Food Protein-Induced Enterocolitis Syndrome - National Organization for Rare Disorders (2023)


NORD gratefully acknowledges Jonathan M. Spergel, MD, PhD, Chief, Allergy Section, Professor of Pediatrics, Stuart E. Starr Endowed Chair in Pediatrics, Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Perelman School of Medicine at Univ. of Pennsylvania, for assistance in the preparation of this report.


  • dietary protein enterocolitis

Diseases Overview


Food protein-induced enterocolitis syndrome (FPIES) is an uncommon disorder characterized by an allergic reaction to food that affects the gastrointestinal system. The term enterocolitis specially refers to inflammation of the small and large intestines. Individuals with FPIES experience profuse vomiting and diarrhea that usually develops approximately 2-6 hours after ingesting the offending food. Additional symptoms include pallor, lethargy, and abdominal swelling (distension). Symptoms can be severe and can potentially cause acute dehydration and/or hypovolemic shock. The most common triggers for an episode are milk, soy, and rice, but the disorder has been associated with a wide range of food proteins. Many children develop a tolerance to the offending foods by the age of three, however, in some cases, the disorder persists. Removal of the offending food should lead to a complete resolution of symptoms. The exact, underlying immune system mechanisms that are involved in the development of FPIES are unknown.


Several different gastrointestinal disorders in children are believed to be caused by an abnormal immunologic reaction to dietary proteins. They are generally classified into three groups: IgE-mediated (as in classic food allergies), non-IgE-mediated, or mixed (a combination of both). IgE stands for immunoglobulin E, an antibody that the immune system creates in response to an allergic reaction and is often implicated in food allergies. Food specific IgE antibodies are typically not involved in FPIES. The disorder is presumed to be cell-mediated. Many researchers consider FPIES the severe end of a spectrum or continuum of disease involving non-IgE-mediated gastrointestinal food allergy disorders. This spectrum also includes proctocolitis and food-protein induced enteropathy.

Signs & Symptoms

The symptoms and severity of FPIES can vary greatly from one individual to another. Some individuals will experience vomiting and diarrhea that is not severe; other individuals can develop severe, even life-threatening complications due to profuse vomiting, diarrhea and other symptoms. Symptoms may be chronic while the offending food remains part of a child’s diet. Onset is usually during the first year of life, although the disorder can develop later during childhood. Specific rare cases due to fish or mollusks have been identified older children and adults.

Vomiting and diarrhea, often profuse and repetitive, are the two most common symptoms associated with FPIES. Vomiting usually occurs 1-4 hours after ingesting the offending food. Diarrhea usually occurs 3-6 hours after ingestion. Bloody diarrhea may occur in severe cases. Additional symptoms often occur including pallor, lethargy, abdominal distension, and cyanosis, a condition characterized by abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood. Decreased body temperature (hypothermia) and abnormally high numbers of platelets, blood cells that aid the blood to clot (thrombocytosis), have also been reported.

Affected infants or children usually recover quickly from an FPIES episode. However, in some cases, an episode can result in severe complications including loss of vital fluids (acute dehydration), low blood pressure (hypotension), and/or hypovolemic shock, a condition in which rapid fluid loss ultimately results in insufficient oxygen delivery to various organs of the body. Hypovolemic shock is an emergency condition that requires immediate medical intervention.

Infants or children who have multiple FPIES episodes may experience weight loss and may fail to grow and gain weight at the rate expected based on gender and age (failure to thrive). Most children outgrown FPIES by two or three years of age, however, in some cases the disorder persists.

Approximately 30% of affected individuals eventually develop an atopic disorder such as a chronic inflammatory disorder of the skin (atopic dermatitis), asthma, or hay fever (allergic rhinitis). Atopic disorders are those that arise because of abnormal immune system responses to environmental allergens.


The exact underlying cause of FPIES is unknown. The disorder occurs due to an improper response of the immune system to proteins found in specific foods. Eating the offending food causes localized inflammation in the small and large intestines. Researchers speculate that this inflammation allows fluids and other substances to pass through the intestinal wall (intestinal permeability and fluid shift).

