Milk Allergy In Infants Research Articles

Hypoallergenic formulas: are they really hypoallergenic?

Central to the management of cow's milk allergy in infancy is the complete elimination of cow's milk protein from the infant's diet for a variable period of time. The principal part of this approach is to provide nutrition for the child by means of hypoallergenic feeding formulas. Although a number of formulas are indeed marketed as hypoallergenic, it is not known with certainty how hypoallergenic they really are. A variety of ways of testing for hypoallergenicity have been developed, including the use of in vivo and in vitro animal model systems, chemical analyses, and patient studies, which are the ultimate test. The purpose of the present report was to review the various ways of testing sensitizing capacity of infant feeding formulas for the treatment of children with cow's milk allergy. English language articles were selected from PubMed, as were selected abstracts that would have immediate, practical clinical implications. The review focuses on themes related to animal models, chemical analysis, and clinical testing and clinical studies of intolerance to hydrolysates. Sensitizing capacity can be tested first in animal models either by in vivo or in vitro techniques. Although the information gained is valuable for preliminary evaluation, such techniques are intrinsically artificial. Second chemical analyses indicate that absence of larger peptides greater than 1,500 Da provides a critical industrial cutoff point. Third clinical effectiveness in child patients is of paramount importance. The results of the present review demonstrate that extensively hydrolyzed formulas are usually effective, but recently intolerance to hydrolysates has been observed. However, use of amino acid-based formulas free of antigens is highly effective in such infants.

Cow's milk allergy: a new understanding from immunology

Because of the high prevalence of cow's milk allergy as one of the most frequent clinical presentations of food allergy in infancy and early childhood, it is important to define the condition accurately. Allergy must be distinguished from the broader term food intolerance, which may be defined as a reproducible adverse reaction to the ingestion of a food or to any of its components, ie, proteins, carbohydrates, fats, and additives, and which includes toxic, metabolic, and allergic reactions. By contrast, food allergy may be defined as an adverse clinical reaction to a specific food component and that is immunologically mediated. The rapid increase in knowledge resulting from research in immunology in recent years has not only led to a better understanding of the basis for cow's milk allergy in infancy, but has also yielded considerable promise for improved diagnosis and management of the condition. To review recent developments in immunology which demonstrate how they may lead to a better understanding of the clinical spectrum of cow's milk allergy in infants and children. English language articles were selected from PubMed and selected abstracts that would have immediate, practical clinical implications. The review focuses on themes related to gastro-enterology, focusing upon the esophagus and small intestine. In cow's milk-sensitive esophagitis, there is dense infiltrate of eosinophils and increased T cell activation with upregulation of the chemokine eotaxin. In cow's milk-sensitive enteropathy, there is T cell activation, and it often results as a sequela of gastro-enteritis. Changing patterns in recent years suggests that sensitization occurs via mother's breastmilk to cow's milk and multiple food antigens. There is evidence of reduced Th1 response in these children. This is related to associated IgA deficiency and low levels of cytokine transforming growth factor beta. The results of the present review demonstrate that the clinical manifestations of cow's milk allergy are very diverse, with differences between developing and developed countries. Understanding the immunologic mechanisms is of key importance in understanding this diversity.

Low frequency of CD4+, but not CD8+, T cells expressing interferon-gamma is related to cow's milk allergy in infancy.

Low interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) production in peripheral blood mononuclear cells (PBMC) from patients with atopic dermatitis and food allergy have been reported previously. However, it remains unclear whether the weak cytokine production is caused by the imbalance of specific T-cell subsets or by dysregulation of T-cell function. In the present study we investigated the intracellular expression of these cytokines at a single-cell level to clarify the background of the disruption. Twelve of 27 breast-fed infants (0.1-8.8 months of age) had challenge-proven cow's milk allergy (CMA), and 15 infants were studied as a healthy control group. PBMC were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin. The frequencies of the cells expressing intracellular IL-4, IFN-gamma, and TNF-alpha were assessed using flow cytometry. In addition, at this time-point leucocyte subsets from the milk of mothers of these infants were evaluated using light microscopy. A lower number of CD8+ T cells and the defective capability of CD4+ T cells to express IFN-gamma in infant's peripheral blood co-existed with a lower number of macrophages in their mother's milk.

