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The prevalence of food allergy has been as high as 19% to 35% by parental reporting in epidemiologic studies, but only 2% to 8% by objective diagnosis by food challenge.1 In the United States, food allergies occur in 6% to 8% of younger persons and 2% of adults. Food allergies are an important component of the “allergic march,” since they often precede, and may potentially promote, the development of other allergic diseases, including allergic rhinitis and asthma.1,2

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Cow’s milk protein allergy (CMPA) is a common food allergy with an estimated prevalence of 2% to 3% in the first year of life.3 CMPA can occur in both breastfed and formula-fed infants, as well as when cow’s milk is introduced into the diet.4 Due to differences in diagnostic criteria and symptoms that often mimic other allergic diseases, CMPA is easily missed or mislabeled in the primary-care setting.4,5

Furthermore, despite the high prevalence of suspected food allergy (including CMPA) by parental reports, relatively few parents or caregivers seek medical care for their children’s food problems.1 Thus, there is a need for parents, caregivers, and clinicians to recognize CMPA as a condition with diverse clinical symptoms and a significant cause of infant distress and to increase their awareness of the factors that contribute to the development of CMPA as well as the importance of an accurate diagnosis.

Case study

Mark B. is an 8-week-old infant whose parents believe may have some type of gastrointestinal (GI) disorder. Mark’s mother breastfed him from birth to age 6 weeks. Since he was born, Mark has experienced intermittent spitting-up and diarrhea; he cries and seems to be in pain after almost every feeding. His previous pediatrician observed that Mark was gaining weight and suggested that the boy was being breastfed too frequently.

Mark’s mother started allotting more time between feedings, and his symptoms nearly disappeared. She recently returned to work and began feeding her son traditional ready-to-feed formula. Over the past week, the boy’s GI symptoms have returned, and he has now developed mild eczema on the backs of his elbows and knees.

Immunopathogenesis and multifactorial pathophysiology of CMPA

CMPA develops as an immunologic reaction to one or more milk proteins, which distinguishes the condition from lactose intolerance and other adverse reactions to cow’s milk protein (CMP).4 CMPA may be mediated by immunoglobulin (Ig) E or by non-IgE factors.1,4,5 IgE-mediated reactions involve relatively simple immunologic mechanisms, eliciting symptoms from several minutes to several hours after contact with the allergen and termed “immediate hypersensitivity” reactions.6 In CMPA, the first stage of an IgE-mediated reaction involves sensitization, in which an aberrant secretion of antibodies against CMP bind to the surfaces of mast cells and basophils.6 Subsequent exposure to milk proteins triggers activation of the mast-cell-bound IgE and a rapid release of inflammatory mediators (e.g., histamine, platelet-activating factor, and others) to produce the allergic reaction.6

A substantial proportion of children with suspected CMPA do not have high levels of cow’s-milk-specific IgE anti­bodies, resulting in negative results on skin-prick and serum-antibody tests; thus, these children have a non-IgE-mediated reaction.6 In these individuals, the CMPA reaction is characterized by a delayed onset of symptoms from one hour to many days after ingestion of CMP.6 These delayed hypersensitivity reactions are thought to be mediated by T helper 1 (Th1) cells, interactions between T lymphocytes, or mast cell and neuronal-mediated changes in intestinal motility.6 There is considerable evidence to suggest a direct relationship between non-IgE-mediated reactions and age, since a high proportion of non-IgE-mediated reactions resolve in children but there is a high prevalence of these reactions in adults.6

The immune system also regulates the balance between oral tolerance and hypersensitivity to CMP through the complex actions of other mediators produced by T lymphocytes.6 Suppression of reactive antigen-specific T-cells and production of T regulatory cells that inhibit the inflammatory response appears to occur in both IgE- and non-IgE-mediated reactions.6 In addition, T-cell dysfunction plays a major role in the lack of tolerance to CMP, while the development of T-cells in childhood is associated with increased tolerance.6

Role of genetics and socioenvironmental factors in the development of CMPA

As with other allergic diseases, both genetics and environmental factors play a role in the development of CMPA.3 The critical time for these factors to come into play with CMPA is in early infancy or even during pregnancy.3

