A Systematic Review of Food Protein-Induced Enterocolitis Syndrome

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated hypersensitivity that affects the gastrointestinal tract after ingestion of certain food culprits [1]. FPIES has been well-characterized clinically but is still poorly understood [2]. It can present in acute or chronic forms, based on the frequency and dosage of the culprit food allergen consumed [2]. FPIES manifests with severe vomiting and diarrhea that can be accompanied by dehydration, lethargy, changes in blood pressure and body temperature, and in some cases, failure to thrive [3]. Because it shares symptoms with other common gastrointestinal diseases, FPIES can commonly be misdiagnosed as a gastrointestinal infection [4]. Unlike most food allergies, symptoms do not present immediately after ingestion of the food allergen and onset usually occurs 1–4 h later [3]. Additionally, skin prick test responses or serum allergen-specific IgE antibody results are typically negative which further complicates diagnosis [4]. Therefore, FPIES diagnosis is challenging [4].

The true prevalence of FPIES is unknown, in part due to a lack of awareness of the condition and because of misdiagnosis [5]. Prevalence varies globally and by food trigger [5]. A study by Alonso et al. demonstrated an incidence of 0.7% in a Spanish cohort, while a population-based study across Australia by Mehr et al. reported an incidence of 15.4/100,000 in infants less than 2 years old [5]. An increase in total FPIES cases has been noted, partly due to the increased awareness of the disease likely associated with online posting of the international guidelines in early 2017 [6].

FPIES typically presents in infancy, although onset varies by form [7]. Acute FPIES is characterized by intermittent and low dosage ingestion of the culprit food and is usually considered a condition of young infants [7]. Chronic FPIES is characterized by frequent ingestion of the culprit food at a higher dose and is generally considered a condition primarily of neonates [8]. Acute FPIES is differentiated from chronic FPIES in that it presents with severe symptoms, whereas chronic FPIES may present with mild intermittent vomiting, diarrhea and failure to thrive [7]. Most patients with FPIES acquire tolerance early in childhood; however, some can continue to present with symptoms into adolescence and adulthood [8]. FPIES cases have also been observed in patients who did not previously present with FPIES symptoms in childhood but experienced an onset of symptoms as adults [9].

Management of FPIES varies on a case-by-case basis; however, avoidance of the food trigger is generally recommended [10]. Acute FPIES reactions can be expected to resolve themselves in 4–12 h after onset, while chronic FPIES reactions resolve after 3–10 days of avoiding the trigger food [10]. Mild reactions typically resolve with oral rehydration, while moderate to severe reactions can require aggressive fluid resuscitations with repeated saline boluses [10]. Corticosteroids have also been recommended for patients with severe symptoms because of the presumed cell-mediated inflammation [10]. Epinephrine is not recommended for FPIES reactions as it is not an IgE-mediated condition [10]. Ondansetron, a serotonin 5-HT3 receptor antagonist, has been approved in pediatric populations to prevent nausea and vomiting [11]. It has recently been found to be more effective than traditional FPIES reaction therapies at improving symptoms such as vomiting, pallor, and lethargy and can shorten time to recovery [11].

Despite the challenges related to the diagnosis of FPIES, oral food challenges (OFCs) are currently considered the “gold standard” test [8]. In most cases, the patient’s history and existing diagnostic criteria allow clinicians to establish a diagnosis with high degree of certainty [8]. However, OFCs are used in some cases to clarify diagnosis when clinical history is unclear, if the culprit food is not easily identifiable, or to determine disease resolution after long-term avoidance of the culprit food [8].

The lack of understanding and awareness of FPIES has hindered and limited the recognition and diagnosis of the disease. The objective of this systematic review is to assess (1) the most common food triggers and (2) the median age at resolution and the resolution rate of FPIES. Our findings will contribute to bridge knowledge gaps related to the recognition and management of FPIES.

A search was performed on PubMed and Embase for peer-reviewed articles in English and French published over the past 10 years, that is, from March 2012 to March 2022, inclusively. The review included studies including the terms “food protein-induced enterocolitis” and “FPIES” in the title/abstract. To select relevant articles, the general topic of each article was reviewed based on the title and abstract. The inclusion criteria were studies in which the food triggers and/or resolution rates in children and/or adults diagnosed with FPIES were reported. The exclusion criteria were literature reviews/systematic reviews, guidelines/practice parameters, studies with a sample size less than 10 (including case reports), studies focusing on the pathophysiology of FPIES, and conference abstracts. The articles were then read completely and were excluded if they did not mention food triggers or disease resolution in patients clinically diagnosed with FPIES (Fig. 1).

