Abstract
Introduction: Food protein-induced enterocolitis syndrome (FPIES) is a form of non-IgE-mediated gastrointestinal food allergy. FPIES is considered a rare food allergy disorder and is often under-recognized. Therefore, clinicians should have a better understanding of its manifestations and maintain a high index of suspicion for a correct diagnosis. To this end, information about differences in the characteristics of caregiver-reported and physician-diagnosed FPIES is important. Methods: The present, national, multicentric, prospective birth cohort study, called the Japan Environment and Children’s Study (JECS), enrolled a general population of 104,062 fetal records. The characteristics of FPIES in 1.5-year-old children were categorized as cases reported by caregivers or as those diagnosed by a physician using questionnaire data. Results: The prevalence of caregiver-reported and physician-diagnosed FPIES cases was 0.69% and 0.06%, respectively. Among the former, the most common causative food was hen’s egg (HE), and the second most common causative food was cow’s milk (CM) (51.0% and 17.1% of patients responded to HE and CM, which accounted for 46% and 15% of all the causative foods, respectively). Conversely, among the physician-diagnosed cases, the most common causative food was CM followed by HE (57.7% and 36.5% of patients responded to CM and HE, which accounted for 46% and 29% of all the causative foods, respectively). CM accounted for a significantly higher proportion of causative foods in physician-diagnosed FPIES while HE accounted for a significantly higher proportion of caregiver-reported FPIES (p < 0.05). Conclusion: A discrepancy was found in reports of the most common causative food between caregiver-reported and physician-diagnosed cases of FPIES.
Introduction
Food protein-induced enterocolitis syndrome (FPIES) is a form of non-immunoglobulin E-mediated gastrointestinal (GI) food allergy. Most patients with acute type FPIES present with recurrent vomiting within 1 to 4 h, and/or diarrhea within 24 h, of ingesting the triggering food [1]. The cumulative incidence of FPIES in infants is estimated to be 0.015–0.7% [2]. While cow’s milk (CM) and soy are common causes of FPIES, grains, including rice, have also been implicated [3]. The frequency of each causative food varies by country and region [4‒6]. Hen’s egg (HE) was recently reported as most commonly causing acute-FPIES episodes in Japan [7], where the prevalence of HE-induced FPIES has dramatically increased in the past decade [8].
Despite this, FPIES is often under-recognized because of its non-specific symptoms and the absence of specific confirmatory tests [9]. Moreover, many primary care and emergency physicians are unaware of FPIES because of its relatively low incidence, and the specific International Classification of Diseases (ICD) code (2015) and diagnostic guidelines for this condition are still in their nascent form (2017) [10]. These considerations suggest that FPIES may be significantly underdiagnosed.
In fact, a previous study found that caregiver-reported as well as physician-diagnosed GI food allergies affected 0.5% of infants in Japan. In contrast, caregiver-reported GI food allergies occurred in 1.4% of children [11]. Thus, the frequency of GI food allergies, including FPIES, shows a discrepancy between physician-diagnosed and caregiver-reported cases.
However, there are no data on the differences in the characteristics of the physician-diagnosed and caregiver-reported FPIES cases. Familiarity with the symptoms of FPIES and vigilance are required to diagnosis the condition [12], and understanding the characteristics of undiagnosed cases may help shed light on the disease and help to determine when FPIES should be suspected or to prevent misdiagnosis or underdiagnosis. Thus, the present study aimed to examine the difference between caregiver-reported and physician-diagnosed FPIES cases in young children in Japan using a national birth cohort drawn from the general population.
