Alessandro Fiocchi

ICON: Food allergy

Food allergies can result in life-threatening reactions and diminish quality of life. In the last several decades, the prevalence of food allergies has increased in several regions throughout the world. Although more than 170 foods have been identified as being potentially allergenic, a minority of these foods cause the majority of reactions, and common food allergens vary between geographic regions. Treatment of food allergy involves strict avoidance of the trigger food. Medications manage symptoms of disease, but currently, there is no cure for food allergy. In light of the increasing burden of allergic diseases, the American Academy of Allergy, Asthma & Immunology; European Academy of Allergy and Clinical Immunology; World Allergy Organization; and American College of Allergy, Asthma & Immunology have come together to increase the communication of information about allergies and asthma at a global level. Within the framework of this collaboration, termed the International Collaboration in Asthma, Allergy and Immunology, a series of consensus documents called International Consensus ON (ICON) are being developed to serve as an important resource and support physicians in managing different allergic diseases. An author group was formed to describe the natural history, prevalence, diagnosis, and treatment of food allergies in the context of the global community.

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

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 cows 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 Cows 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 cows 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 “cows milk intolerance”) and allergic milk hypersensitivity (or “cows 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 cows milk. REFERENCES, SECTION 1American College of Allergy, Asthma, & Immunology. Food allergy: a practice parameter. Ann Allergy Asthma Immunol. 2006;96(Suppl 2):S1–S68.Mukoyama T, Nishima S, Arita M, Ito S, Urisu A, et al. Guidelines for diagnosis and management of pediatric food allergy in Japan. Allergol Int. 2007;56:349–361.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.Muraro A, Dreborg S, Halken S, Høst A, Niggemann B, et al. 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.Muraro A, Dreborg S, Halken S, Høst A, Niggemann B, et al. 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.Muraro A, Dreborg S, Halken S, Høst A, Niggemann B, Aalberse R, et al. 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.Høst A, Koletzko B, Dreborg S, Muraro A, Wahn U, et al. 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.American Academy of Pediatrics Committee on Nutrition. Hypoallergenic infant formulae. Pediatrics. 2000;106:346–349.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.Johansson SG, Bieber T, Dahl R. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, 2003. J Allergy Clin Immunol. 2004;113:832–836.

A global survey of changing patterns of food allergy burden in children

While food allergies and eczema are among the most common chronic non-communicable diseases in children in many countries worldwide, quality data on the burden of these diseases is lacking, particularly in developing countries. This 2012 survey was performed to collect information on existing data on the global patterns and prevalence of food allergy by surveying all the national member societies of the World Allergy Organization, and some of their neighbouring countries. Data were collected from 89 countries, including published data, and changes in the health care burden of food allergy. More than half of the countries surveyed (52/89) did not have any data on food allergy prevalence. Only 10% (9/89) of countries had accurate food allergy prevalence data, based on oral food challenges (OFC). The remaining countries (23/89) had data largely based on parent-reporting of a food allergy diagnosis or symptoms, which is recognised to overestimate the prevalence of food allergy. Based on more accurate measures, the prevalence of clinical (OFC proven) food allergy in preschool children in developed countries is now as high as 10%. In large and rapidly emerging societies of Asia, such as China, where there are documented increases in food allergy, the prevalence of OFC-proven food allergy is now around 7% in pre-schoolers, comparable to the reported prevalence in European regions. While food allergy appears to be increasing in both developed and developing countries in the last 10–15 years, there is a lack of quality comparative data. This survey also highlights inequities in paediatric allergy services, availability of adrenaline auto-injectors and standardised National Anaphylaxis Action plans. In conclusion, there remains a need to gather more accurate data on the prevalence of food allergy in many developed and developing countries to better anticipate and address the rising community and health service burden of food allergy.

Rare, medium, or well done? The effect of heating and food matrix on food protein allergenicity

Purpose of reviewTo review recent advances in the area of food allergen processing and the effect on protein allergenicity. Recent findingsHeating generally decreases protein allergenicity by destroying conformational epitopes. In peanut and shrimp, heat-induced Maillard reaction (glycation) may increase allergenicity. The majority of milk and egg-allergic children tolerate extensively heated (baked with wheat matrix) milk and egg. Introduction of extensively heated milk and egg proteins is associated with decreasing sizes of skin prick test wheals and increasing serum food-specific IgG4 levels. SummaryHeating and other methods of food processing have different effects on food allergens, even those contained in the same complex food. Structural homology does not reliably predict the effect of processing on allergenicity, and individual food allergens have to be tested. Interactions with other proteins, fat, and carbohydrates in the food matrix are complex and poorly understood. Introduction of extensively heated milk and egg proteins into the diet of allergic children may represent an alternative approach to oral tolerance induction. Better characterization of these aspects of food allergy is critical for elucidation of food protein interactions with the gut-associated lymphoid tissue, the ability to induce IgE sensitization, the potential to trigger hypersensitivity reactions, and different clinical phenotypes of food allergy with regard to severity and persistence.

