Protocol for the validation of sensitivity and specificity of the Cow’s Milk-related Symptom Score (CoMiSS) against open food challenge in a single-blinded, prospective, multicentre trial in infants

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Abstract

Introduction

The symptoms of cow’s milk protein allergy (CMPA) in infancy can be non-specific which may delay a correct diagnosis and cause adverse clinical outcomes. The diagnosis of non-IgE-mediated CMPA is particularly complex as it involves a 2 to 4 week elimination diet followed by oral food challenge (OFC). The Cow’s Milk-related Symptom Score (CoMiSS) is a clinical resource for primary healthcare providers which aims to increase awareness of CMPA symptoms to facilitate an earlier diagnosis. The aim of the present study is to assess if the CoMiSS can be used as a potential diagnostic tool in infants with suspected CMPA.

Methods and analysis

Exclusively formula-fed infants aged 0–6 months presenting with symptoms suggestive of CMPA will be included in this prospective, multicentre trial which will be conducted in 10 centres in China. All infants will commence a 2-week trial of an amino acid-based formula (AAF) while eliminating all cow milk protein from their diets. After the AAF treatment period, infants will undergo an open OFC in hospital with standard cow’s milk formula, followed by an open home challenge for another 2 weeks. Clinical symptoms will be documented on standardised symptom scorecards. The CoMiSS will be determined at study entry (CoMiSS 1, before the start of the AAF), after 2 weeks (CoMiSS 2, before the OFC) and after a further period of 2 weeks or when symptoms suggestive of CMPA reappear (CoMiSS 3). Weight and length will be measured at each visit. The difference between CoMiSS 1 and 2 as a predictor of the OFC outcome will also be assessed. The diagnostic accuracy of the baseline CoMiSS will be calculated.

Ethics and dissemination

The study was approved by the Hunan Children’s Hospital Medical Ethics Committee, Hunan, China. The findings of this trial will be submitted for publication in a peer-reviewed journal in paediatric nutrition or gastroenterology. Abstracts will be submitted to the relevant national and international conferences.

Trial registration number

NCT03004729; Pre-results.

Related collections

Most cited references 9

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World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines

Alessandro Fiocchi, Jan Brozek, Holger Schünemann … (2010)