Methods
Participants
The participants were mother-and-child pairs who participated in the Japan Environment and Children’s Study (JECS). The JECS was a large, nationwide, birth cohort study funded by the Ministry of the Environment of Japan. The protocol and baseline data for JECS have been described in previous reports [13, 14]. Between January 2011 and March 2014, the study recruited >100,000 pregnant women who lived in any of 15 regional centers covering a wide geographical area of Japan. The study was performed in accordance with the Declaration of Helsinki and the Japanese Ethical Guidelines for Epidemiological Research published by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare, Japan. The JECS protocol was reviewed and approved by the Japanese Ministry of the Environment’s Institutional Review Board on Epidemiological Studies and the Ethics Committees of all participating institutions. Written informed consent was obtained from all participating women in JECS. The JECS was registered in the UMIN Clinical Trials Registry (UMIN000030786).
A written questionnaire was provided to the caregivers during pregnancy and when the offspring were aged 6 months and 1, 1.5, 2, 2.5, and 3 years. Caregivers answered questions about their child and family. Data input was conducted at locations in all 15 regional centers. Data management was performed by the Programme Office. This study was based on the JECS datasets jecs-ta-20190930, which was released in October 2019.
Outcomes
The study outcome was the incidence of caregiver-reported and physician-diagnosed FPIES in children aged 1.5 years as conducted in previous studies [7, 11]. Information about the outcome was collected using self-administered questionnaires [14]. Regardless of whether GI allergy was diagnosed by a physician or reported by a caregiver, FPIES occurring at the patient age of 1.5 years was defined by the following:
- a.
“Yes” to the question, “has your child ever had a GI allergic reaction?”
- b.
“Yes” to the question, “has the child ever experience any GI symptoms such as repeated vomiting, blood in stool, repeated diarrhea, and loss of weight gain (not due to food poisoning, infectious gastroenteritis, or overeating), between 3 h and a few days after eating a specific food?”
- c.
“Repeated vomiting” as a response to the question about digestive symptoms
If the respondent answered “yes” to (a) and (b), the patient’s condition was categorized as physician-diagnosed FPIES. If the respondent answered “yes” only to (b), the condition was categorized as caregiver-reported FPIES.
Single-food FPIES was defined as a reaction to only one triggering food, such as CM, hypoallergenic formula, maternal milk, soy, HE, wheat, rice, fish, fish roe (FR), bivalve, cephalopod, meat, fruit, vegetable, or other. The classification of these allergens was based on previous studies and the Japanese Food Allergy Guidelines [4, 11, 15, 16]. Multiple-food FPIES was defined as a reaction to two or more foods, including CM, soy, HE, wheat, rice, fish, FR, crustacean, bivalve, cephalopod, meat, fruit, vegetable, etc. Assessment of age at FPIES onset was restricted to patients with single-food FPIES because if a patient were responsive to multiple antigens, the questionnaire would be unable to specify the antigen inducing the symptoms.
Data Collection
The questionnaires were used to collect demographic and clinical data, including the type and number of foods inducing vomiting, age at symptom onset, sex, gestational age, atopic comorbidities, such as atopic dermatitis or bronchial asthma at age 1.5 years, congenital heart disease, Down syndrome, Apgar scores at 1 and 5 min, type of delivery, and family history of allergic disease (e.g., atopic dermatitis, bronchial asthma, allergic rhinitis, allergic conjunctivitis, food allergy, etc.).
Statistical Analyses
The demographic and clinical data were reported as the median and interquartile range (IQR), and the frequency and percentage were calculated for categorical variables. Comparison of caregiver-reported and physician-diagnosed FPIES was separately made using the Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical variable analysis. The χ2 test was used to evaluate the proportion of the most common foods difference. p < 0.05 was considered to indicate statistical significance. Missing values were not imputed. Because the caregivers responded to the questionnaire items only if their children had certain outcomes, the number of missing values was uncertain. R version 3.6.2 for Mac (R Foundation for Statistical Computing, Vienna, Austria) was used for all the statistical analyses.
Results
FPIES Incidence
Figure 1 shows a flowchart of participant selection. In total, 104,062 fetal records were registered during the study period. Finally, 87,780 children were included for analysis. The prevalence of caregiver-reported and physician-diagnosed FPIES was 0.69% and 0.06%, respectively. Table 1 summarizes the characteristics of the groups.
