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

Cow’s milk allergy (CMA) is one of the most common presentations of food allergy seen in early childhood. It is also one of the most complex food allergies, being implicated in IgE‐mediated food allergy as well as diverse manifesta‐ tions of non‐IgE‐mediated food allergy. For example, gastrointestinal CMA may present as food protein induced enteropathy, enterocolitis or proctocolitis. Concerns regarding the early and timely diagnosis of CMA have been high‐ lighted over the years. In response to these, guideline papers from the United Kingdom (UK), Australia, Europe, the Americas and the World Allergy Organisation have been published. The UK guideline, ‘Diagnosis and management of non‐IgE‐mediated cow’s milk allergy in infancy—a UK primary care practical guide’ was published in this journal in 2013. This Milk Allergy in Primary Care (MAP) guideline outlines in simple algorithmic form, both the varying presenta‐ tions of cow’s milk allergy and also focuses on the practical management of the most common presentation, namely mild‐to‐moderate non‐IgE‐mediated allergy. Based on the international uptake of the MAP guideline, it became clear that there was a need for practical guidance beyond the UK. Consequently, this paper presents an international interpretation of the MAP guideline to help practitioners in primary care settings around the world. It incorporates further published UK guidance, feedback from UK healthcare professionals and affected families and, importantly, also international guidance and expertise. © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Background Over the last 2 decades, many countries have seen a significant rise in the number of children suffering from food allergy, defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food [1]. The impact on quality of life for families with food allergy has been shown to be significantly worse than for those with chronic pain disorders [2] or diabetes [3]. For most infants with suspected cow’s milk allergy (CMA) this can be clinically subdivided into either immediate-onset IgE-mediated, where the adverse effects appear usually within minutes following ingestion or delayed onset non-IgE-mediated where the effects develop usually after ≥2 h [4]. It is difficult to define IgE-mediated food allergy into milder and more severe forms as external factors often determine the severity of reaction, with anaphylaxis being the most severe presentation [5]. The spectrum of non-IgE-mediated CMA is broad; encompassing symptoms that range in severity from mild rectal bleeding in milk protein induced proctocolitis to the severe vomiting and collapse that can be seen in food protein induced enterocolitis syndrome (FPIES). Evidence from the United Kingdom Open Access Clinical and Translational Allergy *Correspondence: [email protected] Carina Venter and Trevor Brown are joint first authors. 11 Department of Paediatric Allergy, Guys and St Thomas’ Hospitals NHS Foundation Trust, London, UK Full list of author information is available at the end of the article Page 2 of 9 Venter et al. Clin Transl Allergy (2017) 7:26 (UK) [6] shows that the majority of infants presenting with suspected CMA fall into a ‘mild-to-moderate’ [7] clinical expression of non-IgE-mediated allergy. Although the severities of the non-IgE-mediated reactions were not clearly defined, data from the EuroPrevall study indicates the presence of milder forms of non-IgE-mediated food allergy in Europe, particularly in the Netherlands, Italy and Poland [8]. Whilst attempting to monitor this overall rise in suspected food allergy in children, some controversy has arisen over the true incidence of this ‘mild-to-moderate’ non-IgE-mediated sub-group presenting characteristically in infancy with mostly gastrointestinal-related symptoms such as abdominal discomfort, gastro-oesophageal reflux and abnormal bowel frequency and consistency. In 2015 Schoemaker et al. [8] reported, as part of the EuroPrevall project that the national incidences of CMA in Europe vary across countries with the majority of children with CMA in the UK and the Netherlands suffering from the non-IgE-mediated form. However, the very low incidences reported in some countries have become the subject of debate. Nowak-Wegrzyn et al. [9] and Koletzko et al. [10] argued that the children with non-IgE-mediated CMA in 4 out of the 9 EuroPrevall countries were selectively missed due to clinical unawareness of gastro-intestinal symptoms and their relation to possible CMA. Non-IgE-mediated food allergy is also often reported in Latin America [11]. In line with the previously published MAP (Milk Allergy in Primary Care) guideline [7], the diagnosis of mild-to-moderate non-IgE-mediated CMA requires the strict avoidance of all cow’s milk containing foods for an agreed trial period, i.e. an elimination diet, followed by clinical improvement and then subsequent relapse coincident with reintroduction. This