Drs Trevor Brown, Joanne Walsh, and Adam Fox present the new international version of the MAP Guideline (Milk Allergy in Primary care), emphasising practical changes relevant to primary care practice in the UK

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Dr Trevor Brown

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Read this article to learn more about:

  • the updated international MAP guideline and its algorithms
  • presentation, diagnosis, and management of cow’s milk allergy
  • which children can be managed in primary care.

Key points

Commissioning messages

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Cow’s milk allergy (CMA) continues to be one of the most common presentations of childhood food allergy in the UK. The condition typically presents in the early weeks and months of life, with the UK prevalence reported at between 2% and 3% in 1–3 year olds. The children usually first present to primary care and most could remain there for their management.1 Cow’s milk allergy is proving a significant financial burden to the NHS when correctly managed and even more so when managed inappropriately.2

Background

This article follows on from a 2015 Guidelines in Practice article, ’Cow’s milk allergy in children: a guide for primary care’.3 In this earlier article, Drs Trevor Brown and Carina Venter drew together the then UK recommendations for the primary care management of CMA in children from:

Need for MAP revision

It is recognised that all guidelines should be revisited on a regular basis, and subsequent to the publication of the MAP guideline in 2013 there have been a number of further guidance-related developments:

  • NICE’s updated CKS (last revised 2015) on managing cow’s milk allergy in children signposts primary care to the MAP guideline5
  • NICE quality standard (QS) 118 for Food allergy in children and young people6 was published in 2016 for primary care commissioners and healthcare professionals
  • practical lessons have been learnt from the increasing use of the MAP guideline in the UK and these have been fed back to the original authors
  • the MAP review article,5 first published in Clinical and Translational Allergy, the journal of the European Academy of Allergy and Immunology, has been downloaded over 60,000 times worldwide.

It therefore seemed timely to the original MAP authors, now joined by several international experts, to publish an updated version of MAP—the international MAP guideline,7 referred to below as the ‘iMAP guideline’, which can be used across the world while retaining its value for UK primary care settings.

Wider healthcare professional application of iMAP

The iMAP guideline is addressed to primary care and ’first contact’ clinicians. NICE uses the term ‘first contact’ clinicians1 to emphasise that infants with suspected CMA may present to other healthcare professionals, e.g. community dietitians, pharmacists, accident and emergency doctors, and general paediatricians.

The algorithms

Food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.8 It may then be clinically subdivided into either:

  • immediate onset IgE antibody-mediated, where the adverse effects appear usually within minutes (can be up to 2 hours) after ingestion,1,7 or
  • delayed onset non-IgE antibody -mediated, where the effects develop 2 hours or even days after ingestion.1,7

Cow’s milk allergy can present with either symptoms of IgE-mediated allergy or non-IgE-mediated allergy (uncommonly it presents with a mix of both).1,9 Evidence from the UK2 shows that the large majority of children first present in infancy. They most often have symptoms that fall into a ‘mild-to-moderate’5 clinical expression of non-IgE-mediated allergy and most then remain within primary care for their diagnosis and management.2

Like the MAP guideline, the iMAP guideline7 continues to be centred on two algorithms (see headings and text below) and they continue to be set out in the same format, in keeping with the criteria highlighted above.

iMAP presentation algorithm

The presentation algorithm (see Figure 1) lays out all the likely presenting symptoms and associates them with severity (mild-to-moderate versus severe) and mechanism (non-IgE-mediated versus IgE-mediated).

It then gives guidance on referral and, if needed, the initial category of hypoallergenic formula to be prescribed.

Algorithm designed to assist with assessing an infant with suspected cow's milk allergy on initial presentation

Figure 1: iMAP presentation algorithm

Source: Venter C, Brown T et al. Better recognition, diagnosis and management of non-IgE-mediated cow’s milk allergy in infancy: iMAP—an international interpretation of the MAP (Milk Allergy in Primary Care) guideline. Clin Transl Allergy 2017; 7: 26. Reproduced with permission

CMA=cow’s milk allergy; CMP=cow’s milk protein; eHF=extensively hydrolysed formula; AAF=amino acid formula; GORD=gastroesophageal reflux disease; CVS=cardiovascular system

The allergy-focused clinical history

The presentation algorithm header continues to include the text: ‘…having taken an allergy-focused clinical history’. The need to take such a history has now been reinforced by quality statement 1 in NICE QS118 on Food allergy:6

‘Children and young people with suspected food allergy have an allergy-focused clinical history taken.’

