Food Protein Induced Enterocolitis Syndrome (FPIES) and Gastrointestinal Allergy

wp-1463048179000.jpgFood Protein Induced Enterocolitis Syndrome (FPIES) and Gastrointestinal Allergy

Widodo Judarwanto

Food proteininduced enterocolitis syndrome (FPIES) is a gastrointestinal hypersensitivity disorder with a poorly understood pathophysiology and no biomarkers to aid in diagnosis. FPIES is a complex presentation of non-IgE-mediated food allergy. Food proteininduced enterocolitis syndrome (FPIES) is an under-recognized non-IgE-mediated gastrointestinal food allergy. The diagnosis of FPIES is based on clinical history, sequential symptoms and the timing, after excluding other possible causes. It is definitively diagnosed by an oral food challenge test. Unfortunately, the diagnosis of FPIES is frequently delayed because of non-specific symptoms and insufficient definitive diagnostic biomarkers. FPIES is not well recognized by clinicians; the affected infants are often mismanaged as having viral gastroenteritis, food poisoning, sepsis, or a surgical disease. Familiarity with the clinical features of FPIES and awareness of the indexes of suspicion for FPIES are important to diagnose FPIES. Understanding the recently defined clinical terms and types of FPIES is mandatory to suspect and correctly diagnose FPIES.

Gastrointestinal food allergies are a spectrum of disorders that result from adverse immune responses to dietary antigens. The named disorders include immediate gastrointestinal hypersensitivity (anaphylaxis), oral allergy syndrome, allergic eosinophilic esophagitis, gastritis, and gastroenterocolitis, Food Protein Enterocolitis Induces Proctitis (FPIP) and enteropathy; and celiac disease. Additional disorders sometimes attributed to food allergy include colic, gastroesophageal reflux, and constipation. The pediatrician faces several challenges in dealing with these disorders because diagnosis requires differentiating allergic disorders from many other causes of similar symptoms, and therapy requires identification of causal foods, application of therapeutic diets and/or medications, and monitoring for resolution of these disorders.

FPIES appears to be a more common condition than previously appreciated. Any food can cause FPIES, with the most common triggers being cow’s milk, soy, and rice. Registries are needed to understand the phenotype, triggers, and prevalence of FPIES. OFC remains the gold standard for FPIES diagnosis. Multicenter studies are needed to validate the challenge procedure and positivity criteria. Research on the pathophysiology of FPIES reactions is necessary to develop an evidence-based approach to diagnosis and management of FPIES.


  • There is an increase of reported cases of FPIES in recent years. As the disease presents with nonspecific symptoms, it can be misunderstood in many ways. In 1967, Gryboski reported a series of 21 children who developed vomiting and/or diarrhea after ingestion of milk.8 In 1986, Powell characterized the clinical features of such patients, established diagnostic criteria and coined the term “food protein-induced enterocolitis of infancy”.9 Subsequently, Sicherer et al. established the term “Food Protein-Induced Enterocolitis Syndrome (FPIES)”.
  • FPIES is regarded as a rare non-IgE-mediated gastrointestinal allergic disorder. Older nonpopulation-based studies reported an average of 1-15 cases presenting to allergy clinics a year, but recent studies have reported figures as high as 90 cases a year. The yearly incidence of FPIES in one Australian study was one in 10,000 infants less than 2 years of age. Chronic FPIES typically presents in neonates, whereas acute FPIES is primarily a disorder of young infants. FPIES has a slight male predominance; eczema and a family history of atopy are commonly present at diagnosis; almost one in 10 infants have coexistent IgE food allergies and siblings are rarely affected. There is regional variation in common triggering foods, rates of combined cow milk and soy FPIES and multiple food group FPIES. Understanding of the epidemiology of FPIES is limited by the lack of a universally accepted definition and the publication of few prospective population-based case series.
  • FPIES is not as rare as once thought, but how common it is, what factors predispose to its development, and why there is regional variation needs to be addressed by future well designed population-based studies?


