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Publisher: John Wiley and Sons   (Total: 1579 journals)

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Showing 1 - 200 of 1579 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 12, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 65, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 46, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 51, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 153, SJR: 0.101, h-index: 9)
Acta Geologica Sinica (English Edition)     Hybrid Journal   (Followers: 3, SJR: 0.552, h-index: 41)
Acta Neurologica Scandinavica     Hybrid Journal   (Followers: 5, SJR: 1.203, h-index: 74)
Acta Obstetricia et Gynecologica Scandinavica     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 5, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 56, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 6, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 35, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 6, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 4)
Addiction     Hybrid Journal   (Followers: 35, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 13, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 26, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 26, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 50, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 13, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 258, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 5, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 5)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 19)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 12)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 9)
African Development Review     Hybrid Journal   (Followers: 34, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 15, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 10, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 15, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 45, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 30, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 33, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 50, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 139, SJR: 0.951, h-index: 61)
American Business Law J.     Hybrid Journal   (Followers: 24, SJR: 0.205, h-index: 17)
American Ethnologist     Hybrid Journal   (Followers: 90, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 28, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 33, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 12, SJR: 1.018, h-index: 58)
American J. of Industrial Medicine     Hybrid Journal   (Followers: 16, SJR: 0.993, h-index: 85)
American J. of Medical Genetics Part A     Hybrid Journal   (Followers: 16, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 6, SJR: 2.315, h-index: 79)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 37, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 271, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 17, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 132, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 10, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 16)
Anatomia, Histologia, Embryologia: J. of Veterinary Medicine Series C     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 27)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1, SJR: 0.633, h-index: 24)
Andrologia     Hybrid Journal   (Followers: 2, SJR: 0.528, h-index: 45)
Andrology     Hybrid Journal   (Followers: 2, SJR: 0.979, h-index: 14)
Angewandte Chemie     Hybrid Journal   (Followers: 172)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 216, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 38, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 7, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 47, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 2, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 9, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 13)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 25, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 17, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 15)
Anthropology of Consciousness     Hybrid Journal   (Followers: 11, SJR: 0.172, h-index: 5)
Anthropology of Work Review     Hybrid Journal   (Followers: 11, SJR: 0.256, h-index: 5)
Anthropology Today     Hybrid Journal   (Followers: 90, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 47, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 7, SJR: 0.432, h-index: 59)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apmis     Hybrid Journal   (Followers: 1, SJR: 0.855, h-index: 73)
Applied Cognitive Psychology     Hybrid Journal   (Followers: 69, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 145, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 49, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 14, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 31, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 36, SJR: 1.047, h-index: 57)
Arabian Archaeology and Epigraphy     Hybrid Journal   (Followers: 11, SJR: 0.453, h-index: 11)
Archaeological Prospection     Hybrid Journal   (Followers: 12, SJR: 0.922, h-index: 21)
Archaeology in Oceania     Hybrid Journal   (Followers: 13, SJR: 0.745, h-index: 18)
Archaeometry     Hybrid Journal   (Followers: 27, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 15, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 25, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 4, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 4)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 12, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 238, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 51, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 27, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 14)
Asia & the Pacific Policy Studies     Open Access   (Followers: 15)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 313, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (Followers: 1, SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 8, SJR: 0.345, h-index: 20)
Asia-pacific J. of Clinical Oncology     Hybrid Journal   (Followers: 6, SJR: 0.554, h-index: 14)
Asia-Pacific J. of Financial Studies     Hybrid Journal   (SJR: 0.241, h-index: 7)
Asia-Pacific Psychiatry     Hybrid Journal   (Followers: 4, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 4, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 5, SJR: 1.443, h-index: 19)
Asian J. of Social Psychology     Hybrid Journal   (Followers: 5, SJR: 0.665, h-index: 37)
Asian Politics and Policy     Hybrid Journal   (Followers: 12, SJR: 0.207, h-index: 7)
Asian Social Work and Policy Review     Hybrid Journal   (Followers: 5, SJR: 0.318, h-index: 5)
Asian-pacific Economic Literature     Hybrid Journal   (Followers: 5, SJR: 0.168, h-index: 15)
Assessment Update     Hybrid Journal   (Followers: 4)
Astronomische Nachrichten     Hybrid Journal   (Followers: 2, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 14, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 9, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 8, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 7, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 13, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 4, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 46, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 7, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 4, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 29, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 14, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 18, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 407, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 5, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 71, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 12, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 19, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 32, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 10, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 5, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 9, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 24, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 9, SJR: 0.11, h-index: 5)
Beton- und Stahlbetonbau     Hybrid Journal   (Followers: 2, SJR: 0.493, h-index: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6, SJR: 0.311, h-index: 26)
Bioelectromagnetics     Hybrid Journal   (Followers: 1, SJR: 0.568, h-index: 64)
Bioengineering & Translational Medicine     Open Access  
BioEssays     Hybrid Journal   (Followers: 10, SJR: 3.104, h-index: 155)
Bioethics     Hybrid Journal   (Followers: 14, SJR: 0.686, h-index: 39)
Biofuels, Bioproducts and Biorefining     Hybrid Journal   (Followers: 1, SJR: 1.725, h-index: 56)
Biological J. of the Linnean Society     Hybrid Journal   (Followers: 16, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 3, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 6, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 36, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 45, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 180, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 14, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 20, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 37, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 5, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)
BJOG : An Intl. J. of Obstetrics and Gynaecology     Partially Free   (Followers: 231, SJR: 2.083, h-index: 125)

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Journal Cover Allergy
  [SJR: 3.048]   [H-I: 129]   [50 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0105-4538 - ISSN (Online) 1398-9995
   Published by John Wiley and Sons Homepage  [1579 journals]
  • Quantitative analysis of multiple elements in healthy and remodeled
           epithelium from human upper airway mucosa by using nuclear microscopy
