Drs Carina Venter (left) and Trevor Brown explain how the MAP guideline can help GPs appropriately diagnose and manage infants and children with cow’s milk allergy

  • Practitioners should be aware of the:
    • high prevalence of CMA in infants in the UK
    • signs and symptoms of all forms of CMA and correct use of clinical terminology (e.g. the distinction between IgE- and non-IgE-mediated CMA)
    • questions to ask patients and parents/carers, and the importance of the allergy-focused clinical history in making a diagnosis of CMA
  • Early assessment and consideration of the diagnosis of CMA is important, particularly if one or more gut and/or skin symptoms are involved
  • Be aware of the different specialised/hypoallergenic formulas available in the UK and how to make the most appropriate initial choice
  • Explain the importance of the initial home challenge to parents/carers to confirm a diagnosis of non-IgE-mediated CMA after a period of avoidance, and agree this early with the family
  • Identify those children who need early specialist referral, some urgently
  • Accept and ensure that any infant who needs to continue on a diet free of cow’s milk protein has the support of a dietitian
  • Be aware of:
    • the importance of testing for the development of cow’s milk tolerance and how a home milk ladder can be used in infants with mild to moderate non-IgE-mediated CMA
    • those few infants who may have ‘converted’ to IgE-mediated CMA (particularly those with atopic dermatitits) and who may need onward referral to more specialist care
  • Audit and confirm appropriate changes to your primary care team practice.

C ow’s milk allergy (CMA) is one of the commonest food allergies seen in infants and young children. It covers a wide spectrum of symptoms and it is important to be able to distinguish cow’s milk allergy from lactose intolerance. The first step in ensuring satisfactory management of infants and children with CMA is to make a clear diagnosis and have a good understanding of the immune mechanisms involved. Once a diagnosis is made:

  • dietary advice should be given to parents/carers about the avoidance of cow’s milk
  • the most appropriate hypoallergenic formula should be chosen.

As many children will outgrow their CMA, it is important then to assess for tolerance at regular intervals.

Terminology

According to the European Academy of Allergy and Clinical Immunology, and the World Allergy Organization,1 an adverse hypersensitivity reaction to cow’s milk can be termed a CMA if it involves the immune system. Non-allergic cow’s milk hypersensitivity (lactose intolerance), on the other hand, does not involve the immune system (see text under heading ‘Lactose intolerance’, below).

Cow’s milk allergy can then be divided into two categories:1

  • immunoglobulin E (IgE)-mediated CMA
  • non-IgE-mediated CMA, formerly (and still often incorrectly) referred to as cow’s milk protein intolerance; see Box 1, below.

IgE-mediated and non-IgE-mediated cow’s milk allergy

Symptoms related to IgE-mediated CMA appear within 2 hours, often within minutes, of ingesting cow’s milk; symptoms related to non-IgE-mediated CMA tend to appear over hours or days. Non-IgE-mediated CMA symptoms may, however, occur much more quickly in some cases, for example as projectile vomiting, or (uncommonly) as symptoms mimicking septic shock, related to food-protein-induced enterocolitis. Some presentations of CMA (e.g. atopic dermatitis) may be both IgE- and non-IgE-mediated (i.e. IgE-mediated in some children and non-IgE-mediated in other children; they may also fluctuate between IgE-mediated and non-IgE- mediated in some children). Some children may also exhibit both IgE-mediated symptoms (urticaria) and non-IgE-mediated symptoms (diarrhoea and vomiting).2 This all adds up to making CMA the most complex food allergy to recognise, confirm, and manage optimally.

Lactose intolerance

Children with lactose intolerance present differently: either (uncommonly) after a significant episode of infective gastroenteritis, after which they usually recover naturally after 6–8 weeks, or because of gradually evolving primary lactase enzyme deficiency, but usually not until later childhood.