elimination-reintroduction sequence is the only way of reliably diagnosing gastrointestinal manifestations of non-IgE-mediated CMA in infants such as infantile allergic proctocolitis, mild-to-moderate allergic enteropathy and cow’s milk-induced gastro-oesophageal reflux or constipation because there is no allergy skin or blood test for non-IgE-mediated food allergy. This paper, whilst acknowledging all the possible clinical presentations of CMA in infancy (IgE and non-IgE with their differing diagnostic approaches), will focus primarily on the better recognition, confirmation and management of these infants presenting with suspected mild-to-moderate non-IgE-mediated CMA. The actual management of IgE-mediated CMA and the more severe presentations of non-IgE-mediated CMA, such as FPIES, Eosinophilic Esophagitis and food protein induced enteropathy with faltering growth will not be addressed. This iMAP guideline builds on the strengths of the previous UK MAP guideline, designed with a UK primary care focus, which has been demonstrated to effectively improve the recognition and earlier diagnosis of mild-tomoderate non-IgE-mediated CMA [12] but has now been reviewed with an international focus. The guideline does not represent the views of, nor is it endorsed by, any professional organisation, nor was it supported by any commercial entity at any point in the development process. Considerations behind the publication of the 2013 UK MAP guideline [7] A UK birth cohort study published in 2008 showed that 2–3% of 1–3 year olds suffer from confirmed CMA [13]. Worldwide this prevalence ranges between 1.9 and 4.9% [14], making it one of the most common food allergies in the first years of life. In 2010 a review of 1000 infants with CMA randomly chosen from a UK primary care database [6] showed that 86% were first diagnosed in primary care and that the majority remained there for their care. 42% of the infants were referred on, usually to the care of a general paediatrician. Only a few were seen at a specialist level multidisciplinary paediatric allergy service. The majority presented clinically with mild-to-moderate symptoms of suspected non-IgE-mediated CMA. Significantly smaller numbers could have been categorised as either severe non-IgE-mediated CMA or immediateonset IgE-mediated CMA. The review highlighted evidence of under-recognition, misdiagnosis, significant delay in diagnosis and sub-optimal management of the infants especially in choosing the most appropriate initial alternative formula suitable for the management of CMA, when breast milk is not available. Fewer than 1 in 5 families had received support from a dietitian [6]. The problem of over and under diagnosis of CMA with its inherent undesirable nutritional management is not unique to the UK. Van den Hooge et al. [15] and Vieira et al. [11] report similar problems in the Netherlands and Latin America respectively. To address the need for better diagnosis of food allergy, six international guideline papers were published from the: United States (US) [1], World Allergy Organization (WAO) [14], European Academy of Allergy, Asthma and Clinical Immunology (EAACI) [16], UK, National Institute of Health and Care Excellence (NICE) [17], British Society for Allergy and Clinical Immunology (BSACI) [18] and European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) [19]. The UK NICE 2011 clinical guideline on the ‘Diagnosis and assessment of food allergy in children and young people in primary care and community settings’, Clinical Guideline 116 (CG116) [17], addressed within its given scope only the presentation and initial assessment of any suspected food allergy. As part of the initial assessment, it particularly emphasised the need to clinically Page 3 of 9 Venter et al. Clin Transl Allergy (2017) 7:26 differentiate between non-IgE-mediated and IgE-mediated expressions of food allergy. Subsequently, a subgroup of the clinicians on the NICE guideline development group published the MAP guideline in 2013 [7]. It addressed in a simple algorithm-based pathway the initial presentation of the differing clinical expressions of CMA in infancy (both non-IgE and IgE) and the on-going management in primary care of those children with confirmed mild-to-moderate non-IgEmediated CMA. Considerations behind the publication of this 2017 updated version of MAP Evidence showing the effectiveness of the MAP guideline [7] in positively changing UK prescribing patterns has been published [12]. Since 2013, frequent citations and use of MAP across the world have indicated that it is of practical clinical relevance not only for the UK but also for healthcare professionals working in other national healthcare systems. The important early healthcare contacts where the possibility of CMA needs to be explored between parents and a ‘first contact’ clinician do not essentially change from one healthcare system to another. Significantly, UK NICE has now produced two further publications; in 2015 a