Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E (IgE)-mediated gastrointestinal food hypersensitivity that manifests as profuse, repetitive vomiting, often with diarrhea, leading to dehydration and lethargy in the acute setting, or weight loss and failure to thrive in a chronic form [1-3]. This disease primarily affects infants. It is most commonly caused by cow's milk or soy protein, although other foods can be triggers.
A number of gastrointestinal disorders in children have been attributed to immunologic reactions to dietary proteins. Immunologic reactions to dietary proteins may be classified as IgE mediated, non-IgE mediated (T cell), or mixed (IgE and T cell mediated). The entire gastrointestinal tract can be affected, from the mouth to the rectum. Most of these disorders affect a specific region of the gastrointestinal tract, such as eosinophilic esophagitis (EoE), eosinophilic gastritis, food protein-induced enteropathy, enterocolitis, or proctitis. FPIES has some features that overlap with the other non-IgE-mediated gastrointestinal allergic disorders, food protein-induced enteropathy, and proctocolitis. (See "Food protein-induced proctocolitis of infancy".)
The diagnosis is based upon the presence of consistent clinical features with improvement following withdrawal of the suspected causal protein. Affected children are often misdiagnosed as having acute viral gastrointestinal illness or sepsis, delaying diagnosis of FPIES for many months. An oral food challenge (OFC) is sometimes performed to confirm the diagnosis or to determine resolution of the food allergy. Treatment consists of elimination of the food trigger(s) from the diet.
EPIDEMIOLOGY — Non-immunoglobulin E (IgE)-mediated and mixed gastrointestinal immune reactions to cow's milk proteins are estimated to account for up to 40 percent of cow's milk protein hypersensitivity in infants and young children [1,4]. FPIES represents the severe end of the spectrum of food protein-induced gastrointestinal diseases in infants and is far less common than proctocolitis [5,6]. (See "Food protein-induced proctocolitis of infancy".)
In a large, Israeli, population-based birth cohort, 0.34 percent of infants (44 of 13,019) were diagnosed with FPIES (confirmed by resolution of typical FPIES symptoms with removal of cow's milk from the diet and/or a clinician-supervised oral food challenge [OFC] to cow's milk in the first year of life), suggesting that FPIES may be more common than previously appreciated . The incidence of IgE-mediated milk allergy in this same cohort was 0.5 percent. There are no prevalence studies of FPIES from other populations. There is a slight male predilection (52 to 60 percent) in FPIES [7-9]. Reports of FPIES in siblings of the affected children are rare.
PATHOGENESIS — FPIES is triggered by non-immunoglobulin E (IgE)-mediated food hypersensitivity. However, the exact underlying mechanisms of FPIES are not clearly understood. It is postulated that ingestion of food allergens causes local inflammation mediated by T cells, leading to increased intestinal permeability and fluid shift [10,11]. However, baseline intestinal absorption was normal in a group of infants with FPIES confirmed by oral food challenge (OFC) . Activated peripheral blood mononuclear cells, increased tumor necrosis factor-alpha (TNF-alpha), and decreased expression of transforming growth factor-beta (TGF-beta) receptors in the intestinal mucosa may be involved in the intestinal inflammation .
Systemic food-specific IgE antibodies (determined by serum food-specific IgE and/or skin prick test) are not detected in the majority of patients with FPIES. However, up to 25 percent of children have evidence of specific IgE to the FPIES-inducing food [13-16]. Intestinal mucosal IgE may facilitate the antigen uptake and local intestinal inflammation , but this requires further study. A decrease in serum food-specific immunoglobulin G4 (IgG4) antibody and an increase in serum food-specific immunoglobulin A (IgA) levels were noted in one study . A subsequent study found that both casein-specific IgG4 and IgA antibodies were significantly decreased in milk-induced FPIES .
Food triggers — Although cow's milk and soy protein are the most common triggers, food protein-induced enterocolitis can be triggered by other proteins, such as rice or oat, particularly in infants who have had a previous reaction to cow's milk or soy.
Cow's milk and soy — The most common food triggers in FPIES are cow milk's and soy (classic FPIES), with reactions occurring to infant formula during the first months of life. While several studies have shown that over 50 percent of infants with FPIES react to both foods [14,20], none of the 44 infants diagnosed with cow's milk FPIES in a birth cohort study in Israel showed sensitivity to soy . This difference could be attributed to a milder phenotype reported from a nonselected birth cohort compared with a more severe phenotype reported from allergy and gastroenterology referral populations. Alternatively, this could be attributed to different patterns of soy formula use in infancy.
FPIES to cow's milk in exclusively breastfed infants is rare, suggesting a protective role of breastfeeding that may be attributed to predigested and partially processed food allergens as well as presence of TGF-beta and IgA in mother's milk . Only a few cases of exclusively breastfed infants with cow's milk FPIES have been reported in the literature [21-23], and there are no reports in the literature of soy FPIES in exclusively breastfed infants.
FPIES to goat's milk was reported in an Italian series .
Solid foods — FPIES may be induced by solid food, including grains (rice, oats, barley, corn), meat and poultry (beef, chicken, turkey), eggs (egg white), vegetables and fruit (white potato, sweet potato, squash, string beans, mushroom, banana, apple, tomato), legumes (peanut, green peas, lentils), seafood (fish, crustaceans, molluscs), and the probiotic Saccharomyces boulardii [5,8-10,13,24-36]. Among infants with solid-food FPIES in one series, 80 percent reacted to more than one food, 65 percent were previously diagnosed with cow's milk and/or soy FPIES, and 35 percent were breastfed .
Rice is the most common solid food inducing FPIES . In one case series, rice was responsible for 46 percent of FPIES episodes requiring hospitalization . Children with rice-induced FPIES were more likely to have multiple food sensitivities and severe symptoms requiring intravenous fluid resuscitation compared with children with cow's milk or soy-induced FPIES.