Although it shares with CMA such gut symptoms as loose stools, discomfort, flatulence, and bloating, lactose intolerance does not usually lead to vomiting and is not associated with rashes. Children with lactose intolerance tend to thrive and grow well and can still tolerate most hard cheese. They also often tolerate yoghurts, particularly in small amounts.

Box 1: What is cow’s milk protein intolerance?

The term ‘cow’s milk protein intolerance’ is often used to describe non-IgE-mediated cow’s milk allergy. This term, however, wrongly gives the impression that the immune system is not involved in the symptoms seen in non-IgE-mediated cow’s milk allergy, despite clear evidence of the involvement of immune cells and their cytokines (messengers).

The need for a primary care guideline

NICE Clinical Guideline (CG) 116 on the Diagnosis and assessment of food allergy in children and young people in primary care and community settings3 clearly indicates that the less severe forms of non-IgE-mediated CMA should be diagnosed and managed in UK primary care. A subgroup of clinicians from that guideline’s development group therefore felt that there would be merit in taking the important principles of diagnosis relating to all causes of food allergy as outlined in CG116 and developing a specific guideline for CMA, focusing not only on the diagnosis but also on the ongoing management in primary care. This author subgroup, with the additional expertise of a paediatric gastroenterologist (see Acknowledgements, below) published Diagnosis and management of non-IgE-mediated cow’s milk allergy in infancy— a UK primary care practical guide (the ‘Milk Allergy in Primary Care [MAP] guideline’) in July 2013.4 The MAP guideline includes a number of practical algorithms and figures and can be freely accessed at: www.ctajournal.com/content/3/1/23

Further important reasons for developing the MAP guideline were that:

  • evidence from the Isle of Wight birth cohort study indicates that CMA is the commonest food allergy in infants and young children in the UK5
  • CMA is often the first clinical expression in a child of a personal allergic march and it is poorly understood that symptoms often present within weeks of birth
  • in general, the prognosis for CMA is good, with up to 80%–90% of children developing tolerance before the age of 3 years.6 However, CMA may persist up to school age or beyond and may be associated with the later development of other allergic diseases such as asthma, rhinoconjunctivitis, and atopic dermatitis,7 as well as other disease manifestations such as recurrent abdominal pain.8
  • CMA is the most likely food allergy to have either delayed onset non-IgE- and/or immediate onset IgE-mediated symptoms:
    • this makes CMA the most complex food allergy to recognise, confirm, and manage optimally 9
  • there is supporting evidence from Guest et al10 that in UK primary care, there is under-recognition, incorrect diagnosis, significant delay in diagnosis, and subsequently less than optimal management of infants presenting with CMA, especially in choosing the most appropriate initial hypoallergenic formula for them and ensuring continuing dietetic support
  • there was a need to focus on the commonest clinical expression of CMA in infants (i.e. mild to moderate non-IgE-mediated allergy).

Presentation, diagnosis and management

There are two main aspects to diagnosing the less severe forms of non-IgE-mediated CMA (see Figure 1 and Figure 2, below)4

  • clinical history
  • period of elimination of cow’s milk protein, followed by an early planned home challenge with cow’s milk protein to confirm/exclude a diagnosis of CMA.

Skin prick testing and serum specific IgE assays have no role to play in the diagnosis of non-IgE-mediated CMA.

With regard to the initial clinical presentation and diagnosis of CMA, the MAP guideline4 aims to emphasise the importance of the practitioner:

  • taking an ‘allergy-focused’ history, looking especially for the presence of any clinical atopy in first-degree relatives, and then, in particular, early and evolving gut and/or skin symptoms in the infant
  • distinguishing:
    • the exclusively breast-fed infant from the infant on formula feeds or mixed feeding (i.e. breast and bottle)
    • the delayed onset pattern of symptoms (and therefore a likely non-IgE-immune mediated mechanism) from the immediate onset pattern of symptoms (and therefore a likely IgE-immune-mediated mechanism)
    • the mild to moderate clinical presentation from the severe presentation in each immune-mediated group (i.e. the clear identification of those infants with mild to moderate non-IgE-mediated CMA, who should be managed in primary care, and those with either severe non-IgE-mediated or IgE-mediated CMA, who should be referred to secondary care)
    • those formula-fed infants who need to be started on an extensively hydrolysed formula (eHF) from those requiring an amino acid formula (AAF) for the initial diagnosis of CMA.