    • Authors: Min-Qin Ren; Yu-Tao Zhou, He-Xin Chen, Tian-Ying Li, Saumitra K Vajandar, Thomas Osipowicz, Frank Watt, Chun-Wei Li
      Abstract: Elements are vital in airway mucosal physiology and pathology; but their distribution and levels in the mucosa remain unclear. The present study uses the state-of-the-art nuclear microscopy facility to map and quantify multiple elements in the histology sections of nasal mucosa from patients with nasal polyps or inverted papilloma. Our results demonstrate that P and Ca are the most abundant elements in mucosa and their distinct difference between epithelial and sub-epithelial regions; more importantly, our results reveal decreased amounts of Cu and Zn in the remodelled epithelium as compared to the normal epithelium. These findings suggest that Cu and Zn may be beneficial targets to regulate aberrant epithelial remodeling in airway inflammation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-11T02:05:25.953303-05:
      DOI: 10.1111/all.13329
  • CRD and beyond: multivariable regression models to predict severity of
           hazelnut allergy
    • Authors: Mareen R. Datema; Ronald van Ree, Riccardo Asero, Laura Barreales, Simona Belohlavkova, Frédéric de Blay, Michael Clausen, Ruta Dubakiene, Cristina Fernández-Perez, Philipp Fritsche, David Gislason, Karin Hoffmann-Sommergruber, Monika Jedrzejczak-Czechowicz, Laurian Jongejan, André C. Knulst, Marek Kowalski, Tanya Z. Kralimarkova, Thuy-My Le, Jonas Lidholm, Nikolaos G. Papadopoulos, Todor A. Popov, Nayade del Prado, Ashok Purohit, Isabel Reig, Suranjith L. Seneviratne, Athanassios Sinaniotis, Serge A. Versteeg, Stefan Vieths, A.H. Zwinderman, E.N. Clare Mills, Montserrat Fernández-Rivas, Barbara Ballmer-Weber
      Abstract: BackgroundComponent-resolved diagnosis (CRD) has revealed significant associations between IgE against individual allergens and severity of hazelnut allergy. Less attention has been given to combining them with clinical factors in predicting severity.AimTo analyze associations between severity and sensitization patterns, patient characteristics and clinical history, and to develop models to improve predictive accuracy.MethodsPatients reporting hazelnut allergy (n=423) from 12 European cities were tested for IgE against individual hazelnut allergens. Symptoms (reported and during DBPCFC) were categorized in mild, moderate and severe. Multiple regression models to predict severity were generated from clinical factors and sensitization patterns (CRD- and extract-based). Odds ratios (OR) and areas under receiver operating characteristic (ROC) curves (AUC) were used to evaluate their predictive value.ResultsCor a 9 and 14 were positively (OR 10.5 and 10.1 respectively), and Cor a 1 negatively (OR 0.14) associated with severe symptoms during DBPCFC, with AUCs of 0.70-073. Combining Cor a 1 and 9 improved this to 0.76. A model using a combination of atopic dermatitis (risk), pollen allergy (protection), IgE against Cor a 14 (risk) and walnut (risk), increased the AUC to 0.91. At 92% sensitivity, the specificity was 76.3% and the positive and negative predictive values 62.2% and 95.7%, respectively. For reported symptoms, associations and generated models proved to be almost identical but weaker.ConclusionA model combining CRD with clinical background and extract-based serology is superior to CRD alone in assessing the risk of severe reactions to hazelnut, particular in ruling out severe reactions.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-07T10:35:34.512109-05:
      DOI: 10.1111/all.13328
  • Complete kinetic follow-up of symptoms and complement parameters during a
           hereditary angioedema attack
    • Authors: Nóra Veszeli; Kinga Viktória Kőhalmi, Erika Kajdácsi, Dominik Gulyás, György Temesszentandrási, László Cervenak, Henriette Farkas, Lilian Varga
      Abstract: We studied the kinetics of C1-inhibitor (C1-INH) and other complement parameters in a self-limited edematous attack (EA) in a patient with hereditary angioedema due to C1-INH deficiency to better understand the pathomechanism of the evolution, course, and complete resolution of EAs. C1-INH concentration and functional activity (C1-INHc+f), C1(q,r,s), C3, C4, C3a, C4a, C5a and SC5b-9 levels were measured in blood samples obtained during the 96-hour observation period. The highest C1-INHc+f, C4, and C1(q,r,s) levels were measured at baseline, and their continuous decrease was observed during the entire observation period. C4 depletion started at prodromal phase and C4 was lowest after the maximum severity peak. Compared to baseline, C4a level was four times higher 7 hours before the onset of the attack. C1-INH did not increase after resolution of the attack suggesting that factors other than C1-INH may be important in this process. C4a may be a useful biomarker for the prediction of EAs.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-07T07:24:15.772108-05:
      DOI: 10.1111/all.13327
  • Increased attention-deficit/hyperactivity symptoms in atopic dermatitis
           are associated with history of antihistamine use
    • Authors: Jochen Schmitt; Angelika Buske-Kirschbaum, Falko Tesch, Katharina Trikojat, Victoria Stephan, Susanne Abraham, Andrea Bauer, Katja Nemat, Franziska Plessow, Veit Roessner
      Abstract: BackgroundEpidemiologic evidence indicates a relevant association between atopic dermatitis (AD) and attention-deficit/hyperactivity disorder (ADHD). Underlying mechanisms and ways to best identify subgroups of AD patients at risk for ADHD are poorly understood.Aims of the studyTo compare sociodemographic, clinical, and psychosocial characteristics of children with AD, ADHD, comorbid AD/ADHD, and age-matched healthy controls. To investigate aspects of AD related to ADHD symptoms.MethodsApplying a factorial design we investigated 4 groups of children age 6 to 12 years: AD-only (i.e. without ADHD), ADHD-only (i.e. without AD), AD+ADHD, healthy controls (HC; i.e. no AD/no ADHD). Using validated instruments, ADHD symptoms and other behavioural problems, quality of life, parenting stress, and sleeping problems were compared between groups. In children with AD-only, clinical signs (objective SCORAD), symptoms (POEM, VAS pruritus, VAS sleeping problems), and previous treatment of AD were assessed to investigate disease patterns related to ADHD symptoms.ResultsCompared to HC (n=47), children with AD-only (n=42), ADHD-only (n=34) and comorbid AD+ADHD (n=31) had significantly increased behavioural problems and decreased quality of life. Children with AD-only had significantly higher levels of ADHD symptoms than HC. In children with AD-only, previous use of antihistamines was significantly associated with increased ADHD symptoms (OR 1.88; 95%-CI 1.04-3.39). Current clinical signs and AD-symptoms were unrelated to the level of ADHD symptoms.ConclusionsEven if the clinical diagnosis of ADHD is excluded, children with AD show increased levels of ADHD symptoms. Further investigations need to determine whether early antihistamine exposure is a major risk factor for ADHD or a surrogate for previous AD severity and/or associated sleeping problems.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-04T01:05:33.117042-05:
      DOI: 10.1111/all.13326
  • Nasal protein profiles in work-related asthma caused by different
    • Authors: Hille Suojalehto; Irmeli Lindström, Henrik Wolff, Anne Puustinen
      Abstract: BackgroundThe mechanisms of work-related asthma are incompletely delineated. Nasal cell samples may be informative about processes in the lower airways. Our aim was to determine the nasal protein expression profiles of work-related asthma caused by different kind of exposures.MethodsWe collected nasal brush samples from 82 non-smoking participants, including healthy controls and work-related asthma patients exposed to 1) protein allergens, 2) isocyanates, and 3) welding fumes the day after relevant exposure. The proteome changes in samples were analysed by two-dimensional difference gel electrophoresis and the differentially regulated proteins found were identified by mass spectrometry. Immunological comparison was carried out using Western blot.ResultsWe detected an average of 2500 spots per protein gel. Altogether 228 protein spots were chosen for identification, yielding 77 different proteins. Compared to the controls exposure to protein allergens had the largest effects on the proteome. Hierarchical clustering revealed that protein allergen and isocyanate related asthma had similar profiles, whereas asthma related to welding fumes differed. The highly overrepresented functional categories in the asthma groups were defence response, protease inhibitor activity, inflammatory and calcium signalling, complement activation, and cellular response to oxidative stress. Immunological analysis confirmed the found abundance differences in Galectin 10 and Protein S100-A9 between the groups.ConclusionsWork-related asthma patients exposed to protein allergens and isocyanates elicit similar nasal proteome responses and the profiles of welders and healthy controls were alike. Revealed biological activities of the protein expression changes are associated with allergic inflammation and asthma.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-28T08:50:30.797086-05:
      DOI: 10.1111/all.13325
  • The sex-shift in single disease and multimorbid asthma and rhinitis during
    • Authors: Theresa Keller; C Hohmann, M Standl, A H Wijga, U Gehring, E Melén, C Almqvist, S Lau, E Eller, U Wahn, E Soegaard Christiansen, A v.Berg, J Heinrich, I Lehmann, D Maier, D S Postma, J M Antó, J Bousquet, T Keil, S Roll