Patient flowchart. FPIES, food protein-induced enterocolitis syndrome.
Characteristics of patients with caregiver-reported or physician-diagnosed FPIES
. | Caregiver-reported FPIES (N = 602) . | Physician-diagnosed FPIES (N = 52) . |
---|---|---|
Male sex, n (%) | 310 (51.5) | 31 (59.6) |
Birth week, week (IQR) | 39 (38–40) | 39 (37.75–40) |
Physician-diagnosed atopic comorbidity, n (%) | ||
Atopic dermatitis | 95 (15.8) | 12 (23.1) |
Bronchial asthma* | 34 (5.6) | 12 (23.1) |
Congenital heart disease, n (%) | 6 (1.0) | 0 (0) |
Down’s syndrome, n (%) | 1 (0.2) | 0 (0) |
Apgar score at 1 min (IQR) | 9 (8-9) | 8 (8-9) |
Apgar score at 5 min (IQR) | 9 (9-10) | 9 (9-10) |
Caesarean delivery, n (%) | 114 (18.9) | 5 (9.6) |
Family history of allergic disease | ||
Atopic dermatitis | ||
Mother, n (%) | 117/599 (19.5) | 9/52 (17.3) |
Father, n (%) | 47/311 (15.1) | 2/27 (7.4) |
Bronchial asthma | ||
Mother, n (%) | 77/599 (12.9) | 7/52 (13.5) |
Father, n (%) | 49/311 (15.8) | 4/27 (14.8) |
Allergic rhinitis | ||
Mother, n (%) | 243/599 (40.6) | 22/52 (42.3) |
Father, n (%) | 109/311 (35.0) | 13/27 (48.1) |
Allergic conjunctivitis | ||
Mother, n (%) | 78/599 (13.0) | 4/52 (7.7) |
Father, n (%) | 15/311 (4.8) | 3/27 (11.1) |
Food allergy | ||
Mother, n (%) | 37/599 (6.2) | 1/52 (1.9) |
Father, n (%) | 16/311 (5.1) | 2/27 (7.4) |
. | Caregiver-reported FPIES (N = 602) . | Physician-diagnosed FPIES (N = 52) . |
---|---|---|
Male sex, n (%) | 310 (51.5) | 31 (59.6) |
Birth week, week (IQR) | 39 (38–40) | 39 (37.75–40) |
Physician-diagnosed atopic comorbidity, n (%) | ||
Atopic dermatitis | 95 (15.8) | 12 (23.1) |
Bronchial asthma* | 34 (5.6) | 12 (23.1) |
Congenital heart disease, n (%) | 6 (1.0) | 0 (0) |
Down’s syndrome, n (%) | 1 (0.2) | 0 (0) |
Apgar score at 1 min (IQR) | 9 (8-9) | 8 (8-9) |
Apgar score at 5 min (IQR) | 9 (9-10) | 9 (9-10) |
Caesarean delivery, n (%) | 114 (18.9) | 5 (9.6) |
Family history of allergic disease | ||
Atopic dermatitis | ||
Mother, n (%) | 117/599 (19.5) | 9/52 (17.3) |
Father, n (%) | 47/311 (15.1) | 2/27 (7.4) |
Bronchial asthma | ||
Mother, n (%) | 77/599 (12.9) | 7/52 (13.5) |
Father, n (%) | 49/311 (15.8) | 4/27 (14.8) |
Allergic rhinitis | ||
Mother, n (%) | 243/599 (40.6) | 22/52 (42.3) |
Father, n (%) | 109/311 (35.0) | 13/27 (48.1) |
Allergic conjunctivitis | ||
Mother, n (%) | 78/599 (13.0) | 4/52 (7.7) |
Father, n (%) | 15/311 (4.8) | 3/27 (11.1) |
Food allergy | ||
Mother, n (%) | 37/599 (6.2) | 1/52 (1.9) |
Father, n (%) | 16/311 (5.1) | 2/27 (7.4) |
Comparisons were made using the Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical variables. Statistical significance (p < 0.05) is indicated by *.
