Cow’s Milk Protein Allergy Dr. Zakariya Muhammad QI Fellow in Paediatrics 27/07/2015

CMPA Background Information: Diagnosis: Management: Definition Causes Prevalence Risk Factors Prognosis Complications Diagnosis: When to suspect Assessment DD Management: Suspected CMPA Confirmed CMPA

Definition Cows' milk protein allergy is an immune-mediated allergic response to proteins in milk [Vandenplas et al, 2007; Ludman et al, 2013]. Milk contains casein and whey fractions, each of which have five protein components. A person can be sensitized to one or more components within either group. Cows' milk protein allergy is classified according to the underlying cause [Vandenplas et al, 2007; Caffarelli et al, 2010;NICE, 2011; Koletzko et al, 2012; Ludman et al, 2013]: Immunoglobulin E (IgE)-mediated reactions are acute and frequently have a rapid onset. They occur up to 2 hours after ingestion of cows' milk, usually within 20–30 minutes. Non-IgE-mediated reactions are generally delayed and non-acute. They manifest up to 48 hours or even 1 week after ingestion of cows' milk protein [Koletzko et al, 2012]. Mixed IgE and non-IgE allergic reactions involve a mixture of both IgE and non-IgE responses. Food allergy should not be confused with food intolerance, which is a non-immunological reaction that can be caused by enzyme deficiencies, pharmacological agents, and naturally occurring substances [NICE, 2011].

Causes Cows' milk protein allergy is an abnormal response of the immune system to usually harmless proteins found in cows' milk. The immune system releases a number of chemicals which then trigger an allergic reaction. Immunoglobulin E (IgE)-mediated cows' milk protein allergy is caused by the release of histamine and other mediators from the mast cells and basophils in response to cows' milk protein. Non-IgE-mediated cows' milk protein allergy is thought to be caused by T-cells. [Motola, 2004; Anand, 2014]

Prevalence Cows' milk protein allergy is one of the most common childhood food allergies in the developed world, second to egg allergy [Koletzko et al, 2012; Ludman et al, 2013]. It affects about 7% of formula or mixed-fed (breast and formula-fed) infants, with the highest prevalence during the first year of life [Caffarelli et al, 2010]. Exclusively breastfed babies can also develop cows' milk protein allergy due to protein in the maternal diet transferring through breast milk. However, the incidence is much lower than for formula or mixed-fed infants. Only about 0.5% of exclusively breastfed infants show reproducible clinical reactions to cows' milk protein, and these are mostly mild to moderate in intensity [Vandenplas et al, 2007].

Risk Factors It is difficult to predict which children will develop a food allergy. However, the following risk factors are associated with an increased risk of cows' milk protein allergy [Vandenplas et al, 2007; NICE, 2011; Ludman et al, 2013]: Associated atopic comorbidities (such as asthma and eczema) The frequency of severe reactions is higher in children with asthma, especially those with poorly controlled asthma, than in children without asthma. Family history of atopy Family history of atopy is a risk factor for developing food allergies, although only an allergic predisposition is inherited, not specific allergies. Some experts suggest that babies who are exclusively breastfed during the first 4–6 months of life are less likely to develop cows' milk protein allergy than babies who are formula fed [Vandenplas et al, 2007].

Prognosis Immunoglobulin E (IgE)-mediated cows' milk protein allergy Prospective longitudinal studies on children with IgE-mediated cows' milk protein allergy suggest that 53–57% will be milk tolerant by 5 years of age [Sicherer et al, 2010; Elizur et al, 2012]. However, there is some evidence that IgE-mediated cows' milk protein allergy is more likely to persist in children with asthma or allergic rhinitis; children who have more severe reactions; and children with a larger reaction on skin prick test, or higher milk-specific IgE antibody levels, at diagnosis[Saarinen et al, 2005; Fiocchi et al, 2010; Sicherer et al, 2010; Elizur et al, 2012; Ludman et al, 2013]. Non-IgE-mediated cows' milk protein allergy The prognosis of non-IgE-mediated cows' milk protein allergy is less known [Ludman et al, 2013]. However, studies have shown that most children with non-IgE-mediated cows' milk protein allergy will be milk tolerant by 3 years of age [Sicherer et al, 1998; Saarinen et al, 2005; Venter et al, 2013].

