The Natural History of Cow’s Milk Allergy

Cow’s milk is a leading cause of food allergy especially in infants and children. Cow’s milk allergy (CMA) is the most common food allergy in infants and young children, affecting 2% to 3% of the general population. Most studies have shown the prognosis of developing tolerance to cow’s milk to be good, with most outgrowing their allergy by age 3 years

A significant association between early neonatal exposure to cow’s milk formula feeding and subsequent development of CMPA/CMPI has been documented. The small amounts of ‘foreign’ protein in human milk may rather induce tolerance than allergic sensitization. The findings of specific IgE to individual cow’s milk proteins in cord blood of the majority of infants who later develop CMPA/CMPI suggests a prenatal sensitization may play a role in the pathogenesis of CMPA/CMPI. Perhaps a weak intrauterine education of low IgE-response may need to ‘boosted’ neonatally in order to cause clinical disease. The prognosis of CMPA/CMPI is good with a recovery of about 45-56% at one year, 60-77% at two years and 71-87% at three years. Associated adverse reactions to other foods, especially egg, soy, peanut and citrus develop in about 41-54%. Allergy to potential environmental inhalant allergens has been reported in up to 28% by three years and up to 80% before the age of puberty. Especially, infants with an early increased IgE response to cow’s milk protein have an increased risk of persisting CMPA, development of persistent adverse reactions to other foods and development of allergy against environmental inhalant allergens. Cow’s milk protein/intolerance (CMPA/CMPI), meaning reproducible adverse reactions to cow’s milk protein(s) may be due to the interaction between one or more milk proteins and one or more immune mechanisms, possible any of the four basic types of hypersensitivity reactions. Immunologically mediated reactions are defined as CMPA. Mostly, CMPA is caused by IgE-mediated (type I) reactions, but evidence for type III (immune complex) reactions and type IV (cell mediated reactions) have been demonstrated. Non immunologically reactions against cow’s milk protein(s) are defined as CMPI. However, it should be stressed that many studies on ‘cow’s milk allergy’ have not investigated the immunological basis of the clinical reactions. In most instances of cow’s milk protein hypersensitivity only diagnostic investigations such as skin prick test and RAST indicative of IgE-mediated reactions are performed. In fact, CMPA cannot be ruled out unless extensive diagnostic tests for type II-III-IV reactions have proved negative. Thus, the classification of adverse reactions to cow’s milk proteins depends on the extent and the quality of performed diagnostic tests for immune mediated reactions. At present, no single laboratory test is diagnostic of CMPA/CMPI, and differentiation between CMPA and CMPI cannot be based solely on clinical symptoms. Therefore the diagnosis has to be based on strict well-defined elimination and milk challenge procedure. Preferably, double-blind placebo-controlled challenges (DBPCFC) should be carried out in children older than 1-2 years of age. In infants open controlled challenges have been shown to be reliable when performed under professional observation in a hospital setting

Between 5% and 15% of infants show symptoms suggesting adverse reactions to cow’s milk protein (CMP),1 while estimates of the prevalence of cow’s milk protein allergy (CMPA) vary from 2% to 7.5%.2 Differences in diagnostic criteria and study design contribute to the wide range of prevalence estimates and underline the importance of an accurate diagnosis, which will reduce the number of infants on inappropriate elimination diets. CMPA is easily missed in primary care settings and needs to be considered as a cause of infant distress and diverse clinical symptoms. Accurate diagnosis and management will reassure parents. CMPA can develop in exclusively and partially breast-fed infants, and when CMP is introduced into the feeding regimen. Early diagnosis and adequate treatment decrease the risk of impaired growth

Cow’s milk protein (CMP) is usually one of the first complementary foods to be introduced into the infant’s diet and is commonly consumed throughout childhood as part of a balanced diet. CMP is capable of inducing a multitude of adverse reactions in children, which may involve organs like the skin, gastrointestinal (GI) tract or respiratory system. The diagnosis of CMP-induced adverse reactions requires an understanding of their classification and immunological basis as well as the strengths and limitations of diagnostic modalities. In addition to the well-recognised, immediate-onset IgE-mediated allergies, there is increasing evidence to support the role of CMP-induced allergy in a spectrum of delayed-onset disorders ranging from GI symptoms to chronic eczema. The mainstay of treatment is avoidance of CMP; this requires dietetic input to ensure that this does not lead to any nutritional compromise.

