PAEDIATRIC
Dr Rosan Meyer, RD,PhD Paediatric Research Dietitian, Honorary Senior Lecturer, Imperial College, London and Chair of the BDA Food Allergy and Intolerance Specialist Group
Dr Lisa Waddell, RD,PhD Specialist Community Paediatric Allergy Dietitian and Director of Food Allergy Nottingham Service (FANS)
Dr Carina Venter RD,PhD Assistant Professor, University of Colorado Denver School of Medicine, USA
REFERENCES Please visit the Subscriber zone at NHDmag.com
WHERE NEXT AFTER PUBLICATION OF IMAP GUIDELINES FOR NON-IGE MEDIATED COW’S MILK ALLERGY? The successful iMAP guidelines provide suitable guidance for any child with a mild-to-moderate presentation of non-IgE mediated cow's milk allergy (CMA). This article reports on the updated guidelines and revised six-step milk ladder and looks at next steps in future improvements. CMA remains one of the most common food allergies worldwide, with a prevalence in the United Kingdom of 2-3% in one- to three-year-olds.1 This allergy can present with immediate onset of symptoms; including pruritus and eczema flares, urticaria (hives) and angioedema and, in the most severe cases, anaphylaxis.2 These type of reactions are referred to as Immunoglobulin E (IgE)-mediated food allergy and the pathophysiologic mechanism is well described, with tests available to support the diagnosis. However, this allergy can also present with delayed symptoms, called non-IgE mediated CMA, which can include symptoms like vomiting, feeding difficulties, colic-like abdominal pain, faltering growth, diarrhoea, blood in stools, constipation and exacerbation of atopic eczema.3 The latter group of symptoms overlap with other common disorders in early childhood, such as infantile colic and gastro-oesophageal reflux, lactose intolerance, constipation and atopic eczema, which complicates the recognition and diagnosis of cow’s milk allergy. The pathophysiology of non-IgE mediated CMA is not well established and no accurate non-invasive tests exist to support the healthcare professional (HCP) to make the diagnosis, which includes a spectrum of gastrointestinal conditions (i.e. food induced proctocolitis, enterocolitis, enteropathy).3 It was, therefore, not surprising that in 2010, Sladkevicius et al4 reported that it took on average 4.5 visits to a general practitioner (GP)
over an average of 2.2 months in the UK for children with atopic eczema and gastrointestinal symptoms to be started on the correct treatment. The delayed nature of diagnosis of non-IgE mediated CMA was recognised by a group of HCPs as a particular area that required improvement in the UK and, therefore, the Milk Allergy in Primary (MAP) guidelines were published, targeting mild to moderate non-IgE mediated CMA.5 These guidelines have proven to be extremely successful, not only in the UK, but worldwide, with more than 74,000 downloads (download and citation history is available from http://citations.springer.com/item?d oi=10.1186/2045-7022-3-23), providing the authors with four years of feedback to allow for publication of the improved international (i)MAP guidelines.6 WHAT HAS CHANGED IN THE IMAP GUIDELINES?
The iMAP guideline authors consisted of well-known allergists and dietitians from all over the world, including from resource-poor countries, to provide guidance suitable for any child with a mild-to-moderate presentation of nonIgE mediated CMA. The diagnosis and management of the severe spectrum of non-IgE mediated CMA, including eosinophilic oesophagitis (EoE), food protein enterocolitis syndrome (FPIES) and food protein induced enteropathy with faltering growth, were, therefore, not covered in these guidelines.6 www.NHDmag.com June 2018 - Issue 135
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PAEDIATRIC
Cow’s milk allergy remains one of the most common food allergies worldwide, with a prevalence in the United Kingdom of 2-3% in one- to three-year-olds. The iMAP guidelines had some minor additions with regard to the well-known symptoms of non-IgE mediated CMA, acknowledging that this condition would usually present as multiple symptoms and that treatment resistance to atopic eczema, gastro-oesophageal reflux and constipation may increase the likelihood of the diagnosis of a non-IgE mediated CMA.6 As before, an elimination diet of four weeks (minimum two weeks) is recommended,7 followed by the reintroduction of cow’s milk. Following feedback from the MAP guidelines, the authors of the iMAP guidelines recognised that HCPs required a range of supporting materials to aid diagnosis and to prime parents on the process of diagnosis, including the reintroduction phase to confirm/ refute the diagnosis of a delayed CMA. These supporting documents were developed and are not only available as appendices in the original article, but are available in an easy-to-use format from the Allergy UK Website (www.allergyuk. org/health-professionals/mapguideline). Although changes to the recognition and diagnosis sections within the iMAP guidelines were minor, there have been two major changes in the recommendations of hypoallergenic formulas. As the iMAP guidelines also included representation from resource-poor countries, soya formulas were recognised as an alternative if children (of all ages) were not sensitised to soya.6 However, for the UK (and other European countries and the USA) the guidelines clearly state the avoidance of soya formulas below six months and that these formulas were not a first line choice for mild-moderate non-IgE mediated allergies. This is in line with all current European and US guidelines on CMA.8-11 18
