Specific oral desensitization in children with IgE-mediated cow's milk allergy. Evolution in one year

Cow's milk allergy is the most frequent childhood food allergy. Children older than 5 who have not become tolerant have less probabilities of natural tolerance. Specific oral desensitization methods are being investigated in reference centres. The aims of our study were to assess the efficacy of our guideline of specific oral desensitization to cow's milk in children and to know its suitability for anaphylactic children. Both clinical and specific IgE outcomes were evaluated. Eighty-seven children aged 5 to 16?years with a history of cow's milk allergy were included. Prior to desensitization, skin prick test, specific IgE to cow's milk proteins and a double-blind placebo control food challenge were performed in all. Of the 87 patients, 21 had a negative challenge; they were considered tolerant, and they were told to follow a free diet. Of the positive, 44 were anaphylactic and 22 non-anaphylactic. All of them were included. In non-anaphylactic patients, 6 achieved partial and 16 maximum desensitization after 23.1?weeks. In the anaphylactic group, 7 achieved partial and 35 maximum desensitization after 26.4?weeks. Cow's milk-specific IgE levels and casein-specific IgE levels were significantly lower in the tolerant patients at baseline. One year after desensitization, the medium specific cow's milk levels and casein IgE levels had dropped significantly. Conclusions: Our guideline for specific oral desensitization to cow's milk is efficacious even in patients with anaphylactic reactions to cow's milk and represents a significant life change. Immunological changes in 1?year show a drop in cow's milk protein-specific IgE.     

THE SPECTRUM OF COW'S MILK ALLERGY IN CHILDHOOD Clinical, Gastroenterological and Immunological Studies

Abstract. Seventeen of 52 children suspected of having cow's milk allergy had this diagnosis confirmed after milk challenge in hospital. A broad spectrum of reactions was observed including skin eruptions, respiratory symptoms and gastrointestinal disturbance. Not all patients with gastrointestinal symptoms showed small bowel mucosal damage. Only patients with skin reactions had positive skin tests. IgA deficiency and IgE elevation were common. Four patients had symptoms within 3 days of birth. Twelve children tolerated cow's milk by three years of age. Cow's milk allergy can cause a variety of symptoms. Challenge with milk for several days may be required before allergic manifestations can be demonstrated.     

Allergenicity of milk protein hydrolysate formulae in children with cow's milk allergy

Cow's milk protein hydrolysate formulae have been developed to lower or eliminate the allergenicity of cow's milk proteins, and to reduce the antigenic load and the risk of sensitization. Cross-reactivity between different hydrolysate formulae and cow's milk proteins has been demonstrated. We have studied 20 children (median age 31 months, range 15–76 months) with a history of IgE-mediated cow's milk allergy. All the children had immediate allergic respiratory and/or cutaneous and/or gastro-intestinal reactions to cow's milk ingestion. In addition, the children had positive prick skin tests and positive RAST to cow's milk. Prick skin test, RAST, and double-blind placebo controlled food challenges were performed with three different hydrolysate formulae: a casein hydrolysate formula and two whey formulae, one partially and one extensively hydrolyzed. All 20 children had immediate allergic reactions after the challenge test with cow's milk. Only 2/20 children had a positive challenge test with a casein hydrolysate formula (Alimentum): one developed asthma and one urticaria. Two of the 15 children challenged with an extensively hydrolysed whey formula (Profylac) developed perioral erythema. Nine out of 20 children had a positive challenge test with a partially hydrolysed whey formula (Nidina H.A.): four developed asthma, three urticaria and two lip oedema. All children had positive prick skin tests to cow's milk proteins (casein and/or lactalbumin); 9 to Nidina H.A.; 3 to Profylac, and 3 to Alimentum. Specific IgE antibodies to cow's milk were present in all children; in 13 to Nidina H.A., in 4 to Profylac, and in 3 to Alimentum.     