The MAP guideline also includes:4

  • information about the initial trial and length of the appropriate cow’s-milk- free diet
  • guidance regarding a safe initial early home challenge to confirm the diagnosis.
Figure 1: Different presentations of cow’s milk allergy in infancy4
Different presentations of cow’s milk allergy in infancy
  • IgE=immunoglobulin E; CMA=cow’s milk allergy; GORD=gastro-oesophageal reflux disease; AAF=amino acid based formula; eHF=extensively hydrolysed formula; CVS=cardiovascular system
  • Figures 1 and 2 in this article are adapted from Figures 2 and 3 in: Venter C, Brown T, Shah N et al. Diagnosis and management of non-IgE-mediated cow’s milk allergy in infancy—a UK primary care practical guide. Clin Transl Allergy 2013; 3 (1): 23. Available at: www.ctajournal.com/content/3/1/23
  • © 2013 Venter et al; licensee BioMed Central Ltd. Open Access article distributed under the terms of the Creative Commons Attribution License (creativecommons.org/licenses/by/2.0)
Figure 2: Diagnosis and management of mild to moderate non-IgE-mediated CMA in UK primary care4
Diagnosis and management of mild to moderate non-IgE-mediated CMA in UK primary care
  • IgE=immunoglobulin E; CMA=cow’s milk allergy; AAF=amino acid based formula; eHF=extensively hydrolysed formula.

Clinical history

The allergy-focused clinical history is key to making a diagnosis of CMA or of any food allergy.3,11,12 If the history suggests delayed symptoms in the absence of faltering growth or rectal bleeding in an unwell infant, an elimination diet of 2–6 weeks is recommended, followed by a home challenge with cow’s milk protein. There can be a wide range of delayed symptoms, including:3

  • gastro-oesophageal reflux disease
  • loose or frequent stools
  • constipation
  • delayed onset erythema, itch, or atopic dermatitis.

Home challenge

The home challenge can only be performed if the healthcare professional is confident that the symptoms are of delayed onset only and that there is no involvement of IgE.13 For a suggested home challenge protocol to properly confirm a diagnosis of cow’s milk allergy, see the link, Practical pointers for parents/carers on carrying out the MAP home challenge

What about the breastfeeding mother?
In addition to avoiding cow’s milk in the infant’s diet, the diagnosis and management of CMA involves the added difficulty of (perhaps) helping the breastfeeding mother to avoid cow’s milk in her diet, and choosing the most appropriate formula if a top-up formula is needed. Every effort should be made to encourage mothers to continue to breastfeed where possible, and a trial of cow’s milk avoidance in the breastfeeding mother’s diet is therefore initially recommended for all infants who are symptomatic while being breast-fed; cow’s milk can be re-introduced later into the breastfeeding mother’s diet to observe whether symptoms return in the infant.

Breastfeeding women who are avoiding cow’s milk in their diet should be given:

  • advice on an adequate intake of nutrients
  • supplementation with calcium14 (1000 mg) and vitamin D15 (10 µg) daily.
Which formula?
There are many factors about formulas that should be taken into account when choosing the most appropriate formula for a child with CMA. These factors include:3, 8
  • degree of protein hydrolysis
  • fat source and content
  • presence/absence of lactose
  • cost
  • cultural/religious considerations
  • palatability
  • nutrient profile of the formula
  • nutritional status of the child.