Cow's milk allergy in infancy.

Cow's milk allergy affects approximately 2% of infants under 2 years of age. This review summarizes the recent advances in understanding its pathophysiology and immunological mechanisms. Apart from IgE-mediated atopic manifestations, T cell-mediated reactions have been demonstrated in infants with cow's milk allergy. The clinical spectrum ranges from immediate-type reactions, presenting with urticaria and angioedema to intermediate and late-onset reactions, including atopic dermatitis, infantile colic, gastro-oesophageal reflux, oesophagitis, infantile proctocolitis, food-associated enterocolitis and constipation. The exact mechanisms of these disorders are still poorly understood. Double-blind, placebo controlled food challenge, the definitive diagnostic test for cow's milk allergy, is increasingly being replaced by the measurement of food-specific antibodies, in combination with skin-prick or atopy patch testing. The treatment of cow's milk allergy relies on allergen avoidance and hypoallergenic formulae, or maternal elimination diets in breast-fed infants.

Hydrolysats de protéines : laits hypoallergéniques et formules extensivement hydrolysées. Bases immuno-allergologiques de leur utilisation dans la prévention et le traitement de l’allergie au lait

Allergy to milk has an estimated incidence of 2,5 %. Hypoallergenic milks are partial hydrolysates of proteins with lactose. Extensive hydrolysates of casein are mainly small peptides and do not include lactose in their formula. A primary allergenicity as well as a cross-sensitivity are shown for all partial hydrolysates. Even extensive hydrolysates have a weak potential of cross-allergy. The prevention of cow's milk allergy in infants at peculiar risk, born from atopic parents, is based on breast-feeding and/or partial or extensive hydrolysates. There is no conclusive evidence for the usefulness of eviction of dairy products during pregnancy or during the period of breast-feeding. The treatment needs exclusively extensive casein hydrolysates ensuring a 90 % protection with 95 % confidence intervals. Predictive prick tests in certain cases may help the choice of another hydrolysate. Severe cases with failure to thrive or multiple food intolerance require an amino-acid based formula (Neocate ®). A rational diversification of the diet is advised in order to prevent the onset of a multiple food intolerance syndrome which could avert from the recovery of cow milk allergy.

Increased concentration of fecal alpha1-antitrypsin is associated with cow's milk allergy in infants with atopic eczema.

The use of fecal alpha1-antitrypsin in the monitoring of intestinal inflammation in infants with atopic eczema and food allergy was evaluated. The study material comprised 26 atopic infants with confirmed food allergy. Fecal samples were collected before an elimination diet and 3 months later for the determination of alpha1-antitrypsin. Nine (35%) of the 26 patients demonstrated an increased fecal concentration of alpha1-antitrypsin (median 3 mg/g; range 2.8-6.4 mg/g). In all nine patients (100%) the oral cow's milk challenge was positive as opposed to only six (35%) in those with normal alpha1-antitrypsin concentration (P = 0.0024). No further connections between alpha1-antitrypsin and other food allergies were detected. As a result of an adequate elimination diet, the fecal concentration of alpha1-antitrypsin was normalized in seven patients, with a favourable clinical response in atopic eczema in six and no improvement in one patient. Our results indicate that serial determinations of fecal alpha1-antitrypsin provide a useful non-invasive tool for the detection and follow-up of intestinal inflammation in a certain group of atopic infants with cow's milk allergy and severe inflammation of the gut.

