We reviewed 567 anaphylactic reactions in 283 patients. Of these anaphylactic reactions, 415 (73.3%) reactions were severe, potentially life-threatening anaphylaxis. The 334 (59.2%) reactions included collapse or loss of consciousness while 64 reactions (11.3%) manifested incontinence.
Recurrent anaphylaxis in wheat-dependent, exercise-induced anaphylaxis patients
Eighty-three (70%) patients had experienced more than two prior episodes. In total, the patients had an average of 3.5 ± 3.0 (range 1–30) anaphylaxis episodes, and 11 patients experienced more than 10 previous episodes. Table 2 shows the characteristics of the 11 patients with more than 10 anaphylactic reactions before their visits. The time duration from the first reaction to diagnosis ranged from 2 to 27 months.
Cofactors of wheat-dependent, exercise-induced anaphylaxis
Among the 567 anaphylactic reactions, 75% (425/567) occurred during exercise. Among those 425 reactions, 127 (30%) reactions occurred during relatively high exercise intensity (such as badminton, basketball, running, mountaineering, and table tennis), and the remaining 298 (70%) reactions took place during lower exercise intensity (such as walking and doing housework). The length of time from initiation of exercise to anaphylaxis ranged from 15 to 60 min. A total of 48 reactions occurred after orally taking aspirin.
Diagnostic value of wheat/gluten/ω-5 gliadin
Among 283 patients, 223 patients were detected with all three wheat components. We excluded the remaining 60 patients whose data were incomplete for statistics. The positive and negative number of three wheat allergen in vitro diagnostic tests in WDEIA and control patients are shown in Tables 3 and 4. We used clinical comprehensive evaluation by allergists as the reference gold standard, which mainly depended on the confirmed anaphylactic reactions triggered by wheat. In the patients with clinically diagnosed WDEIA, the sensitivities of the test for wheat-, gluten-, and ω-5 gliadin-specific immunoglobin E (sIgE) were 61.9%, 85.2%, and 76.7%, respectively. The specificities calculated using the data from the control groups were 91.3%, 96.4%, and 98.5% for wheat, gluten, and ω-5 gliadin, respectively. In combination, the sensitivity and specificity of gluten- plus ω-5 gliadin sIgE were 73.1% and 99.0%, respectively. The highest positive predictive value was 97.6%, for the combination of gluten and ω-5 sIgE [Table 5].
To evaluate the diagnostic utility of the in vitro sIgE tests in WDEIA patients, ROC analyses for each diagnostic test were performed. The areas under the curve (AUCs) received from the ROC analysis for each test showed the highest value for the gluten test (0.910), 0.879 for ω-5 gliadin, and 0.794 for wheat.
During the follow-up period, almost all patients avoided further anaphylaxis by abiding to strict avoidance of wheat product in association with exercise or other cofactors. Moreover, 59% of the patients can eat wheat product without severe reactions, as long as they avoid exercise.
This is the largest investigation of pediatric and adult patients with WDEIA in China. Seventy percent of WDEIA patients experienced recurrent anaphylactic reactions before their clinic visits. Our previous study has suggested that wheat allergy was a potential risk factor for life-threatening and recurrent anaphylaxis. Mullins suggested that the highest risk of recurrent anaphylaxis was associated with sensitivity to wheat. Possible explanations for why recurrence is so common are that WDEIA is difficult to diagnose and currently clinically underrecognized in China. Some patients were referred to our clinics with the previous diagnosis of “idiopathic anaphylaxis;” elderly patients were referred to cardiology for recurrent shock. Another reason is that unknowingly ingesting wheat products or wheat allergens hidden in other food may induce recurrent anaphylaxis. Our study documented that WDEIA becomes an important diagnostic consideration in patients presenting with recurrent anaphylaxis without an obvious allergenic trigger.
Our study showed that 64% of WDEIA patients also had a history of recurrent urticaria, which suggested that recurrent urticaria may be a mild presentation of wheat allergy. With the addition of cofactors, such as exercise or aspirin ingestion, severe systemic reactions occurred. In this regard, Wong et al. reported one WDEIA patient who presented with mild urticaria following wheat ingestion, who had exaggerated symptoms if ingestion when followed by physical activity.
The exercise intensity required to induce anaphylaxis varied among patients. In our study, the majority of reactions occurred following lower exercise intensity (such as walking and doing housework). Wong et al. showed that relatively low exercise intensity (walking <15 min) can provoke a reaction in WDEIA patients, so Wong et al. proposed that it may also be worth considering an alternative terminology such as “activity-dependent wheat allergy” to describe WDEIA more accurately.