The two most common foods associated with FPIES are cow’s milk and soy. In approximately 40% of cases, affected individuals may have a reaction to both cow’s milk and soy. Solid foods have also been shown to cause FPIES, including foods that are generally not considered allergens. Rice is the most common solid food associated with the disorder. Wheat, chicken, turkey, fish, mollusks, oats, barley, egg whites, vegetables, peanuts, white potatoes, and sweet potatoes have also been implicated. In recent years, children with FPIES due to ingestion of fruit proteins have also been noted. In approximately 70% of cases, individuals react to one to two foods. FPIES is rarely reported in infants that are exclusively breastfed, which suggests that breastfeeding may have a protective effect. Only four cases of exclusively breastfed infants developing FPIES have been reported in the medical literature.

The underlying immune system process involved in FPIES is unknown, but the disorder is not IgE-mediated as is commonly found in classic food allergies. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e., invading microscopic life-forms [microorganisms]). The T cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses, and some bacteria. A cell-mediated immune response does not involve antibodies such as immunoglobulin E. The B cell system (humoral immune response) fights infection caused by other viruses and bacteria. A humoral immune response does include antibodies.

Some researchers have speculated that T cells play a central role in the development of the localized inflammation in the intestinal tract that characterizes FPIES, but this theory has not been confirmed. One function of T cells is to produce cytokines, which are specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. Cytokines regulate the body’s inflammatory response to disease. Proinflammatory cytokines such as tumor necrosis factor-alpha may be important factors in the development of FPIES.

As yet, no specific genetic or environmental factors have been identified that are involved in FPIES. A family history of atopic disease is present in approximately 40-80% of cases.

Although IgE-mediated disease is not normally associated with FPIES, some affected individuals have developed a food specific IgE as is seen with classic food allergies. These children tend to have a more prolonged course of the disorder. These cases are termed “atypical FPIES”.

(Video) 10/26/15 Diagnoses & Management of Food Protein-Induced Enterocolitis Syndromes (FPIES)

Affected Populations

FPIES is an uncommon disorder that affects males slightly more often than females. The incidence and prevalence is unknown. Like most allergic disorders, the number of FPIES cases has risen in the last few decades. The variable nature of the disorder, the lack of recognition in the medical community, and frequent misdiagnosis make it difficult to determine FPIES true frequency in the general population. The estimate in the United States is 0.28% similar to estimates in Israel and Australia, where the incidence of 0.34%. FPIES most often affects infants or young children. In extremely rare cases, FPIES has developed in older children or adults as a reaction to shellfish.

Related Disorders

Symptoms of the following disorders can be similar to those of FPIES. Comparisons may be useful for a differential diagnosis.

There are numerous conditions that can mimic the symptoms of FPIES. Such conditions include eosinophilic gastroenteritis, viral gastrointestinal illness, proctocolitis, food protein-induced enteropathy, sepsis, isomaltose-sucrose deficiency, various metabolic disorders and Celiac disease. Classic food allergies can be distinguished from FPIES by the presence of common, additional symptoms including skin disease (e.g., hives), asthma, and rapid swelling of the deep layers of the skin (angioedema). FPIES can also be initially mistaken for certain medical conditions involving the intestines such as intussusception, in which a portion of the intestine folds into another portion.


FPIES is a clinical diagnosis based upon the exclusion of other causes, identification of characteristic symptoms and a thorough clinical evaluation including a detailed patient history. The absence of symptoms commonly associated with IgE-mediated food allergies including skin reactions, asthma, and angioedema may be indicative of FPIES. Misdiagnosis and delays in diagnosis of FPIES are common.

Clinical Testing and Work-up
In some cases, an oral food challenge (OFC) may be used to help obtain a diagnosis of FPIES. An OFC is a procedure in which the suspected offending food is gradually given to an affected child in a controlled clinical environment. An OFC for FPIES is a high risk procedure that requires medical supervision and is conducted following a specific protocol. In addition to confirming a diagnosis, an OFC may be also used to determine whether FPIES has resolved or persists as an affected child ages. There is debate within the medical community as to whether follow up OFCs are appropriate in children with FPIES.

There are no diagnostic tests by either skin or blood test that can identify the foods that might be triggering the cause of disease.

Standard Therapies

Removal of the offending food from the diet of an affected individual leads to the disappearance of the symptoms associated with FPIES. Many children will grow out of FPIES over time usually by 3 or 4 years of age.