Residual Intestinal Disease After Milk Allergy in Infancy

ABSTRACTBackgroundThe subsidence of cow's milk allergy (CMA) has been a subject of controversy. In this study the authors examined whether children with this condition in infancy developed full tolerance or whether they continue to have vague gastrointestinal (GI) symptoms relating to the consumption of milk or dairy products and/or signs of mucosal lesion in the GI tract.MethodsThe authors reexamined 56 10‐year‐old subjects who manifested CMA before 1 year of age, and compared the results with a group of 204 randomly selected age‐matched school children. Fifty‐three and 90 subjects respectively attended a reexamination and were evaluated for growth, lactose tolerance, and immunoglobulin A (IgA)‐ and IgG‐class antibodies to whole cow's milk. The subjects reporting milk‐related GI symptoms were encouraged to do a 4‐week blind elimination‐challenge test with 1 week of low‐lactose milk flour. Sixteen of the 25 children were able to complete the trial.ResultsApproximately half the study subjects (45%) reported milk‐related GI symptoms, whereas the respective figure among the control subjects was 10%. Three of six study subjects and seven of 10 control subjects, although completing the challenge, responded with intestinal symptoms. The growth of the former CMA subjects was retarded compared with the control subjects, and the difference in height was most striking in those subjects still reporting milk‐related GI symptoms. However, all subjects had normal hemoglobin and whole‐blood folic acid levels. The CMA subjects had significantly (P = 0.014) lower concentrations of milk antibodies compared with the control subjects. Lactose malabsorption, defined as high counts in a hydrogen breath test and related clinical symptoms, was found in eight CMA subjects (14%) and six control subjects (3%).ConclusionsIn a certain proportion of subjects with CMA in infancy, GI intolerance seems to persist even after small‐dose tolerance has been achieved. The intestinal symptoms and the increased prevalence of lactose intolerance may be caused by a disturbance of the surface epithelial cells—a state to which the authors refer as residual intestinal disease.

Residual intestinal disease after milk allergy in infancy.

The subsidence of cow's milk allergy (CMA) has been a subject of controversy. In this study the authors examined whether children with this condition in infancy developed full tolerance or whether they continue to have vague gastrointestinal (GI) symptoms relating to the consumption of milk or dairy products and/or signs of mucosal lesion in the GI tract. The authors reexamined 56 10-year-old subjects who manifested CMA before 1 year of age, and compared the results with a group of 204 randomly selected age-matched school children. Fifty-three and 90 subjects respectively attended a reexamination and were evaluated for growth, lactose tolerance, and immunoglobulin A (IgA)- and IgG-class antibodies to whole cow's milk. The subjects reporting milk-related GI symptoms were encouraged to do a 4-week blind elimination-challenge test with 1 week of low-lactose milk flour. Sixteen of the 25 children were able to complete the trial. Approximately half the study subjects (45%) reported milk-related GI symptoms, whereas the respective figure among the control subjects was 10%. Three of six study subjects and seven of 10 control subjects, although completing the challenge, responded with intestinal symptoms. The growth of the former CMA subjects was retarded compared with the control subjects, and the difference in height was most striking in those subjects still reporting milk-related GI symptoms. However, all subjects had normal hemoglobin and whole-blood folic acid levels. The CMA subjects had significantly (P = 0.014) lower concentrations of milk antibodies compared with the control subjects. Lactose malabsorption, defined as high counts in a hydrogen breath test and related clinical symptoms, was found in eight CMA subjects (14%) and six control subjects (3%). In a certain proportion of subjects with CMA in infancy, GI intolerance seems to persist even after small-dose tolerance has been achieved. The intestinal symptoms and the increased prevalence of lactose intolerance may be caused by a disturbance of the surface epithelial cells--a state to which the authors refer as residual intestinal disease.