      Abstract: BackgroundCross-sectional studies suggested that allergy prevalence in childhood is higher in boys compared to girls, but it remains unclear if this inequality changes after puberty. We examined the sex-specific prevalence of asthma and rhinitis as single and as multimorbid diseases before and after puberty-onset in longitudinal cohort data.MethodsIn six European population-based birth cohort studies we assessed the outcomes current rhinitis, current asthma, current allergic multimorbidity (i.e. concurrent asthma and rhinitis), puberty status, and allergic sensitization by specific serum antibodies (immunoglobulin E) against aero-allergens. With generalized estimating equations we analysed the effects of sex, age, puberty (yes/no), and possible confounders on the prevalence of asthma and rhinitis, and allergic multimorbidity in each cohort separately and performed individual participant data meta-analysis.FindingsWe included data from 19,013 participants from birth to age 14-20 years. Current rhinitis only affected girls less often than boys before and after puberty onset: adjusted odds ratio for females vs. males 0.79 (95%-confidence interval 0.73-0.86) and 0.86 (0.79-0.94) respectively (sex-puberty interaction p= 0.089).Similarly, for current asthma only, females were less often affected than boys both before and after puberty-onset: 0.71, 0.63-0.81 and 0.81, 0.64-1.02, respectively (sex-puberty interaction p=0.327).The prevalence of allergic multimorbidity showed the strongest sex-effect before puberty onset (female-male-OR 0.55, 0.46-0.64) and a considerable shift towards a sex-balanced prevalence after puberty onset (0.89, 0.74-1.04); sex-puberty interaction: p
      PubDate: 2017-09-27T12:55:20.926528-05:
      DOI: 10.1111/all.13312
  • The pruritogenic mediator endothelin-1 shifts the dendritic cell–T-cell
           response toward Th17/Th1 polarization
    • Authors: T. Nakahara; M. Kido-Nakahara, F. Ohno, D. Ulzii, T. Chiba, G. Tsuji, M. Furue
      Abstract: Endothelin-1 (ET-1) is associated with skin diseases such as atopic dermatitis (AD) and psoriasis. ET-1 is enhanced in the skin of AD and psoriasis patients. In addition, plasma levels of ET-1 are elevated in AD and psoriasis. Although both AD and psoriasis are T cell–mediated skin diseases, the association between ET-1 and the T-cell immune response has not been clarified. To evaluate the role of ET-1 in inflammatory skin disease, we sought to investigate the effects of ET-1 on the functions of dendritic cells (DCs) and subsequent immune responses. For this purpose, we immunohistochemically confirmed the upregulation of ET-1 in the epidermis of patients with AD or psoriasis. ET-1 directly induced phenotypic maturation of bone marrow-derived DCs (BMDCs). In addition, ET-1 augmented the production of several cytokines and allogeneic stimulatory capacity of BMDCs. Interestingly, ET-1–activated BMDCs primed T cells to produce Th1 and Th17 cytokines, but not Th2 cytokines. These findings indicate that ET-1 polarizes the DC–T-cell response towards Th17/1 differentiation and may augment the persistent course of inflammatory skin diseases.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-27T12:50:29.417311-05:
      DOI: 10.1111/all.13322
  • The prevalence of atopic dermatitis beyond childhood: A systematic review
           and meta-analysis of longitudinal studies
    • Authors: Katrina Abuabara; Ashley M. Yu, Jean-Phillip Okhovat, Elaine Allen, Sinéad M. Langan
      Abstract: There are sparse and conflicting data regarding the long-term clinical course of atopic dermatitis (AD). Although often described as a primarily childhood disease, newer population-based estimates suggest the prevalence of pediatric and adult disease may be similar. Our objective was to determine whether there is a decline in the prevalence of AD in population-based cohorts of patients followed longitudinally beyond childhood. We conducted a systematic review and meta-analysis including studies assessing AD prevalence across 3 or more points in time. The primary outcome was weighted overall risk difference (percentage decrease in AD prevalence). Of 2,080 references reviewed, 7 studies with 13,515 participants were included. Participants were assessed at 3-6 time points, ranging from age 3 months to 26 years. The percentage decrease in prevalence after age 12 was 1%, which was not significantly different from zero (95% confidence interval -2% to 5%). Similar results were found with other age cut-offs. In conclusion, the prevalence of AD in longitudinal birth cohort studies is similar in childhood and early adulthood.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-27T12:50:27.135982-05:
      DOI: 10.1111/all.13320
  • Airway pathology in severe asthma is related to airflow obstruction but
           not symptom control
    • Authors: Diogenes S. Ferreira; Regina M. Carvalho-Pinto, Marcelo G. Gregório, Raquel Annoni, Aila M. Teles, Monique Buttignol, Bianca B. Araújo-Paulino, Edgard H. Katayama, Bianca L. Oliveira, Heloisa S. Del Frari, Alberto Cukier, Marisa Dolhnikoff, Rafael Stelmach, Klaus F. Rabe, Thais Mauad
      Abstract: BackgroundPatients with asthma present structural and inflammatory alterations that are believed to play a role in disease severity. However, airway remodeling and inflammation have not been extensively investigated in relation to both symptom control and airflow obstruction in severe asthmatics. We aimed to investigate several inflammatory and structural pathological features in bronchial biopsies of severe asthmatics that could be related to symptom control and airflow obstruction after standardized treatment.Methods50 severe asthmatics received prednisone 40 mg/day for 2 weeks and maintenance therapy with budesonide/formoterol 400/12 μg twice daily + budesonide/formoterol 200/6 μg as needed for 12 weeks. Endobronchial biopsies were performed at the end of 12 weeks. We performed extensive immunopathological analyses of airway tissue inflammation and remodeling features in patients stratified by asthma symptom control and by airflow obstruction.ResultsAirway tissue inflammation and remodeling were not associated with symptom control. Asthmatics with persistent airflow obstruction had greater airway smooth muscle (Asm) area with decreased periostin and transforming growth factor beta positive cells within Asm bundles, in addition to lower numbers of chymase positive mast cells in the submucosa compared to patients with non-persistent obstruction.ConclusionsSymptom control in severe asthmatics was not associated with airway tissue inflammation and remodeling, although persistent airflow obstruction in these patients was associated with bronchial inflammation and airway structural changes.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-27T08:15:23.84731-05:0
      DOI: 10.1111/all.13323
  • The roadmap for Allergology in Europe: the subspecialty of Allergology as
           ‘stop-over’ on the way to a full specialty. An EAACI position
    • Authors: R Gerth van Wijk; I Eguiluz-Gracia, J Gayraud, J Gutermuth, E Hamelmann, E Heffler, T. A Popov, P Schmid-Grendelmeier, P. V Tomazic, O Tsilochistrou, N Muelleneisen
      Abstract: The vision of EAACI and the UEMS Section and Board (S&B) on allergology is to promote and to establish a full specialty of allergology in all European countries. In many European countries a full specialty does not exist. In those countries organ-based (sub)specialists or paediatricians and internists with an expertise in allergology may deliver allergy care. There are no generally accepted requirements for the training of subspecialists available. To fill the gap between the need and availability of experienced and accredited physicians who can deliver optimal care to the allergic patients the EAACI Specialty Committee proposes the minimal requirements for training and certification of subspecialists in allergology. This paper describes the required theoretical knowledge, skills, competences and training facilities (staff and institution). The subspecialist as described in this paper should ideally show the necessary competence in providing good quality care to patients in an environment lacking those full specialists in allergology or tertiary care paediatric subspecialists in allergy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-27T08:05:21.694912-05:
      DOI: 10.1111/all.13321
  • Distinct epitope structures of defensin-like proteins linked to
           proline-rich regions give rise to differences in their allergenic activity
    • Authors: I. Pablos; S. Eichhorn, Y. Machado, P. Briza, A. Neunkirchner, B. Jahn-Schmid, S. Wildner, W. T. Soh, C. Ebner, J.-W. Park, W. F. Pickl, N. Arora, S. Vieths, F. Ferreira, G. Gadermaier
      Abstract: BackgroundArt v 1, Amb a 4, and Par h 1 are allergenic defensin-polyproline–linked proteins present in mugwort, ragweed, and feverfew pollen, respectively. We aimed to investigate the physicochemical and immunological features underlying the different allergenic capacities of those allergens.MethodsRecombinant defensin-polyproline–linked proteins were expressed in E. coli and physicochemically characterized in detail regarding identity, secondary structure, and aggregation status. Allergenic activity was assessed by mediator releases assay, serum IgE reactivity, and IgE inhibition ELISA using sera of patients from Austria, Canada, and Korea. Endolysosomal protein degradation and T-cell cross-reactivity were studied in vitro.ResultsDespite variations in the proline-rich region, similar secondary structure elements were observed in the defensin-like domains. Seventy-four percent and 52% of the Austrian and Canadian patients reacted to all three allergens, while Korean patients were almost exclusively sensitized to Art v 1. This was reflected by IgE inhibition assays demonstrating high cross-reactivity for Austrian, medium for Canadian, and low for Korean sera. In a subgroup of patients, IgE reactivity toward structurally altered Amb a 4 and Par h 1 was not changed suggesting involvement of linear epitopes. Immunologically relevant endolysosomal stability of the defensin-like domain was limited to Art v 1 and no T-cell cross-reactivity with Art v 125-36 was observed.ConclusionsDespite structural similarity, different IgE-binding profiles and proteolytic processing impacted the allergenic capacity of defensin-polyproline–linked molecules. Based on the fact that Amb a 4 demonstrated distinct IgE-binding epitopes, we suggest inclusion in molecule-based allergy diagnosis.
