Prognosis of infantile food protein-induced enterocolitis
syndrome to wheat: A case series
Conflict of interest: Motohiro Ebisawa and Sakura Sato have
received speaker honoraria from Viatris. The other authors declare that
they have no conflicts of interest.
Financial support: This research received no specific grant
from any public, commercial, or not-for-profit funding agency.
Keywords: Food protein-induced enterocolitis syndrome;
Tolerance; Prognosis; Wheat
To the Editor,
Food protein-induced enterocolitis syndrome (FPIES) is a type of
non-IgE-mediated food allergy characterized by repetitive vomiting
1–4 h after ingestion of any
food.1FPIES is commonly caused by foods
such as cow’s milk, soy, hen’s egg, fish, rice, and oat, varying in
prevalence by geographical region; however, wheat-induced FPIES
(wheat-FPIES) is relatively rare.2-4 In Japan, the
incidence of wheat-FPIES has been reported to be increasing, along with
FPIES to cow’s milk, egg, and soy.5 However, to our
knowledge, no study has reported the clinical features and tolerance
acquisition of wheat-FPIES. Therefore, this study aimed to describe the
clinical characteristics of wheat-FPIES and the prognosis at the age of
5 years.
We retrospectively reviewed children who visited our hospital from May
2012 to July 2018 with a suspected diagnosis of wheat-FPIES. The
diagnostic criteria proposed by Nowak-Węgrzyn et al. were used in the
study. Infants who either fulfilled the diagnostic criteria based on the
history of symptoms or symptoms observed during oral food challenge
(OFC) were defined as wheat-FPIES patients.1 Those who
were followed up to age 5 years were included in the study. Wheat- and
ω-5-gliadin-specific immunoglobulin E (sIgE) levels were measured using
ImmunoCAP (Thermo Fisher Scientific/Phadia, Uppsala, Sweden) at the
first visit. Sensitization was defined as a sIgE level of ≥0.35.
All the patients received OFCs with 52 or 390 mg of wheat protein in the
form of boiled udon noodles for diagnosis or to confirm tolerance to the
amount challenged. Patients who passed their initial OFC proceeded to
confirm if they could tolerate 2,600 mg (equivalent to the amount of
wheat protein in half a slice of bread) by receiving stepwise OFCs, by
gradually increasing the amount consumed at home, or by a combination of
the two. Stepwise OFCs were performed by sequentially increasing the
dose from 52 mg to 390, 1300, and ≥2,600 mg on separate days when the
preceding OFC was negative. When a patient failed any OFC, it was
repeated after 6–18 months. The children were considered to have
achieved tolerance when they could consume 2,600 mg without any
symptoms. All OFCs were performed in the hospital under the supervision
of a physician. The challenge amount was administered in a single dose
with monitoring for at least 5 hours. OFCs were determined to be
positive when vomit was induced after >1 hour, and no
IgE-mediated skin or respiratory symptoms were observed.
A total of 11 patients were suspected of having wheat-FPIES. Seven
patients fulfilled the diagnostic criteria based on their history of
symptoms, of which one patient was excluded because he had only been
followed up to the age of 2 years. Of the remaining 4 patients, one
presented with repetitive vomiting, lethargy, and pallor during OFC and
therefore fulfilled the diagnostic criteria based on symptoms during the
OFC. In total, 7 patients were included in the study (Figure 1).
Table 1 presents the characteristics of the 7 patients. The median age
at the onset of symptoms was 7 (range: 6–9) months, and the median age
at the first visit to our hospital was 13 (range: 8–17) months. The
patients had experienced a median of 4 episodes of vomiting before their
first visit. Data concerning wheat consumption before the first episode
of symptoms was available for 5 patients, and they had all previously
consumed wheat without any symptoms. Overall, 2 (29%) patients had
comorbid atopic dermatitis, one had IgE-mediated egg allergy, and two
had FPIES to a different food. All patients were not sensitized to
ω-5-gliadin; however, one patient had a slightly elevated wheat-sIgE
level of 0.42 kUA/L.
