Unusual Food Allergy in Children: Signs of Non-IgE-Mediated Reactions

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Non-IgE-mediated food allergies are on the rise in children and do not always present with an immediate, anaphylaxis-type reaction.

Deciphering between the 2 types of allergic reactions to food in children is challenging. Children with immunoglobulin E (IgE)-mediated allergic reactions typically present with rash, swelling, vomiting, or respiratory distress after consumption of the trigger food. Non-IgE-mediated food allergy is becoming more common and does not always present with an immediate, anaphylaxis-type reaction.

“We see a lot of peanut allergies and IgE allergy, but we’re also seeing some unusual food allergies. I want [nurse practitioners] to have a general idea of how to identify, how to handle it, and when to refer and when to treat,” said Linda Federer, MSA, BC-FNP, at the National Association of Pediatric Nurse Practitioners (NAPNAP) National Conference on Pediatric Health Care held March 15 to 18, 2023, in Orlando, Florida.

“They are cellular-mediated, food-specific T lymphocyte activation involving the gastrointestinal tract,” Federer said. Food protein-induced enterocolitis syndrome (FPIES) and food protein-induced allergic proctocolitis (FPIAP) are non-IgE-mediated, and eosinophilic esophagitis is both an IgE and non-IgE-mediated food allergy reaction. 

To better understand these food allergies, Federer presented 4 case studies.

Case 1
Joey and Janey are 9-month-old twins trying cashew butter for the first time. Joey loves it. Janey immediately develops hives all over her body, vomits once, and has a hoarse cry. The family calls 911. In the emergency department (ED), Janey is given epinephrine. After the family returns home (about 3 hours after ingestion) Joey develops profuse, projectile watery emesis. He is limp and pale and vomits repeatedly. The family returns to the ED where he receives ondansetron and intravenous (IV) fluids. Janey illustrates a usual IgE-mediated reaction and Joey is having an unusual non-IgE-mediated reaction.

Food Protein-Induced Enterocolitis Syndrome

Infants with food protein-induced enterocolitis syndrome (FPIES) have repetitive, profuse, protracted vomiting 1 to 4 hours after the trigger food is ingested. The patients are often lethargic or can even lose consciousness between vomiting bouts. Notably, 20% of FPIES attacks result in the patient going into shock. An FPIES reaction usually occurs at the fourth or fifth ingestion of food following a 1-week or longer gap since the last exposure. Symptoms of an FPIES attack typically resolve within 2 to 24 hours.

The FPIES reaction manifests when a food protein triggers a nonspecific gastrointestinal inflammation. The increase in permeability of the intestine and stomach pulls fluids from intravascular and extravascular spaces resulting in large amounts of emesis and hypotension. Hypotensive shock occurs in 20% of children. No test is currently available to diagnose this condition and clinicians must rely on patient history. Affected patients must have delayed vomiting within 4 hours of trigger food ingestion in the absence of skin or respiratory involvement plus 3 or more of the following minor symptoms:

  • More than 1 episode with the same food, repetitive emesis to another food, lethargy, pallor
  • Emergency department (ED) visit requiring intravenous fluids
  • Diarrhea
  • Hypotension
  • Hypothermia

Differential diagnosis includes gastroenteritis, intussusception, pyloric stenosis, and IgE-mediated reactions. Currently, an estimated 375,000 US children have FPIES.1

Management of FPIES during an acute attack requires ED care, IV fluids, ondansetron, and/or steroids. This reaction should never be treated with epinephrine. After the child is stable, education is essential to prevent future reactions. Avoidance of the trigger food or foods is the mainstay of management. Subsequent food introduction is limited to small amounts over a longer period, avoiding foods that are known to be cross-reactive to the identified trigger foods. The incidence of FPIES to multiple foods is higher when the child is younger and is reduced after approximately 1 year of age. FPIES usually resolves before 3 years of age. Affected children will need a challenge in a center equipped for a high-risk reaction.  

Children with FPIES should also be referred for an allergy test and families should be provided with an emergency plan for accidental ingestion and educated about dietary strategies.

Pediatric providers should recognize the symptoms of these unusual food reactions to provide appropriate care and referrals. “The non-IgE food allergies are diagnosed clinically, based on the patient’s history, which is frankly very frustrating since it is hard to differentiate between FPIES symptoms and other diagnoses like gastroenteritis or intussusception,” said Federer.

Case 2
Tam is a 1-month-old infant who presents to the pediatric provider with “streaks of blood” in his bowel movements for the last 24 hours. He is otherwise playful, breastfeeding well, and sleeping well. His mother is exclusively breastfeeding with a good milk supply. Tam’s diaper shows green/brown mucus stool with streaks of bright red blood. Tam has been gaining weight, as reported at each office visit.  

Food Protein-Induced Allergic Proctocolitis

In food protein-induced allergic proctocolitis (FPIAP) reactions, otherwise healthy infants present with blood and mucus in their stools. A reaction occurs when the immunologic cellular food tolerance is absent (low TGF B and TH 3). Localized eosinophils cause inflammation and bleeding of the rectosigmoid colon. The differential diagnosis for FPIAP includes intussusception, anal fissures, necrotizing enterocolitis, volvulus, and coagulopathy.

