Precision Diagnosis and Tolerance Induction in Children With Immediate-type Wheat Allergy

Study Background

Wheat (Triticum aestivum) is one of the foods with wide global consumption and one of the Big 8 foods causing allergy. IgE-mediated wheat allergy tends to be associated with severe anaphylactic reactions when compared with cow's milk, egg and soy. Wheat proteins can be classified into four fractions, namely albumin, globulin, gliadin and glutenin, according to their solubility. Among these proteins, Nilsson reported that omega-5 gliadin had the highest specificity to diagnose IgE-mediated wheat allergy. Wheat allergic children also showed IgE response to glutenins, alpha-, beta-, gamma-gliadins, and alpha amylase inhibitors. Depending on ethnicity and cooking practices, the major wheat allergens causing clinical allergy vary among populations. The diagnostic accuracy of conventional allergy tests such as skin prick test (SPT) and blood sIgE assays for wheat allergy is suboptimal, while the roles of newer diagnostic methods such as basophil activation test (BAT; based on functional IgE-crosslinking) remains poorly defined for this food allergy.

For wheat-dependent exercise-induced anaphylaxis (WDEIA), omega-5 gliadins and high-molecular-weight glutenin subunits were most often reported as major allergens. SPT and sIgE to wheat might be negative, and even sIgE to omega-5 gliadins were only positive in about 80% of these patients. BAT combined with florescence-activated cell sorting is a new approach to complement wheat-dependent exercise-induced anaphylaxis diagnosis. BAT-derived parameters such as the percentage of CD63+ or CD203c+ basophils have been shown to be sensitive biomarkers for wheat allergy. Expression of CD203c induced by purified native omega-5 gliadin provided the best power for discriminating between wheat allergic and tolerant subjects. On the other hand, there has not been any head-to-head comparison between BAT and conventional allergy tests for wheat allergy or evidence on the optimal stepwise algorithms with these allergy tests for diagnosing wheat allergy. Such unmet clinical need prompts our team to look for precision diagnostic approach to wheat allergy in children.

Unlike cow's milk and egg, many children with wheat allergy have persistent allergy into school-age. A large retrospective study from the United States found that about one-third of wheat allergic patients had persistent disease into adolescence. The standard of care for wheat allergy is strict avoidance and prompt treatment of allergic reactions upon accidental ingestion. However, complete wheat avoidance is difficult in real life as it is widely present in common foods such as cakes, noodles, pasta, bread and even seasoning soya sauce.

Food oral immunotherapy (OIT) is conventionally achieved in a long-enough duration that ultimately induces immunological tolerance of patients to oral intake of the allergenic food. The immunological changes resulted from OIT involved both innate and adaptive mechanisms that included reduced mediator release from mast cells and basophils, initial rise followed by decrease in food-specific IgE and increased food-specific IgG4, expansion and affinity maturation of specific memory B cells, and stimulation of regulatory T cells with release of IL-10 and IFN-gamma. Standard OIT protocols consist of three phases. Typically, patients start the first rush phase by eating a very small dose (equal to the eliciting dose from double-blind, placebo-controlled food challenge [DBPCFC]) of the testing food then incrementally for 6-8 doses per day. This phase carries a high risk of systemic reaction. At the end of this phase, patient will be advised about the safe starting dose for home administration. In the next build-up phase, patients will ingest increasing amount of food every 1-2 weeks until they reach the maintenance dose (usually one serving dose). They will maintain this dose for at least 1-2 years, after which be evaluated for outcomes of desensitization and tolerance (or otherwise called sustained unresponsiveness [SU]). Desensitization denotes a condition in which patients can tolerate maintenance dose while consuming food regularly whereas SU denotes ability to tolerate doses even when patients discontinue the regular dosing. There is limited evidence on the safest and most effective OIT protocol for wheat.