Authorship Alessandro Fiocchi, MD, Pediatric Division, Department of Child and Maternal Medicine, University of Milan Medical School at the Melloni Hospital, Milan 20129, Italy. Holger Schünemann, MD,a Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, 1200 Main Street West Hamilton, ON L8N 3Z5, Canada. Sami L. Bahna, MD, Pediatrics & Medicine, Allergy & Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71130. Andrea Von Berg, MD, Research Institute, Children′s department, Marien-Hospital, Wesel, Germany. Kirsten Beyer, MD, Charité Klinik für Pädiatrie m.S. Pneumologie und Immunologie, Augustenburger Platz 1, d-13353 Berlin, Germany. Martin Bozzola, MD, Department of Pediatrics, British Hospital-Perdriel 74-CABA-Buenos Aires, Argentina. Julia Bradsher, PhD, Food Allergy & Anaphylaxis Network, 11781 Lee Jackson Highway, Suite 160, Fairfax, VA 22033. Jan Brozek, MD,a Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, 1200 Main Street West Hamilton, ON L8N 3Z5, Canada. Enrico Compalati, MD,a Allergy & Respiratory Diseases Clinic, Department of Internal Medicine. University of Genoa, 16132, Genoa, Italy. Motohiro Ebisawa, MD, Department of Allergy, Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, Kanagawa 228-8522, Japan. Maria Antonieta Guzman, MD, Immunology and Allergy Division, Clinical Hospital University of Chile, Santiago, Chile. Santos Dumont 999. Haiqi Li, MD, Professor of Pediatric Division, Department of Primary Child Care, Children's Hospital, Chongqing Medical University, China, 400014. Ralf G. Heine, MD, FRACP, Department of Allergy & Immunology, Royal Children's Hospital, University of Melbourne, Murdoch Children's Research Institute, Melbourne, Australia. Paul Keith, MD, Allergy and Clinical Immunology Division, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Gideon Lack, MD, King's College London, Asthma-UK Centre in Allergic Mechanisms of Asthma, Department of Pediatric Allergy, St Thomas' Hospital, London SE1 7EH, United Kingdom. Massimo Landi, MD, National Pediatric Healthcare System, Italian Federation of Pediatric Medicine, Territorial Pediatric Primary Care Group, Turin, Italy. Alberto Martelli, MD, Pediatric Division, Department of Child and Maternal Medicine, University of Milan Medical School at the Melloni Hospital, Milan 20129, Italy. Fabienne Rancé, MD, Allergologie, Hôpital des Enfants, Pôle Médicochirurgical de Pédiatrie, 330 av. de Grande Bretagne, TSA 70034, 31059 Toulouse CEDEX, France. Hugh Sampson, MD, Jaffe Food Allergy Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, NY 10029-6574. Airton Stein, MD, Conceicao Hospital, Porto Alegre, Brazil. Luigi Terracciano, MD,a Pediatric Division, Department of Child and Maternal Medicine, University of Milan Medical School at the Melloni Hospital, Milan 20129, Italy. Stefan Vieths, MD, Division of Allergology, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Str. 51-59, d-63225 Langen, Germany. aMember of the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) Working Group Revision Panel Amal Assa'ad, MD, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. Carlos Baena-Cagnani, MD, LIBRA foundation Argentina, Division of Immunology and Respiratory Medicine, Department of Pediatric, Infantile Hospital Cordoba, Santa Rosa 381, 5000 Cordoba, Argentina. GR Bouygue, MSc, Pediatric Division, Department of Child and Maternal Medicine, University of Milan Medical School at the Melloni Hospital, Milan 20129, Italy. Walter Canonica, MD, Allergy & Respiratory Diseases Clinic, Department of Internal Medicine. University of Genoa, 16132, Genoa, Italy. Christophe Dupont, MD, Service de gastroentérologie et nutrition, Hôpital Saint Vincent de Paul, 82, avenue Denfert-Rochereau, 75674, Paris CEDEX 14, France. Yehia El-Gamal, MD, Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt. Matthew Fenton, MD, Asthma, Allergy and Inflammation Branch, National Institute of Allergy and Infectious Diseases, NIH, 6610 Rockledge Dr., Bethesda, MD 20892. Rosa Elena Huerta Hernandez, MD, Pediatric Allergy Clinic, Mexico City, Mexico. Manuel Martin-Esteban, MD, Allergy Department, Hospital Universitario La Paz, Madrid, Spain. Anna Nowak-Wegrzyn, MD, Jaffe Food Allergy Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, NY 10029-6574. Ruby Pawankar, MD, Department of Otolaryngology, Nippon Medical School, 1-1-5 Sendagi, Tokyo, 113 Japan. Susan Prescott, MD, School of Pediatrics and Child Health, University of Western Australia, Princess Margaret Hospital for Children, Perth, Australia. Patrizia Restani, PhD, Department of Pharmacological Sciences, Università degli Studi di Milano. Teresita Sarratud, MD, Department of Pediatrics, University of Carabobo Medical School at the Carabobo Hospital, Valencia, Venezuela. Aline Sprikkelmann, MD, Department of Pediatric Respiratory Medicine and Allergy, Emma Children's Hospital Academic Medical Centre, Amsterdam, The Netherlands. SECTIONS 1: Introduction, p. 58. 2: Methodology, p. 59. 3: Epidemiology of CMA, p. 61. 4: Allergens of Cow's Milk, p. 65. 5: Immunological Mechanisms of CMA, p. 71. 6: Clinical History and Symptoms of CMA, p. 76. 7: Diagnosis of CMA According to Preceding Guidelines, p. 85. 8: The Elimination Diet in Work-Up of CMA, p. 88. 9: Guidelines for Diagnosing CMA, p. 89. 10: Oral Food Challenge Procedures in Diagnosis of CMA, p. 100. 11: Natural History of CMA, p. 108. 12: Treatment of CMA According to Preceding Guidelines, p. 112. 13: When Can Milk Proteins Be Eliminated From Diet Without Substituting Cow's Milk?, p. 117. 14: Guidelines for Choosing a Replacement Formula, p. 119. 15: Milks From Different Animals for Substituting Cow's Milk, p. 124. 16: Nutritional Considerations in CMA Treatment, p. 128. 17: Choosing the Appropriate Substitute Formula in Different Presentations, p. 130. 18: Grade Recommendations on Immunotherapy for CMA, p. 131. 19: Unmet Needs, Recommendations for Research, Implementation of DRACMA, p. 133. Acknowledgements, p. 134 Appendix 1: Cow's Milk Allergy Literature Search Algorithms, p. 135 Appendix 2: Evidence Profiles: Diagnosis of CMA, p. 144 Appendix 3: Evidence Profiles: Treatment of CMA, p. 154 Appendix 4: Evidence Profiles: OIT for Treatment of CMA, p. 160 SECTION 1: INTRODUCTION Allergy and clinical immunology societies have issued guidance for the management of food allergy.1,2 Guidelines are now regarded as translational research instruments, designed to provide cutting-edge benchmarks for good practice and bedside evidence for clinicians to use in an interactive learning context with their national or international scientific communities. In the management of cow's milk allergy (CMA), both diagnosis and treatment would benefit from a reappraisal of the more recent literature, for “current” guidelines summarize the achievements of the preceding decade, deal mainly with prevention,3–6 do not always agree on recommendations and date back to the turn of the century. 7,8 In 2008, the World Allergy Organization (WAO) Special Committee on Food Allergy identified CMA as an area in need of a rationale-based approach, informed by the consensus reached through an expert review of the available clinical evidence, to make inroads against a burdensome, world-wide public health problem. It is in this context that the WAO Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines was planned to provide physicians everywhere with a management tool to deal with CMA from suspicion to treatment. Targeted (and tapped for their expertise), both on the DRACMA panel or as nonsitting reviewers, were allergists, pediatricians (allergists and generalists), gastroenterologists, dermatologists, epidemiologists, methodologists, dieticians, food chemists, and representatives of allergic patient organizations. Ultimately, DRACMA is dedicated to our patients, especially the younger ones, whose burden of issues we hope to relieve through an ongoing and collective effort of more interactive debate and integrated learning. Definitions Adverse reactions after the ingestion of cow's milk can occur at any age from birth and even among infants fed exclusively at the breast, but not all such reactions are of an allergic nature. A revision of the allergy nomenclature was issued in Europe in 20019 and was later endorsed by the WAO10 under the overarching definition of “milk hypersensitivity,” to cover nonallergic hypersensitivity (traditionally termed “cow's milk intolerance”) and allergic milk hypersensitivity (or “cow's milk allergy”). The latter definition requires the activation of an underlying immune mechanism to fit. In DRACMA, the term “allergy” will abide by the WAO definition (“allergy is a hypersensitivity reaction initiated by specific immunologic mechanisms”). In most children with CMA, the condition can be immunoglobulin E (IgE)-mediated and is thought to manifest as a phenotypical expression of atopy, together with (or in the absence of) atopic eczema, allergic rhinitis and/or asthma. A subset of patients, however, have non-IgE mediated (probably cell-mediated) allergy and present mainly with gastro-intestinal symptoms in reaction to the ingestion of cow's milk. REFERENCES, SECTION 1 1 American College of Allergy, Asthma, & Immunology. Food allergy: a practice parameter. Ann Allergy Asthma Immunol. 2006;96(Suppl 2):S1–S68 16597066 2 Mukoyama T Nishima S Arita M Ito S Urisu A Guidelines for diagnosis and management of pediatric food allergy in Japan. Allergol Int. 2007;56:349 –361 17965578 3 Prescott SL The Australasian Society of Clinical Immunology and Allergy position statement: Summary of allergy prevention in children. Med J Aust. 2005;182:464–467 15865590 4 Muraro A Dreborg S Halken S Høst A Niggemann B Dietary prevention of allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr Allergy Immunol. 2004;15:291–307 15305938 5 Muraro A Dreborg S Halken S Høst A Niggemann B Dietary prevention of allergic diseases in infants and small children. Part I: immunologic background and criteria for hypoallergenicity. Pediatr Allergy Immunol. 2004;15:103–11 15059185 6 Muraro A Dreborg S Halken S Høst A Niggemann B Aalberse R Dietary prevention of allergic diseases in infants and small children. Part II. Evaluation of methods in allergy prevention studies and sensitization markers. Definitions and diagnostic criteria of allergic diseases. Pediatr Allergy Immunol. 2004;15:196 –205 15209950 7 Høst A Koletzko B Dreborg S Muraro A Wahn U Dietary products used in infants for treatment and prevention of food allergy. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child. 1999;81:80–84 10373144 8 American Academy of Pediatrics Committee on Nutrition Hypoallergenic infant formulae. Pediatrics. 2000;106:346 –349 10920165 9 Johansson SG Hourihane JO Bousquet J A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy. 2001;56:813– 824 11551246 10 Johansson SG Bieber T Dahl R Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, . J Allergy Clin Immunol.2003 2004;113:832–836 SECTION 2: METHODOLOGY The outline of the consensus guideline was the result of the considered opinion of the whole panel. Narrative parts, that is, sections 1–8, 9–13, 15–17, and 19 included the relevant CMA literature as searched using the algorithms reported in Appendix 1. For these sections, the relative weight of the suggestions retained for the purpose of DRACMA reflects the expert opinion of the panel. They may contain general indications, but no evidence-based recommendations. The consensus on these indications was expressed by the panelists using a checklist itemizing the clinical questions considered relevant after analysis of the literature. The collective judgment of the panel is expressed as a percentage of agreement among panelists. The panel decided to use a GRADE methodology for defining some treatments and diagnostic questions. The DRACMA worked with the GRADE members on this panel the clinical questions and their scope after various fine-tuning stages. The GRADE panelists independently searched the relevant literature for sections 9, 14, 18. Their analysis was independent of the other panel lists. For question formulation, guideline panel members explicitly rated the importance of all outcomes on a scale from 1–9, where the upper end of the scale (7–9) identifies outcomes of critical importance for decision making, ratings of 4–6 represent outcomes that are important but not critical and ratings of 1–3 are items of limited importance. Evidence summaries were prepared following the GRADE Working Group's approach1–6 based on systematic reviews done by an independent team of the GRADE Working Group members (JLB and HJS supported by 5 research associates). The GRADE approach suggests that before grading the quality of evidence and strength of each recommendation, guideline developers should first identify a recent well-done systematic review of the appropriate evidence answering the relevant clinical question, or conduct one when none is available. This should be followed by preparing a transparent evidence summary, such as creation of GRADE evidence profiles, on which the guideline panel will base their judgments.7 We prepared 3 systematic reviews addressing the clinical questions covered by the guideline (about the diagnosis, use of formula and immunotherapy of the CMA). We searched MEDLINE, EMBASE, and the Cochrane Library (including Cochrane Central Register of Controlled Trials, DARE, NHS EED) for relevant studies. We included studies published up to September 2009. We developed GRADE evidence profiles (summary of findings tables) for the clinical questions based on the systematic reviews. The summaries of evidence were reviewed by the panel members and corrections and comments were incorporated. We assessed the quality of the evidence according to the methodology described by the GRADE system.1–3,8 In this system quality of supporting evidence is assessed based on explicit methodological criteria and classified as either “high,” “moderate,” “low,” or “very low.” The DRACMA guideline panel reviewed the evidence summaries and the draft guidelines, and made recommendations. We reached consensus on all recommendations. Formulating the recommendations included explicit consideration of the quality of evidence, benefits, harms, burden, cost, and values and preferences described as the “Underlying values and preferences” or in the “Remarks” sections of each recommendation as outlined earlier.9 Statements about the underlying values and preferences and the remarks are integral parts of the recommendations and serve to facilitate accurate interpretation of the recommendations. They cannot be omitted when citing or translating DRACMA guidelines. In this document, the expression “values and preferences” refers to the relative weight one attributes to particular benefits, harms, burdens, and costs to determine their balance. We used the decision framework described previously to determine the strength of recommendations.1,10 Little information about costs of diagnosis and treatment of IgE-mediated cow's milk allergy was available to the panel and it is very likely that it varies considerably across geographical areas and jurisdictions. Cost, therefore, plays a limited role in these recommendations. However, whenever we considered cost and resource expenditure, we used health system perspective.11 For individual patients, cost may not be an issue if the service or treatment strategy is provided at reduced price or free of charge. Clinicians and patients should consider their local resource implications when interpreting these recommendations. After the GRADE approach we classified recommendations in these guidelines as either “strong” or “conditional” (also known as weak)/weak. The strength of recommendations depends on a balance between all desirable and all undesirable effects of an intervention (ie, net clinical benefit), quality of available evidence, values and preferences, and cost (resource utilization).1 In general, the higher the quality of the supporting evidence, the more likely it is for the recommendation to be strong. Strong recommendations based on low or very low quality evidence are rare, but possible.12 For strong recommendations we used words “we recommend” and for conditional recommendations, “we suggest.” We offer the suggested interpretation of “strong” and “weak” recommendations in Table 2-1. Understanding the interpretation of these 2 grades (strong or conditional) of the strength of recommendations is essential for clinical decision making. TABLE 2-1 Interpretation of “Strong” and “Weak” Recommendations How to Use These Recommendations The DRACMA guidelines are not intended to impose a standard of care for individual countries and jurisdictions. They should, as any guideline, provide a basis for rational decisions for clinicians and their patients about the management of cow's milk allergy. Clinicians, patients, third-party payers, institutional review committees, other stakeholders, or the courts should never view these recommendations as dictates. Strong recommendations based on high quality evidence will apply to most patients for whom these recommendations are made, but they may not apply to all patients in all circumstances. No recommendation can take into account all of the often-compelling unique features of individual clinical circumstances. Therefore, nobody charged with evaluating clinicians' actions should attempt to apply the recommendations from the DRACMA guidelines as rote or in a blanket fashion. REFERENCES, SECTION 2 1 Guyatt GH Oxman AD Kunz R Falck-Ytter Y Vist GE Liberati A Schunemann HJ Going from evidence to recommendations BMJ. 2008;336:1049–1051 18467413 2 Guyatt GH Oxman AD Kunz R Vist GE Falck-Ytter Y Schunemann HJ What is “quality of evidence” and why is it important to clinicians? BMJ. 2008;336:995–998 18456631 3 Guyatt GH Oxman AD Vist GE Kunz R Falck-Ytter Y Alonso-Coello P Schunemann HJ GRADE: an emerging consensus on rating quality of evidence and strength of recommendations BMJ. 2008;336:924–926 18436948 4 Schünemann HJ Fretheim A Oxman AD Improving the use of research evidence in guideline development: 9. Grading evidence and recommendations. Health Res Policy Syst. 2006;4:21 17147810 5 Schünemann HJ Oxman AD Fretheim A Improving the use of research evidence in guideline development: 6. Determining which outcomes are important. Health Res Policy Syst. 2006;4:18 17140444 6 World Health Organization Global Programme on Evidence for Health Policy. Guidelines for WHO Guidelines. EIP/GPE/EQC/2003.1. Geneva, 2003; 7 Schünemann HJ Hill SR Kakad M Vist GE Bellamy R Transparent development of the WHO rapid advice guidelines. PLoS Med. 2007;4:e119 17535099 8 Schünemann HJ Oxman AD Brozek J Glasziou P Jaeschke R Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336:1106–1110 18483053 9 Schünemann HJ Munger H Brower S O'Donnell M Crowther M Cook D Guyatt G Methodology for guideline development for the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:174S–178S 15383470 10 Schünemann HJ Jaeschke R Cook DJ Bria WF El-Solh AA An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations. Am J Respir Crit Care Med. 2006;174:605–614 16931644 11 Guyatt GH Oxman AD Kunz R Jaeschke R Helfand M Liberati A Vist GE Schunemann HJ Incorporating considerations of resources use into grading recommendations. BMJ. 2008;336:1170–1173 18497416 12 Brozek JL Baena-Cagnani CE Bonini S Canonica GW Rasi G Methodology for development of the Allergic Rhinitis and its Impact on Asthma guideline 2008 update. Allergy. 2008;63:38–46 18053015 SECTION 3: EPIDEMIOLOGY OF CMA Overview There are no surveys of population and geographical trends in food allergy in adults or children (though the situation is different in pediatric asthma and rhinitis) and this unmet need is particularly felt for CMA. The perception of milk allergy is far more frequent than confirmed CMA. Patient reports of CMA range between 1 and 17.5%, 1 and 13.5%, and 1 to 4% in preschoolers, at children 5 to 16 years of age and adults respectively. Cow's milk-specific IgE sensitization point prevalence progressively decreased from about 4% at 2 years to less than 1% at 10 years of age in the German Multi-Centre Allergy Study. The most reliable data in epidemiology are those from birth cohorts that are free from selection bias. There are 5 such challenge-confirmed studies. The CMA prevalence during infancy ranged from 1.9% in a Finnish study, 2.16% in the Isle of Wight, 2.22% in a study from Denmark, 2.24% in the Netherlands, and up to 4.9% in Norway. Patients with CMA develop gastrointestinal symptoms in 32 to 60% of cases, skin symptoms in 5 to 90%, and anaphylaxis in 0.8 to 9% of cases. This frequency of anaphylaxis is the main concern pointed out in many CMA studies. In a review, nearly one third of children with atopic dermatitis (AD) received a diagnosis of CMA after an elimination diet and an oral food challenge, and about 40 to 50% of children less than a year of age with CMA also had AD. Finally, with actual population and geographical trends remaining unknown, allergists are primarily in need of more detailed epidemiological surveys on a global scale. One large such epidemiological study supported by the European Commission is ongoing and aims to furnish the first prevalence data regarding the suspicion of CMA, sensitization to cow's milk, and oral food challenge-confirmed diagnosis in 10 European birth cohorts. Introduction Around 11–26 million of the European population are estimated to suffer from food allergy.1 If this prevalence was consistent around the world and projected to the 6,659,040,000 people of the world's population,2 it translates into 220–520 million people and represents a major global health burden. Although there are surveys on the natural history and prevalence trends for symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood,3 we do not have a study assessing the prevalence of food allergy and its time-trends. The problem is complicated by the fact that perceived food allergy (ie, the self-reported feeling that a particular food negatively influences health status) is not actual food allergy. Allergy prevalence is much greater in the public's belief than it has ever been reported by double-blind studies. Back in the 1980s, the perceived incidence of allergy to food or food additives in mothers with young children was reported between 174 and 27.5%.5 Thirty percent of women reported that they or some member of their family were allergic to some food product.6 In the after decade, a British study using a food allergy questionnaire reported a 19.9% incidence of food allergy.7 From the mid-1990s onwards, self reports began to be compared with challenge-confirmed diagnoses; reported incidence data of between 12.4 and 25% could be confirmed by oral food challenge in only 1.5 to 3.5% of cases, illustrating how reports of adverse reactions overestimate true food allergy.8,9 This was further confirmed when prevalence figures of 2.3 to 3.6% were confirmed by challenge procedures in unselected patient populations.10,11 In the 1990s, it was also confirmed that only a minority of subjects who report food-related illness also test positive by skin prick test using the same food.12 Thus, 2 separate “food allergy epidemiologies” can be distinguished: a. Self-reported food allergy; although this does not represent actual food allergy epidemiology, it is useful as a proxy measure of the potential demand for allergy medical services, and may guide public health allergy service users between general and specialist medicine,13 and more generally for public health planning. b. Actual food allergy (ie, confirmed by a positive oral food challenge) represents the real extent of this clinical problem. In general, food allergy is more frequent in the pediatric, rather than the adult, population. According to a recent Japanese multicenter trial, the prevalence of CMA is 0.21% in newborns and 0.35% amid extremely premature babies ( 15 eosinophils per 40× high-power field, of the upper and lower esophagus. In infants with EoE, hypersensitivity to multiple foods may be seen. In older children and adults, aeroallergens have been implicated. CMA may also play a significant role88: although the presence of increased numbers of eosinophils, T lymphocytes or mast cells in esophageal biopsy specimens does not reliably predict CMA,89 eosinophilic oesophagitis may occur in infants with CMA,90 and also in adults allergic to goat's and sheep's milk.91 The mechanisms by which food allergens induce eosinophilic oesophagitis are poorly understood. It appears plausible that release of proinflammatory mediators from activated T cells and eosinophils may stimulate the enteric nervous system, either directly or via the release of motility-active gastrointestinal hormones. Upper gastrointestinal dysmotility has been demonstrated during cow's milk challenge in infants with vomiting because of CMA.92 The assessment of the causality of oesophagitis is complicated by overlap between acid-peptic and allergic oesophagitis.93 Therapy may include hypoallergenic diets and swallowed aerosolized steroid.94 Food Protein-Induced Enterocolitis Syndrome (FPIES) FPIES represents the acute, slightly delay-onset end of the spectrum of milk allergy in the gut and is an uncommon disorder, usually presenting with repeated projectile vomiting, hypotonia, pallor, and sometimes diarrhea 1 to 3 hours after ingestion of cow's milk protein.95 Symptoms are severe, protracted, most commonly after ingestion of cows' milk- or soy-based formula (50% of infants react to both), although solid food allergens are occasionally implicated. Progression to dehydration can occur and cause shock in about 20% of cases. Typically, FPIES occurs at the first known introduction of cow's milk protein into the diet. It has not been reported in exclusively breast-fed infants, until cow's milk or cow's milk-based formulas are added to the diet. It may also be caused by other food proteins and may require a careful differential history. Despite the relatively rapid onset after ingestion, the disorder is not IgE-mediated. The most prominent features are failure to gain weight and hypoalbuminaemia.96 Remission usually occurs within the first 3 years of life. Cow's Milk Protein-Induced Enteropathy FPIES is not always immediate-onset. Infants with allergic enteropathy because of cow's milk protein may present with diarrhea, failure to thrive, various degrees of vomiting and, sometimes, hypoproteinaemia and anemia. In younger children metabolic acidosis can develop.97 The clinical signs of secondary lactose intolerance, including perianal excoriation from acidic stools, may be present.98 The clinical features are summarized in Table 6-3.99 Despite the acute nature of the clinical presentation, it is thought to be a non-IgE-mediated disorder. The implicated dietary proteins include cow's milk, but also soy milk, hydrolyzed casein protein, and maternal dietary proteins transferred through breast milk.100 In addition to the clinical features noted above, laboratory observations include stools that contain not only blood but also neutrophils. Mild anemia may progress to significant anemia associated with hypoproteinemia because of protein-losing enteropathy; this is confirmed by increased fecal Alpha-1-antitrypsin. An increased intestinal permeability was shown, and increased inflammatory cells in the lamina propria, lymphoid nodular hyperplasia, and characteristic increase in eosinophilic infiltration of the crypts. TABLE 6-3 Dietary Protein Enterocolitis: Clinical Features Most infants with milk-induced entheropathy respond to the use of extensively hydrolyzed formula, although a significant number of infants require an amino acid–based formula.101 Although initial presentation may implicate a single antigen, many of these infants have multiple–food antigen intolerance with more than half of reported infants allergic to soy. In breast-fed infants, the clinical presentation is often more benign, featuring blood streaked diarrhea, mild anemia, and hypoproteinemia in an otherwise healthy and growing child. The majority can be managed by maternal elimination of cow's milk from the diet.102 Many infants with food-induced entheropathy respond to elimination diet and are challenge-positive, but they show negative specific IgE determinations and skin prick tests to CM, confirming the “non-IgE” nature of the syndrome.97 Constipation Chronic constipation is defined as the infrequent passage of hard, lumpy stools for more than 8 weeks, in association with fecal incontinence, withholding behavior or painful defecation.103 Removal of cows milk protein from the diet may benefit this condition, and CMA has been reported in 70% of children with chronic constipation.104–106 However, whether constipation is a clinical manifestation of CMA in infants and young children is controversial, and in the majority of cases thus remain no more than an intriguing relationship.107 A systematic review supports the hypothesis that a proportion of children with chronic functional constipation respond well to the removal of cow's milk protein from the diet, particularly if serum analysis shows abnormalities of immune mechanisms, but claims for high-level evidence studies to clarify the physiological, immunologic, and biochemical relationships between constipation and CMA are missing.108 Convincing formal demonstration of the link between CMA and constipation include response to dietary avoidance of milk and dairy products, endoscopic and immunohistochemical findings.109 In the reported case studies, the IgE-mediated mechanism predominates in infancy, while non-IgE-mediated reactions are common in adults.110–112 Cow's milk protein-induced constipation is often associated with anal fissures and rectal eosinophilia. In these children, CM may develop painful defecation, perianal erythema or eczema and anal fissures with possible painful fecal retention, thus aggravating constipation.113 For this particular symptom, it has been reported that tolerance is achieved after a mean 12 months of strict cow's milk elimination.114 Severe Irritability (Colic) Unexplained paroxysms of irritability, fussing or crying that persist for more than 3 hours per day, on more than 3 days per week and for at least 3 weeks have been defined as infantile ‘colic’.115 Colic affects between 9 and 19% of infants in the first months of life, with infants appearing generally well, but showing a distressed behavior.116 Although colic is not a feature of IgE-mediated CMA, some studies have demonstrated a high prevalence of colic in infants with CMA,117 and infants with colic have benefited from treatment with hypoallergenic formula or from the elimination of cow's milk from the maternal diet.118–120 Infants with severe colic may also benefit from soy formula but relapse 24 hours after cow's milk challenge.121 Dietary treatment with amino acid-based formula has also been described as useful in severe colic.122 However, the etiology in most cases is multifactorial,123 and many treatment modalities (some not part of the allergist armamentarium) can benefit children with colic.124 Colic can be associated with GER and oesophagitis, so overlaps between these conditions of complex and interrelated etiology. The lack of an identified causal relationship between acid reflux and infantile colic can explain why treatment with antireflux medications, often predicated on an empirical basis, remain unsuccessful in most cases. Thus, in colic, a brief trial of excluding cow's milk protein from the diet may be of help in some cases, but the indication/contraindication for an exclusion diet cannot be based on allergy tests alone. Interestingly, the observation that infants with severe and persistent excessive crying in infancy almost invariably show normal sleeping, feeding and crying behavior when admitted to hospital raises the question of the definition and interpretation of severe irritability, thereby suggesting that parents may regard normal crying behavior as excessive.125 Food Protein-Induced Gastroenteritis and Proctocolitis These diseases of infancy usually show up by the second month and represent the benign end of the spectrum of non-IgE-mediated allergy to milk.126 Infants with allergic proctocolitis because of cow's milk protein allergy can present with relatively normal stools or mild diarrhea and low-grade rectal bleeding but be otherwise well and thriving. If the infant is exclusively breast-fed (breast milk colitis), symptoms may be caused by protein transfer via breast milk. The bleeding is usually observed as stools containing mucus and flecks of blood rather than as frank rectal bleeding. Other systemic features (such as failure-to-thrive or anemia) are usually absent.127 Allergic enterocolitis can occur in the early neonatal period (in preterm neonates even after the first feed128) and should be considered in the differential diagnosis of any newborn developing gastrointestinal bleeding.129 Sometimes the condition may present with acute symptoms mimicking Hirschsprung's disease.130 Laboratory results include testing for peripheral blood eosinophilia, microcytic anemia, mildly elevated serum IgE and low serum albumin.131 Rectal biopsies, which are usually not necessary, may be required to confirm the diagnosis in the more severe or atypical cases. At colonoscopy, the rectal mucosa of an infant with allergic proctocolitis will seem inflamed. The pathologic features which are strongly supportive of a diagnosis of infantile allergic proctocolitis include a marked focal increase in the number of eosinophils in the lamina propria (>60/10 HPF) with a predominance of eosinophils, and crypt abscesses. After some time, the condition resolves so this is usually a temporary disorder of early childhood. The diagnosis is usually made on the basis of a response to the exclusion of cow's milk protein, either from the lactating mother's diet or by substituting an extensively hydrolyzed cow's milk formula. After this, bleeding should resolve in a few days, though persistent bleeding may respond to an amino acid formula. The prognosis is good and spontaneous remission of cow's milk allergy occurs within the first 2 years of life, probably because of maturation of the immune and/or digestive systems.132 III: Milk-Induced Chronic Pulmonary Disease (Heiner's Syndrome) The first report of Heiner's syndrome described a group of 7 children 6 weeks to 17 months old, Heiner's syndrome is characterized by recurrent pulmonary infiltrates associated with chronic cough, recurrent fever, tachypnoea, wheezing, rales, failure-to-thrive and family history of allergy caused by cow's milk ingestion.133 Chest roentgenograms showed patchy infiltrates, frequently associated with atelectasis, consolidation, reticular densities, pleural thickening, or hilar lymphadenopathy. In the original description precipitins to cow's milk proteins were also found. Heiner's syndrome has occasionally been described.134 A more recent study featured children who were responsive to a milk elimination diet, suggesting that infants with an unexplained chronic pulmonary infiltrate should be assessed for precipitating antibodies to bovine milk proteins in their serum.135 Although very rare in the general pediatric population, this syndrome should be considered in the differential diagnosis of pediatric pulmonary complaints. IV: Miscellanea An association between CMA beyond infancy and recurrent abdominal pain has been reported.136 In addition, it has been reported that after clinical resolution and in absence of specific IgE, children with CMA may developed persistent abdominal pain.137 Neurologic syndromes, such as ADHD, have been reported with food allergy and in particular with eczema.138 However, these associations require cautious interpretation and require further validation. REFERENCES, SECTION 6 1 Sampson HA Update on food allergy. 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J Pediatr. 2004;145:606–611 15520758 110 Castro M Diamanti A Mancini S Bella S Papadatou B De Iacobis IT Diagnostic value of food specific IgE antibodies in children with immediate digestive symptoms to cow's milk. J Pediatr. 2004;145:715–716 15520790 111 Daher S Tahan S Solé D Naspitz CK Da Silva Patrício FR Neto UF De Morais MB Cow's milk protein intolerance and chronic constipation in children. Pediatr Allergy Immunol. 2001;12:339–342 11846872 112 Crittenden RG Bennett LE Cow's milk allergy: a complex disorder. J Am Coll Nutr. 2005:24(Suppl):582S–591S 16373958 113 Andiran F Dayi S Mete E Cow's milk consumption in constipation and anal fissure in infants and young children. J Paediatr Child Health. 2003;39:329–331 12887660 114 El-Hodhod MA Younis NT Zaitoun YA Daoud SD Cow's milk allergy related pediatric constipation: appropriate time of milk tolerance. 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Pediatr Surg Int. 2005;21:850–852 16189674 131 Odze RD Bines J Leichtner AM Allergic proctocolitis in infants: a prospective clinical-pathologic biopsy study. Hum Pathol. 1993;24:668–674 8505043 132 Hills SM Milla PJ Colitis caused by food allergy in infants. Arch Dis Child. 1990;65:132–140 2301977 133 Heiner DC Sears JW Chronic respiratory disease associated with multiple circulating precipitins to cow's milk. Am J Dis Child. 1960;100:500–502 134 Fossati G Perri M Careddu G Pulmonary hemosiderosis induced by cow's milk proteins: a discussion of a clinical case. Pediatr Med Chir. 1992;14:203–207 1508757 135 Moissidis I Chaidaroon D Vichyanond P Bahna SL Milk-induced pulmonary disease in infants (Heiner syndrome). Pediatr Allergy Immunol. 2005;16:545–552 16176405 136 Kokkonen J Tikkanen S Karttunen TJ Savilahti E A similar high level of immunoglobulin A and immunoglobulin G class milk antibodies and increment of local lymphoid tissue on the duodenal mucosa in subjects with cow's milk allergy and recurrent abdominal pains. Pediatr Allergy Immunol. 2002;13:129–136 12000486 137 Tikkanen S Kokkonen J Juntti H Niinimäki A Status of children with cow's milk allergy in infancy by 10 years of age. Acta Paediatr. 