Top Tips: Cow's Milk Protein Allergy

Dr Toni Hazell Shares 10 Top Tips on the Primary Care Diagnosis and Management of Cow’s Milk Protein Allergy in Children

Cow’s milk protein allergy (CMPA) in children is defined by NICE as ‘… a reproducible immune-mediated allergic response to one or more proteins in cow’s milk’.¹ It can be complex to diagnose in general practice because there is a wide range of presenting symptoms, which vary depending on whether or not the allergy is mediated by immunoglobulin E (IgE).

Cow’s milk protein allergy is more common in boys than girls and other risk factors include pre-existing personal or family history of atopic disease, such as asthma, eczema, or other food allergy.²

1. Remember Immunology

It is important to understand the two different types of CMPA. IgE-mediated allergy is caused when an antigen, such as cow’s milk protein, binds to two IgE molecules on the surface of mast cells. This causes cross-linking and the mast cell degranulates, releasing mediators such as histamine and causing symptoms.³ Other atopic conditions such as asthma and hay fever are IgE-mediated.³ This process is well understood, in contrast to non-IgE-mediated allergy, about which we know less; it is thought to be T cell-mediated.⁴ The two key clinical differences between these types of allergy lie in how they present, and the ability to test for them in primary care.

2. Consider that Not All Allergy Presents Immediately

Children with IgE-mediated allergy present with symptoms that most doctors, and many of the public, would immediately recognise as being an allergy (see Table 1). Symptoms often occur within minutes of ingesting the substance, and never more than 2 hours later.⁵ They may include an urticarial rash, itch, angioedema, or flare of pre-existing eczema.⁵

In contrast, children with non-IgE-mediated disease present with symptoms at least 2 hours after ingestion of the allergen, and sometimes up to 72 hours afterwards (see Table 1).⁵ This causes a diagnostic challenge as the reaction is not immediately linked to the allergen. Children with non-IgE-mediated allergy can present with an itch, rash, or flare of pre-existing eczema, but also with symptoms not immediately linked to allergy, such as gastroesophageal reflux, loose stools containing blood or mucus, constipation, or redness in the perianal area.⁵ Some children will have even more vague symptoms, such as pallor, tiredness, or failure to thrive.⁵ It is important to have a low threshold for diagnosis of CMPA in children with gastrointestinal symptoms or failure to thrive, even if there are no symptoms that are ‘classic’ for allergy.

Table 1: Symptoms and Signs of Possible IgE- and non-IgE-mediated Cow’s Milk Allergy^A,5

3. Do Not Miss Anaphylaxis

Many children with CMPA will have symptoms that can be managed in primary care, at least initially, but it is important to be alert for anaphylaxis and angioedema.

Anaphylaxis is defined by NICE as: ‘… a severe, life-threatening, generalized or systemic hypersensitivity reaction characterized by rapidly developing airway and/or breathing and/or circulation problems usually associated with skin and mucosal changes.’ ⁶ It causes around 20 deaths in the UK each year, although this may be an underestimate.⁷

Angioedema is defined by NICE as: ‘… swelling of deep dermis, subcutaneous, or submucosal tissue, often affecting the face (lips, tongue, and eyelids), genitalia, hands, or feet. Less commonly, submucosal swelling affects the bowel and airway.’⁶ Angioedema is a less severe reaction as the cardiorespiratory collapse seen in anaphylaxis does not occur in angioedema. The two reactions do, however, have the same mechanism and it may sometimes be appropriate to prescribe an adrenaline auto-injector (AAI) for patients with a history of angioedema but not anaphylaxis.⁸

4.  Take a Good History

Most of us will remember being taught at medical school that 80% of the diagnosis is in the history,⁹ an aphorism that comes from a small study done 46 years ago,¹⁰ which probably still holds true even now that we have so many more investigations at our fingertips.