      PubDate: 2017-09-27T02:30:34.88154-05:0
      DOI: 10.1111/all.13298
  • A composite of exhaled LTB4, LXA4, FeNO and FEV1 as an “asthma
           classification ratio” characterizes childhood asthma
    • Authors: Li-Chen Chen; Hsu-Min Tseng, Ming-Ling Kuo, Chih-Yung Chiu, Sui-Ling Liao, Kuan-Wen Su, Ming-Han Tsai, Man-Chin Hua, Shen-Hao Lai, Tsung-Chieh Yao, Kuo-Wei Yeh, Ai-Hsuan Wu, Jing-Long Huang, Shau-Ku Huang
      Abstract: BackgroundAberrant generation of eicosanoids is associated with asthma, but the evidence remains incomplete and its potential utility as biomarkers is unclear. Major eicosanoids in exhaled breath condensates (EBCs) were assessed as candidate markers for childhood asthma.MethodsTen exhaled eicosanoid species was evaluated using ELISA in the discovery phase, followed by prediction model-building and validation phases.ResultsExhaled LTB4, LTE4, PGE2 and LXA4 showed significant difference between asthmatics (N=60) and controls (N=20). For validation, an expanded study population consisting of 626 subjects with asthma and 161 healthy controls were partitioned into a training subset to establish a prediction model and a test sample subset for validation. Receiver Operating Characteristic (ROC) analyses of the training subset revealed the level of exhaled LTB4 to be the most discriminative among all parameters, including FeNO, and a composite of exhaled LTB4, LXA4, together with FeNO and FEV1, distinguishing asthma with high sensitivity and specificity. Further, the Youden index (J) indicated the cut point value of 0.598 for this composite of markers as having the strongest discriminatory ability (sensitivity = 85.2% and specificity = 83.6%). The predictive algorithm as “asthma classification ratio” was further validated in an independent test sample with sensitivity and specificity being 84.4% and 84.8%, respectively.ConclusionsIn a pediatric study population in Taiwan, the levels of exhaled LTB4, LTE4, LXA4 and PGE2 in asthmatic children were significantly different from those of healthy controls, and the combination of exhaled LTB4 and LXA4, together with FeNO and FEV1, best characterized childhood asthma.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-25T02:55:31.394339-05:
      DOI: 10.1111/all.13318
  • National clinical practice guidelines for Allergen Immunotherapy: an
           international assessment applying AGREE-II
    • Authors: D E S Larenas-Linnemann; D Antolín-Amérigo, C Parisi, A Nakonechna, J A Luna-Pech, B Wedi, I Davila, M Gómez, M Levin, J A Ortega-Martell, L Klimek, N Rosario, A M Muraro, I Agache, J Bousquet, A Sheikh, , O Pfaar
      Abstract: BackgroundSince 1988 numerous allergen immunotherapy guidelines (AIT-GLs) have been developed by national and international organizations to guide physicians in AIT. Even so, AIT is still severely under-used.Objectiveto evaluate AIT-GLs with AGREE-II, developed in 2010 by McMaster University methodologists to comprehensively evaluate GL-quality.MethodsAllergist, from different continents, knowledgeable in AIT and AGREE-II trained were selected into the project team. The project received methodologists’ guidance. AIT-GLs in any language were sought from 1980-2016; AIT-GLs were AGREE II evaluated by at least 2 team-members, independently; discrepancies were resolved in a second round, by team-discussion or methodologists’ consulting.ResultsWe found 31 AIT-GLs (15 post-2010), ranging from local consensus reports to international position papers (EAACI, AAAAI-ACAAI, WAO). Pre-2010 GLs’ scored 1.6-4.6 (23-67%); post-2010 GLs’ 2.1-6 (30-86%), on a 7-point Likert-scale. Best evaluated were: German-Austrian-Swiss (6.0), Mexican (5.1) and the AAAAI/ACAAI AIT-GL (4.7). These were also the only 3 GLs that received ‘yes’ of both evaluators to the item: ‘I would recommend this GL for use’. The domains of ‘Stakeholder involvement’ and ‘Rigor of Development’ only scored 3/7, and ‘Applicability’ scored the lowest. Strikingly, newer GLs only scored clearly better in ‘Editorial independence’ and ‘Global evaluation’.ConclusionsIn AIT-GLs there is still a lot of room for improvement, especially in domains crucial for the dissemination. For some GLs, the ‘Scientific rigor’ domain flawed. When resources are limited, transculturizing a high-quality GL might be preferable over developing a GL from zero. Our study and AGREE-II could help to select the best candidate.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-21T09:26:42.826378-05:
      DOI: 10.1111/all.13316
  • Protease-Activated Receptor-2 blockade inhibits changes seen in a chronic
           murine asthma model
    • Authors: Muhammad Asaduzzaman; Courtney Davidson, Drew Nahirney, Yahya Fiteih, Lakshmi Puttagunta, Harissios Vliagoftis
      Abstract: Proteinase-Activated Receptor-2 (PAR2) is a G protein-coupled receptor activated by serine proteinases. We have shown that PAR2 activation in the airways is involved in the development of allergic inflammation and airway hyperresponsiveness (AHR) in acute murine models. We hypothesize that functional inhibition of PAR2 prevents allergic inflammation, AHR and airway remodeling in chronic allergic airway inflammation models. We developed a 12 week model of cockroach extract (CE)-mediated AHR, airway inflammation and remodeling in BALB/c. These mice exhibit AHR, increased numbers of eosinophils in bronchoalveolar lavage (BAL) and increased collagen content in the lung tissue compared to saline controls. Administration of an anti-PAR2 antibody, SAM-11, after the initial development of airway inflammation significantly inhibited all these parameters. Our data demonstrate that PAR2 signaling plays a key role in CE-induced AHR and airway inflammation/remodeling and that targeting PAR2 activation may be a successful therapeutic strategy for allergic asthma.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-20T05:21:17.596123-05:
      DOI: 10.1111/all.13313
  • Serine protease allergen favours Th2 responses via PAR-2 and STAT-3
           activation in murine model
    • Authors: Komal Agrawal; Naveen Arora
      Abstract: BackgroundProtease activity of Per a 10 favours Th2 responses by differential regulation of IL-12p70 and IL-23 cytokine subunits. The present study aims to elucidate the underlying mechanism of differential regulation of IL-12p70 and IL-23.MethodsPAR-2 activation was blocked in murine model by administering SAM11 before each sensitization. CD11c+ p-STAT3+ cells were measured in lungs by flow cytometry. BMDCs were pre-treated with SAM-11 or isotype control or stattic and stimulated with Per a 10. p-STAT3 levels were measured using Western blot. Transcript levels of IL-12p35, IL12/23p40 and IL-23p19 were measured using RT PCR. Cytokine levels were analysed using ELISA.ResultsProtease activity of Per a 10 increases p-STAT3 levels in mice lungs, which gets reduced on PAR-2 blockage. Percentage of p-STAT3+ CD11c+ cells was higher in Per a 10 administered mice and gets reduced upon PAR-2 blockage. IL-12p35 and IL-12p70 levels were higher, IL-23p19 and IL-23 levels were lower in both SAM-11 treated mice and BMDCs indicating a role of PAR-2 mediated signalling. IL-4, TSLP, IL-17A, EPO activity, total cell count and specific IgE and IgG1 levels were lower in SAM-11 administered mice. Inhibiting STAT3 activation via stattic also leads to lower levels of IL-23p19, IL-23 and higher level of IL-12p35.ConclusionsPer a 10 leads to PAR-2 activation on BMDCs resulting in downstream activation of STAT3 to regulate the balance between IL-12/IL-23 subunits causing a cytokine milieu rich in IL-23 to favour Th2 polarization.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-20T05:16:08.683083-05:
      DOI: 10.1111/all.13315
  • Neonatal BCG-vaccination and atopic dermatitis before 13 months of age. A
           randomised clinical trial
    • Authors: Lisbeth Marianne Thøstesen; Jesper Kjærgaard, Gitte Thybo Pihl, Nina Marie Birk, Thomas Nørrelykke Nissen, Peter Aaby, Aksel Karl Georg Jensen, Annette Wind Olesen, Lone Graff Stensballe, Dorthe Lisbeth Jeppesen, Christine Stabell Benn, Poul-Erik Kofoed
      Abstract: Studies have suggested that Bacillus Calmette-Guérin (BCG) vaccination may reduce the risk of allergic diseases, including atopic dermatitis.The Danish Calmette Study was conducted 2012-2015. Within 7 days of birth new-borns were randomised 1:1 to BCG or no BCG. Exclusion criteria were gestational age
      PubDate: 2017-09-20T03:50:28.913046-05:
      DOI: 10.1111/all.13314
  • AllergoOncology: Opposite Outcomes of Immune Tolerance in Allergy and