2000;89:1174–1180 11083371 138 Schmitt J Romanos M Schmitt NM Meurer M Kirch W Atopic eczema and attention-deficit/hyperactivity disorder in a population-based sample of children and adolescents. JAMA. 2009;301:724–726 19224748 SECTION 7: THE DIAGNOSIS OF CMA ACCORDING TO PRECEDING GUIDELINES Overview The diagnosis of CMA starts with suspicion and ends with an oral food challenge (OFC) carried out under the supervision of a specialist. If patients report reactions to milk, an accurate medical history can facilitate the diagnostic approach. In history-taking, the clinician should be aware that patients and parents may distort history in the reporting. In particular, subjective symptoms as a manifestation of milk allergy should be looked on with suspicion: the symptoms of CMA are cutaneous, respiratory and gastrointestinal. A potential confounder in older children and adults is lactose intolerance. Diagnostic possibilities in the armamentarium include: a.A period of tentative avoidance, followed by an open reintroduction schedule b.The use of “milk-symptom diaries” c.Skin testing, including skin prick test (SPT) and atopy patch test (APT) d.The evaluation of serum food -specific IgE using one of several available methods e.Formal OFCs. Performance, accuracy, and the diagnostic positioning of these methods will be dealt with by the GRADE-rated sections of these Guidelines (section 7). In previous guidelines and recommendations for milk allergy diagnosis, these methods are suggested either in sequence or in combination. Some differences in the diagnostic approach reflect local needs and visions. Decision strategies in the management of CMA include locally changing issues (indicators of human well-being for the country, prevalence of the condition in that population, methods of diagnosis, local availability of formula and their price, availability of potential milk substitutes different from the products available worldwide, reimbursements by healthcare providers, resource availability and different clinical situations). Thus, regional and national documents should be planned for the implementation of DRACMA to allow the most appropriate, but evidence-based approach, to diagnostic strategies worldwide. Introduction Food allergy in general, and CMA in particular, are unique examples in which a systematic approach can be applied. As the disease involves not only the patient, but the whole family and her social supports, these can be protagonist of the diagnosis itself.1 As in any field of medicine, the diagnosis starts from suspicion. If patients reports reactions to milk, an accurate medical history can clarify many aspects of the diagnosis. The after aspects of the history are particular importance: • Age at onset • Nature of symptoms • Frequency of their manifestation • Timing between ingestion and onset of symptoms • Quantity of milk necessary to provoke symptoms • Method of milk preparation • Reproducibility of the reaction • Interval of time since last reaction • Influence of external factors on the manifestation (eg, exercise, hormonal changes, or emotional stress) • Food diary • Growth records • Early feeding details (duration of breast-feeding, type of infant formulas, introduction of weaning solids) • Effect of elimination diets (soy, treatment formulas, diet of the mother during breast-feeding) • Therapeutic interventions.2 In taking history, some general considerations can be of help: 1. Patient history is notoriously inaccurate. 2. Milk allergy is most common in young children, especially with atopic dermatitis. 3. When a child with milk allergy has “new” or “multiple” food allergies, it is most likely that the child is ingesting “hidden” sources of milk. 4. Except in gastrointestinal allergies, most milk-induced allergic symptoms develop within minutes to a few hours of ingesting milk. 5. True milk allergies generally involve “classic” signs and symptoms affecting the skin, gastrointestinal, and/or respiratory systems. 6. Subjective or behavioral symptoms as a sole manifestation of milk allergy are very rare.3 7. Confusion between cows' milk allergy and lactose intolerance is common. If the history does not exclude the possibility of CMA, in particular in delayed manifestations, in primary setting there is the possibility to take a period of tentative avoidance of milk, followed by an open reintroduction. When avoidance coincides with symptom-free periods, an open reintroduction can be useful to identify the offending food (if severe symptoms are anticipated, the procedure should be done under supervision in a medical facility). In children with eczema, reintroduction of the eliminated food should be done cautiously as immediate reactions may occur after a period of dietary elimination. This elimination, reintroduction sequence does not eliminate the need for formal food challenges, but can give some indication on the possibility of CMA.4 Another possible tool in this phase is the use of “milk symptom diaries,” that is, chronologic, accurate records of all ingested foods/beverages with the records of any developed symptoms. The results of these procedures give findings often confusing, because of subjectivity of patients and erratic compliance. Thus, this diagnostic phase which is time-consuming and plagued with inherent difficulties, is not frequently performed. In general, at a specialist level, a sensitization evaluation takes place soon after medical history. We have several methods to evaluate milk sensitization: • Skin testing, including immediate skin prick test (SPT), and atopy patch test (APT) • The evaluation of serum food-specific IgE using one of the several available methods. Performance, accuracy, and the diagnostic positioning of these methods will be presented in the GRADE section of these Guidelines. Sensitization tests are able to confirm or refute the presence of specific IgE against milk or one of its proteins, but used in isolation they cannot confirm a diagnosis of CMA. This is because a number of sensitized patients will not react to the ingestion of CM and a number of children without sensitization will actually suffer from CMA. That a specific IgE determination does not have a diagnostic accuracy of 100% is not surprising, given the heterogeneity of mechanisms underlying CMA. The classic method for diagnosing CMA is by elimination, provocation and re-elimination, using for the provocation phase a double blind, placebo controlled food challenge protocol (DBPCFC).5 This form of challenge is considered the gold standard as up to 70% of the positive test results obtained with open provocation give a false positive outcome not confirmed at a follow up DBPCFC.6 However, in younger children, an open food challenge is generally considered sufficient evidence of CMA, provided that objective symptoms are demonstrated during a challenge. Subjective symptoms (itchy throat, food refusal, nausea, headaches, etc.) are more difficult to interpret and may require DBPCFC for further diagnostic clarification. As even in developed countries this complex procedure is performed only in a few sites per country,7 CMA may be falsely diagnosed in a large number of children. This may expose the various populations to a series of consequences: 1. The epidemiology of CMA is not completely elucidated and studies are necessary to clarify the real incidence of the condition using DBPCFC on a large scale.8 2. A high number of children are overtreated with unnecessary elimination diets, with clinical, social and financial consequences.9 3. The number of false-positive diagnoses plague the evaluation of the natural history of the disease, leading to an overestimate of the condition.10 For these reasons, a series of attempts have been made in the past few years to simplify and standardize the diagnostic procedure. These will be presented in the GRADE section. There are a number of guidelines and recommendations for milk allergy prevention1–4 and a few documents on food allergy in general.5,6 However, there is a paucity of documents on the diagnosis of food and in particular of milk allergy in children7–10 (Table 7-1). National position papers and guidelines have been produced in Germany,21,22 the Netherlands,23 Finland,24 Australia,20 and Argentina,25 reflecting general and local needs and visions. As the decision strategies in the management of CMA include locally changing issues (indicators of human well-being for the country, prevalence of the condition in that population, methods of diagnosis, local availability of formula and their price, availability of potential milk substitutes different from the products available worldwide, reimbursements by the healthcare providers), these documents are not only possible, but necessary. This Special Committee wishes that local documents be produced in the implementation phase of DRACMA to establish a flexible but evidence-based approach to treatment strategies worldwide. TABLE 7-1 Diagnosis of Milk Allergy According to the Current Recommendations In Different Countries REFERENCES, SECTION 7 1 Arroll B Pert H Guyatt G Milk allergy and bottles over the back fence: two single patient trials. Cases J. 2008;1:77–78 18691397 2 Bahna SL Diagnosis of food allergy. Ann Allergy Asthma Immunol. 2003;90:S77–S80 3 Sampson HA Food allergy. Part 2: diagnosis and management. J Allergy Clin Immunol. 1999;103:981–989 10359874 4 Bock SA Diagnostic evaluation. Pediatrics. 2003;111:1638–1644 12777604 5 Nowak-Wegrzyn A Assa'ad AH Bahna SL Bock SA Sicherer SH Teuber SS : Adverse Reactions to Food Committee of American Academy of Allergy, Asthma & Immunology Work Group report: oral food challenge testing. J Allergy Clin Immunol. 2009;123(Suppl):S365–S383 19500710 6 Venter C Pereira B Grundy J Clayton CB Arshad SH Dean T Prevalence of sensitization reported and objectively assessed food hypersensitivity amongst six-year-old children: a population-based study. Pediatr Allergy Immunol. 2006;17:356–363 16846454 7 Martelli A Bouygue GR Fiocchi A Restani P Sarratud T Terracciano L Oral food challenges in children in Italy. Allergy. 2005;60:907–911 15932381 8 Keil T McBride D Grimshaw K Niggemann B Xepapadaki P The multinational birth cohort of EuroPrevall: background, aims and methods. Allergy. 2009 Sep 30. [Epub ahead of print]. 9 Sinagra JL Bordignon V Ferraro C Cristaudo A Di Rocco M Amorosi B Capitanio B Unnecessary milk elimination diets in children with atopic dermatitis. Pediatr Dermatol. 2007;24:1–6 17300640 10 Skripak JM Matsui EC Mudd K Wood RA The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol. 2007;120:1172–1177 17935766 11 Muraro A Dietary prevention of allergic diseases in infants and small children. Part I: immunologic background and criteria for hypoallergenicity. Pediatr Allergy Immunol. 2004;15:103–11 15059185 12 Muraro A Dietary prevention of allergic diseases in infants and small children. Part II. Evaluation of methods in allergy prevention studies and sensitization markers. Definitions and diagnostic criteria of allergic diseases. Pediatr Allergy Immunol. 2004;15:196–205 15209950 13 Muraro A Dietary prevention of allergic diseases in infants and small children. Part III: critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr Allergy Immunol. 2004;15:291–307 15305938 14 Prescott SL The Australasian Society of Clinical Immunology and Allergy position statement: summary of allergy prevention in children. Med J Aust. 2005;182:464–467 15865590 15 Chapman JA Bernstein IL Lee RE Oppenheimer J Nicklas RA Food allergy: a practice parameter. Annals Allergy Asthma Immunol. 2006;96(Suppl 2):S1–S68 16 Bruijnzeel-Koomen C Ortolani C Aas K Bindslev-Jensen C Björkstén B Moneret-Vautrin D Wüthrich B Adverse reactions to food. European Academy of Allergology and Clinical Immunology Subcommittee. Allergy. 1995;50:623–635 7503398 17 Høst A Dietary products used in infants for treatment and prevention of food allergy. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) committee on hypoallergenic formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) committee on nutrition. Arch Dis Child. 1999;81:80–84 10373144 18 Werfel T Ballmer-Weber B Eigenmann PA Niggemann B Rancé F Turjanmaa K Worm M Eczematous reactions to food in atopic eczema: position paper of the EAACI and GA2LEN. Allergy. 2007;62:723–728 17573718 19 Vandenplas Y Koletzko S Isolauri E Hill D Oranje AP Brueton M Staiano A Dupont C Guidelines for the diagnosis and management of cow's milk protein allergy in infants. Arch Dis Child. 2007;92:902–908 17895338 20 Kemp AS Hill DJ Allen KJ Anderson K Davidson GP Guidelines for the use of infant formulas to treat cows milk protein allergy: an Australian consensus panel opinion. Med J Aust. 2008;188:109–112 18205586 21 Niggemann B Friedrichs F Koletzko B Positions papier. Das Vorgehen bei Saüglingen mit Verdacht auf Kuhmilchproteinallergie. Padiatrische Allergologie. 2005;4:14–18 22 Kirchlechner V Dehlink E Szepfalusi Z Cow's milk allergy: guidelines for the diagnostic evaluation. Klin Padiatr. 2007;219:201–205 16586270 23 Kneepkens CMF Van Drongelen KI Aarsen C Landelijke standard voedselallergie bij zuigelingen [National standard for food allergy in infants]. 5th ed Den Haag: Voedingscentrum, 2005:80 24 Finnish Paediatric Society Food allergy in children. Duodecim. 2004;120:1524–1538 15293715 25 Orsia M Fernández A Follett FR Marchisone S Saiege G Busonia VB Tabacco O Toca C Alergia a la proteína de la leche de vaca. Propuesta de Guía para el manejo de los niños con alergia a la proteína de la leche de vaca. Arch Argent Pediatr. 2009;107:459–470 19809770 SECTION 8: THE ELIMINATION DIET IN THE WORK-UP OF CMA Overview In most of cases, a phase of milk elimination is an integral step toward the diagnosis of CMA. If it leads to a definite improvement in symptoms without resorting to medication, it supports the diagnosis until confirmation is made by challenge testing. Substantiating claims of linking cow's milk with symptoms, improving the same when relevant to the condition, and generally minimizing confounders with the view to perform diagnostic challenge should be the aims when planning an avoidance diet. The duration of elimination should be for at least the longest symptom-free interval that has been experienced by the patient. It can be a few to several weeks in cases of chronic or severe gastrointestinal symptoms or atopic eczema. The stricter the degree of elimination, the more likely to be useful in decision making. In addition to avoiding ingestion, exquisitely-sensitive subjects may need to avoid exposure by skin contact or by inhalation, particularly milk vapor. In young children with severe symptoms or with suspected multiple offending foods (by history, skin testing or sIgE testing), the diet may be initially very limited until symptoms improve and a definitive diagnosis is reached. A hypoallergenic formula (extensively hydrolyzed or elemental aminoacid formula) can be the only diet until challenge testing is done. In case of exclusively breast-fed infants, the elimination trial can be applied to the maternal diet. In practice, caution should be applied with all elimination diets for treatment or diagnosis and include carefully thought-out avoidance from accidental ingestion, contact or inhalation of the incriminated food(s). The clinician should also make the patients aware of possible cross-reactions (eg, with buffalo, goat, or ewe's milks) while ensuring nutritional adequacy and promoting compliance through education. Introduction The general treatment for CMA is dietary and consists of eliminating all dairy products from the diet to avoid exposure to the implicated allergen(s).1 For this reason, a period of dairy product avoidance is also part of the work-up to diagnosis in patients presenting with suspected cow's milk allergy. In patients with a history of life-threatening symptoms, particularly if respiratory or involving several organ systems, suspicion of contact with cow's milk proteins alone warrants avoidance. However, because the spectrum of CMA manifestations is so wide, most patients will present with vague complaints in the primary care setting and a precautionary avoidance diet should be prescribed for most patients with suspected CMA until the completion of their allergy work-up to: a. Substantiate diagnostic suspicion; b. Remove the confounding effect of the continued intake of the suspected allergen; c. Improve skin prick test (SPT) outcome by reducing inflammation (especially in atopic dermatitis); d. Anticipate the oral food challenge phase by minimizing confounder effect(s). No study so far has tackled the issue of the optimal duration of the diagnostic elimination phase but it seems reasonable that this phase be shorter for immediate CMA and longer for delayed syndromes. In some cases, such as allergic eosinophilic esophagitis and allergic eosinophilic gastroenteritis, several weeks of an elemental diet will be necessary to stabilize patients before conducting food challenge. On the whole, the rules of application for a diagnostic elimination diet in the workup of CMA are the same as those for treatment. In particular, the clinician should take care to place the patient in a condition to achieve through an elimination diet the after clinical goals: a. Safety from accidental ingestion of cow's milk proteins b. Safety from inhalation or skin contact with cow's milk c. Avoidance of cross-reactive proteins (milk of buffalo, goat, or sheep) d. Nutritional adequacy, especially in children and if prolonged periods of elimination is prescribed e. Clear patient education to encourage compliance. In most age groups, including breast-fed and over-2-year-old children, it may not be necessary to provide a substitute for cow's milk. Nursing mothers should also follow a milk-free diet, with adequate calcium supplements. A substitute formula will be prescribed to nonbreastfed infants and toddlers. It is the consensus of this panel that, considering costs, the least allergenic substitute should be proposed for these children to maximalize the diagnostic power of the elimination diet. Beef avoidance should also be considered in these children unless from a technologically processed source,2 as dairy products and meat contain common antigenic protein3 and up to 20% can be allergic to beef.4 An elimination diet should be continued for at least 2 weeks and up to several weeks in cases of delayed reactions.5,6 If the elimination diet fails to improve the symptoms, the breast-feeding mother and/or the infant should resume their normal diet and a referral to a different specialist (dermatologist, gastroenterologist, etc.) should be considered, depending on the type and severity of symptoms. If the clinical picture improves substantially or issues disappear during the elimination diet, then the child must be referred to an allergy specialist for further diagnostic steps. REFERENCES, SECTION 8 1 Nowak-Wegrzyn A Food allergy to proteins. Nestle Nutr Workshop Ser Pediatr Program. 2007;59:17–31 2 Nowak-Wegrzyn A Fiocchi A Rare, medium, or well done? The effect of heating and food matrix on food protein allergenicity. Curr Opin Allergy Clin Immunol. 2009;9:234–237 19444093 3 Fiocchi A Restani P Riva E Beef allergy in children. Nutrition. 2000;16:454–457 10869903 4 Werfel SJ Cooke SK Sampson HA Clinical reactivity to beef in children allergic to cow's milk. J Allergy Clin Immunol. 1997;99:293–300 9058683 5 Bahna SL Food challenge procedures in research and in clinical practice. Pediatr Allergy Immunol. 1995;6(Suppl 8):49–53 9064065 6 Vandenplas Y Koletzko S Isolauri E Hill D Oranje AP Guidelines for the diagnosis and management of cow's milk protein allergy in infants. Arch Dis Child. 2007;92:902–908 17895338 SECTION 9: GUIDELINES FOR DIAGNOSING CMA The diagnosis of cow's milk allergy (CMA) starts with suspicion and ends with an oral food challenge (OFC) carried out under the supervision of a specialist. Given the limitations of exclusion, reintroduction diets and of “milk-symptom diaries,” the diagnostic panoply of the allergist includes skin prick test (SPT), the evaluation of serum milk-specific IgE using one of several available methods, and OFCs. In this section we will report the guidelines for the use of such tests in the evaluation of patients suspected of CMA. From the analysis of the literature, the use of sensitization tests is clearly dependent on the clinical setting and on the pretest probability of disease. Thus, for the objectives of the present document, we will define conditions of high, medium and low suspicion. Six relevant questions were identified by the panel, and for their evaluation 3877 articles were screened (Fig. 9-1). FIGURE 9-1 PRISMA diagram, questions 1–6. Should skin prick tests or cow's milk-specific IgE test be used for the diagnosis of IgE-mediated CMA? The evidence profiles for this section are to be found in Appendices 2-1; 2-2; 2-3. QUESTION 1 Should skin prick tests be used for the diagnosis of IgE-mediated CMA in patients suspected of CMA? Population: patients suspected of CMA Intervention: skin prick test Comparison: oral food challenge Outcomes: TP: The child will undergo oral food challenge that will turn out positive with risk of anaphylaxis, albeit in controlled environment; burden on time and anxiety for family; exclusion of milk and use of special formula. Some children with high pretest probability of disease and/or at high risk of anaphylactic shock during the challenge will not undergo challenge test and be treated with the same consequences of treatment as those who underwent food challenge. TN: The child will ingest cow's milk at home with no reaction, no exclusion of milk, no burden on family time and decreased use of resources (no challenge test, no formula); anxiety in the child and family may depend on the family; looking for other explanation of the symptoms. FP: The patient will undergo an oral food challenge which will be negative; unnecessary burden on time and anxiety in a family; unnecessary time and resources spent on oral challenge. Some children with high pretest probability of CMA would not undergo challenge test and would be unnecessarily treated with elimination diet and formula that may led to nutritional deficits (eg, failure to thrive, rickets, vitamin D or calcium deficiency); also stress for the family and unnecessary carrying epinephrine self injector which may be costly and delayed diagnosis of the real cause of symptoms. FN: The child will be allowed home and will have an allergic reaction (possibly anaphylactic) to cow's milk at home; high parental anxiety and reluctance to introduce future foods; may lead to multiple exclusion diet. The real cause of symptoms (ie, CMA) will be missed, leading to unnecessary investigations and treatments. Inconclusive results: (either negative positive control or positive negative control): the child would repeat SPT that may be distressing for the child and parent; time spent by a nurse and a repeat clinic appointment would have resource implications; alternatively child would have sIgE measured or undergo food challenge. Complications of a test: SPT can cause discomfort or exacerbation of eczema which can cause distress and parental anxiety; food challenge may cause anaphylaxis and exacerbation of other symptoms. Resource utilization (cost): SPT adds extra time to clinic appointment; however, oral food challenge has much greater resource implications. TP – true positive (being correctly classified as having CMA); TN – true negative (being correctly classified as not having CMA); FP – false positive (being incorrectly classified as having CMA); FN – false negative (being incorrectly classified as not having CMA); these outcomes are always determined compared with a reference standard (ie, food challenge test with cow's milk). TABLE Outcomes: Question 1 Summary of Findings We did not find any existing systematic review of diagnosis of CMA with skin prick testing. However, we found 25 studies that examined the role of skin prick tests in comparison to oral food challenge in patients suspected of CMA.1–25 All but one study used a cut-off of a mean wheal diameter of ≥3 mm; the other study used a cut-off value of 4 mm.7 Four studies included patients with suspected IgE-mediated cow's milk allergy,1,6,10,16 7 explicitly included only patients with atopic eczema,4,9,11,19,21,22,24 and the remaining studies included mixed populations of patients with various conditions in whom CMA was investigated. Using the criteria of methodological quality suggested by the QUADAS questionnaire we found that in many studies the spectrum of patients was not representative of the patients who will receive the test in practice. In most studies the results of a reference standard were very likely interpreted with the knowledge of the results of the skin prick test or vice versa. None of the studies reported uninterpretable or intermediate test results. One study reported 8% inconclusive challenge tests but did not report number of inconclusive skin prick tests.23 The combined sensitivity in these studies was 0.67 (95% CI: 0.64–0.70) and the specificity was 0.74 (95% CI: 0.72–0.77). Skin prick test accuracy was similar when studies in patients with atopic eczema were excluded (16 studies; sensitivity 0.71, 95% CI: 0.68–0.75 and specificity 0.73, 95% CI: 0.70–0.76). In 4 studies that explicitly enrolled patients suspected of immediate reactions to milk sensitivity seemed slightly improved (0.77, 95% CI: 0.68–0.84) on the expense of lower specificity (0.61, 95% CI: 0.52–0.70). We also investigated the influence of child's age on the accuracy of skin prick tests in the diagnosis of CMA. In children suspected of CMA who were on average younger than 12 months sensitivity of skin prick test was lower (0.55, 95% CI: 0.49–0.61 [4 studies]) than in children older than 12 month of age (0.81, 95% CI: 0.77–0.85 [11 studies]). Age seemed not to influence the estimate of specificity (0.75, 95% CI: 0.69–0.80 vs. 0.72, 95% CI: 0.68–0.76). The overall quality of evidence across outcomes was very low. Benefits and Downsides In patients with low pretest probability of CMA (∼10%) based on the history and presenting symptoms a negative result of skin prick test (ie, diameter 12 months). The combined sensitivity in the studies of CAP-RAST and FEIA that used a cut-off of ≥0.7 IU/L was 0.58 (95% CI: 0.52–0.65) and the specificity was 0.76 (95% CI: 0.70–0.81) (see evidence profile 4 for question 2).6,10,20,33 Two studies also estimated the accuracy of cow's milk specific IgE with a threshold of 2.5 IU/L,6 3.5 IU/L,20 and 5.0 IU/L.6 The sensitivity in the studies of CAP-RAST and FEIA that used a cut-off of ≥2.5 IU/L was 0.48 (95% CI: 0.35–0.60) and the specificity was 0.94 (95% CI: 0.88–0.98) (see evidence profile 5 for question 2). The sensitivity in the studies of CAP-RAST and FEIA that used a cut-off of ≥3.5 IU/L was 0.25 (95% CI: 0.17–0.33) and the specificity was 0.98 (95% CI: 0.94–1.00) (see evidence profile 6 for question 2) (20). Further increase of the cut-off of to 5.0 IU/L did not improve the accuracy (sensitivity: 0.30 [95% CI: 0.19–0.42), specificity: 0.99 (95% CI: 0.94–1.00)].6 The overall quality of evidence across outcomes was very low. Benefits and Downsides In patients with low pretest probability of CMA (∼10%) based on the history and presenting symptoms a negative result of cow's milk-specific IgE measurement (ie, 40%) based on the history and presenting symptoms, who have a negative result of a skin prick test (ie, diameter of <3 mm), measurement of cow's milk-specific IgE in serum with a cut-off value of 0.35 IU/L is unlikely to be of benefit. In patients with an average initial probability of CMA one would be able to avoid a food challenge with cow's milk in about 47% of patients with a risk of about 8% false negative results. In patients with a high initial probability of CMA one would be able to avoid a food challenge with cow's milk in about 30% of patients, but a risk of incorrectly classifying a patient as not having CMA would be high (about 17% false negative results). A positive result of milk-specific IgE in patient with a negative skin prick test is likely to lead to performing an oral food challenge test regardless. Conclusions In patients with low initial probability of CMA, who have a negative result of a skin prick test, the net benefit of measuring cow's milk specific IgE instead of oral food challenge with cow's milk is uncertain. Negative results of both skin prick test and milk-specific IgE can help to avoid an oral food challenge in about 60% of patients. However, this benefit is counterbalanced by approximately a 2% risk of falsely classifying a patient as not having CMA. In patients with average or high initial probability of CMA, who have a negative result of a skin prick test, the net benefit of measuring cow's milk specific IgE instead of oral food challenge is unlikely. In patients suspected of CMA, who have a negative result of a skin prick test, a positive result of milk-specific IgE is likely to lead to performing food challenge test. Clinical Recommendations, Question 4 Recommendation 4.1 In patients with a low initial probability of IgE-mediated CMA, who have a negative result of a skin prick test, we recommend measuring cow's milk-specific IgE level as a triage test to avoid food challenge test in those in whom the result of milk-specific IgE turns out negative (strong recommendation/low quality evidence). Underlying Values and Preferences This recommendation places a relatively high value on avoiding burden and resource use with an oral food challenge test (around 60% tests avoided). It places a lower value on avoiding an allergic reaction (possibly a mild one) in around 1 in 50 patients misclassified as not having cow's milk allergy (false negative result). Remarks A low pretest probability of CMA (∼10%) can be estimated based on the history and would represent, for instance, patients with unexplained gastrointestinal symptoms (eg, gastroesophageal reflux). Recommendation 4.2 In patients with an average initial probability of IgE-mediated CMA, who have a negative result of a skin prick test, we suggest oral food challenge rather than measuring cow's milk-specific IgE level (conditional recommendation/low quality evidence). Underlying Values and Preferences This recommendation places a relatively high value on avoiding resource consumption and the risk of anaphylactic reactions at home in patients who would be misclassified as not having CMA by skin prick test and milk-specific IgE tests. It places a lower value on anaphylactic reactions in a controlled setting that can be managed by experienced personnel when oral food challenge is performed. Remarks An average pretest probability of CMA (∼40%) can be estimated based on the history and presenting symptoms and would represent the majority of situations. Recommendation 4.3 In patients with a high initial probability of IgE-mediated CMA, who have a negative result of a skin prick test, we recommend oral food challenge rather than measuring cow's milk-specific IgE level (strong recommendation/low quality evidence). Underlying Values and Preferences This recommendation places a relatively high value on avoiding resource consumption and the risk of anaphylactic reactions at home in a large proportion of patients who would be misclassified as not having a CMA by skin prick test and milk-specific IgE tests. It places a lower value on anaphylactic reactions in a controlled setting that can be managed by experienced personnel when oral food challenge is performed. Remarks A high pretest probability of CMA (∼80%) can be estimated based on the history and would represent, for instance, patients who experienced an anaphylactic reaction in the past. QUESTION 5 Should allergen microarrays or component resolved diagnostics be used for the diagnosis of IgE-mediated CMA in patients suspected of CMA? Population: patients suspected of CMA Intervention: allergen microarrays or component-resolved diagnostics Comparison: oral food challenge Outcomes: TP: The child will undergo oral food challenge that will turn out positive with a risk of anaphylaxis, albeit in controlled environment; burden on time and anxiety for family; exclusion of milk and use of formula. TN: The child will receive cow's milk at home with no reaction, no exclusion of milk, no burden on family time, and decreased use of resources (no challenge test, no formula); anxiety in the child and family may depend on the family; looking for other explanation of the symptoms. FP: The child will undergo an oral food challenge that will be negative; unnecessary burden on time and anxiety in a family; unnecessary time and resources spent on oral challenge. FN: The child will be allowed home and will have an allergic reaction (possibly anaphylactic) to cow's milk at home; high parental anxiety and reluctance to introduce future foods; may lead to multiple exclusion diet. The real cause of symptoms (ie, CMA) will be missed leading to unnecessary investigations and treatments. Inconclusive results: the child would have SPT done and subsequent testing or treatment would depend on its results (see Question 1). Complications of a test: can cause discomfort of blood test and bleeding that can cause distress and parental anxiety; food challenge may cause anaphylaxis and exacerbation of other symptoms. Resource utilization (cost): a very expensive test, but it does not add time to the medical consultation. TP – true positive (being correctly classified as having CMA); TN – true negative (being correctly classified as not having CMA); FP – false positive (being incorrectly classified as having CMA); FN – false negative (being incorrectly classified as not having CMA); these outcomes are always determined compared with a reference standard (ie, food challenge test with cow's milk). TABLE Outcomes: Question 5—Should Allergen Microarrays Be Used for the Diagnosis of IgE-Mediated CMA? TABLE Outcomes: Question 5—Should Component-Resolved Diagnostics Be Used for the Diagnosis of IgE-Mediated CMA? Summary of Findings We did not find any systematic review of the microarrays or component-resolved diagnostics used for the diagnosis of CMA. We found 4 studies that examined the role of cow's milk allergen-specific IgE measurement with microarrays.18,37–39 Two of these studies did not use a reference standard37,38 and one did not report any data on test accuracy.39 These 3 studies used a home-made allergen chip. One study used a commercially available allergen microarray, however, it was custom modified for the purpose of this study.18 This study also examined the role of component-resolved diagnostics in comparison to oral food challenge in patients suspected of CMA using an allergen microarray. We did not identify any study of unmodified commercially available allergen microarray compared with the oral food challenge test used for the diagnosis of CMA. In the study that used customized allergen microarray in children suspected of IgE-mediated cow's milk allergy estimated sensitivity was 0.60 (95% CI: 0.43–0.74) with specificity of 0.84 (95% CI: 0.69–0.93). Conclusions, Question 5 Any clinical benefit resulting from using allergen microarrays in the diagnosis of CMA is currently unknown. Clinical Recommendations, Question 5 Recommendation 5.1 We suggest that allergen microarrays are used only in the context of well designed and executed studies that investigate the accuracy of commercially available allergen microarrays compared with oral food challenge with cow's milk in patients suspected of IgE-mediated CMA. Recommendation 5.2 We suggest that more well designed and executed studies of component-resolved diagnostics compared with oral food challenge with cow's milk are performed in patients suspected of IgE-mediated CMA. REFERENCES, SECTION 9 1 Baehler P Chad Z Gurbindo C Bonin AP Bouthillier L Seidman EG Distinct patterns of cow's milk allergy in infancy defined by prolonged, two-stage double-blind, placebo-controlled food challenges. Clin Exp Allergy. 1996;26:254–261 8729661 2 Berni Canani R Ruotolo S Auricchio L Caldore M Porcaro F Diagnostic accuracy of the atopy patch test in children with food allergy-related gastrointestinal symptoms. Allergy. 2007;62:738–743 17573720 3 Calvani M Alessandri C Frediani T Lucarelli S Miceli SS Correlation between skin prick test using commercial extract of cow's milk protein and fresh milk and food challenge. Pediat Allergy Immunol. 2007;18:583–588 4 Cudowska B Kaczmarski M Atopy patch test in the diagnosis of food allergy in children with atopic eczema dermatitis syndrome. Roczniki Akademii Medycznej W Bialymstoku. 2005;50:261–267 16358980 5 Davidson GP Hill DJ Townley RR Gastrointestinal milk allergy in childhood: a rational approach. Med J Aust. 1976;1:945–947 989881 6 Garcia-Ara C Boyano-Martinez T az-Pena JM Martin-Munoz F Reche-Frutos M Martin-Esteban M Specific IgE levels in the diagnosis of immediate hypersensitivity to cows' milk protein in the infant. J Allergy Clin Immunol. 2001;107:185–190 11150010 7 Hill DJ Duke AM Hosking CS Hudson IL Clinical manifestations of cows' milk allergy in childhood. II. The diagnostic value of skin tests and RAST. Clin Allergy. 1988;18:481–490 3233725 8 Kearney S Israel H Ververeli K Kimmel S Silverman B Schneider A The food challenge risk index: Predicting positive open food challenges to milk, egg, and peanuts in children. Pediatric Asthma, Allergy and Immunol. 2005;18:68–76 9 Kekki OM Turjanmaa K Isolauri E Differences in skin-prick and patch-test reactivity are related to the heterogeneity of atopic eczema in infants. Allergy. 1997;52:755–759 9265992 10 Keskin O Tuncer A Adalioglu G Sekerel BE Sackesen C Kalayci O Evaluation of the utility of atopy patch testing, skin prick testing, and total and specific IgE assays in the diagnosis of cow's milk allergy. Ann Allergy, Asthma, Immunol. 2005;94:553–560 15945559 11 Kim TE Park SW Noh G Lee S Comparison of skin prick test results between crude allergen extracts from foods and commercial allergen extracts in atopic dermatitis by double-blind placebo-controlled food challenge for milk, egg, and soybean. Yonsei Med J. 2002;43:613–620 12402374 12 Majamaa H Moisio P Holm K Kautiainen H Turjanmaa K Cow's milk allergy: diagnostic accuracy of skin prick and patch tests and specific IgE. Allergy. 1999;54:346–351 10371093 13 May CD Remigio L Bock SA Usefulness of measurement of antibodies in serum in diagnosis of sensitivity to cow milk and soy proteins in early childhood. Allergy. 1980;35:301–310 7192498 14 Mehl A Rolinck-Werninghaus C Staden U Verstege A Wahn U Beyer K Niggemann B The atopy patch test in the diagnostic workup of suspected food-related symptoms in children. J Allergy Clin Immunol. 2006;118:923–929 17030247 15 Nielsen RG Bindslev-Jensen C Kruse-Andersen S Husby S Severe gastroesophageal reflux disease and cow milk hypersensitivity in infants and children: disease association and evaluation of a new challenge procedure. J Pediatric Gastroenterol Nutr. 2004;39:383–391 16 Norgaard A Bindslev-Jensen C Egg and milk allergy in adults. Diagnosis and characterization . Allergy. 1992;47:503–509 1283061 17 Osterballe M Andersen KE Bindslev-Jensen C The diagnostic accuracy of the atopy patch test in diagnosing hypersensitivity to cow's milk and hen's egg in unselected children with and without atopic dermatitis. J Am Acad Dermatol. 2004;51:556–562 15389190 18 Ott H Baron JM Heise R Ocklenburg C Stanzel S Merk HF Niggemann B Beyer K Clinical usefulness of microarray-based IgE detection in children with suspected food allergy [see comment]. Allergy. 2008;63:1521–1528 18925888 19 Roehr CC Reibel S Ziegert M Sommerfeld C Wahn U Niggemann B Atopy patch tests, together with determination of specific IgE levels, reduce the need for oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2001;107:548–553 11240959 20 Saarinen KM Suomalainen H Savilahti E Diagnostic value of skin-prick and patch tests and serum eosinophil cationic protein and cow's milk-specific IgE in infants with cow's milk allergy. Clin Exp Allergy. 