NICE Clinical Guideline 116 on Food allergy in under 19s: assessment and diagnosis sets out the components of the ‘allergy-focused clinical history’ (see Box 1).¹¹ It reminds practitioners to set the allergic reaction in a broader context and that the questions will change depending on the child’s age. For infants, it is important to know if the mother is breastfeeding and, if so, whether her diet contains any suspected allergens. Allergic reactions will happen in all settings: does the child have a similar reaction at home, at nursery/school, when they visit grandparents, or anywhere else? Knowing the speed of the reaction will help to determine if it is likely to be IgE-mediated or non-IgE-mediated, which is vital when deciding how to investigate.

It is also very important to find out what has been done already. If a child’s diet has been significantly restricted before the consultation then there may be concerns about nutrition, making dietetic involvement at an early stage an important step.

5. Use Blood Tests Wisely

My GP trainer once told me ‘never do a test if the result won’t affect your management’, and that principle applies to allergy as much as to any other area of medicine. Adult patients and parents of young children often come to the GP with an opening gambit of ‘I need allergy tests, doctor’. Take a step back and think about the interpretation of such tests before requesting them.

There are two ways to diagnose CMPA: skin prick testing (SPT) and blood tests for specific IgE (sIgE).¹ SPT is generally carried out in secondary care or in clinics with a GP with a special interest/extended role, but sIgE tests are available in primary care. Crucially, no tests can diagnose non-IgE-mediated CMPA and it is important to be upfront about this with patients.¹ Requesting an sIgE test in a child with symptoms of non-IgE-mediated CMPA is not a benign decision: the parents will be confused when the test is negative and the child will have undergone a blood test for no reason.

If you suspect IgE-mediated CMPA, or indeed any other food allergy, target the tests at the likely allergen(s). Testing for total IgE is not generally useful: all it will tell you is that the patient is, or is not, atopic and you will already know that from the history. Similarly, do not be tempted to take a ‘scattergun’ approach, testing for a wide range of common allergens; tests should be requested and interpreted in the context of the history.¹¹ It is possible for someone to have a positive sIgE to a food that they eat regularly with no clinical reactions. This is sensitisation, not allergy,^12,13 and diagnosing as an allergy by tests that were not clinically indicated runs the risk of their diet being unnecessarily restricted.

6. Know How to Diagnose Non-IgE-mediated Allergy

Non-IgE-mediated allergy can only be diagnosed by a trial of dietary change; in the case of CMPA this involves eliminating all cow’s milk from the diet for 2–4 weeks.¹ For infants this can be done by the provision of prescribed hypoallergenic formula, or by the elimination of dairy from the mother’s diet if the child is breastfed. Depending on local resources and the urgency and severity of the child’s symptoms, you may be happy to supervise this in primary care or you may feel that referral to a paediatric dietitian is more appropriate.¹ The diagnosis of CMPA can only be made when the symptoms resolve during this elimination period and, crucially, recur when cow’s milk is reintroduced.¹⁴ Reintroduction of cow’s milk is important to avoid a false diagnosis of CMPA leading to unnecessary restriction, but parents can be understandably reluctant to restart giving their child the cow’s milk when it has previously caused them unpleasant symptoms. For this reason, it is important to make it clear at the start of the trial that if symptoms resolve, a reintroduction will be necessary to confirm the diagnosis. With only around 2% of children having a true diagnosis of CMPA, the use of an elimination diet without a reintroduction test is one of the most likely causes of overdiagnosis.¹⁵

7. Start Hypoallergenic Formula Feeds and Refer at the Same Time

Hypoallergenic formula feeds are expensive and so many CCGs¹⁶ have prescribing guidelines limiting their use to those who have been diagnosed with CMPA by a paediatrician. However, there is usually an exemption stating that such formula feeds can be started in primary care while the child is waiting to be seen in secondary care.

