Presentation and evolution
Cow's milk may induce at least two types of reaction:
- Symptoms that are usually labeled lactose intolerance due to decreased capacity of lactose hydrolysis and
- Allergy or true cow’s milk allergy (CMA) due to an immunologically mediated reaction to cow's milk proteins (CMP).
Lactose intolerance
Lactose intolerance is a common disorder or, more precisely, a trait that is found in all mammals except a limited number of Northern Europeans, Arabs and Nilo-Hamitic Africans. It is related to the physiologic decrease of lactase activity following weaning, usually from the fourth to fifth year of age in humans. This benign condition, manifested solely by digestive symptoms (diarrhea, bloating, abdominal pain), lasts a lifetime. Its symptoms are ameliorated by reducing the intake of lactose, by using lactose-hydrolyzing agents, and using fermented milk products that provide endogenous lactase. At the opposite end of the spectrum, CMA predominates in the young infant and may involve the gastro-intestinal tract, skin, respiratory tract, or multiple systems, in other words, systemic anaphylaxis. CMA sometimes represents the first manifestation of an allergic background that may appear in other forms when the child naturally outgrows this disorder, which is typical for most food allergies. Even though it can cause severe morbidity and rarely death, dietary elimination is associated with good prognosis.
CMA
An expert author (Host, 2002) reviewed and synthesized 229 articles on CMA for the years 1967 through 2001. This analysis infers an incidence during infancy of approximately 2 to 3 percent in developed countries. Since symptoms suggestive of CMA occur in 5 to 15 percent of infants, correct diagnosis is important. About 0.5 percent of breastfed infants may have reactions to human milk due to the presence of CMP residues in the mothers. Most CMA symptoms develop before one month of age, often within one week after introduction of CMP-based formula. Approximately 50 to 60 percent have cutaneous symptoms, 50 to 60 percent gastrointestinal symptoms, and 20 to 30 percent respiratory symptoms.
Three groups of infants with CMA have been identified (Hill DJ and Hosking CS, 1995) :
- IgE-sensitized children show features of immediate cutaneous eruptions and anaphylaxis,
- Non-IgE sensitized children who develop gastrointestinal symptoms within hours of ingesting moderate amounts of cow milk, and
- Infants with symptoms of gastrointestinal disturbance with or without bronchitic and/or eczematous.
The exact mechanisms of these disorders are poorly understood, despite the role of IgE in immediate reactions and the possible role of elevated T-cell reactivity to CMP in late reacting non-IgE sensitized patients.
Conditions previously not labeled as allergic are now increasingly attributed to CMA. Thus, CMA may be suggested in the presence of such immediate-type reactions as urticaria and angioedema. It also occurs in intermediate to such late-onset reactions as atopic dermatitis, infantile colic (Hill DJ et al, 1995), gastro-oesophageal reflux (Iacono G et al, 1996, Hill DJ et al, 2000), oesophagitis (Kelly KJ et al, 1995), infantile proctocolitis (Lake AM, 2000), food-associated enterocolitis and constipation (Iacono G et al, 1998). Their underrecognition may lead to inappropriate therapeutic handling and to confusion with primary disorders, resulting in potentially hazardous decisions (for example, unnecessary surgery for gastro-esophageal reflux).
Allergy to milk may be part of a more severe syndrome called multiple food allergy, as defined by Hill et al (Hill DJ et a, 1995). Recognition and understanding of multiple food allergy was greatly advanced by David Hill and colleagues in Australia (Hill DJ et al, 1995). This clinical situation is characterized typically by allergy to usually well-tolerated cow’s milk hydrolysates, which need to be replaced by an amino acid formula, along with allergy to a number of other foods from which the term “multiple food protein intolerance” or “allergy” originates. In a study published in 1995, eighteen infants (median age seven months) with suspected multiple food allergy were given an amino acid formula for two months followed by a seven-day, double-blind, placebo-controlled food challenge with the infant formula that they had best tolerated previously, either whey hydrolysate, casein hydrolysate or soy. Twelve of the infants experienced irritability, vomiting, diarrhoea and/or eczema during the challenge. When the infants were twelve months old, parents also reported adverse reactions with a median of six other low allergen foods (from a panel of ten foods).