NICE Clinical Knowledge Summary (CKS) on the diagnosis and management in primary care of ‘cow’s milk protein allergy in children’ [20], and in 2016 the NICE Quality Standard for food allergy [21]. Since the publication of the MAP guideline in 2013, the BSACI also published their specialist guidelines on cow’s milk allergy [18]. Since then, to our knowledge no other CMA guidelines have been published internationally. This growing number of guidelines with clinical relevance to CMA gives rise to the very real potential for ‘guideline overload’. A recent UK paper surveyed over 400 general practitioners (GPs) and 300 parents looking at the current ‘journey from diagnosis to management of milk allergy’ for parents and the doctors in primary care [22]. The authors suggested an ideal pathway for the better identification and management of CMA by healthcare professionals should include improved education focusing on the current guidelines and the development of simple tools from the guidelines, such as algorithms, to aid diagnosis and management. A required action highlighted by the parents was the development of a simple tool centred on their recording of possible symptoms that they could take to the appointment with their healthcare professional. Meeting such requests will be of practical clinical relevance for healthcare professionals and families in all healthcare systems. These NICE primary care guidelines are UK focused and were not intended to be accessed and interpreted by clinicians based outside of the UK. However, the guidance was widely adopted outside of the UK, suggesting the need for an updated non-UK focused interpretation. The aim of this paper is therefore to both incorporate these recent UK publications and to adapt MAP into a more internationally suited version. Management of Milk Allergy in Primary Care (iMAP), to act as both a UK and international guideline with amended algorithms (Figs. 2, 3), supported by other practical tools for both families and healthcare professionals in primary care (Additional files 1, 2, 3, 4). Clinicians recognise the important role families and carers have in supporting children with food allergy and that ‘family members and carers should be involved in the decision-making process about investigations, treatment and care’ [20]. This iMAP version aims to facilitate that important role. Presentation and recognition of CMA Revisiting CMA nomenclature The UK NICE guidelines along with other national and international guidelines clearly indicate that CMA is broadly divided into IgE-mediated and non-IgE-mediated disease. Although they acknowledge that the non-IgEmediated presentation can be divided into mild-to-moderate and more severe presentations, there is currently no international consensus with clearly agreed definitions of these presentations. Indeed even in terms of Eosinophilic Oesophagitis (EoE), experts and international bodies disagree about whether this is a disease that is primarily non-IgE-mediated [23] or in fact a mixed IgE and nonIgE-mediated disease [1]. The allergy‐focused clinical history The allergy-focused clinical history continues to form the ‘cornerstone of diagnosis’ in food allergy and ‘children and young people with suspected food allergy should have an allergy-focused clinical history taken’ [21]. EAACI also recently published a task force report on how to take an allergy-focused diet history to aid with the diagnosis of a food allergy [24]. This process will support the clinician to distinguish between IgE-mediated and non-IgE-mediated reactions, based primarily on the information provided by the family. This will then inform the healthcare professional with the appropriate competencies/clinical expertise to decide which other tests, if any, are needed to confirm the diagnosis and then how the food allergy should be managed. • Any family history of atopic disease in parents or siblings. • Any history of early atopic disease in the infant. • The infant’s feeding history including growth. Page 4 of 9 Venter et al. Clin Transl Allergy (2017) 7:26 • Presenting symptoms and signs that may be indicating possible CMA. • Details of previous management, including any medication and the perceived response to any treatment or dietary change. Figure 1 provides a list of questions to ask during the allergy-focused history, but in short such a history will focus on the following questions [7]. The symptoms of the infant at first presentation are a key feature in the diagnostic process. It is important to consider that possible symptoms (Fig. 2) can be variable and overlap with common infant health issues such as irritability (colic), gastro-oesophageal reflux and atopic dermatitis that may not necessarily be CMA-related. There is also often confusion between immediate-onset IgE-mediated allergy and delayed-onset non-IgE-mediated allergy symptoms. The iMAP Allergy focused Clinical History for Suspected Cow’s Milk Allergy in Infancy ‘The Cornerstone of the Diagnosis’