Cow's Milk Protein Allergy

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Cow’s milk allergy (CMA) or Cow’s milk protein allergy (CMPA) is diagnostically defined as an immunologically mediated adverse reaction to cow’s milk proteins.

CMPA is the most common food allergy in the pediatric age group in industrialized societies, simply because cow’s milk proteins are most often first encountered in life from susceptible, non-breastfed infants, which may lead to early sensitization. It may also occur in exclusively breastfed infants.


In diagnostic studies, the incidence of cow’s milk protein allergy (CMPA) during the first year of life has been estimated to be about 2–3% in developed countries.

CMA is the most frequent parentally perceived adverse reaction to food with prevalence estimates based on parental perception between 12% and 15% in children under the age of 3 years. However, objective diagnostic testing has revealed that parents overestimate the role of milk as the cause of symptoms in their children. The actual reported prevalence is more likely to be 7.5% at 12 months of age and 5% at 24 months of age.


Similar to other food allergies, cow’s milk protein allergy can be either in the form of immunoglobulin E (IgE) antibody-mediated food allergy, or non-IgE-mediated (cell-mediated) food allergy, the latter primarily affecting the gastrointestinal system.

In infants with cow’s milk protein allergy, non-IgE-mediated mechanisms play an important pathophysiological role. In addition, there is evidence that T-cell activation plays a role in cow’s milk protein allergy in patients with atopic dermatitis, with increase in the T helper 2 (Th2) predominant cytokine profile, IL-4, and IL-13.

There are different proteins in cow’s milk, the most important of which are αs1-casein, one of the casein proteins, and β–lactoglobulin, one of the whey proteins, both responsible for the immunogenic-mediated reactions produced in patients with cow’s milk protein allergy. Allergen-specific IgE and T-cells recognize peptides of varying sizes along the entire chain of αs1-casein. T-cell recognition sites for β–lactoglobulin have been identified in children with cow’s milk protein allergy.

There is increasing evidence that ingested cow’s milk and other food antigens are secreted into human milk and can potentially sensitize the breastfed infant. IgA antibodies in human milk have a protective effect on the sensitization to food allergens as they may prevent antigen entry at the intestinal cell surface of infants.

In a study of breastfed infants, IgA concentrations in the colestrum and human milk were significantly lower in mothers whose infants developed milk protein allergy during the first 12 months of life, suggesting that IgA antibodies in human milk play a role in the sensitization to food allergens.


Most infants with cow’s milk protein allergy develop symptoms before 1 month of age, often within 1 week after the introduction of cow’s milk-based formula.

The majority of infants have two or more symptoms involving two or more organ systems.

  • Cutaneous manifestations include atopic dermatitis, urticaria, angioedema, and contact rash.
  • Gastrointestinal manifestations are in the form of local oral reactions, nausea, vomiting, colic, diarrhea, colitis, eosinophilic gastroenteritis, and protein-losing enteropathy.
  • Respiratory reactions may occur in the form of asthma, laryngeal edema, or otitis media with effusion.

In young children, GERD Opens in new window and dietary protein allergy are difficult to differentiate on the basis of clinical presentation. Cow’s milk protein allergy may cause delay in gastric emptying and has been associated with gastric dysrhythmias and may induce reflex vomiting or exacerbate symptoms of GERD. The presence of other manifestations of cow’s milk protein allergy, such as atopic dermatitis, eosinophilic esophagitis, enterocolitis, or constipation should alert the physician that the etiology of the infant symptoms is not simply GERD.


The diagnosis of milk protein allergy relies upon a careful history, skin prick tests, in vitro measurement of food-specific IgE if applicable, an appropriate elimination diet, and blinded oral food challenges.

Skin prick tests are highly reproducible and are frequently used to screen patients with suspected IgE-mediated food allergies. The skin prick test may be considered an excellent means of excluding IgE-mediated food allergies, but is only suggestive of the presence of clinical food allergies. It is reliable for immediate food allergies, thus, it is more helpful to exclude immediate-type reactions caused by milk protein allergy.

It is noteworthy that there are many false-positive skin prick tests with no clinical significance, so a positive skin test in isolation cannot be considered a proof of clinically relevant hypersensitivity.

In vitro radioallergosorbent tests (RASTs) are also helpful in the evaluation of IgE-mediated food allergy. RAST negative results are very reliable in ruling out an IgE-mediated reaction to a particular food, but a positive result has low specificity. They are likely to be positive in syndromes that are acute in onset after ingestion of the causal protein and in patients with other manifestations of atopic disease.

A trial of elimination diet is a simple, practical, and definitive test to differentiate cow’s milk protein allergy from GERD. A 1- or 2-week trial of a hypoallergenic formula is recommended by North American Society for Pediatric Gastroenterology and Nutrition guidelines for evaluation and treatment of GER in infants and children. If symptoms resolve, an oral challenge testing with milk and other dairies may be considered. As test for specific IgE antibodies are not relevant to milk protein allergy, oral challenges are often the only means of diagnosis.