This systematic review focused on 2 domains: (1) common food triggers that cause FPIES reactions; and (2) resolution ages and rates in studies of patients diagnosed with FPIES. Many articles in the systematic review included both domains due to the nature of the studies (the majority being retrospective reviews of patients referred to hospitals for FPIES).

For all domains, the diagnosis method, the description of the participants, the form of FPIES (chronic or acute), and limitations brought up by the authors were included. For the food triggers domain, the type of food trigger was included. For the resolution domain, the form of food trigger reintroduction (at home or by OFC in a hospital setting) and the frequency of patient follow-up were included.

The following variables were extracted from the articles included in the systematic review for all domains: author, year of publication, country, study design, population type, number of participants, and FPIES form of the participant. Specific variables for the food trigger domain included the distribution of the food triggers in the studied population and the number of triggers reported for each participant. Specific variables for the resolution rate domain included the mean resolution rate of the participants, the median age of resolution of the participants, and the frequency of follow-up in patients enrolled in the study.

The search on PubMed and Embase yielded 352 and 451 articles, respectively, for a total of 803 (Fig. 1). After removing duplicates, 586 articles were reviewed for relevance, 154 were removed for being reviews, and 75 were removed for not being relevant to FPIES. The remaining 357 articles were then read fully, and the following articles were rejected: 167 had a sample size smaller than 10, 46 were missing full text, 38 were not pertinent, 7 were guidelines, and 53 were conference abstracts. The remaining 45 articles were separated into the 2 domains, which are not mutually exclusive. Since most of the articles included were retrospective reviews which studied patients from diagnosis until resolution, most articles fell into both domains. Key study parameters including patient numbers, country of origin, and average patient ages were summarized in online supplementary Table S1 (see www.karger.com/doi/10.1159/000529138 for all online suppl. material).

A total of 42 studies were included in the food trigger domain. Most articles (n = 37, 88%) studied only children diagnosed with FPIES, while 4 articles studied only adults, and the remaining 1 article studied both age groups [3, 5‒7, 9, 11‒49]. The majority of studies were retrospective observational studies (n = 26, 61.9%) [1‒6, 8‒11, 13, 17‒21, 24‒33, 35, 38, 39, 42‒47]. Only one study had an international cohort while the rest focused on the cohort of the country the study was based in [33]. Given the restricted knowledge of FPIES, only a few countries had any data relevant to FPIES and all were high-income countries. The distribution of common triggers varied by country and/or region; however, internationally, cow’s milk (CM), fish, eggs, and grains were most frequently reported (Table 1; Fig. 2). Three studies were conducted in Australia and reported rice as the most reported trigger, followed by CM [26, 27, 34]. Most studies included in the systematic review were based in southern Europe (18/42, 43%) which includes France, Greece, Italy, and Spain, and reported fish and CM as the most common triggers [12, 14‒17, 20‒22, 24, 29‒31, 37, 39, 40, 45, 47, 48, 50]. Of the eight studies conducted in Italy, four studies also reported hen’s egg as a common trigger [12, 17, 30, 48]. Three studies were conducted in the East Mediterranean region, including Turkey, where hen’s eggs and fish were most frequently reported as culprit foods [13, 35, 36].

CM was also reported as the most common trigger in the two studies based in the UK; however, one of these studies by Ludman et al. [3] reported a high incidence of fish as a trigger in the UK [41]. Studies conducted on children in the USA represented 6/42 studies included in the domain and reported CM and grains as the most commonly reported trigger foods [5, 7, 18, 38, 42, 46]. Of the studies based in the USA, four of the six (4/6) studies reported soy as a top trigger food [5, 7, 38, 46], and CM was reported as a top trigger in 4/6 studies [5, 18, 38, 42]. Additionally, grains such as rice and oats were commonly reported as triggers in the USA [42]. In Japan, the common triggers were reported as CM and hen’s egg [6, 43]. A study by Akashi et al. [6] reported a recent dramatic increase in patients in Japan with FPIES to hen’s egg. One study conducted in Sweden by Ullberg et al. [44], reported CM and fish as the top triggers, while a study by Moya et al. [32] based in Chile reported CM, rice, and fish as the top triggers. All aforementioned studies involved children, but the four studies involving adults and adolescents all found that crustaceans were the most common trigger in their age group [9, 22, 28].