FPIES, food protein-induced enterocolitis syndrome; IQR, interquartile range.
Causative Foods in Caregiver-Reported and Physician-Diagnosed FPIES
Table 2 summarizes the causative foods in the two FPIES groups, and Figure 2 shows the breakdown of the causative foods (Fig. 2a, caregiver-reported FPIES; Fig. 2b, physician-diagnosed FPIES). Among the caregiver-reported FPIES cases, the most common causative food was HE followed by CM (51.0% and 17.1% of patients responded to HE and CM, which accounted for 46% and 15% of all the causative foods, respectively). Among the physician-diagnosed FPIES cases, the most common causative food was CM followed by HE (57.7% and 36.5% of patients responded to CM and HE, which accounted for 46% and 29% of all causative foods, respectively). CM accounted for a significantly higher proportion of physician-diagnosed FPIES while HE accounted for a significantly higher proportion of caregiver-reported FPIES (p < 0.05). Table 3 shows that 53 of the caregiver-reported cases (8.8%) and 6 of the physician-diagnosed cases (11.5%) were of multiple-food FPIES.
Number of causative foods in caregiver-reported and physician-diagnosed FPIES
Triggering food . | Caregiver-reported FPIES (N = 602) (0.77%) . | Physician-diagnosed FPIES (N = 52) (0.06%) . |
---|---|---|
CM*, n (%) | 103 (17.1) | 30 (57.7) |
HF, n (%) | 2 (0.3) | 1 (1.9) |
MM*, n (%) | 15 (2.5) | 6 (11.5) |
HE, n (%) | 307 (51.0) | 19 (36.5) |
Rice, n (%) | 4 (0.7) | 0 (0) |
Wheat, n (%) | 41 (6.8) | 4 (7.7) |
Soy*, n (%) | 60 (10.0) | 0 (0) |
Fish, n (%) | 14 (2.3) | 1 (1.9) |
FR, n (%) | 12 (2.0) | 1 (1.9) |
Crustacean, n (%) | 2 (0.3) | 0 (0) |
Bivalve, n (%) | 1 (0.2) | 0 (0) |
Cephalopod, n (%) | 1 (0.2) | 0 (0) |
Meat, n (%) | 5 (0.8) | 1 (1.9) |
Fruit, n (%) | 27 (4.5) | 0 (0) |
Vegetable, n (%) | 5 (0.8) | 0 (0) |
Other, n (%) | 44 (7.3) | 2 (3.8) |
Unknown, n (%) | 28 (4.7) | 0 (0) |
Triggering food . | Caregiver-reported FPIES (N = 602) (0.77%) . | Physician-diagnosed FPIES (N = 52) (0.06%) . |
---|---|---|
CM*, n (%) | 103 (17.1) | 30 (57.7) |
HF, n (%) | 2 (0.3) | 1 (1.9) |
MM*, n (%) | 15 (2.5) | 6 (11.5) |
HE, n (%) | 307 (51.0) | 19 (36.5) |
Rice, n (%) | 4 (0.7) | 0 (0) |
Wheat, n (%) | 41 (6.8) | 4 (7.7) |
Soy*, n (%) | 60 (10.0) | 0 (0) |
Fish, n (%) | 14 (2.3) | 1 (1.9) |
FR, n (%) | 12 (2.0) | 1 (1.9) |
Crustacean, n (%) | 2 (0.3) | 0 (0) |
Bivalve, n (%) | 1 (0.2) | 0 (0) |
Cephalopod, n (%) | 1 (0.2) | 0 (0) |
Meat, n (%) | 5 (0.8) | 1 (1.9) |
Fruit, n (%) | 27 (4.5) | 0 (0) |
Vegetable, n (%) | 5 (0.8) | 0 (0) |
Other, n (%) | 44 (7.3) | 2 (3.8) |
Unknown, n (%) | 28 (4.7) | 0 (0) |
Fisher’s exact test was used for analysis. Statistical significance (p < 0.05) is indicated by *.
