Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E (IgE) mediated food allergy, which normally debuts in infancy and childhood and manifests as repetitive vomiting, sometimes followed by diarrhea. It can be accompanied by lethargy, hypotonia, hypothermia, and hypotension [1].

In recent years, an increasing number of cases of adult-onset FPIES have been described; however, data from these reports suggest some differences with pediatric FPIES [2–11], so the diagnostic criteria proposed in the international consensus may lead to underdiagnosis in adults.

This review aims to describe clinical characteristics, epidemiology, and differences between adult and pediatric FPIES and to propose diagnostic criteria to improve the diagnosis in adults.

Powell [12] first described FPIES in 1976, but it was not until 2015 that FPIES was recognized and codified in the International Classification of Diseases, 10th edition (ICD-10, code K52.2). Although FPIES is regarded as a rare food allergy disorder, the prevalence reported for children in the USA is 0.51% [13], a figure in line with other studies from Israel and Spain [14, 15]. In adults, a cross-sectional, population-based survey of the USA population carried out by Nowak-Wegrzyn et al. [13] from 2015 to 2016 estimated a prevalence of 0.22% [95% confidential interval (CI), 0.17–0.28] based on data from 40,443 adults, 113 of whom reported physician-diagnosed FPIES.

The true prevalence of adult FPIES is likely underestimated due to the combination of underdiagnosis, under-reporting, and non-attendance to healthcare centers for mild cases. In fact, adult case series report a median of 5 episodes to 10 episodes prior to diagnosis, with a median delay of four years [10, 11]. Regional variations in prevalence may also occur, as described in children [16].

Prevalence data for chronic FPIES are unknown and complicated by the similar clinical presentation to food protein enteropathies in childhood [17]. In adults, the disease is rarely recognized, and only one clinical case was communicated in the literature in 2020 [18].

The average age at the onset of adult FPIES is around 35 years but may present anytime from the late teenage years to old age. A clear predominance of women has been observed in all adult series reported (Table 1). Moreover, most series show high rates of atopic diseases, especially IgE mediated food allergy, rhinitis, asthma, and atopic dermatitis, in adults with FPIES, similar to children [3, 6, 9–11].

A higher incidence of gastrointestinal disorders including eosinophilic esophagitis, inflammatory bowel disease, and celiac disease has also been reported in the adult population [10]. As awareness of FPIES grows, future studies will probably report higher incidence rates, especially in the adult population.

The mechanism(s) behind the characteristic symptoms of FPIES is unknown, although some evidence indicates the involvement of the immune system [19–26]. However, these studies were performed in children; there are no data on the adult population.

In adults, FPIES symptoms generally appear after years of previous tolerance, but in some cases, symptoms begin in childhood and persist into adulthood. Currently, no risk factors associated with the development of adult FPIES have been identified, though some authors have speculated that the loss of oral tolerance may be due to environmental influences like diet, use of antimicrobials, infections, pollutants, and detergents driving a shift towards microbial dysbiosis and immune dysregulation [33]. The classic presentation of acute FPIES in children consists of profuse vomiting within 1 h to 4 h after ingestion of the suspected food, accompanied by pallor and lethargy; however, in adults, the onset of symptoms may be delayed up to 6 h [11].

The clinical presentation of FPIES in adults differs considerably from that of children, especially with regard to the presence of vomiting. With the exception of the series by García Paz et al. [9] (where all patients reported this symptom), the most recent published series estimates that only about 64.5% of adults with FPIES experience vomiting (Table 2). The heterogeneous inclusion criteria between the various studies may explain these differences. In adults, the predominant symptom in the published series is abdominal pain, followed by diarrhea. Only around 30% of adult patients experience all three symptoms [5]. Nausea is also common, with 69% of adults reporting this in the Crespo et al. [8] series. Other frequent symptoms in adults include weakness (50%), chills (29%), and lethargy (26%). However, hypothermia, hypotension, and dehydration are less common in adults than in children [10, 11]. Reactions usually resolve within approximately 15 h (range 4–48 h) [11].

The chronic form of FPIES, less common and less well known than the acute form, has been described in infants and is characterized by chronic emesis, watery diarrhea, and failure to thrive [17]. This form has scarcely been described in adults but is associated with weight loss, chronic diarrhea, and episodic vomiting, with some unrelated foods implicated as triggering symptoms [18]. This form in adults is probably frequently misdiagnosed as irritable bowel disease.

Crustaceans, fish, bivalves, and cephalopods are the common triggers described in different adult populations of Australia, Canada, and Spain [3–11]. However, in recent years many other foods have also been reported, including eggs, fruits (e.g., avocado, banana), oats, and other foods that are not usually implicated in IgE mediated reactions, like mushrooms, meats, garlic, and red pepper. It seems that any food may be implicated, suggesting the emergence of new triggers or possibly a higher index of suspicion [10].

Du et al. [5] reported that up to 20% of patients in a series of 25 had symptoms with wheat, and in the Crespo et al. [11] series, up to 4.8% reported symptoms after eating oats. In cases where cereals are the triggers, lack of awareness probably results in patients being underdiagnosed or misdiagnosed with non-celiac gluten sensitivity.

As with cereals, some patients initially labeled as lactose intolerant showed on OFC that milk can also induce FPIES symptoms [5, 10]; however, in adults, most cases of milk FPIES are probably labeled as lactose intolerance.