    • Authors: E Jensen-Jarolim; H J Bax, R Bianchini, S Crescioli, T R Daniels-Wells, D Dombrowicz, E Fiebiger, H J Gould, S Irshad, J Janda, D H Josephs, F Levi-Schaffer, L O′Mahony, G Pellizzari, M L Penichet, F Redegeld, F Roth-Walter, J Singer, E Untersmayr, L Vangelista, S N Karagiannis
      Abstract: While desired for the cure of allergy, regulatory immune cell subsets and non-classical Th2-biased inflammatory mediators in the tumour microenvironment can contribute to immune suppression and escape of tumours from immunological detection and clearance. A key aim in the cancer field is therefore to design interventions that can break immunological tolerance and halt cancer progression, whereas on the contrary allergen immunotherapy exactly aims to induce tolerance. In this position paper, we review insights on immune tolerance derived from allergy and from cancer inflammation, focusing on what is known about the roles of key immune cells and mediators. We propose that research in the field of AllergoOncology that aims to delineate these immunological mechanisms with juxtaposed clinical consequences in allergy and cancer may point to novel avenues for therapeutic interventions that stand to benefit both disciplines.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-16T17:30:35.466711-05:
      DOI: 10.1111/all.13311
  • Mucocutaneous Inflammation in the Ikaros Family Zinc Finger 1 (IKZF1) -
           keratin 5 specifc transgenic mice
    • Authors: Mayumi Ueta; Junji Hamuro, Hiromi Nishigaki, Naomi Nakamura, Katsuhiko Shinomiya, Katsura Mizushima, Yuki Hitomi, Risa Tamagawa-Mineoka, Norihiko Yokoi, Yuji Naito, Katsushi Tokunaga, Norito Katoh, Chie Sotozono, Shigeru Kinoshita
      Abstract: BackgroundOur genome-wide association study documented an association between cold medicine related Stevens-Johnson syndrome / toxic epidermal necrolysis (CM-SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation.MethodsHuman skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal keratinocytes (HEKa) also used for gene expression analysis. We also generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis.ResultsWe found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was up-regulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly up-regulated in the epidermis of Ikzf1 Tg compared with wild-type.ConclusionOur findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-15T10:30:20.658949-05:
      DOI: 10.1111/all.13308
  • The ARIA score of allergic rhinitis using mobile technology correlates
           with quality-of-life: The MASK study
    • Authors: J Bousquet; S Arnavielhe, A Bedbrook, J Fonseca, M Morais Almeida, A Todo Bom, I Annesi-Maesano, D Caimmi, P Demoly, P Devillier, V Siroux, E Menditto, G Passalacqua, C Stellato, M T Ventura, A A Cruz, F S Serpa, J da Silva, D Larenas-Linnemann, M Rodriguez Gonzalez, M T Burguete Cabañas, K C Bergmann, T Keil, L Klimek, R Mösges, S Shamai, T Zuberbier, M Bewick, D Price, D Ryan, A Sheikh, J M Anto, J Mullol, A Valero, T Haahtela, E Valovirta, W J Fokkens, P Kuna, B Samolinski, C Bindslev-Jensen, E Eller, S Bosnic-Anticevich, R E O'Hehir, PV Tomazic, A Yorgancioglu, B Gemicioglu, C Bachert, P W Hellings, I Kull, E Melén, M Wickman, M van Eerd, G De Vries,
      Abstract: Mobile technology has been used to appraise allergic rhinitis control but more data are needed. In order to better assess the importance of mobile technologies in rhinitis control, the ARIA (Allergic Rhinitis and its Impact on Asthma) score ranging from 0 to 4 of the Allergy Diary was compared with EQ-5D (EuroQuol) and WPAI-AS (Work Productivity and Activity Impairment in allergy) in 1,288 users in 18 countries. This study showed that quality-of-life data (EQ-5D visual analogue scale and WPA-IS Question 9) are similar in users without rhinitis and in those with mild rhinitis (scores 0-2). Users with a score of 3 or 4 had a significant impairment in quality-of-life questionnaires.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-14T04:06:27.586892-05:
      DOI: 10.1111/all.13307
  • Validation of patient-reported global severity of atopic dermatitis in
    • Authors: Paras P. Vakharia; Rishi Chopra, Ryan Sacotte, Neha Patel, Supriya Immaneni, Takeshia White, Robert Kantor, Derek Y. Hsu, Jonathan I. Silverberg
      Abstract: BackgroundAtopic dermatitis (AD) is associated with a heterogeneous presentation and clinical course. There is a lack of simple and validated severity assessments that are feasible for clinical practice and epidemiological research.ObjectivesWe sought to validate patient-reported global AD severity in adults.MethodsWe performed a prospective dermatology practice-based study using questionnaires and evaluation by a dermatologist (n=265).ResultsAt baseline and follow-up, patient-reported global AD severity significantly correlated with oSCORAD (Spearman rho=0.56 and 0.49), SCORAD (0.64 and 0.56), EASI (0.56 and 0.50), BSA (0.52 and 0.45), NRS-itch (0.60 and 0.53), POEM (0.50 and 0.48), and DLQI (0.50 and 0.49) (P
      PubDate: 2017-09-14T04:03:16.249451-05:
      DOI: 10.1111/all.13309
  • Mast cells and sphingosine-1-phosphate underlie prelesional remodeling in
           a mouse model of eczema
    • Authors: Piper A. Wedman; Ahmed Aladhami, Alena P. Chumanevich, John W. Fuseler, Carole A. Oskeritzian
      Abstract: Atopic dermatitis (AD) is a chronic skin inflammation that affects children and adults worldwide, but its pathogenesis remains ill-understood. We show that a single application of OVA to mouse skin initiates remodeling and cellular infiltration of the hypodermis measured by a newly developed computer-aided method. Importantly, we demonstrate that skin mast cell (MC) activation and local sphingosine-1-phosphate (S1P) are significantly augmented after OVA treatment in mice. Deficiency in sphingosine kinase (SphK)1, the S1P-producing enzyme, or in MC, remarkably mitigates all signs of OVA-mediated remodeling and MC activation. Furthermore, skin S1P levels remain unchanged in MC-deficient mice exposed to OVA. LPS-free OVA does not recapitulate any of the precursor signs of AD, supporting a triggering contribution of LPS in AD that, per se, suffice to activate local MC and elevate skin S1P. We describe MC and S1P as novel pathogenic effectors that initiate remodeling in AD prior to any skin lesions and reveal the significance of LPS in OVA used in most studies, thus mimicking natural antigen (Ag) exposure.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-14T04:03:10.904811-05:
      DOI: 10.1111/all.13310
  • Current practice of allergy diagnosis and the potential impact of
           regulation in Europe
    • Authors: Victoria Cardona; Pascal Demoly, Sten Dreborg, A. Fusun Kalpaklioglu, Ludger Klimek, Antonella Muraro, Oliver Pfaar, Todor A. Popov, Hans Jürgen Hoffmann
      Abstract: In the European Union (EU), the regulatory framework regarding diagnostic allergen extracts is currently in the process of being implemented at the national level. Due to these regulations, the initial and periodic renewal expenses for the registration of diagnostic allergen extracts may render extract production unprofitable. Consequently, many extracts may be at risk of removal from the market. The current survey, which was conducted by a task force of the European Academy of Allergy and Clinical Immunology, aimed to assess the current practice of allergy diagnosis in Europe. This survey revealed that skin tests continue to be the main diagnostic procedure and are used as the first option in almost 2/3 of all types of allergic diseases and in 90% of individuals suffering from respiratory allergies. Therefore, there is a need to ensure the availability of high-quality allergen extracts to maintain the common diagnostic procedures used by EU professionals. To reach this goal, it is necessary to align efforts and establish active partnerships between manufacturers, relevant scientific societies, consumer organizations and authorities to maintain the availability of these diagnostic tools.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-14T03:12:11.41958-05:0
      DOI: 10.1111/all.13306
  • Drug Repurposing to treat Asthma and Allergic Disorders: Progress and
    • Authors: Robert L. Kruse; Kristine Vanijcharoenkarn
