Pediatr Allergy Immunol 2007: 18: 265271 DOI: 10.1111/j.1399-3038.2006.00528.

2007 The Author Journal compilation 2007 Blackwell Munksgaard

PEDIATRIC ALLERGY AND IMMUNOLOGY

The spectrum of cows milk allergy

Eigenmann PA. The spectrum of cows milk allergy. Pediatr Allergy Immunol 2007: 18: 265271. 2007 The Author Journal compilation 2007 Blackwell Munksgaard Childhood cows milk allergy is a diagnosis encompassing various syndromes. Antigen-immunoglobulin E (IgE) antibody interaction is classically involved in mast cell degranulation in IgE-mediated food allergy, while non-IgE mediated cows milk allergy is mostly mediated by cellular mechanisms. The diagnosis of cows milk allergy largely relies on a good knowledge of the clinical expression of the disease. In this educational review series, we describe three cases of cows milk allergy, rst a 71 2-yr-old girl with persisting IgE-mediated cows milk allergy, second a 8-month-old boy with cows milk induced ares of atopic dermatitis, and third a 6-yr-old boy with sheep and goat milk allergy, in the absence of cows milk allergy. The cases are discussed and summarized with more general recommendations for the clinical management of cows milk allergy. Philippe A. Eigenmann
Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland

Key words: cow's milk allergy; food allergy; goat's milk allergy Philippe A. Eigenmann, University Children's Hospital of Geneva, 6 rue Willy-Donze, 1211 Geneva 14, Switzerland Tel.: +41 22 382 4531 Fax: +41 22 322 4779 E-mail: philippe.eigenmann@hcuge.ch Accepted 30 October 2006

Cows milk allergy has been regarded by pediatricians as prototypic food allergy for several centuries. Over the time, they have recognized various clinical pictures suggestive of this diagnosis. With the emergence of skin testing, and the recognition of the role of immunoglobulin E (IgE) antibodies in the pathogenesis of food allergy, the concept of IgE and non-IgE-mediated food allergy has appeared. However, much of the diagnosis and the follow-up of patients with food allergy rely on a good knowledge of the clinical pictures of cows milk allergy, in particular in nonIgE-mediated cows milk allergy. Various aspects of the spectrum of cows milk allergy will be reviewed by presenting and commenting three dierent cases of cows milk allergy in childhood.
Case 1

ingestion of cows milk was more than 2 yr ago. Her specic IgE to milk has remained constantly high over the years, the most recent value being 88 IU/ml. A food challenge was performed under close medical supervision, starting with a low dose of 0.02 ml of cows milk. No reaction was observed at this dose and neither with 0.5 ml and 1 ml. After 3 ml, she complained of slight oral pruritus. The food challenge was continued until the total amount of 42.57 ml had been consumed. By this point, she developed an urticarial rash on her face and thorax, signs of rhinitis and conjunctivitis as well as a slight wheeze, without lowering her oxygen saturations. The symptoms rapidly resolved after intramuscular injection of adrenaline and administration of oral antihistamines.
Discussion of the case

A girl is referred to the clinic for a follow-up challenge to cows milk. Her history revealed that milk allergy was suspected at 9 months of age, in the presence of severe atopic dermatitis. Since then, she was on a milk restriction diet but occasional accidental ingestions of small amounts have provoked immediate reactions with pruritus and acute wheezing. Furthermore, she has a history of allergy to sesame, sh, kiwi, nuts and peanuts, and of upper airway infection-induced wheezing. Her last accidental

71 2-yr-old

Food allergy aects approximately 58% of children and up to 3% of adults. A large number of foods have been described to cause IgEmediated food allergy, amongst them hens egg, peanut, and milk are the most common in western countries (13). As highlighted in this vignette, the most severe cases of food allergy present with anaphylactic symptoms. Anaphylaxis is dened as a severe, potentially fatal, systemic allergic reaction that occurs suddenly after contact with an allergy causing substance 265