The reaction can occur in formula-fed infants usually around 1 to 4 weeks of age or in breastfed infants 1 to 16 weeks of age. This type of allergic response typically resolves when the trigger food is removed for 1 to 3 weeks. The most common triggers are milk and soy. However, clinicians should be aware that some viral infections can mimic these symptoms.

In most cases, the FPIAP is transient and resolves in a few weeks. In the case of cow milk protein allergies, small amounts of cow milk formula or yogurt can be reintroduced and symptoms monitored. Federer recommends giving the infant a teaspoon of yogurt every day for 5 days and increasing the amount by 1 teaspoon every 5 days. If the yogurt is tolerated, normal levels can be resumed at 1 month. If symptoms reoccur, a retrial in a month is recommended. 

The same is true when the trigger is soy, wheat, or egg. Breastfeeding mothers should avoid milk and soy in their diet.

A fecal occult blood test should not be performed since one-third of healthy infants without symptoms will have positive results.

As with FPIES or any prolonged avoidance, the patient is at risk for IgE-mediated allergic sensitization and it is best to reintroduce the food and have the infant regularly consume whatever amount of the food they can tolerate.

Cases 3 & 4
Howard is a 10-month-old child who presents with feeding concerns. His mother reports he drinks 35 ounces of formula a day and loves purees. Since 6 months of age, he chews solid foods but spits them out. He vomits when he eats dry foods like potatoes and crackers. His weight is normal.   Leigh presents for her 5-year well-child visit with weight loss. Leigh takes 1 to 2 hours to eat every meal, chews for a long time, and drinks lots of water.  She will only eat foods cut into tiny pieces. She vomits 2 to 3 times a week after gagging on foods.

Eosinophilic Esophagitis  

Eosinophilic esophagitis is the most common of the eosinophilic gastrointestinal disorders and it is both IgE and non-IgE mediated. EOE presents differently based on the patient’s age.

  • Infants: vomiting, failure-to-thrive, feeding disorders, and food refusal
  • Toddlers: vomiting, preference for pureed or liquid foods, and difficulty weaning
  • Children: vomiting, gagging, epigastric pain, a strong preference for soft foods, taking small bites, chewing food thoroughly, dry food avoidance, and food impaction
  • Adults: dysphagia, food avoidance, and epigastric pain

“This is a gastroenterology and allergy cooperative effort. Swallowing becomes more difficult and painful over time. [Patients] may tell you there’s burning in their throat, they may tell you it’s hard to swallow, and one little boy told me, ‘there’s rocks when I swallow and I can’t get the food down’,” Federer said.

These symptoms manifest when food proteins trigger an allergic response in the esophagus. This eosinophilic chronic inflammation causes narrowing of the esophagus and difficulty swallowing. Food triggers can be difficult to determine and serum testing is not usually effective. Eosinophilic esophagitis is diagnosed with sequential esophageal biopsies as foods are eliminated and reintroduced and as treatments are initiated. 

The most common eosinophilic esophagitis triggers are milk, soy, egg, and wheat and patients often have multiple triggers. Lifetime resolution of 1 trigger food is less than 10% and all trigger foods is less than 3%.

The treatment of eosinophilic esophagitis includes swallowed topical steroids to coat the esophagus. Proton pump inhibitors are increasingly used in tandem with dietary elimination of the identified food triggers. Dilation may be needed if the esophagus has stenosis. Immune modulators are the newest targeted therapies for adolescents and adults.

Patients with EOE often experience anxiety when they are expected to eat foods prepared by others. Parties, restaurants, and travel can exacerbate this distress leading to social isolation. Infants and children are at risk for oral motor delays and oral aversion when they have been avoiding many foods. Dietary education, counseling, and adapted menus can help.

Food Protein-Induced Enteropathy

Food protein-induced enteropathy (FPE) is a rare non-IgE-mediated food allergy reaction. It typically occurs at 1 to 9 months of age and is associated with chronic diarrhea, interment emesis, steatorrhea, anemia, and slow growth. The most common triggers are milk with an additional food such as wheat, rice, eggs, soy, or shellfish. Treatment includes stabilizing with IV nutrition followed by amino acid formula and avoiding trigger foods. After 4 to 8 weeks of avoidance, patients can be rechallenged in a controlled setting.


Several societies provide resources on allergic reactions of special interest and that have additional tools for patients and their families, such as recipes and food plans, concluded Federer.

Food Allergy Resources

AAAAI (American Academy of Allergy, Asthma & Immunology)Parent handouts for IgE-mediated food allergy
APFED (American Partnership for Eosinophilic Disorders)Recipes, coping strategies, and advice about dining out
ASPEN (American Society for Parenteral and Enteral Nutrition)Formula guides
CFAAR (Center for Food Allergy & Asthma Research)Guides for young adults transitioning to college life
FARE (Food Allergy Research & Education)Family and cultural food plans
FPIES (FPIES Foundation)  Fact sheet, emergency letter for health care providers, and nutrition guidelines
NASPGHAN (North American Society for Pediatric Gastroenterology, Hepatology and Nutrition)Parent and provider resources on pediatric digestive and nutritional disorders
Spokin NorthRestaurant labels and recipe guides

This article originally appeared on Clinical Advisor


Federer L. Strander things: when it is not the usual food allergy. Presented at: NAPNAP National Conference; March 15-18, 2023; Orlando, FL.