Those with a history of FPIES to one grain have a 50 percent chance of developing FPIES to other grains. However, wheat FPIES has not been reported in infants with oat or rice FPIES [4,9]. Egg is a rarely reported trigger of FPIES. However, 3 of 10 young infants with milk or soy FPIES in one series developed acute symptoms to egg OFC that was done as a negative control for milk and soy at a median age of 5.5 months . In addition, 4 of 38 children (11 percent) in an Australian study had FPIES to egg .
Age of onset — Symptoms of classic FPIES usually begin in early infancy, within one to four weeks following introduction of cow's milk or soy protein. In extreme cases, symptoms may begin within the first days of life. The first description of the disorder included nine infants who presented with severe vomiting and diarrhea, developing an average of 11 days after birth (range 4 to 27 days) . In the Israeli birth cohort previously discussed, all 44 infants with cow's milk FPIES presented with symptoms within the first six months of life . Delayed introduction of cow's milk or soy in breastfed infants may result in later onset.
The mean age at onset of solid-food FPIES tends to be later than that of cow's milk and soy FPIES, typically presenting when these foods are first introduced between the ages of four to seven months [8,41]. The development of FPIES upon introduction of foods after one year of age is rare, although onset of a non-immunoglobulin E (IgE)-mediated gastrointestinal food hypersensitivity similar to FPIES, most commonly triggered by shellfish, fish, and/or egg, has been observed in older children and adults [15,41-43].
Chronic versus acute presentation — The disease typically presents in two phases [7,8,39,40]. The initial presentation of cow's milk- or soy-induced FPIES in infancy is that of a chronic disease while the food antigen is ingested on a regular basis. This can be followed by an acute phase if the antigen is removed from the diet and subsequently re-ingested, with symptoms occurring approximately two hours after ingestion. An acute presentation is also seen when the antigen is ingested intermittently. Young infants with FPIES due to cow's milk and/or soy-based formulas usually have a chronic presentation, whereas solid-food FPIES can have an acute or chronic presentation, depending upon the frequency of ingestion of the offending food.
The following clinical vignette describes features of chronic and acute FPIES.
A full-term female infant who was initially exclusively breastfed was started on cow's milk-based formula supplementation at four weeks of age. The baby developed frequent episodes of vomiting, poor weight gain, and watery stools with occasional mucus over a two-week period of daily formula intake (chronic FPIES).
The baby was then returned to exclusive breastfeeding until one feeding with a cow's milk-based formula at 12 weeks of age. Approximately 90 minutes after that feeding, she developed repetitive vomiting and became lethargic (acute FPIES episode). A full sepsis work-up, toxicology, and metabolic screening were done in the emergency department. She received intravenous fluid resuscitation and antibiotics and was observed in the hospital for three days. Blood-tinged diarrhea was noted only the first hospital day. She tolerated an extensively hydrolyzed casein formula and was discharged after three days when cultures were negative.
She avoided cow's milk strictly and tolerated several solid foods introduced from five to seven months of age without symptoms, until an infant jar food-containing cheese was given. Similar to the previous episode, she developed repetitive vomiting and lethargy 90 minutes after ingestion and required intravenous fluid resuscitation (acute FPIES episode).
Nearly all patients present with vomiting, which is repetitive in the acute presentation and intermittent in the chronic setting, and are commonly pale and ill appearing [6-8,15,24,39,40]. Overall, approximately 75 percent of infants with FPIES appear seriously ill, and 15 percent develop hypotension and require hospitalization, particularly with acute episodes . Other symptoms that can occur in both the chronic and acute presentations include diarrhea, abdominal distention, dehydration, and lethargy. In acute FPIES, repetitive emesis usually begins within one to three hours and diarrhea within 2 to 10 hours (mean onset five hours) of ingestion . Patients with acute presentations tend to be sicker and may develop pallor, hypotension/shock, and/or hypothermia. Failure to thrive/poor weight gain (<10 g/day in young infants) and weight loss are seen in patients with chronic FPIES.
Atypical FPIES — Some patients with FPIES have mixed immunologic reactions to the food(s) that causes their FPIES symptoms. Up to 25 percent of infants and children fulfilling the clinical diagnostic criteria for FPIES have or develop IgE antibodies to the trigger food. These patients are referred to as having atypical FPIES because the disorder is primarily considered a cell-mediated allergy [6,44]. They tend to have a more protracted course of FPIES and have the potential for developing symptoms of IgE-mediated allergy (eg, anaphylaxis), in addition to FPIES. In one study, for example, 7 of 17 children with milk-induced FPIES who developed milk IgE positivity progressed to immediate-allergic reactions ranging from mild symptoms to anaphylaxis . (See 'Allergy testing' below.)
Atopic disease — Approximately 30 percent of infants with FPIES develop atopic diseases, such as atopic dermatitis (25 to 65 percent), asthma (3 to 20 percent), or allergic rhinitis (20 percent) [6,8]. In one study, 39 percent of the children with FPIES had concurrent sensitization (positive IgE test) to other foods . Family history of atopic diseases is present in 40 to 80 percent of patients, including a family history of food allergy in approximately 20 percent .
Laboratory and radiographic findings — The common laboratory and radiographic findings are reviewed below and summarized in the table (table 1). Most of these studies are not performed as part of the initial diagnostic evaluation for FPIES, although some may have been performed as part of the evaluation for the patient's presenting symptoms (eg, vomiting and diarrhea, failure to thrive). (See 'Diagnosis' below.)
Blood tests — Laboratory studies reveal anemia, hypoalbuminemia, and an elevated white blood cell count with a left shift and eosinophilia in patients with chronic FPIES . Thrombocytosis (platelets >500 x109/L) was found in 65 percent of acute FPIES episodes with a recorded white blood cell count in one series . Peripheral blood neutrophil counts are usually elevated in positive challenges (acute FPIES) and peak at six hours. Metabolic acidosis (mean pH 7.03 in one series) and methemoglobinemia have been reported in both acute and chronic FPIES . Transient methemoglobinemia was reported in approximately one-third of infants with severe reactions and acidemia in one series, with some requiring methylene blue and bicarbonate treatment . Methemoglobinemia may be caused by severe intestinal inflammation and reduced catalase activity resulting in increased nitrites. Food-specific IgE testing is discussed below. (See 'Allergy testing' below.)