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(4). The reaction classically involves several organs, appears rapidly after exposure to the triggering allergen and carries a high risk of severe, potentially life-threatening reactions (5). Successful treatment of anaphylaxis relies on early administration of adrenaline (6). Food allergy is the leading cause of anaphylaxis in children in most westernized countries. It is estimated that food allergy accounts for about 30,000 anaphylactic reactions and 200 deaths each year, in the USA (7). This clinical vignette highlights a patient with anaphylaxis to cows milk associated with multiple food allergies. Her history also reveals a marked atopic background with atopic dermatitis in infancy and pre-school years, as well as respiratory allergies. It has been demonstrated that patients with food allergies or sensitizations to common food allergens have an increased risk of developing manifestations of respiratory allergies later in life (8, 9). Because of her concomitant asthma, this patient is at increased risk of a severe anaphylactic reaction. It has been shown in several series with near fatal or fatal anaphylactic reactions to food that asthma, especially when not well controlled, is a major risk factor for a severe reaction (5, 10). It has also been observed in anaphylaxis to foods that respiratory symptoms and not cardio-vascular symptoms, dene the outcome of the reaction. This patient will continue to strictly avoid milk in her diet. The benet of this food challenge was to provide information about the threshold dose of reaction and the types of symptoms observed. The threshold dose may vary in a given patient, however, this patient, who had fear of death with trace amounts, received valuable information from this food challenge (11).
Case 2

extensively hydrolyzed formula was started with a marked improvement of the severity of the atopic dermatitis. The positive test and the good clinical response to the milk protein elimination diet suggested a non-IgE-mediated cows milk allergy associated to atopic dermatitis in this child. During the following month, his mother tried on several occasions to reintroduce the cows milk formula, each time with a are of atopic dermatitis on an otherwise clear skin. In addition, she reported after exposure to milk, a signicant lack of appetite lasting for up to 2 wk.
Discussion of the case

An 8-month-old boy, presented to the Pediatric Allergy clinic with a history of mild to moderate atopic dermatitis, diagnosed at 2 months of age. His mother reported that, after each ingestion of a cows milk based formula, she was observing a are of atopic dermatitis within 24 h. The diagnostic work-up included a skin prick test to cows milk with a negative result. The mother was encouraged to continue to feed her child with the cows milk formula. At the follow-up visit 3 wk later, she reported repeated ares of atopic dermatitis that she clearly linked to feeding with the cows milk formula. Additional investigations were performed by atopy patch testing with fresh cows milk. The test elicited an erythema with an induration at the rst observation after 48 h. An 266

Atopic dermatitis is observed in approximately 1015% of young children (12). It is primarily because of the dryness of skin and is linked to hereditary factors, however approximately onethird of patients with moderate to severe atopic dermatitis present with ares of eczema linked to a food allergy (2, 3, 13). Cows milk, hens egg, and peanuts are the foods most frequently involved. The diagnosis is made particularly dicult by the intrinsic propensity of the skin of patients with atopic dermatitis to are without any identiable trigger. While most patients with food allergies and atopic dermatitis have positive IgE tests such as skin prick test or specic IgE antibody in the blood, approximately 10% can present with a non-IgE-mediated form of a food allergy. In these patients, it has been shown that atopy patch tests (APT) represent a valuable diagnostic tool (14, 15). In either case, results of the testing have to be linked with the clinical history of the patient. In most cases similar to the one presented here, a double-blind, placebocontrolled food challenge is necessary to assess the diagnosis (16, 17). Indeed, it has been shown that the role of food allergy in atopic dermatitis is mostly overinterpreted, as up to 50% of food challenges in patients clinically suggestive for food allergy are negative (18). Furthermore, epidemiological studies suggest that it is mostly patients with moderate to severe atopic dermatitis suer from food-allergy induced ares. Up to one-third of these children have a positive food challenge (2, 3, 13, 19, 20). Food challenges need to be performed as a blinded procedure to avoid misinterpretations of ares during the challenge. Extensive research has established the double-blind, placebo-controlled food challenge as a gold standard for the diagnosis of food allergy in these patients (17, 21, 22). This procedure was suggested in our patient but refused by the parents, because of the severe decrease in appetite provoked after each expo-

The spectrum of cows milk allergy

sure to cows milk. Follow-up testing in our patient showed a negative patch test at age 2, with a good tolerance to cows milk in a patient with a normal skin at that time.
Case 3

tolerance as seen in young children with cows milk allergy was also suggested in our patient by continuous reactions to small amounts of sheep and goats milk.
Diagnosis of cow's milk allergy

A 6-yr-old boy, presented with a recent history of oral pruritus, angioedema of the lips, and abdominal pain after ingestion of various cheeses. He had atopic dermatitis in his preschool years and he was also suering from asthma, rhinitis, and conjunctivitis during the grass pollen season. However, cows milk and cows milk containing foods had always been and were also currently well tolerated. A food diary disclosed that the reactions only occurred when he was eating goat and sheep milk-made cheeses. Skin prick tests were positive to goat and sheep milk-made cheeses, but negative to cows milkmade cheeses, as well as to cows milk. Specic IgE measurement in the serum for cows milk, alpha-lactalbumin, beta-lactoglobulin, and casein from cows milk were negative. The patient was instructed to avoid all goat and sheep milkbased products. During the eight following years, he had occasional accidental ingestions after ingesting goat and sheep milk products, resulting each time in an allergic reaction. Cows milk and cows milk-based products continued to be ingested without any symptoms.
Discussion of the case