A practical list of questions to ask parents/carers is given in both the MAP5 and iMAP7 guidelines (see Box 1). It is acknowledged that it can take time to take a full allergy-focused history. This could be facilitated with the use of questionnaires/checklists completed by parents or with the help of other healthcare professionals, e.g. health visitor, practice nurse. If families first approach one of the UK national patient support groups, e.g. Allergy UK, such an initial questionnaire/checklist approach could be also used.

Box 1: The iMAP guideline allergy-focused clinical history7

Ask about:

  • a family history of atopic disease (atopic dermatitis, asthma, allergic rhinitis, or food allergy) in parents or siblings
    • a reported history along with symptoms of suspected cow’s milk allergy makes the diagnosis more likely; this applies to both IgE-mediated and non-IgE-mediated
  • sources of cow’s milk protein and how much is being or was ingested:
    • exclusive breastfeeding: when cow’s milk protein from maternal diet comes through in the breast milk (low risk of clinical allergy)
    • mixed feeding: when cow’s milk protein is given to the breastfeeding infant, e.g. top-up formulas, on weaning with solids
    • formula-feeding infant: the commonest presentation, particularly in countries where there is poor adherence with the WHO guidance9 of exclusive breastfeeding for 6 months
  • presenting symptoms, to include:
    • if more than one symptom, the sequence of clinical presentation of each one 
    • age of first onset
    • timing of onset following ingestion (atopic dermatitis—such ‘timing’ can be very variable):
      • IgE-mediated—usually within minutes, but can be up to 2 hours
      • non-IgE-mediated—usually after 2 hours or even days
    • duration, severity, and frequency
    • reproducibility on repeated exposure
    • amount and form of milk protein that may be causing symptoms
  • details of any concern with feeding difficulties and/or poor growth
  • details of any changes in diet and any apparent response to such changes
  • details of any other previous management, including medication, for the presenting symptoms and any apparent response to this.

Symptoms

The following updates have been made in the iMAP guideline regarding symptoms of suspected mild-to-moderate non-IgE-mediated CMA:

  • ‘Usually several of these symptoms will be present’7 now replaces, ‘One or more of these symptoms5. There had been some feedback on whether the guideline prompted over-diagnosis. This change in wording better emphasises that usually more than one symptom can be expected
  • ’treatment resistance e.g. to atopic dermatitis or reflux, increases likelihood of allergy’ has been added—this reinforces the need to consider CMA when symptoms are not responding to usual management
  • the list of symptoms has been amended, e.g. respiratory symptoms and perianal redness have been removed. Although the MAP symptom list came from NICE CG116,4 the international view was that these particular symptoms were not as clearly related to CMA as the other symptoms in the list.

Guidance on referral

The iMAP guidance on referral (see Figure 1) has been informed by the NICE CKS on CMA,1 NICE QS118,6 and NICE CG134.10

NICE quality standard for food allergy from any food trigger makes the following statement with regard to referral on from primary care (quality statement 4):

‘Children and young people are referred to secondary or specialist care when indicated by their allergy-focused clinical history or diagnostic testing.’

Suspected mild-to-moderate non-IgE-mediated CMA

With regard to suspected non-severe, non-IgE-mediated CMA milk allergy, NICE CKS on CMA1 gives more specific referral guidance and clearly states that these children can remain within primary care for their diagnosis and ongoing care. The iMAP guideline conforms to this and additionally advises the support of a dietitian.7

Suspected severe non-IgE-mediated CMA

NICE CKS advises that children who have suspected severe non-IgE-mediated CMA should be referred to a paediatric specialist allergy service and the CKS sets out the circumstances in which this should be considered.1

As stated in the iMAP guideline,7there is currently no international consensus with clearly agreed definitions’ of these more severe presentations. The iMAP guideline emphasises that any such suspected symptoms should be ‘severe and persistent’ and often ‘one or more’ can be expected. NICE CKS on CMA has highlighted that ‘faltering growth’ may often be associated with these presentations (see also Figure 1).