Cow's milk protein allergy through human milk

Cow's milk protein allergy (CMPA) is the first allergy that affects infants. In this population, the incidence rate reaches 7.5%. The multiplicity and aspecificity of the symptoms makes its diagnosis sometimes complicated, especially in the delayed type (gastrointestinal, dermatological, and cutaneous). CMPA symptoms can develop in exclusively breastfed infants with an incidence rate of 0.5%. It, therefore, raises questions about sensitization to cow's milk proteins through breast milk. Transfer of native bovine proteins such as β-lactoglobulin into the breast milk is controversial: some authors have found bovine proteins in human milk but others point to cross-reactivity between human milk proteins and cow's milk proteins. However, it seems that a small percentage of dietary proteins can resist digestion and become potentially allergenic. Moreover, some authors suspect the transfer of some of these dietary proteins from the maternal bloodstream to breast milk, but the mechanisms governing sensitization are still being studied. Theoretically, CMPA diagnosis is based on clinical observations, prick-test or patch-test results, and cow's milk-specific IgE antibody concentration. A positive food challenge test usually confirms the diagnosis. No laboratory test is available to make a certain diagnosis, but the detection of eosinophil cationic protein (ECP) in the mother's milk, for example, seems to be advantageous since it is linked to CMA. Excluding cow's milk from the mother's diet is the only cure when she still wants to breastfeed. Usually, cow's milk proteins are reintroduced after 6 months of exclusion. Indeed, the prognosis for infants is very good: 80% acquire a tolerance before the age of 3 or 4 years. Mothers should not avoid dairy products during pregnancy and breastfeeding as preventive measures against allergy.     

Helicobacter pylori and specific immunoglobulin E antibodies to food allergens in children

OBJECTIVES: It has been suggested that chronic Helicobacter pylori infection may increase gastric permeability, predisposing infected children for the development of food allergies. We assessed the presence of food-specific immunoglobulin (Ig)E antibodies in H. pylori positive children and controls. METHODS: We measured specific IgE values to six major food allergens (Pharmacia CAP-system) in a group of school-aged Caucasian (n = 36) and non-Caucasian (n = 38) children with a known H. pylori status. All children had undergone upper gastrointestinal endoscopy because of abdominal complaints. RESULTS: Among H. pylori positive children (mean age, 8.8 years; range, 5-15 years, 25 female, 26 male), 33% (17 of 51) had an elevated food-specific IgE level to at least one of the food allergens tested. Unexpectedly, the majority of those with elevated serum food-specific IgE levels (12 of 17) were to cow's milk. Among H. pylori negative children (mean age, 9.3 years; range, 5-15 years, 13 female, 10 male), 26% (6 of 23) of the children had an elevated serum IgE level to at least one of the food allergens tested, and 9% (2 of 23) were positive to cow's milk. The difference in the number of children with an elevated serum IgE level for cow's milk in H. pylori positive and negative children was not significant. The severity of gastritis did not correlate with the presence of food-specific IgEs. CONCLUSIONS: H. pylori infection had no effect on the manifestation of specific IgE to major food allergens in school-aged children. An IgE response to cow's milk was common among these school-aged children.     

Prevention and management of food allergy

The phenotypic expression and natural history of food allergy vary widely according to the patient's age, disease presentation and type of offending food. Prevention of food allergy might be achieved by altering the dietary factors responsible for the sensitization and phenotypic expression of the disease. Owing to the peculiarity of the atopic status, a minute amount of allergens can trigger both sensitization and symptoms in atopic individuals. The oral dose of β-lactoglobulin causing sensitization can be estimated to be between 1 ng and several milligrams. In food allergy, sensitization and treatment are allergen specific; therefore, for primary prevention (avoiding sensitization) and secondary prevention of food allergy (avoiding symptoms in an already sensitized subject), a product without immunogenic and allergenic epitopes should be given in each case. Babies of atopic parents are particularly prone to develop food allergy and for this reason they are called high-risk babies. Cow's milk is the most commonly offending food in both gastrointestinal and cutaneous manifestations. Cow's milk proteins are potent allergens and around 2.5% of infants experience cow's milk allergy in the first years of life. The major risk factors for cow's milk allergy are positive family history of atopy and early exposure to cow's milk proteins. Hydrolysate formulae have been developed for the purpose of reducing the allergenicity of cow's milk proteins. More recently, partially and extensively hydrolysed formulae have also been used for feeding babies with a high risk of atopy for the prevention of cow's milk allergy. However, according to the results of a recent randomized controlled study, only an extensively hydrolysated formula, and not a partially hydrolysated formula, significantly decreased the prevalence of cow's milk allergy.     

