"...an adverse reaction to cows' milk resulting from an immunologic hypersensitivity to one or more milk proteins“ 1 How many infants are affected? Most common food allergy in infancy Affects an estimated 2-7.5% of UK births 1 – 5% would be 38,000 babies/year (imagine filling the 0 2 arena twice over) Generally resolves by 1-3 years of age C OWS ’ MILK PROTEIN ALLERGY ( CMPA ) OR COW MILK PROTEIN INTOLERANCE( CMPI) 1 Hill DJ et al. J Pediatr 1986; 109; Høst A. Ann Allergy Asthma Immunol 2002; 89 (6 Suppl 1):

Cow's milk proteins are most frequently implicated as a cause of food intolerance during infancy. Soybean protein ranks second as an antigen in the first months of life, particularly in infants with primary cow's milk intolerance who are placed on a soy formula. From school age on, egg protein intolerance becomes more prevalent. Several clinical reactions to food proteins have been reported in children and adults. Only a few of these have a clear allergic immunoglobulin E (IgE)– mediated pathogenesis. The term "food protein allergy " is usually preferred to "food protein intolerance “.

Hypersensitivity IgE mediated allergy Non-IgE mediated allergy Food allergy (allergic hypersensitivity) Food intolerance (non-allergic hypersensitivity ) Involving the immune system Not involving the immune system Adapted from Johansson SGO et al A LLERGY VS INTOLERANCE

PATHOPHYSIOLOGY Cow's milk contains more than 20 protein fractions : 4 caseins,S1, S2, S3, S4: 80% of the milk proteins; 20% of the proteins globular proteins (eg, lactalbumin, lactoglobulin, bovine serum albumin) Casein is often considered poorly immunogenic because of its flexible, noncompact structure. Lactoglobulin is the major allergen in cow's milk protein intolerance. The proteins recognized by specific IgE are the lactoglobulin and the casein fraction. However, all milk proteins appear to be potential allergens, even those that are present in milk in trace amounts (eg, serum bovine albumin, immunoglobulins, lactoferrin) In each allergen, numerous epitopes can be recognized by specific IgE presence. Cow's milk proteins introduced with maternal diet can be transferred to the human milk (presence of bovine lactoglobulin throughout human lactation) The GI tract is permeable to intact antigens. The antigen uptake is an endocytotic process that involves intracellular lysosomes.

Morphologic studies have demonstrated the role of GI T lymphocytes (ie, intraepithelial lymphocytes) in the pathogenesis of GI food allergy. Protein intolerance is generally believed to remit by age 5 years, when the infant's mucosal immune system matures and the child becomes immunologically tolerant of milk proteins; In most affected children, symptoms resolve by age 1-2 years. Cow's milk protein intolerance may persist or may initially manifest in older children (characteristic endoscopic and histopathologic features);it occasionally recurs in adults.

EPIDEMIOLOGY Incidence of food allergy in children has been variously estimated at 0.3-8%, and the incidence decreases with age. Food allergies affect 6-8% of infants younger than 2 years. Denmark : incidence of 2.2% the EuroPrevall-INCO project has been developed to evaluate the prevalence of food allergies in China, India, and Russia

Body system affectedSymptoms Oral tract Itching and redness of mouth and lips Respiratory tract Rhinitis Asthma Wheezing Skin Urticaria Angiodema Atopic dermatitis Gastrointestinal tract Vomiting Abdominal pain Diarrhoea CLINICS

The typical history is that of an infant younger than 6 months who is fed for a few weeks with formula and who then develops diarrhea and, eventually, vomiting; the infant can become dehydrated and lose weight; cow's milk enteropathy (rare): malabsorption syndrome develops, with growth failure and hypoalbuminemia. malabsorption syndrome

Cow's milk proteins and soy proteins can cause an uncommon syndrome of chronic diarrhea, weight loss, and failure to thrive, similar to that appearing in celiac disease. Vomiting is present in up to two thirds of patients. Small bowel biopsy findings reveal an enteropathy of variable degrees with villous hypotrophy. Total mucosal atrophy, histologically indistinguishable from celiac disease, is a frequent finding. Intestinal protein and blood losses can aggravate the hypoalbuminemia and anemia that are frequently observed in this syndrome.