Status of children with cow's milk allergy in infancy by 10 years of age

To assess the development of milk protein tolerance and atopic diseases in children diagnosed for cow's milk allergy (CMA) in infancy, we conducted re‐examinations of 56 CMA subjects at the age of 10 y using 204 age‐matched controls. The children underwent clinical examinations and skin prick tests (SPT), and their IgE‐specific antibodies to milk and five other food allergens were determined. By the age of 10 y, all but four subjects had become tolerant to at least small amounts of milk protein. However, gastrointestinal symptoms relating to more abundant milk consumption were reported by 45% of the study subjects and 15% of the controls (p < 0.001). The incidence figures for asthma, allergic rhinitis and dermatitis, as well as the occurrence of recurrent otitis, were three to four times higher than in the controls. Positive SPTs were seen in two‐thirds of the subjects, the figure being highest (83%) in those with dermatitis onset CMA. Seven subjects showed positive titres of IgE‐class milk‐specific antibodies, and five showed a clinical response. Conclusion: This re‐examination study showed that CMA in infancy, even when properly treated, has significant clinical consequences by posing special risks for respiratory atopy and persistence of atopic dermatitis as well as positive SPT and recurrent ear infections. However, each of these clinical manifestations seems to have an independent curriculum unrelated to the persistence of CMA itself.

Status of children with cow's milk allergy in infancy by 10 years of age.

To assess the development of milk protein tolerance and atopic diseases in children diagnosed for cow's milk allergy (CMA) in infancy, we conducted re-examinations of 56 CMA subjects at the age of 10 y using 204 age-matched controls. The children underwent clinical examinations and skin prick tests (SPT), and their IgE-specific antibodies to milk and five other food allergens were determined. By the age of 10 y, all but four subjects had become tolerant to at least small amounts of milk protein. However, gastrointestinal symptoms relating to more abundant milk consumption were reported by 45% of the study subjects and 15% of the controls (p < 0.001). The incidence figures for asthma, allergic rhinitis and dermatitis, as well as the occurrence of recurrent otitis, were three to four times higher than in the controls. Positive SPTs were seen in two-thirds of the subjects, the figure being highest (83%) in those with dermatitis onset CMA. Seven subjects showed positive titres of IgE-class milk-specific antibodies, and five showed a clinical response. This re-examination study showed that CMA in infancy, even when properly treated, has significant clinical consequences by posing special risks for respiratory atopy and persistence of atopic dermatitis as well as positive SPT and recurrent ear infections. However, each of these clinical manifestations seems to have an independent curriculum unrelated to the persistence of CMA itself.

Distinct patterns of cow's milk allergy in infancy defined by prolonged, two‐stage double‐blind, placebo‐controlled food challenges

The clinical manifestations of cow's milk allergy (CMA) are highly variable, and challenges usually identify only immediate, IgE mediated reactions. To clearly identify CMA of immediate and delayed types using a two-stage, double-blind, placebo-controlled food challenge (DBPCFC), and to prospectively compare the clinical history and analyses of specific IgE antibodies to milk in predicting outcome of DBPCFC. A total of 69 patients (33 girls, 36 boys) were recruited for study based on a history highly suggestive of CMA and resolution of symptoms on a bovine protein-free diet. After skin-prick tests (SPTs) and search for allergen-specific serum IgE antibodies by enzyme allergosorbent test (EAST), a two-stage DBPCFC was performed over several days. Of 16 patients (mean age 36.9 months) classified as probable immediate reactors based on the history, 10 (62.5%) had a positive DBPCFC with similar patterns to historical adverse reactions (< or = 2 h after milk exposure). The other 53 (77%) patients (17.3 months) had a history of probable delayed type CMA presenting with predominantly gastrointestimal symptoms from 2 h and up to 6 days after milk exposure. Of these, 15 (28.8%) had a positive DBPCFC, again with a symptom pattern similar to the history. Sensitivity/specificity of SPT was similar to that of EAST for both immediate (70/83% and 62/83% respectively, NS) or delayed (0/97% and 0/97%) CMA confirmed by DBPCFC. Using our two-stage, prolonged DBPCFC, we clearly identified two groups of children with CMA, reflecting different pathogenesis of either immediate-type IgE-dependent, or delayed-type IgE-independent allergy. Although useful in immediate reactors, IgE antibody determination cannot predict the outcome of DBPCFC in delayed reactors. A thorough clinical history was the most helpful tool to predict the type of response in challenge positive patients.