Some infants with FPIES may be treated by being exclusively breastfed. But, nutrition status needs to be monitored as many older infants need additional foods to meet caloric intake. In cases where that is not possible or in infants who are on formula, a casein hydroxylase-based formula is recommended or an elemental-amino acid formula. Casein is a milk protein. Hydroxylase means that the protein is broken down (hydrolyzed) so that the infant’s immune system will not detect them as an allergen. Such formulas are specifically designed for infants with an allergy or intolerance to cow’s milk. In some cases, affected infants will not be able to tolerate a casein hydroxylase-based formula and may require an amino acid formula, which does not contain any milk.

Severe episodes of FPIES require medical intervention including intravenous fluids. Some physicians use anti-inflammatory drugs known as corticosteroids to help treat affected individuals during an episode. For acute FPIES reactions, some physicians have suggested the use of ondansetron intravenous for acute symptoms of vomiting.

Pediatricians, pediatric gastroenterologists, pediatric allergist-immunologist, pediatric nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment (e.g. such as when to attempt to reintroduce foods into an affected child’s diet).

Investigational Therapies

Information on current clinical trials is posted on the Internet at All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [emailprotected]

Some current clinical trials also are posted on the following page on the NORD website:

For information about clinical trials sponsored by private sources, contact:

For information about clinical trials conducted in Europe, contact:


Nowak-Wegrzyn A, Warren CM, Brown-Whitehorn T, Cianferoni A, Schultz-Matney F, Gupta RS. Food Protien-Induced Enterocolitis in United States Population. J Allergy Clin Immunol. 2019 Oct;144(4):1128-1130.

Nowak-Węgrzyn A, Chehade M, Groetch ME et al. International Consensus Guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: Executive Summary-Workgroup Report of the Adverse Reactions to Food Committee, American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2017 Apr;139(4):1111-1126.

Leonard SA, Nowak-Węgrzyn A. Food Protein-Induced Enterocolitis Syndrome. Pediatr. Clin North Am. 2015;6:1463-77.

Miceli Sopo S, Battista a, Greco M and Monaco S. Ondansetron for food protei-induced enterocolitis syndrome. Int Arch Allergy Immunol 2014;164(2) 137-9.

Caubet JC, Ford LS, Sickles L, Järvinen KM, Sicherer SH, Sampson HA, Nowak-Węgrzyn A. Clinical features and resolution of food protein-induced enterocolitis syndrome: 10-year experience. J Allergy Clin Immunol 2014;134: 382-9.

Ruffner MA, Ruymann K, Barni S, Cianferoni A, Brown-Whitehorn T, Spergel JM.
Food protein-induced enterocolitis syndrome: insights from review of a large referral population. J Allergy Clin Immunol Pract 2013;1:343-9.

Holbrook T, Keet CA, Frischmeyer-Guerrerio PA, Wood RA. Use of ondansetron for food protein-induced enterocolitis syndrome. J Allergy Clin Immunol 2013;132:1219-20.

Sopo SM, Giorgio V, Dello Iacono I, Novembre E, Mori F, Onesimo R.
A multicentre retrospective study of 66 Italian children with food protein-induced enterocolitis syndrome: different management for different phenotypes. Clin Exp Allergy 2012;42:1257-65.

Jarvinen KM, Caubet JC, Sickles L, et al. Poor utility of atopy patch test in predicting tolerance development in food protein-induced enterocoloitis syndrome. Ann Allergy Asthma Immunol. 2012;109:221-222.

Bansal AS, Bhaskaran S, Bansal RA. Four infants presenting with severe vomiting in solid food protein-induced enterocolitis syndrome: a case series. J Med Case Rep. 2012;6:160.

Fernandes BN, Boyle RJ, Gore C, Simpson A, Custovic A. Food protein-induced enterocolitis syndrome can occur in adults. J Allergy Clin Immunol. 2012;130:1199-2000.

Leonard SA, Nowak-Wegrzyn A. Food protein-induced enterocolitis syndrome: an update on natural history and review of management. Ann Allergy Asthma Immunol. 2011;107:95-101.

Caubet JC, Nowak-Wegrzyn A. Current understanding of the immune mechanisms of food protein-induced enterocolitis syndrome. Expert Rev Clin Immunol. 2011;7:317-327.

Mehr S, Kakakios A, Frith K, Kemp AS. Food protein-induced enterocolitis syndrome: 16-year experience. Pediatrics. 2009;123:e.459-464.

Nowak-Wegrzyn A, Muraro A. Food protein-induced enterocolitis syndrome. Curr Opin Allergy Clin Immunol. 2009;9:371-377.