  • The histological findings of patients with FPIES have been reported to be uncharacteristic inflammation: edema, villous atrophy and cellular infiltration in the duodenum and jejunum. However, TNF-α expression in the epithelial cells and mononuclear cells in the lamina propria was markedly increased in FPIES patients, especially those having villous atrophy. In addition, TNF-α was highly secreted, antigen-specifically, by PBMC from patients with FPIES and was also increased in the stool after milk challenge of patients with gastrointestinal milk allergy. TNF-α is known to increase intestinal permeability. Therefore, TNF-α could be involved in the pathogenesis of FPIES through alteration of intestinal permeability.
  • Thrombocytosis and leukocytosis after ingestion of offending foods are sometimes observed in patients with FPIES.In addition, C-reactive protein (CRP) is often elevated in the sera from patients with GI allergy. Both reactive thrombocytosis and elevation of CRP are known to be induced by IL-6. We recently found that IL-6 was highly produced, antigen-specifically, by PBMC from patients with GI allergy.46 Thus, in addition to TNF-α, IL-6 may play some role in the pathogenesis of FPIES.
  • Children with milk-FPIES have low levels of csIgG, csIgG4 and csIgA. In particular, children with active FPIES to cow’s milk have deficient T-cell mediated TGF-β responses to casein, rendering TGF-β a promising biomarker in identifying children who are likely to experience FPIES reactions to this allergen. Prospective studies are needed to validate these findings, elucidate their role in FPIES pathophysiology and establish the diagnostic utility of TGF-β in milk-induced FPIES
  • Cell-mediated immune responses  While there is some evidence of T-cell proliferation upon stimulation with food antigens, the stimulation index is not consistently different from control, nonallergic subjects. It is hypothesized that T-cell activation by food allergens may mediate local intestinal inflammation through release of proinflammatory cytokines, causing increased intestinal permeability and fluid shifts. This local inflammation may be mediated by activated peripheral mononuclear cells, increased TNF-α, and decreased expression of TGF-β receptors in the intestinal mucosa. However, baseline antigen absorption is normal and does not predispose to FPIES [41]. Methomoglobinemia described in case of severe acute FPIES have been attributed to the local intestinal inflammation.
  • Neutrophils, platelets, and eosinophils Powell reported leukocytosis with a left shift as a common finding for patients presenting with acute FPIES and included it as one of the diagnostic criteria. In the Powell study, peripheral blood neutrophil counts were elevated in all positive challenges, peaking at 6 h with a mean increase of 9900 cells/μl. These results were confirmed by subsequent studies. Neutrophils have also been found in stool mucous of FPIES patients. This increase in peripheral neutrophils is likely due to the secretion of different cytokines (TNF-α) and chemokines during the inflammatory reaction. Thrombocytosis was recorded in 63% of episodes in one recent Australian report. One possible explanation for this acute thrombocytosis is a response to epinephrine induced by stress, which can shift platelets from the spleen into the circulation. The potential contribution of neutrophils and platelets in FPIES pathophysiology requires further investigation. Eosinophils are present throughout the gastrointestinal tract under physiologic conditions, except in the esophageal squamous mucosa. Eosinophil accumulation in the gastrointestinal tract is commonly found in many gastrointestinal disorders, including classic IgE-mediated food allergy, eosinophilic gastroenteropathies, food-induced proctocolitis, as well as inflammatory bowel diseases and gastroesophageal reflux. Clusters of eosinophils have been found in intestinal biopsies from infants with FPIES. In FPIES with chronic diarrhea, eosinophils and Charcot-Leyden crystals were detected with Hansel’s stain. These findings are not specific for FPIES.
  • Humoral immune responses Humoral responses are poorly characterized in FPIES. Jejunal biopsies reveal increased numbers of IgM- and IgA-containing plasma cells. Elevated serum IgA and IgG antibodies to food proteins have been described in FPIES patients compared with a control group. A recent study showed similar results with a trend for higher specific IgA antibody levels in children with milk FPIES. These studies demonstrated near absence of allergen-specific IgG4 in FPIES. IgG4 antibodies fix complement poorly and could have a protective role in competing with other antibody subclasses that activate complement. The relative lack of IgG4 in FPIES patients may be involved in the pathogenesis of the disease. Systemic specific IgE antibody responses are generally absent in FPIES. However, if skin tests are positive to the causal food, case series suggest that these patients have a decreased probability of developing tolerance. The relationship between IgE and non-IgE mechanisms in FPIES requires further study. The gastrointestinal inflammation caused by FPIES might enhance penetrability of food proteins and their presentation to the immune system with subsequent generation of food-specific IgE antibodies. Conversely, local intestinal mucosal IgE antibodies may facilitate antigen uptake and intestinal inflammation. A recent case series of children with FPIES successfully treated with ondansetron during the supervised OFC raised questions about the role of serotonin signaling in FPIES. Ondansetron is a serotonin 5-HT3 receptor antagonist used mainly to treat nausea and vomiting, often following chemotherapy but also in viral gastroenteritis. It affects both peripheral and central nerves. Ondansetron reduces the activity of the vagus nerve, which deactivates the vomiting center in the medulla oblongata, and blocks serotonin receptors in the chemoreceptor trigger zone. The effectiveness of ondansetron suggests the potential for neural component in FPIES reactions and warrants further study.