      Abstract: Allergy and atopic asthma have continued to become more prevalent in modern society despite the advent of new treatments, representing a major global health problem. Common medications such as antihistamines and steroids may have undesirable long-term side effects and lack efficacy in some resistant patients. Biologic medications are increasingly given to treat resistant patients, but they can represent high costs, complex dosing and management, and are not widely available around the world. The field needs new, cheap and convenient treatment options in order to bring better symptom relief to patients. Beyond continued research and development of new drugs, a focus on drug repurposing could alleviate this problem by repositioning effective and safe small molecule drugs from other fields of medicine and applying them toward the treatment of asthma and allergy. Herein, preclinical models, case reports, and clinical trials of drug repurposing efficacy in allergic disease are reviewed. Novel drugs are also proposed for repositioning based on their mechanism of action to treat asthma and allergy. Overall, drug repurposing could become increasingly important as a way of advancing allergy and atopic asthma treatment, filling a need in treatment for patients today.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-07T02:25:22.472083-05:
      DOI: 10.1111/all.13305
  • Targeting histone-acetyltransferase Tip60 inhibits intestinal allergy
    • Authors: Gui Yang; Bao-Hui Cheng, Shao-Bo Yang, Zhi-Qiang Liu, Shu-Qi Qiu, Li-Tao Yang, Rui-Di Xie, Xiao-Rui Geng, Mao-Gang Li, Lin Gao, Zhi-Gang Liu, Ping-Chang Yang
      Abstract: BackgroundThe over production of IgE plays a critical role in the pathogenesis of allergy; the mechanism is unclear. Histone acetyltransferase (HAT) activities are required in gene transcription of a large number of molecules in the immune system of the body.ObjectivesThis study tests a hypothesis that HAT Tat-interactive protein 60 (Tip60) plays an important role in the initiation of IgE-mediated allergy.MethodsThe effects of Tip60 on regulating IgE expression were assessed with B cells. An intestinal allergy mouse model was developed to assess the role of Tip60 in the induction of IgE-mediated allergic inflammation.ResultsHigh levels of Tip60 were observed in the peripheral B cells of patients with FA. Tip60 was required in the expression of IgE and IgG1 in B cells by inducing the chromatin remolding at the gene locus, in which histone acetylation, signal transducer and activator of transcription 6 (STAT6) and nuclear factor-κB at the locus of Iε promoter were markedly increased. Blocking Tip60 significantly attenuated the allergic inflammation in the mouse intestinal mucosa.ConclusionsTip60 plays an important role in the induction of IgE in B cells. Blocking Tip60 inhibits the allergic inflammation in the intestine, suggesting Tip60 inhibitor may be a potential anti-allergy drug.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-04T21:21:32.519411-05:
      DOI: 10.1111/all.13304
  • Association of Breast Milk Fatty Acids and Allergic Disease Outcomes
           – a Systematic Review
    • Authors: Nilakshi T Waidyatillake; Shyamali C Dharmage, Katrina J. Allen, Caroline J Lodge, Julie A Simpson, Gayan Bowatte, Michael J. Abramson, Adrian J Lowe
      Abstract: IntroductionDietary poly unsaturated fatty acids (PUFA) have immune regulatory properties. Breast milk is rich in PUFA, and it has been hypothesised that these PUFAs may be important in the aetiology of allergic diseases. Despite a growing body of evidence, the associations between breast milk PUFA and allergic disease have not previously been systematically reviewed.MethodsThe search was performed in PubMed and EMBASE databases using breastfeeding, fatty acid and allergic disease terms. Two authors were involved in selecting papers for review according to the inclusion criteria and extracting information on study characteristics and measures of association. Only studies that reported numeric associations between concentration of breast-milk fatty acids and allergic disease outcomes were included.ResultsA total of 18 papers met the inclusion criteria, reporting results from 15 study populations. The majority were cohort studies (n=11), with data from only two case control and two cross sectional studies. Sample size varied between 30 and 352 participants and follow-up time of the cohorts varied between three months and 14 years. Nine studies reported on eczema, seven on sensitisation and only five reported on asthma/wheeze. There was heterogeneity among studies in terms of presenting the association between PUFA and allergy, therefore estimates could not be pooled. Only a few studies observed associations between n-3 and n-6 PUFAs and allergic disease, and the magnitude of this effect varied greatly.ConclusionsThere is insufficient evidence to suggest that colostrum or breast milk poly unsaturated fatty acids influence the risk of childhood allergic diseases.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-04T13:50:49.984054-05:
      DOI: 10.1111/all.13300
  • Hen's egg allergen in house and bed dust is significantly increased after
           hen's egg consumption – a pilot study
    • Authors: Valérie Trendelenburg; Sebastian Tschirner, Bodo Niggemann, Kirsten Beyer
      Abstract: Environmental exposure to food allergens may be a risk factor for cutaneous sensitization. Previous studies could detect peanut allergen in house dust. In this pilot study, we wanted to investigate whether hen's egg allergen is detectable in house dust collected from different household areas and whether levels are increased after intentional hen's egg consumption. Hen's egg protein levels of dust samples were measured using ELISA. In 8/8 households, hen's egg was detectable in dust samples of eating area and bed. 48 hours after intentional hen's egg consumption, hen's egg protein levels were significantly increased in both. Still, further research is necessary to investigate whether hen's egg allergen in house and bed dust plays a role in sensitization via skin.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-02T09:55:23.037145-05:
      DOI: 10.1111/all.13303
  • Response to omalizumab using patient enrichment criteria from trials of
           novel biologics in asthma
    • Authors: Thomas B. Casale; Bradley E. Chipps, Karin Rosén, Benjamin Trzaskoma, Tmirah Haselkorn, Theodore A. Omachi, Steven Greenberg, Nicola A. Hanania
      Abstract: BackgroundRecent efficacy studies of asthma biologics have included highly enriched patient populations. Using a similar approach, we examined factors that predict response to omalizumab to facilitate selection of patients most likely to derive the greatest clinical benefit from therapy.MethodsData from two phase III clinical trials of omalizumab in patients with allergic asthma were examined. Differences in rates of asthma exacerbations between omalizumab and placebo groups during the 16-week inhaled corticosteroid (ICS) dose-stable phase were evaluated with respect to baseline blood eosinophil counts (eosinophils
      PubDate: 2017-08-31T16:55:29.380888-05:
      DOI: 10.1111/all.13302
  • Allergic FcεRI- and pseudo-allergic MRGPRX2-triggered mast cell
           activation routes are independent and inversely regulated by SCF
    • Authors: Magda Babina; Sven Guhl, Metin Artuc, Torsten Zuberbier
      Abstract: While allergic mast cell (MC) degranulation occurs by FcεRI-aggregation and varies in strength among subjects, the analogous pseudo-allergic route was recently uncovered to proceed via MRGPRX2. Here, we examine inter-individual variability in skin MC responses to FcεRI-triggering versus those evoked by MRGPRX2. While population-based variability is comparable between the routes, FcεRI- and MRGPRX2-stimulated pathways are completely independent from each other, and responsiveness to one has therefore no predictive value for the other. Conversely, degranulation triggered by compound 48/80 is highly correlated to the process elicited by Substance P. MRGPRX2 mRNA shows pronounced population-based variability (coefficient of variation 102.9%). Surprisingly, SCF as the MC-supportive mediator par excellence potently inhibits pseudo-allergic degranulation, while it simultaneously promotes allergic stimulation via FcεRI. We conclude that SCF can have selective MC-dampening functions. Clinically, the data imply that subjects highly reactive in one pathway are not automatically hyper-responsive in terms of the alternative route.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-31T16:55:27.456066-05:
      DOI: 10.1111/all.13301
  • 12-OH-17,18-epoxyeicosatetraenoic acid alleviates eosinophilic airway
           inflammation in murine lungs
    • Authors: Takao Mochimaru; Koichi Fukunaga, Jun Miyata, Masako Matsusaka, Katsunori Masaki, Hiroki Kabata, Soichiro Ueda, Yusuke Suzuki, Tomomi Goto, Daisuke Urabe, Masayuki Inoue, Yosuke Isobe, Makoto Arita, Tomoko Betsuyaku