Fogg MI, Brown-Whitehorn TA, Pawlowski NA, Spergel JM. Atopy patch test for diagnosis of food protein-induced entercololitis syndrome. Pediatr Allergy Immunol. 2006;17:351-355.

Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH. Food protein-induced enterocolitis syndrome caused by solid food proteins. Pediatrics. 2003;111:829-835.

Sampson HA, Anderson JA. Summary and recommendations: classification of gastrointestinal manifestations due to immunologic reactions to food in infants and young children. J Pediatr Gastroenterol Nutr. 2000;30:S87-S84.

Sicherer SH. Food protein-induced enterocolitis syndrome: clinical perspectives. J Pediatr Gastroenterol Nutr. 2000;30:S45-S49.

(Video) FPIES, a Rare Food Allergy

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(Video) Food protein-induced enterocolitis syndrome (FPIES)


Is FPIES a rare disease? ›

Food protein-induced enterocolitis syndrome (FPIES) is a rare food allergy that affects the gastrointestinal (GI) tract. Unlike most food allergies, symptoms of FPIES do not begin immediately after eating. Instead, it can take hours before severe symptoms begin.

Who can diagnose FPIES? ›

Diagnosing FPIES

An allergist / immunologist will take a detailed history, including foods eaten and a timeline of reactions.

Can a child grow out of FPIES? ›

Fortunately, most children outgrow milk and soy FPIES by 3 years of age, although resolution of solid food FPIES may take longer.

What foods should be avoided with FPIES? ›

Foods that cause FPIES:

​High risk foods​include milk, soy, rice, oats and poultry. Also sweet potatoes, peas, banana, egg and fish can be a trigger. Moderate risk foods​that trigger FPIES include squash, carrot, white potato, green beans, apple, pear, orange, beef, grits, corn, wheat, barley, peanut and other legumes.

What are the long term effects of FPIES? ›

Most children outgrown FPIES by two or three years of age, however, in some cases the disorder persists. Approximately 30% of affected individuals eventually develop an atopic disorder such as a chronic inflammatory disorder of the skin (atopic dermatitis), asthma, or hay fever (allergic rhinitis).

Does FPIES run in families? ›

But you may not see symptoms until 2 to 8 hours later. About 40% to 80% of kids who have the allergy have family members who also have other types of allergies such as hay fever or eczema skin rashes. Only 20% of kids with FPIES have family members with food allergies.

What foods trigger FPIES? ›

Like other food allergies, FPIES reactions are triggered by eating a particular food. The most common triggers include cow milk, soy and grains (rice, barley, oats). The most severe forms of FPIES can lead to drop in energy, change in body temperature and low blood pressure leading to hospitalization.

Is FPIES an autoimmune disease? ›

There is a lack of evidence for an autoimmune component in FPIES, but there is an association between FPIES and atopy 4, 5.

How do you get rid of FPIES? ›

Is there a cure for FPIES? Unfortunately, there is currently no curative treatment for FPIES. The treatment is to avoid the trigger food, allow time to pass, and consider medically-supervised food exposure (oral food challenge) to assess for resolution of the allergy.

Can peanut butter cause FPIES? ›

While peanut has not been reported as a common trigger of food protein-induced enterocolitis syndrome (FPIES), it is possible that earlier introduction could lead to an increase in peanut-related FPIES (prFPIES). We report 3 cases of prFPIES seen in our practice in the past 8 months.

What do you feed kids with FPIES? ›

Meats/protein: Lamb, Chicken, Turkey, Beef (may delay if FPIES is related to Cow's Milk), Fish, Eggs, soft/ mashed Beans: Garbanzo, Black, Pinto, and Cannellini. Fats: Suggest Olive oil, Coconut oil, Canola oil, Avocado. No butter or ghee if FPIES is related to Cow's milk. Dairy: No liquid cow's milk until age 1 year.

Is Avocado an FPIES trigger? ›

Five patients (A-E) with avocado-induced FPIES were identified. All had repetitive vomiting and dehydration following avocado ingestion between the ages of 5 to 9 months. Four had previously been diagnosed with FPIES to common triggers such as milk, oat, and rice.

What are the signs and symptoms of FPIES? ›

The signs and symptoms of FPIES include:
  • chronic or recurrent vomiting.
  • diarrhea.
  • dehydration.
  • lethargy.
  • changes in blood pressure.
  • body temperature fluctuations.
  • weight loss.
  • stunted growth.
Jan 8, 2018

What percentage of kids have FPIES? ›

FPIES affects estimated 0.5% of US children and 0.2% of adults (approximately 900,000 people).