Clinical Manifestation

  • Patients with FPIES experience repetitive vomiting, starting one or two hours after ingestion of offending foods, followed by diarrhea.9-16 However, these patients do not develop acute cutaneous or respiratory symptoms, which commonly accompany IgE-mediated food allergy,  Although most patients develop symptoms at least one hour after ingestion of offending foods, total nine patients who have developed symptoms within one hour after ingestion of offending foods were reported.
  • Food proteininduced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food hypersensitivity that manifests as profuse, repetitive vomiting, often with diarrhea, leading to acute dehydration and lethargy or weight loss and failure to thrive if chronic. FPIES is elicited most commonly by milk and soy proteins; however, rice, oat, and other solid foods may also elicit FPIES. Certain FPIES features overlap with food proteininduced enteropathy and proctocolitis, whereas others overlap with anaphylaxis. FPIES is not well recognized among pediatricians and emergency department physicians; the affected children are often mismanaged as having acute viral gastrointestinal illness, sepsis, or surgical disease, delaying diagnosis of FPIES for many months.
  • Food proteininduced enterocolitis syndrome (FPIES) represents the severe end of the spectrum of gastrointestinal food hypersensitivity; its acute episodes can culminate in severe dehydration and hypovolemic shock, and its chronic form entails considerable morbidity associated with feeding difficulty and failure to thrive. Nevertheless, awareness for this syndrome remains rather low. Many factors hamper the establishment of FPIES diagnosis. Such factors pertain to the pathophysiological mechanism of the syndrome, causal food proteins, clinical manifestations, diagnostic procedures, differential diagnosis considerations, and prevailing perceptions which may require critical appraisal. FPIES typically resolves by age 5 years. Milk FPIES, especially with detectable food-specific IgE, can have a protracted course and eventually transition to acute reactions.
  • FPIES is sometimes accompanied by systemic symptoms such as hypotension, lethargy, pallor,hypothermia,bloody stool, ileus,methemoglobinemia and thrombocytosis. Some FPIES patients also develop a high fever, with neutrophilia. Therefore, these patients are sometimes initially mistakenly diagnosed as sepsis or surgical abdominal emergency, etc.
  • Although comparatively acute onset after ingestion of offending foods is a characteristic feature of FPIES compared with other GI allergy entities, as stated above, some patients with FPIES exhibit a chronic clinical course. The reason for this remains unclear.
  • The most common causal foods of FPIES are cow’s milk and soy-based formulas. However, solid foods such as rice, oats, eggs, barley, sweet potato, chicken, turkey, peas, bananas, fish, lamb, corn,and orange juice have also been reported as causal foods. Breast feeding was previously thought to be a protective factor, but recent reports documented five patients with FPIES who reacted to cow’s milk or soy protein passed through the breast milk.
  • A prospective population-based study in Israel reported that the incidence of milk-induced FPIES was 0.34%.38 Age at onset of typical FPIES caused by cow’s milk or soy-based formula was reported to be less than 9 months of age. However, some patients develop FPIES later than 9 months.10-12 In addition, the mean age at onset of FPIES caused by solid foods tends to be higher than that of FPIES caused by cow’s milk or soy-based formula. A recent report indicates that even adults may develop FPIES caused by solid foods