2001;31:423–429 11260154 21 Sampson HA Albergo R Comparison of results of skin tests, RAST, and double-blind, placebo-controlled food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 1984;74:26–33 6547461 22 Sampson HA Ho DG Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol. 1997;100:444–451 9338535 23 Sporik R Hill DJ Hosking CS Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children.[see comment]. Clin Exp Allergy. 2000;30:1540–1546 11069561 24 Stromberg L Diagnostic accuracy of the atopy patch test and the skin-prick test for the diagnosis of food allergy in young children with atopic eczema/dermatitis syndrome. Acta Paediatrica. 2002;91:1044–1049 12434888 25 Verstege A Mehl A Rolinck-Werninghaus C Staden U Nocon M Beyer K Niggemann B The predictive value of the skin prick test weal size for the outcome of oral food challenges. Clin Exp Allergy. 2005;35:1220–1226 16164451 26 Björkstén B Ahlstedt S Björkstén F Carlsson B Fallstrom SP Immunoglobulin E and immunoglobulin G4 antibodies to cow's milk in children with cow's milk allergy. Allergy. 1983;38:119–124 6846737 27 Bonifazi E Garofalo L Monterisi A Meneghini CL Food allergy in atopic dermatitis: experimental observations. Acta Dermato-Venereologica. 1978;58:349–352 82331 28 Breuer K Heratizadeh A Wulf A Baumann U Constien A Tetau D Kapp A Werfel T Late eczematous reactions to food in children with atopic dermatitis. Clin Exp Allergy. 2004;34:817–824 15144477 29 Cantani A Arcese G Serra A Lucenti P Results of skin tests, RAST, and food challenges in children with atopic dermatitis associated with food allergy. Padiatrie und Padologie. 1995;30:113–117 30 Celik-Bilgili S Mehl A Verstege A Staden U Nocon M Beyer K Niggemann B The predictive value of specific immunoglobulin E levels in serum for the outcome of oral food challenges [see comment]. Clin Exp Allergy. 2005;35:268–273 15784102 31 Cudowska B Kaczmarski M Atopowe testy płatkowe w diagnostyce alergii na mleko krowie i niemowląt i małych dzieci [Atopy patch test for diagnosing cow's milk allergy in infants and young children]. Alergia Asthma Immunologia. 2005;10:133–138 32 de Boissieu D Waguet JC Dupont C The atopy patch tests for detection of cow's milk allergy with digestive symptoms [see comment]. J Pediat. 2003;142:203–205 12584547 33 Krogulska A Wasowska-Krolikowska K Dynowski J Przydatność atopowych testów płatkowych z alergenami pokarmowymi w diagnostyce alergii pokarmowej u dzieci z atopowym zapaleniem skóry [Usefulness of atopy patch tests with food allergens in diagnosis of food allergy in children with dermatitis atopica]. Przeglad Pediatryczny. 2007;37:245–249 34 Norgaard A Bindslev-Jensen C Skov PS Poulsen LK Specific serum IgE in the diagnosis of egg and milk allergy in adults. Allergy. 1995;50:636–647 7503399 35 Perry TT Matsui EC Kay Conover-Walker M Wood RA The relationship of allergen-specific IgE levels and oral food challenge outcome [see comment]. J Allergy Clin Immunol. 2004;114:144–149 15241358 36 Tainio VM Savilahti E Value of immunologic tests in cow milk allergy. Allergy. 1990;45:189–196 2327558 37 Gaudin JC Rabesona H Choiset Y Yeretssian G Chobert JM Sakanyan V Drouet M Haertle T Assessment of the immunoglobulin E-mediated immune response to milk-specific proteins in allergic patients using microarrays. Clin Exp Allergy. 2008;38:686–693 18307527 38 Kim TE Park SW Cho NY Choi SY Yong TS Nahm BH Lee S Noh G Quantitative measurement of serum allergen-specific IgE on protein chip. Exp Molec Med. 2002;34:152–158 12085991 39 Noh G Ahn HS Cho NY Lee S Oh JW The clinical significance of food specific IgE/IgG4 in food specific atopic dermatitis. Pediat Allergy Immunol. 2007;18:63–70 SECTION 10: ORAL FOOD CHALLENGE PROCEDURES IN THE DIAGNOSIS OF CMA Overview The oral food challenge (OFC) is considered the standard reference test for diagnosing CMA. It is warranted in the after situations: a. Confirmation of suspicion of cow's milk allergy (CMA) b. periodical follow-up of the condition and monitoring of the resolution of CMA c. Assessment of tolerance in SPT-positive breast-fed infants suspected of CMA who have not yet ingested cow's milk (CM) proteins d. Assessment of tolerance of cross-reactive foods (beef, mare's milk, donkey's milk, etc) e. Evaluation of CM reactivity in persons with multiple dietary restrictions, usually because of subjective complaints f. Exclusion of possible immediate reactions to milk in chronic conditions such as atopic dermatitis or allergic eosinophilic esophagitis g. Evaluation of the tolerance threshold to CM proteins A double-blind, placebo-controlled food challenge (DBPCFC) is the method of choice for research and delayed reaction settings. It should be performed in the face of an open challenge with uncertain outcome. In all the other situations, challenges can be performed openly. Except when dealing with delayed allergic reaction (chronic diarrhea, colitis, allergic proctocolitis, gastroesophageal reflux) without CM-specific IgE, OFCs with CM must be performed in a hospital setting. Low-risk challenges in cooperative patients are appropriate for the office setting. However, all challenge procedures carry a certain risk and are labor-, time-consuming, and costly. OFC is essential for planning avoidance regimens, reduce of the risk of inadvertent exposure, and validate efforts to avoid CM. Negative OFC expands dietary options and thereby nutrition and quality of life. It is also cost-sparing and reduces the use of special formula. Introduction The diagnosis of CMA can be achieved with certainty only after direct observation of clinical events after milk ingestion. In fact, the common tests to identify CM sensitization (at cutaneous level or using specific IgE determination) have no absolute accuracy.1 They can return often falsely positive in children who tolerate milk, or conversely can be negative even in the presence of a delayed, non-IgE mediated, CMA. The OFC and in particular the DBPCFC is considered today, according to the literature, the “gold standard” for diagnosing food allergies,2,3 able to minimize false positive diagnoses. Such a specific diagnosis will prevent unnecessary and potentially deleterious dietary restrictions when a suspected CMA is not present. Unfortunately, in the world not all children can avail themselves of the OFC in milk allergy evaluation.4,5 Resources for the practical planning and carrying-out of OFCs are available through many scientific societies6–8 and lay organizations.9 DEFINITIONS OFC OFCs with cow's milk are in vivo diagnostic tests performed to definitely confirm a preliminary suspicion of CMA. OFCs can be performed in 3 different ways: a.Open, where everyone is aware that milk is brought to the child that day b.Single-blinded, where the pediatrician is aware of the content but child and parents do not c.DBPCFC when neither the pediatrician nor the child or parents know the day when milk will be administered. Positive/Negative OFC An OFC resulting in a clinical reaction is defined a “positive” or “failed” challenge, whereas an OFC without a clinical reaction is termed a “negative” or “passed” challenge. For the purpose of this document, the authors chose to use positive and negative terminology. A positive challenge will give indication of the tolerated dose, if any, thus allowing the planning of elimination diets with complete or partial exclusion of CM proteins. Immediate and Delayed Reactions After OFC According to the majority of authors, allergic reactions are defined as immediate when occurring within 2 hours after administration of the intake of milk, delayed when appearing after more than 2 hours10,11 (see also Mechanisms). Some authors evaluated delayed reactions occurring up to 7,12 9,13 or 14 days.14 Within those periods, however, the diagnosis of delayed reaction may be difficult because when the child returns home, multiple environmental factors (infections, dietary factors, emotional, casual contacts, sports-related physical activity) may impinge diagnostic interpretation. Frequently, immediate and delayed symptoms are present concomitantly in the same child.15 Indications for OFCs The AAAAI work group6 recently re-evaluated the indications for an OFC to be performed, adding some not contained in previous statements including the European statement. Specifically for cow's milk, this panel agrees that the after should be indications to a diagnostic challenge: • Initial diagnosis of CMA after acute reactions • Evaluation of the tolerance threshold to CM proteins • Periodical follow-up of the condition and monitoring of the resolution of CMA • Assessment of tolerance in SPT-positive breast-fed infants which have not yet directly taken CM proteins • Exclusion of possible immediate reactions to milk in chronic conditions such as atopic dermatitis or allergic eosinophilic esophagitis • Evaluation of CM reactivity in persons with multiple dietary restrictions, usually because of subjective complaints • Assessment of tolerance to cross-reactive foods (beef, equine milks, etc) • Assessment of the effect of food processing on food tolerability, eg, beef tolerated in cooked form. OFC is a complex test, requiring several hours for both the pediatrician, his or her staff and the family, and not without risks for the patient. Given the frequency of suspected CMA, indications for performing an oral food challenge should be weighed carefully. Furthermore, although it is considered for years the gold standard in diagnosis of CMA, there are still many controversial issues about which children must undergo an OFC, and what is the best way to perform the study. Open Challenge This is the simplest procedure, requiring less commitment to the pediatrician, the patients and their families and thus lowering costs for the health facilities. After a thorough physical examination, the linchpin for a comparative assessment of pre- and postchallenge, CM is administered openly in increasing doses up to the dose liable to be responsible for symptoms. Clinical observation will be carried–out for about 2 hours after the last dose of milk for immediate reactions and, after discharge, an appointment should be scheduled in the clinic for observation of delayed reactions. Given its simplicity, open challenge can be considered a reasonable first choice to evaluate an adverse reaction to milk. However, it has been shown even in children that up to half of positive open challenges are not reproduced in DBPCFC.1 Single-Blinded Challenge Single-blind is a procedure in which the pediatrician is aware of which food is given to the child at that moment. It is used less than open or DBPCFC, because it entails in principle the same difficulties found with a DBPCFC, but is a bit less reliable as it introduces the possible bias of subjective interpretation by observer. Single-blind OFC may be conducted with or without placebo, depending on the physician's judgment of the potential for subjective symptoms and the patient's anxiety.6 In case of immediate reactions, it will consist of 2 sessions, one with CM and one with placebo, completed on one day with at least a 2-hour period separating the 2 sessions, or on separate days. If 2 foods are tested on the same day, the sequence of the foods is not revealed to the child. We must underline that this option is valid only when delayed symptoms can be excluded in advance. For patients reporting delayed onset of symptoms, sessions of blinded OFC should be separated by several days or weeks.16,17 In patients suspected of having a psychologic response, the verum might be tested first. In this case, a negative challenge will spare a second day of procedure. If symptoms develop, CM should be retested for reproducibility in a DBPCFC.3,7 After a negative blind challenge, CM would be administered openly: this recommendation is based on the possibility of detecting a reaction to an open feeding in children with delayed CM reactions.18 Double-Blind, Placebo-Controlled Food Challenge (DBPCFC) A DBPCFC is the oral administration, usually on different days, of placebo and increasing amounts of milk. First used in 1973 by May19 in the assessment of allergic reactions to foods in children with bronchial asthma, the DBPCFC is now the test of choice in the diagnosis of CMA. In this procedure, only personnel who prepared the test is aware of the food offered at the time: CM (verum) or placebo. Such personnel, not in contact with either the child or the family or the doctor, is the only one to prepare the meals and, in principle, to decide the randomization. The randomization code is prepared in closed envelopes. A major problem in the preparation of the placebo is the avoidance of possibly sensitizing foods. In general, for milk challenges the use of amino acid mixtures make the test safe from misinterpretations. If another placebo is used, the absence of sensitization should be tested by SPT. To enhance masking of appearance and flavor, it is necessary that the amount of placebo in the verum is approximately half the cow's milk. On completion of the challenges, the code is broken, and results are discussed with the patient or parent. Placebo reactions are infrequent, but possible.20 Open or Blinded? General Indications The choice of the procedure has to be done according to the indications listed in Table 10-1 (general indications) and Table 10-2 (indications according to clinical history). Challenges should not be performed in general when a negative skin test, undetectable serum milk-specific IgE level, and no history of convincing symptoms of immediate CMA make the condition very unlikely. In these cases, gradual home introduction of milk may be attempted. For those patients who have a history of convincing immediate allergic reactions to milk (within 2 hours) or who present with a history of anaphylaxis, even in the setting of negative laboratory and skin tests, a physician-supervised OFC is needed to confirm or refute allergy to this food. TABLE 10-1 Open or Blinded? General Indications TABLE 10-2 Open or Blinded? Indications According to Clinical History Preliminary Evaluation of CM Sensitization In DRACMA, specific recommendations are made for allergy evaluation using SPT, APT, and/or specific IgE determinations. Whatever test is done, it should be remembered that serum CM-specific IgE levels and sizes of SPT wheals do not predict the severity of the clinical reactions.3,27 These guidelines for deciding when to perform an OFC on the basis of the results of serum CM-specific IgE and SPT are constantly evolving and need to be frequently updated according to new evidence. Diagnostic Elimination Diet A trial elimination diet may be helpful to determine if a disorder with frequent or chronic symptoms is responsive to dietary manipulation. Trial elimination diets are diagnostic and therapeutic procedures that may be used in children with presumed CMA (see section on Diagnostic Elimination Diets).28,29 Clinical Assessment To undergo challenge procedures, the patient must be well, without intercurrent fever episodes, vomiting, diarrhea, nor seasonal rhinitis and/or asthma.30 Atopic dermatitis should be stabilized in the weeks preceding the OFC, and not subject to significant fluctuations that would make the test difficult to interpret. A 10-point increase in postchallenge SCORAD is considered the minimum threshold for defining a significant worsening of atopic dermatitis.31 The child should discontinue antihistamine therapies long enough to get a normal histamine skin reactivity,32 and at least for 72 hours before OFC.11 OFC Benefits The benefits of a positive OFC include a conclusive diagnosis of CMA demonstrating the need for continued counseling in strict avoidance of cow's milk, reduction of the risk of inadvertent exposures, reduction of anxiety about the unknown, and validation of the patients and families efforts to avoid the food. It allows accurate prescription of elimination diet. A positive OFC may induce fear of reactions, thus leading to closer monitoring of avoidance. The benefits of a negative OFC include expansion of the diet and improvement of the patient's nutrition and quality of life. This can spare unnecessary health expenses and reduce the use of special formula. OFC Limitations Challenge procedures are risky, labor- and time-consuming, and costly. Before performing a challenge, procedural details, risks and benefits must be discussed with the patient and his or her family.3 Immediate systemic reactions can be severe. They are unpredictable on the basis of sensitization, but an association can be found between clinical history of severe symptoms and symptoms after OFC.33,34 Similarly, a number of risk factors for more severe reactions have been suggested: unstable or severe asthma, progressively more severe reactions, reactions to small quantities of cow's milk or treatment with beta-adrenergic antagonists.6 To minimize these risks, venous access should be maintained during CM challenges, in particular when a severe systemic reaction seems possible. In Europe it has been recommended that for young children intravenous access should be applied only in selected cases7. These recommendations take into account the fact that deaths from anaphylaxis are more frequently described after the age of 5 years. Given these considerations, it is essential that be conducted under the observation of a team with specific expertise in pediatric allergy and supplied with all equipment and drugs for emergency treatment.35 OFCs are more standardized for IgE- than for non-IgE-mediated reactions; in the latter case, the observation should be prolonged for an extended period of time. Thus, a diagnostic elimination diet is generally prescribed and sensitization tests are usually carried-out before DBPCFC. The state of the art CMA work-up uses the informed prescription of DBPCFC and various diagnostic tests according to clinical context. The combination of prechallenge test in DRACMA is object of GRADE evaluation (see section on GRADE Assessment of CMA Diagnosis). OFCs In Children With Previous Anaphylactic Reaction A recent anaphylactic reaction to cow's milk contraindicates OFCs except in the after situations: • If the severe reaction occurred immediately after simultaneous introduction of many foods at the same time: typical example is the introduction of the first solid meal including CM proteins (and many other putative food allergens) in a breast-fed • For the assessment of tolerance to cow's milk after a reasonable period from previous anaphylactic reaction. In these cases, the hospital setting with ICU availability is mandatory. OFC Setting The challenges are generally labor-intensive and carry some risk to the patient. Anyone who performs such challenges on children and adults with suspected CM allergies must have the background and equipment to recognize symptoms of allergy and to treat anaphylactic reactions.36 The first step is to consider whether the test can be performed at home or needs to be under direct physician supervision. There are many specific issues that must be considered in this particular decision. In general, whenever there is an even remote potential for an acute and/or severe reaction, physician supervision is mandatory. This decision for a supervised challenge includes, but is not limited to, a history of prior significant reactions and/or positive tests for IgE to milk.3 The ideal setting is hospital, both at an in-patient and out-patient level.37 When there is a very high risk for a severe reaction but OFC is required, challenges preferably should be done in the intensive care unit. Low-risk challenges in cooperative patients are appropriate for the office setting. Times and doses can vary according to clinical history. For a suspected FPIES, the procedure should be administered with intravenous access with prolonged observation. For immediate reactions, a limited observation time can ensure appropriate diagnostic accuracy. In delayed forms, longer observation periods will be necessary. Challenges requiring exercise to precipitate symptoms need to be performed where suitable exercise equipment is available.38 Challenge Preparation: Vehicles and Masking Evidence indicates that processing, including heating (and presumably drying), has no effect on the allergenicity of cows' milk.39 Thus, liquid whole milk, nonfat dry milk, and infant formula have been used as challenge materials in various clinics.40 For the placebo to be used, it is relevant that eHF, safe for most of cows' milk-allergic infants, can determine occasional allergic reactions in exquisitely allergic infants.41–44 In general cow's milk hydrolysate or soy formula are supported as placebo in the literature45 and amino acid formula are considered an advance in clinical and research contexts.46,47 When challenges are done using dehydrated cow's milk in capsules, lactose is used as placebo. However, the “capsule” is not the ideal presentation as it escapes the oral phase and lactose has been associated with reactivity in CM–allergic children.48,49 Challenge Procedure In absence of comparative studies between different challenge protocols, there is no universal consensus on timing and doses for milk challenge administration. The consensus documents published in this field6,7 report some example of procedures, but the suggestion to individualize doses and times based on the clinical history remains valid.57,58 Initial doses has been suggested to be 0.1 mL,7 but can vary according to the risk of reaction and type of milk allergy (IgE vs. non-IgE-mediated).6 Labial CM challenges have been suggested as a safe starting point for oral challenges by some researchers. This procedure begins with placing a drop of milk on the lower lip for 2 minutes and observing for local or systemic reactions in the ensuing 30 minutes.59 TABLE 10-3 The OFC With Milk: Methodological Details Given these observations, this panel recommends the after for milk challenges in IgE-mediated CMA: 1.Total dose should be calculated according to the maximum consumed per serving or based on the total weight of the patient;6 2.Use the same type of milk the patient will be consuming everyday in case of negative challenge; 3.Chose the least allergenic placebo possible, with preference for the type of milk the patient will be administered everyday in case of positive challenge; 4.Start with a dose clearly under the expected threshold dose, for example, the amount that the patient reacted to previously; 5.In general, one drop, or a 0.1 mL dose, is suitable for starting, but in high-risk cases one drop of CM:water 1:100 can be used; 6.Give a dose every 20–30 minutes; this will minimize the risk of severe allergic reaction and allow precise identification of the lowest provoking dose; 7.Increase the doses using a logarithmical modality, for instance: 0.1, 0.2, 0.5, 1.5, 4.5, 15, 40, and 150 mL (total 212 mL60); or 0.1, 0.3, 1.0, 3.0, 10, 30, and 100 mL (total 145 mL61); or 0,1; 0,3; 1, 3, 10, 30, and 100 mL (total 144 mL11,46); 8.To minimize the possibilities of identification, dilute the verum with the placebo 50:50 when administering CM; 9.Administer a placebo sequence in identical doses on a separate day; 10.Discontinue the procedure on first onset of objective symptoms or if no symptom develop after challenge; 11.Consider only reactions occurring within 2–3 hours after stopping the procedure; 12.Complete a negative procedure with open administration of CM. For delayed reactions, the same rules apply except: Rule 4: start with a 0.1 mL dose. Rule 5: does not apply. Rule 6: the interval in that case should be calculated according to the clinical history. Rule 11: consider reactions occurring within 24–48 hours after stopping the procedure. Challenge Interpretation An OFC with milk should be stopped at the first onset of objective symptoms.62 Even mild objective signs, such as a few skin wheals in the absence of gastrointestinal or respiratory symptoms, may not be diagnostic of CMA and can be contradicted by a subsequent DBPCFC.63,64 For this reason, during OFCs skin contact with milk must be carefully avoided. Subjective symptoms include itching, nausea or dysphagia, sensation of respiratory obstruction, dyspnoea, change in behavior, prostration, headache, or refusal of milk. Objective symptoms include: Generalized urticaria Erythematous rash with itching and scratching Vomiting or abdominal pain Nasal congestion Repetitive sneezing Watery rhinorrhea Rhino-conjunctivitis Changes in tone of voice Stridor Laryngospasm Inspiratory stridor Cough and/or wheezing Abnormal pallor Change in behavior62 Increased heart rate by at least 20% (this can occur by anxiety) Decreased blood pressure by more than 20% Collapse Anaphylaxis Sometimes subjective symptoms may be the harbinger of an incipient allergic reaction.6 If the child is able to ingest milk without any reaction, the challenge may be considered negative for immediate reaction, but at least 24–48 hours are necessary to exclude the possibility of delayed reactions. Laboratory Data for OFC Interpretation Attempts to use laboratory studies to validate the results of OFCs have a long history. Serum tryptase and urinary 1-methylhistamine have been evaluated as parameters for monitoring oral milk challenges in children, but their accuracy characteristics are lacking.65 Decreases in peripheral blood eosinophils and increases in serum eosinophil cationic protein (ECP), 8 to 24 hours after a positive challenge have been suggested as indicating a positive food challenge,66 but this finding has not been reproduced.67 FENO values are not predictive and not related to the occurrence of a positive reaction during cow's milk challenges in infants, suggesting that a positive reaction may not result from eosinophilic activation.68 Infants with atopic eczema and CMA exhibit markedly increased systemic pro-allergenic IL-4 responses on intestinal antigen contact.69,70 While a failed oral challenge with cow's milk is associated with increase in both ECP and tumor necrosis factor (TNF)-α, allergic infants with delayed intestinal manifestations show an elevation of fecal TNF-α.71 These observations, however, are of scarce utility for diagnostic judgment. Delayed Reactions Interpretation A protocol for two-stage DBPCFC has been proposed to clarify delayed type CMA in patients presenting with predominantly gastrointestinal symptoms from 2 hours and up to 6 days after milk exposure. This procedure is able to differentiate immediate-type IgE-dependent, or delayed-type IgE-independent CMA.72 In non-IgE-mediated food protein–induced enterocolitis syndrome, in which there is a low risk for immediate reactions in the first hour, with symptoms usually starting within 1 to 4 hours after milk ingestion, the entire portion of the challenge may be administered gradually over a period of 45 minutes and divided into 3 smaller portions.6,73 After the Challenge… A negative “remission” challenge ends up with the open reintroduction of cow's milk and dairy products. This represents for the patient an important step toward a “normal” personal and social life. 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Allergy. 2007;62:905–912 17620068 21 Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol. 2005;115:483–523 22 Lieberman P Decker W Camargo CA Jr O'Connor R Oppenheimer J Simons FE SAFE: a multidisciplinary approach to anaphylaxis education in the emergency department. Ann Allergy Asthma Immunol. 2007;98:519–523 17601263 23 Niggemann B Sielaff B Beyer K Binder C Wahn U Outcome of double-blind, placebo-controlled food challenge tests in 107 children with atopic dermatitis. Clin Exp Allergy. 1999;29:91–96 10051707 24 Venter C Prevalence of sensitization reported and objectively assessed food hypersensitivity amongst six-year-old children: a population-based study. Pediatr Allergy Immunol. 2006;17:356–363 16846454 25 Flinterman AE Knulst AC Meijer Y Bruijnzeel-Koomen CA Pasmans SG Acute allergic reactions in children with AEDS after prolonged cow's milk elimination diets. Allergy. 2006;61:370–374 16436148 26 Niggemann B Beyer K Diagnosis of food allergy in children: toward a standardization of food challenge. J Pediatr Gastroenterol Nutr. 2007;45:399–404 18030203 27 Eigenmann PA Sampson HA Interpreting skin prick tests in the evaluation of food allergy in children. Pediatr Allergy Immunol. 1998;9:186–191 9920216 28 Markowitz JE Spergel JM Ruchelli E Liacouras CA Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents. Am J Gastroenterol. 2003;98:777–782 12738455 29 Werfel T Ballmer-Weber B Eigenmann PA Niggemann B Rancé F Turjanmaa K Worm M Eczematous reactions to food in atopic eczema: position paper of the EAACI and GA2LEN. Allergy. 2007;62:723–728 17573718 30 Niggemann B Beyer K Diagnosis of food allergy in children: toward a standardization of food challenge. J Pediatr Gastroenterol Nutr. 2007;45:399–404 18030203 31 Niggemann B Reibel S Wahn The atopy patch test (APT): a useful tool for the diagnosis of food allergy in children with atopic dermatitis. Allergy. 2000;55:281–285 10753020 32 Bock SA In: vivo diagnosis: Skin testing and oral challenge procedures. Metcalfe DD Sampson HA Simon RA , eds. Food allergy: Adverse Reactions to Foods and Food Additives. 2nd ed. Cambridge MA:Blackwell Science; 1997 33 Spergel JM Beausoleil JL Fiedler JM Ginsberg J Wagner K Pawlowski NA Relation of initial food reactions to observed reactions on challenges. Ann Allergy Asthma Immunol. 2004;92:217–224 14989389 34 Sicherer SH Morrow EH Sapmson HA Dose-response in double-blind, placebo controlled oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2000;105:582–586 10719311 35 Perry TT Matsui EC Conover-Walker MK Wood RA Risks of oral food challenges. J Allergy Clin Immunol. 2004;114:1164–1168 15536426 36 Bock SA Diagnostic evaluation. Pediatrics. 2003;111:1638–1644 12777604 37 Wuthrich B Ambulatory oral provocation testing. Hautarzt. 1995;46:352–353 7607902 38 Fiocchi A Mirri GP Santini I Ottoboni F Riva E Exercise-induced anaphylaxis following food-contaminant ingestion at Double-Blinded, Placebo-Controlled, Food-Exercise Challenge. J Allergy Clin Immunol. 1997;100:424–425 9314357 39 Høst A Samuelsson EG Allergic reactions to raw, pasteurized, and homogenized/pasteurized cow milk: a comparison. Allergy. 1988;43:113–118 3284399 40 Taylor SL Hefle SL Bindslev-Jensen C Factors affecting the determination of threshold doses for allergenic foods: how much is too much. J Allergy Clin Immunol. 2002;109:24–30 11799361 41 Saylor JD Bahna SL Anaphylaxis to casein hydrolysate formula. J Pediatr. 1991;118:71–74 1986102 42 Rosenthal E Schlesinger Y Birnbaum Goldstein R Benderly A Freier S Intolerance to casein hydrolysate formula. Acta Paediatr Scand. 1991;80:958–960 1755304 43 De Boissieu D Matarazzo P Dupont C Allergy to extensively hydrolyzed cow milk proteins in infants: identification and treatment with an amino acid-based formula. J Pediatr. 1997;131:744–747 9403657 44 Nilsson C Oman H Hallden G Lilja G Lundberg M Harfast B A case of allergy to cow's milk hydrolysate. Allergy. 1999;54:1322–1326 10688438 45 Klemola T Vanto T Juntunen-Backman K Kalimo K Korpela R Varjonen E Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cow's milk allergy: a prospective, randomized study with a follow-up to the age of 2 years. J Pediatr. 2002;140:219–224 11865274 46 Roehr CC Reibel S Ziegert M Sommerfeld C Wahn U Niggemann B Atopy patch tests, together with determination of specific IgE levels, reduce the need for oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2001;107:548–553 11240959 47 Kaila M Isolauri E Diagnosis of cow's milk allergy: open or blinded? J Allergy Clin Immunol. 1997;100:714–715 9389306 48 Fiocchi A Restani P Leo G Martelli A Bouygue GR Clinical tolerance to lactose in children with cow's milk allergy. Pediatrics. 2003;112:359–356 12897287 49 Nowak-Wegrzyn A Shapiro GG Beyer K Bardina L Sampson HA Contamination of dry powder inhalers for asthma with milk proteins containing lactose. J Allergy Clin Immunol. 2004;113:558–560 15007361 50 Bock SA Sampson HA Atkins F Double-blind, placebo- controlled food challenge (DBPCFC) as an office procedure: a manual. J Allergy Clin Immunol. 1988;82:986–997 3060514 51 Sicherer SH Morrow EH Sampson HA Dose-response in double-blind, placebo-controlled oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2000;105:582–586 10719311 52 Rance F Kanny G Dutau G Moneret-Vautrin D Food hypersensitivity in children: clinical aspects and distribution of allergens. Pediatr Allergy Immunol. 1999;10:33–38 10410915 53 Sporik R Hill DJ Hosking CS Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children. Clin Exp Allergy. 2000;30:1540–1546 11069561 54 Saarinen KM Suomalainen H Savilahti E Diagnostic value of skin-prick and patch tests and serum eosinophil cationic protein and cow's milk-specific IgE in infants with cow's milk allergy. Clin Exp Allergy. 2001;31:423–429 11260154 55 Majamaa H Moisio P Holm K Kautiainen H Turjanmaa K Cow's milk allergy: diagnostic accuracy of skin prick and patch tests and specific IgE. Allergy. 1999;54:346–351 10371093 56 Eigenmann PA Calza AM Diagnosis of IgE-mediated food allergy among Swiss children with atopic dermatitis. Pediatr Allergy Immunol. 2000;11:95–100 10893011 57 Rancé F Deschildre A Villard-Truc F Gomez SA Paty E Santos C Couderc L Fauquert JL De Blic J Bidat E Dupont C Eigenmann P Lack G Scheinmann P ; SFAIC and SP2A Workgroup on OFC in Children Oral food challenge in children: an expert review. Eur Ann Allergy Clin Immunol. 2009;41:35–49 19585859 58 Bahna SL Diagnosis of food allergy. Ann Allergy Asthma Immunol. 2003;90:S77–S80 59 Rancé F Dutau G Labial food challenge in children with food allergy. Pediatr Allergy Immunol. 1997;8:41–44 9260218 60 Morisset M Moneret-Vautrin DA Kanny G Guénard L Beaudouin E Flabbée J Hatahet R Thresholds of clinical reactivity to milk, egg, peanut and sesame in immunoglobulin E-dependent allergies: evaluation by double-blind or single blind placebo-controlled oral challenges. Clin Exp Allergy. 2003;33:1046–1051 12911777 61 Fiocchi A Terracciano L Bouygue GR Veglia F Sarratud T Martelli A Restani P Incremental prognostic factors associated with cow's milk allergy outcomes in infant and child referrals: the Milan Cow's Milk Allergy Cohort study. Ann Allergy Asthma Immunol. 2008;101:166–173 18727472 62 Niggemann B When is a food challenge positive? Allergy. 2010;65:2–6 19796198 63 Niggeman B Beyer K Pitfalls in double blind placebo controlled food challenge. Allergy. 2007;62:729–732 17573719 64 Williams LW Bock SA Skin testing and food challenges in allergy. Clin Rev Allergy Clin Immunol. 1999;17:323–338 65 Beyer K Niggemann B Schulze S Wahn U Serum tryptase and urinary 1-methylhistamine as parameters for monitoring oral food challenges in children. Int Arch Allergy Immunol. 1994;104:348–351 8038613 66 Niggemann B Beyer K Wahn U The role of eosinophils and eosinophil cationic protein in monitoring oral challenge tests in children with food-sensitive atopic dermatitis. J Allergy Clin Immunol. 1994;94:963–971 7798544 67 Beyer K Lorenz H Wahn U Niggemann B Changes in blood leukocyte distribution during double-blind, placebo-controlled food challenges in children with atopic dermatitis and suspected food allergy. Int Arch Allergy Immunol. 1998;116:110–115 9652303 68 Gabriele C de Benedictis FM de Jongste JC Exhaled nitric oxide measurements in the first 2 years of life: methodological issues, clinical and epidemiological applications. Ital J Pediatr. 2009;35:21–23 19712438 69 Sutas Y Kekki M Isolauri E Late onset reactions to oral food challenge are linked to low serum interleukin-10 concentrations in patients with atopic dermatitis and food allergy. Clin Exp Allergy. 2000;30:1121–1128 10931119 70 Rautava S Isolauri E Cow's milk allergy in infants with atopic eczema is associated with aberrant production of interleukin-4 during oral cow's milk challenge. J Pediatr Gastroenterol Nutr. 2004;39:529–535 15572894 71 Kapel N Matarazzo P Haouchine D Abiola N Guérin S Fecal tumor necrosis factor alpha, eosinophil cationic protein and IgE levels in infants with cow's milk allergy and gastrointestinal manifestations. Clin Chem Lab Med. 1999;37:29–32 10094375 72 Baehler P Chad Z Gurbindo C Bonin AP Bouthillier L Seidman EG Distinct patterns of cow's milk allergy in infancy defined by prolonged, two-stage double-blind, placebo-controlled food challenges. Clin Exp Allergy. 1996;26:254–261 8729661 73 Burks AW Casteel HB Fiedorek SC Willaims LW Pumphrey CL Prospective oral food challenge study of two soybean protein isolates in patients with possible milk or soy protein enterocolitis. Pediatr Allergy Immunol. 1994;5:40–45 8173638 74 Eigenmann PA Caubet JC Zamora SA Continuing food-avoidance diets after negative food challenges. Pediatr Allergy Immunol. 