World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics

BackgroundPrevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10% and reaches 20–30% in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Probiotics have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention.ObjectiveThe World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of probiotics in the prevention of allergy.MethodsWe identified the most relevant clinical questions and performed a systematic review of randomized controlled trials of probiotics for the prevention of allergy. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. We searched for and reviewed the evidence about health effects, patient values and preferences, and resource use (up to November 2014). We followed the GRADE evidence-to-decision framework to develop recommendations.ResultsCurrently available evidence does not indicate that probiotic supplementation reduces the risk of developing allergy in children. However, considering all critical outcomes in this context, the WAO guideline panel determined that there is a likely net benefit from using probiotics resulting primarily from prevention of eczema. The WAO guideline panel suggests: a) using probiotics in pregnant women at high risk for having an allergic child; b) using probiotics in women who breastfeed infants at high risk of developing allergy; and c) using probiotics in infants at high risk of developing allergy. All recommendations are conditional and supported by very low quality evidence.ConclusionsWAO recommendations about probiotic supplementation for prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether to use probiotics in pregnancy and during breastfeeding, and whether to give them to infants.

Oral immunotherapy for IgE-mediated cow's milk allergy: a systematic review and meta-analysis.

Cows milk is a common cause of food allergy in children. Children usually outgrow cows milk allergy by the age of 3–5 years, but some will have persistent symptoms beyond childhood. We performed a systematic review of randomized controlled trials (RCTs) and observational studies to assess the evidence supporting the use of oral immunotherapy in IgE‐mediated cows milk allergy to inform the World Allergy Organization guidelines. Of 1034 screened articles published until May 2011, five RCTs and five observational studies fulfilled a priori specified inclusion criteria. RCTs including 218 patients showed that oral immunotherapy, compared to elimination diet alone, increased the likelihood of achieving full tolerance of cows milk [relative risk: 10.0 (95% CI: 4.1–24.2)]. Adverse effects of immunotherapy include frequent local symptoms (16% of doses), mild laryngospasm [relative risk: 12.9 (1.7–98.6)], mild asthma [rate ratio: 3.8 (2.9–5.0)], reactions requiring oral glucocorticosteroids [relative risk: 11.3 (2.7–46.5)] or intramuscular epinephrine injection [rate ratio 5.8 (1.6–21.9)]. Results of observational studies were consistent with those of RCTs. Despite the availability of RCTs, the overall low quality of evidence leaves important uncertainty about anticipated effects of immunotherapy due to very serious imprecision of the estimates of effects and the likelihood of publication bias for some of the critical outcomes. A potentially large benefit of oral immunotherapy in patients with cows milk allergy may be counterbalanced by frequent and sometimes serious adverse effects. Additional, larger RCTs measuring all patient‐important outcomes are still needed.

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

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, 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, Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, 1200 Main Street West Hamilton, ON L8N 3Z5, Canada. Enrico Compalati, MD, 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, 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-EhrlichInstitut, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Str. 51-59, D-63225 Langen, Germany.

Cross-reactivity between milk proteins from different animal species

Cows milk allergy is quite frequent in the first years of human life. When breast‐feeding is not possible, a cows milk substitute must be provided for allergic subjects. Different alternatives to cows milk have been suggested as protein sources (soy, hydrolysed proteins, goats milk, etc.), but all these dietetic solutions are not without risks for polyallergic or more sensitive subjects.

Cross-reactivity between mammalian proteins

BACKGROUND Cross-reactivity between food allergens occurs when they share part of their amino acid sequence, or when their three-dimensional molecular structure causes them to have a similar capacity to bind specific antibodies. OBJECTIVES To review data from our laboratory on cross-reactivity between mammalian proteins (milk and meat allergens). METHODS Studies used immunoelectrophoresis (sodium dodecyl sulfate-polyacrylamide gel electrophoresis/polyacrylamide gel electrophoresis and immunoblotting), and animal monoclonal antibodies. RESULTS The findings suggest that animal monoclonal antibodies specific for cows milk proteins are able to recognize the major part of milk proteins from mammals bred in Mediterranean countries (sheep, goat, and buffalo); weak cross-reactivity was observed with milk proteins from mares and donkeys. None of the antibodies used in our studies reacted with proteins from an exotic mammalian species: the camel. Similar cross-reactions were found with human circulating immunoglobulin E from children allergic to milk. With regard to beef allergy, monoclonal antibodies specific for bovine serum albumin cross-reacted only with ovine serum albumin, whereas the number of sera from allergic children able to recognize other mammalian serum albumins depended directly on the closeness of phylogenetic relationship between animal species and inversely on the percent identity with human serum albumin in the main epitopic sequence. CONCLUSION An area of heterogeneity between animal and human species in a critical amino acid sequence (epitope) of an allergen can determine the degree of immunogenic activity.

Grading quality of evidence and strength of recommendations in clinical practice guidelines Part 3 of 3. The GRADE approach to developing recommendations

To cite this article: Brożek JL, Akl EA, Compalati E, Kreis J, Terracciano L, Fiocchi A, Ueffing E, Andrews J, Alonso‐Coello P, Meerpohl JJ, Lang DM, Jaeschke R, Williams JW Jr, Phillips B, Lethaby A, Bossuyt P, Glasziou P, Helfand M, Watine J, Afilalo M, Welch V, Montedori A, Abraha I, Horvath AR, Bousquet J, Guyatt GH, Schünemann HJ, for the GRADE Working Group. Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 3 of 3. The GRADE approach to developing recommendations. Allergy 2011; 66: 588–595.