CM, cow’s milk; FPIES, food protein-induced enterocolitis syndrome; FR, fish roe; HE, hen’s egg; HF, hypoallergenic formula; MM, maternal milk.
Breakdown of causative foods in FPIES in the JECS cohort. a Caregiver-reported FPIES. b Physician-diagnosed FPIES. CM, cow’s milk; FR, fish roe; HE, hen’s egg; HF, hypoallergic formula; MM, maternal milk.
Breakdown of causative foods in FPIES in the JECS cohort. a Caregiver-reported FPIES. b Physician-diagnosed FPIES. CM, cow’s milk; FR, fish roe; HE, hen’s egg; HF, hypoallergic formula; MM, maternal milk.
Number of single- or multiple-food FPIES cases
Triggering food number . | Caregiver-reported FPIES (N = 602) . | Physician-diagnosed FPIES (N = 52) . |
---|---|---|
Single, n (%) | 549 (91.2) | 46 (88.5) |
Multiple, n (%) | 53 (8.8) | 6 (11.5) |
2, n (%) | 46 (7.6) | 4 (7.7) |
≧ 3, n (%) | 7 (1.2) | 2 (3.8) |
Triggering food number . | Caregiver-reported FPIES (N = 602) . | Physician-diagnosed FPIES (N = 52) . |
---|---|---|
Single, n (%) | 549 (91.2) | 46 (88.5) |
Multiple, n (%) | 53 (8.8) | 6 (11.5) |
2, n (%) | 46 (7.6) | 4 (7.7) |
≧ 3, n (%) | 7 (1.2) | 2 (3.8) |
Each fish, fish roe, fruit, meat, and vegetable counted as a single food.
Fisher’s exact test was used for analysis. No statistically significant results were obtained.
FPIES, food protein-induced enterocolitis syndrome.
Timing of FPIES Onset
Table 4 shows the ages at FPIES onset in the entire cohort and by trigger food. The median age at onset in the caregiver-reported and physician-diagnosed group, including cases of single- and multiple-food FPIES, was 8.0 months (IQR: 7.0–11.0 months) and 6.0 months (IQR: 2.8–9.0 months), respectively. The age at onset was earlier in the physician-diagnosed group (p < 0.001). In both groups, the age at onset was relatively early when the causative food was CM or MM. In the caregiver-reported group, the age at onset was late when the causative food was seafood, such as FR, crustacean, or bivalve. In the physician-diagnosed group, the age at onset was relatively late when the causative food was HE.
Timing of FPIES onset
Triggering food . | Caregiver-reported FPIES . | Physician-diagnosed FPIES . |
---|---|---|
median age, months (IQR) . | median age, months (IQR) . | |
Overall* | 8.0 (7.0–11.0), n = 602 | 6.0 (2.8–9.0), n = 52 |
CM | 5.5 (3.0–9.5), n = 75 | 4.0 (2.0–6.0), n = 21 |
HF | NA | NA |
MM | 4.0 (3.0–4.0), n = 5 | 0.0 (0.0–0.0), n = 1 |
HE | 9.0 (8.0–11.0), n = 265 | 9.0 (8.0–11.8), n = 14 |
Rice | 6.0 (6.0–6.0), n = 1 | NA |
Wheat | 8.0 (6.5–9.0), n = 23 | 7.0 (7.0–7.0), n = 1 |
Soy | 7.0 (7.0–8.0), n = 51 | NA |
Fish | 10.0 (7.0–11.3), n = 8 | NA |
FR | 17.0 (15.5–17.0), n = 10 | NA |
Crustacean | 14.5 (13.3–15.8), n = 2 | NA |
Bivalve | 14.0 (14.0–14.0), n = 1 | NA |
Cephalopod | 12.0 (12.0–12.0), n = 1 | NA |
Meat | 14.0 (9.0–15.0), n = 5 | 13.0 (13.0–13.0), n = 1 |
Fruit | 9.0 (8.0–10.5), n = 24 | NA |
Vegetable | 12.0 (10.5–14.5), n = 4 | NA |
Triggering food . | Caregiver-reported FPIES . | Physician-diagnosed FPIES . |
---|---|---|
median age, months (IQR) . | median age, months (IQR) . | |
Overall* | 8.0 (7.0–11.0), n = 602 | 6.0 (2.8–9.0), n = 52 |
CM | 5.5 (3.0–9.5), n = 75 | 4.0 (2.0–6.0), n = 21 |
HF | NA | NA |
MM | 4.0 (3.0–4.0), n = 5 | 0.0 (0.0–0.0), n = 1 |
HE | 9.0 (8.0–11.0), n = 265 | 9.0 (8.0–11.8), n = 14 |
Rice | 6.0 (6.0–6.0), n = 1 | NA |
Wheat | 8.0 (6.5–9.0), n = 23 | 7.0 (7.0–7.0), n = 1 |
