Food Protein-Induced Enterocolitis Syndrome (FPIES)

Special thanks to Nutricia, maker of Neocate®, for supporting our educational blog series on managing food allergies in infants and toddlers. This post is the second in a three-part series.

Updated Oct. 1, 2015

Food protein-induced enterocolitis syndrome (FPIES) is a serious, non-IgE-mediated type of food allergy. FPIES is usually triggered by cow’s milk or soy, though some cereal grains, especially rice and oat, and other foods may cause it.

The symptoms typically include severe vomiting and diarrhea and reactions are often delayed by 2-3 hours after the trigger food is eaten. There are different types of food allergies, and it is important to understand some of the different symptoms each can present.


By Anna Nowak-Węgrzyn, M. D.

The following account from a mother of a 1-year-old boy gives a vivid and accurate description of food protein-induced enterocolitis syndrome (FPIES).

My son was mostly breastfed. He was given cow’s milk-based formula at birth in the hospital a few times, and tolerated it well. But when he was given a bottle of the same brand formula at 3 months, he became sick and vomited for hours starting about two hours after ingestion.

He again was given a bottle of this formula at 4 months and had the same response. I thought he had the stomach flu. Throughout the last eight months, my son has had reactions to rice cereal (with and without soy), peas, green beans, squash, sweet potatoes, a lick of ice cream, and cow’s milk-based formula. I only gave him one food at a time and maybe a teaspoon or a tablespoon with each feeding.

His reactions are always the same: severe vomiting (with bile and dry heaving) 2 to 4 hours after ingestion, and he is lethargic and limp. I basically just wrap him in towels and hold him for hours while he sleeps and vomits. I never know if I should take him to the emergency room. He doesn't have chronic rashes or diarrhea and has always been in the 95th percentile in weight.

FPIES is called a “syndrome” and not a “disease” because we don’t know the exact mechanism. Symptoms occur later than with classic food allergy, and allergy evaluation typically fails to detect any allergic antibody (immunoglobulin E, IgE) directed against the causal food. Therefore, FPIES is frequently referred to as a non-IgE, cell-mediated food allergy.

It is assumed that T-lymphocytes (a type of white blood cell) in the gut react to the offending food protein and release a number of chemicals (mediators) that cause intense inflammation locally in the gut, and perhaps cause a more generalized response in the bone marrow with the release of white cells and platelets, and leakage in the small blood vessels.

Key Features of FPIES

  • Usually occurs in formula-fed infants, rarely reported in infants while exclusively breast feeding
  • Profuse vomiting (within 2 to 3 hours) and diarrhea causing profound dehydration and lethargy upon acute exposure
  • Poor growth when the offending food is ingested on a regular basis
  • Resolution of symptoms when the offending food is removed
  • Negative prick skin tests and serum food-specific IgE tests
  • Treatment of acute reactions with vigorous intravenous fluids
  • Reintroduction of the suspected foods under doctor supervision with intravenous line in place
  • Most children outgrow FPIES by age 3 to 4 years

How common is FPIES?

There are no data on how common FPIES is, but it has been considered a rare food allergy. However, over the past 10 years, it seems that we have seen steadily increasing numbers of children with FPIES-like symptoms, including infants who react to multiple and unrelated food proteins.

Symptoms of FPIES

FPIES typically occur in formula-fed infants, and is characterized by repetitive vomiting within 2 to 3 hours following food ingestion that may later be followed by diarrhea. In severe reactions, children become lethargic, dehydrated, and have low blood pressure. Laboratory tests in those severely ill children may reveal acidosis (increased acidity of blood), hyponatremia (low blood sodium level), leukocytosis with bandemia (elevated white blood cells and immature forms of white blood cells typically seen during a bacterial infection), and increased platelets. Elevated methemoglobin has been reported in a significant number of patients (about 1 in 3) who come to the emergency department with severe symptoms, and on presentation, these patients have a dusky appearance.