Stool studies — In young infants with chronic FPIES with diarrhea, results from stool examination were nonspecific, showing occult blood, polymorphonuclear neutrophils, eosinophils, Charcot-Leyden crystals, and reducing substances . Stool contained frank or occult blood, mucus, sheets of leukocytes and eosinophils, and increased carbohydrate content in patients with diarrhea from acute FPIES .
Gastric juice studies — Symptoms, such as severe vomiting and bloody diarrhea, and results of intestinal biopsies both indicate the presence of gastrointestinal inflammation in FPIES. Thus, gastric juice analysis was performed in infants with suspected cow's milk FPIES at baseline and three hours after an oral food challenge (OFC) in one series to look for early signs of inflammation occurring with OFC . An elevated level of gastric juice leukocytes, with >10 leukocytes/hpf, was seen in 15 of 16 positive challenges after three hours, including two infants without early symptoms of emesis or lethargy, and was not seen in eight control infants with negative challenges.
Gastric juice is obtained by placing a nasogastric tube and aspirating gastric fluid. Gastric juice analysis is a research test that is a potential confirmatory test in patients with equivocal OFC results. However, it needs further validation in larger groups of patients and may not be a practical test in every setting.
Histology — Endoscopies with biopsies were more frequently performed in symptomatic infants with cow's milk and/or soy FPIES prior to the establishment of clinical diagnostic criteria. These endoscopies revealed friable mucosa with rectal ulceration and bleeding . Biopsies showed varying degrees of villous atrophy, tissue edema, crypt abscesses, and an inflammatory cell infiltrated with increased lymphocytes, eosinophils, and mast cells [25,47-49]. Immunohistochemical studies showed plasma cells displaying immunoglobulin M (IgM) and immunoglobulin A (IgA) [50,51].
Radiographic features — Radiologic studies are not part of the routine diagnostic work-up for FPIES, but were performed in some older studies. In one series of infants with FPIES and chronic diarrhea, rectal bleeding, and/or failure to thrive, abdominal radiographs showed air fluid levels, nonspecific narrowing and thumb-printing of the rectum and sigmoid, and thickening of the plicae circulares in the duodenum and jejunum with excess luminal fluid . Distension of small bowel loops and thickening of the wall of jejunum distal to Treitz's ligament with diffuse subserosal bleeding was reported in patients who underwent laparotomy for suspected ileus. Intramural gas seen on abdominal radiographs may lead to the misdiagnosis of necrotizing enterocolitis (NEC) [6,8]. Resolution of radiologic abnormalities after dietary restriction has been documented .
Allergy testing — Overall, the majority of patients have negative skin prick tests and undetectable serum food-specific IgE at diagnosis [7,9,13,15,16,24]. Approximately 21 percent of patients with solid-food FPIES and 18 to 30 percent with cow's milk or soy FPIES have detectable food-specific IgE to the same food, and up to 39 percent of children with FPIES have sensitization (positive IgE test) to different foods. (See 'Atypical FPIES' above.)
Atopy patch testing (APT) was evaluated in 19 infants aged 5 to 30 months with challenge-confirmed FPIES . APT correctly predicted 28 of 33 outcomes of OFCs. All positive OFCs had a positive APT, although five patients with positive APT did not react upon OFC. These results have not been confirmed by other studies. Thus, further evaluation is required to determine the role of APT in the diagnosis of FPIES.
DIAGNOSIS — The diagnosis of FPIES is based upon the history, constellation of typical clinical symptoms (table 1) with clinical improvement following withdrawal of the suspected causal protein, exclusion of other etiologies, and, if necessary, results of an oral food challenge (OFC) [40,54]. There are no laboratory and radiographic findings specific to FPIES. However, obtaining a complete blood count with differential during an acute presentation may be useful in that an elevated white blood cell count with a left shift is suggestive of FPIES or sepsis. In addition, an elevated methemoglobin level in a child that appears ashen, gray, or cyanotic and very ill also suggests the diagnosis of FPIES. (See 'Blood tests' above and 'Infections' below and 'Congenital methemoglobinemia' below.)
Endoscopy and biopsy are not routinely performed, but may be indicated to rule out other pathology of the gastrointestinal tract in cases where symptoms are unusually severe and do not resolve with bowel rest or amino acid-based formula. Skin prick testing and/or serum food-specific immunoglobulin E (IgE) testing is usually performed as part of the evaluation to rule out sensitization to particular foods and possible concomitant IgE-mediated disease. (See 'Differential diagnosis' below and 'Laboratory and radiographic findings' above.)
Infants often present with multiple reactions and extensive evaluations before the diagnosis of FPIES is considered, especially when FPIES is caused by solid foods [8,9]. Nonspecific symptoms and lack of definitive diagnostic tests can contribute to the delay in diagnosis. Delayed diagnosis of solid-food FPIES may also be due to the perception that grains (eg, rice and oats) and vegetables have low-allergenic potential and are not usually suspected as triggers of allergic reactions.
Oral food challenge — OFC is the gold standard for diagnosis of FPIES. However, infants do not usually require confirmatory challenges for initial diagnosis if they have a classic history (table 1) and symptoms resolve after removal of the offending food from the diet. Clinician-supervised OFCs are necessary, however, if the history is unclear and a specific food trigger has not been identified, if the time course symptoms are atypical (eg, severe emesis within minutes of food ingestion in the absence of food-specific IgE), or if the child has persistent symptoms on an allergen-restricted diet, with the goal in this case of identifying the relevant food(s) and avoiding unnecessary food restrictions.