Beta-lactoglobulin, casein, and alpha-lactalbumin are the major allergens of milk (23). There is a strong structural homology between milk proteins from dierent mammals. It has been observed by several investigators that there is a clinical cross-reactivity to most mammal milks in up to 90% of the patients (2426). However, patients with cows milk allergy tend to tolerate mare and camels milk (27). It is unusual for a patient to present with an allergy to the milk of a mammal other than cow, without also being cows milk allergic. However, several cases have been reported (2830). Furthermore, it is uncommon to diagnose milk allergy in school children and adults, as an overwhelming majority of milk allergy presents within the rst year of life (31). Cows milk allergy diagnosed in infancy is a selflimiting disease outgrown in most cases after 23 yr, while later onset milk allergy tends to be long lasting (32). Follow-up of our patient showed a persistent clinical sensitivity to goat and sheep milk products during a follow-up period of 8 yr. Absence of naturally occurring

Prospective series of cows milk allergy in infants have shown that they may present as an IgEmediated type or a non-IgE-mediated type allergy (31, 33). Therefore, the diagnosis relies both on IgE tests such as skin prick test or measurement of serum specic IgE antibody levels to cows milk, and standardized food challenges (Fig. 1). In the absence of positive tests in non-IgE mediated cows milk allergy, the initial diagnosis mostly relies on a suggestive history. Milkinduced enterocolitis is characterized by initial symptoms occurring during the rst months of life as repeated vomiting episodes sometimes leading to dehydration (3436). A characteristic feature of this syndrome is a symptom free interval of up to several hours between ingestion of milk, most often a cows milk protein-based formula, and the rst symptoms. Symptoms might be very severe and mimic sepsis. Milkinduced proctocolitis is mostly observed in young infants while exclusively breast-fed (37, 38). The oending allergens are in small amounts in breast milk from mothers on a milk protein containing diet. These patients present with episodes of isolated bloody stools in otherwise healthy infants. Recovery is observed after initiation of a cows milk free diet in the nursing mother after a 45 days washout period. Not infrequently, infants might present with non-specic gastrointestinal symptoms such as chronic diarrhea or vomiting, or failure-to-thrive attributed to cows milk (33, 39). In these patients, the diagnosis mostly relies on a successful milk avoidance diet with clinical relapses after re-exposure to cows milk proteins. Finally, patients with non-IgEmediated cows milk allergy can present with chronic relapsing reux, and abdominal pain associated with an eosinophilic inltration in the lower esophagus. This condition, allergic eosinophilic esophagitis is mostly diagnosed by esophagogastroscopy and biopsies (4042). In patients with atopic dermatitis in whom a non-IgE-mediated cows milk allergy is suspected, APT can be a helpful diagnostic tool. In all cases, in particular non-IgE-mediated cows milk allergy, the diagnosis must correlate with a clear clinical history. Food challenges remain the gold standard of the diagnosis of cows milk allergy. In patients with active atopic dermatitis, or 267

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Symptoms suggestive of IgE - mediated cows milk allergy

Positive SPT or spIgE

Negative SPT or sp IgE

spIgE values or SPT size suggestive of cows milk allergy

Low clinical suspicion in absence atopic dermatitis Consider no n- IgE mediated cows milk allergy

Patient with atopic dermatitis

Avoidance diet

Unconclusive results

Normal diet

Consider APT and food challenge

Follow-up of cows milk allergy

Standardised food challenge

Relapsing symptoms

Negative food challenge

Positive food challenge

Consider cows milk intolerance

Normal diet

Avoidance diet

Follow-up of cows milk allergy

Symptoms suggestive of non - IgE - mediated cows milk allergy

Successful diagnostic avoidance diet

Unsuccessful test avoidance diet

Follow-up of cows milk allergy

Standardised food challenge

Positive food challenge

Negative food challenge

Avoidance diet

Normal diet

Follow-up of cows milk allergy

Fig. 1. Diagnostic ow-charts.