2006;17:601–605 17121588 SECTION 11: THE NATURAL HISTORY OF CMA Overview Cow's milk allergy (CMA) does not often persist into adulthood. Our current knowledge of its natural history suffers from a fragmentary epidemiology of risk and prognostic factors. CMA is often the first step of the allergic march. It can develop from the neonatal period and peaks during the first year of life, tending to remit in childhood. In the 1990s, a Danish birth cohort study found that more than 50% of children outgrow their CMA at 1 year of age. Subsequent such studies have reported a longer duration of CMA with tolerance developing in 51% of cases within the 2 years after diagnosis. Referral studies indicate that 80% of patients achieve tolerance within 3 to 4 years. In several studies, children with delayed reactions became tolerant faster than those with immediate reactions. In retrospective studies, the duration of CMA differs in different settings. In a population of breast-fed infants with cow's milk-induced allergic proctitis, tolerance developed between 6 and 23 months. A universal natural history of CMA cannot be written at this time because the conditions described lack uniformity. IgE status, genetics, method of evaluation, selection criteria, frequency of rechallenge, and standards of reporting and study designs vary. Children with respiratory symptoms at onset, sensitization to multiple foods and initial sensitization to respiratory allergens carry a higher risk of a longer duration of disease. The onset of CMA is related to antigen exposure. A cow's milk avoidance diet, once thought of as the only treatment for CMA, has recently been challenged by opposite theories on the basis of human and animal studies. A family history of progression to atopic asthma, rhinitis, eczema, early respiratory symptoms with skin and/or gastrointestinal symptoms, or severe symptoms are considered risk factors for persistent CMA. A larger wheal diameter at SPT with fresh milk significantly correlates with CMA persistence. Levels of specific IgE, especially to casein, and antibody binding to other ingestant and inhalant allergens, have also been linked to longer duration of CMA. However, in a population of children with a family history of atopy, sensitivity toward food and inhalant allergens during the first year of life were predictive of atopic disease by the age of six. A smaller eliciting dose at oral food challenge also correlates with duration of CMA. Low milk-specific IgE levels correlate with earlier onset of tolerance and a 99% reduction in specific IgE concentrations more than 12 months translates into a 94% likelihood of achieving tolerance to cow's milk protein within that period. It has been proposed that tolerance of cow's milk protein correlates with reduced concentrations of IgE- and IgG-binding casein epitopes, and an involvement of tertiary or linear casein epitope structures has been hypothesized. However, the maintenance of tolerance in atopic patients is associated with persistently elevated milk-specific IgG4 antibody concentrations. Introduction Pediatricians and allergists often have to face parents who are aware that CMA is not a lifelong condition and therefore wish to know how long CMA is likely to last. Adults who have been diagnosed with CMA are few and far between but the severity of disease is often more worrisome. Answering these legitimate questions implies practical acquaintance with CMA in both age groups regardless of prevention and treatment effect. Our actual knowledge of the natural history of CMA, however, remains hampered by the fragmentary epidemiology of risk and prognostic factors that is the flip side of our extensive clinical literature. WHEN DOES CMA DEVELOP? Food-linked hypersensitivity disorders are likely to have followed the general trend of allergic disease.1 Commonly, symptoms of CMA are seen during the first 2 months of life.2–4 According to a Japanese multicenter trial, the prevalence of CMA among newborns is 0.21 and 0.35% amid extremely low birth weight preemies.5 CMA prevalence peaks during the first 12 months of life and tends to subside with age in a time frame that seems to differ from other food allergies.6–10 Thus, egg allergy follows more or less a similar pattern, with a mean duration of about 3 years,11,12 in fish and nut allergy the duration of disease is not predictable, and there are reports of reactions recurring even after tolerance has been documented.13–15 Cross-sectional studies indicate that infancy is the period when most milk allergy develops and suggest that the most pediatric patients will “outgrow CMA.”16 The clinical symptoms of CMA follow a general age-related pattern, and infants allergic to cow's milk frequently develop an evolving pattern of allergic symptoms, the so-called “allergic march.” This typical sequence begins with early sensitization to food allergens and progresses to atopic dermatitis and may go on to sensitization to inhalant allergens and asthma. Until recently, it seemed to provide a useful clinical model for describing the sequence of manifestations of the atopic phenotype. While it is still a useful paradigm for research and understanding the natural history of allergies, some findings have begun to cast doubts on the transition from manifestations of one organ-related allergy to another is actually sequential in terms of timing or dependent on diverse pathogenic mechanisms. Several trials have actually shown that different populations do not always display the same succession of allergic symptoms. The MAS study7 reported that a subgroup of children with earlier or more severe atopic dermatitis (AD) had a higher prevalence of early-onset bronchospasm compared with those with AD or mild AD (46.3% vs. 32.1% (P = 0.001). These children had a characteristic and distinct sensitization pattern, and by the age of 7 their respiratory function was significantly more severely affected than that of other children. These observations suggest the possibility that a different disease phenotype may be at work, in which the allergic march does not develop, since AD and asthma can coexist from the earliest expression of atopic disease. Similarly, in a cohort of English children, atopic phenotypes were divided into several groups: never atopic (68%), early atopic (4.3%), late atopic (11.2%), and chronic atopic (16.5%), based on skin prick tests performed at age 4 and 10.17 This again suggests that, at least in the chronic atopic group, the whole process may be set off quite early on (as suggested by the elevated IgE antibody levels found in cord blood from birth cohort patients) and persists over time, and the skin and airways are simultaneous organ targets. It is possible, therefore, that “chronic atopic” children with CMA develop a distinct clinical course consistent with a yet-to-be-described phenotype. HOW LONG DOES CMA LAST? The average time span from diagnosis to resolution of CMA is the best (albeit approximate) measure of duration of disease (when inferred from prospective studies). Birth cohorts from the general population and clinical studies of selected patients presenting for referral are our best data sources for this purpose. The results obtained from these 2 kinds of sources is practical for the purpose of describing natural history, but referred patients are likely to present for, or to have undergone, treatment in some form such as prevention measures, special diets or therapy course(s), and birth cohort studies are expensive to conduct and consequently rare. In the earlier birth cohorts, CMA was estimated to run its course within 1 year.18 In these populations of children patients had grown out of their allergy at 1, 2, 3, 5, 10, and 15 years of age in 56, 77, 87, 92, 92, and 97% of cases, respectively.19 Subsequent birth cohort studies reported a longer duration of disease with tolerance developing in 44% of cases at 1.6 and in 51% of cases within the 2 years after diagnosis. Referral studies indicate that in most cases (80%) tolerance is achieved within 3 to 4 years,20–22 but results vary according to the method of follow-up. Methodologically speaking, an oral food challenge to assess both disease at entry and development of tolerance during follow-up provides gold-standard information. In a Finnish study, children with delayed reactions were found to develop tolerance sooner than those with immediate reactions (64, 92, and 96% compared with 31, 53 and 63%, respectively at study end point of 2, 3, and 4 years, respectively.23 Several studies report that among allergy clinic patients, 15% of children with IgE-mediated CMA were still allergic after 8.6 years whereas all children with non IgE-mediated disease reached tolerance earlier at an average of 5.0 years.19,23,24 In a cohort of pediatric patients referred to a tertiary center in Italy for DBPCFC to cow's milk, the median duration of CMA was 23 months while 23% of children acquired tolerance 13 months after diagnosis and 75% after 43 months.22 In retrospective referral studies, the duration of CMA differs with settings. In a population of breast-fed infants less than 3 months presenting with CMA-linked allergic proctitis tolerance was achieved between the ages of 6 and 23 months.25 In an Israeli study, less than half of the children diagnosed with IgE-mediated CMA during the first 9 years of life outgrew it.26 A US study reported a duration of CMA far longer than that found in prospective studies, showing tolerance in only 54% of children after a median period of observation of 54 months, and that 80% of the children did not tolerate milk until 16 years of age.27 The authors acknowledged that several issues could lead to an overestimation of the duration of disease. Among them, children assumed to still have milk allergy could have had actually outgrown their allergy but had not undergone oral food challenge. That the natural history of CMA appears to vary according to open or selective settings, IgE status, method of evaluation (open versus blinded experimental conditions) and frequency of rechallenge at follow-up, suggests that our understanding of the natural history of CMA remains fraught with procedural variability and requires further prospective studies of large unselected cohorts. Generalizing from these studies is further complicated by the adoption of different population selection criteria.21,23,28 Sometimes even the age of onset of symptoms is not reported.24 Overall, the diverse standards of reporting and the retrospective design of many of these studies provide information only for generating hypotheses about the natural history of CMA.26,27 Another possibly major influence on CMA outcomes for which there is a paucity of data are genetics. Children in whom respiratory symptoms develop at onset, with sensitization to multiple foods and initial sensitization to common respiratory allergens show a longer duration of disease.22 These results, echoing the findings of earlier epidemiological studies,7,17 suggest that the influence of allergic phenotypes beyond immediate environmental factors may play a role in the onset of CMA. Taken together, these studies are consistent with the suspicion that the allergic march model might be applicable only in certain phenotypes rather than to all atopic individuals: in the case of CMA, there may be several different phenotypes that if identified, could lead to personalized medicine treatment strategies for different populations of atopic patients. What Factors Can Alter the Course of CMA? The onset of CMA is related to antigen exposure, with an increasingly recognized role of costimulating molecules at the level of the antigen-presenting cells of the mucous membranes (see Mechanisms).29,30 Milk allergy is the result of repeated exposure to a milk protein trigger and exclusion of this food, once identified, can prevent food allergy. Total exclusion of food allergens like peanut or milk, however, is difficult to obtain and repeated unintentional minor exposures via the cutaneous, respiratory or gastrointestinal barriers could be more likely to sensitize than providing larger quantities of the allergen by the oral route to induce tolerance. Animal studies have shown that, under certain circumstances, tolerance can develop via apoptosis on exposure to high antigen loads.31 Different studies have shown that the tendency of T-cells to become tolerant can be triggered by the ingestion of minimal quantities of the incriminated allergen.32,33 The wide array of allergens that can be introduced in the diet is an obvious risk factor for developing allergy very early on, when the immune system is still functionally immature, and the jury is still out on whether early contact with potential antigen can modulate the response of the organism either way toward hyper-responsiveness or tolerance. Similarly, the impact of early or delayed introduction of solid foods on the development of allergy or CMA remains inconclusive.34 There is evidence that exposure to minute doses of milk in the neonatal period increases the likelihood of becoming sensitized to milk later in childhood24,35 and exposure to residual amounts of cow's milk proteins is associated with the risk of longer duration of CMA.36 What Factors Predict the Duration of CMA? A positive family history of atopic disease, clinical progression to asthma, rhinitis, and eczema,37 and early respiratory symptoms (asthma and rhinitis) with skin and/or gastrointestinal symptoms are considered risk factors for persistence through the involvement of several target organs and result in slower resolution of CMA22,27 Severe symptoms reported at the time of diagnosis are consistent with worse prognosis for duration of disease.22,38–40 In one cohort study of pediatric referrals, a larger weal diameter at SPT with fresh milk was significantly correlated with the failure to achieve tolerance,22 although this has not been seen in all studies. All patients with CMA and a negative SPT at 1 year of life had developed tolerance by their third year of life. However, 25% of 1-year-old infants with a positive skin prick test were still allergic at the same time. Cosensitization assessed by skin and specific serum antibody tests with, in particular, beef, eggs, wheat, and soy were also predictive of longer duration, as were cosensitization to common inhalant allergens and high levels of cow's milk IgE antibodies identified at diagnosis and during the course of disease. It has been reported that a reduction in milk-specific IgE levels correlates with the development of tolerance23 and that a 99% reduction in milk-specific IgE antibody concentrations more than 12 months translates into a 94% likelihood of achieving tolerance to cow's milk protein within that time span.28 Correspondingly, the time required to achieve tolerance to cow's milk protein can be predicted by the decrease in milk-specific IgE levels.28 However, other studies41 conclude that this predictability applies only in those patients with atopic dermatitis, while the milk-specific IgE antibody levels may be useful a the time of first diagnosis, they cannot be reliably used for predicting tolerance in the general milk-allergic population. The eliciting dose at oral food challenge has also been found to correlate with duration of CMA. In one cohort study, the smaller the dose of cow's milk sufficient to trigger a positive reaction at diagnosis, the longer the disease appears to last.22 The levels of cow's milk-specific IgE antibodies vary over time and this has also been linked with duration of CMA.21,27,28 As is the case with SPTs, the association between tolerance achievement and antibody concentrations should be considered (especially for casein) and for other food (such as beef, soy, eggs, and wheat)22,27 and inhalant allergens.22 There is a significant correlation between initial IgE-antibody specific to the most common allergens and a delay in achieving tolerance to cow's milk protein, irrespective of family history. However, in a population of children with a family history of atopy, sensitivity toward common food and inhalant allergens during the first year of life were significant and predictive of developing atopic disease by the age of 6.42 Sensitization to α-1 casein,43 β-casein, and κ-casein has been associated with persistent milk allergy regardless of the age of the patient with allergic symptoms related to cow's milk protein ingestion. Several studies have suggested that milk-allergic patients that generate IgE antibodies to large numbers of sequential epitopes have more persistent allergy than those who generate antibodies primarily to conformational epitopes. Whether tolerance of cow's milk protein is correlated with reduced concentrations of T-cell epitopes of casein in either IgE-44,45 or non-IgE-mediated allergy is also unknown, although a different involvement of tertiary (IgE-mediated) or linear (non-IgE-mediated)46 casein epitope structure with a consequent shift in predominance to milk-specific IgA antibodies could be involved. However, the maintenance of tolerance in atopic patients is known to be associated with persistently elevated milk-specific IgG4 antibody concentrations.47 On the basis of these observations, it remains to be seen whether patients with CMA can be screened for these milk epitope-specific IgE antibodies, with a positive result indicating persistent allergy, age notwithstanding, and whether these parameters make clinical sense in various patient subsets as knowledge of the natural history of the disease increases. 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Allergy. 2003;58:1067–1068 14510728 16 Steinke M Fiocchi A Kirchlechner V Ballmer-Weber B Brockow K Food allergy in children and potential allergy medicine users in Europe. A randomised telephone survey of children in 10 European nations. Int Arch Allergy Immunol. 2007;143:290–295 17356296 17 Kurukulaaratchy RJ Matthews S Arshad SH Defining childhood atopic phenotypes to investigate the association of atopic sensitization with allergic disease. Allergy. 2005;60:1280–1286 16134995 18 Høst A Cow's milk protein allergy and intolerance in infancy. Some clinical, epidemiological and immunological aspects. Pediatr Allergy Immunol. 1994;5:1–136 19 Høst A Halken S Jacobsen HP Christensen AE Herskind AM Plesner K Clinical course of cow's milk protein allergy/intolerance and atopic diseases in childhood. Pediatr. Allergy Immunol. 2002;3:23–28 20 Hill DJ Firer MA Ball G Hosking CS Natural history of cows' milk allergy in children: immunological outcome over 2 years. Clin Exp Allergy. 1993;23:124–131 8448679 21 García-Ara MC Boyano-Martínez MT Díaz-Pena JM Martín-Muñoz MF Martín-Esteban M Cow's milk-specific immunoglobulin E levels as predictors of clinical reactivity in the follow-up of the cow's milk allergy infants. Clin Exp Allergy. 2004;34:866–870 15196272 22 Fiocchi A Terracciano L Bouygue GR Veglia F Sarratud T Martelli A Restani P Incremental prognostic factors associated with cow's milk allergy outcomes in infant and child referrals: the Milan Cow's Milk Allergy Cohort study. Ann Allergy Asthma Immunol. 2008;101:166–173 18727472 23 Vanto T Helppila S Juntunen-Backman K Prediction of the development of tolerance to milk in children with cow milk hypersensitivity. J Pediatr. 2004;144:218–222 14760265 24 Saarinen KM Pelkonen AS Makela MJ Savilahti E Clinical course and prognosis of cow's milk allergy are dependent on milk-specific IgE status. J Allergy Clin Immunol. 2005;116:869–875 16210063 25 Sorea S Dabadie A Bridoux-Henno L Balancon-Morival M Jouan H Le Gall E Hemorrhagic colitis in exclusively breast-fed infants. Arch Pediatr. 2003;10:772–775 12972203 26 Levy Y Segal N Garty B Danon YL Lessons from the clinical course of IgE-mediated cow milk allergy in Israel. Pediatr Allergy Immunol. 2007;18:589–593 17561928 27 Skripak JM Matsui EC Mudd K Wood RA The natural history of IgE-mediated cow's milk allergy. J Allergy Clin Immunol. 2007;120:1172–1177 17935766 28 Shek LP Soderstrom L Ahlstedt S Beyer K Sampson HA Determination of food specific IgE levels over time can predict the development of tolerance in cow's milk and hen's egg allergy. J Allergy Clin Immunol. 2004;114:387–391 15316521 29 Nagler-Anderson C Tolerance and immunity in the intestinal immune system. Crit Rev Immunol. 2000;20:103–120 10872893 30 Mayer L Sperber K Chan L Oral tolerance to protein antigens. Allergy. 2001;56:12–15 11297999 31 Chen Y Inobe J Marks R Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature. 1995;376:177–180 7603570 32 Weiner HL Friedman F Miller A Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu Rev Immunol. 1994;12:809–837 8011298 33 Faria AM Weiner HL Oral tolerance. Immunol Rev. 2005;206:232–259 16048553 34 Immune Tolerance Network. About the LEAP Study. Retrieved from http://www.leapstudy.com/study_about.html Accessed December 1, 2009. 35 Saarinen KM Juntunen-Backman K Järvenpää AL Kuitunen P Lope L Supplementary feeding in maternity hospitals and the risk of cow's milk allergy: a prospective study of 6209 infants. J Allergy Clin Immunol. 1999;104:457–461 10452771 36 Terracciano L Bouygue GR Sarratud T Veglia F Martelli A Fiocchi A Impact of dietary regimen on the duration of cow's milk allergy. A random allocation study. Clin Experim Allergy. 2010 [Epub ahead of print]. 37 Notarbartolo A Carroccio A Persistent cow's milk protein intolerance in infants: the changing faces of the same disease. Clin Exp Allergy. 1998;28:817–823 9720815 38 Bock SA The natural history of food sensitivity. J Allergy Clin Immunol. 1982;69:173–177 6895758 39 Sampson HA Scanlon SM Natural history of food hypersensitivity in children with atopic dermatitis. J Pediatr. 1989;115:23–27 2738792 40 James JM Sampson HA Immunologic changes associated with the development of tolerance in children with cow milk allergy. J Pediatr. 1992;121:371–377 1517910 41 Niggemann B Celik-Bilgili S Ziegert M Reibel S Sommerfeld C Wahn U Specific IgE levels do not indicate persistence or transience of food allergy in children with atopic dermatitis. J Investig Allergol Clin Immunol. 2004;14:98–103 42 Brockow I Zutavern A Hoffmann U Grübl A von Berg A Early allergic sensitizations and their relevance to atopic diseases in children aged 6 years: results of the GINI Study. J Investig Allergol Clin Immunol. 2009;19:180–187 43 Chatchatee P Jarvinen K-M Bardina L Beyer K Sampson HA Identification of IgE- and IgG-binding epitopes on αs1-casein: differences in patients with persistent and transient cow's milk allergy. J Allergy Clin Immunol. 2001;107:379–383 11174208 44 Vila L Beyer K Jarvinen KM Chatchatee P Bardina L Sampson HA Role of conformational and linear epitopes in the achievement of tolerance in cow's milk allergy. Clin Exp Allergy. 2001;31:1599–1606 11678861 45 Järvinen KM Beyer K Vila L Chatchatee P Busse PJ Sampson HA B-cell epitopes as a screening instrument for persistent cow's milk allergy. J Allergy Clin Immunol. 2002;110:293–297 12170271 46 Sletten GB Halvorsen R Egaas E Halstensen TS Casein-specific immunoglobulins in cow's milk allergic patient subgroups reveal a shift to IgA dominance in tolerant patients. Pediatr Allergy Immunol. 2007;18:71–80 17295802 47 Ruiter B Knol EF van Neerven RJ Garssen J Bruijnzeel-Koomen CA Knulst AC van Hoffen E Maintenance of tolerance to cow's milk in atopic individuals is characterized by high levels of specific immunoglobulin G4. Clin Exp Allergy. 2007;37:1103–1110 17581206 SECTION 12: THE TREATMENT OF CMA ACCORDING TO PRECEDING GUIDELINES The key principle in the treatment of cow's milk allergy (CMA) is the dietary elimination of cow's milk (CM) protein. During breast-feeding, and in children 2 years of age or older, a substitute formula may not be necessary. In nonbreastfed infants and in children less than 2 years, replacement with a substitute formula is mandatory. In this case, the choice of formula must take into account a series of considerations. The following factors should be considered for the treatment of CMA: The elimination diet must be effective and complete. Some children may tolerate some baked products. Inhalation and skin contact should also be prevented. Consumers' rights as to ingredients awareness should be reflected in adequate labeling legislation. Beef allergy implies milk allergy in most cases but the reverse is not generally true. All elimination diets should be nutritionally safe particularly in the first and the second semester of life. Dietary compliance should be closely monitored throughout. Periodical review through diagnostic challenge should be carried out to prevent unnecessarily prolonged elimination diets. Table 12-1 summarizes the recommendations made by international scientific societies, as well as several consensus documents on the treatment of CMA. TABLE 12-1 Treatment of Milk Allergy according to the Current Recommendations in Different Countries As a food allergy, CM is not an exception to the general rule that “the management relies primarily on avoidance of exposure to the suspected or proven foods.”1 Thus, the key principle in the treatment of CMA, irrespective of the clinical type, is the dietary elimination of CMP. In breast-fed infants, and in children after 2 years of age, a substitute formula may not be necessary. In infants and children less than 2 years of age, replacement with a substitute formula is mandatory. In this case, the choice of formula must take into account a series of considerations (see GRADE evaluation). Basically, in all cases the factors to be considered are the after: To avoid untoward effects of persistent symptoms, elimination diet must be effective and complete.2 Thus, to inform the choices of parents, lists of acceptable foods and suitable substitutes must be provided with the help of a dietician. As CM proteins may be encountered in inhalant or contact forms, either of which are able to trigger severe reactions,3–5 such exposures must be monitored to avoid accidental exposure. As CM proteins may be accidentally ingested in food preparations, legislation ensuring that unambiguous labeling is clearly detailed for processed or prepackaged foods is needed worldwide. As cross-reactivity between CM proteins and beef is not the rule, avoidance of other bovine proteins should be evaluated on a case by case basis: while practically all children allergic to beef are allergic to milk,6 the opposite is not true.7 Particular attention must be paid to the prescription of a nutritionally safe diet. Low intake of energy, fat and protein has been reported in CMA children on cows' milk-free diets.8 As cases of severe malnutrition have been reported in children treated with milk elimination for different reasons,9–11 this is not just a theoretical issue. Thus, CMA elimination diets need to be formally assessed for their nutritional adequacy with regard to protein, energy, calcium, vitamin D, and other micronutrient contents. Good quality alternative protein sources must be found, both from the allergy and the nutritional point if view. Particular attention must be paid to data assessing the nutritional safety of CM substitutes in vulnerable periods as the first12 and the second13 years of life. Compliance with dietetic advice should be verified throughout the therapeutic phase. In some cultural contexts, full compliance with elimination diets are not always feasible for CM,14 and alternative strategies used for children with severe CMA unable to avoid accidental exposures to CM have been based on this observation.15 When the diagnostic challenge indicates that the child is tolerating small doses of CM, complete milk avoidance may not always be required. Milk-limited diets, including limited, extensively heated milk have been reported not to induce acute milk-induced allergic reactions.16 Such an approach could provide a substantial improvement to the quality of life of milk-allergic individuals,17 but studies with baked-milk products are still in their early stages and it is premature to suggest this as a general recommendation. As the natural history shows that many CMA children outgrow their condition, a periodical re-evaluation of CM tolerance through diagnostic challenges is mandatory to prevent children with this condition from continuing unnecessary elimination diets. Table 12-1 reports the recommendations so far issued by official documents of international scientific societies18–20 and largely circulated consensuses on CMA treatment.21,22 These are not the only documents in the field. National position papers and guidelines have been produced in Germany,23,24 the Netherlands,25 Finland,26 and Argentina,27 reflecting general and local needs and visions. As the decision strategies in the management of CMA include locally changing issues (indicators of human well-being for the country, prevalence of the condition in that population, methods of diagnosis, local availability of formula, and their price, availability of potential milk substitutes differ from the products available worldwide, reimbursements by the healthcare providers), these documents are not only possible, but necessary. REFERENCES, SECTION 12 1 American College of Allergy, Asthma, & Immunology Food allergy: a practice parameter. Ann Allergy Asthma Immunol. 2006;96(Suppl 2):S1–S68 16597066 2 Fiocchi A Bouygue GR Martelli A Terracciano L Sarratud T Dietary treatment of childhood atopic eczema/dermatitis syndrome (AEDS). Allergy. 2004;59(Suppl 78):78–85 15245364 3 Tan BM Sher MR Good RA Bahna SL Severe food allergies by skin contact. Ann Allergy Asthma Immunol. 2001;86:583–586 11379811 4 Roberts G Lack G Relevance of inhalational exposure to food allergens. Curr Opin Allergy Clin Immunol. 2003;3:211–215 12840705 5 Fiocchi A Bouygue GR Restani P Gaiaschi A Terracciano L Martelli A Anaphylaxis to rice by inhalation. J Allergy Clin Immunol. 2003;111:193–195 12532119 6 Fiocchi A Travaini M Sala M Silano M Fontana P Riva E Allergy to cow's milk in beef-allergic children. Ann Allergy Asthma Immunol. 2001;86:64 7 Werfel SJ Cooke SK Sampson HA Clinical reactivity to beef in children allergic to cow's milk. J Allergy Clin Immunol. 1997;99:293–300 9058683 8 Henriksen C Eggesbø M Halvorsen R Botten G Nutrient intake among two-year-old children on cows' milk-restricted diets. Acta Paediatr. 2000;89:272–278 10772273 9 Novembre E Leo G Cianferoni A Bernardini R Pucci N Vierucci A Severe hypoproteinemia in infant with AD. Allergy. 2003;58:88–89 12580819 10 Carvalho NF Kenney RD Carrington PH Hall DE Severe nutritional deficiencies in toddlers resulting from health food milk alternatives. Pediatrics. 2001;107:E46 11335767 11 Nguyen J Cazassus F Atallah A Baba N Sibille G Coriatt D Kwashiorkor after an exclusion diet for eczema. Presse Med. 2001;30:1496–1497 11712207 12 Isolauri E Sütas Y Mäkinen-Kiljunen S Oja SS Isosomppi R Turjanmaa K Efficacy and safety of hydrolyzed cow milk and amino acid-derived formulas in infants with cow milk allergy. J Pediatr. 1995;127:550–557 7562275 13 Agostoni C Fiocchi A Riva E Terracciano L Sarratud T Growth of infants with IgE-mediated cow's milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol. 2007;18:599–606 17561927 14 Vlieg-Boerstra BJ van der Heide S Bijleveld CMA Kukler J Duiverman EJ Wolt-Plompen SAA Dubois AEJ Dietary assessment in children adhering to a food allergen avoidance diet for allergy prevention. Eur J Clin Nutr. 2006;60:1384–1390 16823406 15 Longo G Barbi E Berti I Meneghetti R Pittalis A Ronfani L Ventura A Specific oral tolerance induction in children with very severe cow's milk induced reactions. J Allergy Clin Immunol. 2008;121:343–347 18158176 16 Nowak-Wegrzyn A Bloom KA Sicherer SH Shreffler WG Noone S Wanich N Sampson HA Tolerance to extensively heated milk in children with cow's milk allergy. J Allergy Clin Immunol. 2008;122:342–347 18620743 17 Skripak JM Wood RA Mammalian milk allergy: avoidance strategies and oral desensitization. Curr Opin Allergy Clin Immunol. 2009;9:259–264 19365261 18 Businco L Dreborg S Einarsson R Giampietro PG Høst A Keller KM Strobel S Wahn U Björkstén B Kjellman MN Hydrolysed cow's milk formulae. Allergenicity and use in treatment and prevention. An ESPACI position paper. European Society of Pediatric Allergy and Clinical Immunology. Pediatr Allergy Immunol. 1993;4:101–111 8220797 19 Høst A Dietary products used in infants for treatment and prevention of food allergy. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child. 1999;81:80–84 10373144 20 American Academy of Pediatrics. Committee on Nutrition Hypoallergenic infant formulas. Pediatrics. 2000;106(Pt 1):346–349 10920165 21 Vandenplas Y Koletzko S Isolauri E Hill D Oranje AP Brueton M Staiano A Dupont C Guidelines for the diagnosis and management of cow's milk protein allergy in infants. Arch Dis Child. 2007;92:902–908 17895338 22 Kemp AS Hill DJ Allen KJ Anderson K Davidson GP Guidelines for the use of infant formulas to treat cow's milk protein allergy: an Australian consensus panel opinion. Med J Aust. 2008;188:109–112 18205586 23 Niggemann B Friedrichs F Koletzko B Positions papier. Das Vorgehen bei Saüglingen mit Verdacht auf Kuhmilchproteinallergie. Padiatrische Allergologie. 2005;4:14–18 24 Kirchlechner V Dehlink E Szepfalusi Z Cow's milk allergy: guidelines for the diagnostic evaluation. Klin Padiatr. 2007;219:201–205 16586270 25 Kneepkens CMF Van Drongelen KI Aarsen C Landelijke standard voedselallergie bij zuigelingen [National standard for food allergy in infants]. 5th ed. Den Haag: Voedingscentrum; 2005:80 26 Finnish Paediatric Society Food allergy in children. Duodecim. 2004;120:1524–1538 15293715 27 Orsia M Fernández A Follett FR Marchisone S Saiege G Alergia a la proteína de la leche de vaca. Propuesta de Guía para el manejo de los niños con alergia a la proteína de la leche de vaca. Arch Argent Pediatr. 2009;107:459–470 19809770 SECTION 13: WHEN CAN MILK PROTEINS BE ELIMINATED FROM THE DIET WITHOUT SUBSTITUTING COW'S MILK? Overview The simplest way to deal with cow's milk allergy (CMA) is avoidance of cow's milk proteins. A CM-based diet is necessary until 2 years of age. Before this time, a CM substitute of adequate nutritional value is necessary: For breast-fed infants, mothers should been advised to continue breast-feeding while avoiding dairy products. The mother will require calcium supplements while on a dairy-free diet. For nonbreastfed infants, available substitutes include extensively hydrolyzed cow's milk whey and/or casein formula, soy formula, soy and rice hydrolysates, and amino acid-based formula. The value of such formula is subjected to GRADE evaluation in the relevant sections. Alternative milks will not be GRADE-evaluated and can be used on an individual basis. In either case, lists of acceptable foods and suitable substitutes congruent with national context and clinical setting must be drawn from various sources and adapted to the individual patient's needs and values. It is DRACMA contention that all dietary interventions and avoidance strategies be re-evaluated with patients and their families on a yearly basis ideally through an oral food challenge carried out under medical supervision (see Diagnosis section). Convincing symptoms after accidental ingestion can be considered equivalent to positive oral food challenge and the follow-up procedure can be rescheduled accordingly. Introduction Fully breast-fed infants and toddlers more than 2 years may not need to substitute cow's milk if an adequate supply of calcium (600–800 mg/day) is provided. From these patients' perspective, avoidance means meeting obstacles unshared by their nonallergic peers, thereby curtailing their quality of life; from the physician's outlook, patient and parent education, encouraging compliance, and receptiveness in both patient and caregiver are the major didactic concerns. The cues for a successful avoidance phase result from a dialectical assessment of these competing factors in concert with all parties concerned. PRESCRIBING AN EFFECTIVE DIET A successful avoidance strategy planned with the patient's family rests on achieving the absolute avoidance of contact with cow's milk proteins. For breast-fed infants, this entails to provide mothers with the advice to continue breast-feeding while avoiding dairy products altogether.1 Milk proteins are found in breast milk and may cause adverse reactions during exclusive breast-feeding in sensitized infants.2 The mother will also require calcium supplements (1000 mg/day divided into several doses) while after a milk-free diet. For the nonbreastfed infants, a substitute formula will be proposed. Current guidelines define a therapeutic formula as one that is tolerated by at least 90% (with 95% CI) of CMPA infants.3 These criteria are met by some extensively hydrolyzed cow's milk whey and/or casein formula, soy and rice hydrolysates, and by amino acid-based formula (AAF). To maximize the diagnostic significance of the elimination phase, the least allergenic substitute should be proposed. Children may react to residual allergens in eHF, with a risk of failure up to 10% of children with CMA.4 The residual allergens in eHF account for failure of therapy in this setting,5 and such formula are more likely to produce gastrointestinal and other non-IgE-associated manifestations compared with AAF.6,7 However, immediate reactions have also been reported in connection with eHF treatment.8 In such cases, clinicians should consider either rice hydrolyzed formula (HRF) or AAF, the safety of which is well documented9,10 and that provide adequate nutrition,8,11 promote weight gain, and foster growth. Planning a dietary regimen avoiding all cow's milk proteins from dairy or processed food products for these infants and children is a collaborative consensus between scientific societies, primary care physicians and caregivers that goes beyond office procedures. For infant foods in particular, lists of acceptable foods and suitable substitutes congruent with national context and clinical setting must be drawn from various sources and adapted to the individual patient's needs and values.12 A dietician can be of help and specific lists are available to inform the everyday choices of parents and patients. For children and adolescents, who are major consumers of prepackaged industrially processed foods, recognizing the danger signals can be more difficult than in adult populations. Inadvertent milk contamination is difficult and costly to consistently eliminate from the food chain and, for infants and children, good quality alternative protein sources must be found that are also attractive. To compound the problem, milk allergen inhalant, ingestant, or skin contact forms are all liable to trigger severe reactions.13,14 PREVENTION OF ACCIDENTAL EXPOSURE In an effort to meet the needs of food allergic patients, regulators have come up with legislation ensuring that unambiguous labeling for the main categories of food allergens is clearly detailed for processed or prepackaged foods. Since 2005 (after the review of a labeling directive issued in September 2001 by the European Union), 12 foods, including dairy milk, are required to seem as disclosure of content on the label of all processed or prepackaged foods. Similar legislation is in effect in the US, where the Food Allergen Labeling and Consumer Protection Act provides that all milk products require an ingredient statement. Thus, hidden allergens previously not requiring labeling because found in ingredients/additives exempt from specific indication (ie, colors and flavorings, etc.) must now be disclosed. On both the sides of Atlantic, however, these regulatory efforts have raised the concern of a labeling overkill, which could restrict even further the range of potentially safe choices for allergic consumers. The threshold concept, on which avoidance should be objectively predicated is elusive and the issue of eliciting dose, either for diagnosis or for real-life situations is likely to rely on individual intrinsic and extrinsic factors.15 Current legislation does not enforce disclosure of potential contaminants, but many manufacturers include a “may contain . . .” warning of hypothetical contamination during food processing to ward off litigation. Even in the case of contaminants, blanket eliminations should be avoided if one is to maintain a wide range of food options especially with the cow's milk allergic consumer in mind. A case in point is lactose, which textbooks,16 reviews,17 and position papers18,19 single out as a possible cause of adverse reactions in children with CMA. The literature does not report a single case of an adverse reaction to lactose ingestion among children with CMA, and a prospective study of the allergenicity of whey-derived lactose investigated by serology and DBPCFC did not document such reactions.20 Thus, even if lactose ingestion may per se carry risks of cow's milk protein contamination (as seen from incidents after inhalation of lactose-containing drugs21), the total elimination of lactose from the diet of children with CMA is not warranted. Some of the products intended for use by milk-allergic children may contain lactose.22 AWARENESS OF CROSS-REACTIVE FOODS While the need for casual contact avoidance is easy enough to grasp, this is not the case with the phenomenon of cross-reactivity among seemingly unrelated food families where cultural habits interfere. Multiple food allergies are actually rare in the general population and oral food challenge confirms allergy to no more than one or 2 foods, while a dozen foods or so account for most food-induced hypersensitivities.23 It follows that, as extensive elimination diets are seldom necessary, so are avoidance strategies based on presumed cross-reactions between different proteins.24 In the context of CMA, a case in point is beef, as dairy products and meat contain common antigenic protein25 and cross-reactivity could be alleged in favor of elimination because of amino acid sequence homology.26 Nutritionally and economically, dairy products and beef are important protein sources in the western diet (30 kg of beef per person are consumed in the US annually27) but CMA is more frequent than hypersensitivity to beef, with point prevalence of 10% in one study of children with CMA.28 While almost all children allergic to beef are also allergic to milk,29 industrial treatment, more than home cooking, may modify the allergic reactivity of this meat in beef-sensitive children,30 thus making industrially freeze-dried or homogenized beef safe alternatives to butcher's meat cooked at home. Thus, total avoidance of beef by all cow's milk-allergic children is not justified. In this setting, an allergist's evaluation of cross-sensitization makes sense during the diagnostic work-up of CMA. PRESCRIBING A NUTRITIONALLY ADEQUATE DIET Formulating the diet of infants and children during the CMA work-up requires a careful evaluation of all nutritional aspects and requirements on a strictly individual patient basis. There has long been a consensus is in the food allergy literature that “extensive [elimination] diets should be used as a diagnostic tool only for a short period of time”31 and that “it is crucial to provide a balanced diet which contains sufficient proteins, calories, trace elements, and vitamins.”32 This is particularly relevant for infants with CMA, since their nutritional requirements demand a balanced calorie-protein ratio, amino-acid composition and an adequate calcium source.33 Ignoring these principles can lead to inappropriate diets, sometimes with dramatic effects.34 As far as cow's milk substitutes are concerned, studies demonstrating their nutritional safety even in the first35 and the second36 semester of life are part of the body of evidence underlying the consensus treatment of CMA. COMPLIANCE WITH AVOIDANCE MEASURES A Dutch study of children who had followed an avoidance diet from birth for primary prevention of CMA has brought into question the very feasibility of enforcing absolute compliance.37 The main lessons to be drawn for diagnostic diets from such a study include the difficulty of enforcement and the need for epidemiological and clinical studies on compliance breakdown in the context of CMA. PERIODIC RE-EVALUATION OF CMA As a prognostic index is currently lacking, remission of CMA should be periodically reviewed (see Natural history section). It is the consensus of this panel that all dietary interventions and avoidance strategies should be re-evaluated with patients and their families on a yearly basis. In practice, this reappraisal takes the form of an oral food challenge under medical supervision (see Diagnosis section). Challenges may be carried out earlier if inadvertent cow's milk ingestion without symptoms is reported. Convincing symptoms after accidental ingestion can be considered equivalent to positive oral food challenge and the follow-up procedure can be rescheduled accordingly. REFERENCES, SECTION 13 1 Vandenplas Y Koletzko S Isolauri E Hill D Oranje AP Guidelines for the diagnosis and management of cow's milk protein allergy in infants. Arch Dis Child. 