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      IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper

      research-article
      , MD, PhD a , 1 , , , MD b , 1 , , MD c , 1 , , MD, PhD d , 1 , , MD, PhD e , 1 , , MD, PhD f , 1 , , MD g , 1 , , MD h , 1 , , MD, PhD i , 1 , , MD, PhD j , 1 , , MD, PhD k , 1 , , MD l , 1 , , MD m , 1 , , MD n , 1 , , MD o , , MD p , , MD, PhD q , r , s , t , u , , MD, PhD v , , MBBS w , , MD, PhD x , y , , MD z , , MD aa , , MD, PhD ab , , MD, PhD ac , , MD ad , , MD ae , , MD af , , MD, PhD ag , , MD, PhD ah , , MD ai , , MD aj , , MD ak , , MD, PhD al , , PhD am , , MD, PhD an , , MD, PhD ao , , MD, PhD ap , , MD, PhD aq , , MD ar , , MD as , , MD at , , MD au , , MD av , , MBBS, PHD aw , , MD ax , , MD ay , az , ba , , MD bb , , MD, PhD bc
      The World Allergy Organization Journal
      World Allergy Organization
      IgE, Allergy, In vitro tests, Skin tests, Diagnostic strategies, AAAAI, American Academy of Allergy Asthma and Immunology, ABA, Allergen Bead Array, ACAAI, American College of Allergy Asthma and Immunology, AIT, allergen immunotherapy, AEC, Allergen Exposure Chambers, Anti-IgE, Antibody against IgE, AP, Alkaline Phosphatase, AU/mL, Allergenic Units milliLiter, BAT, Basophil Activation Test, BAU/mL, Biologic Allergenic Units milliLiter, CaFE, Calibrated Fluorescence Enhancement, CBA, Cytometric Bead Array, CCD, Cross-reactive Carbohydrate Determinants, CDER, Center for Drug Evaluation and Research (USA), CL, Chemiluminescence, DBPCFC, Double-Blind Placebo-Controlled Food Challenge, EAACI, European Academy of Allergy and Immunology, EIA, Enzyme Immune Assay, ELISA, Enzyme Linked Immuno Sorbent Analysis, EMEA, European MEdicine Agencies, ENPP-3, EctoNucleotide Pyrophosphatase/Phosphodiesterase 3, FACS, Fluorescence-Activated Cell Sorting, FDA, Food and Drug Administration (U.S. Department of Health and Human Services), FEIA, Fluorescent Enzyme Immunoassays, FcεRI, High affinity IgE receptor, H1, Histamine 1 receptor, H2, Histamine 2 receptor, HPO, Horseradish Peroxidase, IDT, Intradermal Test, IgE, immunoglobulin E, ISAC, Immuno-Solid phase Allergen Chip, IUIS, International Union of Immunological Societies, IVD, in vitro diagnostic tool, kUA/L, kilo Units of Allergen/Liter for allergen-specific IgE antibody assays, LAMP-3, Lysosomal-Associated Membrane Protein, mAb, Monoclonal Antibody, MRGPRX2, Mas-related G protein receptor 2, MBAD, Molecule Based Allergy Diagnostics, NIH, National Institutes of Health (USA), NMBAs, NeuroMuscular Blocking Agents, NPA, Negative Percent Agreement, NSAIDs, Non-Steroidal Anti-Inflammatory Drugs, pNPP, p-Nitrophenylphosphate, PPA, Positive Percent Agreement, PPT, Prick-Prick Test, sIgE, specific IgE, RAST, Radio Allergo Sorbent Test, SCAR, severe cutaneous adverse drug reactions, SPT, Skin prick test, w/v, weight /volume

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          Abstract

          Currently, testing for immunoglobulin E (IgE) sensitization is the cornerstone of diagnostic evaluation in suspected allergic conditions. This review provides a thorough and updated critical appraisal of the most frequently used diagnostic tests, both in vivo and in vitro. It discusses skin tests, challenges, and serological and cellular in vitro tests, and provides an overview of indications, advantages and disadvantages of each in conditions such as respiratory, food, venom, drug, and occupational allergy. Skin prick testing remains the first line approach in most instances; the added value of serum specific IgE to whole allergen extracts or components, as well as the role of basophil activation tests, is evaluated. Unproven, non-validated, diagnostic tests are also discussed. Throughout the review, the reader must bear in mind the relevance of differentiating between sensitization and allergy; the latter entails not only allergic sensitization, but also clinically relevant symptoms triggered by the culprit allergen.

