• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report
Select language / seleccionar idioma:

Food Protein-Induced Enterocolitis Syndrome

Print

This condition does not meet the definition of a rare disease in the U.S. (fewer than 200,000 Americans). There may be forms of this condition that are rare. NORD posts this report because limited information is available about this condition and it may be underdiagnosed.

Last updated: 3/21/2024
Years published: 2013, 2016, 2019, 2023, 2024


Acknowledgment

NORD gratefully acknowledges Gioconda Alyea, Brazilian MD, MS, National Organization for Rare Disorders and 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 University of Pennsylvania, for assistance in the preparation of this report.


Disease Overview

Summary
Food protein-induced enterocolitis syndrome (FPIES) is a 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 have 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. In children, 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. In adults, shellfish is the most common trigger food. Many children develop a tolerance to the offending foods by the age of three, however, in some people, 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.

Introduction
Several different gastrointestinal disorders in children are thought 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 of disease involving non-IgE-mediated gastrointestinal food allergy disorders. This spectrum also includes proctocolitis and food-protein induced enteropathy.

It is estimated that FPIES affects about 900,000 people in United States. However, it is important to note that FPIES remains poorly understood and likely underdiagnosed.

  • Next section >
  • < Previous section
  • Next section >

Synonyms

  • dietary protein enterocolitis
  • FPIES
  • < Previous section
  • Next section >
  • < Previous section
  • Next section >

Signs & Symptoms

The symptoms and severity of FPIES can vary greatly from one individual to another. Some individuals have 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 in older children and adults.

Vomiting and diarrhea, often profuse and repetitive, are the two most common symptoms. Vomiting usually occurs 1-4 hours after eating the offending food. Diarrhea usually occurs 3-6 hours after eating (bloody diarrhea may occur in severe cases.).

Other signs and symptoms may include:

• Pale appearance
• Lethargy
• Abdominal distension
• Abnormal bluish discoloration of the skin due to low levels of circulating oxygen in the blood (cyanosis)
• Decreased body temperature (hypothermia)
• Abnormally high numbers of platelets, blood cells that aid the blood to clot (thrombocytosis)
• Atopic disorders that arise because of abnormal immune system responses to environmental allergens and that may include:
o Chronic inflammatory disorder of the skin (atopic dermatitis), in about 30% of cases
o Asthma
o Hay fever (allergic rhinitis)

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)
• Hypovolemic shock, a condition in which rapid fluid loss ultimately results in insufficient oxygen delivery to various organs of the body, and that is considered an emergency condition that requires immediate medical care

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

  • < Previous section
  • Next section >
  • < Previous section
  • Next section >

Causes

The exact underlying cause of FPIES is unknown. FPIES is not an IgE-mediated process like the classic food allergies. It is not clear how specific food triggers induce the symptoms. Recent studies suggest that it 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. About 40% of affected people 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. Shellfish is the most common trigger food in adults. In recent years, children with FPIES due to eating fruit proteins have also been noted. In approximately 70-90% 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. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents.

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. Though it may be that the innate immune response primarily drives the FPIES reaction, as commented above, the cell-mediated response likely also contributes. The extent of this contribution, however, is still not well understood. 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 and thymus and activation regulated chemokine (TARC) may be important factors in the development of FPIES.

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”.

  • < Previous section
  • Next section >
  • < Previous section
  • Next section >

Affected populations

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 makes it difficult to determine FPIES true frequency in the general population.

FPIES was initially thought to be rare, but newly published data show that it is now known to be the most common non-IgE mediated food allergy disorder globally. Based on population-weighted estimates obtained from a large study in United Sates, physician-diagnosed FPIES was reported by an overall 0.28% (0.24–0.33%) of Americans, corresponding to over 900,000 people. The FPIES prevalence estimate of 0.51% reported for U.S. children is similar to data from the single center population-based birth cohorts from Israel, Spain and Australia. In 2021 another study estimated that the incidence of FPIES in the U.S.ranges from 0.14% to 0.28%.

FPIES most often affects infants or young children, and it affects males slightly more often than females. In extremely rare cases, FPIES has developed in older children or adults as a reaction to shellfish.

  • < Previous section
  • Next section >
  • < Previous section
  • Next section >

Diagnosis

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

FPIES can be difficult to diagnose due to the variability of symptoms, similarity to other diseases and because there is no blood or skin testing available for diagnosis. As a result, misdiagnosis and delays in diagnosis are common.

In 2017, the first international consensus guidelines for FPIES was published. These guidelines distinguish among acute and chronic FPIES. For chronic FPIES, the most important diagnostic criterion is resolution of the symptoms within days of eliminating the trigger food and acute recurrence upon reintroduction.

Clinical Testing and Work-up
An oral food challenge (OFC) may be used to help diagnose 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.

  • < Previous section
  • Next section >
  • < Previous section
  • Next section >

Standard Therapies

Treatment
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 2/3 of the patients by 2 years of age and most 3-4 years of age.

Some infants with FPIES may be treated by being exclusively breastfed. However, nutrition status needs to be monitored as many older infants need additional foods to get enough calories. For 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 it as an allergen. Some 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.