2007;92:902–908 17895338 2 Isolauri E Tahvanainen A Peltola T Breast-feeding of allergic infants. J Pediatr. 1999;134:27–32 9880445 3 American Academy of Pediatrics. Committee on Nutrition Hypoallergenic infant formulas. Pediatrics. 2000;106:346–349 10920165 4 de Boissieu D Dupont C Allergy to extensively hydrolysed cows' milk proteins in infants: safety and duration of amino acid-based formula. J Pediatr. 2002;141:271–273 12183726 5 Terracciano L Isoardi P Arrigoni S Zoja A Martelli A Milk, soy and rice hydrolysates. Ann Allergy, Asthma & Immunology. 2002;89:86–90 12487212 6 Giampietro PG Kjellman NIM Oldaeus G Hypoallergenicity of an extensively hydrolyzed whey formula. Pediatr Allergy Immunol. 2001;12:83–86 11338291 7 Sicherer SH Noone SA Koerner CB Hypoallergenicity and efficacy of an amino acid-based formula in children with cows' milk and multiple food hypersensitivities. J Pediatr. 2001;138:688–693 11343044 8 Ragno V Giampietro PG Bruno G Businco L Allergenicity of milk proteins hydrolysate formula in children with cow's milk allergy. Eur J Pediatr. 1993;152:760–762 8223811 9 Vanderhoof JA Hypoallergenicity and effects on growth and tolerance of a new amino acid-based formula with DHA and ARA. J Pediatr Gastroenterol Nutr. 2008;47(Suppl 2):S60–S61 18931605 10 Fiocchi A Travaini M D'Auria E Banderali G Bernardo L Riva E Tolerance to a rice hydrolysate formula in children allergic to cow's milk and soy. Clin Exp Allergy. 2003;33:1576–1580 14616871 11 DAuria E Sala M Lodi F Radaelli G Riva E Giovannini M Nutritional value of a rice-hydrolysate formula in infants with cow's milk protein allergy: a randomized pilot study Journal of International Medical Research. 2003;31:215–222 12 Chapman JA Bernstein IL Lee RE Oppenheimer J Nicklas RA Food allergy: a practice parameter. Annals Allergy Asthma Immunol. 2006;96:S3, 1–68 13 Tan BM Sher MR Good RA Bahna SL Severe food allergies by skin contact. Ann Allergy Asthma Immunol. 2001;86:583–586 11379811 14 Roberts G Lack G Relevance of inhalational exposure to food allergens. Curr Opin Allergy Clin Immunol. 2003;3:211–215 12840705 15 Hourihane JO'B The threshold concept in food safety and its applicability to food allergy. Allergy. 2001;36(Suppl 67):86–90 16 Barnes Koerner C Sampson HA Diets and Nutrition In: Metcalfe DD Sampson HA Simon RA , eds. Food Allergy: Adverse Reactions to Foods and Food Additives. Cambridge MA: Blackwell Science; 1991:332–354 17 Taylor SL Hefle SL Ingredient and labeling issues associated with allergenic foods. Allergy. 2001;56(Suppl 67):S64–S69 18 Comité de Nutrition de la Société Française de Pediatrie Infant formulas and soy protein-based formulas: current data. Arch Pediatr. 2001;8:1226–1233 11760676 19 Host A Koletzko B Dreborg S Dietary products used in infants for treatment and prevention of food allergy. Arch Dis Child. 1999;81:80–84 10373144 20 Fiocchi A Restani P Leo G Martelli A Bouygue GR Terracciano L Ballabio C Valsasina R Clinical tolerance to lactose in children with cow's milk allergy. Pediatrics. 2003;112:359–356 12897287 21 Nowak-Wegrzyn A Shapiro GG Beyer K Bardina L Sampson HA Contamination of dry powder inhalers for asthma with milk proteins containing lactose. J Allergy Clin Immunol. 2004;113:558–560 15007361 22 Nasirpour A Scher J Desobry S Baby foods: formulations and interactions (a review). Crit Rev Food Sci Nutr. 2006;46:665–681 17092831 23 Bock SA In vivo diagnosis: Skin testing and oral challenge proceduresIn: Metcalfe DD Sampson HA Simon RA , eds. Food Allergy: Adverse Reactions to Foods and Food Additives. 2nd ed Cambridge MA: Blackwell Science; 1997:161 24 Giovannini M Fiocchi A Agostoni C Riva E Nutrition in infancy and childhoodIn: Wuthrich B Ortolani C , eds. Highlights in Food Allergy: Monogr Allergy. Basel: Karger; 1996;25–29 25 Fiocchi A Restani P Riva E Beef allergy in children. Nutrition. 2000;16:454–457 10869903 26 Hirayama K Akashi S Furuya M Fukuhara KI Confirmation and revision of the primary structure of bovine-serum albumin by esims and frit-FAB LC-MS. Biochem Biophys Res Commun. 1990;173:639–646 2260975 27 Ayuso R Lehrer SB Tanaka L Ibanez MD Pascual C IgE antibody response to vertebrate meat proteins including tropomyosin. Ann Allergy Asthma Immunol. 1999;83:399–405 10582720 28 Werfel SJ Cooke SK Sampson HA Clinical reactivity to beef in children allergic to cow's milk. J Allergy Clin Immunol. 1997;99:293–300 9058683 29 Fiocchi A Travaini M Sala M Silano M Fontana P Riva E Allergy to cow's milk in beef-allergic children. Ann Allergy Asthma Immunol. 2001;86:64 30 Fiocchi A Restani P Riva E Mirri GP Santini I Bernardo L Galli CL Heat treatment modifies the allergenicity of beef and bovine serum albumin. Allergy. 1998;53:798–802 9722230 31 Crawford LV Allergy diets In: Bierman CW Pearlman DS , eds. Allergic Diseases of Infancy, Childhood and Adolescence. Philadelphia:Saunders;1980: 394–400 32 Reinhardt MC Food allergy: pathogenesis, manifestations, diagnosis, and management.. In: Businco L , ed. Advances in Pediatric Allergy. Amsterdam: Elsevier; 1983:155–194 33 Black RE Children who avoid drinking cow milk have low dietary calcium intakes and poor bone health. Am J Clin Nutr. 2002;76:675–680 12198017 34 Nguyen J Cazassus F Atallah A Baba N Sibille G Coriatt D Kwashiorkor after an exclusion diet for eczema. Presse Med. 2001;30:1496–1497 11712207 35 Isolauri E Sütas Y Mäkinen-Kiljunen S Oja SS Isosomppi R Turjanmaa K Efficacy and safety of hydrolyzed cow milk and amino acid-derived formulas in infants with cow milk allergy. J Pediatr. 1995;127:550–557 7562275 36 Agostoni C Fiocchi A Riva E Terracciano L Sarratud T Growth of infants with IgE-mediated cow's milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol. 2007;18:599–606 17561927 37 Vlieg-Boerstra BJ van der Heide S Bijleveld CMA Kukler J Duiverman EJ Wolt-Plompen SAA Dubois AEJ Dietary assessment in children adhering to a food allergen avoidance diet for allergy prevention. Eur J Clin Nutr. 2006;60:1384–1390 16823406 SECTION 14: GUIDELINES FOR CHOOSING A REPLACEMENT FORMULA INTRODUCTION Treating cow's milk allergy (CMA) entails a nutritional risk, as milk is a staple food in particular for children less than 2 years of age. When a replacement formula is needed, the allergist can avail themselves with different types of formula: Amino acid formula (AAF) Extensively hydrolyzed formula of cow's milk proteins (eHF) Soy formula (SF) Rice extensively hydrolyzed formula (RHF) Soy hydrolyzed formula (SHE) Other mammal's milks. After an evaluation of the literature, the DRACMA panel decided to commend to the GRADE specialists the analysis of the formula 1–4. For SHF and other mammal's milks, it was decided not to go into similar analysis given the paucity of information. DRACMA will deal with mammal's milks in section 13. Thus, this section reports the guidelines for the use of AAF, eHF, SF, and RHF as replacement formula in infants confirmed to have CMA. After the complete evaluation of randomized trials, 1,579 of which were screened (Fig. 14-1), the panel asked the GRADE group to analyze also the observational studies. For this analysis, 2,954 studies were assessed (Fig. 14-2). This supplementary investigation did not change the recommendations. FIGURE 14-1 PRISMA diagram, randomized trials. Should extensively hydrolyzed milk, soy, amino acid or extensively hydrolyzed rice formula be used in patients with cow's milk allergy? FIGURE 14-2 PRISMA diagram, observational studies. Should extensively hydrolyzed milk, soy, amino acid or extensively hydrolyzed rice formula be used in patients with cow's milk allergy? QUESTION 7 Should amino acid formula, extensively hydrolyzed whey or casein formula, soy formula or rice formula be used in children with IgE-mediated CMA? Population: children with CMA Interventions (management options): Amino acid-based formula Extensively hydrolyzed whey or casein formula Soy formula Rice extensively hydrolyzed formula Table Outcomes of Interest, Question 7 Summary of Findings Systematic Reviews One systematic review assessed the efficacy of amino acid-based formulas in relieving the symptoms of cow's milk allergy.1 We could not use this review to directly inform these recommendations since it did not assess the methodological quality of included studies, did not combine the results of individual studies, and included studies done in children without confirmed CMA.2,3 We assessed all the studies identified in this review and used those that met our prespecified criteria (see description of individual studies below). We identified one additional randomized trial of amino acid versus extensively hydrolyzed formula4 that appeared after Hill and colleagues' review was published.1 We did not identify any systematic review assessing the relative benefits and downsides of using extensively hydrolyzed formula compared with soy formula or rice formula or comparing soy to rice formula in children with CMA. Individual Studies Altogether we identified 3 randomized trials comparing amino acid-based formula to an extensively hydrolyzed whey formulas.4–6 All studies used Neocate (SHS International) amino acid-based formula and 3 different whey hydrolyzed formulas: Peptidi-Nutteli (Valio),5,6 Alfare (Nestlé),6 and Althera (Nestlé).4 All studies had methodological limitations, none reported a method of randomization, concealment of allocation, and only one reported blinding (it was not blinded and only results of per protocol analysis were reported). Studies did not measure or report most outcomes of interest (see evidence profile Appendix 3). We also identified 2 randomized short-term food challenge trials that compared amino acid-based formula to extensively hydrolyzed casein formula7,8 and to soy formula.7 Sampson and colleagues enrolled 28 children (aged 11 months to 12 years) with confirmed CMA and allergy to several other foods.8 Children were challenged with an amino acid formula (Neocate) and an extensively hydrolyzed casein formula (Nutramigen). There were no reactions during the challenge with amino acid formula and one child reacted to extensively hydrolyzed formula with vomiting, erythema, rhinitis, laryngeal edema, and wheezing. Caffarelli and colleagues enrolled twenty children (aged 11 months to 9 years) with confirmed CMA fed with soy formula with no symptoms.7 This study suffered from major limitations with 20% of children not being challenged with extensively hydrolyzed formula and 50% not being challenged with amino acid formula. Two children challenged with amino acid formula developed a delayed eczema, one child receiving extensively hydrolyzed casein formula had immediate diarrhea, and 3 children challenged with extensively hydrolyzed whey formula developed symptoms of allergy: vomiting and diarrhea (one), urticaria (one), and delayed eczema (one). No study using amino acid formula reported laryngeal edema, severe asthma, anaphylaxis, enteropathy, or entero/proctocolitis. No study measured protein and nutrients deficiency, and quality of life of both children and parents. We did not identify any study comparing amino acid-based formula to soy formula or rice hydrolysate. We identified 2 studies that compared extensively hydrolyzed cow's milk formula to soy formula9,10. Extensively hydrolyzed formulas used were Nutramigen regular (Mead Johnson)9 and Peptidi-Tutteli (Valio)10 and the soy formulas were Isomil-2 (Ross Abbott)9 and Soija Tutteli (Valio).10 All studies had methodological limitations, none reported a method of randomization, concealment of allocation, and they were not blinded. In one study only results of per protocol analysis were reported.9 Most outcomes of interest did not occur in the studies (see evidence profile, Table A3-3 in Appendix 3). Only one randomized trial compared extensively hydrolyzed formula to rice formula.9 A extensively hydrolyzed rice formula used in one study was Risolac (Heinz) (see evidence profile, Table A3-2 in Appendix 3). We found 2 randomized trials comparing soy formula to rice formula published by the same group of investigators, one was the abovementioned study by Agostoni and colleagues9 and the other was a study by D'Auria and colleagues11 (see evidence profile, Table A3-4 in Appendix 3). Because the information from randomized trials was sparse, we searched for observational studies with an independent control group that compared different formula in children with cow's milk allergy. We identified 5 observational studies.12–16 Two of them reported comparing different extensively hydrolyzed milk formula only.12,15 One study described 51 children with immediate allergic reactions to cow's milk protein in whom extensively hydrolyzed milk, soy or amino acid formula were used.13 The formula were selected by the clinician and the selection was not described. Allergic reaction to selected formula was observed in 3 of the 8 children receiving extensively hydrolyzed milk formula, and none of the children receiving either soy (29 children) or amino acid formula (6 children). Another study described a cohort of 25 children “sensitized to cow's milk proteins” (authors did not report the criteria for diagnosis) that received either soy formula or extensively hydrolyzed casein formula for 12 months.14 Authors measured body height, mass and upper arm circumference and found no difference between the groups. The third study described 58 children with atopic eczema and CMA, who received a rice hydrolysate formula, soy formula or an extensively hydrolyzed casein formula.16 The choice of the formula was reported as being “based on allergometric tests, clinical features at the beginning of the diet and age.” Authors measured weight of the children and observed no difference in the weight-for-age z-score among the groups. Amino Acid Formula Versus Extensively Hydrolyzed Whey or Casein Formula (Table A3-1 in Appendix 3) Benefits In children with atopic eczema extensively hydrolyzed whey formula had similar impact on the severity of eczema compared with amino acid-based formula (mean difference in SCORAD score: 1.39 point higher; 95% CI: 1.08 lower to 3.86 higher). Growth, as measured by relative length and weight, were similar in both groups, although the results were imprecise (see evidence profile, Table A3-1 in Appendix 3). Downsides Vomiting was noted in fewer children receiving extensively hydrolyzed whey formula compared with amino acid formula (relative risk: 0.12 [95% CI: 0.02–0.88]; risk difference: 235 fewer per 1000 [from 32 fewer to 261 fewer]), however, this estimate is based on 9 events only. One study estimated the cost treatment. The use of extensively hydrolyzed whey formula was associated with direct cost of €149 per child per month and amino acid formula €318 per child per month (difference: €169 less per child per month). However, this estimate can only serve as a rough guide for decisions in other settings. Direct cost measured in one country and jurisdiction at some point in time will likely not be applicable to different settings. Direct cost may be estimated considering that the children in the study (mean age 8 months) consumed about 600 mL (±200) of formula daily. Conclusions Net clinical benefit of substituting cow's milk with amino acid formula compared with extensively hydrolyzed whey formula is uncertain. Most outcomes of interest were not measured in clinical studies and the estimates of outcomes that were measured are very imprecise. The direct cost of amino acid formula is higher than extensively hydrolyzed whey formula. There is no information from controlled clinical studies about the relative benefits and downsides of using amino acid formula compared with soy or rice formula.1 Further research, if done, will have important impact on this recommendation. Extensively Hydrolyzed Whey or Casein Formula Versus Soy Formula Benefits Growth, as measured by length and weight for age z-score, were similar in both groups, although there was a trend toward improved growth in the group receiving extensively hydrolyzed formula compared with soy formula (length for age z-score – mean difference: 0.27 SD higher; 95% CI: 0.19 lower to 0.73 higher, and weight for age z-score, mean difference: 0.23 SD higher; 95% CI: 0.01–0.45 higher). However, the results were again imprecise and it is not certain to what extent these measures of child's growth relate to outcomes that are important to patients. Downsides Fewer children with CMA experienced allergic reaction to extensively hydrolyzed formula than to soy formula (relative risk: 0.18; 95% CI: 0.05–0.71) and developed secondary sensitization confirmed by the presence of specific IgE in serum (relative risk: 0.14; 95% CI: 0.03–0.76). However, very few events occurred in both groups, thus the results are imprecise. Quality of life was not measured in these studies, but investigators recorded “acceptance” of a formula.9 All 37 children receiving soy formula accepted it well, but 4 of 35 children receiving extensively hydrolyzed formula accepted it poorly (relative risk: 0.89; 95% CI: 0.75–1.02). Conclusions Net clinical benefit of substituting cow's milk with extensively hydrolyzed formula compared with soy formula is uncertain. Most outcomes of interest were not measured in clinical trials and the estimates of the outcomes that were measured are very imprecise. Further research, if done, will have important impact on this recommendation. Extensively Hydrolyzed Whey or Casein Formula Versus Extensively Hydrolyzed Rice Formula (Table A3-2 in Appendix 3) Benefits Growth, as measured by length and weight for age z-score, was similar in the group receiving extensively hydrolyzed casein formula compared with hydrolyzed rice formula (length for age z-score, mean difference: 0.33 SD higher; 95% CI: 0.13 lower to 0.79 higher, and weight for age z-score; mean difference: 0.04 SD higher; 95% CI: 0.53 lower to 0.45 higher). The results were imprecise and it is not certain to what extent these measures of child's growth relate to outcomes that are important to patients. Downsides No allergic reaction to extensively hydrolyzed formula or to rice formula occurred in this study.9 Acceptance of extensively hydrolyzed whey formula and extensively hydrolyzed rice formula was similar (relative benefit: RR 1.06; 95% CI: 0.86–1.32), but the results were very imprecise not excluding appreciable benefit or appreciable harm. Hydrolyzed rice formulas are not available in many countries. Conclusions Net clinical benefit of substituting cow's milk with extensively hydrolyzed formula compared with rice formula is uncertain. Only one relatively small randomized trial is available that did not report most outcomes of interest and the estimates of the outcomes that were measured are very imprecise. Further research, if done, will have important impact on this recommendation. Soy Formula Versus Extensively Hydrolyzed Rice Formula (Table A3-4 in Appendix 3) Benefits There was no apparent difference in length and weight for age z-scores between children receiving soy formula compared with rice formula (length for age z-score, mean difference: 0.33 SD higher; 95% CI: 0.13 lower to 0.79 higher, and weight for age z-score, mean difference: 0.04 SD lower; 95% CI: 0.53–0.45 higher). In a study that enrolled children with atopic eczema its severity was similar in both groups both at baseline and at the end of the study, but 11/16 children had SCORAD scores <20 at baseline.9,11 Downsides Fewer children with CMA experienced allergic reaction to hydrolyzed rice formula that to soy formula (0/43 versus 5/44; relative risk: 0.08; 95% CI: 0.00–1.52). However, very few events occurred, thus the results are imprecise. Conclusions Net clinical benefit of substituting cow's milk with soy formula compared with extensively hydrolyzed rice formula is unknown. Most outcomes of interest were not measured and the estimates of the outcomes that were measured are very imprecise. The guideline panel felt that any recommendation is not warranted until further research is done comparing the effects of using a soy formula versus a hydrolyzed rice formula. Summary for Research There is a need for rigorously designed and executed randomized trials comparing different types of formula used long-term (as opposed to single-dose challenge) in patients with cow's milk allergy that would measure and properly report17,18 patient-important outcomes and adverse effects. Clinical Recommendations, Question 7 Recommendation 7.1 In children with IgE-mediated CMA at high risk of anaphylactic reactions (prior history of anaphylaxis and currently not using extensively hydrolyzed milk formula), we suggest amino acid formula rather than extensively hydrolyzed milk formula (conditional recommendation/very low quality evidence). Underlying Values and Preferences This recommendation places a relatively high value on avoiding possible anaphylactic reactions and a lower value on avoiding the direct cost of amino acid formula in settings where the cost of amino acid formulas is high. Remarks In controlled settings a trial feeding with an extensively hydrolyzed milk formula may be appropriate. Recommendation 7.2 In children with IgE-mediated CMA at low risk of anaphylactic reactions (no prior history of anaphylaxis or currently on extensively hydrolyzed milk formula), we suggest extensively hydrolyzed milk formula over amino acid formula (conditional recommendation/very low quality evidence). Underlying Values and Preferences This recommendation places a relatively high value on avoiding the direct cost of amino acid formula in settings where the cost of amino acid formula is high. In settings where the cost of amino acid formula is lower the use of amino acid formula may be equally reasonable. Remarks Extensively hydrolyzed milk formula should be tested in clinical studies before being used.19 If a new formula is introduced, one should carefully monitor if any adverse reactions develop after first administration. Recommendation 7.3 In children with IgE-mediated CMA, we suggest extensively hydrolyzed milk formula rather than soy formula (conditional recommendation/very low quality evidence). Underlying Values and Preferences This recommendation places a relatively high value on avoiding adverse reactions to soy formula, and a relatively low value on an inferior acceptance of the extensively hydrolyzed formula and resource utilization. In settings where relative importance of resource expenditure is lower an alternative choice may be equally reasonable. Remarks Soy should not be used in first 6 months of life, because of nutritional risks. Recommendation 7.4 In children with IgE-mediated CMA, we suggest extensively hydrolyzed milk formula rather than extensively hydrolyzed rice formula (conditional recommendation/very low quality evidence). Underlying Values and Preferences This recommendation places a relatively high value on wide availability of extensively hydrolyzed milk formula relative to hydrolyzed rice formula. Recommendation 7.5 We suggest that more well designed and executed randomized trials comparing soy formula to extensively hydrolyzed rice formula are performed in patients suspected of IgE-mediated CMA. Remarks There is very sparse evidence suggesting possible benefit from using extensively hydrolyzed formula compared with soy formula, but more research is needed to confirm these observations. REFERENCES, SECTION 14 1 Hill DJ Murch SH Rafferty K Wallis P Green CJ The efficacy of amino acid-based formulas in relieving the symptoms of cow's milk allergy: a systematic review. Clin Exp Allergy. 2007;37:808–822 17517094 2 Hill DJ Cameron DJ Francis DE Gonzalez-Andaya AM Hosking CS Challenge confirmation of late-onset reactions to extensively hydrolyzed formulas in infants with multiple food protein intolerance. J Allergy Clin Immunol. 1995;96:386–394 7560641 3 McLeish CM MacDonald A Booth IW Comparison of an elemental with a hydrolysed whey formula in intolerance to cows' milk. Archives of Disease in Childhood. 1995;73:211–215 7492157 4 Niggemann B von BA Bollrath C Berdel D Schauer U Safety and efficacy of a new extensively hydrolyzed formula for infants with cow's milk protein allergy. Pediatr Allergy Immunol. 2008;19:348–354 18167160 5 Isolauri E Sutas Y Makinen-Kiljunen S Oja SS Isosomppi R Turjanmaa K Efficacy and safety of hydrolyzed cow milk and amino acid-derived formulas in infants with cow milk allergy. J Pediatr. 1995;127:550–557 7562275 6 Niggemann B Binder C Dupont C Hadji S Arvola T Isolauri E Prospective, controlled, multi-center study on the effect of an amino-acid-based formula in infants with cow's milk allergy/intolerance and atopic dermatitis. Pediatr Allergy Immunol. 2001;12:78–82 11338290 7 Caffarelli C Plebani A Poiesi C Petroccione T Spattini A Cavagni G Determination of allergenicity to three cow's milk hydrolysates and an amino acid-derived formula in children with cow's milk allergy. Clin Exp Allergy. 2002;32:74–79 12002741 8 Sampson HA James JM Bernhisel-Broadbent J Safety of an amino acid-derived infant formula in children allergic to cow milk. Pediatrics. 1992;90:463–465 1518709 9 Agostoni C Fiocchi A Riva E Terracciano L Sarratud T Martelli A Lodi F D'Auria E Zuccotti G Giovannini M Growth of infants with IgE-mediated cow's milk allergy fed different formulas in the complementary feeding period. Pediatr Allergy Immunol. 2007;18:599–606 17561927 10 Klemola T Vanto T Juntunen-Backman K Kalimo K Korpela R Varjonen E Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cow's milk allergy: a prospective, randomized study with a follow-up to the age of 2 years. J Pediatr. 2002;140:219–224 11865274 11 D'Auria E Sala M Lodi F Radaelli G Riva E Giovannini M Nutritional value of a rice-hydrolysate formula in infants with cows' milk protein allergy: a randomized pilot study. J Intl Med Res. 2003;31:215–222 12 Kaczmarski M Wasilewska J Lasota M Hypersensitivity to hydrolyzed cow's milk protein formula in infants and young children with atopic eczema/dermatitis syndrome with cow's milk protein allergy. Roczniki Akademii Medycznej W Bialymstoku. 2005;50:274–278 16358982 13 Mehr SS Kemp AS Feeding choice for children with immediate allergic reactions to cow's milk protein. Med J Australia. 2008;189:178–179 18673111 14 Palczewska I Szilagyi-Pagowska I Wawrzyniak M Bulawa E [Somatic development assessment of children with food allergy treated with milk free diet]. [Polish] Medycyna Wieku Rozwojowego. 2002;6:233–243 12637778 15 Plebani A Albertini A Scotta S Ugazio AG IgE antibodies to hydrolysates of cow milk proteins in children with cow milk allergy. Ann Allergy. 1990;64:279–280 2310057 16 Savino F Castagno E Monti G Serraino P Peltran A Z-score of weight for age of infants with atopic dermatitis and cow's milk allergy fed with a rice-hydrolysate formula during the first two years of life. Acta Paediatrica Suppl. 2005;94:115–119 17 Gagnier JJ Boon H Rochon P Moher D Barnes J Bombardier C Reporting randomized, controlled trials of herbal interventions: an elaborated CONSORT statement. Ann Intern Med. 2006;144:364–367 16520478 18 Ioannidis JP Evans SJ Gotzsche PC O'Neill RT Altman DG Schulz K Moher D Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med. 2004;141:781–788 15545678 19 American Academy of Pediatrics Committee on Nutrition Hypoallergenic infant formulas. Pediatrics. 2000;106:346–349 10920165 SECTION 15: MILKS FROM DIFFERENT ANIMALS FOR SUBSTITUTING COW'S MILK Overview The milks of goat, ewe, mare, donkey, or camel or formulas based on lamb or chicken, where available, have been proposed as substitutes in the management of CMA in infants and children. The nutritional value of a milk substitute must be taken into account less than 2 years of life when a substitute is needed. As human milk composition differs both in component ratios and structure from other milks, the composition of infant formula should serve to meet the particular nutritional requirements and to promote normal growth and development of the infants for whom they are intended. This is valid also for other milks, which are not currently fulfilling all human infants' nutritional requirements. The DRACMA panel reviewed the literature on the tolerance of mammalian milks on the light of the existing cross-reactivity between mammalian proteins. The after clinical questions were asked for each milk considered in this section: a. Is it tolerated by children with CMA? b. How many children with CMA immediately react after ingestion? c. How many children with CMA experience a delayed reaction after ingestion? d. What about children with multiple food allergies? e. Is it nutritionally safe? f. Is it affordable? g. Is it palatable? Most of these questions have currently no answer for individual milks. It was concluded that the lack of suitable formulations for infant nutrition limits the use of alternative milks before the third year of life, when most children have outgrown their allergy, and where it persists, a substitute for CM is no longer needed. In particular, there is a consensus that: In the developed world, other milks could be considered only in the impossibility to use another formula (eHF, SF, HRF, HSF, AAF) for a valid clinical reason. The option of another milk rather than another formula should be weighed against allergy, clinical and nutritional considerations on an individual basis. Goat's, ewe's and buffalo's milks should not be used for the treatment of CMA, as they can expose patients to severe reactions. Camel's milk can be considered a valid substitute for children after 2 years. Equine milks can be considered as valid CM substitutes, in particular (but not exclusively) for children with delayed-onset CMA. Introduction Milks from different animals (the goat, ewe, mare, donkey, or camel) or formulas based on lamb or chicken have been widely marketed as substitutes for CM in the management of CMA in infants and children. The substitute source reflects local culture, availability and costs but a comprehensive survey of substitutes for children with CMA is currently lacking. As described in CM Allergen section, cross-reactivity between mammalian proteins is in part explained by bovine taxonomy (Table 15-1), with similarities and differences: TABLE 15-1 Mammalian Taxonomy: Milk Protein Composition and Homology5 Human milk composition differs both in component ratios and structure from other milks. The protein content of human milk is lower than that of ruminant dairy animals: cow, buffalo, yak, camel, goat, sheep, reindeer, but is closer to that of donkey's and mare's milk.1 Human milk does not contain beta-lactoglobulin (BLG), one of the major allergens in cow milk, similarly to camel's and dromedary's milks.2 BLG is a major whey protein of cow's, buffalo's, sheep's, goat's, mare's, and donkey's milks. The proportion of casein within the total protein fraction is lower in whole human milk, serum proteins are higher than in cow's, buffalo's, and ewe's milks and more similar to donkey's and mare's milks. The ratio of casein to whey protein is very similar among Bovidae (between 70:30 and 80:20). Mare's and donkey's milks have a lower total protein content (similar to human milk) and a lower casein-to-whey protein ratio. There is substantial homology between cow's, ewe's, or goat's milks protein fractions. There is less structural similarity with the milk from swine, equines and camelids, and human milk.3 Human milk, camel's and dromedary's milks do not contain beta-lactoglobulin. Table 15-1 also shows the percentage of homology between individual CM protein and those from other animal species, including humans. Data were obtained from the Expasy Website, using the SIM alignment tool for protein sequences.4 The use of other milks to manage CMA in children has been widely discussed. While there has been no significant breakthrough showing the efficacy of this dietary approach, it has been suggested that certain milks could benefit patients. This body of research has been reviewed by the Panel, using a search strategy similar to that described in the GRADE approach to milk substitutes and essentially aimed at the after clinical questions for each milk: a. Is it tolerated by children with CMA? b. How many children with CMA immediately react to ingestion? c. How many children with CMA experience a delayed reaction to ingestion? d. What about children with multiple food allergies? e. Is it nutritionally safe? f. Is it affordable? g. Is it palatable? Most of these questions have currently no answer for individual milks as there is a paucity of research in this particular field. Goat's and Ewe's Milks The most frequently suggested alternative to CM is goat's milk, although evidence of its tolerability is reported by only a few clinical studies. Goat's milk is in widespread use in Mediterranean and Middle Eastern countries, in Australia, New Zealand, and Taiwan.6 Similarly to CM, goat's milk is not suitable for infant use unless modified and fortified to meet infant formula regulations. In Australia and New Zealand, where the economical aspects of prescription have been surveyed, goat's milk is available at a cost which is similar to that of soy formulas, while both are typically 20–50% more expensive than standard cow milk-based formula. In New Zealand, the use of goat's milk now exceeds the use of soy-based formulas and comprises ∼5% of infant formula purchased. It has been surmised that goat's milk could be less allergenic than CM because of its lower alpha-casein content.7 Alpha-casein may act as a carrier for other CM allergens such as beta-lactoglobulin, which is tightly linked to casein micelles and therefore more difficult to digest. The lower alpha-casein content of goat's milk might allow a better digestion of beta-lactoglobulin and other allergens.8 In a murine model of food allergy, goat's milk given as a first source of protein after weaning was found less immunogenic than CM in pups in which it induced a weaker TH2-biased response.9 A 1997 clinical trial in France found that many children with CM allergy tolerated goat's milk for periods ranging from 8 days to 1 year,10 but several studies have since demonstrated that subjects with IgE-mediated CMA do not tolerate goat's and sheep's milk to this extent.6,11 As 95% of children with CMA react to goat's milk, it has been suggested that a warning on the lack of safety of goat's milk for children with CMA should feature on the label of goat's milk formulas to prevent severe allergic reactions in infants with CMA.6 Such reasonable suggestion remains to be complied with even in the parts of the world covered by labeling legislation. In one study of children with atopic dermatitis and IgE-mediated CMA which documented delayed reactions and excluded children with soy allergy, it was reported that goat's milk was tolerated by most of these patients.12 Furthermore, selective allergy to caprine or ovine, but not to bovine, milk has also been reported in patients with severe allergic reactions.13–18 The cross-reactivity between goat's and ewe's milk is incontrovertible.19 Allergy to ewe's milk can also evolve into allergy to CM.20 From a nutritional point of view, the literature is almost silent. A major concern is the protein content, which is higher in goat's and ewe's milks than in human milk (Table 15-2). This could determine an excessive solute renal load.21 Goat's milk lacks vitamins B12 and B9 and must thus be enriched with these vitamins.22 TABLE 15-2 Protein Content of Different Milks (in g/100 mL) Data from a Malagasy report document that among malnourished children aged 1–5 years fed high-energy formulations made from goat's or CM weight gain does not