The protocol for conducting OFCs for FPIES is outlined in the table (table 2) [4,13,20,40,55-57]. An OFC for FPIES is considered a high-risk procedure. It should be conducted in a setting where intravenous access can be secured, rapid fluid resuscitation given if a reaction occurs, and prolonged observation can occur if necessary. An inpatient setting is the most appropriate for FPIES OFCs, but outpatient settings equipped with resuscitation capabilities and with access to a laboratory (for neutrophil counts and stool analysis) can be used. Performing FPIES OFCs in an intensive care unit is unnecessary, unless the patient has a history of near fatality with an episode .
Symptoms typically resolve within two to four hours with standard management (eg, intravenous fluids with or without intravenous glucocorticoids). Results from a case series of five consecutive patients suggest that ondansetron hydrochloride is an effective therapy that hastens symptom resolution in patients who develop profuse vomiting and systemic symptoms (eg, pallor, irritability, lethargy, confusion) during an OFC . These patients received intravenous ondansetron (0.08 to 0.16 mg/kg) in addition to normal saline fluid replacement. All patients had complete resolution of symptoms within 10 to 15 minutes. One patient had initially received oral ondansetron with only partial resolution of symptoms. Another patient had a recurrence of symptoms an hour after improving that responded to a second dose of ondansetron. This case series suggests that ondansetron may be a therapeutic option for severe FPIES episodes, but additional studies are needed to confirm efficacy.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of FPIES is extensive and includes other allergic food disorders, infectious diseases, intestinal obstruction due to anatomic or functional etiologies, severe gastroesophageal reflux disease, and metabolic, neurologic, and cardiac diseases. A comprehensive differential diagnosis is presented in the table (table 3).
Gastrointestinal food allergy disorders — The gastrointestinal disorders caused by food allergy that may have a presentation similar to FPIES include both immunoglobulin E (IgE)-mediated (eg, anaphylaxis), mixed (eg, eosinophilic gastrointestinal disorders), and non-IgE-mediated (eg, allergic proctocolitis) disorders.
Allergic food protein-induced proctocolitis and enteropathy — Cow's milk and soy are the most common food proteins implicated in these non-IgE-mediated gastrointestinal food hypersensitivities. Skin prick testing and serum food-specific IgE are usually negative in these conditions.
●Food protein-indued proctocolitis – This benign, transient condition typically begins in the first few months of life with blood-streaked stools. These infants are well appearing and thriving, unlike the typical infant with FPIES. Over one-half of infants with proctocolitis are exclusively breastfed. Mild anemia and, rarely, hypoalbuminemia may be present. Eosinophilic infiltration of colonic biopsies is prominent, and peripheral blood eosinophilia is occasionally seen. (See "Food protein-induced proctocolitis of infancy".)
●Food protein-induced enteropathy – This non-IgE-mediated inflammatory response to food causes small bowel injury, leading to malabsorption, intermittent vomiting, diarrhea, failure to thrive, and, rarely, bloody stools [59-63]. It is similar to celiac disease (also known as gluten-sensitive enteropathy), although less severe. Clinical manifestations seen in FPIES that are not typically seen in patients with food protein-induced enteropathy are lethargy, pallor, dehydration, abdominal distension, hypotension, and hypothermia.
Food protein-induced enteropathy is usually induced by cow's milk protein and is most likely to occur in infants fed unmodified (nonformula) cow's milk prior to nine months of age. It has also been described in response to other foods, including soy, eggs, rice, poultry, fish, or shellfish. In some cases, the onset coincides with an episode of gastroenteritis . Anemia and hypoalbuminemia may be present but not methemoglobinemia or acidemia, which can also help differentiate it from FPIES.
The diagnosis is suspected based upon the clinical features and is confirmed by endoscopy with biopsy of the proximal small intestine that demonstrates patchy villous atrophy with a cellular infiltrate. Celiac disease should be specifically excluded by antibody testing (typically immunoglobulin A antibodies to tissue transglutaminase [IgA-tTG]) and histologic features. The histopathologic features of food protein-induced enteropathy are similar to those of celiac disease (villous blunting, intraepithelial lymphocytes, and crypt hyperplasia) but are generally less severe.
Food protein-induced enteropathy is managed by strict elimination of the offending protein, just as celiac disease is managed by elimination of gluten. The disorder generally resolves spontaneously after two years of age .
Eosinophilic gastrointestinal disorders — Eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis are mixed pathophysiology disorders. Sensitization to food allergens is more common in the eosinophilic gastrointestinal disorders than in FPIES, with approximately one-half of patients having detectable food-specific IgE antibodies. Disease onset ranges from a few days of age to adulthood. Symptoms are usually chronic, evolving over days to weeks following food exposure, and may include nausea, vomiting, poor appetite, early satiety, abdominal pain, and diarrhea with blood or mucus. The course is insidious, chronic, and not characterized by acute episodes of severe, repetitive vomiting or lethargy. Difficulty swallowing and food impaction may be the presenting symptom in teenagers and adults with EoE. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis" and "Eosinophilic gastroenteritis".)
Anaphylaxis — Anaphylaxis may present with acute onset of repetitive vomiting, diarrhea, and/or lethargy, usually within minutes to one to two hours following food ingestion. However, these manifestations occur in association with other symptoms (table 4) that are absent in FPIES. Cardiovascular shock may develop, but, unlike in FPIES, it usually ensues within minutes of exposure and is mostly responsive to treatment with intramuscular epinephrine. (See "Anaphylaxis: Emergency treatment" and "Anaphylaxis: Confirming the diagnosis and determining the cause(s)" and "Food-induced anaphylaxis" and "Anaphylaxis in infants".)
Infections — Gastrointestinal viral or bacterial (Salmonella, Shigella, Campylobacter, Yersinia) infections can also present with acute vomiting, diarrhea, and dehydration. Patients with FPIES will not have a history of fever or sick contacts. However, this history may also be absent in patients' acute viral illness. Often, it is the recurrence of repetitive emesis hours after ingestion of a particular food that points to food intolerance and not an acute microbial illness. (See "Acute viral gastroenteritis in children in resource-rich countries: Clinical features and diagnosis" and "Approach to the infant or child with nausea and vomiting" and "Approach to diarrhea in children in resource-rich countries".)