Soy | 7.0 (7.0–8.0), n = 51 | NA |
Fish | 10.0 (7.0–11.3), n = 8 | NA |
FR | 17.0 (15.5–17.0), n = 10 | NA |
Crustacean | 14.5 (13.3–15.8), n = 2 | NA |
Bivalve | 14.0 (14.0–14.0), n = 1 | NA |
Cephalopod | 12.0 (12.0–12.0), n = 1 | NA |
Meat | 14.0 (9.0–15.0), n = 5 | 13.0 (13.0–13.0), n = 1 |
Fruit | 9.0 (8.0–10.5), n = 24 | NA |
Vegetable | 12.0 (10.5–14.5), n = 4 | NA |
Age at FPIES onset by food was assessed in patients with only one triggering food.
Comparisons were made using the Mann-Whitney U test. Statistical significance (p < 0.05) is indicated by *.
CM, cow’s milk; FPIES, food protein-induced enterocolitis syndrome; FR, fish roe; HE, hen’s egg; HF, hypoallergenic formula; IQR, interquartile range; MM, maternal milk; NA, not available.
Discussion
The present study is the first to demonstrate a discrepancy in characteristics between caregiver-reported and physician-diagnosed FPIES cases in the JECS cohort. FPIES is characterized by regional variations in the frequency of the causative antigen [1]. Interestingly, the present study revealed a discrepancy in the breakdown of causative foods in the two groups. About half of caregiver-reported FPIES cases compared to about one-third of physician-diagnosed cases were caused by HE. A retrospective cohort study reported a dramatic increase in cases of FPIES triggered by HE in Japan, especially in 2018-2019 [8]. This phenomenon was thought to be partly influenced by the early introduction of HE to high-risk infants following the issuance of the 2017 recommendations. This idea was based on evidence showing that the number of peanut-induced FPIES cases also increased in the USA after a change in the guidelines supporting the early introduction of peanut into the diet [17, 18]. However, the present findings indicated the possibility of there being a considerable number of undiagnosed cases of HE-induced FPIES. The publication of the international consensus guidelines in 2017 [19] might have raised physicians’ awareness of this condition, leading to the recent increase in the number of HE-induced FPIES diagnoses in Japan. In any case, it is important to be able to identify FPIES, especially if the symptoms involve vomiting after the ingestion of HE, the main, causative food.
The prevalence of physician-diagnosed FPIES in this study was 0.06%. Katz et al. [20] reported a cumulative incidence of CM FPIES of 0.34% using a population-based case study prospectively enrolling more than 13,000 infants. Ludman et al. [21] reported an incidence of 0.36% after performing a retrospective audit of patients at a tertiary London pediatric allergy clinic [20]. Sopo et al. [22] estimated a FPIES prevalence of around 1% based on cases at a pediatric allergy outpatient clinic [20]. Thus, the prevalence of physician-diagnosed FPIES in the present study was lower than in other studies. On the other hand, among the infants of pregnant women enrolled between January 2011 and March 2014 in the present study, the proportion of those with symptoms of FPIES was 0.75%, which does not differ greatly from the figure reported by epidemiological studies in other countries. The previous, Japanese, food allergy guidelines published in 2011 and 2014 mention only CM as a common causative food in GI allergy [23, 24]. These facts possibly indicate a rather low awareness of the FPIES due to causes other than CM.