Two types of formula feed are available: extensively hydrolysed formula (eHF) and amino acid formula (AAF). eHF, in which the cow’s milk protein has been broken down into smaller peptides, should always be used first-line and will be tolerated by most children. eHF is cheaper than AAF and, anecdotally, it tastes better. A minority of children will not tolerate eHF and a trial of AAF, in which there are no peptides, may be indicated. An infant who is fully formula fed will usually need 2–3 tins of formula per week,¹⁷ with the amounts reducing as the child gets older. Guidelines on the specific brands to prescribe may be available from your local CCG, and the British Dietetic Association provides fact sheets on milk allergy and suitable milks for children with CMPA.^18,19

Parents should not use soya milk as an initial substitute for formula feed during the diagnostic process as some patients with CMPA will also react to soya.¹⁷ It also has a weak oestrogenic action, although the clinical significance of this is unclear. NICE advises against the use of soya milk in infants under the age of 6 months.¹⁷ Similarly, the poor nutritional value of other milks such as almond, oat, and coconut means that they should not be used in children under the age of 1 year. Milk from sheep or goats should not be used because of the risk of cross-reactivity in those with CMPA.¹⁷

8. Remember that Most Children with Allergy Do Not Need an AAI

Adrenaline auto-injectors have been in the news over the past few years for different reasons, including concerns about the length of the needle²⁰ and drug shortages,²¹ which led to official advice to use some devices beyond their expiry date.²² GPs could be forgiven for being confused about what to prescribe and when.

All patients with a history of anaphylaxis should be prescribed an AAI. NICE recommends seeking specialist advice about prescribing an AAI for people at high risk of anaphylaxis while they are awaiting specialist review.⁸ The high-risk group includes those who have had angioedema and also have asthma, chronic obstructive pulmonary disease, or heart disease, as well as people who have had angioedema with trace amounts of an allergen, and those who cannot easily avoid an allergen.⁸ If specialist advice is not available rapidly, pragmatically it may be necessary to give this group an AAI pending specialist review, making it clear in your referral that you have done this as a temporising measure and would like advice from the specialist if it needs to be continued. Three brands of AAI are available in the UK (Emerade®, Jext®, and EpiPen®) and the dose varies depending on the weight of the child.²³

9. Prepare for Parents to Ask if Their Child Will Grow Out of CMPA

Broadly speaking, children with non-IgE-mediated allergy are more likely to grow out of it than those with IgE-mediated allergy.¹ One large prospective study identified CMPA in 55 of 12,000 children.²⁴ At 1 year after diagnosis, 32 of these children were re-evaluated with a double-blind, placebo-controlled food challenge and it was found that 22 (69%) could tolerate cow’s milk. The allergy had resolved in all the children with non-IgE-mediated allergy and in 57% of those with IgE-mediated allergy.²⁴

A retrospective review carried out in 2007 also found high levels of resolution, with 79% of the cohort of 807 children having grown out of their allergy by the age of 16 years.²⁵ Factors associated with non-resolution include:²⁵

• coexisting asthma or allergic rhinitis (or a family history of atopy)
• severe symptoms
• strongly positive tests (larger reaction on SPT or higher sIgE values)
• a history of multiple food allergies.

10. Remember that Most Children Can Reintroduce Cow’s Milk at Home

If we know that many children will grow out of their CMPA, it follows that it is important to reintroduce cow’s milk protein regularly, in a safe and controlled way, so that children can eat a less restricted diet. Introduction should follow the principles of the milk ladder²⁶ produced by the international Milk Allergy in Primary Care guideline team. The ladder is based on the principle that cow’s milk protein is less allergenic the more it has been cooked. The six-step ladder starts with a biscuit and builds up to milk or infant formula. It is usually supervised by a dietitian, with the amount of time spent on each step varying from child to child. Clearly, it is important to use caution for children who have had an anaphylactic reaction to cow’s milk and they will generally be managed in the hospital setting.

Summary

It is important to work out whether CMPA is IgE-mediated or non-IgE-mediated; the latter may present up to 72 hours after ingestion of the allergen. There are no tests for non-IgE-mediated allergy, which is diagnosed by making dietary changes and seeing if the symptoms resolve. Hypoallergenic formula can be started in primary care while the child is waiting to see a paediatrician. Most children with CMPA will not need an AAI. Many children will grow out of their CMPA—milk challenges can be done at home if there is no history of anaphylaxis.

Dr Toni Hazell

Part-time GP, Greater London