Luigi Terracciano

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.

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.

Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND Allergic diseases are considered a health burden because of their high and constantly increasing prevalence, high direct and indirect costs, and undesirable effects on quality of life. Probiotics have been suggested as an intervention to prevent allergic diseases. OBJECTIVE We sought to synthesize the evidence supporting use of probiotics for the prevention of allergies and inform World Allergy Organization guidelines on probiotic use. METHODS We performed a systematic review of randomized trials assessing the effects of any probiotic administered to pregnant women, breast-feeding mothers, and/or infants. RESULTS Of 2403 articles published until December 2014 identified in Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, 29 studies fulfilled a priori specified inclusion criteria for the analyses. Probiotics reduced the risk of eczema when used by women during the last trimester of pregnancy (relative risk [RR], 0.71; 95% CI, 0.60-0.84), when used by breast-feeding mothers (RR, 0.57; 95% CI, 0.47-0.69), or when given to infants (RR, 0.80; 95% CI, 0.68-0.94). Evidence did not support an effect on other allergies, nutrition status, or incidence of adverse effects. The certainty in the evidence according to the Grading of Recommendation Assessment Development and Evaluation approach is low or very low because of the risk of bias, inconsistency and imprecision of results, and indirectness of available research. CONCLUSION Probiotics used by pregnant women or breast-feeding mothers and/or given to infants reduced the risk of eczema in infants; however, the certainty in the evidence is low. No effect was observed for the prevention of other allergic conditions.

Perceived food allergy in children in 10 European nations. A randomised telephone survey.

Background: Food allergy is targeted as a public health priority by the European Union Commission. Parental perception of food allergy in their offspring is a proxy measure of the potential demand for allergy medicine services in the paediatric population. Methods: A representative sample of the general population was contacted by a randomised telephone survey in Austria, Belgium, Denmark, Finland, Germany, Greece, Italy, Poland, Slovenia and Switzerland. A standardised questionnaire was administered regarding parentally perceived food allergy reports, symptoms, foods and medical service use by their live-in children. Results: 40,246 adults were polled, yielding data on 8,825 children. Parentally perceived food allergy prevalence was 4.7% (90% CI 4.2–5.2%). The most affected age group was 2- to 3-year olds (7.2%). Single-country incidence ranged between 1.7% (Austria) to 11.7% (Finland). Milk (38.5%), fruits (29.5%), eggs (19.0%) and vegetables (13.5%) were most often implicated, although with significant age-linked variations. Medical treatment was needed by 75.7% of affected children because of a food reaction. This translates into a proxy measure for food allergy prevalence of 3.75%. Skin symptoms were widespread (71.5%), followed by gastrointestinal (27.6%) and respiratory (18.5%) symptoms. Discussion: We provide the first point prevalence of parentally perceived food allergy in the general paediatric population across the European Union. Parental reports confirm the public health significance of adverse reactions to some foods in specified age groups. Our data may inform intervention planning, cost of illness assessments and quality-of-life-enhancing public health measures.

Application of GRADE: Making evidence-based recommendations about diagnostic tests in clinical practice guidelines

BackgroundAccurate diagnosis is a fundamental aspect of appropriate healthcare. However, clinicians need guidance when implementing diagnostic tests given the number of tests available and resource constraints in healthcare. Practitioners of health often feel compelled to implement recommendations in guidelines, including recommendations about the use of diagnostic tests. However, the understanding about diagnostic tests by guideline panels and the methodology for developing recommendations is far from completely explored. Therefore, we evaluated the factors that guideline developers and users need to consider for the development of implementable recommendations about diagnostic tests.MethodsUsing a critical analysis of the process, we present the results of a case study using the Grading of Recommendations Applicability, Development and Evaluation (GRADE) approach to develop a clinical practice guideline for the diagnosis of Cow Milk Allergy with the World Allergy Organization.ResultsTo ensure that guideline panels can develop informed recommendations about diagnostic tests, it appears that more emphasis needs to be placed on group processes, including question formulation, defining patient-important outcomes for diagnostic tests, and summarizing evidence. Explicit consideration of concepts of diagnosis from evidence-based medicine, such as pre-test probability and treatment threshold, is required to facilitate the work of a guideline panel and to formulate implementable recommendations.DiscussionThis case study provides useful guidance for guideline developers and clinicians about what they ought to demand from clinical practice guidelines to facilitate implementation and strengthen confidence in recommendations about diagnostic tests. Applying a structured framework like the GRADE approach with its requirement for transparency in the description of the evidence and factors that influence recommendations facilitates laying out the process and decision factors that are required for the development, interpretation, and implementation of recommendations about diagnostic tests.

