Cow milk protein allergy mimics in infancy

Table 1 Differentiation between IgE-mediated and non-IgE-mediated cow milk protein allergy

Feature	IgE-mediated CMPA	Non-IgE-mediated CMPA
Mechanism of allergy	Allergic reactions mediated by IgE antibodies binding to allergens, mast cells, and basophils, triggering mast cell degranulation and histamine release	T-cell mediated immune response leading to inflammation without IgE involvement
Pathophysiology	Immune response involving IgE antibodies	Immune response without IgE involvement
Onset of symptoms	Rapid onset, usually within minutes to hours after ingesting cow’s milk protein	Delayed onset, typically hours to days after ingestion
Common presentation age	It is more common after initial exposure to cow’s milk protein through formula or food introduction	It often occurs early in infancy, even in exclusively formula-fed infants
Symptoms	Urticaria, angioedema, anaphylaxis; Respiratory symptoms (wheezing, nasal congestion); Immediate gastrointestinal symptoms (vomiting)	Chronic diarrhea, constipation, blood-streaked stools; Gastroesophageal reflux-like symptoms; Poor feeding, colic, and failure to thrive
Systemic involvement	Systemic reactions, including anaphylaxis, are common	Limited to localized inflammation, primarily in the gastrointestinal tract
Severity	It can be life-threatening (e.g., anaphylaxis)	Symptoms are generally less acute but may lead to chronic complications
Duration of symptoms	Symptoms resolve quickly once exposure ceases	Symptoms persist until the trigger is eliminated for an extended period
Diagnostic tools	Skin prick test; Serum-specific IgE testing; Food challenge (confirmation)	Diagnosis of exclusion; Elimination diet and reintroduction challenge; No reliable specific tests available
Management	Strict avoidance of cow’s milk protein and use of emergency medication (e.g., epinephrine for anaphylaxis)	Strict avoidance of cow’s milk protein, ensuring nutritional adequacy of alternatives
Resolution	It may persist longer, though some children outgrow it by school age	Often resolves by 1-3 years of age

This table shows the underlying mechanisms of allergy, providing a more comprehensive comparison of IgE-mediated and non-IgE-mediated cow milk protein allergy. CMPA: Cow milk protein allergy.

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.

Table 3 Comparison between casein A1–induced intolerance and cow milk protein allergy

Aspect	Casein A1–induced intolerance	CMPA
Mechanism	Non-immune-mediated; caused by the release of BCM-7 during digestion of A1 β-casein	Immune-mediated response to milk proteins (e.g., casein, whey) via IgE or T-cell pathways
Primary trigger	A1 β-casein found in milk from breeds like Holstein and Friesian cows	Any cow’s milk protein, including casein and whey
Symptoms	Gastrointestinal symptoms: Constipation, bloating, abdominal pain. No systemic manifestations	Wide range: Gastrointestinal (vomiting, diarrhea), skin (eczema, rash), respiratory (wheezing), or systemic reactions (anaphylaxis)
Onset	Dose-dependent; occurs after consuming significant amounts of A1 β-casein	It can occur after small amounts of milk protein; onset may be immediate (IgE-mediated) or delayed (non-IgE-mediated)
Age of onset	It is more common in older infants and children and rare in newborns	Typically manifests in infancy, often within the first year of life
Diagnosis	Clinical observation with symptom resolution following a switch to A2 milk. No specific diagnostic tests were available	Based on clinical history, specific IgE tests, skin prick tests, and elimination diets with oral food challenges
Management	Substituting with A2 milk, there is no need for hypoallergenic formulas unless other sensitivities coexist	Avoid all cow’s milk proteins; use extensively hydrolyzed or amino acid-based formulas for infants
Systemic involvement	Absent; symptoms are limited to the gastrointestinal system	Possible, particularly in IgE-mediated cases (e.g., respiratory or skin involvement)
Prognosis	Symptoms resolve with dietary modification, such as switching to A2 milk	Many children outgrow CMPA by 3-5 years; strict dietary management is required until the resolution is reached
Nutritional impact	Minimal if A2 milk or suitable dietary alternatives are included	Risk of nutritional deficiencies if dietary restrictions are not appropriately managed

This comparison underscores the distinct mechanisms, symptoms, and management strategies for casein A1–induced intolerance and cow milk protein allergy. Accurate diagnosis is critical to avoid unnecessary treatments or dietary restrictions and to ensure optimal care. A2 milk: Milk containing only A2 beta-casein. BCM-7: Beta-casomorphin-7; CMPA: Cow milk protein allergy.