Prevention and management of food allergy

The phenotypic expression and natural history of food allergy vary widely according to the patient's age, disease presentation and type of offending food. Prevention of food allergy might be achieved by altering the dietary factors responsible for the sensitization and phenotypic expression of the disease. Owing to the peculiarity of the atopic status, a minute amount of allergens can trigger both sensitization and symptoms in atopic individuals. The oral dose of beta-lactoglobulin causing sensitization can be estimated to be between 1 ng and several milligrams. In food allergy, sensitization and treatment are allergen specific; therefore, for primary prevention (avoiding sensitization) and secondary prevention of food allergy (avoiding symptoms in an already sensitized subject), a product without immunogenic and allergenic epitopes should be given in each case. Babies of atopic parents are particularly prone to develop food allergy and for this reason they are called high-risk babies. Cow's milk is the most commonly offending food in both gastrointestinal and cutaneous manifestations. Cow's milk proteins are potent allergens and around 2.5% of infants experience cow's milk allergy in the first years of life. The major risk factors for cow's milk allergy are positive family history of atopy and early exposure to cow's milk proteins. Hydrolysate formulae have been developed for the purpose of reducing the allergenicity of cow's milk proteins. More recently, partially and extensively hydrolysed formulae have also been used for feeding babies with a high risk of atopy for the prevention of cow's milk allergy. However, according to the results of a recent randomized controlled study, only an extensively hydrolysated formula, and not a partially hydrolysated formula, significantly decreased the prevalence of cow's milk allergy.     

Cow's milk protein intolerance and chronic constipation in children

Cow's milk protein (CMP) allergy was investigated in 25 children (age-range 3 months to 11 years) with chronic constipation. A diagnosis of constipation was made on the basis of a history of painful elimination of hard stools for at least 1 month, whether or not associated with a reduced frequency of stools or soiling. The children were evaluated using clinical parameters and the following laboratory tests: total serum immunoglobulin E (IgE); specific IgE (radioallergosorbent test [RAST]) for whole cow's milk, α-lactoalbumin, β-lactoglobulin, and a food group; and skin-prick tests with whole milk, α-lactoalbumin, β-lactoglobulin, and casein. Following the evaluation, the children were submitted to a CMP-free diet for a period of 4 weeks. In seven patients (28%), constipation disappeared during the CMP-free diet and reappeared within 48–72 h following challenge with cow's milk. In two infants a rectal biopsy revealed allergic colitis and they therefore did not undergo the challenge. High serum levels of total IgE were observed in five of the children who showed a clinical improvement (71%), a positive skin-test in two (29%), and detectable specific IgE in two (29%). These results suggest that CMP allergy or intolerance should be considered as a cause of chronic refractory constipation in children, although the underlying mechanism still require further investigation.     

