Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 14, Issue 1, 2014

Since the 1930’s the scientific literature on cow’s milk protein allergy (CMPA) has accumulated. Over the last decade new diagnostic tools and treatment approaches have been developed. The diagnosis of reproducible adverse reactions to cow’s milk proteins (CMP), i.e. CMPA, still has to be confirmed by controlled elimination and challenge procedures. Advanced diagnostic testing using epitope and microarray technology may in the future improve the diagnostic accuracy of CMPA by determination of specific IgE against specific allergen components of cow’s milk protein. The incidence of CMPA in early childhood is approximately 2-3% in developed countries. Symptoms suggestive of CMPA may be encountered in 5-15% of infants emphasizing the importance of controlled elimination/milk challenge procedures. Reproducible clinical reactions to CMP in human milk have been reported in 0.5% of breastfed infants. Most infants with CMPA develop symptoms before 1 month of age, often within 1 week after inter introduction of CMP-based formula. The majority has two or more symptoms from two or more organ systems. Approximately 50-70% have cutaneous symptoms, 50-60% gastrointestinal symptoms and 20-30% respiratory symptoms. Symptoms may occur within 1 hour after milk intake (immediate reactions) or after 1 hour (late reactions). The prognosis of CMPA is good with a remission rate of approximately 45 to 50% at 1 year, 60 to 75% at 2 years and 85 to 90% at 3 years. Associated adverse reactions to other foods develop in up to 50% and allergy against inhalants in 50 to 80%. The basic treatment of CMPA is avoidance of CMP. In early childhood a milk substitute is needed. Documented extensively hydrolysed formulas are recommended, whereas partially hydrolysed formulas should not be used because of a high degree of antigenicity and allergenicity associated with adverse reactions. In case of intolerance to extensively hydrolysed formulas and multiple food allergies a formula based on aminoacids is recommended. Alternative milk substitutes such as sheep’s and goat’s milk should not be used because of a high degree of cross reactivity with CMP. Milk from other mammals such as mare and donkey may be tolerated by some children with CMPA. Soy protein is as allergenic as CMP and soy formula is not recommended for young children with CMPA because of a great risk of development of allergy to soy, whereas soymilk is normally tolerated in older children with CMPA. Recent treatment modalities are oral immunotherapy (OIT) involving the ingestion of increasing amounts of milk allergen on a regular basis to desensitize and potentially permanently tolerize patients to CMP. OIT can increase the reaction thresholds to CMP, but questions about safety and long-term efficacy remain. Anti-IgE therapy with Omalizumab may improve the safety and efficacy of OIT and may provide benefit in monotherapy.

Breast milk and colostrum are the first feeding sources for a child, providing nutrients, growth factors and immunological components, which are crucial for the newborn’s correct development and health. Length of exclusive breastfeeding and time of solid foods introduction is a key factor that may influence allergy development. There is an emerging evidence of a relationship between breastfeeding, milk composition and lower risk of chronic diseases, such as diabetes, obesity, hypertension and allergies. This review examines current evidence regarding humoral and cellular characteristics of breast-milk, and potential role of environment, maternal diet and breastfeeding on the allergy development in children.

In this review, clinical and epidemiological aspects of milk allergy along with current data on the structure and function of the main cow's milk allergens, are presented. Milk allergy is the most frequent food allergy in childhood. One of the reasons why allergy to cow’s milk shows its highest prevalence in children is its early introduction into the diets of infants when breast feeding is not possible. The major allergens are caseins, a-lactalbumin and β-lactoglobulin, but allergies to other minor proteins (immunoglobulins, bovine serum albumin) have also been reported. Milk allergenicity can be reduced by various processing methods (mainly hydrolysis), and processed formulas based on cow’s milk can often be safely introduced to children allergic to milk proteins. Cross reactivity has been described between different mammalian milks and between milk and meat or animal dander.

Nowadays, donkey's and goat's milk consumption has been reevaluated for its potential benefits to human health. For example, in infants with intolerance to cow’s milk, donkey’s milk represents a good alternative due to its chemical characteristics similar to those of human milk. On the other hand, goat's milk in virtue of its higher content in short chain, medium chain, mono and polyunsaturated fatty acids than that of cow’s milk, is more digestible than the bovine counterpart. From an immunological point of view, donkey's milk is able to induce release of inflammatory and anti-inflammatory cytokines from normal human peripheral blood lymphomononuclear cells, thus maintaining a condition of immune homeostasis. Similarly, goat's milk has been shown to trigger innate and adaptive immune responses in an in vitro human system, also inhibiting the endotoxin-induced activation of monocytes. Finally, in these milks the presence of their own microbiota may normalize the human intestinal microbiota with a cascade of protective effects at intestinal mucosal sites, even including triggering of intestinal T regulatory cells. In the light of the above considerations, donkey's and goat's milk should be recommended as a dietary supplement in individuals with inflammatory and allergic conditions, even including elderly people.

