Cow’s milk protein allergy (CMPA) is something that every GP is likely to come across on a regular basis when working with infants. It is one of the most common childhood food allergies; affecting around 7% formula and mixed-fed infants,1 0.5% exclusively breastfed infants,2 and 2-3% of 1-3 year-old children3 in the UK.

There are different classifications of CMPA, and these are detailed below. The majority of infants in the UK present with mild to moderate non-IgE CMPA and will be diagnosed and managed in primary care.4 The role of GPs and other first contact clinicians in correctly diagnosing the type of CMPA and distinguishing it from other commonly presenting infantile disorders such as gastroesophageal reflux (GOR) is paramount to offer the correct management and refer to the appropriate healthcare professionals as needed. However, historically, this has not been the case. A 2010 review of a UK primary care database found that CMPA was routinely being misdiagnosed, diagnosis was being delayed, management was suboptimal and very few families were being referred to a paediatric dietitian for support.4

                        

The majority of infants in the UK present with mild to moderate non-IgE CMPA and will be diagnosed and managed in primary care

            

In an attempt to address this, in 2013 a group of clinicians that had previously worked on the 2011 NICE Food Allergy in Children and Young People guidance5 developed the Milk Allergy in Primary Care (MAP) guideline.6 This included a simple algorithm to help with diagnosis and management of CMPA and explained when referral to other health professionals was necessary. Due to its positive impact on UK prescribing practices,7 ease of use and popularity, MAP was updated in 2017. The new version is known as iMAP (https://www.allergyuk.org/health-professionals/mapguideline8), and has incorporated new guidelines and evidence published since 2013,9,10,11 along with international expertise. It is now suitable for use beyond the UK. It still provides easy-to-use algorithms, with additional factsheets and tools for health professionals and caregivers. This article will focus largely around this guidance, helping you to distinguish between the different types of CMPA and how they should be managed with a primary care focus.  

What is CMPA?

CMPA is an immune mediated allergic response to the protein found in cow’s milk. Infants can present with a wide range of symptoms with varying onset and severity, but broadly it can be divided into the following categories:9

  • IgE-mediated: in these reactions, the production of IgE antibodies in response to exposure to cow’s milk protein causes the release of histamine and other chemicals from mast cells and basophils. Symptoms develop rapidly, usually apparent within 20-30 minutes, but can take up to 2 hours.9
  • Non IgE-mediated: these reactions are thought to be caused by T-cells and symptoms take longer to develop, usually ≥2 hours after exposure.9
  • Mixed (IgE and non-IgE).9

A summary of the presenting symptoms for each classification of CMPA is shown in Figure 1.8

Diagnosing suspected CMPA

To exclude other conditions and establish the type and severity of a suspected CMPA, an allergy-focused clinical history is essential and the best place to start for a first contact consultation.10 This almost exclusively uses information given by the parents or caregivers and should include the following questions:5

  • Is there any history of atopic disease in the immediate family, e.g. atopic dermatitis, asthma, allergic rhinitis or food allergy? A family history of atopy makes the likelihood of a food allergy significantly higher.
  • What is the infant’s feeding history and current mode of feeding? How much cow’s milk is being ingested and what is the source?
  • Are they exclusively breastfed? If so, what is the maternal diet? Note: these infants have a much lower risk of clinical allergy.
  • Have there been any changes to the infant’s diet? Have top up formula feeds been introduced to the breastfed infant recently, or have complementary foods been introduced?
  • Is the infant formula fed? (these infants most commonly present with CMPA).
  • What are the presenting symptoms?
  • When did they first occur? And if multiple symptoms, in what order?
  • How long after the ingestion of cow’s milk do the symptoms occur? What is the duration, severity and frequency of the symptoms?
  • Do the symptoms recur when exposure to cow’s milk is repeated? What amount and form of cow’s milk protein seems to be causing the symptoms?
  • Are there any concerns with feeding difficulties and/or faltering growth?
  • Has there been any previous management for the reported symptoms? Any success or response?

This clinical history should be accompanied by a physical examination to check for conditions such as atopic dermatitis and perform anthropometric measurements (weight, length and head circumference).9 If CMPA is suspected, the iMAP Presentation Algorithm can then be used to ascertain which of the four symptom complexes (see Figure 1) the clinician feels applies to the infant and which initial management strategies should be applied.8

Don’t I also need to arrange for allergy testing to diagnose a food allergy?