differ between the 2 groups.23 Similarly, a study from New-Zealand shows that adequate grow this reached within the first semester in infants who are fed goat's milk.4 No data are available on the palatability of goat's milk, but it is reasonable to expect that it is better than that of eHF, HSF, and HRF. Costs also vary, given that a global market for goat's milk does not exist. Camel's Milk In many parts of the world (North-East Africa,2 the Middle East,24 the Arabic Peninsula, and China25), camel's and dromedary's milks are used as human milk substitutes for bottle-fed infants. Camel milk contains only 2% fat, consisting mainly of polyunsaturated fatty acids, and is rich in trace elements.26 Its protein composition makes it a possible alternative to CM for allergic subjects because of the low sequence homology of its protein fraction with that of CM and its lack of BLG.27 Tolerance of camel milk has been anecdotally reported in a limited case series of children suffering from severe, not challenge-confirmed, CMA with immediate and delayed symptoms.28 No comparative data are available on the palatability of camel's milk, but it is also reasonable to expect it to taste better than eHF, HSF, and HRF. In large geographical area of the world, camel's milk is used for the production of dairy and baked products, and an ingredient of prepackaged processed foods and there is a market for camel's and dromedary's milks. Mare's and Donkey's Milks Mare's and donkey's milks have a composition closer to human's than CM.29,30 Their low protein content (1.3–2.8 g/100 mL) does not carry the risk of an excessive solute renal load. The protein fraction is rich in whey proteins (35–50%). Its Ca/P ratio of 1.7, which is close to the optimal value for calcium absorption and metabolism.31 Mare's milk also contains large amounts of linoleic and linolenic acids. Because of differences between the amino acid sequences of bovine and equine proteins, the epitopes relevant for IgE binding to CM are different or completely lacking and cross reactivity between equine and bovine milks is low (see Allergens). This explains why the use of mare's milk has proved useful for some patients. In a group of 25 children with severe IgE-mediated CMA, only one tested positive at DBPCFC with mare's milk.32 Thus, although appropriate modification in chemical composition and hygiene controls are necessary, equine milks are a possible alternative cows' milk substitute in CMA. Donkey's milk is similar to mare's milk in composition and is easily available in some Mediterranean countries. Studies on its allergenicity and tolerability among patients with gastrointestinal symptoms concluded that this is a possible CM substitute in the dietary management of these delayed-onset, IgE and non-IgE mediated conditions.33,34 In exquisite-contact acquired IgE-mediated CMA, an 82.6% tolerance of CM was reported in a cohort of children with CMA with heterogeneous symptoms.35 In this particular study, 21.2% of children with immediate CMA reacted to donkey's milk. Thus, the risk of potential cross-reactivity between cow's and donkey's milk proteins is far from theoretical, suggesting that more in vivo and in vitro studies are required before this milk can be recommended in this setting.36 In a population of children with atopic dermatitis and mild CMA most of whom tolerated goat's milk, donkey's milk was also tolerated by 88% of children (excluding those with immediate symptoms).12 Sow's, Yak's, and Reindeer CMs The milks of these 3 species are probably only locally consumed, and the literature on the topic is non medical. However, an Israeli study suggested allergy to artiodactyls and ruminants such as cow, sheep, and goat to be because of the “kosher epitope.” Patients allergic to CM tested positive to skin prick test with goat's, buffalo's, and deer's milk, but only one-fifth tested positive to sow's milk and 25% to camel's milk.37 Interestingly, although reindeer is also considered a ruminant only partial cross-reactivity exists between cow's and reindeer cow's milks BLG.38 CONCLUSIONS In the opinion of the DRACMA Panel, the types and methods of current studies on the use of other milks for the dietary management of CMA does not warrant a GRADE evaluation. So far, the lack of nutritionally suitable formulations for infant use limits alternative milk prescription before the second year of life, when most children have outgrown their allergy, and when it persists, substituting CM is no longer an issue. However, there was a consensus that: a. In the developed world, other milks can never constitute the treatment of choice for CMA. They may be considered only in the impossibility to use another formula (eHF, SF, HRF, HSF, AAF) for a valid clinical reason. The use of alternative milks remains an option for convenience, religious or economical considerations provided parental guidance is provided. b. The option of an alternative milk rather than formula should always be weighed against allergy, clinical, and nutritional status and expectations on an individual basis. The generic consideration that an alternative milk is a “health food” should not be approved by physicians. c. Goat's, ewe's, and ewe's milks should not be used for the treatment of CMA, as they can expose patients to severe reactions. d. Camel's milk can be considered a valid substitute for children after 2 years. e. Equine milks can be considered as valid CM substitutes, in particular, but not exclusively, for children with delayed-onset CMA. As their availability is limited and they are not used in the food industry, it is probably not economical to adapt them for infant use. However, given their protein quality, appropriately processed commercial products would probably make this protein source suitable for infants with CMA. REFERENCES, SECTION 15 1 El-Agamy EI The challenge of cow milk protein allergy. Small Ruminant Research. 2007;68:64–72 2 El-Agamy EI Nawar MA Nutritive and immunological values of camel milk: a comparative study with milk of other species. In: Second International Camelid Conference: Agroeconomics of Camelid Farming, Almaty, Kazakhstan, 8–12 September 2000, 33–45. 3 Spitzauer S Allergy to mammalian proteins: at the borderline between foreign and self? Int Arch Allergy Immunol. 1999;120:259–269 10640909 4 Swiss Institute of Bioinformatics. ExPASy Proteomics Server, binary alignment (SIM + LANVIEW). Retrieved from http://www.expasy.org/ Accessed July 20, 2009. 5 Restani P Ballabio C Di Lorenzo C Tripodi S Fiocchi A Molecular aspects of milk allergens and their role in clinical events. Anal Bioanal Chem 2009 [Epub ahead of print] 6 Grant C Rotherham B Sharpe S Scragg R Thompson J Randomized, double-blind comparison of growth in infants receiving goat milk formula versus cow milk infant formula. J Paediatr Child Health. 2005;41:564–568 16398838 7 Bellioni-Businco B Paganelli R Lucenti P Giampietro PG Perborn H Businco L Allergenicity of goat's milk in children with cow's milk allergy. J Allergy Clin Immunol. 1999;103:1191–1194 10359905 8 Bevilacqua C Martin P Chándal C Goat's milk of defective alphas1-casein genotype decreases intestinal and systemic sensitization to beta-lactoglobulin in guinea pigs. J Dairy Res. 2001;68:217–227 11504386 9 Lara-Villoslada F Olivares M Jiménez J Boza J Xaus J Goat milk is less immunogenic than cow milk in a murine model of atopy. J Pediatr Gastroenterol Nutr. 2004;39:354–360 15448424 10 Freund G Proceeding of the meeting Interest nutritionnel et dietetique dulait de chevre Niort, France, November 7, 1996, INRA Paris France. 11 Restani P Beretta B Fiocchi A Ballabio C Galli CL Cross-reactivity between mammalian proteins. Ann Allergy, Asthma & Immunology. 2002;89:S11–S15 12 Vita D Passalacqua G Di Pasquale G Caminiti L Crisafulli G Rulli I Pajno GB Ass's milk in children with atopic dermatitis and cow's milk allergy: crossover comparison with goat's milk. Pediatr Allergy Immunol. 2007;18:594–598 18001430 13 Ah-Leung S Bernard H Bidat E Paty E Rance F Scheinmann P Allergy to goat and sheep milk without allergy to cow's milk. Allergy. 2006;61:1358–1365 17002714 14 Bidat E Rancé F Baranès T Goulamhoussen S Goat's milk and sheep's milk allergies in children in the absence of cow's milk allergy. Rev Fr Allergol Immunol Clin. 2003;43:273–277 15 Alvarez MJ Lombardero M IgE-mediated anaphylaxis to sheep's and goat's milk. Allergy. 2002;57:1091–1092 12359023 16 Tavares B Pereira C Rodrigues F Loureiro G Chieira C Goat's milk allergy. Allergol Immunopathol (Madr). 2007;35:113–116 17594876 17 Pessler F Nejat M Anaphylactic reaction to goat's milk in a cow's milk-allergic infant. Pediatr Allergy Immunol. 2004;15:183–185 15059197 18 Calvani M Jr Alessandri C Anaphylaxis to sheep's milk cheese in a child unaffected by cow's milk protein allergy. Eur J Pediatr. 1998;157:17–19 9461357 19 Martins P Borrego LM Pires G Pinto PL Afonso AR Rosado-Pinto J Sheep and goat's milk allergy: a case study. Allergy. 2005;60:129–130 15575947 20 Fiocchi A Decet E Mirri GP Travaini M Riva E Allergy to ewe's milk can evolve into allergy to cow's milk. Allergy. 1999;54:401–402 10371103 21 Muraro MA Giampietro PG Galli E Soy formulas and non bovine milk. Ann Allergy Asthma Immunol. 2002;89(Suppl 1):97–101 12487214 22 McDonald A Which formula in cow's milk protein intolerance? The dietitian's dilemma. Eur J of Clin Nutr. 1995;49:S56–S63 8647064 23 Razafindrakoto O Ravelomanana N Rasolofo A Goat's milk as a substitute for cow's milk in undernourished children: a randomized double-blind clinical trial. Pediatrics. 1994;94:65–69 8008540 24 Al-Hreashy FA Tamim HM Al-Baz N Al-Kharji NH Al-Amer A Al-Ajmi H Eldemerdash AA Patterns of breastfeeding practice during the first 6 months of life in Saudi Arabia. Saudi Med J. 2008;29:427–431 18327373 25 Zhao XX Milk production of Chinese Bactrian camel (Camelus bactrianus). Proceedings of the Workshop on Dromedaries and Camels, Milking Animals, Nouakchott Mauritania, October 24–26, 1994, pp. 101–105 26 Al-Awadi FM Srikumar TS Trace elements and their distribution in protein fractions of camel milk in comparison to other commonly consumed milks. J Dairy Res. 2001;68:463–469 11694048 27 Restani P Gaiaschi A Plebani A Beretta B Cavagni G Cross reactivity between milk proteins from different animal species. Clin Exp Allergy. 1999;29:997–1004 10383602 28 Shabo Y Barzel R Margoulis M Yagil R Camel milk for food allergies in children. Isr Med Assoc J. 2005;7:796–798 16382703 29 Docena G Rozenfeld P Fernández R Fossati CA Evaluation of the residual antigenicity and allergenicity of cow's milk substitutes by in vitro tests. Allergy. 2002;57:83–91 11929409 30 Pagliarini F Solaroli G Peri C Chemical and physical characteristics mare's milk. Ital J Food Sci. 1993;5:323–332 31 Solaroli G Pagliarini E Peri C Composition and nutritional quality of mare's milk. Ital J Food Sci. 1993;5:3–10 32 Businco L Giampietro PG Lucenti P Allergenicity of mare's milk in children with cow's milk allergy. J Allergy Clin Immunol. 2000;105:1031–1034 10808187 33 Iacono G Carroccio A Cavataio F Montalto G Soresi M Balsamo V Use of ass's milk in multiple food allergy. J Pediatr Gastroenterol Nutr. 1992;14:177–181 1593372 34 Carroccio A Cavataio F Montalto G Intolerance to hydrolysed cow's milk proteins in infants: clinical characteristics and dietary treatment. Clin Exp Allergy. 2000;30:1597–1603 11069569 35 Monti G Bertino E Muratore MC Coscia A Cresi F Silvestro L Efficacy of donkey's milk in treating highly problematic cow's milk allergic children: an in vivo and in vitro study. Pediatr Allergy Immunol. 2007;18:258–264 17433003 36 Alessandri C Mari A Efficacy of donkey's milk in treating cow's milk allergic children: major concerns. Pediatr Allergy Immunol. 2007;18:625–626 18001434 37 Katz Y Goldberg MR Zadik-Mnuhin G Leshno M Heyman E Cross-sensitization between milk proteins: reactivity to a “kosher” epitope? Isr Med Assoc J. 2008;10:85–88 18300584 38 Suutari TJ Valkonen KH Karttunen TJ Ehn BM Ekstrand B Bengtsson U IgE cross reactivity between reindeer and bovine milk beta-lactoglobulins in cow's milk allergic patients. J Investig Allergol Clin Immunol. 2006;16:296–302 SECTION 16: NUTRITIONAL CONSIDERATIONS IN CMA TREATMENT Overview In previous sections it has been reported that diet therapy for the long-term management of CMA is fraught with nutritional risks. In this section such risks are re-evaluated through the few studies addressing these clinical issues. The major risk is rickets as a result of dietary manipulation. Poor growth has been found in children with CMA, possibly linked to the nutritional efficiency of substitute formula. Some nutritional aspects of the use of cow's milk hydrolysates and (to a lesser extent) soy formula in the first semester has been nutritionally evaluated in prevention studies, where the former have been found associated with normal growth. Few data are available for amino acid formula and no data for rice hydrolysates during the first months, but their use in the second semester onwards seem nutritionally warranted. Composition tables of the special formula are hereunder provided. The dietary modulation of nutritional factors through pre, pro- and synbiotic preparations and polyunsaturated fatty acids (PUFA) represent a novel research hypothesis and a challenge for nutritionists and pediatric allergists. The modulation of the immune system using functional foods is a promising research hypothesis in the attempt to induce a tolerogenic immune environment. Some studies suggested a positive effect of probiotic interventions on atopic dermatitis, but meta-analyses have failed to confirm it. Another area of potential nutraceutical interest is the use of traditional Chinese herbal remedies. Introduction The use of diet therapy for the long-term management of CMA is fraught with nutritional risk. The growth and biochemical parameters of children with CMA should approach the standards of reference. Unfortunately, very few studies address these clinical issues. There is also an interest in the dietary modulation of nutritional factors through the use of pre, pro-, symbiotic preparations and polyunsaturated fatty acids (PUFA) representing a new research hypothesis for both nutritionists and pediatric allergists. Meeting Nutrition Needs Children with CMA have been described with vitamin D deficiency rickets as a result of dietary manipulation,1,2 and the whole nutritional equilibrium of such children is at issue. Poor growth has been found in children with atopic dermatitis in the first years3 and in children with CMA at 6 months.4 Among the causes of growth limitation, the nutritional efficiency of substitute formula has been investigated.5 Formulae designed for infant nutrition when human milk is not available should “achieve both an acceptable growth rate and blood proteins and amino acid profile that approach a reference standard, presumably that based on metabolic data from breast-fed infants.”6 Investigations about the nutritional adequacy of special formula used for CMA treatment have been known for a long time.7 Earlier studies indicated lower values of body mass index and higher blood urea nitrogen by infants fed extensively hydrolyzed formula (eHF), with differences in plasma amino acidograms showing higher essential amino acids (AA)/total AA ratio in soy formula (SF)- and eHF-fed compared with breast-fed infants. Also, a lower branch-chain AA/essential AA ratio was reported.8 More recently, clinical trials have investigated growth in infants with CMA fed different formula (eHF or SF), up to 48 months of age,9 suggesting that in general nutritional adequacy is guaranteed by these formula. Differences in the increase of standardized growth indices (weight-for-age, length-for-age, and weight-for-length z-scores) in infants with CMA have been found suggesting that infants fed hydrolyzed products (eHF, HRF) show a trend toward higher weight-for-age z-score increments than children fed SF in the 6 to 12 months period.10 Not only the total amount, but protein quality seems to be important for both symptomatic treatment and growth. Thus, the use of cow's milk or rice hydrolysates has not been explored during the first months, when breast- or formula-milk represent the only food source,11 but their use in the second semester onwards may have decreased local inflammatory responses, positively affecting the absorption of nutrients from the other solid foods. This is only an example of the potentially complex effects of substitute formula in nutrition of children with CMA. Table 16-1 reports the most relevant nutritional parameters to be assessed in individual formula by the pediatrician when planning a special diet for CMA treatment. The nutritional parameters of the special formula currently available in the world are reported in the repository found on the WAO website. TABLE 16-1 Nutritional Parameters to Be Assessed In Individual Formula By the Pediatrician When Planning a Special Diet In CMA Prebiotics, Probiotics, and Synbiotics for CMA Treatment The modulation of the immune system using functional foods is a promising research hypothesis in the attempt to induce a tolerogenic immune environment. To skew the immune response toward a more TH1/Treg polarized phenotype after the onset of CMA remains a clinical possibility for the future when we will have the know-how and the control over desensitization to ultimately induce oral tolerance. Although it is widely believed that intervention should begin as early in life as possible, several studies have shown that successful treatment of atopic dermatitis in children above the age of 2 may be possible further suggesting that the immune system is amenable to manipulation through functional foods later in childhood.12–14 In contrast, several other studies and some metanalysises failed to show a positive effect of a probiotic intervention on atopic dermatitis.15,16 Currently, we may only conclude, with a review of the evidence, that “more RCTs need to be conducted to elucidate whether probiotics are useful for the treatment of AD.”17 Polyunsaturated Fatty Acids (PUFAs) for the Treatment of CMA Clinical trials focusing on the effect of gamma-linolenic acid and n-3 long-chain polyunsaturated fatty acids in patients suffering from atopic eczema have not lived to their expectation.18 Essential fatty acids (EFA) promote the renewal of the protective hydrolipidic film layer of the skin. An altered EFA metabolism has been associated with the pathogenesis of atopic dermatitis (AD). Reduced levels of gamma linolenic acid (18:3 n-6) and of dihomo-gamma-linolenic acid (20:3 n-6) have been found in the plasma phospholipids and in the erythrocyte membranes of patients with AD, supporting the hypothesis of a deficiency in delta-6 desaturase activity. The 20:3 n-6 chain is the direct precursor of prostaglandin (PGE1) and probably competes with PGE2, a potent inflammatory mediator derived from arachidonic acid. Both PGE1 and PGE2 may also be involved in more complex T-cell mediated regulatory mechanisms. In this context, treatment with gamma-linolenic acid has been successfully attempted19 but has also been called into question.20 More recently, on the basis of new studies concerning the possible curative properties of PUFA supplements in allergic disease,21 the question has become topical again. This panel is of the opinion that the use of PUFA to treat CMA could be attempted in some well-defined cases but that there is a need for more and comprehensive (pre-clinical data for widespread recommendation). Chinese Herbal Medicines Complementary and alternative medicine has raised interest in the field of allergic asthma treatment. Additional scientific evidence for the treatment of food allergy is also accruing.22,23 Studies are in the preclinical stage to treat food allergy with a traditional Chinese herbal remedy.24–26 Two different formula have been tested. The FA herbal formula (FAHF)-1 and FAHF-2 mix 9 to11 different herbs. Traditionally, these herbs have been prescribed for gastrointestinal disorders such as diarrhea and vomiting and therefore ought to be effective in food allergy. The safety of these compounds has been investigated in a phase I clinical trial in humans.27 REFERENCES, SECTION 16 1 Levy Y Davidovits M Nutritional rickets in children with cows' milk allergy: calcium deficiency or vitamin D deficiency? Pediatr Allergy Immunol. 2005;16:553 16176406 2 Fox AT Du Toit G Lang A Lack G Food allergy as a risk factor for nutritional rickets. Pediatr Allergy Immunol. 2004;15:566–569 15610373 3 Patel L Clayton PE Addison GM Price DA David TJ Linear growth in prepubertal children with atopic dermatitis. Arch Dis Child. 1998;79:169–172 9797602 4 Agostoni C Fiocchi A Riva E Terracciano L Sarratud T Growth of infants with IgE-mediated cow's milk allergy fed different formulae in the complementary feeding period. Pediatr Allergy Immunol. 2007;18:599–606 17561927 5 Isolauri E Sutas Y Salo MK Isosomppi R Kaila M Elimination diet in cow's milk allergy: risk for impaired growth in young children. J Pediatr. 1998;132:1004–1009 9627594 6 Atkinson SA Feeding the normal term infant: human milk and formulaIn: Sinclair JC Bracken MB , eds. Effective Care of the Newborn Infant. Oxford: Oxford University Press; 1992:79–92 7 Giovannini M Fiocchi A Agostoni C Riva E Nutrition in infancy and childhood In: Wuthrich B Ortolani C , eds. Highlights in Food Allergy - Monogr Allergy 32, Basel:Karger, 1996;25–29 8 Giovannini M Agostoni C Fiocchi A Bellù R Trojan S Riva E Antigen-reduced infant formulae versus human milk: growth and metabolic parameters in the first 6 months of life. J Am Coll Nutr. 1994;13:357–363 7963141 9 Seppo L Korpela R Lonnerdal B A follow-up study of nutrient intake, nutritional status, and growth in infants with cow milk allergy fed either a soy formula or an extensively hydrolyzed whey formula. Am J Clin Nutr. 2005;82:140–145 16002812 10 Agostoni C Grandi F Scaglioni S Gianni ML Torcoletti M Growth pattern of breastfed and nonbreastfed infants with atopic dermatitis in the first year of life. Pediatrics. 2000;106:73 11 Vandenplas Y Hauser B Blecker U The nutritional value of a whey hydrolysate formula compared with a whey-predominant formula in healthy infants. J Pediatr Gastroenterol Nutr. 1993;17:92–96 8350218 12 Isolauri E Arvola T Sütas Y Moilanen E Salminen S Probiotics in the management of atopic eczema. Clin Exp Allergy. 2000;30:1604–1610 11069570 13 Rosenfeldt V Effect of prebiotic Lactobacillus strains in children with atopic dermatitis. J Allergy Clin Immunol. 2003;111:389–395 12589361 14 Passeron T Prebiotics and synbiotics: two promising approaches for the treatment of atopic dermatitis in children above 2 years. Allergy. 2006;61:431–437 16512804 15 Sistek D Is the effect of probiotics on atopic dermatitis confined to food sensitized children? Clin Exp Allergy. 2006;36:629–633 16650048 16 Brouwer ML No effects of probiotics on atopic dermatitis syndrome in infancy: a randomized placebo-controlled trial. Clin Exp Allergy. 2006;36:899–906 16839405 17 Betsi GI Papadavid E Falagas ME Probiotics for the treatment or prevention of atopic dermatitis: a review of the evidence from randomized controlled trials. Am J Clin Dermatol. 2008;9:93–103 18284263 18 Horrobin DF Fatty acid metabolism in health and disease: the role of delta-6 desaturase. Am J Clin Nutr. 1993;52:732S–735S 8386433 19 Wright S Burton JL Oral evening-primrose-seed oil improves atopic eczema. Lancet. 1982;2:1120–1122 6128449 20 Berth-Jones J Graham-Brown RAC Placebo-controlled trial of essential fatty acid supplementation in atopic dermatitis. Lancet. 1993;341:1557–1560 8099640 21 Calder PC Fatty acids and lymphocyte functions. Br J Nutr. 2002;47 Suppl 2):S60–S61 22 Li XM Brown L Efficacy and mechanisms of action of traditional Chinese medicines for treating asthma and allergy. J Allergy Clin Immunol. 2009;123:297–306 19203653 23 Li XM Traditional Chinese herbal remedies for asthma and food allergy. J Allergy Clin Immunol. 2007;120:25–31 17560638 24 Li XM Food Allergy Herbal Formula-1 (FAHF-1) blocks peanut-induced anaphylaxis in a murine model. J Allergy Clin Immunol. 2001;108:639–646 11590394 25 Srivastava KD Kattan JD Zou ZM Li JH Zhang L The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. J Allergy Clin Immunol. 2005;115:171–178 15637565 26 Qu C Induction of tolerance after establishment of peanut allergy by the food allergy herbal formula-2 is associated with up-regulation of interferon-gamma. Clin Exp Allergy. 2007;37:846–855 17517098 27 Chehade M IgE and non-IgE-mediated food allergy: treatment in 2007. Curr Opin Allergy Clin Immunol. 2007;7:264–268 17489046 SECTION 17: CHOOSING THE APPROPRIATE SUBSTITUTE FORMULA IN DIFFERENT PRESENTATIONS The DRACMA recommendations about the most appropriate choice of the substitute formula when breastfeeding is not available (7.1–7.5) are all conditional, i.e. they should be interpreted with special attention to patient's preferences, individual clinical circumstances and cost. It is not possible for any guideline to take into consideration all of the often compelling individual clinical circumstances or patient characteristics because recommendations in guidelines are for typical patients. The DRACMA guideline panel made recommendations for use of substitute formulas specifically for patients with IgE-mediated CMA. However, the choice of the formula may be different for patients with non IgE-mediated CMA or in patients with other specific presentations such as allergic eosinophilic oesophagitis or food protein-induced enterocolitis syndrome (FPIES). The use of formulas in patients with these conditions will be addressed in the future updates of the DRACMA guidelines. Against this background, table 17 reports a quick reference guide to the recommendations. TABLE 17-1 Reference Guide to the Recommendations SECTION 18: GRADE RECOMMENDATIONS ON IMMUNOTHERAPY FOR CMA Should oral immunotherapy be used in patients with cow's milk allergy? Population: patients with cow's milk allergy (CMA) Intervention: immunotherapy (specific oral tolerance induction) and elimination diet Comparison: usual care and elimination diet Outcomes, Oral Immunotherapy Summary of Findings We did not find any systematic review of immunotherapy for CMA. We found 3 randomized trials1–3 and 3 observational studies4–6 that examined specific tolerance induction to cow's milk in children with cow's milk allergy. Two randomized trials1,3 included children (mean age 9 years; range 5–17) with CMA confirmed with a blinded placebo-controlled food challenge test. One study used oral immunotherapy with whole milk for 12 months in children with a history of at least 1 severe allergic reaction and milk-specific IgE levels greater than 85 kUA/L (assessed with Phadia CAP System FEIA) who were not able to tolerate more than 0.8 mL of milk during the challenge test.1 The other study used preparation of dry nonfat powdered milk for 6 months in children with a history of IgE-mediated milk allergy (no history of anaphylaxis requiring hospitalization, intubation, or severe asthma), a positive skin prick test (SPT) result to milk extract or milk-specific IgE level greater than 0.35 kU/L (assessed with Phadia CAP System FEIA) who were not able to tolerate more than 75 mL of milk during the challenge test.3 We used information from these studies to prepare summaries of evidence for immunotherapy in patients with CMA. A third study included children aged 2.2 years (range: 1–6.5) of whom 90% had atopic eczema and were able to tolerate at least 60 mL of milk; diagnosis was established based on the results of food challenge test, SPT or serum milk-specific IgE determination2. We did not combine the results of this study with the results of the other 2 studies, because the diagnosis of CMA in included children was uncertain. Three observational studies reported by the same group of investigators used oral milk immunotherapy in children aged 3 to 14 years with CMA confirmed by a blinded placebo-controlled food challenge test.4–6 No study measured the quality of life of children or their parents. Benefits Two randomized trials showed that the probability of tolerating at least 150 mL of milk and eat any dairy and milk-containing products) was 17 times higher (95% CI: 2.4–123.2) in children receiving immunotherapy compared with placebo or no immunotherapy.1,3 The probability of achieving partial tolerance (being able to tolerate between 5 and 150 mL of milk) was also higher with immunotherapy (relative benefit: 20.7; 95% CI: 2.9–147.0). These effects were similar in observational studies (the relative benefit of achieving full tolerance was 8.7; 95% CI: 1.9–40.6).4–6 One study in children with atopic eczema who initially were able to tolerate up to 60 mL of milk showed a very modest effect of immunotherapy (relative benefit of achieving full tolerance: 1.44; 95% CI: 0.98–2.11)2. Downsides Local symptoms were the most frequent adverse effects of immunotherapy occurring during the administration of 16% of doses (rate ratio: 4.5; 95% CI: 3.9–5.2). Lip and/or mouth pruritus was more than 800 times more frequent in children receiving immunotherapy than in children not receiving it (rate ratio: 880.1; 95% CI: 54.6–14, 185.8). Other adverse effects were also more frequent in children receiving immunotherapy included the after: perioral urticaria (rate ratio: 9.9; 95% CI: 4.3–22.9), generalized erythema or urticaria (rate ratio: 16.8; 95% CI: 4.5–63.4), abdominal pain and/or vomiting (rate ratio: 25.8; 95% CI: 5.9–113.3), rhinoconjunctivitis (rate ratio: 15.5 95% CI: 3.7–64.7), mild laryngospasm (rate ratio: 40.9; 95% CI: 2.5–671.8), mild bronchospasm (rate ratio: 11.0; 95% CI: 0.97–124.0), the need for oral glucocorticosteroids (rate ratio: 50.9; 95% CI: 7.0–368.7), need for nebulised epinephrine (rate ratio: 62.8; 95% CI: 3.8–1032.8), and the need for intramuscular epinephrine (rate ratio: 6.4; 95% CI: 1.2–34.1). Severe reactions occur rarely, however, once they develop they may pose a serious problem, since they may occur at home. Immunotherapy for CMA requires long-term compliance and a significant commitment of the child's family, availability of medical support 24-hour a day, and resources to treat adverse effects immediately. Other Considerations The immunologic mechanism of immunotherapy for CMA is not known. It has not been established whether this is a true tolerance induction with a long-lasting effect on IgE production or a desensitization with a temporary reduction of milk-specific IgE levels (similar to tolerating antibiotics or aspirin). Long-term observations are needed to elucidate this and estimate the safety of immunotherapy for CMA. Conclusions The net clinical benefit of oral immunotherapy for CMA is very uncertain. Potentially large benefit seems counter-balanced by frequent and serious adverse reactions. There is a need for rigorously designed and executed randomized trials of immunotherapy in children and adults with cow's milk allergy that measure and properly report7,8 patient-important outcomes and adverse effects. Further research, if done, will have important impact on this recommendation. Clinical Recommendation In patients with IgE-mediated CMA, we recommend that clinicians do not administer oral immunotherapy with cow's milk, unless this is done in the context of formal clinical research (strong recommendation/very low quality evidence). Underlying Values and Preferences This recommendation places a relatively high value on avoiding serious adverse effects of oral immunotherapy, and a relatively low value on the increased probability of desensitization to milk. FIGURE 18-1 PRISMA diagram, immunotherapy. Should immunotherapy be used in patients with cow's milk allergy?. REFERENCES, SECTION 18 1 Longo G Barbi E Berti I Meneghetti R Pittalis A Ronfani L Ventura A Specific oral tolerance induction in children with very severe cow's milk-induced reactions. J Allergy Clin Immunol. 2008;121:343–347 18158176 2 Morisset M Moneret-Vautrin DA Guenard L Cuny JM Frentz P Oral desensitization in children with milk and egg allergies obtains recovery in a significant proportion of cases. A randomized study in 60 children with cow's milk allergy and 90 children with egg allergy. Eur Ann Allergy Clin Immunol. 2007;39:12–19 17375736 3 Skripak JM Nash SD Rowley H Brereton NH Oh S A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy. J Allergy Clin Immunol. 2008;122:1154–1160 18951617 4 Patriarca G Buonomo A Roncallo C Del NM Pollastrini E Oral desensitization in cow milk allergy: immunological findings. Int J Immunopathol Pharmacol. 2002;15:53–58 12593788 5 Patriarca G Nucera E Pollastrini E Roncallo C De PT Oral specific desensitization in food-allergic children. Digestive Diseases Sci. 2007;52:1662–1672 6 Patriarca G Schiavino D Nucera E Schinco G Milani A Gasbarrini GB Food allergy in children: results of a standardized protocol for oral desensitization. Hepato-Gastroenterol. 1998;45:52–58 7 Gagnier JJ Boon H Rochon P Moher D Barnes J Bombardier C Reporting randomized, controlled trials of herbal interventions: an elaborated CONSORT statement. Ann Intern Med. 2006;144:364–367 16520478 8 Ioannidis JP Evans SJ Gotzsche PC O'Neill RT Altman DG Schulz K Moher D Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med. 2004;141:781–788 15545678 SECTION 19: UNMET NEEDS, RECOMMENDATIONS FOR RESEARCH, IMPLEMENTATION OF DRACMA In the opinion of this panel, research into new formula and diagnostic tools is entering a new phase with the advent of international initiatives to promote the growth of translational research bringing to the average pediatrician and practitioner a like the benefits of ten years of CMA research as synthesized in the present document. However, much work remains to be done and many multidisciplinary approaches await the exploration of an emergent international field in allergy medicine. The present section offers in outline some relevant questions for future discussion. This panel believes that the after are important areas for the development of research in CMA. Epidemiology An assessment of symptomatic, clinician-diagnosed, and self-reported prevalence of CMA and its time-trends worldwide, reproducible over time, similar to the International Study of Asthma and Allergies in Childhood (ISAAC)1 More studies on the prevalence of self-reported CMA (relevant for the food industry, the tertiary level of care and other stakeholders) versus challenge-confirmed CMA (relevant for patients and clinicians) Studies on prevalence of challenge-confirmed CMA in southern Europe, the U.S., the Middle East, the Asian, African, and Australian regions based on shared challenge methods. These studies should aim at clarifying the geographical trends of CMA Birth cohorts studies carried out outside the European context Studies expressly addressing the prevalence of non-IgE-mediated CMA based on shared challenge procedures Repeated cross-sectional or birth cohort studies aimed at clarifying the time trends of CMA Studies on the prevalence of CMA in adulthood Genetics Family clustering of food and respiratory allergies suggests a genetic basis for the disease The specific genetic study of CMA remains largely terra incognita The disease genotypes are still unknown The prevalence of susceptibility genes and their distribution across various populations remains unspecified Even the clinical impact of family history is still unexplored The genetic basis of the variability in individual responses to CM would be an important breakthrough Allergens Diagnostic and prognostic values of the sensitization to each specific CM allergen (mainly Bos d 4, Bos d 5, Bos d 6, Bos d 7) Sensitization patterns versus single epitopes and their diagnostic and prognostic values Molecular studies of cross-reactivity Mechanisms Development of animal models of CMA Basic immunology of the innate and adaptive immune response to ingested CM allergens The whole area of CD4+ CD25+ T regulatory cells remains to be investigated in the context of CMA Whether CD4+ CD25+ Foxp3+ T regulatory cells can be harnessed for immunotherapy remains to be investigated Role of exposure to CM allergens in the development of allergy Role of exposure to CM allergens in the development of tolerance Clinical Presentations Identification of patient profiles (disease pehnotypes) in CMA CMA in adulthood Studies on QoL of children with CMA Comorbidities in CMA and cognate diseases Role/impact/interactions in cognate conditions such as infantile colic, gastro-esophageal reflux disease, constipation, etc Role/impact/interactions in other inflammatory conditions such as inflammatory bowel diseases Diagnosis Accuracy of the atopy patch test in non-IgE mediated CMA Proteomics (component-resolved diagnosis and microarray technologies) and their value in CMA Diagnostic markers for non-IgE-mediated CMA Comparative studies between different challenge protocols Assessing the economical consequences of a positive or negative challenge Studies on the risks of diagnostic challenge in office settings Studies on eliciting thresholds for cow's milk allergen Natural History Prospective assessment of tolerance to cow's milk through periodic oral challenge procedures Natural history of non-IgE-mediated CMA Natural history of the different CMA phenotypes, incorporating risk factors for longer duration of disease Formulae Extensively hydrolyzed versus soy or hydrolyzed rice formula comparative studies Soy and hydrolyzed rice formula comparative studies Amino acid formula studies Extensive hydrolysate studies Amino acid-based formula versus soy formula or rice hydrolysate comparative studies Rice hydrolysate in non IgE-mediated CMA Studies on growth and nutritional indices in infants less than 6 months fed vegetable-based formula Comparative studies of the palatabilty and acceptability of various formula in infants and children with CMA Studies of other animals' milks Detailed proteomic analysis: insight into its hypoallergenicity Impact of dietary regimen on the duration of CMA Epidemiological and clinical studies on compliance to dietetic advice Induction of Tolerance Strategies to induce tolerance development in children with CMA Identification of CMA phenotypes with high probability to respond to SOTI Probiotic supplementation in CMA treatment Immunotherapy (anti-IgE antibody therapy) for CMA Recommendation for the Implementation of the DRACMA Guidelines: Periodical Update of DRACMA Special attention must be given to overcoming barriers to the implementation of CMA management programs in developing countries where resources are limited. DRACMA publication: WAO Journal, April 2010 Milan Meeting proceedings: JACI 2010 GLORIA educational modules World allergy societies endorsement and input sought World sister societies endorsement and input sought DRACMA symposia during allergy and nutrition society meetings Outreach toward patient organizations Creation of an international bureau for dissemination and update REFERENCE, SECTION 19 1 ISAAC Phase Three Study Group Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368:733–743 16935684