Soy milk formula has limited medical indications for infants feeding, although in several parts of the world it has been used as a source of nutrition in a large number of children. It used to be the main alternative feeding for infants allergic to cow’s milk who did not breastfeed before the introduction of extensively hydrolyzed formulas. Although there is a debate, the fact that some children are allergic to soy or some children with cow’s milk allergy can present with concomitant soy allergy, restricted the use of soy formulas for treatment of infants allergic to cow’s milk. Other grainbased formulas like the rice-based ones are promising in infants with cow’s milk allergy. Grain-based formulas could be an alternative and cheaper way of nutrition for infants allergic to cow’s milk than extensively hydrolyzed formulas. Further large scale longitudinal clinical studies are required to clarify the safety of soy and other grain-based formulas for treatment of cow’s milk allergy.

Food allergy is the primary cause of anaphylaxis in paediatric age affecting roughly 4% of children and their families worldwide, and requiring changes in dietary habits. The prognosis for food allergy in children has traditionally been regarded as good for the most frequent allergens, however the prognosis for cow’s milk allergy in the pediatric age is currently considered to be worse than previously believed. There is now enough evidence that measures of avoidance for children at risk did not have any preventive effect whatsoever, but they still came to be counterproductive by avoiding the physiological interaction between food allergens and gastrointestinal mucosal immune system. Programs of specific oral tolerance induction (SOTI) have obtained interesting results in the treatment of food allergy supporting the idea that antigen exposure through gastrointestinal section is important to allow the development of tolerance. Nevertheless this approach is not yet considered “ready” for community recommendations. In this paper we describe our experience in the field of SOTI in children with cow’s milk allergy.

Even though cow’s milk protein allergy (CMPA) is one of the most common food allergies in childhood, its prognosis is generally good and cow’s milk (CM) is usually reintroduced in the patient’s diet. The natural history of CMPA shows heterogeneity and is closely related to the immunological and clinical phenotype by which CMPA presents. Children with non-IgE-mediated CMPA tend to develop tolerance at an earlier age and at a higher percentage compared to those with IgE-mediated disease. In subjects with severe symptoms CMPA may persist for longer or ever. Although, the majority of children will outgrow their allergy, the individual timing of tolerance acquisition is largely unknown. Most of the current guidelines on the diagnosis and management of CMPA suggest reevaluation of milk- allergic children every 6- 12 months, and reintroduction of CM after a negative Oral Food Challenge (OFC). However, OFC procedure is time consuming, expensive and not without risk. Clinical variables and the measurements of sIgE levels and SPT wheal sizes to crude (whole) CM protein and individual milk protein components may provide some useful prognostic information in the course of CMPA. However, no clear-cut clinical or laboratory criteria exist to predict which children and at what age are more likely to pass a repeat (reintroduction) OFC. The identification of factors that could accurately predict the outcome of reintroduction OFC and the timing of tolerance development would be extremely useful in daily clinical practice. Until recently, reintroduction of CM was commonly attempted when children with CMPA were more likely to have become tolerant. Over the last years, a different approach in the management of milk and egg allergy has emerged with specific oral tolerance induction (SOTI) as a promising method for the treatment of food allergies. Furthermore, a number of studies have shown evidence that introduction of heated milk and egg protein into the diet of allergic patients may induce the acquisition of tolerance. Still, the question of when and how to reintroduce cow’s milk in milk-allergic children remains challenging and further research in this important field is necessary to provide both clinicians and anxious parents with the desirable answer.

The arm of this review was to help general pediatricians and primary care physicians in diagnosing and managing cow’s milk protein allergy in exclusively breast-fed infants. Allergic proctocolitis is a cause of rectal bleeding in exclusively breast-fed infants aged from 1 to 6 months.It is due to cow’s milk protein transferred via breast milk. Diagnosis is based on clinical features and recovery after dietetic therapy. Rectal bleeding generally resolves within 72-96 hours of cow’s milk protein maternal avoidance. Most infants tolerate cow’s milk by their first birthday.

Food intolerances are an increasing global health problem. Interactions between genetics and environmental changes such as microbial- and stress factors remain poorly understood. Whereas the analyses of IgE mediated allergic responses is based on solid concepts, the roles of microbiota, gut permeability, and IgG antibodies remain widely unclear and are under fierce discussion for scientific relevance. The present pilot study analyzes forty participants, under consultation of nutritional health professionals, for gastrointestinal discomfort and claimed food intolerances. Food frequency questionnaire addresses nutrition, lifestyle and present discomfort. Feces samples are analyzed for dominant microbiota using 16S rDNA based methods and the fecal marker Calprotectin. Blood samples are analyzed for IgG4 levels. The total microbial abundance significantly correlates with claimed discomfort (R=-0.37; p=0.02). The abundance and diversity of microbiota significantly correlates with low Calprotectin values (R=-0.35; p=0.01) and with higher abundance of Faecalibacterium prausnitzii (R=0.78; p<0.01) and Akkermansia (R=0.82; p<0.01). Participants with low discomfort show enhanced Clostridium Cluster XIVa (p=0.008). An increased diversity is also correlating with reduced antibodies against IgG4 of egg white (R=0.68; p<0.01). Data suggest an interaction of low gut permeability and reduced inflammation with an established microbial equilibrium. Self-reported abdominal inconvenience of participants relates mainly to characteristics of microbiota and gut permeability. Anti-inflammatory effects of Faecalibacterium prausnitzii or Lactobacilli and gut barrier functions of Akkermansia may have a key role in food intolerances. The role of IgG4 linking food immune responses with intolerances remains unclear.