Many parents and caregivers will assume that their child will require an allergy test to confirm the presence of a food allergy. It is always worth enquiring as to whether any alternative tests have been carried out as these are widely available in the community and are not medically approved or accurate (e.g. hair testing, kinesiology).11 Skin prick or specific IgE antibody blood testing is only required if an IgE mediated allergy is suspected.11 Even then, a positive result only shows sensitisation and must be interpreted by a clinician with appropriate training and skills10 – this almost always means a referral to secondary care. There are no validated tests to check for the presence of a non-IgE mediated allergy.5

Managing suspected CMPA

Initial management

The iMAP presentation algorithm provides clear guidance for the initial management of the different types of suspected CMPA.8 In all cases, except an acute severe IgE-mediated reaction – which is very rare and would require emergency treatment – the first thing to advise is the elimination of cow’s milk from the infant’s diet.8 In an exclusively breastfed infant this will mean taking a maternal diet history and advising complete avoidance of all cow’s milk in her diet, a suitable milk alternative, and for her to take a daily calcium and vitamin D supplement.8 Support from a dietitian is preferable, and a referral should be made if possible.8

If the infant is mixed or formula-fed, then an appropriate cow’s milk free infant formula needs to be prescribed. These come under the following categories (see also Table 1):

  • Extensively hydrolysed infant formulas (eHFs): enzymes, heat, pressure and ultrafiltration are used to break the cow’s milk protein molecules into small pieces (<3000Da) which are less likely to mount an immune response.12 It is estimated that around 90% of infants with CMPA should tolerate an eHF,10 and they are also around a third of the price and amino acid formulas. This means that an eHF should almost always be the first line cow’s milk free infant formula prescribed to an infant presenting to primary care, the exception being severe presentations.8
  • Amino acid infant formulas (AAFs): the protein faction in this group of formulas is made up of individual amino acids. They are indicated in severe presentations of CMPA, anaphylaxis and for infants who have not tolerated eHFs. Infants on AAFs will therefore usually be managed in secondary care.10

If complementary foods have been introduced, support from a paediatric dietitian will be needed to advise on effective elimination of cow’s milk, a suitable milk alternative, and to ensure nutritional adequacy.8

Onwards referral

Once this initial advice has been given, suspected IgE-mediated CMPA, and severe presentations of non-IgE mediated CMPA should be referred to secondary care or a specialist allergy service if available.8 For the most part, mild to moderate presentations of non-IgE mediated CMPA can be managed in primary care along with the support from a paediatric dietitian.8

                                     

But aren’t there other infant formulas that can be used for CMPA?

You may find that infants come into your practice taking the following formulas, but they are not appropriate for treating CMPA:

Soya formula (e.g. SMA Wysoy): These formulas are based on soy protein and are not recommended for infants under six months due to concerns that high levels of phyto-oestrogens present may pose a potential risk to future reproductive health.13 Furthermore, a significant proportion of infants with CMPA will also be allergic to soy.14  

Partially hydrolysed cow’s milk (HA) formula (e.g. SMA HA, Hipp Combiotic Comfort, Aptamil Comfort): These are available to buy over the counter and can claim to prevent CMPA in at-risk infants with a family history of atopy. There is currently insufficient evidence to support these claims, and care should be taken that they are not given to infants already diagnosed with CMPA.15

Goat’s milk formula (e.g. Holle Organic Infant Goat Milk Formula 1, NANNYcare First Infant Milk): Infant formulas based on other mammalian milk proteins such as goat are not recommended for the treatment of CMPA as there is a high risk of allergenic cross-reactivity.9

Lactose free formula (e.g. Aptamil Lactose Free, SMA LF): The only difference between these formulas and standard infant formula is that the carbohydrate component is glucose rather than lactose.15 They are therefore not suitable for treating CMPA.

 

            

Ongoing management of mild to moderate non-IgE mediated CMPA

For the proportion of infants diagnosed with suspected mild to moderate non-IgE CMPA that have had initial advice on elimination of cow’s milk from their diet/the maternal diet, the iMAP Management Algorithm (Figure 2) details what to do next.

