Cow’s Milk Protein Allergy (CMPA): Classification, Etiology, Diagnostics, and Treatment Strategy

Currently, the issue of breastfeeding has been resolved through the wide production of adapted milk formulas (AMF). Facing issues in organizing proper breastfeeding, parents, and sometimes pediatricians, prefer bottle feeding. The ratio of proteins, fats, and carbohydrates in infant formula is as close as possible to that in human breast milk. However, the nature of the molecules remains foreign to the child, and their excessive intake by an infant with an immature gut wall and immune response can lead to sensitization and allergy.

Practically any protein molecule poses a risk of becoming an allergen to the human body. Since the primary food for a child is milk or formula, one of the most common allergic reactions in children under one year is considered cow’s milk protein allergy.

Cow’s milk protein allergy (CMPA) represents a pathological immune-mediated response to cow’s milk proteins. With the intensive increase in formula feeding, the issue of CMPA has been discussed increasingly among pediatricians, yet the diagnosis of CMPA in infants and young children remains a clinical problem, as many symptoms are often seen in healthy infants and do not necessarily indicate a disorder but can mimic symptoms of other diseases.

Epidemiology

Determining the exact prevalence of CMPA is complicated by the lack of clear and unified diagnostic criteria.

CMPA is a leading cause of allergy in infants and children under 3 years of age, but the reported prevalence of Cow’s Milk Protein Allergy varies significantly depending on the population considered. 5–15% of infants exhibit symptoms characteristic of an allergic reaction to cow’s milk protein; however, the actual prevalence of CMPA ranges from 2 to 7.5%.

Population studies report a prevalence ranging from 1.9% to 4.9% in young children, with this value decreasing to 1% in children over 6 years old. The frequency of CMPA in exclusively breastfed children, according to various studies, is 0.4–0.5%.

Definition and etiology

Cow’s milk protein allergy (CMPA) is a pathological hypersensitivity reaction to one or more proteins of cow’s milk, mediated by an immune mechanism.

Cow’s milk proteins consist of two major fractions: casein (76–86%) and whey proteins (14–24%), which include β-lactoglobulin, α-lactalbumin, serum albumin, and serum immunoglobulins. Among them, casein and β-lactoglobulin are the most allergenic and heat-resistant proteins, with individual sensitivity to each varying among people.

Pathogenesis and classification of CMPA

In the pathogenesis of CMPA in infants, feeding with milk formulas, which leads to early excessive intake of foreign protein, plays a significant role. Considering the immature and imperfect intestinal barrier and immune response, this leads to sensitization. One should be aware that children who are breastfed can also develop CMPA due to the penetration of proteins from the maternal diet into breast milk.

Proteins ingested via milk or formula are broken down by acids and enzymes in the infant’s gastrointestinal tract. When the intestinal mucosa comes into contact with cow’s milk antigens (proteins), antigen-presenting cells (APCs) interact with T- and B-cells. In allergy, activated T- and B-cells of lymphoid follicles migrate through the lymphatic system and blood vessels to various organs, causing an inflammatory reaction at the target organ, increasing intestinal permeability, and developing clinical manifestations.

Milk from other mammals, such as goats, can act as cross-reactive allergens, causing cross-allergic reactions in children with CMPA or independently serve as allergens, causing severe reactions in patients tolerant to cow’s milk.

CMPA can be classified as:

1. IgE-mediated reaction, an immediate-type reaction. These are anaphylactic reactions involving multiple systems, including acute urticaria, angioedema, vomiting, and hypotension.

2. Non-IgE-mediated reaction is a delayed-type reaction; the most common of such reactions are as follows:

• Food Protein-Induced Allergic Proctocolitis (FPIAP): rectal bleeding ± mucus;
• Food Protein-Induced Enteropathy (FPE): diarrhea and failure to thrive (insufficient weight gain);
• Food Protein-Induced Enterocolitis Syndrome (FPIES): diarrhea, vomiting, and lethargy.

3. Mixed-type reactions. Symptoms are delayed and depend on the degree of eosinophilic infiltration of the affected organs:

• Eosinophilic esophagitis (EoE): vomiting or dysphagia (swallowing disorder);
• Allergic eosinophilic gastrointestinal disorders (EGIDs): diarrhea ± rectal bleeding.

Clinical presentation

In most infants, the reaction to cow’s milk proteins can be IgE-mediated, non-IgE-mediated, or of mixed type, but it is not difficult to clinically differentiate them.

In IgE-mediated allergy, symptoms usually appear within minutes after eating the product. In non-IgE-mediated allergy, symptom onset is delayed and generally develops ≥2 hours later, most often within 6 to 72 hours.

Comparative characterization of IgE-mediated and non-IgE-mediated reactions

The spectrum of non-IgE-mediated CMPA is quite broad and includes symptoms ranging in severity from mild rectal bleeding in cow’s milk protein-induced allergic proctocolitis to severe vomiting and a clinical presentation resembling sepsis, which can occur in Food Protein-Induced Enterocolitis Syndrome (FPIES).

According to British studies, most infants with suspected CMPA showcase a mild to moderate course of non-IgE-mediated allergy. Clinical manifestations of non-IgE-mediated allergy are mostly cutaneous (70–75%), less often gastrointestinal (13–34%), and respiratory (1–8%).

In the context of gastrointestinal symptoms, allergenic proctocolitis, induced by dietary proteins (FPIAP), and Food Protein-Induced Enterocolitis Syndrome (FPIES) warrant particular attention.