Choosing a formula to confirm or exclude a diagnosis of CMA, or to manage the child with subsequently confirmed CMA, is still a dilemma for many healthcare professionals and clear recommendations are not available. Based on the limited evidence available, the MAP guideline recommends that:4

  • breastfeeding is always the preferred way to feed any infant. In any case where there is a need to exclude cow’s milk from the maternal diet and a top-up formula is needed, the authors suggest an amino acid based formula (AAF). This is because the beta-lactoglobulin levels and peptide sizes of eHFs are similar to the ranges of beta-lactoglobulin seen in breast milk.
  • amino acid based formula (AAF) should be a first-line treatment for infants with:
    • history of anaphylaxis to cow’s milk
    • severe gastrointestinal and/or skin presentations, particularly where these are associated with faltering growth
    • eosinophilic oesophagitis
    • Heiner syndrome
  • extensively hydrolysed formula (eHF) should be a first-line of choice for infants with:
    • mild to moderate presentations of both non-IgE- and IgE-mediated CMA (i.e. infants having either type or both types together, with symptoms of e.g. colic, reflux, diarrhoea, vomiting, urticaria, eczema), in the absence of faltering growth
    • extensively hydrolysed formula containing whey may not be suitable as a first-line treatment for those infants with CMA who have possible associated secondary lactose intolerance
  • soya formula can be used in infants over 6 months of age who do not tolerate eHF, particularly if they have IgE-mediated CMA in the absence of any IgE sensitisation to soya.

Dietary management of children with cow’s milk allergy

Once the diagnosis of CMA is confirmed, cow’s milk should continue to be avoided in the child’s diet. Ensure that the infant has been referred to a dietitian.

With regard to the management of infants diagnosed with suspected mild to moderate non-IgE-mediated CMA, the MAP guideline4 gives advice on:

  • the length of time the child should remain on a diet free of cow’s milk protein
  • selecting those infants who should be reintroduced at home onto the MAP graduated milk ladder16 (see link below) to test for acquired natural tolerance, or when liaison is indicated with the local paediatric specialist support to consider a supervised challenge to test for acquired natural tolerance.

Avoid all foods containing cow’s milk?

Some infants and children with food allergy need strictly to avoid all forms of an allergen, even trace amounts. These tend to be the children with the more severe expressions of both IgE- and non-IgE-mediated allergies. Such very strict measures of avoidance should, however, not usually be required by patients with mild to moderate non-IgE-mediated CMA. Dietitians are best placed to give patients the necessary advice, for example on food label-reading; it should be emphasised that the ingredient list, rather than the allergen box, is the most trustworthy source of information on food labels.17 Allergen boxes will disappear from food labels from December 2014.

Food challenge or food reintroduction to test for acquired natural tolerance?

Children aged 9–12 months, who have had a cow’s-milk-free diet for at least 6 months, and who have no history of immediate symptoms to cow’s milk or no previous IgE sensitisation status, can undergo a home reintroduction using a milk ladder; for a suggested milk ladder for children with non-IgE-mediated CMA (i.e. an absence of detectable specific IgE levels), see the MAP graduated milk ladder at:
cowsmilkallergy4gp.org/Cows_milk_allergy/Patient_resources_files/Milk%20Ladder%2011.pdf).16

Care should be taken when food is reintroduced to children who have atopic eczema; it may be useful to perform a skin prick test or blood test in these children before reintroducing any food at home, particularly after a prolonged period of cow’s milk avoidance.18 These tests may uncover infants/children who have ‘converted’ to IgE-mediated CMA.

How should these infants be weaned on to the other infant foods?

There are many unanswered questions regarding the weaning of infants with CMA, including:

  • when can other highly allergenic foods (e.g. egg, soya, wheat, fish/shellfish, peanuts/treenuts) be introduced?
  • should we test for other food allergies—and what do we do when the tests are positive?