The present study’s assessment of patients’ age at FPIES onset in the two groups found that the physician-diagnosed cases were associated with a younger age at onset. The FPIES in this group was chiefly caused by CM and developed at a relatively early age, when it was more likely that the condition would be diagnosed at a hospital. FPIES usually presents in infants younger than the age of 9 months (median age 5.5 months) [1]. However, the age at presentation greatly varies and can range anywhere from a few days of life to 12 months of age but is usually before the age of 6 months following the first or second ingestion of the causative food [25]. In the present study, the median age at onset in the caregiver-reported CM-FPIES cases was 5.5 months, and the IQR was relatively broad (3.0–9.5 months). The age at solid food-FPIES onset is reportedly higher (median: 12.1 months) possibly because of the later introduction of solid foods into the diet [26]. In either case, the occurrence of vomiting after the introduction of baby food should lead to the suspicion of FPIES, which requires confirmation of the food ingested within 4 h of symptom presentation. However, the present study analyzed only single-food FPIES cases to assess the age at FPIES onset by food. Therefore, our data were inadequate for accurately determining age at onset. Further, prospective studies are needed to confirm the age at FPIES onset by food item, especially in cases of multiple-food FPIES.
In the present study, multiple-food FPIES occurred in 8.8% of caregiver-reported cases and 11.5% of physician-diagnosed cases. In their population-based study, Mehr et al. [4] reported that 27% patients with FPIES in Australia reacted to two or more food groups. Also, 15.8% of 120 cases in a multicentric study in Spain involved two or more triggering foods at the time of study enrollment [5]. Thirty-nine percent of a pediatric cohort of 74 children in the USA had multiple-food FPIES [27]. Our findings and those of previous studies suggested that the frequency of multiple-food FPIES in Japan may be lower than in other countries. Furthermore, the rate of multiple-food FPIES was higher in the physician-diagnosed group. Patients with a single, causative antigen may have fewer hospital visits and be less likely to receive the diagnosis of FPIES than those with multiple antigens. However, the previously mentioned retrospective study of the pediatric cohort of 74 children demonstrated that more than half the patients visited the emergency department after an acute FPIES episode [27]. FPIES should be suspected in patients presenting to a clinic or emergency department with typical, clinical symptoms, such as profuse vomiting or altered consciousness, especially if they improve rapidly [12]. A careful clinical history is necessary to determine if there were similar episodes in the past after certain foods were consumed.
The present study has some limitations. First, the process of diagnosing FPIES is uncertain because the diagnostic criteria were published more recently than the recruitment for the JECS, and the present study used a questionnaire to collect patient data. However, vomiting at around 3 h after ingestion, typically the time of onset of an immediate food allergy, was included in the diagnostic criteria and combined with physician-diagnosed GI allergy as in a previous study [11]. However, no studies have validated the accuracy of using a questionnaire to identify patients with FPIES and to diagnose the condition accurately. Given the difficulty of diagnosing FPIES, the true FPIES prevalence may fall between the prevalence of physician-diagnosed FPIES and caregiver-reported FPIES. Validation of the present study’s findings as well as further epidemiological research using stringent diagnostic criteria are warranted. Second, the JECS included only 15 regions in Japan; therefore, the study might have included a sampling bias. Third, information about age at the onset of the symptoms by food was lacking, and only single-food FPIES patients was analyzed. However, relatively few cases of FPIES associated with multiple antigens have been reported in Japan. This may be precisely because there were no reliable and clear diagnostic criteria. Fourth, our study used only information from a questionnaire administered to caregivers with offspring aged 1.5 years as means of identifying patients with FPIES. Therefore, the study lacked information about FPIES with later onset. To assess the cumulative incidence of FPIES, further investigation using data from older patients is needed.