Of all 42 articles which studied the most popular FPIES triggers, 19 (45%) studied the number of triggers reported per individual [5, 7, 9, 18, 19, 21, 24‒26, 29, 32‒34, 38, 40, 44‒46]. Again, the distribution varied internationally. All European countries included (11/19) reported a higher proportion of patients reacting to only one trigger [17, 19, 21, 24, 25, 29, 31, 39, 40, 44, 45]. Of the studies conducted in the USA (5/19), three reported a higher prevalence of patients who reacted to more than one trigger, while one paper by Caubet et al. [7] reported that 65% of patients reacted to only one trigger [5, 18, 38, 46]. An Australian study by Mehr S et al. [34] found that 68% of patients reacted to only one trigger. Overall, onset of CM-FPIES was reported at an earlier age compared to other food triggers, while fish-FPIES and egg-FPIES onsets were reported at a later age (Fig. 3). No sex differences were reported amongst any of the studies, and while only 31 studies reported patients with concomitant allergic disorders, no significant conclusions were made (online suppl. Table S1).

A total of 26 studies were included in the FPIES resolution domain. Most studies included were retrospective (19/26, 73%). Of the 26 studies included, 22 mentioned that tests to determine tolerance were infrequent or inconsistent across patients [5, 7, 13, 21, 22, 25‒27, 29, 30, 35, 36, 42, 44, 46, 47, 49‒51]. There was only one study following patients every 6 months, while other studies reported resolution rates based on a follow-up after the study period ended [39]. Three other studies conducted OFCs every 12 months after diagnosis [24, 38, 40]. Again, the resolution rate and time varied by food trigger. Of the 26 studies included in this domain, 13 (50%) mentioned the overall resolution rates and ages of their cohort. Frequency of retesting the participants varied by study. The resolution rates ranged from 60% to 85% for all foods, while the median reported age of resolution for all foods ranged from two to 5 years old. Of these 13 studies, 7 (53.8%) found that 55–60% of patients acquired tolerance by the age of three [5, 21, 25, 36, 39, 40, 42, 46, 50]. One of these studies by Ruffner et al. [5] later revealed that more than 85% of patients enrolled in their study acquired tolerance by age five. A study conducted by Sopo et al. [40] evaluated patients over a 12-month cycle and reported that 60% of FPIES patients re-evaluated with OFC in a hospital setting were resolved at a median age of 29.3 months. They also found that all 9 of their patients who reintroduced the trigger food at home achieved tolerance at a median age of 37.5 months [40]. Two studies which reviewed cases over a 5 year period found that 60% of patients achieved tolerance by age four [13, 24]. One study conducted in the UK by Meyer et al. reported that 75% of patients acquired tolerance by age eight.

Overall patterns were noted to depend on the type of culprit food. All nine papers studying patients who reacted to CM noted a shorter period of resolution compared to other foods (Fig. 3). Of these nine studies, six suggested resolution rates higher than 50% for CM-FPIES by the age of two [35, 39, 40, 44, 47, 51]. One study by Katz et al. [51] which performed scheduled OFCs found that CM-FPIES patients resolved at a median age of 16 months. The other three studies evaluated resolution of FPIES only at one time point and reported that most patients acquired tolerance to CM by age three [27, 46].

In contrast to CM-FPIES, FPIES triggered by fish and hen’s egg is less likely to resolve. The median ages of resolution for fish-FPIES ranged from 37 months to 7 years in the seven studies [21, 24, 27, 29, 45, 47, 50]. In studies assessing resolution of egg-FPIES, the median age at time of resolution ranged from 18 months to 63 months [30, 35, 47, 50] (Fig. 3). One study by Miceli-Sopo et al. [30] also found differences in the age and rate of resolution when raw egg or cooked egg was consumed. In this study, patients with egg-FPIES were subjected to OFCs with raw egg and cooked egg [30]. This study also found that 77% of participants acquired tolerance to cooked egg at a median age of 38.2 months while 32% acquired tolerance to raw egg with a median age of 43.9 months [30].