Many children with FPIES, especially those with multiple food FPIES, may develop food aversion, poor weight gain and nutritional deficiencies.  Dietary management currently entails avoiding the food that trigger the symptoms, adding additional foods to encourage normal growth and development and providing families with detailed individualized feeding plans to ease the burden on caregivers when possible. 

One study investigated another option for treatment known as oral desensitization with some good results, but more studies are needed. Oral desensitization, also known as oral immunotherapy treatment (OIT), is often utilized in the dietary management of IgE-mediated food allergy to desensitize the body to the allergen, allowing the patient to eat the food without the chance of an allergic reaction.

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

Additional detailed information is available in the International consensus guidelines for the diagnosis and management of food protein–induced enterocolitis syndrome: Executive summary—Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology.

The International FPIES Association (I-FPIES) provides additional information and resources.

  • < Previous section
  • Next section >
  • < Previous section
  • Next section >

Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. 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: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact: https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

  • < Previous section
  • Next section >
  • < Previous section
  • Next section >

References

JOURNAL ARTICLES
Crespo J, Pérez-Pallise ME, Skrabski F, et al. The natural course of adult-onset food protein-induced enterocolitis syndrome. J Allergy Clin Immunol Pract. 2022;10(11):2986-2992. doi:10.1016/j.jaip.2022.06.013

Lemoine A, Colas AS, Le S, Delacourt C, Tounian P, Lezmi G. Food protein-induced enterocolitis syndrome: A large French multicentric experience. Clin Transl Allergy. 2022;12(2):e12112. doi:10.1002/clt2.12112

Mathew M, Leeds S, Nowak-Węgrzyn A. Recent Update in Food Protein-Induced Enterocolitis Syndrome: Pathophysiology, Diagnosis, and Management. Allergy Asthma Immunol Res. 2022;14(6):587-603. doi:10.4168/aair.2022.14.6.587

Nishimura K, Yamamoto-Hanada K, Sato M, et al. Remission of acute food protein-induced enterocolitis syndrome confirmed by oral food challenges in Japan. Nutrients. 2022;14(19):4158. Published 2022 Oct 7. doi:10.3390/nu14194158

Nowak-Wegrzyn A, Berin MC, Mehr S. Food protein-induced  enterocolitis syndrome. J Allergy Clin Immunol Pract. 2020;8(1):24-35. doi:10.1016/j.jaip.2019.08.020

Ruffner MA, Wang KY, Dudley JW, et al. Elevated atopic comorbidity in patients with food protein-induced enterocolitis. J Allergy Clin Immunol Pract. 2020;8(3):1039-1046. doi:10.1016/j.jaip.2019.10.047

Nowak-Wegrzyn A, Warren CM, Brown-Whitehorn T, Cianferoni A, Schultz-Matney F, Gupta RS. Food protein-induced enterocolitis in United States population. J Allergy Clin Immunol. 2019 Oct;144(4):1128-1130. https://www.ncbi.nlm.nih.gov/pubmed/31288044

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. https://www.ncbi.nlm.nih.gov/pubmed/28167094

Leonard SA, Nowak-Węgrzyn A. Food protein-induced enterocolitis syndrome. Pediatr. Clin North Am. 2015;6:1463-77. https://www.ncbi.nlm.nih.gov/pubmed/26456444

Miceli Sopo S, Battista a, Greco M and Monaco S. Ondansetron for food protein-induced enterocolitis syndrome. Int Arch Allergy Immunol 2014;164(2) 137-9. https://www.ncbi.nlm.nih.gov/pubmed/24993542

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. https://www.ncbi.nlm.nih.gov/pubmed/24880634

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. https://www.ncbi.nlm.nih.gov/pubmed/24565539

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. https://www.ncbi.nlm.nih.gov/pubmed/23890754

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. https://www.ncbi.nlm.nih.gov/pubmed/22805473

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. https://www.ncbi.nlm.nih.gov/pubmed/22920080

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. https://www.ncbi.nlm.nih.gov/pubmed/22734807

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. https://www.ncbi.nlm.nih.gov/pubmed/22835404

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. https://www.ncbi.nlm.nih.gov/pubmed/21802016

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. https://www.ncbi.nlm.nih.gov/pubmed/21595598

Mehr S, Kakakios A, Frith K, Kemp AS. Food protein-induced enterocolitis syndrome: 16-year experience. Pediatrics. 2009;123:e.459-464. https://www.ncbi.nlm.nih.gov/pubmed/19188266

Nowak-Wegrzyn A, Muraro A. Food protein-induced enterocolitis syndrome. Curr Opin Allergy Clin Immunol. 2009;9:371-377. https://www.ncbi.nlm.nih.gov/pubmed/19474706

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. https://www.ncbi.nlm.nih.gov/pubmed/16846453

Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH. Food protein-induced enterocolitis syndrome caused by solid food proteins. Pediatrics. 2003;111:829-835. https://www.ncbi.nlm.nih.gov/pubmed/12671120

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. https://www.ncbi.nlm.nih.gov/pubmed/10634304

Sicherer SH. Food protein-induced enterocolitis syndrome: clinical perspectives. J Pediatr Gastroenterol Nutr. 2000;30:S45-S49. https://www.ncbi.nlm.nih.gov/pubmed/10634298

  • < Previous section
  • Next section >

Programs & Resources

RareCare® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Patient Organizations


National Organization for Rare Disorders