Sepsis should be considered in patients who present with acute dehydration and lethargy. Hypotension and/or an elevated white blood cell count with a left shift support this diagnosis (table 5). Patients with FPIES do not present with a fever or respiratory symptoms and typically recover rapidly with vigorous rehydration alone. (See "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis" and "Septic shock: Rapid recognition and initial resuscitation in children" and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants".)
Necrotizing enterocolitis — Necrotizing enterocolitis (NEC) shares a number of possible presenting features with FPIES, including lethargy, poor feeding, vomiting, diarrhea, shock, and abdominal distension on abdominal radiograph. Systemic and abdominal signs and symptoms seen in patients with NEC that are not typical of FPIES include apnea, respiratory failure, temperature instability, intramural gas on abdominal radiograph, and gastric retention . (See "Clinical features and diagnosis of necrotizing enterocolitis in newborns".)
Intestinal obstruction — There are reports of exploratory laparotomy performed when acute FPIES was mistaken for ileus . Both conditions improve with bowel rest and intravenous hydration and may be associated with an elevated white blood cell count, but, in FPIES, there is usually a history of recurrent episodes upon food reexposures. (See "Causes of acute abdominal pain in children and adolescents" and "Emergent evaluation of the child with acute abdominal pain" and "Intussusception in children".)
Other gastrointestinal disorders — A number of other gastrointestinal conditions may lead to severe projectile emesis (eg, pyloric stenosis), chronic emesis with poor weight gain (eg, gastroesophageal reflux disease), or abdominal distension, severe emesis, and failure to thrive (eg, Hirschsprung disease). In contrast to FPIES, there is no history of recurrence of symptoms upon food re-exposure. (See "Infantile hypertrophic pyloric stenosis" and "Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents" and "Management of gastroesophageal reflux disease in children and adolescents" and "Congenital aganglionic megacolon (Hirschsprung disease)".)
Metabolic disorders — Metabolic disorders can present acutely with episodic vomiting, dehydration, and lethargy and chronically with failure to thrive. They should be considered in the differential diagnosis if metabolic acidosis is present. Patients with metabolic disorders may have other associated features, such as hypoglycemia, hyperpnea, hematologic abnormalities (eg, anemia, neutropenia, thrombocytopenia), liver dysfunction (eg, organomegaly, jaundice), renal disease, and developmental delay. Hyperammonemia is a common finding in patients with a metabolic disorder, although the ammonia level can be normal in patients who are not acutely ill. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Inborn errors of metabolism: Metabolic emergencies".)
Congenital methemoglobinemia — Congenital methemoglobinemia should be considered if methemoglobin levels are elevated. However, unlike patients with FPIES, most patients with congenital methemoglobinemia are asymptomatic or may only complain of headache and easy fatigability. Patients with the rarer type II disease have severe developmental abnormalities and failure to thrive. (See "Clinical features, diagnosis, and treatment of methemoglobinemia" and "Genetics and pathogenesis of methemoglobinemia", section on 'Cytochrome b5 reductase deficiency'.)
INITIAL MANAGEMENT — Management consists of elimination of the offending food from the diet and an emergency treatment plan for acute episodes due to accidental exposures.
Dietary elimination — A casein hydrolysate-based (hypoallergenic) formula is recommended in the infant with cow's milk FPIES if breastfeeding is not possible or the infant is exclusively formula fed due to frequent concomitant cow's milk and soy FPIES. In the rare case of FPIES in the nursing infant, the mother should completely eliminate the triggering food(s) from her diet. Infants presenting with chronic symptoms usually improve within 3 to 10 days of switching to a casein hydrolysate-based formula with or without temporary intravenous fluids . Approximately 10 to 20 percent may require an amino acid-based formula . (See "Management of food allergy: Avoidance" and "Management of food allergy: Nutritional issues".)
Introduction of yellow fruits and vegetables at six months of age instead of cereals is suggested because approximately one-third of infants with cow's milk or soy FPIES develop solid-food FPIES and reactions to rice and other grains represent the most common types of solid-food FPIES [9,67]. Delaying introduction of grains, legumes, and poultry until the first year of life is suggested in infants with solid-food FPIES because of the high rate of reactions to multiple foods . However, the decision regarding when to introduce these foods is best left to the discretion of the treating clinician given the paucity of evidence. Introduction of cow's milk and soy in these infants may be attempted after one year of age (preferably under clinician supervision) if there is no prior history of reactivity to these foods. Tolerance to one food from each high-risk group, for example, soy for legumes, chicken for poultry, or oat for grains, increases the likelihood of tolerance to other foods in the same group . These recommendations are based upon a single-center clinical experience and may change as more data become available.
Many children with immunoglobulin E (IgE)-mediated cow's milk allergy can tolerate milk in baked goods. However, this approach has not been studied in FPIES. The concern is that baking does not alter sequential epitopes that would continue to be recognized by T cells, presumed to be the effector cells of allergic inflammation in FPIES. Thus, we suggest that patients with FPIES avoid all forms of cow's milk/dairy, including products with advisory labeling for milk.
Emergency treatment plan — An emergency treatment letter that outlines the clinical features and management of acute FPIES should be provided to the patient/caregiver for presentation to an emergency department clinician. The emergency letter template can be accessed at the website of the International FPIES Association as well as through the reference . (See "Initial management of shock in children" and "Treatment of hypovolemia (dehydration) in children".)
The emergency treatment for acute FPIES is the same as the treatment for a reaction outlined in the oral food challenge (OFC) protocol (table 2). There are no studies to support a particular protocol. In general, the child should be taken to the emergency department for evaluation and intravenous fluid administration if the episode is severe, manifesting with multiple episodes of projectile emesis, lethargy, and a pale or ashen appearance.
