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.