      Abstract: BackgroundAsthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs.MethodsMale C57BL6 mice were sensitized and challenged by OVA. After EPA treatment, we evaluated the cell count of BALF, mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA in vivo and vitro study.ResultsEPA treatment reduced accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4.ConclusionThese results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-30T10:45:50.841587-05:
      DOI: 10.1111/all.13297
  • Altered miR-193a-5p expression in children with cow's milk allergy
    • Authors: Valeria D'Argenio; Valentina Del Monaco, Lorella Paparo, Fatima Domenica Elisa De Palma, Rita Nocerino, Francesca D'Alessio, Feliciano Visconte, Valentina Discepolo, Luigi Del Vecchio, Francesco Salvatore, Roberto Berni Canani
      Abstract: BackgroundCow's milk allergy (CMA) is one of the most common food allergies in children. Epigenetic mechanisms have been suggested to play a role in CMA pathogenesis. We shown that DNA methylation of Th1/Th2 cytokine genes and FoxP3 affects CMA disease course. Preliminary evidence suggest that also the miRNome could be implicated in the pathogenesis of allergy. Main study outcome was to comparatively evaluate miRNome in children with CMA and in healthy controls.MethodsPeripheral blood mononuclear cells were obtained from children aged 4-18 months: 10 CMA patients, 9 CMA patients who outgrew CMA, and 11 healthy controls. Small RNA libraries were sequenced using a next-generation sequencing-based approach. Functional assessment of IL-4 expression was also performed.ResultsAmong the miRNAs differently expressed, 2 were up-regulated and 14 were down-regulated in children with active CMA compared to healthy controls. miR-193a-5p resulted the most down-regulated miRNA in children with active CMA compared to healthy controls. The predicted targets of miR-193a-5p resulted up-regulated in CMA patients compared to healthy controls. Peripheral blood CD4+ T cells transfected with a miR193a-5 inhibitor showed a significant up-regulation of IL-4 mRNA and its protein expression. Children who outgrew CMA showed miRNA-193a-5p level, and its related targets expression, similar to that observed in healthy controls.ConclusionsOur results suggest that miR-193a-5p is a post-transcriptional regulator of IL-4 expression and could have a role in IgE-mediated CMA. This miRNA could be a novel diagnostic and therapeutic target for this common form of food allergy in childhood.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-30T09:55:23.21213-05:0
      DOI: 10.1111/all.13299
  • 5-/12-lipoxygenase-linked cascade contributes to the IL-33-induced
           synthesis of IL-13 in mast cells, thus promoting asthma development
    • Authors: MyungJa Ro; A-Jin Lee, Jae-Hong Kim
      Abstract: BackgroundAs asthma progresses, the levels of IL-33 in serum are markedly increased and contribute to asthmatic development and exacerbation. Mast cells, one of the principal effector cells in the pathogenesis of asthma, express high levels of the IL-33 receptor ST2 and have been shown to be activated by IL-33. Thus, IL-33 stimulates mast cells to produce Th2-type cytokines such as IL-13, thus contributing to asthmatic development. However, the signaling mechanism for IL-33-induced synthesis of Th2 cytokines, particularly IL-13, has not been fully elucidated in mast cells.MethodsThe role of 5- or 12-LO in the IL-33-induced synthesis of IL-13 was investigated using knockdown or pharmacological inhibitors in BMMCs and animal model.ResultsBlockade of 5- or 12-LO significantly suppressed IL-33-induced synthesis of IL-13 in BMMCs. The subsequent action of 5- and 12-LO metabolites through their specific receptor, BLT2, was also critical for IL-33-induced synthesis of IL-13. We also demonstrated that the MyD88-p38 kinase cascade lies upstream of 5-/12-LO and that NF-κB lies downstream of 5-/12-LO to mediate the IL-33-induced synthesis of IL-13 in mast cells. Consistent with these findings, we observed that in an IL-33-administered asthmatic airway inflammation model, IL-13 levels were markedly increased in bronchoalveolar lavage fluid, but its levels were markedly suppressed by treatment with inhibitors of 5-LO, 12-LO or BLT2, further suggesting roles of 5-/12-LO in IL-33-induced IL-13 production.ConclusionOur results suggest that ‘MyD88-5-/12-LO-BLT2-NF-κB’ cascade significantly contributes to the IL-33-induced synthesis of IL-13 in mast cells, thus potentially contributing to asthmatic development and exacerbation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-30T09:50:45.874536-05:
      DOI: 10.1111/all.13294
  • Pathogenicity of memory Th2 cells is linked to stage of allergic rhinitis
    • Authors: Tomohisa Iinuma; Yoshitaka Okamoto, Yuki Morimoto, Tomoyuki Arai, Toshioki Sakurai, Syuji Yonekura, Daiju Sakurai, Kiyoshi Hirahara, Toshinori Nakayama
      Abstract: BackgroundAllergic rhinitis (AR) consists of three developmental stages that are based on the presence/absence of antigen-specific IgE and symptoms. The pathogenic Th2 (Tpath2) cells constitute a population of Th2 cells with additional potentially pathogenic characteristics. We examined the relationship between Tpath2 cells and the stages of allergic rhinitis by focusing on ST2, which is an IL-33 receptor.MethodsPatients with Japanese cedar pollen-induced AR (JCP-AR) and healthy volunteers were divided into “non-sensitized,” “asymptomatic sensitized (AS),” and “JCP-AR” groups. We analyzed the ST2 expression and the Th2 function of cultured CD4+ T cells. Next, we observed the progress of patients in the AS stage around the time of seasonal pollen dispersal, with the characteristics of Th2 cells.ResultsThe ST2 expression of T cells was only upregulated in the AR group. The production of IL-4 and IL-13 was found in CD4+ T cells obtained from AS by stimulation with JCP, but reactivity to IL-33 was not observed. Although IL-33 did not induce the elevation of IL-4 production in the JCP-AR group, IL-33 substantially increased the production of IL-5 and IL-13 in comparison to antigen stimulation alone. In newly afflicted patients, the increased expression of ST2 and elevated reactivity to IL-33 was observed, even before the pollen dispersal season.ConclusionsOur study demonstrated that the pathogenicity of memory Th2 cells is linked to sensitization and the stage of allergic rhinitis. Therefore, Tpath2 cells may provide useful insights into the mechanism of the onset and progression of allergic rhinitis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-30T09:50:36.50883-05:0
      DOI: 10.1111/all.13295
  • Simultaneous induction of HSP70 expression, and degranulation, in
           IgE/Ag-stimulated or extracellular HSP70-stimulated mast cells (129/200)
    • Authors: Xian Li; Shiro Kanegasaki, Fansi Jin, Yifeng Deng, Jae-Ryong Kim, Hyeun Wook Chang, Tomoko Tsuchiya
      Abstract: BackgroundIn mast cells, induction of HSP70 expression during antigen stimulation has not been reported.MethodsMouse bone marrow derived mast cells (BMMC) were stimulated with IgE/Ag or HSP70. Induction of HSP70 expression, and signaling protein phosphorylation, were evaluated by immunoblotting.ResultsHSP70 expression is induced in BMMC at an early stage of IgE/Ag-dependent stimulation, some of which is released from the cells in a granule-associated form. Induction of HSP70 expression was also observed with an IgE/Ag-stimulated human basophilic cell line, indicating that the phenomenon is not restricted to mouse BMMC. The induction of HSP70 expression, and its release, followed a similar time course to that of degranulation. Released HSP70 seems to be responsible for degranulation and production of eicosanoids, at least in part, since a neutralizing anti-HSP70 antibody mitigated these activities, and since exogenous HSP70 not only induced immediate degranulation followed by autocrine HSP70 expression but also enhanced degranulation in IgE/Ag stimulated BMMC. Extracellular HSP70 was found to induce phosphorylation of Linker for activation of T cells (LAT) and a series of downstream signaling molecules in BMMC. We further found that Fyn, Lyn and spleen tyrosine kinase (Syk), which are known to concern LAT phosphorylation in IgE/Ag stimulated BMMC, were not phosphorylated in HSP70-stimulated BMMC, whereas lymphocyte-specific-protein tyrosine kinase (Lck) was phosphorylated.ConclusionFcεRI stimulation in BMMC and basophils induces HSP70 expression and its release. Extracellular HSP70 induces degranulation and mediator release via phosphorylation of LAT.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-30T09:50:24.361171-05:
      DOI: 10.1111/all.13296
  • Challenges in the implementation of the EAACI AIT guidelines: A
           situational analysis of current provision of allergen immunotherapy