Identification of immunogenic maize proteins in a casein hydrolysate formula

Cow's milk‐based formulas used for infants with cow's milk allergy are based on hydrolyzed proteins. The formulas that are successful in preventing allergic responses are extensively hydrolyzed. Nevertheless, reactions to such formulas are occasionally reported, and protein material of higher molecular weight than expected has been detected by binding immunoglobulin E (IgE) from patients' sera. This paper presents the identification of high‐molecular‐weight material in the extensively hydrolyzed casein formula, Nutramigen. The material was concentrated by simple centrifugation. The proteins in the pellet were separated by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE), and protein‐containing bands were analyzed by protein sequencing after electroblotting. The proteins were identified as maize zeins, which are water‐insoluble proteins of apparent M_r 20 000 and 23 000, presumably originating from the maize starch in Nutramigen. Rabbits immunized with this formula developed antibodies against zeins but not against milk proteins. The maize zeins are probably identical to the recently reported components in Nutramigen ( 1 ), detected by binding of IgE from milk allergic patients, but not correlated to clinical allergic reactivity. The clinical relevance of maize proteins in Nutramigen remains to be established.     

Anaphylaxis to sheep's milk cheese in a child unaffected by cow's milk protein allergy

A 5-year-old atopic boy unaffected by cow's milk protein allergy experienced several anaphylactic reactions after eating food containing “pecorino” cheese made from sheep's milk. Prick-prick tests were strongly positive to sheep's buttermilk curd and `pecorino' sheep's cheese. Skin prick tests to fresh sheep's milk and to goat's milk were also positive, whereas they were negative to all cow's milk proteins, to whole pasteurized cow's milk and to cheese made from cow's milk. Specific IgE antibodies were negative to all cow's milk proteins. Conclusion Sheep's milk and cheese derived from sheep's milk may cause severe allergic reactions in children affected and, as we report, in children not affected by cow's milk protein allergy. Received: 14 January 1997 and in revised form: 20 June 1997 / Accepted: 8 July 1997     

Severe cow's milk induced colitis in an exclusively breast-fed neonate. Case report and clinical review of cow's milk allergy

Cow's milk induced eosinophilic colitis presenting in the first week of life has been reported, but is very rare. The authors describe a 4-day-old female infant who presented with profuse rectal bleeding resulting in a hematocrit fall from 38% to 30% within 8 hr after hospital admission. Sigmoidoscopy revealed colonic mucosa that was red, edematous, and friable, with punctate hemorrhages. Rectal biopsy showed marked eosinophilic infiltration with multifocal hemorrhage. Further history indicated that while the infant had been exclusively breast-fed since birth, the nursing mother had been drinking 4-5 glasses of cow's milk per day since delivery. Prick puncture skin testing of the infant was positive for cow's milk protein. A serum radioallergosorbent test (RAST) for cow's milk protein was positive. The infant's serum IgE was 1.5 IU/ml. Rectal bleeding resolved when the patient was given a casein hydrolysate formula (Nutramigen, Mead Johnson Nutrition, Evansville, IN), and endoscopy one week later showed improvement, with only scattered areas of erythema, and no friability. We conclude that since the infant was exclusively breast-fed, the milk protein must have passed into the breast milk antigenically intact. Prenatal sensitization probably occurred. Cow's milk induced allergic colitis should be considered in the differential diagnosis of colitis in breast-fed neonates.     

Frequent IgE sensitization to latex, cow's milk, and egg in children with short bowel syndrome

Children with short bowel syndrome (SBS) undergo frequent operations, so they are at risk for sensitizing to latex. There have been isolated reports of sensitization to food in these children. In a cross-sectional study, we assessed sensitization to latex, cow's milk, and egg with skin prick tests (SPT) and serum-specific immunoglobulin E (IgE) in 14 children with SBS. Data were collected about the number of operations with latex devices, serum total IgE, and history of feeding with milk formula. Ten children were sensitized to latex (specific IgE median: 6.7 kU/l, range: 0.5–33). Compared with those non-sensitized, sensitized children had significantly (p < 0.05) higher levels of serum total IgE in z-units (mean rank 3.25 vs. 9.2, respectively), and more operations with latex devices (mean rank 3.75 vs. 9). Eight children were sensitized to cow's milk, one with only positive SPT, the other seven with serum-specific IgE (median: 3.5, range: 0.5–21.1 kU/l), and five to egg (specific IgE median: 0.68, range: 0.58–2.17 kU/l). Except for some isolated days with cow's milk formula, the children had been initially fed with a diet without intact cow's milk proteins. Sensitization to latex, cow's milk, and egg is very frequent in children with SBS. They should be treated in a latex-free environment since the very early stages of the disease, and should be routinely studied regarding food sensitization, as this might contribute as an added factor in the chronic diarrhea of these patients.     

