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.
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.Introduction
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.
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”.
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. However, in studies in Israel and Australia, they estimated 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.
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.
Atopy patch testing (APT) was used in one study of 19 individuals with FPIES confirmed by OFC. During an APT, the offending food is made into a paste, place into a tiny metal chamber that resembles a bottle cap, and then placed on the skin. After a period of time, the paste is removed to see whether an allergic reaction has occurred. Generally, in the 19-patient study, the test was effective in predicting tolerance (and thus avoiding future OFCs). However, a recent study in 2012 challenged these findings and detailed poor results when using ATP as a predictor of tolerance in children with FPIES. Consequently, the use of ATP remains controversial. More research is necessary to determine whether APT has a role in diagnosing FPIES or guiding the disorder’s treatment (e.g., determining tolerance).
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, two recent publications 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).
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