Complications Cows' milk protein allergy may result in poor nutritional intake or malabsorption, leading to possible: Chronic iron deficiency anaemia. Faltering growth, with the associated consequences in a growing child. Rare cases of anaphylactic shock leading to death have been reported following cows' milk protein ingestion in sensitized children. Heiner's syndrome, a milk-induced pulmonary disease, is a rare complication of cows' milk protein allergy in children. Severe cases may be complicated with pulmonary haemosiderosis, which should be suspected in the presence of anaemia or haemoptysis [Moissidis et al, 2005]. [Koletzko et al, 2012]

Diagnosis When to suspect Assessment DD

When to suspect Suspect cows' milk protein allergy in children: Who have one or more of the signs and symptoms listed in Table 1, paying particular attention to children with persistent symptoms that involve different organ systems. Whose symptoms do not respond adequately to treatment for atopic eczema, gastro-oesophageal reflux disease, and/or chronic gastrointestinal symptoms (including chronic constipation). If cows' milk protein allergy is suspected in a child, take an allergy-focused clinical history tailored to the presenting symptoms.

Table 1 . Symptoms and signs of possible food allergy.*

IgE-mediated cows' milk protein allergy Speed of onset of symptoms Acute and frequently has a rapid onset (up to 2 hours after ingestion)

Skin reactions Pruritus Erythema Acute urticaria — localized or generalized Acute angio-oedema — most commonly of the lips, face, and around the eyes

Gastrointestinal symptoms Angioedema of the lips, tongue, and palate Oral pruritus Nausea Colicky abdominal pain Vomiting Diarrhoea

Respiratory symptoms (usually in combination with one or more of the above symptoms and signs) Lower respiratory tract symptoms (cough, chest tightness, wheezing, or shortness of breath) Upper respiratory tract symptoms (nasal itching, sneezing, rhinorrhoea, or congestion [with or without conjunctivitis])

Other symptoms Symptoms and signs of anaphylaxis or other systemic allergic reactions

Non-IgE-mediated cows' milk protein allergy Speed of onset of symptoms Non-acute and generally delayed (manifest up to 48 hours or even 1 week after ingestion)

Skin reactions Pruritus Erythema Atopic eczema

Gastrointestinal symptoms Gastro-oesophageal reflux disease Loose or frequent stools Blood and/or mucus in stools Abdominal pain Infantile colic Food refusal or aversion Constipation Perianal redness Pallor and tiredness Faltering growth in conjunction with at least one or more gastrointestinal symptoms above (with or without significant atopic eczema)

Respiratory symptoms (usually in combination with one or more of the above symptoms and signs) Lower respiratory tract symptoms (cough, chest tightness, wheezing, or shortness of breath)

Assessment If cows' milk protein allergy is suspected, take an allergy-focused clinical history tailored to the presenting symptoms and the age of the child.

Ask about: Any history of atopic disease (asthma, eczema, or allergic rhinitis) or food allergy. Any family history of atopic disease or food allergy in parents or siblings. Details of any foods that are avoided and the reasons why. Cultural and religious factors that affect the foods they eat. Who has raised the concern about the suspected food allergy, and what the suspected allergen is. The child’s feeding history, including the age at which they were weaned and whether they were breastfed or formula fed. If the child is currently being breastfed, ask about the mother’s diet. Details of any previous treatment, including medication such as antihistamines, for the presenting symptoms and the response to this. Any response to the elimination and reintroduction of foods.

Assess the presenting symptoms and other symptoms that may be associated with food allergy. Ask about: The age of the child when symptoms first started. Speed of onset of symptoms following food contact, duration of symptoms, severity of reaction, and frequency of occurrence. Setting of reaction (for example at school or home). Reproducibility of symptoms on repeated exposure. What food, and how much exposure to it, causes a reaction.

The European Academy of Allergy and Clinical Immunology (EAACI) has published an extensiveAllergy-Focussed Diet History tool for healthcare professionals.

Based on the findings of the allergy-focused clinical history, physically examine the child, paying particular attention to: Growth and physical signs of malnutrition. Signs indicating other comorbidities (such as atopic eczema, asthma, or allergic rhinitis). Signs indicating an alternative diagnosis.

Differential diagnosis Differential diagnoses of cows' milk protein allergy include: Food intolerance, for example lactose intolerance — this may present with abdominal pain and diarrhoea following ingestion of foods containing lactose. Note that symptoms of lactose intolerance rarely occur before the age of 6 years, but acquired or secondary lactose intolerance can occur when the intestine is damaged, for example following gastroenteritis. Allergic reactions to other food allergens (such as hens' eggs, soya, and wheat) or other substances (such as animal dander, moulds, and dust). Anatomical abnormalities, such as Meckel's diverticulum. Chronic gastrointestinal conditions, such as: Gastro-oesophageal reflux disease Crohn's disease Coeliac disease Constipation Gatroenteritis Ulcerative colitis Pancreatic insufficiency (such as in cystic fibrosis). Infections (for example urinary tract infections)

Management Suspected cows' milk protein allergy : covers the management of children and young people with suspected cows' milk protein allergy. Confirmed cows' milk protein allergy : covers the management of children and young people with confirmed cows' milk protein allergy.

Management will be discussed later