Cow’s milk protein allergy in children: identification and treatment

Allergy is an adverse overreaction by the immune system to a harmless substance. A food allergy occurs when specific components of a food (typically proteins) are recognised by allergen-specific antibodies or cells, eliciting specific immunological reactions that result in characteristic symptoms^[1]
. Food allergy is an important public health problem that affects both adults and children^[1]
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Cow’s milk protein allergy (CMPA) is the abnormal response to proteins found in cow’s milk or products containing milk proteins. The reported prevalence of CMPA varies owing to possible misinterpretations of presumed reactions to milk and diagnostic criteria, and is often overestimated. A pan-European study using the gold standard food challenge test for diagnosis confirmed CMPA in around 1% of children aged up to two years^[2]
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Identification of CMPA can be difficult because the typical symptoms are not specific to CMPA alone, and instead are common in children (e.g. skin rashes, reflux, colic and diarrhoea). If left untreated, CMPA can lead to faltering growth, persistent unpleasant symptoms and in rare instances can be life-threatening. Furthermore, CMPA is often confused with lactose intolerance, making diagnosis even more difficult^[3],[4]
. Lactose is a component of milk and dairy products; an intolerance may occur when lactase, the enzyme required to break lactose into glucose and galactose, is lacking. This malabsorption leads to gastrointestinal side effects (e.g. bloating, diarrhoea and flatulence), but lactose intolerance is highly unlikely in a child aged under three years unless they have a history of a gastrointestinal infection^[5]
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This article provides an overview of how pharmacists, pharmacy teams and other healthcare professionals can help to identify a child with possible CMPA, ensuring a timely diagnosis and initiation of the most appropriate management plan. Further information can be found in the Milk Allergy in Primary Care (MAP) guideline^[6]
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How does cow’s milk protein allergy occur?

Cow’s milk protein can be present in breast milk if the mother has cow’s milk in her diet, and it is also in cow’s milk protein formula. Reactions can be either immunoglobulin E (IgE) mediated or non-IgE mediated.

IgE-mediated reactions

These reactions are usually rapid in onset and occur when the milk protein (the allergen) binds to a milk-specific IgE on the surface of mast cells (on skin and in the blood) that recognise the protein as harmful. In response to this, IgE initiates a process of intracellular signalling, leading to the release of histamine and other inflammatory markers that produce local tissue responses characteristic of an allergic reaction (see Table 1).

IgE-mediated reactions occur most commonly in formula-fed children or at the onset of mixed feeding^[6]
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Non-IgE-mediated reactions

Diagnosis of non-IgE-mediated milk allergy is more challenging because there is no temporal relationship with ingestion. The symptoms are also commonly seen in children who do not have CMPA. Symptoms can appear after a couple of hours but can also be delayed for up to 72 hours post-ingestion of cow’s milk protein; the child may be formula fed, exclusively breastfed, or it may occur at the onset of mixed feeding. Symptoms tend to intensify with increasing exposure to the allergen; therefore, they are seen to build up over a period of time following recurrent exposure through feeding (see Table 2).

Evidence from the UK shows that the majority of children presenting with suspected CMPA fall into a ‘mild-to-moderate’ clinical expression of non-IgE-mediated allergy^[7]
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Risk factors

Children who have other confirmed food allergies or have comorbidities (e.g. eczema) are more likely to have CMPA. There is also an increased likelihood if there is a family history of atopy, such as allergies or asthma^[5],[7]
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Symptoms

Often, symptoms experienced with CMPA are common presentations that may not have any association with CMPA. Generally, CMPA should be suspected in children presenting with one or more of the signs and symptoms listed (see Table 1 and Table 2), and particularly for those with persistent symptoms involving different organ systems. CMPA should also be suspected in children with symptoms that do not respond adequately to usual management and a referral should be made to the GP for further investigation^[6]
. Questioning parents and carers about their child’s symptoms will aid diagnosis (see Box 1).

Diagnosis

The clinical manifestations of CMPA are variable in type and severity, making it a difficult allergy to diagnose. A careful age- and disease-specific history is needed, with relevant investigations, guided by the suspected mechanism of the reaction. For children with immediate IgE-mediated reactions, allergy testing (e.g. skin prick tests or specific IgE antibody blood testing) will need to be undertaken to confirm the diagnosis^[6]
. It may also be appropriate for the child’s GP to refer them to an allergy clinic for further advice.

For suspected non-IgE-mediated CMPA, the investigations will include a diagnostic elimination diet to see if symptoms improve, followed by a planned reintroduction to test if the symptoms recur when milk is added back into the diet. Determination of which investigations are needed and the formal diagnosis are usually undertaken by the GP or a paediatrician with an interest in allergy.

Treatment

In infants, eczema may start with a dry itchy rash on the cheeks, which spreads all over the body. Treatment with routine use of emollients will prevent skin dryness and should reduce the itch. Topical corticosteroids may be recommended if emollients alone are not effective^[8]
. Flare-ups after ingestion of cow’s milk may indicate CMPA, especially if there are other concomitant symptoms present.

