‘Thickening’ Is Clue to Acute Food Protein-Induced Enterocolitis Diagnosis

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Children's Doctor

Terri F. Brown-Whitehorn, MD Terri F. Brown-Whitehorn, MD Owen is a healthy 6-month-old, breast-fed infant with mild gastroesophageal reflux who presents to the Emergency Department twice in 2 weeks. Initial symptoms for the first visit include severe vomiting followed by diarrhea. No fever. He was diagnosed with viral gastroenteritis and was discharged home after tolerating breastmilk. The following day, he was better. His diet otherwise includes sweet potato, squash, apples, and bananas. He does receive pumped breast milk at times. Family has tried thickening bottle.

He presents again to the ED with prolonged episode of vomiting. He now appears pale and lethargic without any rash. In the ED, he requires IV fluid, which helped his condition improve. He was given an abdominal ultrasound, which was negative for pyloric stenosis.


Owen’s diagnosis is not clear from the original history. The top two concerns would be infection/sepsis/gastroenteritis and/or structural abnormality. However, keeping in mind broader differential is key. As Sir William Osler said: “Listen to your patient; he is telling you the diagnosis.” In this case, baby cereal is being added to bottle to help with mild reflux concerns. And, a few hours later, he develops severe vomiting and is quite ill. This story is a classic case of acute food protein-induced enterocolitis.

Food protein-induced enterocolitis (FPIES) is a non-IgE mediated food allergy divided into 2 phenotypes, acute and chronic. Unlike IgE mediated food allergy reactions where patients have immediate symptoms of hives, breathing problems, abdominal pain, and/or vomiting; patients with FPIES do not have hives or breathing problems and vomiting occurs hours after ingestion. In addition, traditional allergy skin testing is typically negative and medications such as epinephrine and antihistamines are ineffective.

FPIES occurs mainly in young infants and toddlers when formula and solid foods are introduced. Over time, many outgrow these reactions although some patients have persistence of symptoms through adolescence. Shellfish may lead to acute FPIES in adults.

In acute FPIES, infants and toddlers present with delayed severe vomiting, lethargy, “floppiness,” +/- diarrhea 2 to 4 hours after ingestion of a specific food. During these episodes, patients are often quite ill appearing, pale, cyanotic, and require emergency care. Twenty percent of patients present in shock. Patients may develop acidosis, hyponatremia, leukocytosis, neutrophilia, bandemia, and/or methemoglobinemia. Outside of these food reactions and exposures, these patients are often well appearing, robust, and are developing normally.

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. Once the triggering food is removed, there is significant improvement. However, with re-exposure, the patient will develop the more acute phenotype. The differential diagnosis in an ill-appearing infant with poor growth is extensive and includes infection, very early onset inflammatory bowel disease/underlying immunodeficiency, and endocrine, metabolic, and/or mitochondrial defects. We propose keeping chronic FPIES in the differential.

The diagnosis of FPIES remains clinical. CHOP physicians were involved in the recently published international consensus guidelines, which suggest a more exact approach to diagnosis and introduce a system of major and minor criteria for acute FPIES; however, there are no such guidelines for chronic FPIES. Given the broad differential, the diagnosis is often delayed and most patients have between 2 to 5 episodes before being diagnosed. If diagnosis is uncertain, food challenges can be performed.

Consensus Guidelines For Acute FPIES Diagnosis

Major criteria:

  • Repetitive vomiting 1-4 hours after eating the suspect food and absence of IgE mediated skin or respiratory symptoms

Minor criteria: 

  • A second (or more) episode of repetitive vomiting after eating the same food
  • Repetitive vomiting episode 1-4 hours after eating a different food
  • Extreme lethargy with any suspected reaction
  • Marked pallor with any suspected reaction
  • Need for ER visit with any suspected reaction 
  • Need for IVF support with any suspected reaction
  • Diarrhea in 24 hours (usually 5-10 hours)
  • Hypotension
  • Hypothermia

Above: from Nowak-Wegrzyn A, Chehade M, Groetch ME, et al. International consensus guidelines for the diagnosis and management of food protein induced enterocolitis syndrome: executive summary-Work Group Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2017;139(4):1111-1126.

The most common inciting foods include milk, soy, and grains (rice and oat). Less common triggering foods may be sweet potatoes, peas, chicken, eggs, and more recently, peanuts. Dietary guidelines are available to assist in new food introduction promoting foods less likely to cause reactions first.

For the majority of infants, breastfeeding is thought to be protective, at least from acute FPIES. Some bottle-fed infants with milk and/or soy FPIES will tolerate an extensively hydrolyzed milk protein formula. For those who do not, an amino acid formula is recommended.

Treatment and prognosis

Treatment of an acute FPIES reaction should include intravenous fluids and supportive care. Ondansetron may be effective in reducing symptom severity; however, it should be avoided in those with underlying heart defects or arrhythmias. After diagnosis, the child must avoid the causative food. The family should be given an informational letter for healthcare professionals in the event of a subsequent reaction, while keeping in mind other diagnosis remain a possibility.

The overall prognosis is quite good, as many infants outgrow these reactions, typically after avoidance of food for 18 months. We often recommend oral food challenges (OFC), with specific protocol, to assess whether a child has outgrown the food trigger.

While some children with FPIES are managed by their pediatrician and allergist or gastroenterologist, others benefit from a multisubspecialty approach. CHOP developed the first multispecialty FPIES clinic in the nation, where patients are seen by Allergy, Gastroenterology and Nutrition at the same time. During one convenient visit, the team answers nutrition and feeding questions, seeks alternative or concomitant diagnoses, and provides an individualized care plan.

References and further reading
  1. Nowak-Wegrzyn A, Chehade M, Groetch ME, Spergel JM, Wood RA, Allen K, et al. International consensus guidelines for the diagnosis and management of food protein induced enterocolitis syndrome: executive summary-work group report of the adverse reactions to foods committee, American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 2017;139(4):1111-1126.
  2. 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 Jul-Aug;1(4):343-9.
  3. Wang KY, Lee J, Cianferoni A, Ruffner MA, Dean A, Molleston JM, et al. Food protein induced enterocolitis syndrome food challenges: experience from a large referral center. J Allergy Clin Immunol Pract 2019;7:444-450.
  4. Food Protein Induced Enterocolitis: Management and Diagnosis, ed. Terri Brown Whitehorn and Antonella Cianferoni, Springer Publishers, Switzerland, 2019.


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