Food protein‐induced enterocolitis syndrome: A large French multicentric experience

Abstract Background Food protein‐induced enterocolitis syndrome (FPIES) is a non‐IgE‐mediated food allergy, with potential dehydration secondary to vomiting. Differences exist regarding culprit foods, and age of tolerance depending on the country of origin. We aimed at describing the characteristics of a French population of children with FPIES, and define risk factors for failure during challenge. Methods Data from 179 children who were referred for FPIES in two pediatric tertiary centers between 2014 and 2020 were retrospectively collected. The diagnosis of FPIES was based on international consensus guidelines. Clinical characteristics, culprit food, and age at resolution were assessed. Tolerance was defined as no adverse reaction after OFC or accidental exposure. Results In the 192 described FPIES, the age at first symptoms was 5.8 months old. The main offending foods were cow's milk (60.3%), hen's egg (16.2%), and fish (11.7%). Single FPIES was observed in 94.4% and multiple FPIES in 5.6% of cases. The age at resolution of FPIES was 2.2 years old, and resolution occurred later for fish than for milk (2.9 years vs. 2.0, p = 0.01). Severe acute FPIES was a risk factor for delayed resolution (RR: 3.3 [1.2–9.2]), but not IgE sensitization. Performing a food challenge within 12 months after the first reaction increased the risk of failure (OR: 2.6 [1.1–6.6]). Conclusion In this French cohort of children with FPIES, the main culprit foods were ubiquitous. Rice, oat, and soy were rarely or not involved. Multiple FPIES was infrequent. Our data confirmed the overall good prognosis of FPIES, the later resolution of FPIES to fish and in the case of severe acute FPIES.


| INTRODUCTION
Food protein-induced enterocolitis syndrome (FPIES) is a non-IgEmediated food allergy. Its incidence is estimated between 0.015% and 0.7%. [1][2][3][4] In the absence of biomarkers, the diagnosis of FPIES is based on clinical presentation. International diagnosis criteria have recently been proposed to improve its diagnosis. 5 Acute FPIES is defined by typical repetitive vomiting starting 1-4 h after ingestion of the culprit food, in association with at least 3 minor criteria. 5 These include some other episode of repetitive vomiting after eating the same or different foods, lethargy, pallor, the need for an emergency department visit or intravenous fluid support; diarrhea, hypotension, or hypothermia. 5 Chronic FPIES occurs when the food is regularly consumed, and is mainly reported with cow's milk (CM) and soy formula ingestion. The diagnosis of chronic FPIES is based on the presence of intermittent emesis, chronic diarrhea, poor weight gain or failure to thrive, which improve after several days to weeks of exclusion of the offending food. After a period of avoidance, acute typical symptoms occur upon reexposure. 6 Severe forms of acute FPIES may lead to dehydration, and hypovolemic shock is reported in 15%-33% of acute FPIES cases. [7][8][9] IgE sensitization to the culprit food is unusual but may be observed in atypical FPIES. 5 Although oral food challenges (OFCs) are not necessary for diagnosis when the typical symptoms are present, they are useful in doubtful cases to confirm the diagnosis. 5 The offending foods depend on geographic origins. 6 The most frequent culprit foods are CM in Europe and North America, [10][11][12][13][14][15][16][17] soya, rice, and grains in North America and Australia, 2,4,8,16,18 and fish in Mediterranean countries. 11,19 Resolution of FPIES is expected by school age in the majority of cases. 6 OFCs are performed to assess tolerance to the food in question, generally 12-18 months after the last reaction. 5 In this study, we aimed to describe FPIES in a large population of French children for the first time, using international diagnosis criteria, to describe its natural history, and to define risk factors for failure during OFC.

| Subjects
Data from children with FPIES, referred consecutively to two French pediatric centers (Trousseau and Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris) between January 2014 and April 2020 were retrospectively collected. The diagnosis of acute FPIES was confirmed if recurrent vomiting was associated with at least three minor criteria, 5 or in the presence of typical vomiting after performance of an OFC. 5,20 The diagnosis of acute FPIES was presumptive when the recurrent vomiting was associated with only two minor criteria, in the absence of skin or respiratory symptoms, and without any argument for a differential diagnosis. 5,6 The diagnosis of chronic FPIES was confirmed in the presence of acute-on-chronic typical symptoms. 5 The diagnosis of chronic FPIES was considered to be presumptive in the absence of any acute phase, in children with compatible symptoms, including chronic diarrhea, vomiting, with significant improvement within a few days after avoidance of the offending food, and after exclusion of differential diagnosis (food protein-induced enteropathy, gastrointestinal reflux, cyclic vomiting, anatomical gastrointestinal obstruction, infectious gastroenteritis and inborn errors of metabolism). 5,6 When the diagnosis criteria of FPIES were lacking, children were excluded from the study.