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          Identification of a mast cell specific receptor crucial for pseudo-allergic drug reactions

          Mast cells are primary effectors in allergic reactions, and may have significant roles in diseases by secreting histamine and various inflammatory and immunomodulatory substances 1,2 . While classically they are activated by IgE antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions 1,3 . Roles for these substances in pathology have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, MrgprB2, the orthologue of the human G-protein coupled receptor (GPCR) MrgprX2. Secretagogue-induced histamine release, inflammation, and airway contraction are abolished in MrgprB2 null mutant mice. Further, we show that most classes of FDA-approved peptidergic drugs associated with allergic-type injection-site reactions also activate MrgprB2 and MrgprX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that MrgprB2 and MrgprX2 are targets of many small molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice, and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MrgprX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.
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            Drug allergy: an updated practice parameter.

            , , (2010)
            Adverse drug reactions (ADRs) result in major health problems in the United States in both the inpatient and outpatient setting. ADRs are broadly categorized into predictable (type A and unpredictable (type B) reactions. Predictable reactions are usually dose dependent, are related to the known pharmacologic actions of the drug, and occur in otherwise healthy individuals, They are estimated to comprise approximately 80% of all ADRs. Unpredictable are generally dose independent, are unrelated to the pharmacologic actions of the drug, and occur only in susceptible individuals. Unpredictable reactions are subdivided into drug intolerance, drug idiosyncrasy, drug allergy, and pseudoallergic reactions. Both type A and B reactions may be influenced by genetic predisposition of the patient
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              Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose.

              Carbohydrate moieties are frequently encountered in food and can elicit IgE responses, the clinical significance of which has been unclear. Recent work, however, has shown that IgE antibodies to galactose-alpha-1,3-galactose (alpha-gal), a carbohydrate commonly expressed on nonprimate mammalian proteins, are capable of eliciting serious, even fatal, reactions. We sought to determine whether IgE antibodies to alpha-gal are present in sera from patients who report anaphylaxis or urticaria after eating beef, pork, or lamb. Detailed histories were taken from patients presenting to the University of Virginia Allergy Clinic. Skin prick tests (SPTs), intradermal skin tests, and serum IgE antibody analysis were performed for common indoor, outdoor, and food allergens. Twenty-four patients with IgE antibodies to alpha-gal were identified. These patients described a similar history of anaphylaxis or urticaria 3 to 6 hours after the ingestion of meat and reported fewer or no episodes when following an avoidance diet. SPTs to mammalian meat produced wheals of usually less than 4 mm, whereas intradermal or fresh-food SPTs provided larger and more consistent wheal responses. CAP-RAST testing revealed specific IgE antibodies to beef, pork, lamb, cow's milk, cat, and dog but not turkey, chicken, or fish. Absorption experiments indicated that this pattern of sensitivity was explained by an IgE antibody specific for alpha-gal. We report a novel and severe food allergy related to IgE antibodies to the carbohydrate epitope alpha-gal. These patients experience delayed symptoms of anaphylaxis, angioedema, or urticaria associated with eating beef, pork, or lamb.
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                Author and article information