Note Children with severe symptoms often present to secondary care and some may have earlier onset symptoms manifested as food protein induced enterocolitis syndrome (FPIES). This typically presents in infants and is characterised by repetitive, protracted vomiting that begins approximately 1–4 hours following the ingestion of a causal food (e.g. cow’s milk protein). The vomiting is often associated with decreased activity or lethargy and pallor, and potentially later followed by diarrhoea. While FPIES is not common, it is also not rare; one study reported a cumulative incidence of around 3 in 1000 new born infants at a single hospital over 2 years.11 For further information, visit the FPIES UK website

Suspected mild-to-moderate IgE-mediated CMA

There has been more uncertainty about where infants presenting with symptoms of suspected mild-to-moderate IgE-mediated CMA should be managed. NICE CKS1 now gives the following more specific guidance:1

‘[NICE] CKS recognises that the expertise to choose, perform and interpret these tests for suspected IgE-mediated milk allergy may not be readily available in primary care; therefore the diagnosis and subsequent management is more likely to be done in secondary care.’

Suspected severe IgE-mediated CMA

Children with suspected severe IgE-mediated CMA (i.e. suspected anaphylaxis) are advised to be referred to a paediatric specialist allergy service.1,10 These patients often present to secondary care initially as a medical emergency and their subsequent management falls under the recommendations of the NICE CG134 anaphylaxis guideline.10

Role of hypoallergenic formulas

Breastfeeding is always the preferred way for any infant to be fed.

Whether the infant is referred or not, the GP will usually be required to initiate a cow’s milk protein free diet.

The iMAP algorithms7 (see Figures 1 and 2) continue to advise when a hypoallergenic formula is indicated and whether it should be initially an extensively hydrolysed formula (eHF) or an amino acid-based formula (AAF). To be licensed, eHFs need to have been shown to be tolerated by 90% of children with confirmed CMA.1 Given that the large majority of infants will be presenting with symptoms suggestive of a mild-to-moderate expression of non-IgE-mediated CMA,2 an eHF should be therefore tolerated by most of these infants.

Note In the iMAP diagnosis and management algorithm, there remains the provision of substituting the eHF for an AAF trial— if the initial eHF trial of up to 4 weeks (minimum of 2 weeks) has not shown a ‘clear improvement’ and CMA is still strongly suspected (see Figure 2).

Amino acid-based formulas, made up of the individual building blocks of proteins (amino acids), are reserved for the more severe presentations of suspected CMA (see Figure 1).

The cost price of amino acid-based formulas is two-and-a-half times more than eHFs and there is some published evidence that infants with CMA may well be more likely to regain natural tolerance to cow’s milk protein earlier if they can tolerate an eHF.12

iMAP diagnosis and management algorithm

The diagnosis and management algorithm (see Figure 2) focuses only on the diagnosis of infants suspected of having mild-to-moderate non-IgE-mediated CMA. It then addresses the ongoing management within primary care.

Mild-to-moderate non-IgE-mediated CMA was formerly (and now erroneously) referred to as ‘cow’s milk protein intolerance’.

Algorithm designed to support the diagnosis and management of cow's milk allergy

Figure 2: iMAP diagnosis and management algorithm

Source: Venter C, Brown T et al. Better recognition, diagnosis and management of non-IgE-mediated cow’s milk allergy in infancy: iMAP—an international interpretation of the MAP (Milk Allergy in Primary Care) guideline. Clin Transl Allergy 2017; 7: 26. Reproduced with permission

CMP=cow’s milk protein; CMA=cow’s milk allergy; eHF=extensively hydrolysed formula; AAF=amino acid formula

Early home reintroduction

Requirement for an early home reintroduction to confirm or exclude the diagnosis of mild-to-moderate non-IgE-mediated CMA

It can be very challenging to agree with families that a home reintroduction is needed to confirm the diagnosis of CMA in any infant suspected of mild-to-moderate non-IgE-mediated CMA. This is understandable, as often a family is so relieved at seeing a clear improvement in their infant’s previously distressing symptoms and they do not wish to risk provoking a return to them. Unless a home reintroduction is carried out, some infants will continue unnecessarily on a restricted and costly diet with a reduced quality of life for them and their families. NICE has emphasised this through quality statement 3 of their 2016 Food allergy quality standard:6

Children and young people whose allergy-focused clinical history suggests a non-IgE-mediated food allergy, and who have not had a severe delayed reaction, are offered a trial elimination of the suspected allergen and subsequent reintroduction.