Whether breast milk can protect against the development of food allergy and other atopic diseases has been examined in a number of studies.8,9  Breastfeeding can protect infants of mothers without atopic disease against allergies, but there is little evidence to support maternal dietary restrictions during pregnancy or lactation as a means of preventing the development of food allergy in infants.8

On the other hand, mothers with atopic disease tend to have higher levels of cytokines and chemokines associated with allergy in their breast milk and a lower level of a specific cytokine that promotes tolerance to foods, which may increase the risk that the infants of these mothers develop food allergies during lactation.7,9,10

Sensitization to food allergens occurs primarily in the first year of life, and CMPA is often the first allergy to appear in sensitized infants.7  A number of prenatal and perinatal factors may contribute to an increased risk of development of CMPA.3 In a Swedish population-based study, infants of mothers aged 30 to 34 years at delivery were 58% more likely to develop CMPA than were babies born to mothers younger than age 25 years, and cesarean section increased the risk by 18% compared with vaginal delivery.3

In contrast, a greater number of previous deliveries, multiple pregnancies, and smoking were associated with about a 30% lower risk.3 Other factors that may increase the risk for food allergy include prematurity and low birth weight, although study results are inconsistent.3

Socioeconomic factors also seem to contribute to the development of food allergy. In the Infant Feeding Practices Study II (IFPS II) of 2005-2007, a survey of 2,441 U.S. mothers of healthy singletons younger than age 1 year, several demographic, maternal, and family history characteristics were associated with probable food allergy in the infants, including higher maternal education; living in rural or urban areas; black race; male gender; and a family history of food allergy, type 1 diabetes, or obesity.1

Challenges in diagnosing CMPA

The foundation of CMPA diagnosis is a comprehensive history—including a family history of atopic disease—a careful physical examination, and allergy testing.4,11,12 Unfortunately, no single symptom is indicative of CMPA, a factor that contributes to the difficulties distinguishing CMPA from nonallergic food problems and other allergic conditions.1,4

The most frequently reported symptoms of CMPA (Table 1) are manifested in the GI tract (50% to 60%), skin (50% to 60%), and respiratory tract (20% to 30%), and usually target more than one organ or system.2,4,12 Symptoms often occur within the first few weeks after introduction of CMP and may be mild, moderate, or severe based on subjective parental descriptions.4,12 Infants also may exhibit persistent distress or colic for several hours a day at least three days a week to suggest an allergic reaction.4

Table 1. Clinical manifestations suggesting CMPA

Organ system Severe manifestations Moderate-to-mild manifestations
GI Failure to thrive
Iron deficiency anemia
Regurgitation and vomiting
Colic/abdominal pain
Skin Exfoliation/severe atopic dermatitis Atopic dermatitis
Swollen lips
Respiratory tract Laryngeal edema Rhinitis
General Anaphylaxis Irritability
Source: De Greef E, Hauser B, Devreker T, et al. Diagnosis and management of cow’s milk protein allergy in infants. World J Pediatr. 2012;8:19-24.

The timing and pattern of symptoms can aid in a differential diagnosis.4 A child with IgE-mediated CMPA typically presents with urticaria, vomiting, cough and wheeze, and less commonly, hypotension, within one to two minutes of ingesting cow’s milk.5 Non-IgE-mediated reactions to cow’s milk may present with predominantly GI symptoms—repetitive vomiting with or without diarrhea, abdominal pain, and bloody stools—that develop several hours after ingesting cow’s milk.5

Atopic dermatitis is sometimes associated with food-specific IgE-reaction, and a worsening of eczema is often considered an expression of CMPA.5

Skin-prick tests for determination of specific IgE can be performed, but these tests indicate sensitization to the substrate and are not necessarily proof of an allergic reaction.12 Patch tests may be helpful in the diagnosis of non-IgE-mediated reactions.12 The double-blind, placebo-controlled food challenge is the gold standard for the diagnosis of CMPA.11,12  Because such testing is expensive and time-consuming, however, open food challenge is often used in clinical practice.12