Growth of infants with IgE-mediated cow's milk allergy fed different formulas in the complementary feeding period

Observational studies have shown that allergic infants, irrespective of the type of diet, show various degrees of growth depression in the first year of life. We investigated whether the type of milk in the complementary feeding period (6–12 months of age) is associated with differences in the increase of standardized growth indices (weight‐for‐age, WA; length‐for‐age, LA; and weight‐for‐length, WL, z‐scores) in infants with cows milk allergy (CMA). Infants with immunoglobulin E‐mediated CMA breastfed at least 4 months and progressively weaned in the 5‐ to 6‐month period were randomly assigned to three special formulas, a soy formula (n = 32), a casein hydrolysate (n = 31), and a rice hydrolysate (n = 30). A fourth, non‐randomized group was made up by allergic infants still breastfed up to 12 months (n = 32). Groups were compared for WA, LA, and WL z‐scores at 6, 9 and 12 months of age. All groups showed low WA and LA z‐scores at 6 months of age. Infants fed hydrolyzed products showed a trend toward higher WA z‐score increments in the 6‐ to 12‐month period. The use of casein‐ and rice‐based hydrolyzed formulas resulted in higher changes in WA compared with soy formula. Further research should be aimed at optimizing the dietary needs and feeding regimens for infants with CMA.

Use of hydrolysates in the treatment of cow's milk allergy

BACKGROUND Hydrolyzed formulas (HFs) are in general well tolerated by children with cows milk allergy (CMA), although cases of allergic reactions have been reported and residual allergenicity of HF has been demonstrated OBJECTIVE To review the most relevant studies of the HFs for residual allergenicity, tolerance, and safety in the past 20 years. DATA SOURCES AND METHODS MEDLINE searches for the years 1970 to 2001 using the following algorithm (hydrolysate and allergy; food intolerance/allergy; protein hydrolysate). RESULTS The literature confirmed that although some antigenicity remains, HFs are well tolerated by children with CMA. Rice HF has proven safe when tested by double-blind, placebo-controlled food challenge in a study population of 18 children allergic both to cows milk (CM) and soy protein. CONCLUSIONS Absolute avoidance of CM proteins means substitution by soy-, rice-, or amino acid-based formulas. As 8 to 14% of infants allergic to CM react to soy and amino acid-based formulas are expensive, scientific societies recommend the use of formulas based on extensively hydrolyzed CM proteins as first alternatives in children with CMA. Although both soy- and rice-based HFs have now been shown to be safe for these children, further nutritional and clinical studies are needed.

Incremental prognostic factors associated with cow's milk allergy outcomes in infant and child referrals : the Milan Cow's Milk Allergy Cohort study

BACKGROUND The prognosis for many children with cows milk allergy (CMA) is remission within 3 years, and the clinical parameters that predict duration of disease have not been measured incrementally. OBJECTIVE To prospectively determine prognostic predictors of tolerance in a random cohort of referrals using CMA workup outcomes as covariates and tolerance as the status variable in a duration model of CMA. METHODS The 2001-2006 Milan Cows Milk Allergy Cohort (MiCMAC) enrolled children referrals using double-blind, placebo-controlled food challenges (DBPCFCs) as study end points (confirmation of CMA; onset of tolerance). The Cox regression model was used to analyze all clinical factors that contributed to tolerance. Covariates analyzed were skin, gastrointestinal, and respiratory symptoms; history and demographics at presentation; age at diagnosis and DBPCFC outcomes; sensitization (skin and serum) by cows milk protein fractions; sensitization to other food and inhalant allergens; total IgE levels; specific IgE concentrations for cows milk protein fractions, other ingestants, and aeroallergens; and threshold doses at DBPCFC. Sensitization and DBPCFC were performed at 6-month intervals. RESULTS A total of 112 infants were enrolled (mean [SD] age, 13.85 [9.84] months), and 59 achieved tolerance (mean [SD] age when tolerance was achieved, 27.58 [11.81] months). On univariate analysis, asthma and/or rhinitis at presentation was an independent predictor of persistence (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.26-3.82). On multivariate analysis, predictors of persistence were a fresh milk wheal diameter increment of 1 mm (HR, 1.18; 95% CI, 1.07-1.31) and a positive skin prick test result with soy (HR, 6.99; 95% CI, 1.56-31.25). CONCLUSIONS This is the first study, to our knowledge, to identify incremental biological predictors of delayed tolerance to cows milk in children that should be integrated into DBPCFC schedules for CMA in infants.