Essentially this quality statement reinforces the principle that the diagnosis has not been confirmed until this reintroduction has taken place.

To help overcome this frequent parental reluctance to reintroduce milk protein after a short elimination trial, the iMAP guideline recommends that on the initial suspicion of mild-to-moderate non-IgE CMA, the family should be given an information sheet. This will explain that CMA is only suspected at this stage and that a home reintroduction will be needed to confirm or exclude the diagnosis. There is a new iMAP Additional File7 with an example of such an information sheet. This can be freely downloaded and given to the family.

The home reintroduction is usually carried out within 2–4 weeks (a minimum of 2 weeks) of commencing the elimination diet. It should be manageable by the primary care team with the supporting tool, The iMAP home reintroduction protocol to confirm diagnosis, in the iMAP guideline,7 which explains to the family how this can be done for both breast-fed and formula-fed infants.

For the exclusively breast-fed infant, the mother simply and gradually reintroduces cow’s milk products and cow’s milk into her own diet over a 1-week period. In a formula-fed or mixed-fed infant, an increasing number of scoops of the hypoallergenic formula are replaced with scoops of ordinary milk formula over a 1-week period. This is in the first bottle each morning to allow the onset of possible symptoms to be more easily observed during the daytime hours. Should the symptoms clearly begin to return, the parents can return to the full exclusion diet. The diagnosis of CMA is then confirmed as the child’s symptoms gradually settle again. However, if by the end of the week the infant tolerates either one whole bottle of cow’s milk formula daily or dairy products reintroduced again in the maternal diet, the diagnosis of milk allergy has been excluded and the infant should return to an unrestricted diet. In practice this elimination/reintroduction will importantly serve to exclude CMA in a number of these presenting infants.7

Dietitian support

NICE suggests referral to a dietitian when all cow’s milk protein is excluded from any infant’s diet.1 There are widespread areas in the UK (especially within the community) where such dietetic services are limited. Therefore, it may be worth considering that in such areas referral should only be made when the diagnosis is confirmed in either the formula- fed or mixed-fed infant. The exception to this is when the presenting infant has already been started on solid foods. iMAP has adopted this guidance position (see Figure 2).

Suspecting CMA in an exclusively breast-fed infant is less common. To then exclude all cow’s milk protein completely from the mother’s diet is significantly more challenging. Skilled advice will need to be given to ensure that the ongoing nutritional needs of both the mother and the infant are being met, e.g. the mother will need to be advised how much additional daily calcium and vitamin D supplementation she will need to take. The MAP algorithm (i.e. Figure 3 of the MAP guideline)5 gave recommended daily doses for calcium and vitamin D but ideally these should be individualised for each mother. For these reasons, it is still considered advisable to enlist the early support of a dietitian at suspicion of the diagnosis and consideration of an elimination diet for an exclusively breastfeeding mother (see Figure 2).

Hypoallergenic formula recommendations—one change

When CMA has been confirmed as the cause of symptoms in an exclusively breast-fed infant, MAP5 advised that an AAF should be used if that infant subsequently needed any formula feeds. Because these are infants who have presented with only mild-to-moderate symptoms, iMAP is now recommending:7

If top-up formula feeds should later be neededeHF may well be tolerated: if notreplace with AAF.’ 

In other words, an eHF should always be tried first in those infants with mild-to-moderate symptoms.

Later reintroduction to test for naturally reacquired tolerance

In the diagnosis and management of suspected mild-to-moderate non-IgE-mediated cow’s milk allergy, two planned reintroductions are required1,6—the first to confirm or exclude the diagnosis and the second, on confirmation, to later test for naturally reacquired tolerance.