Conclusion
The present study found a noticeable discrepancy in the most common causative foods between caregiver-reported and physician-diagnosed FPIES cases. In the former, the most common causative food was HE while in the latter it was CM. A pediatric patient presenting with vomiting should raise the index of suspicion of FPIES, and a dietary history should be taken to determine whether any food commonly associated with the condition, like egg, was consumed. Further epidemiological research based on stringent diagnostic criteria is necessary to clarify the demographic changes in the number and characteristics of FPIES cases in Japan.
Acknowledgments
We thank all the participants in JECS and individuals involved in data collection. Members of the JECS Group as of 2023: Michihiro Kamijima (principal investigator, Nagoya City University, Nagoya, Japan), Shin Yamazaki (National Institute for Environmental Studies, Tsukuba, Japan), Yukihiro Ohya (National Center for Child Health and Development, Tokyo, Japan), Reiko Kishi (Hokkaido University, Sapporo, Japan), Nobuo Yaegashi (Tohoku University, Sendai, Japan), Koichi Hashimoto (Fukushima Medical University, Fukushima, Japan), Chisato Mori (Chiba University, Chiba, Japan), Shuichi Ito (Yokohama City University, Yokohama, Japan), Zentaro Yamagata (University of Yamanashi, Chuo, Japan), Hidekuni Inadera (University of Toyama, Toyama, Japan), Takeo Nakayama (Kyoto University, Kyoto, Japan), Tomotaka Sobue (Osaka University, Suita, Japan), Masayuki Shima (Hyogo Medical University, Nishinomiya, Japan), Seiji Kageyama (Tottori University, Yonago, Japan), Narufumi Suganuma (Kochi University, Nankoku, Japan), Shoichi Ohga (Kyushu University, Fukuoka, Japan), and Takahiko Katoh (Kumamoto University, Kumamoto, Japan). We also thank Mr. James Robert Valera for his assistance with editing this manuscript.
Statement of Ethics
The JECS protocol was approved by the Ministry of the Environment’s Institutional Review Board on Epidemiological Studies (IRB No.: 100910001) and by the Ethics Committees of all participating institutions. Written informed consent was obtained from all participants.
Conflict of Interest Statement
The authors declare no conflicts of interest.
Funding Sources
This study was funded by the Ministry of the Environment of Japan. The findings and conclusions of this article are solely the responsibility of the authors and do not represent the official views of the government.
Author Contributions
Naoki Kajita designed the study, had full access to all the data in the study, analyzed the data, wrote the manuscript, and takes responsibility for their integrity and the accuracy of their analysis. Makoto Kaneko designed the study, reviewed the data, and edited the manuscript. Makoto Kuroki, Makoto Tomita, and Chihiro Kawakami reviewed the data and edited the manuscript. Shuichi Ito edited the manuscript and supervised the study. All the authors and the JECS group contributed to the critical review of the manuscript. The JECS group obtained funding. All the authors reviewed and approved the final version of the manuscript.
Additional Information
Edited by: H.-U. Simon, Bern.Study group members are listed in the Acknowledgements.
Data Availability Statement
Data are unsuitable for public deposition due to ethical restrictions and legal framework of Japan. It is prohibited by the Act on the Protection of Personal Information (Act No. 57 of May 30, 2003, amendment on September 9, 2015) to publicly deposit the data containing personal information. Ethical Guidelines for Medical and Health Research Involving Human Subjects enforced by the Japan Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare restrict the open sharing of the epidemiologic data. All inquiries about access to data should be sent to [email protected]. The person responsible for handling inquiries sent to this e-mail address is Dr Shoji F. Nakayama, JECS Programme Office, National Institute for Environmental Studies (URL: https://www.env.go.jp/chemi/ceh/en/index.html). The authors had no special access privileges to the data others would not have.