Oral challenge may cause severe allergic reactions; therefore, it should be performed under physician supervision and with the availability of emergency medications and equipment to treat allergic reactions.

A study by Iacono et al. found that 42% of patients with GER proven by intraesophageal pH monitoring study and endoscopic evidence of esophagitis had cow’s milk protein allergy.

During the 24-h esophageal pH monitoring study, the authors found that all the patients who had cow’s milk protein allergy demonstrated a characteristic gradual decrease in esophageal pH between one meal and the next, the characteristic typical “phasic” pattern. Another study failed to find any characteristic esophageal pH-metric pattern distinguishing patients with GER and cow’s milk protein allergy from those patients with GER alone.

To differentiate GER Opens in new window from cow’s milk protein allergy, a study was conducted on 25 infants with persistent vomiting, with the authors comparing a noninvasive test of small bowel permeability with more invasive tests involving endoscopy, mucosal biopsy, and esophageal pH monitoring. Each infant underwent a celobiose/mannitol permeability study, upper endoscopy with small bowel biopsies and a 24-h pH study.

Results of the permeability test were abnormal in only 6% of the patients with GER, but in 100% of those with GER and cow’s milk protein allergy alone. This study suggested that such permeability test could avoid more invasive diagnostic tests in the evaluation of infants with persistent vomiting. However, adoption of this noninvasive test in clinical practice will not be established until further studies are conducted to prove its reproducibility.


The treatment of cow’s milk protein allergy follows the general principles of allergen avoidance—there are three modalities for the management of food-allergen and cow’s milk protein allergy is not an exception:

  1. elimination and avoidance of specific allergens,
  2. pharmacologic therapies, and
  3. preventive measures.

At the present time, however, there is no practical or effective therapy other than complete elimination of cow’s milk protein from the infant’s diet for a variable period of time. The removal of cow’s milk protein from the diet requires consideration for alternative sources of nutrition when breast-feeding is not available.

The appropriate choice of a cow’s milk substitute should meet essential criteria:

  1. It should fulfill the nutritional needs of the infant providing an adequate growth and development
  2. It should have no or little cross-reactivity with CMPs
  3. It should have good palatability

Soy protein-based formula is often used as a cow’s milk substitute. A significant proportion of infants with cow’s milk protein allergy may also be sensitized to soy protein.

The introduction of highly allergenic food items such as eggs, peanuts, and tree nuts should be deferred in these infants until the second year of life.

It has been estimated that approximately 10% of infants with cow’s milk protein allergy are still intolerant to extensively hydrolyzed formulas. In these infants, amino acid-based formula has proved effective and safe.

In breastfed infants, maternal elimination of diet that contains milk, soy, and milk and soy products, is often effective. Dietary calcium supplementation to the mothers may be required.

Approximately 85% of infants with milk protein allergy will develop tolerance to cow’s milk protein by 3 years of age. Although allergen avoidance appears to hasten the subsequent development of antigen tolerance, it remains unclear to what extent dietary manipulations alter the course of food allergies.

See also:
  1. Sampson HA. Food allergy. Part 1: immunopathogenesis and clinical disorders. J Allergy Clin Immunol 1999; 103:717-728.
  2. Heine RG, Elsayed S, Hosking CS, Hill DJ. Cow’s milk allergy in infancy. Curr Opin Allergy Clin Immunol 2002; 2: 217-225.
  3. Seidman EG, Singer S. Therapeutic modalities for cow’s milk allergy. Ann Allergy Asthma Immunol 2003; 90 (suppl 3):104-111.
  4. Hᴓst A. Frequency of cow’s milk allergy in childhood. Ann Allergy Asthma Immunol 2002;89(6 Suppl 1): 33-37.
  5. Hᴓst A, Halken S, Jacobsen HP, Christensen AE, Herskind AM, Plesner K. Clinical course of cow’s milk protein allergy/intolerance and atopic diseases in childhood. Pediatr Allergy Immunol 2002; 13 Suppl 15:23-8.
  6. Sicherer SH, Munoz-Furlong A, Murphy R, Wood RA, Sampson HA. Symposium: Pediatric Food Allergy. Pediatrics 2003;111(6):1591-4.
  7. Sicherer SH. Food allergy. Lancet. 2002; 360:701-710.
  8. Walker-Smith J. Cow’s milk allergy: a new understanding from immunology. Ann Allergy Asthma Immunol 2003; 90(6 Suppl 3): 81-3.
  9. Mofidi S. Nutritional management of pediatric food hypersensitivity. Pediatrics 2003; 111: 1645-53.
  10. Zeiger RS, Sampson HA, Bock SA, Burks A W Jr, Harden K, et al. Soy allergy in infants and children with IgE-associated cow’s milk allergy. J Pediatr 1999;134:614-22.