  • Defined FPIES based on four criteria. (1) Disappearance of the symptoms of vomiting and diarrhea, and of blood and leukocytes in the stool, after all antigens are removed from the diet. (2) No other cause for the colitis is demonstrable. (3) Symptoms do not recur and weight gain is normal for one month on a low-antigen formula. (4) Challenge with milk or soy formula, or other offending food antigens, reproduces symptoms.
  • Method for oral food challenge (OFC) as a diagnostic test and criteria for positive responses. Briefly, when more than three of the following five criteria are positive, the challenge is considered positive: (1) vomiting and/or diarrhea symptoms, (2) blood in the stool, (3) leukocytes in the stool, (4) eosinophils in the stool and (5) a change in the blood polymorphonuclear neutrophil count. Although OFC is the most conclusive diagnostic method, it has been associated with a risk of systemic reactions. Therefore, OFC for diagnostic confirmation can be omitted when the clinical course is typical.15 In recent years, the diagnostic criteria described by Sicherer have been more commonly used.10 They are: (1) younger than 9 months of age at initial diagnosis, (2) repeated exposure to the incriminated food elicited diarrhea and/or repetitive vomiting within 24 hours without any other plausible cause for the symptoms, (3) there were no symptoms other than gastrointestinal symptoms elicited by the incriminated food and (4) removal of the offending protein from the diet resulted in resolution of the symptoms, and/or a standardized food challenge elicited diarrhea and/or vomiting within 24 hours after administration of the food.
  • The skin-prick test (SPT) and specific IgE antibodies for offending foods in the serum are negative in the majority of patients with FPIES at the time of diagnosis. However, some patients have detectable IgE and positive SPT reactions to offending foods. The symptoms in these patients tend to persist and those patients often develop IgE-mediated food allergy.However, the role of such specific IgE antibodies in the pathogenesis of FPIES remains unclear.
  • The antigen-specific lymphocyte stimulation test (ALST) is a well-known method for investigating antigen-specific T-cell responses and theoretically should be suitable for diagnosis of FPIES that is thought to be cell-mediated. However, the usefulness of ALST for diagnosis of FPIES has been controversial.42-45 We recently found that certain amounts of lipopolysaccharide (LPS) that contaminated commercially available cow’s milk proteins used in previous reports are able to induce proliferative responses that are antigen-non-specific. In addition, the lymphoproliferative response to LPS was higher in neonates than in young children. Therefore, ALST could be a helpful tool for diagnosis of FPIES if LPS-depleted cow’s milk protein preparations are used.
  • Fogg reported the usefulness of the atopy patch test (APT) for initial diagnosis of FPIES, with 100% sensitivity, 71% specificity, 75% positive predictive value and 100% negative predictive value.47 However, a more recent report found that APT does not predict outgrowing of FPIES (11.8% sensitivity, 85.7% specificity, 40% positive predictive value and 54.5% negative predictive value).48 Further studies are needed to elucidate the usefulness of APT for initial diagnosis and prediction of outgrowing FPIES.
  • The diagnosis of food allergy is based upon a favorable response to an elimination diet and a response to a challenge with the suspected food. The condition is treated by eliminating the allergenic food from diet for as long as 9-12 months in case of cow’s milk allergy. While exclusive breast-feeding for the initial four months or more reduces the chances of development of food allergy, the role of diet restrictions in the mother in reducing the incidence of food allergy in the infant is controversial. Data on food allergy from developing countries are limited. This may be due to lack of diagnosis or less attention given to the condition relative to other diseases including infectious diarrheas and acute respiratory infections. The role of cow’s milk allergy in the pathogenesis of persistent diarrhoea, a major problem in the developing world, remains speculative. Frequent intestinal infections and reduced secretory IgA, which are associated with malnutrition, alter intestinal permeability and result in an increased uptake of food antigens. The increased antigenic load combined with factors such as an atopic predisposition may initiate an abnormal mucosal immune response resulting in chronic enteropathy.
  • Clinical diagnosis requires the exclusion of nonimmunologic diseases that have similar gastrointestinal symptoms. In food allergy, the immune reactions involved can be immunoglobulin (Ig)E-mediated, cell-mediated or both. Symptoms in other target organs are common in cases of IgE-mediated disorders, but not in the cell-mediated disorders in which symptoms are usually localized to the gut. Diagnosis utilizes detailed medical history, clinical evaluation, skin testing, food-specific IgE antibodies, responses to elimination diet and oral food challenges. Endoscopic biopsies are essential in cell-mediated disorders and allergic eosinophilic gastropathies. Treatment includes avoidance of the offending food by a restriction diet in children and the use of hydrolyzed or amino acid-based formulas in young infants. Topical and/or systemic corticosteroids can also be used in eosinophilic esophagitis.
  • The pediatrician faces several challenges in dealing with these disorders because diagnosis requires differentiating allergic disorders from many other causes of similar symptoms, and therapy requires identification of causal foods, application of therapeutic diets and/or medications, and monitoring for resolution of these disorders.