Distinct patterns of cow's milk allergy in infancy defined by prolonged, two-stage double-blind, placebo-controlled food challenges

Distinct patterns of cow's milk allergy in infancy defined by prolonged, two-stage double-blind, placebo-controlled food challenges

Gastroesophageal reflux and cow's milk allergy in infants: A prospective study

Recent reports have suggested that gastroesophageal reflux in pediatric patients may be caused by food allergy. The aim of our study was to determine the frequency of the association of gastroesophageal reflux with cow's milk protein allergy in patients win the first year of life. We studied 204 consecutive patients (median age, 6.3 months) who had been diagnosed as having gastroesophageal reflux on the basis of 24-hour continuous pH monitoring and histologic examination of the esophageal mucosa. Clinical history suggested diagnosis of cow's milk allergy in 19 infants, and 93 others had positive test results (serum IgE anti-lactoglobulin, prick tests, circulating or fecal or nasal mucus eosinophils) but did not have symptoms indicating cow's milk allergy. The cow's milk-free diet and two successive blind challenges confirmed the diagnosis of cow's milk allergy in 85 of the 204 patients with gastroesophageal reflux. The clinical presentations of the infants with gastroesophageal reflux alone were different, in view of the greater frequency of diarrhea (p less than 0.0001) and atopic dermatitis (p less than 0.0002). In all, gastroesophageal reflux was associated with, and probably caused by cow's milk allergy, in 85 of 204 cases (41.8%). Considering the frequency of this association, patients younger than 12 months old with symptoms of gastroesophageal reflux should be carefully examined to determine whether this disorder is primary or caused by cow's milk allergy.

Ulcerative Colitis in Children 10 Years Old or Younger

SummaryThe onset and course of ulcerative colitis diagnosed in 38 children at or before 10 years of age were reviewed. The mean age at onset was 5.9 years. A family history of inflammatory bowel disease was present in 24% of patients, and 13% had a history of cow milk allergy in infancy. Initially, by radiologic or colonoscopic studies, 71% had total colonic disease, 13% had left‐sided colitis, and 6% had proctitis: extensive examination was not performed in 4 patients. Four patients (11%) presented with severe colitis. 14 (37%) with moderate colitis, and 20 (53%) with mild colitis. The most frequent symptoms were abdominal pain (94%), diarrhea (84%), and rectal bleeding (84%). Between 2 and 10 years after diagnosis, 89% of children had total colonic disease and 11% had left‐sided disease. All four patients with severe disease at onset responded to medical therapy with one having a colectomy 15 years later with pathology consistent with Crohn's disease. Of those with moderate disease, half had infrequent moderate recurrences and half had intermittent mild disease. One patient had colectomy at 21 years for intractable disease. Of the 20 with mild disease, 16 continued to have intermittent mild recurrences, I had chronic mild disease. 2 had moderate recurrent disease, and 1 has remained asymptomatic for 5 years. Psychiatric disturbances requiring therapy were identified in 5 (13%) children. Results are encouraging: after the first 2 years of illness, two thirds of the children have had subsequent mild colitis with infrequent relapses and three quarters consider their life to be of good quality.

Ulcerative Colitis in Children 10 Years Old or Younger

The onset and course of ulcerative colitis diagnosed in 38 children at or before 10 years of age were reviewed. The mean age at onset was 5.9 years. A family history of inflammatory bowel disease was present in 24% of patients, and 13% had a history of cow milk allergy in infancy. Initially, by radiologic or colonoscopic studies, 71% had total colonic disease, 13% had left-sided colitis, and 6% had proctitis; extensive examination was not performed in 4 patients. Four patients (11%) presented with severe colitis, 14 (37%) with moderate colitis, and 20 (53%) with mild colitis. The most frequent symptoms were abdominal pain (94%), diarrhea (84%), and rectal bleeding (84%). Between 2 and 10 years after diagnosis, 89% of children had total colonic disease and 11% had left-sided disease. All four patients with severe disease at onset responded to medical therapy with one having a colectomy 15 years later with pathology consistent with Crohn's disease. Of those with moderate disease, half had infrequent moderate recurrences and half had intermittent mild disease. One patient had colectomy at 21 years for intractable disease. Of the 20 with mild disease, 16 continued to have intermittent mild recurrences, 1 had chronic mild disease, 2 had moderate recurrent disease, and 1 has remained asymptomatic for 5 years. Psychiatric disturbances requiring therapy were identified in 5 (13%) children. Results are encouraging: after the first 2 years of illness, two thirds of the children have had subsequent mild colitis with infrequent relapses and three quarters consider their life to be of good quality.

