Perspectives on Non-IgE-Mediated Gastrointestinal Food Allergy in Pediatrics: A Review of Current Evidence and Guidelines

Figures & data

Figure 1 Classification of non-IgE-mediated food hypersensitivity.

Table 1 Non-IgE-Mediated Allergic Disorders, Symptoms, and Differential Diagnoses (Taken from the European Academy for Allergy and Clinical Immunology Position Paper on the Management of Non-IgE-Mediated Allergies in Breastfed Infants)

Non-IgE-Mediated Food Allergy	Cardinal Symptoms	Additional Symptoms	Differential Diagnoses
Food protein-induced enterocolitis syndrome (FPIES)^Citation3	Acute FPIES: Vomiting 1–4 hours after ingestion Chronic FPIES: Intermittent but progressive vomiting and diarrhea	Acute FPIES: Pallor, lethargy, hypovolemia, hypotension, diarrhea Chronic FPIES: Faltering growth	Gastro-esophageal reflux disease, sepsis, inborn errors of metabolism, pyloric stenosis, malrotation, intussusception, gastroenteritis with vomiting
Food protein-induced allergic proctocolitis (FPIAP)	Blood in stool	Occasional loose stools, mucous in the stools, painful flatus, anal excoriation	Gastrointestinal infections, fissures Infantile polyp, necrotizing enterocolitis, Meckel’s diverticulum, intussusception, infantile inflammatory bowel disease (rare)
Eosinophilic esophagitis (EoE)	Intermittent vomiting, abdominal discomfort, feeding difficulties	Faltering growth	Gastro-esophageal reflux of infancy, infantile inflammatory bowel disease
Food protein-induced constipation	Straining with soft stools	Fecal impaction, bloating, abdominal pain	Normal straining associated with infancy, idiopathic constipation, Hirschsprung’s disease
Food protein-induced gastro-esophageal reflux disease	Intermittent painful vomiting/regurgitation	Faltering growth, feeding difficulties, back-arching with pain	Gastro-esophageal reflux of infancy, acute gastroenteritis, food poisoning
Food protein-induced enteropathy (FPE)	Failure to thrive, diarrhea	Mucus and, bloating, abdominal pain, faltering growth, hypoalbunemia	Sepsis, congenital disaccharide malabsorption, metabolic disorders, chronic kidney disease, neglect, secondary lactose intolerance, chronic FPIES, autoimmune enteropathies, epithelial dysplasia syndromes, cystic fibrosis, immunodeficiencies and/or chronic infection, coeliac disease

Note: Used with permission of John Wiley & Sons - Books from Diagnosis and management of Non-IgE gastrointestinal allergies in breastfed infants-An EAACI position paper. Meyer R, Chebar Lozinsky A, Fleischer DM, et al. 75(1), 2020. Permission conveyed through Copyright Clearance Center, Inc.⁴⁷

Table 2 Key Investigation Findings of FPIAP, FPIES, and FPE

	FPIES		FPIAP	FPE
Blood tests findings
Low hemoglobin level	Moderate		Mild, infrequent	Moderate
Low albumin level	Acute		Mild, infrequent	Moderate
Malabsorption	Absent		Absent	Present
Leukocytosis with neutrophils	Prominent		Absent	Absent
Allergy evaluation
Food skin prick test	May be positive in up to 30%		Negative	Negative
Serum food-allergen IgE	May be positive in up to 30%		Negative	Negative
Total IgE	Normal or high		Normal or high	Normal
Peripheral blood eosinophilia	Absent		Occasional	Absent
Biopsy findings
Villous injury	Patchy, variable		Absent	Variable, increased crypt length
Colitis	Prominent		Focal	Absent
Mucosal erosions	Occasional		Occasional, linear	Absent
Lymphoid nodular hyperplasia	Absent		Common	Absent
Eosinophils	Prominent		Prominent	Few
OFC
	Vomiting, lethargy, pallor in 1–6 h; diarrhea in 5–8 h	Rectal bleeding in 6–72 h		Vomiting and/or diarrhea in 40–72 h

Note: Adapted from Connors L, O’Keefe A, Rosenfield L, Kim H. Non-IgE-mediated food hypersensitivity. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):56. doi:10.1186/s13223-018-0285-2. Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).²

Table 3 Food Triggers for FPIES, from Most to Least Common

Food Category	Specific Food	Rates (%)
Milk		67
Soy		41
Grains	Rice>Oat>Wheat>Corn>Barley	25.3
Egg		11
Meats/Fish	Chicken>Turkey>Beef>Pork>Lamb>Salmon>Crab	<10
Vegetables	Sweet potato>Pea>Potato>Carrot>Squash>Kidney bean>Green bean	<10
Fruits	Banana>Apple>Pear>Peach>Plum>Strawberry>Watermelon>Avocado	<10
Peanut/Tree nut	Peanut>Tree nut	<10

Note: Data from Ruffner et al.⁶¹ Used with permission of Oxford University Press - Journals, from Non-IgE-mediated food allergy: Evaluation and management, Canadian Paediatric Society, 26, 3, 1996; permission conveyed through Copyright Clearance Center, Inc.⁶³

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