Skin Tests

  • Skin testing has become an integral part in the evaluation settings of GI food allergic disorders. It should be performed by a specialist for allergy testing and in a hospital equipped for emergency interventions. The intradermal skin testing has been abandoned in infants and children owing to the high false-positive rate and the increased risk of systemic reactions.
  • Skin-prick Test: This test is considered a safe and rapid (within 15 min) means to assess IgE-mediated food allergy. It can be performed at any age, including in young infants, with useful results. SPT has a high sensitivity (up to 90%) but low specificity (50%). The interpretation of SPT results should be coupled with clinical history suggestive of allergy to the tested protein. Therefore, it should not be used to screen patients for allergy by testing with a broad panel of food allergens without considerate clinical history, as it is likely to produce false-positive results. In addition, young infants may be less reactive to SPT yielding false-negative results in some cases. There is debate regarding the usefulness of commercial extract versus fresh foods (prick-by-prick), and the optimal cut-off values of SPT to predict a positive OFC are still undetermined.
  • Atopy Patch Test: This is a relatively recent diagnostic tool in cell-mediated food allergies, but is still under research trials and needs standardization in terms of the reagents used in the test, application methods and guidelines for interpretation. Reports concerning research works on atopy patch test (APT) have demonstrated that the test is helpful in the diagnosis of GI food allergic disorders.Moreover, the diagnostic accuracy of APT with fresh food is much better than that of commercial APT assay with freeze-dried purified food. In EE, the combined use of SPT and ATP gives high sensitivity and positive-predictive value, which indicates that false-negative results are very unlikely when both tests are negative. This was clear in the study of Spergel and associates who found that the combination of SPT and APT had excellent negative predictive value (88-100%) for all tested foods except milk, which was very low at 41%. The positive predictive value was greater than 74% for most common foods (milk, egg and soy) but dropped off as the food became a less common cause of EE (such as oat: 50% and apple: 57%). They concluded that the combination of SPT and APT in designing a diet plan has high success rate for food elimination or food reintroduction in EE.
  • In vitro IgE Tests: Food-specific IgE antibodies in the serum can be measured by two methods, the radioallergosorbent test (RAST) and the fluorescent enzyme immunoassay (FEIA) test, to identify food-specific IgE antibodies in vitro. The in vitro test is considered less sensitive than SPT. However, serum testing is useful when skin testing cannot be performed, for example in conditions when antihistamines or corticosteroids cannot be discontinued, in children with a history of severe reactions and in those with associated atopic dermatitis.[43,44] In addition, in young children with very high levels of specific IgE who usually have a major risk of adverse reactions to foods, food challenges should not be tried.
  • Gastrointestinal Test Several GI procedures are currently used in the diagnostic work-up and follow-up of children with food allergy, especially those with non-IgE-mediated and mixed IgE and non-IgE-mediated disorders. These include endoscopic procedures, histologic evaluation and esophageal pH monitoring.

