As the most widely consumed food grain in China, wheat is reported as the commonest allergen of food-dependent exercise-induced anaphylaxis [12]. Unfortunately, WDEIA is a life-threatening disorder with no cure. To prevent future anaphylaxis, a wheat-free diet or the avoidance of wheat ingestion combined with cofactors is recommended [4, 15]. However, we have observed that after diagnosis, the dietary/lifestyle patterns selected by patients with WDEIA vary greatly, and some patients experienced recurrent anaphylaxis.

Similar with the population in previous studies [10, 11, 17], 54%–60% of the patients with WDEIA were men, and the median age of diagnosis was 41–44 years. Moreover, the median age of men at the time of diagnosis has been reported to be more than that of women [11], although the difference was not significant (38.5 years vs 35.0 years, P = 0.119) in our study. The relationship between the time of disease diagnosis and sex requires further analysis. In this study, the proportion of patients was higher from North China than from South China, which may be related to the different dietary habits of different regions.

Diagnosing WDEIA has long been challenging [18]. Our research revealed that the median duration of anaphylaxis was 16 months before diagnosis, and 52.7% of the patients experienced significant delays in diagnosis of > 1 year. The delay time of diagnosis was different between studies. In a study by Wong et al. [19], the average time taken for WDEIA to be diagnosed was 28.5 (2–62) months. The delay was 32 to 62 months before diagnosis in half of the patients. Meanwhile, in Kennard et al.’s [11] retrospective study of 132 patients with WDEIA in four UK centers, 66.7% of patients had a delay in diagnosis of > 1 year, including 40% of patients with a delay in diagnosis of 1 to 5 years and 29% with a delay in diagnosis of > 5 years. The time of misdiagnosis in our study may be shorter than that in previous studies [20], although we did not find a decreasing trend in the past 13 years. This may be because most patients had taken wheat as a staple grain for a long time without allergic symptoms, and they may not experience anaphylaxis after each wheat ingestion, leading to challenges in identifying wheat as the responsible allergen by both the physicians and patients.

In line with a study done by Kraft et al. [3], our study demonstrated that cardiovascular symptoms presented frequently and respiratory symptoms presented less commonly in anaphylaxis to wheat. Cofactors play important roles in anaphylaxis reactions in patients with WDEIA [21]. Exercise has been reported as a cofactor in 82.8% of reactions to wheat in adults [3], which is consistent with our data. Alcohol has been reported as a cofactor in 25% ofpatients [11], which is higher than that in our study. This may be related to different dietary habits. Exercise, NSAIDs, and alcohol have been reported to increase gastrointestinal permeability, thus inducing absorption of allergens from the gastrointestinal tract into the circulation [22,23,24]. Additionally, exercise may increase immunogenicity of ω-5 gliadin, and NSAIDs may affect mast cell degranulation [21, 25]. Similarly, Kennard et al. [11] reported that 11% of patients with WDEIA had no identifiable cofactor and it has been shown that cofactors may not be necessary if wheat intake is high enough [18], indicating that cofactors mainly reduce the threshold of immune response to wheat, which provides a possible explanation for why cofactors are not always identified. In addition, the definition of exercise varies widely among individual patients, which is difficult to evaluate. In this study, the positive rate of specific IgE to wheat, gluten, and ω-5 gliadin was 52.7%, 86.5%, and 98.1%, respectively. Similarly, Kennard et al. 11 have reported that in 132 patients, 59%, 76%, and 100%, were positive for specific IgE to wheat, gluten, and ω-5 gliadin, respectively. ω-5 gliadin and high molecular weight-gluten subunit (HMW-glutenin) are two main wheat allergens for WDEIA [9, 26]. The sensitivity of specific IgE antibodies to ω-5 gliadin and gluten was identified 18 to be both 100%, with specificities of 97% and 95%, respectively. Our previous study has identified that the sensitivity and specificity of combined specific IgE to gluten and omega-5 gliadin were 73.1% and 99%, respectively, which are valuable for the diagnosis of WDEIA [10]. We found that there is in vitro cross-reaction with rye, barley, or oat in a small number of patients with WDEIA, which has also been observed in another study [11]. Therefore, attention should be paid to potential cross-reactivity with other cereals. Herein, 80.0% of patients had no anaphylaxis post-diagnosis. A total wheat-free diet or the avoidance of wheat ingestion combined with cofactors is recommended to prevent further episodes of WDEIA [4, 15]. A wheat-free diet was the most effective management in this study. Meanwhile, in another study [11], a wheat-free diet led to only a 29% reduction in the risk of future anaphylaxis, and this may be due to different dietary/lifestyle habits between countries and patients. Similar to previous studies [12, 20], complete avoidance of wheat intake or avoidance of wheat products combined with exercise helped patients with WDEIA avoid further anaphylaxis effectively. Christensen et al. [27] have reported that the threshold in WDEIA may decrease in patients on a wheat-free diet, whereas the opposite is observed in patients with regular wheat intake. As a main staple, wheat can be difficult for patients to avoid. The avoidance of wheat in combination with exercise or reduced wheat ingestion combined with exercise avoidance could be selected, if considered safe for the patients. However, attention should be paid to the effect of unintentional exercise after wheat consumption.

Wheat tolerance can be achieved in 76% of children with wheat allergy within 18 years of age [28]. Meanwhile, studies have suggested that 20.5%, 54.2%, and 66.3% of children with a history of immediate-type allergic reaction to wheat, acquired tolerance to 200 g of udon noodles at 3, 5, and 6 years of age, respectively [29]. In a cohort study [30], 10 adult patients with wheat allergy were followed up for 5 years, and nine of them achieved wheat tolerance at the end of the follow-up, including two patients with wheat-dependent exercise-induced urticaria. However, there is a lack of long-term follow-up studies for patients with WDEIA. Among the 155 patients with WDEIA in our study, only one reported achieving wheat tolerance. Due to ethical reasons, evaluating the changes of wheat tolerance in these patients was impossible. The prognosis of WDEIA appears to be less favorable than that of wheat allergy. Further studies are needed to investigate the different mechanisms of allergen tolerance between WDEIA and wheat allergy.

As the first long-term follow-up study to investigate the management and outcomes of patients with WDEIA in China, this study provides reference for the treatment of WDEIA. However, this study had some limitations. First this study might have recall bias owing to its retrospective nature. Second, it was not possible to follow-up with all patients because the follow-up data of 155 patients were obtained by telephone, and 42 patients changed their telephone number or refused to answer the call. Thirdly, a provocation food challenge was not performed to confirm the diagnosis due to ethical concerns. Furthermore, wheat challenges are needed to determine changes in the threshold in WDEIA.