In young infants who are fed cow’s milk-based or soy-based formula from birth or shortly thereafter, symptoms may be more chronic in nature. These infants commonly have poor growth and low blood albumin level in conjunction with chronic vomiting and diarrhea. When the causal food is removed and later re-introduced by challenge or by accident, repetitive vomiting within 2 to 3 hours and late-onset diarrhea recur.

Which food may cause FPIES?

Cow’s milk and soy are the foods most commonly implicated in FPIES. Approximately 50 percent of children reactive to milk also react to soy. Solid foods such as oat, rice, barley, chicken, turkey and fish have been reported in FPIES, requiring a high index of suspicion. We have also seen children reporting FPIES-like symptoms with fruits, vegetables, egg, beef and peanut. Some older children and adults report FPIES-like reactions to shellfish.

How is FPIES diagnosed?

Diagnosis of FPIES relies on accurate medical history, identifying the typical symptoms, and excluding other possible causes such as infections, metabolic disease and anatomic abnormalities of the gastrointestinal tract. Frequently, a “classic” history of repeated reactions (severe, repetitive vomiting starting within 2 to 3 hours following food ingestion) is enough to establish the diagnosis. In other less clear-cut cases, a doctor-supervised oral feeding test may be necessary to confirm FPIES diagnosis and to avoid repeated reactions, as well as excessive elimination diets.

Since FPIES is not a classic IgE-mediated disorder, allergy evaluations including skin prick tests and serum IgE antibodies against the causal food are typically negative. However, if skin tests are positive, case series suggest that these patients will take longer to outgrow FPIES to that food. Allergy confirmation requires a negative evaluation for other diseases, disappearance of symptom with removal of the causal food, and recurrence of symptoms with an oral food challenge.

How is FPIES treated?

The treatment relies on avoidance of the food. For cow’s milk and soy, changing to a casein hydrolysate formula is typically recommended. In such formulas, casein (protein from cow’s milk) is broken down by digestive enzymes, and the small fragments are not capable of triggering T-cells in the gut. In some cases, symptoms do not improve on a hydrolysate formula and for those, an amino acid-based formula is necessary. The vast majority of infants tolerate mother’s breast milk, although there are very rare reports of acute and chronic FPIES due to the allergens in breast milk.

Parents must have an action plan in place in case of an accidental ingestion. FPIES symptoms usually occur approximately 2 hours after ingestion and may result in dehydration due to fluid loss because of vomiting and fluid shift. For severe reactions, first-line treatment is via rapid intravenous fluid replacement rather than epinephrine and antihistamines, although in case of a severe shock, epinephrine and other drugs elevating blood pressure may be necessary.

Will my child outgrow FPIES?

Most children with FPIES become tolerant to the offending food, usually by age 3 or 4 years. Although there are individual cases of FPIES that persist past this age. Oral food challenges are required prior to food reintroduction and should be performed in a controlled medical environment. If symptoms appear, the patient is typically kept under observation for about 4 to 6 hours from the resolution of symptoms. The timing of the follow-up oral food challenges is not standardized. In my experience, the food re-introductions are recommended every 12 to 18 months following a period of food avoidance without any accidental reactions.

As stated by The FPIES Foundation, "The good news is that FPIES usually resolves with time. Your child will need to be closely followed by his/her doctor to discuss what foods are safe to eat and when it may be time to determine if FPIES has resolved. With proper medical attention and a personalized dietary plan to ensure proper nutrition, children with FPIES can grow and thrive."

Anna Nowak-Węgrzyn, M.D. is an associate professor of pediatrics, allergy and immunology at the Icahn School of Medicine at Mount Sinai, Department of Pediatrics, Division of Allergy and Immunology and Jaffe Food Allergy Institute, New York, N.Y.

More information about FPIES is available from the FPIES Foundation and the International Association for Food Protein Enterocolitis.

This blog series is made possible through a gift from Nutricia, maker of Neocate®.