                Contributors
                Journal
                World Allergy Organ J
                World Allergy Organ J
                The World Allergy Organization Journal
                World Allergy Organization
                1939-4551
                25 February 2020
                February 2020
                25 February 2020
                : 13
                : 2
                : 100080
                Affiliations
                [a ]Hospital Quironsalud Bizkaia, Bilbao-Erandio, Spain
                [b ]Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
                [c ]Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Personalized Medicine, Asthma and Allergy, Humanitas Research Hospital, Rozzano, Milan, Italy
                [d ]Institute for Immunological Research, University of Cartagena, Cartagena, Colombia
                [e ]Azienda Sanitaria Locale di Vercelli, S.C. Pneumologia, Vercelli, Italia
                [f ]Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, Sagamihara, Kanagawa, Japan
                [g ]Allergy and Respiratory Diseases, IRCCS Policlinico San Martino, University of Genoa, Genoa, Italy
                [h ]Ospedale Civile, Gossolengo, PC, Italy
                [i ]Department of Immunology - Allergology - Rheumatology, Antwerp University Hospital, Antwerp University, Department Immunology and Allergology, AZ Jan Palfijn Gent, Ghent, Belgium
                [j ]Universidad Católica de Salta, Fundación Ayre, Buenos Aires, Argentina
                [k ]Allergy Section, Department of Internal Medicine, Vall d’Hebron University Hospital, Barcelona, Spain
                [l ]Pulmonary & Allergy Associates, Denville, NJ, USA
                [m ]Institute for Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, The Interuniversity Messerli Research Institute, University of Veterinary Medicine Vienna, Medical University Vienna, Vienna, Austria
                [n ]Fischer Medicine Professional Corporation, Barrie, Ontario, Canada
                [o ]Skin and Allergy Hospital, University of Helsinki, Helsinki, Finland
                [p ]Clínica de Alergía, Sorocaba, São Paulo, Brazil
                [q ]MACVIA-France, Montpellier, France
                [r ]INSERM, Villejuif, France
                [s ]Université Versailles St-Quentin-en-Yvelines, Montigny le Bretonneux, France
                [t ]Euforea, Brussels, Belgium
                [u ]CHU Montpellier, France
                [v ]Universitat Autónoma de Barcelona, Hospital Universitario Vall d'Hebron, Servicio de Medicina Interna, Sección de Alergología, Barcelona, Spain
                [w ]Mount Elizabeth Medical Centre, Chiang Children's Allergy & Asthma Clinic, Singapore, Singapore
                [x ]University Hospital Montpellier, Montpellier, France
                [y ]Sorbonne Université, Paris, France
                [z ]Immunology Research Institute of New England, Gardner, MA, USA
                [aa ]The Unidad de Educación Médica, Department of Medical Education, School of Medicine, Clinica Universitad de Navarra, Navarra, Spain
                [ab ]Erasmus MC, Sector Allergologie, Rotterdam, the Netherlands
                [ac ]Universidad Autónoma de Nuevo León, Hospital Universitario, Monterrey, Nuevo León, Mexico
                [ad ]Department of Allergy, Mayo Clinic, Jacksonville, FL, USA
                [ae ]Femeca Femedica, Buenos Aires, Argentina
                [af ]Kirikkale Universitesi, Tip Fakultesi, Kirikkale, Turkey
                [ag ]Hospital Sírio Libanês, University of São Paulo, São Paulo, Brazil
                [ah ]Faculty of Medicine, Department of Clinical Immunology & Allergy, Medical University of Łódź, Łódź, Poland
                [ai ]University of South Florida College of Medicine, Tampa, FL, USA
                [aj ]Allergology Unit, San Juan de Dios Hospital, University of Costa Rica, San José, Costa Rica
                [ak ]Hospital CUF-Descobertas, Lisbon, Portugal
                [al ]Department of Otorhinolaryngology, Head and Neck Surgery, Section of Rhinology and Allergy, University Hospital Marburg, Philipps-Universität Marburg, Marburg, Germany
                [am ]Gentofte University Hospital, Lab for Allergology, Allergy Clinic, Hellerup, Denmark
                [an ]Nippon Medical School, Dept. of Otolaryngology, Tokyo, Japan
                [ao ]University Hospital GI & MR GmbH, Institute of Laboratory Medicine & Pathology, Standort Marburg, Marburg, Germany
                [ap ]Stallergenes, Rome, Italy
                [aq ]University of Parana, Curitiba, PR, Brazil
                [ar ]University of Missouri at Kansas City, School of Medicine, Kansas City, MO, USA
                [as ]Centro Médico Docente La Trinidad, Caracas, Venezuela
                [at ]Experimental Allergy Unit, Istituto Dermopatico dell'Immacolata, Rome, Italy
                [au ]Ospedale Civile Maggiore, Verona, Italy
                [av ]Allergy & Asthma Institute, Asunción, Paraguay
                [aw ]Royal Children's Hospital, Department of Allergy & Immunology, Parkville, Victoria, Australia
                [ax ]Tan Tock Seng Hospital, Deptartment of Rheumatology, Allergy & Immunology, Singapore, Singapore
                [ay ]Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
                [az ]NRC Institute of Immunology FMBA of Russia, Moscow, Russia
                [ba ]Laboratory of Immunopathology, Department of Clinical Immunology and Allergy, Sechenov First Moscow State Medical University, Moscow, Russia
                [bb ]Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
                [bc ]Campus Charite Mitte, Klinik fur Dermatologie & Allergologie, Berlin, Germany
                Author notes
                [] Corresponding author. ignacioansotegui@ 123456gmail.com
                [1]