Milk and soy allergy

Cow's milk allergy (CMA) affects 2% to 3% of young children and presents with a wide range of IgE and non-IgE-mediated clinical syndromes, which have a significant economic and lifestyle effect. It is logical that a review of CMA would be linked to a review of soy allergy because soy formula is often an alternative source of nutrition for infants who do not tolerate cow's milk. This review examines the epidemiology, pathogenesis, clinical features, natural history, and diagnosis of cow's milk and soy allergy. Cross-reactivity and management of milk allergy are also discussed.     

Formula feeding during cow's milk allergy

Cow's milk allergy (CMA) is an immunologically mediated reaction to cow's milk proteins, which affects infant and young children. Cow milk elimination requires either breast-feeding, with or without elimination diet in mother or the use of specific formulas, based on cow's milk protein extensively hydrolyzed, which fit 90-95% of children with cow's milk allergy. In others, still reactive to allergic remnants in hydrolysates, an amino acid based formula is the optimal option. The good tolerance of soy formulas in a reasonable proportion of children with cow's milk allergy make them useful, including as a 1(st)-choice alternative, except probably for those below the age of 6 months. Any elimination diet in children is at risk of nutritional deficiency so that a constant monitoring of the growth parameters should be kept in those children.     

Prospective, controlled, multi-center study on the effect of an amino-acid-based formula in infants with cow's milk allergy/intolerance and atopic dermatitis

Cow's milk allergy/intolerance is treated by complete avoidance of cow's milk proteins. Because cow's milk is an important food for infants, its avoidance may lead to an increased risk of growth impairment. Whilst there is evidence for the beneficial effects of extensively hydrolyzed cow's milk formulae (eHF) in infants with cow's milk allergy/intolerance, little is known about the effects of amino-acid-based formulae (AA) in such infants. We therefore performed a prospective, controlled, multi-center trial to study the efficacy of AA in comparison with eHF, on the growth and clinical symptoms of 73 infants (median age 5.7 months) with cow's milk allergy/intolerance and atopic dermatitis. Cow's milk allergy/intolerance was proven in all infants by double-blind, placebo-controlled food-challenge. We observed a significant improvement in the SCORAD index in both groups, from a mean of 24.6, at entry, to a mean of 10.7 (p < 0.0001) after 6 months. In the AA group there was a significant increase in the length standard deviation score (p < 0.04), whilst there was no difference in the eHF group. The weight-for-length values were stable in both groups. The energy intake during the study was similar in both groups. Both an AA and eHF resulted in a significant clinical improvement in infants with an early onset of symptoms of cow's milk allergy/intolerance. Feeding an AA resulted in improved growth compared with feeding eHF, despite similar dietary intakes, and may therefore be considered as a beneficial alternative in infants with severe cow's milk allergy intolerance.     

Time course of allergy to extensively hydrolyzed cow's milk proteins in infants

We report on the follow-up of 22 infants allergic to cow's milk proteins who did not tolerate extensively hydrolyzed protein formulas. After successful use of an amino acid-based diet for a duration of 11.8 +/- 8.7 months, evolution differed according to the presence or absence of associated allergy to other foods. Cow's milk protein tolerance occurred earlier in the patients (n = 9) whose allergy was limited to cow's milk proteins and to extensively hydrolyzed protein formulas.     