The new iMAP milk ladder

The iMAP diagnosis and management algorithm (Figure 2) continues to recommend that children with confirmed mild-to-moderate non-IgE-mediated milk allergy should remain on a supervised cow’s milk protein exclusion diet until 9–12 months of age and for at least 6 months. Then most can be gradually and successfully reintroduced at home to food containing cow’s milk protein to test for naturally reacquired tolerance. This reintroduction is usually carried out in the form of a graduated ‘milk ladder’.

The iMAP guideline contains the new iMAP milk ladder and some implementation advice.7

Since the publication of the MAP milk ladder,5 there has been concern in the UK about it being used for the reintroduction of milk protein to the diet of infants with severe non-IgE-mediated CMA or even IgE-mediated CMA. It is therefore more clearly stated on the iMAP ladder and its accompanying information sheet that it must only be used in mild-to-moderate expressions of non-IgE-mediated allergy.

The rationale for using such a graduated ladder of milk products is that the more heated cow’s milk protein is, particularly within the matrix effect of wheat and fat (e.g. biscuit, muffin, and pancake), the less allergenic it is rendered.9,13

Ideally at this stage a dietitian will be taking the lead in implementing the use of the ladder in each child. In the development of this new iMAP milk ladder, a number of factors were taken into account by the two dietetic authors (Drs Carina Venter and Rosan Meyer), such as:

  • the amount of cow’s milk protein provided, and for the earlier steps, the timing and temperature of heating, as well as the matrix effect of wheat and fat13
  • feedback from UK dietitians with regard to their use of the MAP ladder
  • healthy eating, and general feeding practices across the world.

As a result, the iMAP ladder has now been reduced from the 12 steps of the MAP ladder to just 6 steps. New home recipes are provided for steps 1, 2, and 3.

It is, however, acknowledged that some families may not be confident with home baking and then the dietitian may find it more practical to recommend an alternative, locally available, commercially baked milk product that meets as closely as possible the baked milk requirement of the step being implemented.

Can all children with mild-to-moderate non-IgE CMA be put on the iMAP milk ladder at home?

The iMAP authors want to ensure that home reintroduction of milk is safe, particularly in children who may not have been assessed by allergy specialists. It is therefore recommended that at the time of considering starting the iMAP milk ladder, allergy testing may first be required in some infants and advice may need to be sought from the local paediatric allergy service in the following clinical circumstances (see Figure 2):

  • if there is a history of significant atopic dermatitis—not just an isolated patch of dry skin—specific IgE blood testing (or skin-prick testing if available) for cow’s milk protein should be carried out to ensure the child has not now been sensitised to milk and is potentially at risk of an immediate-onset reaction (i.e. suspected IgE mechanism) on reintroduction. This is unlikely but possible and so if the test is positive, then advice from the local paediatric allergy service should be sought. If the test is negative, home reintroduction can be considered
  • if the child, from confirmation of the diagnosis of mild-to-moderate non-IgE CMA, has subsequently ever had what sounds like an accidentally triggered cow’s milk protein immediate onset reaction, the same specific allergy testing will also be indicated and the continuing support of the local paediatric allergy service should be sought.

In some cases, the specialist advice may be still to proceed to a home reintroduction with baked milk. Provided it is considered clinically safe, it is both easier for the family and carries significant health service cost savings for this gradual reintroduction to occur within the home rather than under observation within the specialist allergy service.

Support for families

The following UK national patient support groups can be of significant ongoing help to families:

Conclusion

Suspicion of milk allergy in an infant continues to be the most common presentation of early childhood food allergy in the UK. Clinically it is complex due to its differing possible presentations, making it challenging to diagnose. Most infants who present with suspected CMA have non-IgE-mediated manifestations with delayed-onset, mild-to-moderate symptoms. NICE clearly recommends that such children should be diagnosed and managed in primary care and the MAP management algorithm addressed that. However, those infants who present with either immediate-onset IgE-mediated symptoms or those who progress to more severe non-IgE-mediated symptoms need to be promptly and reliably identified in order to allow early referral. The MAP presentation algorithm addressed that.