When should you go to the hospital for FPIES? ›

It is important to keep your child comfortable and get to medical attention for treatment. If your child has had prior severe FPIES reactions, is vomiting repeatedly, appears ashen-gray or lethargic, call 911 immediately.

What age does FPIES go away? ›

Most children outgrow FPIES by three years of age, but some children will outgrow their allergy earlier or later than this. A plan for when and how to reintroduce the FPIES trigger food/s will be determined by your child's allergy specialist.

Do FPIES reactions get worse? ›

In chronic FPIES, infants present with failure to thrive, “falling off growth curve”, vomiting, irritability, and diarrhea. Infants are chronically exposed, most often with formula (milk or soy based), and symptoms worsen over time.

What is protein induced enterocolitis syndrome in adults? ›

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE, cell-mediated food allergy, commonly diagnosed in infants and young children. In recent years, new-onset adult FPIES has been recognized.

Is there a test for FPIES? ›

With no lab test to identify FPIES, it must be diagnosed the classic way: with an interview and physical exam by a doctor. An allergist or pediatric gastroenterologist will take a detailed history of the symptoms, including foods eaten and a timeline of reactions.

How common is FPIES in breastfed babies? ›

FPIES in exclusively breastfed babies is a very rare clinical condition and only few cases have been reported in the medical literature.

Can an Allergist diagnose FPIES? ›

FPIES can be difficult to diagnose because symptoms of vomiting and diarrhea may at first look like stomach flu. In fact, it is not uncommon for families to go through several visits to the ER and their GP before a referral and a diagnosis are made (usually by an allergist or gastroenterologist).

What foods should I avoid if I have a protein intolerance? ›

Avoid all foods that contain whey, casein, caseinate, nonfat milk solids, lactoglobulin, cow's milk protein, nougat, curds, sodium caseinate, or lactalbumin. Look carefully at butter, margarine, ice cream, cakes, puddings, sorbet, breads, soups, vegetables with sauces, and more.

Are babies born with FPIES? ›

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E cell-mediated gastrointestinal food allergy that primarily presents in infancy, as early as the first hours of life.

Can breastfed babies have FPIES? ›

Proteins in breast milk may cause FPIES in exclusively breast‐fed infants, but it is very rare and few cases have been reported so far. 5, 6, 7 Cow's milk is the culprit food of the majority of the reported cases of FPIES in breast‐fed infants. The clinical presentation seems to be similar to chronic FPIES.

How long does an FPIES episode last? ›

Acute FPIES resolves within 4–12 hours of eliminating the trigger food. Chronic FPIES resolves within 3–10 days of eliminating the food. Children with FPIES typically outgrow their allergy by 3–5 years of age. Food challenges to determine whether a child has outgrown their allergy should not be done at home.

How common is FPIES? ›

Food protein-induced enterocolitis syndrome (FPIES), is a delayed (non-IgE mediated) gut allergic reaction to a food(s), usually presenting in the first two years of life, with an estimated incidence in this age group of 1 in 7,000 children. FPIES can occur in adults, although this is uncommon.

How prevalent is FPIES? ›

FPIES represents the severe end of the spectrum of food protein-induced gastrointestinal diseases in infants and is far less common than proctocolitis [8,9]. The incidence ranges from 0.015 to 0.7 percent [10,11].

Does FPIES show up on blood test? ›

Unlike most food allergies there is no blood or skin testing available for diagnosis. The primary treatment is strict avoidance of the triggering food. Most children outgrow FPIES by age 3 or 4.

Is FPIES an emergency? ›

Thankfully, there are no reported deaths from FPIES, but hypotension and shock are dangerous. This is why patients having an FPIES reaction are instructed to seek care in an emergency room.


1. FPIES and EoE Explained- Part 1
(aussie allergymum)
2. FPIES: An Overview by Dr. Nasir, MD
3. A Slice of FPIES: A Review of Non-IGE Mediated Food Allergy Disorders in Children
(ETSU CME Enduring Materials)
4. FPIES: A Conversation with Dr. Anna Nowak-Wegzryn
5. WAO Scientific Interviews with Experts - Prof. Nowak Wegrzyn on FPIES
(WAO Secretariat)
6. Managing FPIES reactions
(Nutrition4Kids & Nutrition4IBD)
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