Table 4 How clinical history can help differentiate cow milk protein allergy from other mimicking conditions

Condition	Key features in clinical history	How clinical history helps differentiate from CMPA
CMPA (IgE-mediated and non-IgE-mediated)	Symptoms often begin in the first few months after cow's milk introduction; Can present with gastrointestinal (vomiting, diarrhea), dermatological (eczema, urticaria), respiratory (wheezing, coughing), and systemic (anaphylaxis) symptoms	Symptoms directly linked to cow's milk exposure; May involve multiple systems (gastrointestinal, skin, respiratory) simultaneously; Family history of atopic diseases increases the likelihood of CMPA
GERD	Common in infants, often linked with post-feeding regurgitation, vomiting, irritability, & back arching; Often exacerbated by overfeeding, positional changes, or lying down	GERD symptoms are primarily gastrointestinal (vomiting, regurgitation) and often responsive to anti-reflux treatments (H2 blockers or proton pump inhibitors); No skin, respiratory, or systemic involvement
Lactose intolerance	Usually present after the introduction of dairy (often after weaning) or with high-lactose-containing formula or milk; Symptoms mainly gastrointestinal (bloating, diarrhea, abdominal cramping)	Symptoms occur specifically after lactose ingestion and are not associated with other systemic reactions (e.g., skin rashes or respiratory symptoms); Rare in infants but can occur in older children
FPIES	Presents with delayed gastrointestinal symptoms (vomiting, diarrhea, lethargy) after ingestion of a trigger protein (cow's milk, soy); Episodes often occur hours after ingestion	Symptoms typically emerge hours after milk ingestion (delayed reaction); No allergic (IgE-mediated) symptoms like urticaria or anaphylaxis; Symptoms resolve with dietary elimination of the trigger
EoE	Chronic symptoms of reflux, vomiting, dysphagia, or food impaction; History of food allergies or atopic diseases is common; Symptoms may persist despite reflux treatments	EoE often presents with chronic vomiting or feeding difficulties, but without systemic allergic manifestations; No immediate or IgE-mediated reactions; Requires biopsy for diagnosis
Casomorphin-induced gastrointestinal disorders	May include symptoms like bloating, diarrhea, and abdominal pain after milk consumption; History may show improvement with dairy-free diet	Symptoms are generally isolated to gastrointestinal issues, unlike CMPA, which involves a broader spectrum (e.g., skin, respiratory); No immediate allergic response or anaphylaxis

The table shows that each condition has distinct features in terms of symptom timing, response to dietary changes, and involvement of multiple organ systems, all of which can guide the clinician toward the correct diagnosis. H2 blockers: Histamine-2 receptor antagonists. CMPA: Cow milk protein allergy; EoE: Eosinophilic esophagitis; FPIES: Food protein-induced enterocolitis syndrome; GERD: Gastroesophageal reflux disease.

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.

Table 6 Some of the biomarkers that are associated with the severity and persistence of cow milk protein allergy

Biomarker	Type	Associated with severity	Associated with persistence	Comments
SPT	Clinical test	≥ 8 mm indicates high reaction risk during OFC	Related to milk allergy persistence	Predictive of OFC outcomes, useful for identifying high-risk patients
EPT	Clinical test	High risk of anaphylaxis during food challenges	Marker for milk allergy persistence	Described as more useful than SPT for identifying severe milk allergy risk
sIgE	Serum biomarker	Severe allergic reactions in peanut and milk	Higher levels linked with persistent allergies	sIgE cutoffs can predict OFC outcomes
BAT	Cellular biomarker	High CD63 ratio linked to severe reactions	Associated with severe clinical milk reactivity	High proportions of activated basophils indicate severe allergic reactions
Cytokines (interleukin-13, interleukin-10)	Immune biomarker	Higher levels during allergic inflammation	Linked to persistent milk and egg allergies	Elevated in both milk and egg allergy studies, indicating immune dysregulation
Calprotectin	Fecal biomarker	Not specified	Associated with persistent gastrointestinal inflammation	Useful for differentiating non-IgE-mediated allergies from other GI conditions
EDN	Fecal biomarker	Not specified	Associated with persistent gastrointestinal inflammation	Indicates eosinophilic inflammation in the gastrointestinal tract

This table illustrates the growing complexity of allergy diagnostics and highlights emerging biomarkers that may improve the differentiation and management of cow milk protein allergy. SPT: Skin prick tests; OFC: Oral food challenge; EPT: Endpoint test; sIgE: Specific IgE; BAT: Basophil activation test; EDN: Eosinophil-derived neurotoxin.