Children who develop dehydration, tachycardia, and hypotension should receive methylprednisolone as well as any necessary supportive therapy, such as oxygen or vasopressors to maintain blood pressure. The use of glucocorticoids is based upon the presumption that a cellular inflammatory response is the primary etiology of the reaction, although no studies have been conducted to confirm the efficacy of glucocorticoids in this setting. Epinephrine is used in patients with shock, but, anecdotally, it has not been helpful in resolution of other acute FPIES symptoms . (See 'Pathogenesis' above.)
Small case series have reported that intravenous or intramuscular ondansetron administered at the onset of acute FPIES symptoms elicited during a supervised OFC was effective in treating emesis and abdominal pain [58,68]. Ondansteron is a serotonin receptor antagonist approved for prophylaxis and treatment of chemotherapy-induced nausea and emesis in patients older than six months. It is increasingly used for managing emesis due to a variety of causes in children, such as viral gastroenteritis or otitis media. Ondansetron inhibits peripheral and central activity of the vagus nerve. Empiric use of intravenous or intramuscular ondansetron is an option in the management of acute FPIES in a medical facility. The efficacy of ondansetron for managing acute FPIES outside of a medical setting has not been studied.
Patients with mild reactions of one to two episodes of emesis may be rehydrated carefully at home. The exception is children who have had severe FPIES reactions in the past. These children should also be taken to the emergency department immediately.
NATURAL HISTORY — Cow's milk and soy FPIES resolve in a majority of patients by age three years. However, patients with solid-food FPIES and/or those with concomitant detectable food-specific immunoglobulin E (IgE) may have a more protracted course. An oral food challenge (OFC) is used to determine if FPIES has resolved.
Cow's milk and soy FPIES — Resolution of FPIES appears to be population dependent, particularly for cow's milk and soy. The Korean cohort showed over 60 percent resolution by 10 months, the Israeli birth cohort showed 90 percent resolution by age three years, and the mean age at resolution was 24 months in the Italian series [7,9,13,24,46]. In contrast, the median age of resolution of cow's milk-induced FPIES was 13.8 years in a cohort of 160 patients at the author’s institution. However, the median age of resolution was 5.1 years among those with undetectable milk IgE, whereas none of the patients with detectable cow's milk IgE had resolution of cow's milk-induced FPIES while in the study . This confirms prior observations that IgE positivity is associated with a more protracted course of FPIES. In addition, only 25 percent of soy FPIES resolved by age three years in the United States study, while, in the Korean cohort, over 90 percent of children showed resolution of soy FPIES by 10 months [9,46]. This difference may be explained by the higher proportion of subjects with detectable food-specific IgE levels and atopic dermatitis in the United States study compared with the Israeli and Korean studies.
Solid-food FPIES natural history — In the studies on solid-food FPIES at the author's institution, resolution by age three years occurred in 67 percent for vegetables, 66 percent for oat, and 40 percent for rice [8,9]. The mean age of resolution for solid foods and soy in the Italian series was 53 months of age .
FOLLOW-UP EVALUATION — An oral food challenge (OFC) is also used to determine whether FPIES has resolved before the food is reintroduced into the diet. We conservatively recommend follow-up challenges every 18 to 24 months in patients without recent reactions . However, in a study of 27 Korean infants with cow's milk FPIES, 64 percent tolerated cow's milk at 10 months, and 92 percent tolerated soy at 10 months . The investigators recommended that follow-up challenge be undertaken sooner: after 12 months of age for cow's milk and between six to eight months of age for soy. Further studies are needed to establish the optimal timing of follow-up challenges.
The follow-up evaluation should include testing for food-specific immunoglobulin E (IgE) prior to the OFC because patients initially presenting with or later developing food-specific IgE antibodies are at risk for persistent FPIES. Determination of when and how to perform a follow-up OFC in the small proportion of patients that develop positive skin prick tests and/or detectable food-specific IgE levels should also take into consideration the possibility of an acute IgE-mediated reaction. A modified OFC protocol with more incremental food-dose administration and availability of appropriate medications, such as epinephrine and an antihistamine, is recommended in these cases . (See "Oral food challenges for diagnosis and management of food allergies".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Food allergy".)
●Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E (IgE)-mediated food allergy that primarily presents in infancy. The most common food triggers are cow's milk and soy formulas, although FPIES can also be caused by solid foods. (See 'Epidemiology' above and 'Pathogenesis' above.)
●FPIES manifests as profuse, repetitive vomiting, often with diarrhea, leading to dehydration and lethargy in the acute setting, or weight loss and failure to thrive in a chronic form. The common laboratory and radiographic findings are reviewed in the table (table 1). (See 'Clinical features' above.)
●The diagnosis of FPIES is based upon the history, constellation of typical clinical symptoms (table 1) with clinical improvement following withdrawal of the suspected causal protein, exclusion of other etiologies, and, if necessary, results of an oral food challenge (OFC) (table 2). (See 'Diagnosis' above.)
●The differential diagnosis of FPIES includes other allergic food disorders, infectious diseases, intestinal obstruction due to anatomic or functional etiologies, severe gastroesophageal reflux disease, and metabolic, neurologic, and cardiac diseases (table 3). (See 'Differential diagnosis' above.)
●Initial management consists of elimination of the offending food from the diet and an emergency treatment plan for acute episodes due to accidental exposures. (See 'Initial management' above.)
●Cow's milk and soy FPIES resolve in a majority of patients by age three years. However, patients with solid-food FPIES and/or those with concomitant detectable food-specific IgE may have a more protracted course. The recommended frequency of oral rechallenges to determine resolution of disease is uncertain, and the decision is at the discretion of the treating clinician; in our practice, we usually perform these OFCs approximately every 18 to 24 months. (See 'Natural history' above and 'Follow-up evaluation' above.)
- NIAID-Sponsored Expert Panel, Boyce JA, Assa'ad A, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol 2010; 126:S1.
- Sampson HA, Aceves S, Bock SA, et al. Food allergy: a practice parameter update-2014. J Allergy Clin Immunol 2014; 134:1016.