These are important questions to address in order to strike a balance between avoiding other allergenic foods unnecessarily and ensuring the infant’s safety during this period of weaning, which is always the first priority.11

In the absence of specific evidence, a common-sense approach would be to:3, 11, 12, 19

  • start with low-allergenic foods (e.g. most fruit and vegetables)
  • try a cooked version of a new food first and increase amounts gradually
  • ensure that allergy tests are only performed if the team is able to interpret these results and can perform food challenges if needed
  • advise parents/carers to try new foods early in the day, and make sure that they know how to deal with allergic reactions. They should take extra care when allergenic foods are introduced to infants with wheeze/suspected asthma.20

Impact of the guideline on patient care

Improved patient care has already been demonstrated in the ongoing monthly primary care prescribing data trends in the Northern Ireland Region of the NHS where the MAP guideline has been the regional endorsed primary care guideline for CMA since March 2013.21

It is hoped that the MAP guideline4 will:

  • promote best practice in primary care and improve patient care
  • encourage earlier consideration of the diagnosis of CMA
  • give early indication of those infants with suspected CMA who should be referred for specialist care
  • in the commonest group of CMA infants, the ones with mild to moderate non-IgE-mediated allergy, guide between the differential diagnosis of CMA from ‘reflux’ and ‘colic’
  • guide the distinction between:
    • the majority of infants with milder expressions of atopic eczema, who are unlikely to have CMA
    • those infants with more moderate to severe eczema, who are more likely to have a food allergy (usually cow’s milk and/or egg)
  • safely allow an early home challenge to confirm the diagnosis, then later safely allow the home reintroduction of cow’s milk protein products, using a graduated milk ladder, to confirm the acquisition of natural tolerance
  • emphasise the important need for continuing dietetic support.

Barriers to implementation

For the MAP guideline4 to be implemented successfully in UK primary care, the following challenges need to be faced and overcome:

  • the perception that CMA does not usually cause serious clinical morbidity, coupled with the underestimation of the very real reduced quality of life issues that it does cause both the infants and their carers
  • the large numbers of guidelines competing for GPs’ attention
  • the lack of training opportunities
  • (e.g. half-day workshops with clinical cases and interactive discussion) to enable the guideline to be fully understood
  • the need for better communication and a more commonly shared approach to the management of CMA between GPs and other primary care based clinicians, especially health visitors
  • the current overall poor NHS resourcing of dietetic support in primary care and community settings.

Conclusion

Cow’s milk allergy is highly prevalent in infants and young children and presents with a range of symptoms. The allergy-focused clinical history is key and will indicate which diagnostic pathway should be followed. Management of CMA in infants and children involves guiding parents/carers on the appropriate avoidance of cow’s milk and may involve advice to breastfeeding mothers, as well as advice to parents/carers on choosing the most appropriate formula. Weaning advice in this group of children can be particularly challenging; the dietitian plays a crucial role.3

Acknowledgements

Authors of the MAP guideline4 were a subgroup of the guideline development group for NICE CG116:3 Dr Adam T Fox, Dr Trevor Brown, Dr Jo Walsh, Dr Carina Venter. Additional expertise was provided by Consultant Paediatric Gastroenterologist, Dr Neil Shah.

Some useful sources of further information can be found at:
www.allergyuk.org and
www.anaphylaxis.org.uk

written by Dr David Jenner, NHS Alliance GMS contract/PBC Lead
  • CMA represents a complex set of presenting symptoms, which can be difficult for primary care clinicians to identify and diagnose accurately
  • The new MAP guidelines for primary care include useful, simple-to-read algorithms that can be shared with relevant healthcare professionals to aid diagnosis and management
  • Commissioners should ensure that contracted health-visiting services have clear pathways for the management of CMA, with guidelines for trials of alternative formulas and ‘milk ladder’ reintroduction as detailed in the MAP guidelines
  • Triggers for referral to paediatric specialist services (so alternative diagnoses or more complex management can be considered) should also be clear within these pathways
  • Commissioners should consider multi-professional training for GPs and health visitors to increase awareness CMA and ensure that there is agreement regarding the choice of prescribed alternative formula feeds, where indicated
  • Community paediatric dietetic services, if commissioned, could provide a useful support service to GPs and health visitors and avoid specialist referral with its associated costs.
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