We conducted the first systematic review to assess culprits and resolution of FPIES. We found that the most common FPIES food triggers varied by country/region. Globally, the most reported FPIES trigger was CM, followed by fish, hen’s eggs, and grains. Reactions to various fruits and vegetables were also noted; however, the types of fruits and vegetables varied by study and were in low proportions. In Australia, rice is the most common trigger, and it has been suggested that this is because rice is a common part of the Australian diet and because Australian guidelines in 2003 recommended rice as one of the first solids to be introduced into an infant’s diet [13, 52]. Additionally, rice cereal is a common first solid introduced in infants (70%) [52]. In the USA, soy and CM are the most common triggers. Several authors hypothesized that this is likely because of the common use of soy-based and CM-based formulas to feed children [7, 21, 46]. The same pattern was observed for infants with CM-FPIES in infants in the UK. In both the Eastern Mediterranean and Southern Mediterranean regions, CM and fish were the most reported triggers. In studies reviewing fish-FPIES in infants, all authors noted that fish is commonly introduced early in the diet of children in these regions. Fish was also a common trigger in Germany, where it is an integral part of an early infant’s diet [25]. This contrasts with the USA and Australia where fish is less commonly introduced at a young age [26, 27, 34]. Finally, hen’s egg was the most reported trigger in Japan. Authors Akashi et al. noted a recent dramatic increase in cases with egg-FPIES, possibly because of a change in guidelines in Japan promoting the earlier introduction of egg in high risk patients [6]. It is frequently hypothesized that the different patterns across the globe exist because of different styles of diet and lifestyles [5, 21, 31, 40]. It is speculated that foods that are introduced first have a higher risk of triggering FPIES; thus, timing could be a key factor [25]. Authors Sopo et al. [40] hypothesized that the different patterns may actually be due to different FPIES phenotypes rather than dietary habits. They also suggested that other factors could be involved including obstetrical practices and pre- and postnatal environmental exposures [40].

Three studies also looked at FPIES in adults and adolescents and found that the most common trigger was crustaceans [9, 22, 42]. Adult-onset FPIES is believed to be a variant of FPIES; however, not much information is known about the condition as few cases have been recognized [9].

The resolution rate and median age of resolution varied by type of FPIES trigger. Several studies found that in most populations, resolution of FPIES occurred in ∼60% of infants by the age of three. Overall, FPIES cases with CM were reported to resolve earlier than FPIES cases with fish or egg. Timing of the introduction of the foods is hypothesized to play a key role. Since milk is a liquid food that is introduced at an earlier age, it is suggested that tolerance is acquired at an earlier age [40]. The resolution for FPIES varied greatly across the studies included; however, the median ages of resolution for egg-FPIES was later than for CM-FPIES. A study by Miceli Sopo et al. [30] and a study by Watanabe et al. [49] both found that tolerance to egg was achieved earlier when the egg was cooked compared to when raw egg was tested. They hypothesize that this is because processing the egg by cooking can change its allergenicity [30].

Patients with fish-FPIES were found to have the lowest rates of resolution and the highest median ages of resolution [24]. There are several contributing factors, including the later introduction of fish into the diet. Additionally, as fish is not typically seen as necessary to the diet, parents are less likely to reintroduce it into their child’s diet [21]. Because of the severity of reactions when exposed to fish, parents of children with fish-FPIES are less willing to feed their children fish and delay reintroduction into adulthood [24, 29]. These reasons aside, it is unknown why fish-FPIES is more persistent in patients who are tested often from a young age [24].

Our study has some limitations. Most of the papers included in the resolution domain did not frequently follow-up with patients or followed-up with patients after different timeframes. This could explain why a lot of variation was noted when comparing resolution rates and median ages. Several reasons for poor follow-up were provided. One common reason was that the time to reintroduce a food varied as it was decided by the parent, physician, or allergist [25]. Additionally, many parents did not want to participate in the resolution studies or delayed participation for fear of severe reactions. Finally, OFCs in hospitals require substantial resources and are often time consuming and hence are not done frequently [46]. Additionally, in studies where OFCs were performed, not all patients were tested via this method (online suppl. Table S1). It is therefore possible that tolerance to the food might have occurred earlier.

FPIES was once considered a rare disease; however, increased awareness amongst physicians and the publication of guidelines in 2017 have resulted in an increase in diagnosis of FPIES [6, 40]. Although FPIES resolves in most children by the time they reach adolescence, some patients never acquire tolerance to certain foods. Despite the publication of diagnosis guidelines, accurate diagnosis remains challenging, and OFCs are often considered too dangerous [4]. The development of more sensitive and specific diagnostic tools and guidelines is warranted. The studies included in this review were mostly concentrated in southern Europe, the USA, the UK, and Australia. There is sparce data regarding FPIES in Asia, South America, Eastern Europe, Africa, and Middle Eastern countries. Additionally, better monitoring of resolution is needed so that more accurate rates and ages of resolution can be determined. This knowledge would aid physicians in deciding when to try reintroducing foods based on the patient’s age and food trigger. Finally, the emergence of adult-onset FPIES should be further studied to better characterize FPIES and improve its management in adults.

An ethics statement is not applicable because this study is based exclusively on published literature.

All authors declare that they have no conflicts of interest.

No funding was received.

Catherine Prattico, Pasquale Mulé, and Moshe Ben-Shoshan were involved in data generation, analysis, and manuscript revision.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.

Edited by: Hans-Uwe Simon, Bern.