In some patients, more than one group of unrelated foods are responsible for symptoms, ranging from 7% in García Paz et al. [9] series to 44% in Crespo et al. [11]. The most common association observed was between different seafoods, such as crustaceans, mollusks, and cephalopods [6, 10, 11]. This clustering pattern has also been observed in the pediatric population, probably due to taxonomical relationships [34].

The lack of vomiting observed in many adults with FPIES is not the only difference with respect to children (Table 3). Unlike the pediatric population, in adults, there is a clear predominance of women in all the series reported [3, 5–11]. A hormonal influence has been postulated, although a recent study failed to demonstrate this fact [10]. The profile of implicated foods constitutes another difference between the pediatric and adult population. This might be a result of different dietary patterns; however, in older children as in adults, seafood is an important trigger [35, 36].

The severity of the disease also seems to differ between populations. Up to 31% of children were treated in the emergency department in Caubet et al. [37] series, while just 6.4% to 21.1% of adults required emergency care in the published series [3, 10, 11]. However, variations in the severity of FPIES are difficult to prove due to the many confounders. For example, adults carry less risk of food transgressions than children. Moreover, care seeking may be more frequent at the pediatric age, regardless of the severity of the reaction.

There are no published cases of adults treated in intensive care unit, unlike the pediatric population. Dehydration and metabolic changes also seem uncommon in adults; however, some severe cases have been reported [2–4, 6, 10, 11].

OFC outcomes also provide information about disease severity. In the largest adult series, 31 of 49 OFCs were positive, and only 33.3% of cases required treatment [10]. In the same series, 12.9% presented hypotension, weakness, and lethargy as a reaction to fish and eggs, in addition to digestive symptoms [10].

In another recent series [11], 9 of 21 OFCs were positive; in addition to digestive symptoms, three patients presented lethargy and three chills. Strikingly, none had emesis, and only four received intravenous saline solution. These data contrast with Wang et al. [38] results in a large pediatric population, in whom 169 OFCs were performed and 30 were positive; up to 50% of the children required intravenous fluid, and 3 required hospitalizations, including one in the intensive care unit. However, as Crespo et al. [11] note, adults with a history of severe symptoms often refuse OFC.

The natural history of the syndrome may also differ by age. Although in adults this is not well known, some authors have described a worse prognosis than in children [10, 11].

Otherwise, unlike the pediatric population, in which up to 20% of patients may show sIgE, especially in milk-induced FPIES, the percentage in adults is lower. Around 4% of patients showed sIgE to the offending food [10, 11]. Skin testing or sIgE can be considered in patients with FPIES at follow-up visits before OFC; however, the prognostic value in adults is unknown.

As in the pediatric population, diagnosis is based on a clinical history of typical signs and symptoms after the ingestion of the trigger food and remission after avoiding it. In the clinical history, aspects like reproducibility of symptoms after exposure, symptoms with other foods, and the latency period must be considered. In most cases, the first episodes are misdiagnosed as viral gastroenteritis or food poisoning.

In a significant percentage of adults, the main diagnostic criteria proposed in the international consensus [1], vomiting, is absent, while abdominal pain or cramping is the most common finding, usually associated with nausea or diarrhea. Due to the lack of any specific biomarkers for diagnosing and monitoring the disease, and given the unspecific nature of symptoms, a thorough clinical history should be followed by an OFC to confirm the diagnosis of FPIES in adults.

If no food transgressions have occurred over several previous years, an OFC should be performed at regular intervals to determine whether the disease has resolved.

In patients with multiple implicated foods and recurrent symptoms, a gastroenterology study is recommended. Once other causes are excluded, an elimination period for suspected triggers, followed by an OFC to confirm the diagnosis is recommended.

Differential diagnosis must consider anisakiasis; food poisoning; fructose, lactose, and sorbitol intolerances; and celiac disease (Table 4). In cases where multiple foods trigger FPIES symptoms, differential diagnosis with irritable bowel diseases may be difficult.

Most FPIES cases with childhood-onset resolve by 3–5 years of age. Age at resolution depends mainly on the type of food. Milk and cereals are usually tolerated earlier, while the period for achieving tolerance is longer for egg and fish FPIES. However, patients with multiple FPIES triggers do not appear to become tolerant at an older age than those with a single trigger [16]. Data on the acquisition of tolerance in adults are scarce, but it seems to take longer than in children, and in many cases, it may be persistent [6, 8, 10, 11].

Recent studies [10, 11] in adults have provided more insights into the natural history of FPIES in this age group. One prospective study [10] with a median follow-up period of 6.2 years observed that 16.8% of patients achieved tolerance after a median of 3.5 years. However, other patients in the cohort had not overcome the disease even after 40 years, a finding also described elsewhere [2]. An inverse correlation between disease duration and resolution was observed [10]. Crespo et al. [11] reported that in a population of 15 patients in which OFC was performed, 40% tolerated the offending food after a median of 7 years from the first reaction.

The international consensus [1] provides a useful tool for the diagnosis and management of FPIES; however, a considerable proportion of adults go undiagnosed using the criteria proposed.

Due to the lack of any specific biomarkers for diagnosing and monitoring the disease, and given the unspecific nature of symptoms, a thorough clinical history should be followed by an OFC to confirm the diagnosis of FPIES in adults. The latest reports [10, 11] confirm that in adults, some patients achieve tolerance after a period of avoidance.

More studies are needed to better understand the characteristics of adult FPIES, its pathogenesis, and its natural history, and it is essential to identify a biomarker to diagnose and monitor the disease.