The child usually outgrows CMA. The remission rate is close to 45-50 percent at one year, 60-75 percent at two years, and 85-90 percent at three years. However, the clinical pattern may indicate variations in the spontaneous course of the disease. Isolated gastrointestinal symptoms are more frequently associated with allergy limited to CMA and usually have a good prognosis (De Boissieu D et al, 2000, 2002). An early increased IgE-response to CMP is associated with an increased risk of persistent allergy to CMP, development of adverse reactions to other foods, and development of asthma and rhinoconjunctivitis later in childhood. Adverse reactions to other foods may develop in up to 50 percent and allergy against inhalants in 50 to 80 percent before puberty. In a certain proportion of subjects with CMA in infancy, gastro-intestinal intolerance seems to persist even after small-dose tolerance has been achieved, a state to which the authors refer as residual intestinal disease (Kokkonen J et al, 2001). Such a state may be manifested by intestinal symptoms and an increased prevalence of lactose intolerance, and may be caused by a disturbance of the surface epithelial cells.
Diagnosis tools
The diagnosis of CMA relies more or less on the usual tools of allergenic investigation, but all diagnoses have to be confirmed by food elimination/challenge trials.
Skin prick tests are the most common ones to be carried out during first line investigation. Their positive predictive accuracies, the correlation between positivity of the test and reality of food sensitization, vary between 69 and 100 percent and the negative predictive ones between 20 to 86 percent for cow's milk (Fiocchi A et al, 2002).
Measuring the concentrations of food-specific IgE antibodies may prove useful when identifying a subset of patients highly likely (greater than 95 percent risk) to experience clinical reactions to milk, which occurs at results equal to or greater than 32 kU/L (Sampson HA, Ho DG, 1997). This level of milk specific IgE was a useful test for diagnosing symptomatic allergy to milk in the pediatric population and could eliminate the need to perform double-blind, placebo-controlled food challenges in a significant number of children (Sampson HA, 2001).
Prick tests may be negative and specific IgE absent especially in children with delayed reactions, a clinical difficulty which may be overcome by using the atopy patch test (APT). In atopic dermatitis, Niggemann et al (2000) found an association between immediate-type reactions and positive skin prick test and specific IgE, whereas late-phase reactions were associated with a positive APT (sensitivity 76 percent, specificity 95 percent). In patients with atopic dermatitis, the APT might be the best single predictor for evaluating CMA (Roehr et al, 2001) and in combination with skin prick, significantly enhances the diagnosis accuracy of specific dietary allergies (Isolauri E, Turjanmaa K, 1996, Niggemann B et al, 2000, 2002 (Isolauri E and Turjanmaa K (1996).
The APT was more recently proposed in the diagnosis of children with digestive symptoms of CMA (Majamaa et al, 1995). In a recent study, D de Boissieu et al reported 79 percent positivity of patch testing in children with CMA and gastrointestinal symptoms, contrasting with 9 percent positivity in the control group in accordance with the dominant delayed-type of allergic reactions usually reported (de Boissieu D et al, 2003, Carroccio A et al, 2000). The combination of skin prick and patch testing was recently proposed to identify potential causative foods that contribute to the pathogenesis of eosinophilic esophagitis (Spergel JM et al, 2002).
Most of the time, however, food challenge tests are mandatory. The double-blind, placebo-controlled, food challenge, the definitive diagnostic test for cow's milk allergy still required for research purposes, is increasingly being replaced in clinical practice by the measurement of food-specific antibodies in combination with skin-prick or atopy patch testing (Heine RG et al, 2002). Medical practitioners responsible for the care of children with suspected CMA must be prepared to conduct challenges in a safe environment with available facilities for resuscitation. After initiating a cow’s milk restriction diet, the clinical manifestations triggered by the first challenge are difficult to predict. In contrast, if the first challenge fails, further ones may result in severe symptoms.
See Also: Cow's Milk Allergy, Part 2.
Bibliography
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This material has been prepared by members of the IFM’s Advisory Committee on Child Health and Nutrition.
December 2003
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