- Muraro A, Werfel T, Hoffmann-Sommergruber K, et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy 2014; 69:1008.
- Sicherer SH. Food protein-induced enterocolitis syndrome: case presentations and management lessons. J Allergy Clin Immunol 2005; 115:149.
- Lake AM. Dietary Protein Enterocolitis. Immunol Allergy Clin North Am 1999; 19:553.
- Nowak-Wegrzyn A, Muraro A. Food protein-induced enterocolitis syndrome. Curr Opin Allergy Clin Immunol 2009; 9:371.
- Katz Y, Goldberg MR, Rajuan N, et al. The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study. J Allergy Clin Immunol 2011; 127:647.
- Mehr S, Kakakios A, Frith K, Kemp AS. Food protein-induced enterocolitis syndrome: 16-year experience. Pediatrics 2009; 123:e459.
- Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH. Food protein-induced enterocolitis syndrome caused by solid food proteins. Pediatrics 2003; 111:829.
- Caubet JC, Nowak-Węgrzyn A. Food protein-induced enterocolitis to hen's egg. J Allergy Clin Immunol 2011; 128:1386.
- Caubet JC, Nowak-Węgrzyn A. Current understanding of the immune mechanisms of food protein-induced enterocolitis syndrome. Expert Rev Clin Immunol 2011; 7:317.
- Powell GK, McDonald PJ, Van Sickle GJ, Goldblum RM. Absorption of food protein antigen in infants with food protein-induced enterocolitis. Dig Dis Sci 1989; 34:781.
- Sicherer SH, Eigenmann PA, Sampson HA. Clinical features of food protein-induced enterocolitis syndrome. J Pediatr 1998; 133:214.
- Burks AW, Casteel HB, Fiedorek SC, et al. Prospective oral food challenge study of two soybean protein isolates in patients with possible milk or soy protein enterocolitis. Pediatr Allergy Immunol 1994; 5:40.
- Caubet JC, Ford LS, Sickles L, et al. Clinical features and resolution of food protein-induced enterocolitis syndrome: 10-year experience. J Allergy Clin Immunol 2014; 134:382.
- Ruffner MA, Ruymann K, Barni S, et al. Food protein-induced enterocolitis syndrome: insights from review of a large referral population. J Allergy Clin Immunol Pract 2013; 1:343.
- Berin MC. Mucosal antibodies in the regulation of tolerance and allergy to foods. Semin Immunopathol 2012; 34:633.
- Shek LP, Soderstrom L, Ahlstedt S, et al. Determination of food specific IgE levels over time can predict the development of tolerance in cow's milk and hen's egg allergy. J Allergy Clin Immunol 2004; 114:387.
- Konstantinou GN, Bencharitiwong R, Grishin A, et al. The role of casein-specific IgA and TGF-β in children with food protein-induced enterocolitis syndrome to milk. Pediatr Allergy Immunol 2014; 25:651.
- McDonald PJ, Goldblum RM, Van Sickle GJ, Powell GK. Food protein-induced enterocolitis: altered antibody response to ingested antigen. Pediatr Res 1984; 18:751.
- Monti G, Castagno E, Liguori SA, et al. Food protein-induced enterocolitis syndrome by cow's milk proteins passed through breast milk. J Allergy Clin Immunol 2011; 127:679.
- Nomura I, Morita H, Hosokawa S, et al. Four distinct subtypes of non-IgE-mediated gastrointestinal food allergies in neonates and infants, distinguished by their initial symptoms. J Allergy Clin Immunol 2011; 127:685.
- Kaya A, Toyran M, Civelek E, et al. Food protein-induced enterocolitis syndrome in two exclusively breastfed infants. Pediatr Allergy Immunol 2016; 27:749.
- Sopo SM, Giorgio V, Dello Iacono I, et al. A multicentre retrospective study of 66 Italian children with food protein-induced enterocolitis syndrome: different management for different phenotypes. Clin Exp Allergy 2012; 42:1257.
- Jenkins HR, Pincott JR, Soothill JF, et al. Food allergy: the major cause of infantile colitis. Arch Dis Child 1984; 59:326.
- Levy Y, Danon YL. Food protein-induced enterocolitis syndrome--not only due to cow's milk and soy. Pediatr Allergy Immunol 2003; 14:325.
- Hojsak I, Kljaić-Turkalj M, Misak Z, Kolacek S. Rice protein-induced enterocolitis syndrome. Clin Nutr 2006; 25:533.
- Zapatero Remón L, Alonso Lebrero E, Martín Fernández E, Martínez Molero MI. Food-protein-induced enterocolitis syndrome caused by fish. Allergol Immunopathol (Madr) 2005; 33:312.
- Hwang JB, Kang KJ, Kang YN, Kim AS. Probiotic gastrointestinal allergic reaction caused by Saccharomyces boulardii. Ann Allergy Asthma Immunol 2009; 103:87.
- Bruni F, Peroni DG, Piacentini GL, et al. Fruit proteins: another cause of food protein-induced enterocolitis syndrome. Allergy 2008; 63:1645.
- Monti G, Viola S, Tarasco V, et al. A case of severe allergic reaction to cooked potato. Acta Paediatr 2011; 100:e236.
- Coates RW, Weaver KR, Lloyd R, et al. Food protein-induced enterocolitis syndrome as a cause for infant hypotension. West J Emerg Med 2011; 12:512.
- Fiocchi A, Dionisi-Vici C, Cotugno G, et al. Fruit-induced FPIES masquerading as hereditary fructose intolerance. Pediatrics 2014; 134:e602.
- Serafini S, Bergmann MM, Nowak-Węgrzyn A, et al. A case of food protein-induced enterocolitis syndrome to mushrooms challenging currently used diagnostic criteria. J Allergy Clin Immunol Pract 2015; 3:135.
- Miceli Sopo S, Monaco S, Badina L, et al. Food protein-induced enterocolitis syndrome caused by fish and/or shellfish in Italy. Pediatr Allergy Immunol 2015; 26:731.