Cow milk allergy in infancy and hypoallergenic formulas

Substitute feedings have been used to treat infants with cow milk protein allergy for most of this century. For the past 50 years, several infant formulas based on animal proteins, both intact and chemically modified, or on vegetable protein have been labeled "hypoallergenic." Because of the risk of anaphylaxis and other serious adverse reactions, formulas that are claimed to be hypoallergenic should be subjected to rigorous preclinical and clinical testing. At a minimum, such formulas should not provoke any allergic signs or symptoms in 90% of infants with documented cow milk protein allergy when tested in double-blind, placebo-controlled trials. A standardized definition of "hypoallergenic" will allow clinicians and parents to understand the true risks to a cow milk-allergic infant fed such hypoallergenic formulas.

Food-Induced Anaphylaxis

Food-induced anaphylaxis is most frequently caused by proteins in peanut, fish, tree nuts, crustaceans, milk, egg, or soy; in many instances, the individual allergens have been isolated and characterized. Although persons sensitized to one food are often advised not to eat other foods from the same food family, recent studies using DBPCFC feedings suggest that clinically significant cross-allergenicity among legumes and among fish may be less common than formerly suspected. Cow’s milk allergy in infants may disappear spontaneously with time, but sensitivity to peanut, fish, or nuts is usually long-lasting. Newer hypoallergenic formulas prepared from casein or whey hydrolysates are not completely allergen-free and may pose risks to infants highly sensitive to cow’s milk. The diagnosis of food-induced anaphylaxis is made from the clinical history and can be confirmed by puncture skin testing or by in vitro demonstration of food-specific IgE antibodies. Immunoassays have been developed for "hidden" or contaminating allergens that are not listed on food product labels. The drug of choice for treatment of food-induced anaphylaxis is subcutaneous epinephrine, and sensitive persons should carry epinephrine and be familiar with its use. Most cases of fatal food-induced anaphylaxis occur away from home, and food-sensitive persons need to develop an anticipatory action plan to deal with reactions that occur at work, at school, or in distant communities. The number of anaphylaxis fatalities could be reduced by better patient education, better food labeling, and a greater awareness of food allergy by restaurant service personnel and paramedical rescue teams.

Cow's Milk Allergy in Infants and Children

Children's Clinic, Seattle, WA, USA Int Arch Allergy 1958; 13: 245–56Reviewed by Damien Downing MBBS

Cow's Milk Formula and Infantile Colic

No experienced pediatric clinician doubts the existence of cow's milk allergy in infants. The controversy concerns how often cow's milk proteins cause excessive crying or "colic" in otherwise well young infants. Three interesting papers from our colleagues in Malmö, Sweden, leave the question unanswered despite the considerable sophistication in their research design. In their first report in 1982, they concluded that in a double-blind study "cow's milk seems to be a major cause of infantile colic in formula-fed infants." However, in the only part that was double-blind, fewer infants improved while receiving soy formula (18%) than did those receiving cow's milk formula (29%).

Insomnia and Cow's Milk Allergy in Infants

To the Editor.— From a pragmatic view, after perusal of the paper by Kahn et al (Pediatrics 1985;76:880-884), I was most impressed that the authors were making much ado about the commonly encountered clinical entity usually called "infantile colic." This syndrome has been attributed to many causative factors, among which is cow's milk hypersensitivity. Often, the pediatrician or practitioner will eliminate this food and use a soy replacement, particularly if there is a genetic background of atopy in the family and other clinical manifestations of allergy.