Elimination of cow’s milk should be agreed for a minimum of 2 weeks and up to 4 weeks.8 It is important at this stage to explain to families that a home reintroduction step will be required to confirm the diagnosis. Many can be reluctant to undertake this, especially if there has been an improvement in symptoms. However, this step is vital in determining whether the symptoms have naturally improved with time or are due to a genuine CMPA.8 The iMAP website provides a factsheet for parents to take away with them outlining this, which can be helpful.16

If the infant’s symptoms improved on the elimination diet and then returned with the home reintroduction, then the diagnosis of CMPA is confirmed and the cow’s milk free diet should continue until 9-12 months of age or for at least 6 months.8 If it hasn’t been done already, a referral to a paediatric dietitian should be made at this stage.8

It is thought that most children with non-IgE mediated CMPA will be tolerant to cow’s milk by 3 years of age,9 therefore, it is important to check tolerance once the child has been avoiding cow’s milk for the specified time mentioned above.8 For most infants/children this can be in the form of a home reintroduction using a ‘milk ladder’, with a dietitian taking the lead.8 However, if there is any atopic dermatitis or any history of immediate onset symptoms, then allergy testing needs to be arranged and the pathways followed on the management algorithm (Figure 2).8

What is a Milk Ladder?

A milk ladder is a staged approach to reintroducing cow’s milk protein, starting with very well-cooked forms, and working towards raw cow’s milk. This is based on the premise that heat treatment alters the structure of the protein and reduces the allergenicity.9

The iMAP guidelines provide a ready to use milk ladder.

 

Where can I find more information?

As well as the iMAP guidelines,8,16 it is prudent to be aware of guidelines that exist in your local area and the local health professionals that children with CMPA can be referred to.

References

1. Caffarelli C, Baldi F, Bendandi B. et al. Italian Journal of Pediatrics. 2010. 36(5)
2. Vandenplas Y, Brueton M, Dupont C, et al. Archives of Disease in Childhood. 2007. 92(10), 902-908
3. Venter C, Pereira B, Voigt K, Grundy J, Clayton CB, Higgins B, et al. Allergy. 2008. 63(3):354–9.
4. Sladkevicius E, Nagy E, Lack G, Guest JF. Journal of Medical Economics. 2010. 13(1):119–28
5. National Institute for Health and Clinical Excellence (2011). Food allergy in children and young people. Available at: https://www.nice.org.uk/guidance/cg116/resources/cg116-food-allergy-in-children-and-young-people-full-guideline3 (accessed March 2018)
6. Venter C, Brown T, Shah N, Walsh J, Fox AT. Clinical and Translational Allergy. 2013. 3(1):23.
7. Wauters L, Brown T, Venter C, Dziubak R, Meyer R, Brogan B, et al. Journal of Pediatric Gastroenterology and Nutrition. 2016. 62(5):765–70
8. Venter C, Brown T, Meyer R, Walsh J, Shah N, et al. Clinical and Translational Allergy. 2017. 7:26
9. National Institute for Health and Clinical Excellence (2015). Cow’s milk protein allergy in children, clinical knowledge summary. Available at: http://www.cks.nice.org.uk/cows-milk-protein-allergy-in-children (accessed March 2018)
10. National Institute for Health and Clinical Excellence (2016). Quality standard for food allergy. Available at: http://www.nice.org.uk/guidance/qs118 (accessed March 2018)
11. Luyt D, Ball H, Makwana N, Green MR, Bravin K, Nasser SM, et al. Clinical & Experimental Allergy. 2014. 44(5):642–72
12. Ludman S, Shah N,Fox A. British Medical Journal. 2013. 347: f5424
13. Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (2003). Phytoestrogens and Health. Available at: https://cot.food.gov.uk/sites/default/files/cot/phytoreport0503.pdf (accessed March 2018)
14. Agostoni C, Axelsson I, Goulet O, et al. Journal of Pediatric Gastroenterology and Nutrition 2006. 42:352-361
15. First Steps Nutrition Trust (2018). Specialised Infant Milks in the UK: Infants 0-6 months. Information for Health Professionals. Available at: http://www.firststepsnutrition.org/pdfs/Specialised_infant_milks_January_2018b.pdf (accessed March 2018)
16. iMAP Guideline. Available at: https://www.allergyuk.org/health-professionals/mapguideline (accessed March 2018).

                        

Rychelle Winstone Clinical Lead Paediatric Dietitian, Hywel Dda District Health Board

            

References

  1. References available online at www.bjfm.co.uk