Food Protein-Induced Allergic Proctocolitis (FPIAP)

Food Protein-Induced Allergic Proctocolitis (previously known as Allergic or Eosinophilic Proctocolitis) is a non-IgE-mediated condition, typically manifesting in otherwise healthy infants.

Key clinical manifestations:

• Hematochezia (blood-streaked stools);
• Persistent diarrhea with mucus;
• The general condition of the child is usually unaffected.

Important: green or mucous stools without blood in a healthy infant are not considered a symptom of CMPA.

Food Protein-Induced Enterocolitis Syndrome (FPIES)

Food Protein-Induced Enterocolitis Syndrome (FPIES) is a non-IgE-mediated food allergy, with cow’s milk protein being one of the most common triggers.

Key clinical manifestations – acute FPIES (most typical):

• Repeated, severe vomiting 1–4 hours after food intake;
• Lethargy, pallor;
• Diarrhea, often watery, sometimes with blood and mucus (appears within 5–10 hours, may persist up to 24 hours);
• Absence of cutaneous and respiratory symptoms, distinguishing FPIES from anaphylaxis.

Severe FPIES includes hypothermia, hypotension, metabolic acidosis, methemoglobinemia, and a clinical presentation mimicking sepsis.

Except for anaphylaxis, in the case of IgE-mediated allergy (which occurs in approximately 1-4% of CMPA cases), there are no specific symptoms.

Diagnosis

Accurate diagnosis of CMPA poses a challenge to healthcare workers due to the absence of specific (pathognomonic) symptoms and lack of diagnostic tests with sufficient specificity and sensitivity, especially regarding non-IgE-mediated CMPA.

In suspected cases of CMPA, the following diagnostic measures may be undertaken:

• Elimination diet. Excluding cow’s milk proteins from the diet results in full or partial disappearance of symptoms; for diagnostic purposes, the diet duration is 2–4 weeks.
• Elimination diet for the breastfeeding mother. Excluding cow’s milk proteins from the mother’s diet results in full or partial disappearance of symptoms; for diagnostic purposes, the diet duration is 2–4 weeks.
• Total IgE serum. It is not specific but can be utilized in infants with severe atopic dermatitis.
• Specific IgE to cow’s milk proteins. Elevation of specific IgE reflects sensitization to cow’s milk proteins, but does not confirm allergy and may be elevated in healthy patients.
• Skin prick or patch tests. Positive tests reflect sensitization to cow’s milk proteins, but do not confirm allergy and may be positive in healthy patients.

The gold standard for diagnosing CMPA is an oral food challenge conducted under medical supervision. However, it is not recommended when the clinical history is typical due to the dangers and risks to the patient, and thus it is rarely used.

Thus, all diagnostic procedures available to the pediatrician cannot completely confirm or exclude CMPA. The diagnosis is most often established clinically following an elimination diet.

Differential diagnosis

In IgE-mediated allergies, differential diagnosis is conducted with allergies to other proteins, as the general characteristics of immediate-type reactions are practically the same.

As a rule, differential diagnosis is relevant in non-IgE-mediated reactions in infants. The main diseases or conditions requiring differential diagnosis with CMPA are as follows:

• Isolated atopic dermatitis (without association with cow’s milk proteins);
• Other skin diseases (contact dermatitis, diaper dermatitis, etc.);
• Lactase deficiency;
• Carbohydrate malabsorption;
• Functional gastrointestinal disorders and infant colic;
• Celiac disease;
• GERD;
• Toxic reactions to food;
• Colitis and enteritis of viral and/or bacterial etiology.

Particular attention should be paid to the differential diagnosis between CMPA in infants and lactase deficiency.

Differential diagnosis of CMPA and lactase deficiency in infants

Please note! CMPA leads to secondary lactase deficiency due to allergic inflammation and destruction of microvilli of intestinal mucosal cells, which produce the enzyme lactase. Therefore, it can be stated that CMPA is one of the causes of secondary lactase deficiency.

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CMPA treatment

The main principle of CMPA treatment is the exclusion from the diet of all products containing cow’s milk protein, including beef.

Mothers of children receiving breast milk who show symptoms of CMPA are also advised to adhere to a strict diet excluding all cow’s milk-based products and beef.

For formula-fed children, milk formula is replaced with specialized ones where whole cow protein is partially or completely broken down during production.

Any protein, including cow’s milk protein, is a complex molecule consisting of amino acids linked in chains called peptides, which, in turn, link together to form a complete protein globule.

Depending on the severity of CMPA, the following are prescribed:

• Extensively hydrolyzed formulas (EHFs). Hydrolyzed (broken down) cow’s milk protein to oligopeptides. This formula is more often suitable for children with non-IgE-mediated CMPA of mild to moderate severity.
• Amino acid formulas (AAFs). A mixture of natural and synthetic amino acids. This formula is more often suitable for children with IgE-mediated CMPA.
• Formulas based on plant (soy, rice) protein. Not used in children under 6 months of age. Should be prescribed with caution in the absence of sensitization to soy protein.

Treatment of non-IgE-mediated CMPA begins with a diagnostic elimination diet lasting 2–4 weeks. If symptoms disappear, the elimination diet is continued for at least 6 months, depending on the severity of the condition.

Treatment of IgE-mediated CMPA is also based on an elimination diet. However, it is most often continued for a long time (years) with regular assessment of sensitization.

Prognosis

The prognosis of the disease course depends on the form of CMPA and the severity of the course. With timely initiated therapy, the prognosis is predominantly favorable.