| Description of FPIES
Clinical data related to FPIES were collected: age at onset of first symptoms, age at diagnosis, culprit food(s), description of symptoms, age at OFC, age at acquisition of tolerance (defined as age at negative OFC or claimed regular consumption of the food in question without any reaction), and personal and familial first-degree relative history of atopic disease. Atopic disorder was defined as a history of IgEmediated food allergy, allergic rhinoconjunctivitis, asthma or atopic dermatitis and/or a positive skin prick test (SPT) or specific IgE. SPTs were performed with the offending food using either a commercial allergen extract or as a prick-by-prick using fresh food or milk. The SPT was considered to be positive if the diameter of the wheal was at least 3 mm larger than the negative control (saline). 21 Specific IgE values were considered to be positive if higher than 0.35 kU/L (ImmunoCap™, Thermo Fisher Scientific, Phadia AB, Uppsala, Sweden). 21 Multiple FPIES was defined as FPIES to several groups of foods, as opposed to single FPIES. Several species of fish were considered as a unique food group, as were vegetables from the cucurbit family for example, Solid foods referred to food other than mammal's milk.
Acute FPIES was defined as severe if the patient had needed a rapid vascular filling and/or hospitalization due to dehydration or hypovolemic shock, persistent hypotonia or malaise.
Persistent FPIES was defined as FPIES without the acquisition of tolerance at the end of the follow-up and after at least 1 year after the first symptoms.

| Oral food challenges
OFCs were mainly performed to confirm or exclude the tolerance in patients previously diagnosed with FPIES, in medical day units. After 2017, OFC protocols were adapted from the international consensus.
An appropriate age-serving size was given in a single portion or in two to three equal doses administered over 30 min, with a peripheral intravenous access, followed by an observation period of 4 h 5 This timing and the interval were let to the judgment of the allergist, depending on history of severe reaction and type of food, according to the international recommendations. 5 Children were considered to be tolerant if no symptoms occurred within 4 h after ingestion of the food in question, and they were able to tolerate one age-appropriate serving regularly at home. We took into account the successful reintroduction performed at home (accidental or voluntary exposure). An OFC failure was diagnosed in the case of recurrence of vomiting, even if isolated, as suggested by Leonard et al. 20

| Statistical analyses
Continuous values were expressed as median and interquartile range (IQR) values, or in raw values with a percentage. Statistical analyses and figures were performed using GraphPad Prism version 5.3 for Windows and R statistical analysis software. Mann-Whitney U-tests were performed to compare non-parametric variables. Spearman's coefficients were calculated to assess non-parametric correlations.
Proportions and risk factors were compared using Chi 2 test or Fisher's exact test where appropriated. Multivariable logistic regression analysis was performed to determine their independent contributions to failure of first OFC (relative risk: RR and odds ratio: OR were expressed with the confidence interval 95%). A p < 0.05 was considered to be significant. Kaplan-Meier survival analyses were performed to estimate the likelihood of outgrowing FPIES by age.
The non-tolerant patients were censored at the age of the last follow-up (OFC, consultation or last attempt at a phone call if contact lost, as a follow-up).

| Ethics
The study was approved by the French Pediatric Hepato-Gastroenterology and Nutrition's Ethics Committee (no. 2020-023 of May 2020).

| General characteristics of the population
One hundred and seventy-nine (n = 179) children with FPIES were included ( Figure 1). The female to male ratio was 0.88 (53.1% of boys; Table 1). The median age at the onset of the first symptoms of FPIES was 5.8 months (3.0-8.0) and was younger for CM than for solid foods ( Table 2). Personal and familial histories of atopic disease are presented in Table 1.

| FPIES characteristics
A total of 192 FPIES cases were reported ( Figure 1). The diagnosis of FPIES was confirmed in 151 cases and was presumptive in 41 cases (Table 3). Children with confirmed or presumptive FPIES did not differ in terms of sex ratio, atopic status, age at tolerance or tolerance rate (Table 3). Acute or recurrent chronic vomiting were present in all of the children. intravenous fluid support were more often found in confirmed FPIES cases (p < 0.01; Table 3).
F I G U R E 1 Flow chart. *Multiple FPIES n = 10: (1) acute confirmed form to soy and chronic confirmed to cow's milk; (2) acute confirmed form to maize and hen's egg and chronic confirmed to cow's milk; (3) acute confirmed form to cow's milk, chicken, hen's egg and green beans; (4) acute confirmed form to cow's milk and acute presumptive form to beef; (5) acute confirmed form to tomato and coconut; (6) acute presumptive form to hen's egg and rice; (7) acute confirmed form to beef and chronic confirmed form to cow's milk; (8) acute confirmed form to rice and banana; (9) acute confirmed form to cow's milk and raspberries; (10) acute confirmed form to avocado and cashew nuts LEMOINE ET AL.   Note: Age expressed in median months or years (interquartile range). OFC: Oral Food Challenge. Comparison between cow's milk and the other foods, except for difference between tolerance for milk and meat ("Meat" group too low).
-5 of 10 identified. CM was involved in 108 children (60.3%), hen's egg in 29 (16.2%), and fish in 21 (11.7%; Figure 2). Among the 10 multiple FPIES cases reported, CM was involved in six cases. One child had FPIES to 4 foods (CM, chicken, hen's egg, and green beans), another one to three foods (CM, hen's egg, and maize), and eight to two foods: CM and beef/veal (n = 2), CM and soy, CM and raspberry, rice and hen's egg, rice and banana, coconut and tomato, avocado and cashew nuts.