Besides exercise, our present study indicated that aspirin was an important cofactor of severe anaphylaxis reactions in WDEIA patients. We have reported 20 WDEIA cases in which life-threatening reactions were experienced after taking aspirin. Several WDEIA cases were previously reported[11, 12] where anaphylaxis was induced by aspirin but not by exercise after wheat ingestion. Aspirin is known to cause damage to the intracellular tight junction in the GI mucosa, which could lead to changes in GI permeability and increase skin testing reactions.[13, 14, 15] It is thus speculated that the absorption of food allergens through the GI tract provokes and enhances anaphylactic symptoms in patients with food allergy.
Our study revealed that the gluten sIgE (f79) rather than omega-5 gliadin sIgE (f416) showed the best diagnostic value, based on ROC analysis. Gluten sIgE combined with omega-5 gliadin sIgE showed the best diagnostic value. Our findings were different from prior studies which suggested that omega-5 gliadin was the best marker for the diagnosis of WDEIA. Kennard et al. reported 132 WDEIA patients in four UK centers that the positive omega-5 gliadin sIgE was 100% and for wheat and gluten were 59% and 76%, respectively. Matsuo et al. documented that the highest AUC (0.850) was observed in the test for ω-5 gliadin, and the sensitivities of the allergen-specific IgE tests for wheat, gluten, and ω-5 gliadin were 48%, 56%, and 80%, respectively. Similar finding from Takahashi et al.'s study showed that the sensitivity and specificity of omega-5 gliadin were 81.3% and 100%, respectively, or 93.8% and 92.9% when combined with high-molecular-weight glutenin (HMW glutenin). In this regard, Matsuo et al. indicated that there is another minor subgroup of patients who have IgE antibodies that mainly reacts to an HMW glutenin subunit of gluten.
We propose new diagnostic criteria and new management of WDEIA patients based on the present data, alongside the anaphylaxis NIAID 2006 criteria and recently published diagnosis and management in FDEIA patients in the outpatient setting.
Clinical criteria for diagnosing wheat-dependent, exercise-induced anaphylaxis in China
WDEIA is highly likely when criteria 1, 2, 3, and 4 or 1, 2, 3, and 5 are fulfilled
- Signs and symptoms consistent with anaphylaxis that occurred during exercise but only when exercise was preceded by wheat product ingestion were:
- Acute onset (minutes to several hours) with involvement of the skin and/or mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, and swollen lips-tongue-uvula) and at least one of the following.
- Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, and hypoxemia)
- Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypertonia, syncope, and incontinence).
- Two or more of the following occurring rapidly after exposure to a wheat allergen (minutes to several hours):
- Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, and swollen lips-tongue-uvula)
- Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, and hypoxemia)
- Reduced BP or associated symptoms (e.g., hypotonia, syncope, and incontinence)
- Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, and vomiting).
- Onset when patients undertook exercise within 6 hours after eating a wheat product.
- Evidence of type I hypersensitivity to wheat: positive specific IgE to wheat extracts, especially to gluten and/or ω-5-gliadin, or positive skin testing to gluten and/or gliadins.
- Successful avoidance of WDEIA when avoiding consumption of wheat products or when avoiding exercise within 6 hours after eating wheat related foods.
- Symptoms may occur without exercise involvement; however, in the presence of other augmenting factors such as nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and alcohol.
Clinical recommendations for patients with WDEIA and Management of WDEIA patients:
- Avoid wheat products for 4–6 h before exercise
- Avoid other possible augmenting factors when taking wheat products (such as NSAIDs, alcohol, infection)
- Patients with cardiovascular diseases prescribed daily aspirin should strictly avoid wheat products or food containing gluten
- Epinephrine injections and a mobile phone should always be available when exercising
- Take first-generation H1 antihistamines (such as Cetirizine dihydrochloride oral drops) when early skin symptoms occur
- Inhale short-acting β2-adrenoceptor agonists (such as salbutamol) when asthmatic symptoms occur.
In conclusion, WDEIA is under-diagnosed and underestimated in China. WDEIA should be included in the differential diagnosis of patients presenting with idiopathic allergic reactions and recurrent urticaria. Alternative terminology such as “activity-dependent wheat allergy” might more accurately describe this condition. Confirmed anaphylactic reactions triggered by wheat with positive sIgE response to ω-5-gliadin or gluten can provide supporting evidence for clinicians to make the diagnosis with no food exercise challenge test. Efforts to raise clinical awareness, and use of these targeted sIgE tests, will be valuable for the diagnosis and management of this condition.
Financial support and sponsorship
This study was supported by grants from the CAMS Innovation Fund for Medical Sciences (No. 2016-I2M-1-003) and the Natural Science Foundation of China (No. 81273277).
Conflicts of interest
There are no conflicts of interest.
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Edited by: Qiang Shi
Keywords:© 2018 Chinese Medical Association
Anaphylaxis; China; Gliadin; Oral Food Challenge; Wheat-Dependent Exercise-Induced Anaphylaxis