To the Editor,
Food protein-induced enterocolitis syndrome (FPIES) is a
non-immunoglobulin E (IgE) mediated food allergy that predominantly
affects infants and is characterized by repetitive vomiting that occurs
1–4 h after the ingestion of causative food. The etiology and
underlying mechanisms of FPIES are not well understood. Recently, egg
yolk (EY) has been recognized as a major causative food of
FPIES.1,2 Most FPIES patients achieve tolerance with
age;3 however, the practice management of
EY-associated FPIES (EY-FPIES) has yet to be established. In a
preliminary analysis of EY-FPIES, we found that the patients who
acquired tolerance to EY had been diagnosed at a significantly younger
age than non-tolerated patients despite no difference in the age of
onset between both patients. This suggested that the early diagnosis and
intervention is beneficial for tolerance acquisition in EY-FPIES. To
investigate this further, we compared clinical outcomes between the
early and late diagnosis of EY-FPIES.
The present study enrolled 21 patients with EY-FPIES (1) diagnosed by
positive oral food challenge (OFC) tests at our hospital between April
2018 and April 2021 who (2) subsequently underwent OFC to evaluate
tolerance acquisition (re-OFC) at least once. The open OFC was performed
by ingestion of a single dose once or three divided doses every 30
minutes. OFC was considered positive for FPIES based on delayed
abdominal reactions without immediate skin or respiratory reactions.
After confirmation by OFC, we instructed all patients to continue
complete elimination of EY, regardless of threshold doses of OFC. We
retrospectively collected data from electronic medical records on sex,
age of first ingestion of EY, disease onset, first visit to our
hospital, diagnosis, specific IgE (sIgE) to EY measured by ImmunoCAP
test at diagnosis, asymptomatic histories of EY consumption before
onset, the number of symptomatic episodes before diagnosis, the period
between the first ingestion of EY and diagnosis of EY-FPIES, and age of
tolerance acquisition. Tolerance acquisition was defined by (1) negative
OFC and (2) the ability of daily EY consumption without FPIES reactions
for three months at home. We divided the patients into the following two
groups according to their age at the time of diagnosis: the early
diagnosis (ED) group (<12 months) and the late diagnosis (LD)
group (≥12 months), and compared the clinical features between both
groups. A sIgE value higher than 0.35 UA/ml was defined
as positive. Statistical analyses were performed using GraphPad Prism 9.
The Mann-Whitney U test was used to compare nonparametric independent
samples between the groups. Tolerance acquisition during follow-up was
analyzed using a Kaplan–Meier survival curve and the log-rank test.
P-value <0.05 was considered statistically significant. This
study was approved by the Institutional Review Board of the KKR Sapporo
Medical Center (2021-06).
Patients’ characteristics are shown in Table 1. The ED group consisted
of 12 patients (57.1%), 10 (83.3%) of whom acquired tolerance to EY,
and the LD group consisted of nine patients (42.9%), three (33.3%) of
whom acquired tolerance to EY. Among 21 patients with EY-associated
FPIES, a total of 35 re-OFCs were performed, with a median interval of
seven months (interquartile range [IQR], 6–11 months) (Figure 1).
The median ages that re-OFC proved negative in ED and LD groups were 16
and 26 months, respectively (p = 0.014) (Table 1). The time to tolerance
acquisition was significantly longer in the LD group than that in the ED
group, as shown in the Kaplan–Meier analysis (log-rank, p = 0.0015)
(Figure 2). The median ages of onset and first visit to our hospital
were significantly younger in the ED group than those in the LD group
(Table 1). All patients had a history of three episodes (IQR 2–6) of
asymptomatic consumption before onset. Although the median age of the
first introduction of EY in the ED group was younger than that in the LD
group (six months vs. eight months, p = 0.004), there was no significant
difference in the median number of asymptomatic consumptions before
onset and the period between the first introduction and onset between
the groups. The period between the first introduction of EY and FPIES
diagnosis was shorter in the ED group than that in the LD group (2.5
months vs. 7 months, p = 0.0002).
We demonstrated that the ED group achieved tolerance at a higher rate
than the LD group, suggesting that early diagnosis and intervention
predict favorable prognosis in EY-FPIES. Consistent with a previous
report,4 all patients with EY-FPIES had histories of
asymptomatic consumption before disease onset. Involvement of both
innate and adaptive immunities with resultant proinflammatory cytokine
production has been suggested in the pathology of acute
FPIES.5 Our results suggest that the development of
EY-FPIES requires sensitization of the adaptive immune system. T helper
(Th)2 and Th17 cells are considered as key players of the immune
response in FPIES,6 which is reflected by local
infiltration of eosinophils and neutrophils, respectively. Adaptive
immunity of infants shows dynamic changes with a rapid decline of
regulatory T cells and maturation of Th17, while Th2 dominance is
preserved.7 Additionally, the intestinal barrier
function immaturity was also observed, resulting in a higher
permeability of antigens across the intestines.8 Thus,
early infants may be predisposed to FPIES because of immunological as
well as anatomical immaturity. Although both ED and LD groups shared a
similar interval between the first introduction of EY and onset, the
period between the onset and diagnosis in the ED group was significantly
shorter than that in the LD group. Our results suggest that an earlier
elimination of EY after onset prevents the complete development of
EY-FPIES.
The median age at onset in the 21 patients with EY-FPIES was 8 months
(IQR, 7–9 months), which is comparable to previous
reports.9 Similar to another
report,9 13 patients (65.0%) achieved tolerance at
the median age of 16 months. This is earlier than the median age
reported in a European series that demonstrates a 50% cumulative
probability of resolution at the age of 41 months.10Notably, the median age of diagnosis is older (12 months) in that study
compared with that in our series. Thus, the different clinical courses
may attribute to differences in age of diagnosis. Otherwise, the
clinical course may depend on ethnicity. In 2017, the Japanese Society
of Pediatric Allergy and Clinical Immunology recommended the early
introduction of EY to infants with a high risk for IgE-mediated egg
allergy. This might have increased the number of early-onset EY-FPIES in
Japan. Our results suggest that a first re-OFC seven months after the
diagnosis is reasonable for preventing unnecessary food avoidance in
EY-FPIES.
Our study is limited by a retrospective review of a small number of
patients from a single institute. Additionally, accidental exposures
after diagnosis occurred in one patient in the LD group, influencing the
scheduling of re-OFC. Moreover, we evaluated solely patients with a
confirmational diagnosis by OFC, which might be insufficient to reflect
the whole heterogeneity of EY-FPIES.
Conclusively, the ED group achieved tolerance in EY-FPIES earlier
compared with the LD group. Early diagnosis and complete elimination of
EY may be beneficial for EY-FPIES.