| IgE sensitization
IgE sensitization to the culprit food at any moment was found in 28  For milk, the first OFC was performed at the median age of 1.8 years, which was earlier than for other foods (p < 0.001), fish (p < 0.001), meat and vegetables/legumes/fruits (p < 0.01), but not different from hen's egg and rice ( Table 2).

| OFC
Nineteen OFCs were still not performed, because patients were too young and/or their last reaction was too recent and/or because of family refusal. Nine children were lost in the follow-up, including six without the performance of any OFCs, and three after one attempt at an OFC. Five out of these nine lost patients had FPIES to fish.

| Evolution and risk factor of failure of OFCs or prolonged FPIES
The median age at the last review of medical records was 2.   Table 4).

| DISCUSSION
In this study, we described the characteristics of a large population of 179 French children with FPIES according to international guidelines. We found that (i) culprit foods were ubiquitous as in other international cohorts, but some specific characteristics existed, (ii) persistent FPIES was more frequent for fish than for other foods, and in case of severe acute FPIES, but IgE sensitization was not associated with longer duration of FPIES, (iii) performing OFC within 12 months after the first reaction increased the risk of failure.
Cross-reactivity between CM and beef is estimated at up to 20% in IgE-mediated allergies. 38 This meat is frequently avoided by caregivers of FPIES-children. 9 However, the prevalence of FPIES to beef is estimated between 0.8% and 3.0% of children with FPIES. 2,4,8,10,18,25,29 Although beef is considered as a "moderate-risk" food, 20 our data suggest that having FPIES to CM does not increase the risk of associated FPIES to beef. 33 The overall age of resolution of FPIES was 2.2 years of age for all foods. The age at resolution was based on the day of performance of an OFC and thus may be overestimated. 6  Some minor criteria (such as hypothermia, hypotension, pallor, and lethargy) are difficult to identify during the in-depth family interviews, and even worse in retrospective reviews of medical records. 30 We included patients suffering from acute and chronic presumptive FPIES if the history was compatible with the diagnosis of FPIES without an argument for a differential diagnosis, as previously described. 5,6 The hypothesis that this may affect our results is unlikely because general characteristics and the prognosis in chil- Performing an OFC in the first year after the diagnosis resulted in an increased risk of failure, confirming that an OFC should generally be considered at least 12 months after the last reaction. 6 For fish, one must be even more patient, because experts recommend postponing the performance of an OFC until 5 years of age or older, 6 and testing tolerance to alternative fish to avoid an unnecessarily fish-free diet. 39 Like Infante et al., 39 we found that severe reactions at any moment were associated with a risk of longer duration of FPIES.
Limited data suggest that atypical FPIES with positive specific IgE is associated with delayed tolerance. 6,8,16 This was not confirmed in our study population, like in the recent Swedish 29 and Greek cohorts, 44  We reported a lower frequency of multiple FPIES (5.6%) than in the literature which is commonly reported at around 30%. 2,8,10,12,15,22,26,33 This may result from the use of stringent criteria for the diagnosis of FPIES and the retrospective design of the study.
Despite medical charts studied, for multiple FPIES in 13.4% of cases as per other series, 13,17,25,27,[29][30][31] we only retained FPIES with a specific clinical description. The prevalence of multiple FPIES ranges from 5.1% 19 to 69.0%. 18 These variations of prevalence could be explained by the fact that patients had been referred to tertiary centers in the case of multiple and more complex cases of FPIES. Secondly, it may be easier to diagnose multiple FPIES in children with a previous diagnosis of FPIES. 5 It is interesting to note that, even if the incidence of single FPIES is generally more prevalent than multiple FPIES, families report in 69.7% of cases an avoidance of at least two food groups. 9 Consequently, the risk of developing food aversion is significantly increased in FPIES triggered by three or more foods, by a factor of 3. 34 Therefore, avoidance should be limited only to the confirmed offending foods. Supervised introduction allows for the prevention of unnecessary exclusion 20 and overdiagnosis of multiple FPIES.
Our study had certain limitations. The decision to include patients with acute vomiting and only two minor criteria could be one such limit, as previously explained. The retrospective aspect of our study is another limitation, owing to missing data, and in particular in terms of the description of minor criteria and multiple FPIES. Familial history of atopic disease was selfreported, which leads to a typical bias of over-reporting allergic symptoms. 47 In terms of further studies, researching a link between maternal feeding, mode of delivery, previous antiacid treatment and frequency of antibiotic use and the occurrence of FPIES could be interesting, by exploring the field of gut dysbiosis.

| CONCLUSION
In summary, we reviewed a large French cohort of children with FPIES. The main culprit foods were CM, hen's egg, and fish. The overall prognosis remained good, as half of the cohort had outgrown FPIES by 2 years of age. FPIES to seafood products and severe forms of FPIES were associated with delayed tolerance. IgE sensitization was not a risk factor for persistent FPIES.