                These authors equally contributed to this manuscript

                Article
                S1939-4551(19)31236-0 100080
                10.1016/j.waojou.2019.100080
                7044795
                32128023
                03b9aefc-244a-4a51-bc78-de740645a9f9
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 15 August 2019
                : 8 October 2019
                Categories
                Article

                Immunology
                ige,allergy,in vitro tests,skin tests,diagnostic strategies,aaaai, american academy of allergy asthma and immunology,aba, allergen bead array,acaai, american college of allergy asthma and immunology,ait, allergen immunotherapy,aec, allergen exposure chambers,anti-ige, antibody against ige,ap, alkaline phosphatase,au/ml, allergenic units milliliter,bat, basophil activation test,bau/ml, biologic allergenic units milliliter,cafe, calibrated fluorescence enhancement,cba, cytometric bead array,ccd, cross-reactive carbohydrate determinants,cder, center for drug evaluation and research (usa),cl, chemiluminescence,dbpcfc, double-blind placebo-controlled food challenge,eaaci, european academy of allergy and immunology,eia, enzyme immune assay,elisa, enzyme linked immuno sorbent analysis,emea, european medicine agencies,enpp-3, ectonucleotide pyrophosphatase/phosphodiesterase 3,facs, fluorescence-activated cell sorting,fda, food and drug administration (u.s. department of health and human services),feia, fluorescent enzyme immunoassays,fcεri, high affinity ige receptor,h1, histamine 1 receptor,h2, histamine 2 receptor,hpo, horseradish peroxidase,idt, intradermal test,ige, immunoglobulin e,isac, immuno-solid phase allergen chip,iuis, international union of immunological societies,ivd, in vitro diagnostic tool,kua/l, kilo units of allergen/liter for allergen-specific ige antibody assays,lamp-3, lysosomal-associated membrane protein,mab, monoclonal antibody,mrgprx2, mas-related g protein receptor 2,mbad, molecule based allergy diagnostics,nih, national institutes of health (usa),nmbas, neuromuscular blocking agents,npa, negative percent agreement,nsaids, non-steroidal anti-inflammatory drugs,pnpp, p-nitrophenylphosphate,ppa, positive percent agreement,ppt, prick-prick test,sige, specific ige,rast, radio allergo sorbent test,scar, severe cutaneous adverse drug reactions,spt, skin prick test,w/v, weight /volume
                Immunology
                ige, allergy, in vitro tests, skin tests, diagnostic strategies, aaaai, american academy of allergy asthma and immunology, aba, allergen bead array, acaai, american college of allergy asthma and immunology, ait, allergen immunotherapy, aec, allergen exposure chambers, anti-ige, antibody against ige, ap, alkaline phosphatase, au/ml, allergenic units milliliter, bat, basophil activation test, bau/ml, biologic allergenic units milliliter, cafe, calibrated fluorescence enhancement, cba, cytometric bead array, ccd, cross-reactive carbohydrate determinants, cder, center for drug evaluation and research (usa), cl, chemiluminescence, dbpcfc, double-blind placebo-controlled food challenge, eaaci, european academy of allergy and immunology, eia, enzyme immune assay, elisa, enzyme linked immuno sorbent analysis, emea, european medicine agencies, enpp-3, ectonucleotide pyrophosphatase/phosphodiesterase 3, facs, fluorescence-activated cell sorting, fda, food and drug administration (u.s. department of health and human services), feia, fluorescent enzyme immunoassays, fcεri, high affinity ige receptor, h1, histamine 1 receptor, h2, histamine 2 receptor, hpo, horseradish peroxidase, idt, intradermal test, ige, immunoglobulin e, isac, immuno-solid phase allergen chip, iuis, international union of immunological societies, ivd, in vitro diagnostic tool, kua/l, kilo units of allergen/liter for allergen-specific ige antibody assays, lamp-3, lysosomal-associated membrane protein, mab, monoclonal antibody, mrgprx2, mas-related g protein receptor 2, mbad, molecule based allergy diagnostics, nih, national institutes of health (usa), nmbas, neuromuscular blocking agents, npa, negative percent agreement, nsaids, non-steroidal anti-inflammatory drugs, pnpp, p-nitrophenylphosphate, ppa, positive percent agreement, ppt, prick-prick test, sige, specific ige, rast, radio allergo sorbent test, scar, severe cutaneous adverse drug reactions, spt, skin prick test, w/v, weight /volume

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