doubtful symptoms, a double-blind placebocontrolled food challenge must be performed. In other patients, especially in follow-up challenges for cows milk allergy, open food challenge can be performed as a rst line. However, challenges with equivocal results have to be conrmed with double-blind placebo-controlled food challenge (17). Interpretation of skin prick test and specic IgE tests are mostly hampered by patients sensitized to cows milk in the absence of clinical symptoms. Various studies have provided cut-o values either for skin prick tests or for specic IgE values. Initially, Sampson (43) reported a specic IgE value in the serum of 15 kU/l to be 95% predictive of cows milk allergy in a population of predominantly children with atopic dermatitis. More recently, a large study including over 500 children mostly with atopic dermatitis found for the same predictive value a cut-o of 88.8 kU/l (44). With regard to skin prick tests, a major limitation of a wide usage of cut-o values from the literature is the type of 268

extract used, which may vary in-between investigators (45, 46). It is most obvious that these values rely on a given population i.e., on the age of the patients as well as of the type of symptoms, and that they should be interpreted accordingly.
Treatment of cow's milk allergy

Patients with cows milk allergy must strictly avoid cows milk and cows milk protein-based products. Products containing milk from other mammals should be avoided. Patients and their families must be instructed to read labels and identify milk-containing products. Particularly in young children, a well-balanced diet with sucient intake of calcium and other essential nutriments must be warranted. The input of a pediatric dietician is most helpful in these patients. Several uncontrolled studies have shown some benet for oral desensitization procedures to cows milk (47, 48). While the concept could provide promising options for treatment of cows

The spectrum of cows milk allergy

milk allergy, it needs to be validated by wellcontrolled studies. Unfortunately, no proactive treatment of cows milk allergy exists to-date (49). Infants can be supplemented with extensively hydrolyzed formulas with a proven hypoallergenicity, although a few cases of reactions to these preparations have been described. Soy formula is also a suitable alternative in these patients, in particular those over 6 months of age.
Natural history of cow's milk allergy

A. They have more frequent reactions to foods. B. The use of beta-adrenergic medications diminishes the potency of adrenaline given during an anaphylactic reaction by blocking adrenergic receptors. C. They have more severe reactions to foods, i.e., more severe respiratory reactions. D. Asthma is not a risk factor in food allergic patients. Question 3. Food allergy should be suspected in infants with atopic dermatitis: A. In all patients, including those with mild lesions. B. Also in patients with negative skin prick tests or food-specic IgE antibodies in the serum. C. On the basis of positive skin prick tests alone. A food challenge is almost never necessary to implement the diagnosis. D. Mostly when peri-oral reactions to tomato are reported. This is a very frequent manifestation of food allergy in atopic dermatitis. Question 4. The following symptoms are not suggestive of a non-IgE mediated cows milk allergy: A. Repeated episodes of vomiting 3 h after ingestion of a cows milk protein-based formula in a 3-month-old infant. B. Chronic, treatment-resistant reux in an 8-yr-old child. C. Visible traces of blood on the stools of an healthy looking breast-fed infant. D. Repeated episodes of otitis media in a 15-month-old toddler. Correct responses to MCQ: 1:B, 2:C, 3:B, 4:D.
References

It has been demonstrated that cows milk allergy presenting in infancy has a good prognosis for natural outgrowing within 23 yr of follow-up (8). Therefore, these patients must be regularly re-evaluated. Measurement of specic IgE can provide some help. Shek et al. (50) have demonstrated that a diminution of 90% of specic IgE values to cows milk over 12 months predict a 66% probability of having outgrown the allergy. However, follow-up assessment of cows milk allergy remains mostly based on medically supervised cows milk challenge.
Conclusion

Cows milk allergy is one of the most frequent manifestations of food allergy and may present as an IgE or non-IgE-mediated disease. These patients are at risk of potentially severe allergic reactions and they need to follow a strict elimination diet. The diagnosis of cows milk allergy mostly relies on skin prick testing and in vitro measurement of specic IgE. APT can be helpful in selected patients, however, the diagnosis must always rely on a clear correlation with clinical symptoms often revealed by standardized food challenges.
MCQ

Question 1. Which of the following is not true regarding anaphylaxis in children? A. Food allergy is the leading cause of anaphylaxis in children. B. Anaphylaxis is a severe, systemic allergic reaction that occurs gradually after contact with an allergy causing substance. C. Injectable adrenaline is the most ecient treatment of anaphylaxis. D. The estimated rate of death because of food-induced anaphylaxis in the USA is 0.5 per million inhabitants per year. Question 2. Why is concomitant asthma a risk factor in food allergic patients?

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