)

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a rare IgE-mediated systemic hypersensitivity reaction caused by the combination of wheat product ingestion and cofactors, such as physical exercise, acetylsalicylic acid and alcohol.1-3 For diagnosis, an appropriate patient's history has to be associated with a sensitization to wheat flour and gluten proteins as detected by skin prick test (SPT), specific IgE and /or basophil activation test (BAT). Confirmation of the diagnosis by oral challenge test (OCT) with gluten and cofactors allows to determine the patient's individual threshold.4 It has been shown that using high amounts of pure gluten for a challenge, a reaction can even be elicited even without cofactors.5 Dietary recommendations range from total avoidance of gluten to temporal separation of wheat ingestion from cofactors. Gluten avoidance has been associated with lower reaction thresholds.6 Currently, no curative treatment such as immunotherapy (IT) has been developed. We describe three patients with WDEIA, who have been treated with a sublingual gluten IT (SLIT) over a course of 3 years. The clinical study was approved by local ethics committee. For this exploratory study, three female patients with a history of several reactions only to a combination of wheat products plus cofactors and positive challenge with pure gluten were diagnosed with WDEIA and gave their informed consent for SLIT. Titrated SPT with pure wheat gluten and wheat protein hydrolysates (Solpro 508) were performed. Levels of specific IgE to wheat flour, gluten, omega-5 gliadin and alpha/beta/gamma-gliadin were measured. BAT was done with wheat gluten and wheat protein hydrolysates in titrated concentrations. The individual threshold for each patient was determined by OCT with gluten and additional cofactors until a reaction was elicited. Immunotherapy was performed by daily sublingual application of 1 mg gluten flour (Kröner, Ibbenbeuren, Germany), which was added with water to form a paste. After 2 min, the gluten had to be chewed and swallowed. All patients were advised to separate wheat ingestion from cofactors by 4 h, but had no formal restrictions. After 6, 12, 18, 24 and 36 months of titrated SPTs, measurements of specific IgE and BAT were repeated. OCT was repeated after 12, 24 and 36 months (overview see Figure 1). All patients performed SLIT regularly. Patients 1 and 2 had no side effects, whereas patient 3 had local sensation of prickling under the tongue in 50% of applications. The titrated SPT showed no relevant change over time. In patient 2 specific IgE levels to omega-5 gliadin decreased from 16.6 kU/L to 10.6 kU/L and to alpha/beta/gamma-gliadins from 2.42 kU/L to 0.35 kU/L. IgE levels in patient 3 did not change at all and were not detectable at all in patient 1. BAT showed a continuous reduction in basophil activation with gluten and Solpro 508 in patient 1 and had an undulant development in patients 2 and 3. The individual thresholds of all patients increased during SLIT. In patient 1, it went from 70 g gluten to a cumulative dosage of 120 g gluten with cofactors, in patient 2 from 20 g gluten to 40 g gluten with cofactors and in patient 3 from 5 g gluten to 80 g gluten with cofactors (Table 1). Of note, no patient developed anaphylaxis despite continuous consumption of wheat products during the treatment. After 6 and 9 months of treatment, patient 2 developed urticaria after eating pancake and patient 3 after consuming spaghetti, both followed by mild exercise. No further systemic reactions occurred afterwards. The results of this first study demonstrate that SLIT with gluten increases the reaction threshold of tolerated gluten with / without cofactors. Titrated SPT, specific IgE and BAT seem not to be predictive parameters, hence OCT remains gold standard for threshold determination. These results are in agreement with a Danish study assessing the influence of diet on wheat intake tolerance reporting a diet without total avoidance of gluten products to be associated with developing an increased reaction threshold.6 However, further studies with a larger population are necessary to confirm our results in this pilot study. This work was supported by the authors' institutes and by research and development grant from the German Federal Ministry of Education and Research (BMBF), project ABROGATE (funding number: 01EA2106A). The authors report no conflict of interest.