What is the differential diagnosis for a previously well toddler with a history of cow's milk protein allergy, presenting with frequent emesis, no distress, and no recent exposure to cow's milk products?

Differential Diagnosis for Frequent Emesis in a Toddler with Cow's Milk Protein Allergy History

The most critical consideration in this previously well toddler with known cow's milk protein allergy presenting with frequent emesis and no distress is Food Protein-Induced Enterocolitis Syndrome (FPIES) to a newly introduced or cross-reactive food trigger, followed by other non-IgE-mediated food allergies, infectious gastroenteritis, and cyclic vomiting syndrome. 1

Primary Differential Considerations

Food Protein-Induced Enterocolitis Syndrome (FPIES)

• FPIES is the leading concern given the child's history of cow's milk protein allergy and presentation of repetitive emesis without distress, as children with one non-IgE-mediated food allergy are at increased risk for developing FPIES to other foods 1, 2
• Characteristic features include profuse, repetitive vomiting starting 1-4 hours after ingestion of trigger food (commonly rice, oat, soy in toddlers), often accompanied by lethargy and pallor 1, 2
• The absence of distress may be misleading—look specifically for extreme lethargy, marked pallor, and potential dehydration as these indicate severe FPIES requiring IV fluid support 1, 2
• Laboratory findings supportive of FPIES include elevated white blood cell count with neutrophilia, thrombocytosis, and metabolic acidosis in severe cases 2
• IgE testing is typically negative in FPIES, distinguishing it from IgE-mediated anaphylaxis 1, 2

Food Protein-Induced Allergic Proctocolitis (AP)

• AP can manifest as chronic emesis, diarrhea, and failure to thrive in addition to the classic blood-streaked stools 1
• Upon re-exposure after elimination, a subacute syndrome presents with repetitive emesis and dehydration 2-3 hours following ingestion 1
• This is particularly relevant if the child has been inadvertently exposed to cow's milk protein or has developed AP to a new food protein 1
• Most commonly associated with cow's milk, soy milk, or other protein sources in toddlers 1

Food Protein-Induced Enteropathy Syndrome

• Presents with chronic diarrhea (steatorrhea in up to 80%), weight loss, and growth failure in addition to emesis 1
• Most often due to milk allergy but also reported with soy, chicken, rice, and fish 1
• Characterized by generalized malabsorption of fat, carbohydrates, and other nutrients 1
• May present with moderate anemia, hypoproteinemia, and vitamin K deficiency 1

Secondary Differential Considerations

Infectious Gastroenteritis

• Distinguished by single episode of illness, fever, and sick contacts rather than recurrent episodes related to specific food intake 1
• Symptoms typically resolve with fluid resuscitation alone without dietary modification 1

Cyclic Vomiting Syndrome

• Characterized by no relation to specific food intake and episodic nature unrelated to dietary triggers 1
• Neurologic disorder with recurrent stereotypical episodes of vomiting 1

Gastroesophageal Reflux Disease (GERD)

• Emesis is more chronic and not usually severe (does not lead to dehydration), with only upper gastrointestinal symptoms present 1
• Lacks the acute, profuse, repetitive nature of FPIES 1

Eosinophilic Gastroenteropathies

• Symptoms are usually not temporally associated with specific food intake and are more chronic than episodic 1
• Vomiting is less severe compared to FPIES 1
• Most commonly implicated foods are cow's milk, soy, wheat, and egg white 1
• More likely to have positive IgE test results than FPIES 1

Less Likely but Important Considerations

Inborn Errors of Metabolism

• Consider if there is developmental delay, neurologic manifestations, organomegaly, or reactions specifically to fruits 1
• Includes urea cycle defects, hereditary fructose intolerance, hyperammonemic syndromes, and mitochondrial disorders 1

Obstructive Problems

• Malrotation, Ladd bands, or volvulus would show evidence of obstruction on radiologic studies and are not related to specific food intake 1
• Typically present with more acute distress than described 1

Lactose Intolerance

• In severe form presents with gas, bloating, cramps, diarrhea, borborygmi, and vomiting after ingestion of liquid milk and large doses of dairy products with lactose 1
• Less likely in a toddler avoiding cow's milk products 1

Critical Diagnostic Approach

History Taking Priorities

• Detailed dietary history focusing on timing of emesis relative to specific food ingestion (1-4 hour window suggests FPIES) 1, 2
• Document all new foods introduced, particularly rice, oat, soy, and other grains common in toddler diets 1, 2
• Assess for extreme lethargy, marked pallor, and dehydration which indicate severe reactions requiring immediate intervention 1, 2
• Determine if symptoms resolve completely between episodes (suggests food-triggered rather than chronic GI disease) 1

Physical Examination Focus

• Evaluate hydration status, growth parameters (weight, height, weight-for-height) 1
• Assess for signs of shock (hypotension, tachycardia, poor perfusion) 1, 2
• Look for pallor, lethargy level, and abdominal distention 1, 2

Laboratory Evaluation

• Complete blood count with differential (elevated WBC with neutrophilia and thrombocytosis support FPIES) 2
• Metabolic panel to assess for acidosis and electrolyte disturbances 2
• Stool studies for leukocytes, occult blood, and carbohydrate content 2
• IgE testing is typically negative in non-IgE-mediated disorders but may help distinguish from IgE-mediated anaphylaxis 1, 2

Common Pitfalls to Avoid

• Do not assume the child is "fine" because they appear non-distressed—extreme lethargy in FPIES can be mistaken for calm behavior and may precede shock 1, 2
• Do not perform oral food challenges at home for suspected FPIES triggers, as up to 50% require IV fluid treatment 1
• Do not rely on IgE testing alone to rule out food allergy in this population, as non-IgE-mediated reactions are common and IgE tests will be negative 1, 2
• Do not overlook cross-reactivity—children with cow's milk protein allergy have increased risk of reactions to soy (up to 40% cross-reactivity) and other proteins 3, 4
• Do not dismiss the diagnosis without proper elimination and rechallenge under medical supervision, as this is the gold standard for diagnosis 1