Discussion
Evidence on EIARD after slow OIT is scarce. Herein, EIARDs were observed in some patients with IgE-mediated wheat or CM allergy after slow OIT. Although we could not identify the factors associated with developing EIARDs, to the best of our knowledge, this is the first case-control study of EIARD after slow OIT.
FDEIA is another type of food allergy induced by exercise after ingestion of the causative antigen despite there being no immediate history of allergy with the causal food in the past. Although wheat is a major causative antigen of FDEIA, CM as a causative agent is rare.20 EIARDs are considered to be the residual symptoms of immediate food allergies at the time of incomplete desensitization. This indicates that EIARDs and FDEIAs have completely different pathologies.
Although the pathophysiology of EIARDs is currently unclear, exercise reduces the symptom-provoked threshold by 45% in patients with a peanut allergy.21 Thus, even patients who become desensitized by more than a full dose may still develop allergic symptoms by the lowering of the symptom-provoking threshold with exercise. Increasing the amount of absorbed antigen with exercise might affect this phenomenon.22
Exercise should be avoided for two hours after ingestion of the antigen during OIT, including during the maintenance phase, to reduce the risk of inducing allergic symptoms.23 Therefore, evaluation of the absence of EIARDs is important to ensure safety during daily meals, including school meals. The definitive evaluation using an EPT is desirable in those patients who have an unstable occurrence of allergic symptoms during OIT, or in those who have a suspected episode of EIARD after OIT. However, one negative EPT is not enough to exclude the possibility of having EIARD. The absence of allergic symptoms should be reconfirmed at home. Although it is not easy to completely exclude EIARD, this procedure is important to avoid unnecessary restrictions on combining consumption with exercise.24 In addition, once the presence of EIARD is diagnosed, subsequent EPTs may be worthwhile to evaluate the cessation of EIARD.
With respect to risk factors of EIARDs, we were unable to identify predictive factors among patients who developed desensitization. In terms of antibody titers, in most cases, the post-OIT sIgE level was lower than the pre-OIT level. This may have been due to the effect of the OIT.25 However, there were no significant differences in either CM or wheat sIgE before OIT, nor any changes in the values before or after OIT between the EIARD-positive and EIARD-negative groups. Moreover, there were some cases of negative ω-5 gliadin sIgE levels after OIT among patients in the wheat EIARD-positive group. One patient in the CM EIARD-positive group was also negative for both CM and casein sIgE measured after the OIT. In previously reported cases of EIARDs, after slow OIT, casein and ω-5 gliadin sIgE levels measured immediately before OIT were negative.12,14These findings support the conclusion that blood antibody titers are not predictive of EIARDs.
Sustained unresponsiveness (SU) has been identified as an indicator of the therapeutic effect of OIT.8 However, the relationship between SU and EIARDs has not been evaluated in the present study. We instructed the patients to introduce CM and wheat products in their daily diet, preferably to enable routine consumption rather than to evaluate the achievement of SU. One institution in Japan reported that 41% of patients who were confirmed to have 2 weeks of SU after OIT experienced allergic symptoms including anaphylaxis within 4 years of confirmation of SU.26 Importantly, the most common trigger of the symptoms was exercise. Therefore, even patients diagnosed with SU may still be at risk of EIARDs.
This study found that EIARDs may remain for several years after slow OIT, in patients who continued to consume daily amounts of antigen. Thus, EIARDs are an indicator of a state of desensitization that has not yet reached tolerance. Considering the patient’s daily life after OIT, the use of EIARDs as an indicator of the effectiveness of OITs, in addition to SU, should be expanded.
We did not routinely examine EPTs in patients who developed uneventful desensitization to the full antigen dose accompanied by physical exercise. At our institution, approximately 30 patients per year achieve desensitization to the full dose of CM and wheat without developing EIARD. This suggested that roughly 5-10% of the patients who achieved desensitization after slow OIT developed EIARD.
A nationwide survey in Japan found that OITs were performed more frequently in 2015 than in 2011.27 Consequently, occurrence of allergic symptoms during exercise in desensitized children has become a significant issue at school. Physicians are expected to evaluate the possibility of an EIARD before permitting patients to consume the target food in their daily meals, especially at school. Currently, EPT is the only, if not the best, procedure to determine the appearance of an EIARD. However, performing an EPT requires big medical resources. Furthermore, it is burdensome for the patients and is accompanied by the risk of anaphylaxis. Further studies are needed to identify the risk factors of EIARD and develop alternative diagnostic methods.
This study has some limitations. First, owing to the retrospective nature of the study, we could not calculate the actual frequency of EIARD occurrence after OIT. Second, we categorized into EIARD-positive and negative, only those patients who had undergone an EPT because they were identified to have a high risk of developing EIARDs. The risk factors of EIARD should be assessed in a prospective manner, in desensitized patients who are not suspected of developing an EIARD. Further prospective studies are warranted to determine the predictive factors and alternative diagnostic methods of EIARDs.
In conclusion, EIARDs were observed after slow OIT for CM and wheat. EIARD influences the daily meals of even those patients, who are desensitized to the full dose of the allergen. Evaluation of EIARDs after OIT should be important in the clinical management of patients with food allergies. Further research into the predictive factors of EIARDs is needed to understand its clinical manifestations.