Elimination Diet

  • An elimination diet is employed during the diagnostic settings to confirm whether the suspected food(s) is the cause of allergic symptoms or not, and is also indicated for the treatment of food allergy. Recently, guidelines for the diagnosis and management of cow’s milk allergy in infants were proposed in an attempt to aid physicians and general pediatricians while dealing with infants with food allergy. These guidelines highlighted the importance of maintaining breastfeeding in allergic infants with mild-to-moderate manifestations and that elimination diet for the mothers should be constructed according to the causal food. The duration of elimination diet depends on the response of elimination and reintroduction of food, in general, not less than 2 weeks and up to 4 weeks in atopic eczema or allergic colitis. The mothers are advised to receive calcium supplement during the period of elimination diet. Infants with severe symptoms that interfere with normal growth or those not responding to elimination diet of mothers should be referred to a specialist for reassessment. When solid foods are introduced (preferably not before 9-12 months of age), care should be taken to ensure solids are free from the food protein that the infant is allergic to. When considering weaning, infants with cow’s milk protein allergy should receive extensive hydrolyzed formulas (eHF) as a source of milk. In formula-fed infants with cow’s milk allergy, eHF is the first choice. Amino acid-based formula (AAF) should be reserved for infants refusing eHF because of its bitter taste, or if the symptoms do not improve as some infants may react to the residual allergens in eHF. In some situations, the infant may be initially switched to an AAF, especially if they experience multiple food allergies, specific GI manifestations, or both. In these conditions, the potential benefits of AAF overweigh its higher cost. However, the risk of failure of eHF is no more than 10% in children with cow’s milk allergy.
  • In 97% of young children with EE, elemental diet (AAF) proved to cause resolution of symptoms and to normalize the eosinophil count in the esophagus. However, owing to the unpleasant taste of elemental formulas and their higher cost, Spergel and colleagues demonstrated that an elimination diet, guided by results of combined SPT and APT, led to clinical and histological improvement in 77% of EE patients. Kagalwalla et al. tried another dietary approach. They examined two different diet plans, elemental versus a six-food elimination diet (cow’s milk, eggs, soy, wheat, peanuts and seafood), and found that improvement of clinical and histological findings were achieved in 74% of patients on a six-food elimination compared with 88% of patients on an elemental diet.

Oral Food Challenge

  • The oral challenge is an integral part of the work up for the diagnosis of food allergy. The test can either confirm or rule out the diagnosis of allergy to the tested food.[33] In addition, during follow-up settings, the test is repeated (rechallenge), to assess the timing at which the child might have outgrown allergy to the tested food.
  • The OFC begins with small amounts of the allergen and the dose is increased as tolerated; the test procedures are best described in other review articles. In cases of previous anaphylaxis, a challenge is contraindicated unless SPTs and/or specific IgE measurements show improvement. In such cases, the challenge test should be done in hospital under the supervision of an allergist. The foods selected for testing must be based upon history and results of skin and/or in vitro testing. The suspected food should be eliminated for 7 to 17 days before the challenge for IgE-mediated disorders and up to 12 weeks in some GI disorders. The open challenge means the patients knows that the tested food is the one that has caused the symptoms in the past, and this can lead to a bias in interpretation of the response to that food because the patient will be afraid or feel anxious to experience the same symptoms developed in the past. However, this is unlikely to be the case in young infants and open food challenge is considered reliable and practical. The double-blind, placebo-controlled, food challenge (DBPCFC) is considered the gold standard for the diagnosis of food allergies. It is not liable for bias like open challenge because both the patient and the physician do not know which doses contain the challenge food.
  • Several research studies have been published recently on the topic of food challenge aiming to standardize the procedure. The main problems with food challenge tests are related to the wide range of symptoms, possibly related to food allergy, that lead to difficulties in the interpretation of the test results and to the optimal timing and dosage of this procedure. The choice of optimal timing should be oriented by the type of symptoms from 2 weeks for GERD and up to 8 weeks in the case of EE. The choice of open challenge or DBPCFC, or both, is another point of difference. It has been suggested that when multiple foods are suspected, open challenge may help to identify the specific food to be further tested by DBPCFC. Furthermore, open challenge may be suitable for the diagnosis of immediate symptoms (mostly objective) whereas a DBPCFC may be indicated for the diagnosis of delayed symptoms (mostly subjective), or in research settings. The false-negative rate of DBPCFC is approximately 3%, therefore, negative challenges should always be followed by supervised open feeding of normal portion of the tested food in its commonly prepared state.