CLINICS GI symptoms Oral allergy syndrome: Oral allergy syndrome is a form of IgE-mediated contact allergy that is almost exclusively confined to the oropharynx and is most commonly associated with the ingestion of various fresh fruits and vegetables. Symptoms : itching; burning; and angioedema of the lips, tongue, palate, and throat. The clinical picture is usually short-lived, but symptoms may be more prominent after the ragweed season.

Eosinophilic esophagitis occurs in children and adults but rarely occurs in infants and is characterized by chronic esophagitis, with or without reflux. Children younger than 2 years often present with food refusal, irritability, vomiting, and abdominal pain. In older children, dysphagia, anorexia, and early satiety can help distinguish eosinophilic gastroenteritis from gastroesophageal refluxgastroesophageal reflux Eosinophilic gastritis: Eosinophilic gastritis that is responsive to elimination diets has occasionally been reported. Symptoms: postprandial vomiting, abdominal pain, anorexia, early satiety, and failure to thrive. Approximately half of these patients have atopic features. Eosinophilic gastroenteritis: Symptoms include protracted vomiting and diarrhea. Vomiting generally occurs 1-3 hours after feeding, and diarrhea occurs 5-8 hours after feeding.

Blood in the stools Chronic constipation Infantile colic Endoscopic finding of lymphonodular hyperplasia Multiple food protein intolerance of infancy

Dermatologic symptoms urticaria, angioedema, rashes, and atopic eczema. atopic dermatitis is one of the most common symptoms of protein intolerance % of children younger than 1 year with protein intolerance have atopic dermatitis. Most children with atopic dermatitis and protein intolerance develop a complete tolerance in a few years. Umbilical and periumbilical disappeares within the second week on elimination diet, and reappears within 24 hours after challenge

Respiratory symptoms: rhinitis and asthma. General symptoms Nonspecific symptoms: oral aphthae, pyloric stenosis, and bowel edema and obstruction The infant with enterocolitis syndrome can be dehydrated as a consequence of diarrhea, vomiting, or both. Signs of dehydration include blunted eyes, dry mucous membranes, and hypoelastic skin. Dystrophy, growth failure, edema (hypoalbuminemia), rickets (vitamin D malabsorption), and hemorrhages (vitamin K malabsorption)

Differential Diagnoses Crohn Disease Gastroenteritis Gastroesophageal Reflux Ulcerative Colitis Celiac disease Lactose intolerance Prolonged post-enteritis syndrome Autoimmune enteropathy Common variable immunodeficiency Food allergy Infections (Giardia, Helicobacter, Cryptosporidium, viruses) Food allergy Drug reactions (NSAIDS, chemotherapy) Immune system abnormalities (GVHD, autoimmune enteropathy, other autoimmune diseases)

Laboratory Studies Skin test responses to cow's milk or other food proteins and detection of food-specific immunoglobulin E (IgE) antibodies are usually positive in children with IgE-mediated food allergy. Serum immunoassays: Serum immunoassays to determine food-specific IgE antibodies are often used to screen for antigen-specific IgE in the patient's serum. Enzyme-linked immunosorbent assays (ELISAs) have been replacing methods that use radiation (eg, radioallergosorbent test [RAST]). Fecal leukocyte testing: Fecal eosinophils are a significant clue to the diagnosis of allergic colitis. Atopy patch testing: Elimination diets: elimination of suspected food antigens from the diet for 2-4 weeks or longer. An elimination diet for days should precede a food challenge test. Total serum IgE is within the reference range or slightly elevated.