The natural history of CMA

CMA is primarily of pediatric onset, is generally outgrown, and is often the first stage of the “allergic march.” The take-home message about the latest developments regarding the natural history of CMA

Large, prospective population-based studies on clinical course, development of tolerance, and risk for other atopy in children with cow’s milk allergy (CMA) are lacking. IgE-mediated CMA often persists to school age and is a risk factor for other atopy; non-IgE-mediated CMA, by contrast, is a benign infantile condition.

Cow’s milk allergy (CMA) is a disease of infancy and usually appears in the first few months of life. The evaluation of infants for possible CMA is one of the more common problems shared by pediatricians. The role of foods in determining and/or aggravating the clinical features of atopic dermatitis (AD) has been stressed in the last decades.  natural history of CMA is not well-known, since not many related studies have been done in children. The several predictive factors, all in a negative sense, may be the norm in atopic children. We suggest possible areas of intervention in children at risk due to parental atopy. Preventive measures may induce a dramatic improvement in children with food allergy, but we stress that the long-term prognosis is challenging, since asthma prevalence may increase up to 54% during a long follow-up. Therefore, the natural history of IgE-mediated AD in atopic children sensitized to several allergens may be less optimistic than generally reported.

Of an initial cohort of 100 children with challenge-proven cow milk allergy, 97 were reviewed after 5 years to determine the effect of prolonged cow milk avoidance on clinical features, the reported frequency of adverse reactions to other foods, and the reported emergence of other atopic disorders. The mean age at diagnosis was 16 months, and at final follow-up 99 months. Cow milk tolerance by challenge was demonstrated in 28% of patients by 2 years of age, 56% by 4 years, and 78% by 6 years. Only 25% of children were allergic to cow milk alone; parents reported associated adverse reactions to many other foods, including egg (58%), soy milk (47%), and peanut (34%). Exclusion of cow milk from the diet of infants and young children with cow milk allergy did not prevent the subsequent development of atopic disorders. At final follow-up, 40% of patients reportedly had asthma, 21% atopic eczema, and 43% allergic rhinitis. It is unclear whether independent mechanisms control the development of cow milk allergy and other atopic conditions.

Natural history of CMA at a glance

Temporal pattern: In the 1990s, a Danish birth cohort study found that more than 50% of children outgrow their CMA at 1 year of age. Subsequent studies have reported a longer duration of CMA, with tolerance developing in 51% of patients within 2 years after diagnosis.
Tolerance: Referral studies indicate that 80% of patients achieve tolerance within 3 to 4 years. In several studies children with delayed reactions became tolerant faster than those with immediate reactions
Duration: In retrospective studies the duration of CMA differs in different settings.1 In a population of breast-fed infants with cow’s milk–induced allergic proctocolitis, tolerance developed between 6 and 23 months.
Onset: The onset of CMA is related to antigen exposure. A cow’s milk avoidance diet, once thought of as the only treatment for CMA, has recently been challenged by opposite theories on the basis of human and animal studies.
Risk factors: A family history of progression to atopic asthma, rhinitis, eczema, early respiratory symptoms with skin and/or gastrointestinal symptoms, or severe symptoms are considered risk factors for persistent CMA. A larger wheal diameter on SPTs with fresh milk significantly correlates with CMA persistence. A smaller eliciting dose on OFCs also correlates with longer duration of CMA. Severe symptoms reported at diagnosis are consistent with the worse prognosis for duration. Children with earlier or more severe AD have a higher prevalence of early-onset bronchospasm compared with those with AD or mild AD
Phenotypes: There might be different CMA phenotypes that, once identified, could lead to personalized treatment strategies for different populations of atopic patients.
Tolerance factors: Low milk-specific IgE levels correlate with earlier onset of tolerance, and a 99% reduction in sIgE concentrations over 12 months translates into a 94% likelihood of achieving tolerance to cow’s milk protein within that period. Tolerance of cow’s milk protein might correlate with reduced concentrations of IgE- and IgG-binding casein epitopes, and an involvement of tertiary or linear casein epitope structures has been hypothesized.However, the maintenance of tolerance in atopic patients is associated with persistently increased milk-specific IgG4 antibody concentrations. Tolerance of cow’s milk protein might correlate with a shift toward IgA and reduced concentrations of T-cell epitopes of casein in either IgE-mediated or non–IgE-mediated allergy. Tolerance maintenance is associated with persistently increased milk-specific IgG4 antibody concentrations.


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