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Guidelines for the diagnosis and management of cow's milk protein allergy in infants.

David Hill, A P Oranje, Martin Brueton … (2007)

Our aim was to develop guidance for general paediatricians and primary care physicians in diagnosing and managing cow's milk protein allergy in infants. The guidelines were developed by discussion based on existing national recommendations and standards, clinical experience and, whenever possible, evidence from the literature. Separate algorithms cover breast-fed and formula-fed infants. The recommendations emphasise the importance of comprehensive history taking and careful physical examination. Patients with severe symptoms need to be referred to a specialist. Elimination of cow's milk protein from the infant's or mother's diet and challenges are the gold standard for diagnosis. This guidance is intended as a basis for local discussion, implementation and prospective evaluation. The algorithms should be regularly assessed using clinical audit standards. Once validated, the diagnostic framework could provide a standardised approach in epidemiological and therapeutic studies.

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A workshop report on the development of the Cow's Milk-related Symptom Score awareness tool for young children.

Yvan Vandenplas, Christophe Dupont, Philippe Eigenmann … (2015)

Clinicians with expertise in managing children with gastrointestinal problems and/or atopic diseases attended a workshop in Brussels in September 2014 to review the literature and determine whether a clinical score derived from symptoms associated with the ingestion of cow's milk proteins could help primary healthcare providers. The Cow's Milk-related Symptom Score (CoMiSS), which considers general manifestations, dermatological, gastrointestinal and respiratory symptoms, was developed as an awareness tool for cow's milk-related symptoms. It can also be used to evaluate and quantify the evolution of symptoms during therapeutic interventions, but does not diagnose cow's milk protein allergy and does not replace a food challenge. Its usefulness needs to be evaluated by a prospective randomised study.

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Author and article information

Journal

Journal ID (nlm-ta): BMJ Open

Journal ID (iso-abbrev): BMJ Open

Journal ID (hwp): bmjopen

Journal ID (publisher-id): bmjopen

Title: BMJ Open

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2044-6055

Publication date Collection: 2018

Publication date (Electronic): 17 May 2018

Volume: 8

Issue: 5

Electronic Location Identifier: e019968

Affiliations

[1 ] Kidz Health Castle, UZ Brussel, Vrije Universiteit Brussel , Brussels, Belgium

[2 ] Cytel Software Corp , Cambridge, Massachusetts, USA

[3 ] Hôpital Necker-Enfants Malades, Université de Paris Descartes , Paris, France

[4 ] Clinique Pédiatrique Saint Antoine, Hôpital Saint Vincent de Paul, Groupement des Hôpitaux de l’Institut Catholique de Lille , Lille, France

[5 ] departmentPaediatric Allergy Unit , University Hospitals of Geneva , Geneva, Switzerland

[6 ] departmentDepartment of Paediatrics , Hans Christian Andersen Children’s Hospital, Odense University Hospital , Odense, Denmark

[7 ] Children’s Hospital, University of Helsinki and Helsinki University Central Hospital , Helsinki, Finland

[8 ] departmentPaediatric Gastroenterology and Hepatology Unit , La Fe University Hospital , Valencia, Spain

[9 ] Great Ormond Street Hospital for Children , London, UK

[10 ] Katholieke Universiteit Leuven , Leuven, Belgium

[11 ] departmentDepartment of Paediatrics , The Medical University of Warsaw , Warsaw, Poland

[12 ] departmentDepartment of Paediatrics , Research Institute, Marien-Hospital , Wezel, Germany

[13 ] Nestle Health Science , Vevey, Switzerland

[14 ] Children’s Hospital Zhejiang, University School of Medicine , Hangzhou, China

Author notes

[Correspondence to ] Dr Yvan Vandenplas; yvan.vandenplas@ 123456uzbrussel.be

Article

Publisher ID: bmjopen-2017-019968

DOI: 10.1136/bmjopen-2017-019968

PMC ID: 5961578

PubMed ID: 29773698

SO-VID: c9124ed2-5e58-40d4-b22e-989309f0a39b

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This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

History

Date received : 11 October 2017

Date revision received : 26 February 2018

Date accepted : 07 March 2018

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ScienceOpen disciplines: Medicine

Keywords: cow’s milk protein allergy,infant,symptom score,validation,diagnosis,study design

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ScienceOpen disciplines: Medicine

Keywords: cow’s milk protein allergy, infant, symptom score, validation, diagnosis, study design

Protocol for the validation of sensitivity and specificity of the Cow’s Milk-related Symptom Score (CoMiSS) against open food challenge in a single-blinded, prospective, multicentre trial in infants

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World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines

Guidelines for the diagnosis and management of cow's milk protein allergy in infants.

A workshop report on the development of the Cow's Milk-related Symptom Score awareness tool for young children.

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