Table 3. Differential diagnoses to consider in FPIES.

Condition		Distinguishing clinical features
Infectious
	1. Gastroenteritis (viral, bacterial)	1. Fever, presence of sick contacts
	2. Sepsis	2. Positive bacterial/viral cultures and tests, improvement with antibiotics, lack of spontaneous resolution following food withdrawal
	3. Necrotizing enterocolitis	3. Presentation in neonatal period (particularly in preterm infants), presence of pneumatosis intestinalis, fever, absence of peripheral blood eosinophilia
Allergic/Immunologic
	1. IgE-mediated food allergy/anaphylaxis	1. Immediate onset after food exposure, positive serum IgE or skin testing, associated respiratory and cutaneous symptoms
	2. FPIAP	2. Primarily blood ± mucus in stool, typical resolution by 1 year of age59
	3. FPE	3. Chronic non-bloody diarrhea that can be triggered by gastroenteritis, resolves by 2 years of age59,60
	4. Inflammatory bowel disease	4. Chronic abdominal symptoms, often associated family history of autoimmunity
	5. Primary immunodeficiency	5. Frequent, severe, and opportunistic infections
Gastrointestinal
	1. Lactose intolerance	1. Gas, bloating, and diarrhea with milk exposures
	2. Gastroesophageal reflux disease	2. Frequent spit up, difficulty feeding, weight loss
	3. Celiac disease	3. Nutritional deficiencies from malabsorption, including anemia
	4. EGID	4. Mixed IgE and cell-mediated process not related to specific food intake, likely presence of food-specific IgE, inappropriate accumulation of eosinophils in gastrointestinal tract on biopsy resulting in organ dysfunction i.e., dysphagia, less severe vomiting70
Anatomic
	1. Hirschsprung disease	1. Delayed passage of meconium, significant abdominal distension
	2. Obstruction (i.e., volvulus, malrotation)	2. Bilious vomiting
Metabolic
	1. Mitochondrial disorders	1. Developmental delay, progressive neurological deterioration, organomegaly, seizures, electrolyte derangements triggered by infection/stressors
	2. Pyruvate dehydrogenase deficiency
	3. Fructose intolerance
	4. Ketothiolase deficiency
Behavioral
	1. Food aversion	1. Associated with neurodevelopmental disorders, psychosocial stressors

Adapted from Nowak-Węgrzyn et al. ¹²

FPIES, food protein-induced enterocolitis syndrome; IgE, immunoglobulin E; FPIAP, food protein induced allergic proctocolitis; FPE, food protein-induced enteropathy; EGID, eosinophilic gastrointestinal disorders.