Upper GI and lower( colonoscopy) endoscopies : hyperemia of the mucosa, rings, and plaques focal erythema and frequent nodularity eosinophilic infiltration, most prominent in the lamina propria, can be observed in the biopsy specimens

TREATMENT The definitive treatment of food protein intolerance is strict elimination of the offending food from the diet dietary therapy of 3 possible regimens: strict use of amino acid–based formula, dietary restriction based on allergy testing, or dietary restriction based on eliminating the most likely food antigens. The committee also recommended that topical steroids should be considered for both initial and maintenance therapy ( 2011)

Topical or orally and intranasally inhaled corticosteroids are used to treat dermatologic or respiratory symptoms (Triamcinolone topical, Hydrocortisone topical )Triamcinolone topical Hydrocortisone topical Antihistamines and inhaled bronchodilatators (Beclomethasone) Infants with elevated cord serum immunoglobulin E (IgE) and a positive family history of atopy are at risk for the development of atopic disease. In some infants at high risk, exclusive breastfeeding with delayed introduction of solid foods until the infant is aged 6 months may delay or possibly prevent the onset of food allergy. avoidance of allergenic foods by lactating mothers

The American Academy of Pediatrics (AAP): avoid eggs until age 2 years; peanuts, tree nuts, and fish until age 3 years for infants who are at risk of developing atopic disease. The Committee on Nutrition and Section on Allergy and Immunology of the AAP states that this raises serious questions about the benefit of delaying the introduction of solid foods that are thought to be highly allergic beyond age 4-6 months The intestinal microflora interacts with the mucosal immune system, and, in germ-free mice, does not develop a normal oral tolerance. The intestinal flora of children with atopy has been found to differ from that of controls. These observations suggest that the normal flora can play a role in the prevention of food allergies. A potential role for probiotics can be hypothesized (Lactobacillus rhamnosus)

MANAGEMENT IN BREAST FED INFANTS MILD TO MODERATE: 1.CONTINUE BREAST FEEDING BUT ELIMINATION IN MOTHER ‘ DIET 2-4 WEEKS WITH CA SUPPLEMENT AND NO EGG 2.IF IMPROVEMENT REINTRODUCE CMP AND CHECK SYMPTOMS – IF YES THEN eHF AFTER BF, SOLIDS WITHOUT CMP UNTIL 9-12 MONTHS AND AT LEAST FOR 6/12. EGG TO BE ADDED IF NO SYMPTOMS. SEVERE CMPA: 1.REFER PAEDIATRICS AND IN MEANTIME ELIMINATION DIET IN MOTHER PLUS CA SUPPLEMENT

Breastfeeding is the gold standard in infant nutrition to 6 months Breastmilk content per 100ml 1 Less eczema Less smelly nappies Protection against diarrhoea and upset stomach Lower risk of diabetes Protection against chest infections and wheezing Protectio n against ear infections Better mental development Fat 3.4g Vits & mins 0.173g Carbohydrates 6.7g Prebiotic OS 1.0g Other 0.2g Protein 1.2g

Soya-based formulas -historically used for the management of food hypersensitivity (e.g. lactose intolerance and CMPA) However, studies have shown that some 30-50% of infants given a soya-based formula for the management of CMPA present with concomitant soya protein allergy Soya-based formulas should not be first choice for the management of infants with proven cows’ milk sensitivity due to the potential risk from their high phytoestrogen levels Soya-based formulas should only be used in exceptional circumstances to ensure adequate nutrition, e.g. for vegans or infants who find alternatives unacceptable ESPGHAN are also in agreement and state that "Soya protein formula should not be used in infants with allergy during the first 6 months of life”. They also raise concerns over their use post 6 months and suggest that soya tolerance "should first be established by clinical challenge” 2

ProductIndicationsUses Cows’ milk protein intolerance ± secondary lactose intolerance Cows’ milk protein allergy/intolerance Disaccharide ± whole protein intolerance, or where amino acids and peptides are indicated for use with MCT Complex multiple food intolerances and malabsorption Disaccharide ± whole protein intolerance Cows’ milk protein allergy Cows' milk allergy, multiple food protein intolerance and other conditions where an elemental diet is indicated Severe cows’ milk allergy and multiple food intolerances Prescribable indications

CONCLUSION CONSIDER CMPA EARLY- REMEMBER GOR IS AS COMMON AND DOES NOT NEED ELIMINATION DIET TREAT EARLY AVOID SOY BASED FORMULAE UNTIL AT LEAST 6 MONTHS. AVOID GOAT’S MILK, RICE MILK (ARSENIC) AS NOT APPROPRIATE CALORIES AND NUTRITION IF IN DOUBT DISCUSS WITH COLLEAGUES