In a 2‑month‑old infant with two weeks of loose stools, what laboratory and allergy tests should be ordered to evaluate for cow's‑milk‑protein allergy?

Evaluation for Cow's Milk Protein Allergy in a 2-Month-Old Infant

In a 2-month-old infant with two weeks of loose stools, do NOT order routine allergy testing—instead, start with a maternal elimination diet (if breastfeeding) or switch to an extensively hydrolyzed formula (if formula-feeding) for 2-4 weeks, as non-IgE-mediated cow's milk protein allergy (CMPA) presenting with isolated loose stools cannot be diagnosed by IgE testing. 1, 2

Understanding the Clinical Context

This presentation is most consistent with non-IgE-mediated CMPA, specifically food protein-induced allergic proctocolitis (FPIAP) or enteropathy, which accounts for approximately half of all cow's milk allergies in infants. 3, 4

Key Clinical Features:

• Non-IgE-mediated reactions present with chronic gastrointestinal symptoms including diarrhea, blood-streaked stools, failure to thrive, and enteropathy, typically occurring in the first year of life 2
• These disorders occur without IgE antibodies, making standard allergy testing useless 1
• FPIAP is the most common manifestation of CMPA in infants, presenting in healthy, well-appearing babies with rectal bleeding or loose stools 3

What NOT to Order

Avoid these tests in this clinical scenario:

• Skin prick testing (SPT): Only useful for IgE-mediated reactions that occur within minutes to 2 hours of ingestion with symptoms like hives, angioedema, wheezing, or anaphylaxis 2, 5
• Serum-specific IgE (sIgE) testing: Similarly useless for non-IgE-mediated disease 1, 2
• Routine laboratory tests: No laboratory test can definitively diagnose non-IgE-mediated CMPA 4

Critical Pitfall:

A positive IgE test without clinical symptoms of immediate reaction does not constitute food allergy—it only indicates sensitization, which occurs in up to 93% of children who actually tolerate the food. 1

The Diagnostic Algorithm

Step 1: Clinical History Assessment

Determine if symptoms suggest IgE-mediated versus non-IgE-mediated disease:

IgE-mediated features (NOT present in your case):

• Symptoms within minutes to 2 hours after milk ingestion 2, 5
• Urticaria, angioedema, wheezing, vomiting, facial swelling 2
• Anaphylaxis 1

Non-IgE-mediated features (MATCHES your case):

• Chronic diarrhea or loose stools 2
• Blood-streaked or mucoid stools 1, 3
• Symptoms developing over days to weeks 4
• Otherwise well-appearing infant 3

Step 2: Therapeutic Elimination Trial (The Diagnostic Test)

For breastfed infants:

• Implement strict maternal cow's milk protein elimination diet for 2-4 weeks 2, 3
• Cow's milk proteins transfer into breast milk and can trigger symptoms in exclusively breastfed infants (incidence 0.5%) 6
• Clinical improvement within 2-4 weeks supports the diagnosis 4

For formula-fed infants:

• Switch to extensively hydrolyzed whey or casein formula (NOT partially hydrolyzed) 2
• Partially hydrolyzed formulas are insufficient for treatment of diagnosed CMPA 2
• Do NOT use soy formula in infants under 6 months due to cross-reactivity risk 2

Step 3: Confirmation via Oral Challenge

After symptom resolution (typically 2-4 weeks):

• Reintroduce cow's milk protein (maternal diet or formula) 3, 4
• Re-emergence of symptoms confirms the diagnosis 3, 4
• This oral food challenge is the gold standard for non-IgE-mediated CMPA 4

When IgE Testing IS Indicated

Order SPT or sIgE testing only if the infant has:

1. History of immediate reaction within minutes to 2 hours after milk ingestion (hives, vomiting, wheezing, facial swelling) 2, 5
2. Moderate-to-severe atopic dermatitis that persists despite optimized topical corticosteroids and emollient use 1, 2, 5

Important Caveats:

• Even with positive testing, referral to allergist for supervised oral food challenge is mandatory to confirm clinical allergy 2, 5
• Negative IgE tests have excellent negative predictive value (>95%), effectively ruling out IgE-mediated allergy 2, 5
• Positive tests have poor positive predictive value (40-60%), requiring clinical correlation 2

Management After Diagnosis

If CMPA is confirmed:

• Continue elimination diet for at least 6 months before attempting reintroduction 6
• Prescribe epinephrine autoinjector if any IgE-mediated features are present (even mild), as coexistence of asthma increases risk of severe reactions 1, 2
• Provide written emergency action plan 2
• Refer to allergist for longitudinal care and supervised reintroduction 2, 5
• Arrange nutritional consultation, especially if multiple food avoidances are required 2

Prognosis

• 80% of infants with CMPA develop tolerance by age 3-4 years 6
• Most children with non-IgE-mediated disease develop tolerance by 2-3 years 2
• Majority with IgE-mediated disease regain tolerance within the first 5 years 2

Special Considerations for This Case

Given the presentation of isolated loose stools without blood, failure to thrive, or systemic symptoms:

• Consider other diagnoses including viral gastroenteritis, lactose intolerance (rare at 2 months), or normal stool variation 2
• Lactose intolerance causes bloating, flatulence, and diarrhea without immune involvement and is distinct from milk allergy 2
• If symptoms persist despite 4 weeks of elimination, reconsider the diagnosis and evaluate for alternative causes 4