Cow milk protein allergy mimics in infancy

Table 5 The potential for bias in the diagnostic tools for cow milk protein allergy

Diagnostic tool	Potential for bias	False positives	False negatives	Limitations/considerations
SPT	Inaccurate representation of clinical allergy; positive result indicates sensitization, not clinical allergy	Positive results may occur in sensitized individuals without clinical allergy	False negatives may occur due to antihistamine use or insufficient IgE production in infants	Cannot differentiate between sensitization and clinical allergy; sensitivity may be reduced in young infants or due to medication interference (e.g., antihistamines)
Serum-specific IgE testing	Positive result indicates sensitization, but not severity of clinical allergy	Positive results in sensitized individuals without clinical allergy	False negatives may occur if IgE production is insufficient or if the patient has non-IgE-mediated CMPA	Cannot distinguish between clinically relevant allergy and simple sensitization; may not detect non-IgE-mediated CMPA or EoE
OFC	Potential for overdiagnosis if patient reacts to low doses or testing is not closely supervised	Rare in non-IgE mediated conditions, though some allergic reactions may be overlooked	High risk of severe allergic reactions, including anaphylaxis	Requires controlled medical supervision; not suitable for infants with severe allergic reactions; may not diagnose non-IgE-mediated forms of CMPA
Elimination diet and reintroduction	Limited by subjective reporting; dependent on strict adherence to dietary changes	Positive result may be due to coincidental improvement (e.g., GERD or FPIES improvement)	Symptom recurrence may be delayed, leading to false negatives or difficulty in confirming diagnosis	Requires long observation periods and careful monitoring; does not confirm IgE-mediated immune mechanism; subjective reports may lead to bias
Lactose intolerance testing (hydrogen breath test)	Confounding variables (e.g., gastrointestinal disorders) may affect results	Rare but possible due to non-lactose-related gastrointestinal issues	May fail in detecting lactose intolerance in some infants with undetectable hydrogen levels	Requires cooperation from patient; less useful in younger infants; may not detect milk protein allergies or CMPA
EoE testing (endoscopy/biopsy)	Diagnostic procedure complexity; may not show food triggers in some cases	False positive due to eosinophils' presence in other esophageal conditions	False negative if eosinophil count is low or in the absence of endoscopic evidence	Highly invasive; may not detect food triggers in every case of EoE; expensive and time-consuming
FPIES	Clinical history-based diagnosis may be subjective and lead to overdiagnosis or misdiagnosis	Misdiagnosis with other gastrointestinal conditions (e.g., gastroenteritis, GERD)	False negative if symptoms are subtle or only occur with larger quantities of the trigger	Diagnosis largely based on clinical history and symptoms; may not detect non-IgE-mediated CMPA or other gastrointestinal disorders

This table summarizes how diagnostic tools for cow milk protein allergy might introduce bias in their results and what factors should be considered for a more accurate diagnosis. SPT: Skin prick tests; CMPA: Cow milk protein allergy; EoE: Eosinophilic esophagitis; OFC: Oral food challenge; FPIES: Food protein-induced enterocolitis syndrome; GERD: Gastroesophageal reflux disease.