Sensitization to serum albumins in children allergic to cow''s milk and epithelia

Patients with persistent milk allergy and specific immunoglobulin E (IgE) to bovine serum albumin (BSA) have a greater risk of rhinoconjunctivitis and asthma because of animal dander. To prove the cross-reactivity between serum albumin (SA) of different mammals in milk, meat, and epithelia and determine if heat treatment of meats decrease the allergenicity of albumins. The study was performed using SDS-PAGE and IgE-immunoblotting using sera from eight patients sensitized to milk, BSA, and animal danders. Sera from non-allergic and only animal dander allergic subjects served as a control. With one exception, all patients' sera recognized SA in different meats (beef, lamb, deer, and pork), epithelia (dog, cat, and cow), and cow's milk. Some patients even were only sensitized to SA in meat and epithelia. Danders' allergic only recognized other proteins in epithelia but not SA. No patients reacted to SA from heated meat extracts. Serum albumin is an important allergen involved in milk, meat, and epithelia allergy. The first contact with SA was through cow's milk and patients developed sensitization to epithelia SA even without direct contact with animals. Patients with both BSA and cow's milk allergy must avoid raw meats and furry pets.     

In vivo and in vitro studies on the residual allergenicity of partially hydrolysed infant formulae

AIM: Because allergen-reduced formulae are widely used in the prevention and treatment of cow's milk allergy in children and because anaphylactic reactions have been reported for some hydrolysed formulae, it is of clinical relevance to know about the residual allergenicity of so-called hypoallergenic formulae. METHOD: We therefore studied the reactions of 20 children (mean age 1.6 years) with proven cow's milk allergy to a variety of formulae, using skin prick test, specific IgE in serum, protein content and RAST inhibition. RESULTS: Whereas all but two children with a clinically relevant cow's milk allergy had a positive skin prick test to cow's milk, some children still showed positive responses to the partially hydrolysed formulae. No child had a positive skin test to the amino acid formula. Specific IgE to the partially hydrolysed whey formula (median 0.28 U/ml) was significantly lower (p < 0.003) than to cow's milk. Specific IgE to the partially hydrolysed whey/casein formula, soy/pork collagen hydrolysate and the amino acid formula was in a low range (median values 0.19, 0.23 and 0.21 U/ml, respectively). While determination of the protein content of the formulae gave no valid information, RAST/EAST inhibition was highest for cow's milk, followed by the partially hydrolysed whey formula, partially hydrolysed whey/casein formula, soy/pork collagen formula, and the amino acid formula. CONCLUSION: Skin prick test and RAST inhibition test are suitable methods for determining the residual allergenicity of hydrolysed infant formulae, while determination of protein content using the applied modified Lowry method is not helpful.     

Is cow's milk harmful to a child's health?

Discussions and debates have recently emerged on the potential positive and negative effects of cow's milk in the paediatric community, also under the pressure of public opinion. The negative effects of cow's-milk consumption seem to be limited to iron status up to 9 to 12 months; then no negative effects are observed, provided that cow's milk, up to a maximum daily intake of 500?mL, is adequately complemented with iron-enriched foods. Lactose intolerance can be easily managed and up to 250?mL/day of milk can be consumed. Allergy to cow's-milk proteins is usually transient. Atopic children may independently be at risk for poor growth, and the contribution of dairy nutrients to their diet should be considered. The connection of cow's milk to autistic spectrum disorders is lacking, and even a cause-effect relation with type 1 diabetes mellitus has not been established because many factors may concur. Although it is true that cow's milk stimulates insulin-like growth factor-1 and may affect linear growth, association with chronic degenerative, noncommunicable diseases has not been established. Finally, fat-reduced milk, if needed, should be considered after 24 to 36 months. Cow's milk represents a major source of high nutritional quality protein as well as of calcium. Moreover, it has growth-promoting effects independent of specific compounds. Its protein and fat composition, together with the micronutrient content, is suggestive of a functional food, whose positive effects are emphasised by regular consumption, particularly under conditions of diets poor in some limiting nutrients, although in industrialised countries cow's milk's optimal daily intake should be around 500?mL, adequately complemented with other relevant nutrients.