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.
In our study, the main culprit food was CM, followed by hen’s egg, and fish, which differs from the findings in other countries.13,16,18,23–29 The most frequent culprit food was fish (54%) in Greece20 and Spain (70.6%),28,30 rice in Australia31–33 and the USA,19 and oats (34.5%) in Taiwan.34 Soy is frequently reported as a trigger food by North American, British, Australian and Israeli cohorts4,10,12,17,33,35,36 and was infrequent in our population. Food habits, geographic origins, genetic factors, microbiota, and other environmental pre- or postnatal factors may explain these differences.1,12,37
Among the 108 patients with FPIES to CM, only 2 had a documented FPIES to beef or veal. One patient had single FPIES to beef. 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.11 However, the prevalence of FPIES to beef is estimated between 0.8% to 3.0% of children with FPIES.2,4,10,12,19,26 Although beef is considered as a “moderate-risk” food,21 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.8 Some data suggests that tolerance occurred later for solid foods than for CM, but results diverge.4,6,17 Miceli Sopo et al . reported an age of tolerance of 2.0 years for FPIES to CM and 4.4 years for other foods (p<0.0006),6 whereas other authors did not find any difference.4,17 We found that the acquisition of tolerance was delayed by 6 months for solid foods compared to CM. Previous studies suggested that the later age of tolerance relates to the ingestion of seafood products8,13,33,39 and may occur more frequently in cases of multiple FPIES.8 Resolution of FPIES to fish is around 18.8% to 57.0% of cases between 3 to 4.5 years of age.20,32,39–41 We found a similar rate of 38% tolerance at 4.0 years of age, with an older age of resolution for fish than CM. Due to the low prevalence of multiple FPIES in our cohort, we were unable to compare the age of resolution of single and multiple FPIES.
The recurrence of repetitive vomiting, lethargy and pallor were the 3 most frequently observed minor criteria. Lethargy and pallor are criteria with large variability in studies (from 3.8%20 to 100%18 for lethargy; from 14%5 to 98.7%20 for pallor). We did not find any hypothermia in FPIES histories, as is the case for Dieme et al. 27 Hypothermia is indeed an uncommon symptom, from 6% in Spain-Italy30 to 10% in Australia,2,31 but up to 31.2% of patients according to caregivers from the International FPIES Association.11 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.7,8 The hypothesis that this may affect our results is unlikely because general characteristics and the prognosis in children with confirmed and presumptive FPIES did not differ. Recent data demonstrated how the different FPIES diagnostic criteria proposed over time provide conflicting results in patients with a high clinical suspected likelihood of acute FPIES.30 Despite multiple reactions to the same offending food, one quarter of the cohort of Vazquez-Ortiz et al. 30 did not meet the criteria from the “2017 consensus”7, especially when severity was mild,30 as was the case for us. Accordingly, we cross-referenced our 145 acute FPIES patients to other definitions. We found 61.4% of patients who fulfilled the Powell criteria modified by Sicherer/1998,9 61.4% (up to 84.8% without the age criteria) according to Leonard/2012,42 24.1% with Miceli Sopo’s 2013 definition (up to 27.6% without the age criteria),4391.1% according to Lee/2017.32 Different phenotypes of FPIES may exist depending on geographic origins or culprit foods which could explain the variability of the symptoms previously described.30
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.8 For fish, one must be even more patient, because experts recommend postponing the performance of an OFC until 5 years of age or older,8 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.8,10,17 This was not confirmed in our cohort, although sensitization (IgE and/or skin prick test) (14.7%) were similar compared to other studies (11.1%-34%).12,13,19,23,26,27 Atopic disorder was found in 41% of patients and eczema in 29%. This is concordant with American and Australian cohorts where eczema is reported in 11% to 57% of patients with FPIES.7 Children with FPIES often have associated atopic conditions (atopic dermatitis, IgE-food allergy, asthma, allergic rhinitis).4 Even if FPIES is not an atopic disease per se , this suggests that FPIES and other atopic comorbidities share common pathophysiology.44,45
We reported a lower frequency of multiple FPIES (5.6%) than in the literature which is commonly reported at around 30%.2,10,12,14,16,23,27,33 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,6,18,26,28,30,31 we only retained FPIES with a specific clinical description. The prevalence of multiple FPIES ranges from 5.1%20 to 69.0%.19 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.7It 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 2 food groups.11Consequently, the risk of developing food aversion is significantly increased in FPIES triggered by 3 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 exclusion21 and overdiagnosis of multiple FPIES.
Our study had certain limitations. The decision to include patients with acute vomiting and only 2 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 self-reported, which leads to a typical bias of over-reporting allergic symptoms.46 In terms of further studies, researching a link between maternal feeding, mode of delivery, previous anti-acid treatment and frequency of antibiotic use and the occurrence of FPIES could be interesting, by exploring the field of gut dysbiosis.