Thickened feeds are formulated to reduce the severity and occurrence of regurgitation; however, it can be common for children to experience frequent vomiting and abdominal pain post-feeding. Sodium alginate may also be trialled in children to ease such symptoms^[9]
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Colic is another common presentation in pharmacies and is defined as when an otherwise healthy baby cries for at least three hours a day, for three days a week, for at least three weeks and can be caused by trapped wind. Parents should be advised to hold the baby upright to help any wind pass and, if breastfeeding, the mother should be advised to avoid caffeine, alcohol, spicy foods and chocolate as these may aggravate colic in the child. Although there is little evidence for use, antifoaming agents or products containing sodium bicarbonate (e.g. gripe water) may be tried^[8]
. CMPA should be considered a possibility if these options are unsuccessful.

Many children suffer from constipation that will generally resolve without treatment. Similarly, diarrhoea should resolve within 24 hours in infants aged under one year or within 48 hours in children aged under three years. An infant with chronic constipation or diarrhoea should be referred to the GP for further investigation^[8]
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Parents should be advised to keep their child (if aged over six months) adequately hydrated with water if there is any ongoing vomiting or diarrhoea until these symptoms are resolved. If CMPA is suspected, parents should not be advised to try other over-the-counter milk substitutes.

Suspected CMPA

If CMPA is suspected or diagnosed, an appropriate hypoallergenic formula should be prescribed for the child (see Table 3).

Treatment for mild-to-moderate symptoms: IgE- and non-IgE-mediated CMPA

If the mother is exclusively breastfeeding, she should be advised to exclude all cow’s milk and cow’s milk products from her diet^[2]
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If the child is being formula fed, they should be trialled with an extensively hydrolysed formula (eHF).

If the child is receiving both breast milk and formula, the mother should exclude cow’s milk from her diet and use eHF when top-ups are needed. If the child was asymptomatic being breastfed alone, the mother can continue to consume milk in her diet^[6]
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If the cause of these symptoms is CMPA, they should no longer occur in suspected IgE-mediated disease where there is an immediate reaction. In suspected non-IgE-mediated disease, however, symptoms will usually resolve within two to four weeks of starting the exclusion diet.

In non-IgE-mediated disease, the diagnosis is proven by the reintroduction of milk, either with a reintroduction of formula or by adding milk back into the mother’s diet. Milk protein should be avoided for up to four weeks (minimum of two weeks) until there has been a clear improvement in symptoms because they could have been caused by other factors. Reintroduction should not be considered if the child is unwell. Cow’s milk should be reintroduced slowly and parents should keep a record of what the child consumes during the reintroduction period, as well as any possible symptoms (e.g. vomiting, bowel changes, rashes or changes in their eczema)^[6]
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Treatment for severe symptoms: IgE mediated

Immediate reactions with severe respiratory and/or cardiovascular system symptoms require emergency treatment and admission to hospital. Once diagnosed, consumption of cow’s milk should be excluded by the mother if the child is being breastfed and an amino acid formula (AAF) should be used if the child is formula fed. The child should also be under the care of a paediatric allergy service^[6]
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Treatment for severe symptoms: non-IgE mediated

With severe symptoms, consumption of cow’s milk should be excluded by the mother if there are symptoms from breastfeeding alone and an AAF will be needed if the child is formula fed. AAF may also be prescribed following a trial of eHF if there has not been a clear improvement in symptoms. However, parents need to be aware that it may take up to four weeks for symptoms to settle once an infant is started on an exclusion diet^[6]
. All children with severe symptoms need an urgent referral to their GP for further referral to a paediatric allergy clinic.

Formula options

Soy-based products are not recommended for infants aged under six months because they contain phytoestrogens. Furthermore, some children may also be allergic to soya. IgE-mediated soya allergy, concomitant to CMPA, is estimated at 7–14%, but is much higher in non-IgE-mediated soya allergy, concomitant to CMPA, at around 30–50%^[10]
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Partially hydrolysed formulas sold in supermarkets have proteins that are only partially broken down and can also cause an allergic reaction. Formula based on goat’s milk will also cause reactions in the vast majority of children with CMPA. Therefore, it is recommended that children with a confirmed diagnosis of CMPA are prescribed the appropriate formula (see Table 3). If parents suspect their child has CMPA, they should be advised to seek medical attention and not to buy other products.

Advice for parents worried about their child with suspected CMPA

As a pharmacist, it is important to consider CMPA as a possible diagnosis for infants with unresolved symptoms that do not respond to conventional treatment. If CMPA is suspected, parents should be advised to take their child to their GP. They should also keep a diary of ingestion of milk (even if they are exclusively breastfeeding) and record the onset of symptoms because this will help the diagnosis. Pharmacists should reassure parents that there are alternative milk substitutes available if their infant is diagnosed with CMPA and there are no associated long-term complications. Studies suggest that most children with non-IgE-mediated CMPA and IgE-mediated CMPA will be milk tolerant by the age of three and five years, respectively^[11],[12]
. Reintroduction of cow’s milk using the milk ladder should be done under supervision of a healthcare professional, usually a dietitian. It may be useful to direct parents to national patient support websites (see useful resources).