Cow milk protein allergy mimics in infancy

Table 2 Differentiating cow milk protein allergy from its mimics

Feature	CMPA (IgE & non-IgE)	Lactose intolerance	GERD	FPIES	EoE	Casomorphin-induced disorders
Pathophysiology	Immune-mediated (IgE/non-IgE) reaction to milk proteins	Enzyme deficiency (lactase) leading to lactose malabsorption	Acid reflux due to lower esophageal sphincter immaturity	Non-IgE-mediated immune reaction to food proteins	Chronic Th2-mediated inflammation with eosinophil infiltration	Opioid-like activity of BCM-7
Primary triggers	Cow’s milk proteins (casein, whey)	Lactose-containing dairy products	Overfeeding, positional factors, immature lower esophageal sphincter	Cow’s milk, soy, grains (e.g., rice, oats)	Food allergens (including cow’s milk), environmental triggers	A1 beta-casein from certain cow breeds (e.g., Holstein, Friesian)
Primary symptoms	Gastrointestinal (diarrhea, vomiting), skin (eczema, urticaria), respiratory (wheezing, anaphylaxis)	Bloating, diarrhea, gas, abdominal pain	Regurgitation, vomiting, irritability, poor weight gain	Severe vomiting, diarrhea, dehydration, lethargy	Feeding difficulties, vomiting, failure to thrive	Constipation, bloating, colic, abdominal pain
Onset of symptoms	Immediate (IgE) or delayed (non-IgE) after milk ingestion	30 min–2 hours after lactose consumption	Typically post-feeding; worsens when lying down	1-4 hours after ingestion	Chronic, develops over weeks/months	Dose-dependent after consuming A1 milk
Age of onset	Typically within the first year of life	Rare in infancy; more common in older children and adults	Common in infancy, peaks at 4-6 months	Usually presents in infancy, often within the first few months	Infancy to early childhood	More common in older infants and children, rare in newborns
Diagnosis	Skin prick test, serum IgE, elimination diet, oral food challenge	Hydrogen breath test, stool acidity test	Clinical evaluation, pH monitoring, endoscopy	Clinical history, symptom resolution after food elimination	Endoscopy with biopsy (≥ 15 eosinophils/HPF)	Clinical observation, symptom resolution with A2 milk
Treatment	Elimination of cow’s milk proteins, hypoallergenic formula	Lactose-free diet or lactase enzyme supplementation	Positional therapy, thickened feeds, acid suppressants (PPIs, H2 blockers)	Avoid trigger food, supportive care for acute episodes	Elimination diet (milk and other allergens), topical steroids	Switch to A2 milk or eliminate cow’s milk
Systemic Involvement	Possible (especially in IgE-mediated cases)	No systemic symptoms	No systemic symptoms	Severe systemic effects (hypovolemia, shock)	Limited to the esophagus, no systemic effects	No systemic involvement
Nutritional Impact	Risk of deficiencies in calcium, vitamin D, and protein if improperly managed	Minimal if alternative lactose-free dairy is included	Generally no direct nutritional impact	Risk of malnutrition if multiple food eliminations are required	Risk of poor growth if untreated	Minimal if A2 milk or other dairy substitutes are used
Prognosis	Most outgrow by 3-5 years	Symptoms persist if lactose is consumed	Often resolves by 1 year	Tolerance develops by 3-5 years	Chronic, requiring long-term management	Symptoms resolve with dietary modification

Casomorphin-induced disorders: Conditions resulting from the opioid-like effects of beta-casomorphin-7, a peptide released during the digestion of A1 beta-casein, leading to gastrointestinal symptoms. Cow milk protein allergy: An immune-mediated response to cow’s milk proteins, which can be IgE-mediated (immediate) or non-IgE-mediated (delayed). Eosinophilic esophagitis: A chronic allergic condition characterized by eosinophilic inflammation of the esophagus, often triggered by food allergens like cow’s milk. Food protein-induced enterocolitis syndrome: A non-IgE-mediated immune reaction that leads to severe gastrointestinal symptoms like vomiting and diarrhea, typically after food ingestion. Gastroesophageal reflux disease: A condition where stomach contents reflux into the esophagus, causing regurgitation, vomiting, and feeding difficulties. Lactose intolerance: A non-immune reaction due to lactase enzyme deficiency, leading to malabsorption of lactose and gastrointestinal symptoms. BCM-7: Beta-casomorphin-7; CMPA: Cow milk protein allergy; EoE: Eosinophilic esophagitis; FPIES: Food protein-induced enterocolitis syndrome; GERD: Gastroesophageal reflux disease; HPF: High-power field; PPI: Proton pump inhibitor.