Initial OFCs were performed at a median age of 18 (range: 8–45) months.
The proportion of patients who became tolerant to wheat increased with
age, and at the age of 5 years, 6 (86%) patients were confirmed to have
achieved tolerance, and the remaining patient was able to consume 52 mg
of wheat protein (Figure 2). The patient sensitized to wheat achieved
tolerance at the age of four. The patient who was not confirmed to have
achieved tolerance at the age of 5 years had a positive initial OFC to
52 mg at 45 months and underwent a repeat OFC with the same dose at 62
months, which was negative. Whether the patient could consume larger
amounts was not examined at the time because he refused to eat during
the following OFCs. Among the 6 patients who achieved tolerance, 2
patients gradually increased the amount consumed at home after a
negative OFC with 390 mg, 2 patients received stepwise OFCs up to 1,300
mg and then gradually increased the amount consumed at home, and 2
patients received stepwise OFCs up to ≥2,600 mg. The median age of the
last reaction to wheat was 18 (range: 8-45) months, and the median time
from the last reaction to when the patient was confirmed to have
acquired tolerance was 24 (range: 5-32) months.
In this study,
although the number of patients is
limited, we found that most Japanese infants with wheat-FPIES achieved
tolerance by 5 years. Patients with solid FPIES have been considered to
acquire tolerance later than those with FPIES to cow’s milk and
soy.6-8 However, recent studies from the US have
reported tolerance for FPIES to cow’s milk at approximately 5 years of
age.3,5 Patients with solid FPIES to grains such as
oat and rice have been reported to acquire tolerance at a median age of
4 and 4.7 years, respectively.3 In Spain, 75% of
patients with FPIES to egg and fish have been reported to achieve
tolerance by the age of 5 years .9 The rate of
tolerance acquisition in Japanese children with wheat-FPIES in our study
was comparable to these previous results, with 86% of the patients
acquiring tolerance by the age of 5 years. These results suggest that
although a subset of patients may have prolonged FPIES, most patients
achieve tolerance before school age.
Caubet et al. have reported that for patients with FPIES to cow’s milk,
sensitization to milk was a factor that predicted poor
outcomes.3 However, the patient sensitized to wheat in
our study achieved tolerance at the age of 4 years.
A study limitation is that owing to the retrospective nature, the age at
initial OFCs, the intervals between stepwise OFCs, and the rate at which
the dose consumed at home was increased varied across patients. In
addition, when OFCs were positive, they were repeated after a period of
6–18 months. Only after repeated OFCs were confirmed to be negative,
did the patients receive the proceeding stepwise OFCs and/or increase
the amount consumed at home to confirm tolerance. Thus, it took a median
of 24 months from the last reaction caused by wheat to the time
tolerance was confirmed. Therefore, some of the patients assumably
achieved tolerance earlier than it is described in our study.
In conclusion, most Japanese infants with wheat-FPIES in our study
acquired tolerance by the age of 5 years. OFCs must be repeated to
assess tolerance, given that most patients outgrow their wheat-FPIES
before school age. Further
prospective studies are warranted with routine OFCs to determine a more
accurate prognosis.
Makoto Nishino1,2, MD; Noriyuki
Yanagida1,3, MD; Sakura Sato1, MD;
Ken-ichi Nagakura3,4, MD, PhD; Kyohei
Takahashi3, MD, PhD; Kiyotake
Ogura1, MD, PhD; Motohiro Ebisawa3,
MD, PhD.
1 Clinical Research Center for Allergy and
Rheumatology, National Hospital Organization Sagamihara National
Hospital, Kanagawa, Japan
2 Ushiku Aiwa General Hospital, Ibaraki, Japan
3 Department of Pediatrics, National Hospital
Organization Sagamihara National Hospital, Kanagawa, Japan
4 Department of Pediatrics, Jikei University School of
Medicine, Tokyo, Japan