Oral food challenge in food protein-induced enterocolitis syndrome

Basic requirements Physician supervision
Secure intravenous (i.v.) access
Immediate availability of fluid resuscitation
Baseline laboratory tests Peripheral neutrophil count (CBC with differential)
Challenge administration Food amount is calculated as 0.06–0.6 g/kg body weight in three equal doses, generally not to exceed total 3 g protein or 10 g of total food (100 ml of liquid) for an initial feedinga
Food is divided in three equal portions and fed over 30 min if food-specific IgE is negative
Modification of the challenge and more incremental dosing is used for patients with positive food-specific IgE
Treatment of the reaction Fluid resuscitation: 20 ml/kg i.v. boluses of 0.9% sodium chloride (NaCl)
Steroids: methylprednisolone 1 mg/kg IV, max 60–80 mg
A majority (>50%) of positive challenges require treatment with i.v. fluids and steroids
The role of intravenous ondansetron in the management of acute FPIES reactions is being currently evaluated
Epinephrine and antihistamines are not effective in FPIES
Postchallenge laboratory tests Peripheral neutrophil count (CBC with differential): at 6 h if the patient reacted or at discharge if the patients tolerated the challenge
If stool sample available: test for occult blood and stool smear for leukocytes
Postchallenge observation About 6 h after the resolution of symptoms or 4 h after feeding in case of no symptoms

CBC, complete blood count.

aIf no reaction in 2–3 h, administer an age appropriate serving of the food followed by several hours of observation.

Interpretation of the food protein-induced enterocolitis syndrome oral food challenge results

Symptoms 1. Emesis (onset 1–3 h)
2. Diarrhea (onset 2–10 h, mean 5 h)
Laboratory 3. Elevated neutrophil count (>3500 cells/ml, peaks at 6 h)
4. Fecal leukocytes
5. Fecal eosinophils
Positive challenge Three of five criteria met
Equivocal challenge Two of five criteria met

The Differential Diagnosis

  • The differential diagnosis includes, in acute presentations, the following: sepsis, other infectious diseases, acute gastrointestinal episodes, surgical emergencies, food allergies. In its chronic forms, FPIES may mimic malabsorption syndromes, metabolic disorders, primary immunodeficiencies, neurological conditions, coagulation defects, and other types of non-IgE-mediated food allergy.
  • A thorough clinical evaluation, including symptoms, signs, and laboratory findings, is necessary to lead the clinicians toward the diagnosis of FPIES. The major reason for delayed diagnosis appears to be the lack of knowledge of the disease.


  • Dietary management is complicated as both common food allergens as well as atypical food allergens can trigger FPIES. Sound nutritional advice is required to ensure appropriate food avoidance, adequate consumption of other foods and sufficient nutritional intake to maintain and ensure growth and development.
  • The primary therapy for FPIES is to avoid the causal food antigens, just as for IgE-mediated food allergies. In infantile cases of FPIES caused by cow’s milk, breastfeeding tends to be protective.
  • Exclusive breastfeeding is recommended when possible. However, a small number patients with FPIES react to cow’s milk or soy protein passed through the breast milk. Some account should be taken of this possibility.
  • If exclusive breastfeeding is impossible, cow’s milk should be replaced with other nutrition, such as a hydrolysate-based formula, soy-based formula or amino acid formula. Among those formulas, hydrolysate-based formula is preferable to soy-based formula, because it was reported that about half of FPIES patients are sensitive to both milk and soy.
  • However, recent reports indicate that the rates of coexisting milk and soy sensitivity are much lower than formerly thought.
  • On the other hand, some patients tend to react even to hydrolysate-based formula.51-53 For them, an amino acid formula is needed.


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