The current authors have published a study showing the positive effect on UK infant prescribing patterns by following a set of guidelines, which included the MAP guideline algorithms.14 With the increasing use of MAP throughout UK primary care, important lessons have been learnt and fed back to the authors. This, along with the now wider range of relevant UK NICE publications and the additional input of international clinical experts, has led to this newer international MAP guideline version.

The iMAP guideline, with its amended algorithms and growing portfolio of accompanying freely downloadable additional file tools, should help primary care clinicians to work well with families to further improve the quality of care. Hopefully this will lead to more improved UK health outcomes, including:

  • better awareness of when CMA should be suspected
  • early referral of children requiring specialist allergy assessment
  • early identification of those remaining children who can be effectively and safely managed in primary care following proper confirmation of their diagnosis.

The increasing interest in the MAP guideline in the rest of the medical world has been encouraging. Therefore, having enlisted the help of six international colleagues, iMAP is now very intentionally also presented as a potentially useful guideline for primary care and ‘first contact’ clinical colleagues throughout the wider medical world.

Acknowledgements

The authors of this article thank and acknowledge their fellow iMAP authors:

UK Dr Rosan Meyer, Dr Neil Shah

USA Dr Carina Venter, Prof Anna Nowak-Wegrzyn, Prof David M. Fleischer

China Prof Tong-Xin Chen

Australia Dr Ralf G. Heine

South Africa Prof Michael Levin

Brazil Dr Mario C. Vieira

iMAP milk ladder dietetic authors Drs Carina Venter and Dr Rosan Meyer.

Key points

  • In the UK, 2–3% of 1–3 year olds have confirmed CMA—a substantial burden to the NHS
  • The large majority of CMA is diagnosed in primary care and most children can be safely managed there
  • The varying presentations of CMA can be clinically grouped into:
    • mild-to-moderate non-IgE delayed onset
    • severe non-IgE delayed onset
    • mild-to-moderate IgE immediate onset
    • severe IgE immediate onset (anaphylaxis)
  • The majority of infants with suspected CMA will present with mild-to-moderate non-IgE symptoms and NICE advises that they should be diagnosed and managed in primary care providing that referral is not indicated:6
    • the diagnosis must first be confirmed by a trial elimination diet followed by an early planned home reintroduction of cow’s milk protein
  • The remaining children (with suspected severe non-IgE or IgE CMA) need to be identified and appropriate early onward specialist referral considered
  • For all infants presenting with suspected CMA, if an initial hypoallergenic formula needs to be prescribed in primary care, the correct one must be chosen:
    • usually an extensively hydrolysed formula is prescribed initially
  • NICE advises that the ongoing management of confirmed CMA in any infant should be supported by a dietitian6
  • The iMAP downloadable parent information sheets can help:7
    • explain the suspected diagnosis
    • highlight the tests needed, and
    • support the reintroduction of milk, both for testing the diagnosis and also at a later stage to see if children are growing out of the condition.

CMA=cow’s milk allergy; iMAP=international MAP (Milk Allergy in Primary care) guideline

GP commissioning take home messages for England

written by Dr David Jenner, GP, Cullompton, Devon

  • Cow’s milk protein allergy is a common condition but its diagnosis is not straightforward
    • it often takes significant time to take the history, make the diagnosis and, in particular, persuade parents to undertake an early reintroduction of CMP
  • Commissioners should ensure that:
    • GPs are supported by trained health visitors or dietitians
    • onward referral is a simple process
  • Local formularies should include:
    • details of eHF and AAF milk formulas
    • details of leaflets that prescribers can share with parents about the need for early CMP reintroduction
    • links to the iMAP guideline and algorithms to ensure that these formulas are used correctly
  • Local care pathways should clearly identify when referral should be made and to whom.

CMP=cow’s milk protein; eHF=extensively hydrolysed formula; AAF=amino acid-based formula; iMAP=international MAP (Milk Allergy in Primary care) guideline


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Read the Guidelines summary of the iMAP group guideline on Better recognition, diagnosis and management of non-IgE-mediated cow’s milk allergy in infancy for more recommendations on how to handle cow’s milk allergy in young children