- González-Delgado P, Caparrós E, Moreno MV, et al. Clinical and immunological characteristics of a pediatric population with food protein-induced enterocolitis syndrome (FPIES) to fish. Pediatr Allergy Immunol 2016; 27:269.
- Mehr SS, Kakakios AM, Kemp AS. Rice: a common and severe cause of food protein-induced enterocolitis syndrome. Arch Dis Child 2009; 94:220.
- Hsu P, Mehr S. Egg: a frequent trigger of food protein-induced enterocolitis syndrome. J Allergy Clin Immunol 2013; 131:241.
- Murray KF, Christie DL. Dietary protein intolerance in infants with transient methemoglobinemia and diarrhea. J Pediatr 1993; 122:90.
- Powell GK. Milk- and soy-induced enterocolitis of infancy. Clinical features and standardization of challenge. J Pediatr 1978; 93:553.
- Sampson HA, Anderson JA. Summary and recommendations: Classification of gastrointestinal manifestations due to immunologic reactions to foods in infants and young children. J Pediatr Gastroenterol Nutr 2000; 30 Suppl:S87.
- Fernandes BN, Boyle RJ, Gore C, et al. Food protein-induced enterocolitis syndrome can occur in adults. J Allergy Clin Immunol 2012; 130:1199.
- Tan JA, Smith WB. Non-IgE-mediated gastrointestinal food hypersensitivity syndrome in adults. J Allergy Clin Immunol Pract 2014; 2:355.
- Onesimo R, Dello Iacono I, Giorgio V, et al. Can food protein induced enterocolitis syndrome shift to immediate gastrointestinal hypersensitivity? A report of two cases. Eur Ann Allergy Clin Immunol 2011; 43:61.
- Hwang JB, Lee SH, Kang YN, et al. Indexes of suspicion of typical cow's milk protein-induced enterocolitis. J Korean Med Sci 2007; 22:993.
- Hwang JB, Sohn SM, Kim AS. Prospective follow-up oral food challenge in food protein-induced enterocolitis syndrome. Arch Dis Child 2009; 94:425.
- Goldman H, Proujansky R. Allergic proctitis and gastroenteritis in children. Clinical and mucosal biopsy features in 53 cases. Am J Surg Pathol 1986; 10:75.
- Gryboski JD. Gastrointestinal milk allergy in infants. Pediatrics 1967; 40:354.
- Halpin TC, Byrne WJ, Ament ME. Colitis, persistent diarrhea, and soy protein intolerance. J Pediatr 1977; 91:404.
- Fontaine JL, Navarro J. Small intestinal biopsy in cows milk protein allergy in infancy. Arch Dis Child 1975; 50:357.
- Chung HL, Hwang JB, Kwon YD, et al. Deposition of eosinophil-granule major basic protein and expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the mucosa of the small intestine in infants with cow's milk-sensitive enteropathy. J Allergy Clin Immunol 1999; 103:1195.
- Jayasooriya S, Fox AT, Murch SH. Do not laparotomize food-protein-induced enterocolitis syndrome. Pediatr Emerg Care 2007; 23:173.
- Fogg MI, Brown-Whitehorn TA, Pawlowski NA, Spergel JM. Atopy patch test for the diagnosis of food protein-induced enterocolitis syndrome. Pediatr Allergy Immunol 2006; 17:351.
- Powell GK. Enterocolitis in low-birth-weight infants associated with milk and soy protein intolerance. J Pediatr 1976; 88:840.
- Nowak-Wegrzyn A, Assa'ad AH, Bahna SL, et al. Work Group report: oral food challenge testing. J Allergy Clin Immunol 2009; 123:S365.
- Hwang JB, Song JY, Kang YN, et al. The significance of gastric juice analysis for a positive challenge by a standard oral challenge test in typical cow's milk protein-induced enterocolitis. J Korean Med Sci 2008; 23:251.
- Powell GK. Food protein-induced enterocolitis of infancy: differential diagnosis and management. Compr Ther 1986; 12:28.
- Holbrook T, Keet CA, Frischmeyer-Guerrerio PA, Wood RA. Use of ondansetron for food protein-induced enterocolitis syndrome. J Allergy Clin Immunol 2013; 132:1219.
- Kuitunen P, Visakorpi JK, Savilahti E, Pelkonen P. Malabsorption syndrome with cow's milk intolerance. Clinical findings and course in 54 cases. Arch Dis Child 1975; 50:351.
- Iyngkaran N, Yadav M, Boey CG, Lam KL. Severity and extent of upper small bowel mucosal damage in cow's milk protein-sensitive enteropathy. J Pediatr Gastroenterol Nutr 1988; 7:667.
- Walker-Smith JA. Cow milk-sensitive enteropathy: predisposing factors and treatment. J Pediatr 1992; 121:S111.
- Iyngkaran N, Robinson MJ, Prathap K, et al. Cows' milk protein-sensitive enteropathy. Combined clinical and histological criteria for diagnosis. Arch Dis Child 1978; 53:20.
- Yssing M, Jensen H, Jarnum S. Dietary treatment of protein-losing enteropathy. Acta Paediatr Scand 1967; 56:173.
- Kleinman RE. Milk protein enteropathy after acute infectious gastroenteritis: experimental and clinical observations. J Pediatr 1991; 118:S111.
- Murch SH. Cow's-milk protein as a specific immunological trigger of necrotising enterocolitis--or food protein-induced enterocolitis syndrome in disguise? J Pediatr Gastroenterol Nutr 2013; 56:3.
- de Boissieu D, Matarazzo P, Dupont C. Allergy to extensively hydrolyzed cow milk proteins in infants: identification and treatment with an amino acid-based formula. J Pediatr 1997; 131:744.
- Liu AH, Jaramillo R, Sicherer SH, et al. National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol 2010; 126:798.
- Miceli Sopo S, Battista A, Greco M, Monaco S. Ondansetron for food protein-induced enterocolitis syndrome. Int Arch Allergy Immunol 2014; 164:137.