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In the MAP guidelines from 2013, amino acid formulas (AAF) were recommended for breastfed infants with non-IgE mediated CMA who required a top-up formula.5 Those recommendations originated from data produced by Host et al,12 who found that β-lactoglobulin, one of the cow’s milk proteins, was present in the vast majority of cow’s milk consuming breastfeeding mothers at levels that were comparable to the residual β-lactoglobulin detected in both whey or casein extensively hydrolysed formulas (EHF). This implied that breastfed infants with CMA would also react to an EHF. However, a recent review on the appropriate use of AAF has not found sufficient evidence to justify such a recommendation.13 Data on FPIES and food protein induced proctocolitis found that the majority of children had symptom resolution with an EHF.14,15 It was found that infants with non-IgE mediated CMA who presented with a combination of multiple food eliminations, enteropathy/enterocolitis syndromes and faltering growth, as well as EoE, would benefit from an AAF.13 However, these aforementioned conditions were deemed severe presentations of non-IgE mediated CMA and, therefore, not covered in the iMAP guidelines. As a result, the guidelines now suggest that an EHF be considered in breastfed infants with mild to moderate non-IgE mediated CMA as a top-up formula.6 THE MILK LADDER
The original MAP guidelines in 2013 included the first published milk ladder, which has proven to be a very popular worldwide, as a home-based method of reintroducing cow’s milk in a graded way, based on the effects of heating and fermentation on the allergenicity of cow’s
Figure 1: MAP (left) and the new iMAP milk ladder (right)5,6
milk proteins.5,16 Although very limited data was available at the time of writing the first milk ladder on tolerance of heated/fermented milk products in non-IgE mediated CMA, a recent study by Uncuoglu et al,17 found that significantly more children with this form of CMA tolerated heated and fermented cow’s milk products than did those with IgE mediated CMA. A study by Athanasopolou et al18 found that baked milk challenges were commonly used in non-IgE mediated CMA and were particularly useful in settings with insufficient facilities for hospital challenge. This study, however, acknowledged country specific differences which require further exploration. User feedback of the MAP ladder included the high refined sugar (>5% refined sugar as recommended by the World Health Organisation) and salt content (i.e. biscuits, cupcakes, lasagne, etc) of foods in the ladder, the length of the ladder (12 steps) and finally the absence of exact milk protein dosages, to allow for the ladder to be studied further.19,20 All of these aspects were addressed in the new iMAP ladder that is now shorter (six steps), has recipes that are salt free, low in sugar and describe the exact milk protein dosages.
WHERE DO WE GO NEXT?
The iMAP guidelines have allowed for the update of both diagnosis and management of non-IgE mediated allergies, reflecting the newly published data and also addressing feedback from HCPs. However, with every new published guideline comes the responsibility of reviewing and updating to reflect new research. This is also the case for the iMAP guidelines; feedback has already been received on content and for the milk ladder. Authors have already been made aware of new publications, most notably, the joint ESPGHAN and NASPGHAN guidelines on diagnosis and management of gastroesophageal reflux disease, which will need to be taken into account with future review of iMAP guidelines.21 These guidelines now suggest a trial of maternal elimination of cow’s milk in breastfed infants, or hypoallergenic formula following conservative management, before the use of antacid medications (H2 receptor antagonists/proton pump inhibitors). The European Academy for Allergy and Clinical Immunology also has a Task Force that is working on practice guidelines for non-IgE mediated allergies, with an imminent publication on breastfed infants with non-IgE www.NHDmag.com June 2018 - Issue 135
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PAEDIATRIC mediated allergies and a future publication on controversies of non-IgE mediated allergies in non-breastfed infants. Although the new iMAP ladder recipes have made it possible to provide standardised recipes across different countries that can be made at home and can be used in research settings, the practicality also needs to be considered. Great care was taken to trial the recipes of the biscuits/muffins/pancakes in many countries, although it is acknowledged that associated cooking methods (baking/frying) may not be universally accepted; in Asia for example, steaming is more common. In addition, not all parents have the time or skills to make these recipes at home and acceptance of foods in all children has also been highlighted. In particular, younger children need to be considered who may not yet have the oral motor skills for chewing biscuits/muffins. Challenges remain for the authors of the milk ladder to adapt the current ladder to include commercial foods and recipes that are suitable for all cultures and that can be adjusted for children without the necessary oral motor skills.
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Although the current milk ladder offers practical challenges for parents, it does for the first time allow research centres to study each step from an immunological perspective, due to the known amount of milk protein, the type of milk protein (milk powder versus fresh milk) and the exact cooking methods (i.e. temperature of baking and frying). There is a need to establish in vitro and, subsequently, in vivo, effects of each step immunologically to determine the role of the milk ladder in clinical practice. CONCLUSION
The iMAP guidelines on mild to moderate non-IgE mediated CMA have contributed significantly towards improving the diagnosis and management of CMA in the UK and now worldwide. They offer easy-to-use algorithms and newly added supporting material, as well as an updated milk ladder. The next step for the authors of this guideline is to ensure optimal dissemination and implementation, but also to stay abreast of new research and listen to HCPs on how to improve the guidelines further in the future.