    • Authors: D Ryan; R Gerth van Wijk, E Angier, M Kristiansen, H Zaman, A Sheikh, V Cardona, C Vidal, A Warner, I Agache, S Arasi, M Fernandez-Rivas, S Halken, M Jutel, S Lau, G Pajno, O Pfaar, G Roberts, G Sturm, E M Varga, R Van Ree, A Muraro
      Abstract: PurposeThe European Academy of Allergy and Clinical Immunology (EAACI) has produced Guidelines on Allergen Immunotherapy (AIT). We sought to gauge the preparedness of primary care to participate in the delivery of AIT in Europe.MethodsWe undertook a mixed-methods, situational analysis. This involved a purposeful literature search, and two surveys: one to primary care clinicians and the other to a wider group of stakeholders across Europe.ResultsThe 10 papers identified all pointed out gaps or deficiencies in allergy care provision in primary care. The surveys also highlighted similar concerns, particularly in relation to concerns about lack of knowledge, skills, infrastructural weaknesses, reimbursement policies and communication with specialists as barriers to evidence-based care. Almost all countries (92%) reported the availability of AIT. In spite of that, only 28% and 44% of the countries reported the availability of guidelines for primary care physicians and specialists, respectively. Agreed pathways between specialists and primary care physicians were reported as existing in 32-48% of countries. Reimbursement appeared to be an important barrier as AIT was only fully reimbursed in 32% of countries. Additionally, 44% of respondents considered accessibility to AIT and 36% stating patient costs were barriers.ConclusionsSuccessful working with primary care providers is essential to scaling-up AIT provision in Europe, but to achieve this the identified barriers must be overcome. Development of primary care interpretation of guidelines to aid patient selection, establishment of disease management pathways and collaboration with specialist groups are required as a matter of urgency.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-29T02:31:23.647522-05:
      DOI: 10.1111/all.13264
  • Local allergic rhinitis is an independent rhinitis phenotype: The results
           of a 10-years follow-up study
    • Authors: Carmen Rondon; Paloma Campo, Ibon Eguiluz Gracia, Carmen Plaza, Gador Bogas, Pedro Galindo, C Mayorga, M J Torres
      Abstract: BackgroundThe knowledge about the natural history of local allergic rhinitis (LAR) is limited. One unmeet question is to demonstrate whether LAR should be considered the first step in the development of allergic rhinitis (AR) or an independent phenotype. The aim of this study was to prospectively evaluate the natural history of a population with LAR, the potential conversion to AR with systemic atopy, and the development of asthma during 10 years.MethodsThis is the second phase of a 10 year follow-up study of a cohort of 176 patients with LAR of recent onset and 115 age- and sex-matched healthy controls prospectively evaluated from 2005 to 2016. Clinical-demographic questionnaire, spirometry, skin prick-test, and specific-IgE were evaluated yearly. Nasal allergen provocation tests (NAPT) with D. pteronyssinus, Alternaria alternata, Olea europaea, and grass pollen were performed at baseline, and after 5 and 10 years.ResultsAfter 10 years LAR patients experienced a significant and clinically relevant worsening of the rhinitis, with increase of emergency assistance, development of asthma, loss of allergen tolerance, and impairment of the quality of life. This worsening became significant after 5 years and progressed throughout 10 years.A similar rate of development of AR with systemic atopy was detected in patients and controls (9.7% vs 7.8%, Log-rank p=0.623). In 5 patients conversion to systemic atopy occurred>10 years (3%).ConclusionsLAR is a well-differentiated clinical entity with a low rate of development of systemic atopy, a natural evolution towards worsening and a risk factor for suffering asthma.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-22T20:25:28.551386-05:
      DOI: 10.1111/all.13272
  • Comparison and Interpretability of the available Urticaria Activity Scores
    • Authors: T. Hawro; T. Ohanyan, N. Schoepke, M. Metz, A. Peveling-Oberhag, P. Staubach, M. Maurer, K. Weller
      Abstract: The urticaria activity score (UAS) is the gold standard for assessing disease activity in patients with chronic spontaneous urticaria (CSU). Two different versions, the UAS7 and UAS7TD, are currently used in clinical trials and routine care. To compare both versions and to obtain data on their interpretability, 130 CSU patients applied both versions and globally rated their disease activity as none, mild, moderate, or severe. UAS7 and UAS7TD values correlated strongly (r=0.90, P
      PubDate: 2017-08-16T04:25:20.036967-05:
      DOI: 10.1111/all.13271
  • Hereditary angioedema with a mutation in the plasminogen gene
    • Authors: K. Bork; K. Wulff, L. Steinmüller-Magin, I. Braenne, P. Staubach-Renz, G. Witzke, J. Hardt
      Abstract: BackgroundHereditary angioedema (HAE) with normal C1-INH (HAEnCI) may be linked to specific mutations in the coagulation factor 12 (FXII) gene (HAE-FXII) or functional mutations in other genes that are still unknown. We sought to identify and characterize a hitherto unknown type of HAE with normal C1-INH and without mutation in the F12 gene.MethodsThe study comprised analysis of whole exome sequencing, Sanger sequencing, and clinical data of patients.ResultsWe detected a mutation in the plasminogen gene in patients with HAEnCI. The mutation c.9886A>G was located in exon 9 leading to the missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of the plasminogen protein. The mutation was identified by next generation sequencing in 14 patients with HAEnCI belonging to 4 of 7 families. Family studies revealed that this type of HAE was transmitted as an autosomal dominant trait. The plasminogen gene mutation was present in all studied symptomatic patients and was also found in 9 out of 38 index patients from 38 further families with HAEnCI. Most patients had swelling of face/lips (78.3%) and tongue (78.3%). 331 out of all 3.795 tongue swellings (8.7%) were associated with dyspnea, voice changes and imminent asphyxiation. Two women died by asphyxiation due to a tongue swelling.ConclusionsHAE with a mutation in the plasminogen gene is a novel type of HAE. It is associated with a high risk of tongue swellings.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-10T04:45:22.173062-05:
      DOI: 10.1111/all.13270
  • Evolution of the IgE and IgG repertoire to a comprehensive array of
           allergen molecules in the first decade of life
    • Authors: Xinyuan Huang; Olympia Tsilochristou, Serena Perna, Stephanie Hofmaier, Antonio Cappella, Carl-Peter Bauer, Ute Hoffman, Johannes Forster, Fred Zepp, Antje Schuster, Raffaele D'Amelio, Ulrich Wahn, Thomas Keil, Susanne Lau, Paolo Maria Matricardi
      Abstract: BackgroundIn early childhood, the allergen-specific IgG repertoire is mainly directed to animal and vegetable food molecules and infrequently to airborne molecules. It is unknown whether this early pattern is maintained throughout childhood.ObjectiveTo investigate the evolution of IgG and IgE responses to a broad panel of allergenic molecules from birth to age 10yrs.MethodsWe examined the sera collected between birth and age 10yrs from participants in the German Multicentre Allergy Study, a birth cohort born in 1990. The IgE (cut-off ≥0.30 ISU) and IgG (cut-off ≥0.10 ISU) responses to 35 genuine allergenic molecules were measured with a multiplex microarray approach (ImmunoCAP ISAC™).ResultsIgE responses were mostly directed against a restricted group of airborne molecules, with a sequence and prevalence hierarchy (Phl p 1> Bet v 1> Fel d 1> Phl p 5> Der p 2> Der p 1) largely maintained over time. Conversely, the IgG repertoire was much broader, starting with animal foodborne, then spreading to vegetable foodborne and finally to airborne molecules. A strong and persistent IgG response to a given airborne molecule almost invariably preceded or accompanied an IgE response to that molecule.ConclusionsThe evolution of IgG and IgE responses throughout childhood differs widely at population level. IgG responses are mostly directed to animal food allergens while IgE responses are dominated by airborne allergens. However, a strong IgG response almost invariably precedes or accompanies the appearance of IgE to the same molecule in specifically sensitized subjects.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-08T19:00:44.103373-05:
      DOI: 10.1111/all.13269
  • Allergens displayed on Virus-Like Particles are highly immunogenic but
           fail to activate human mast cells
    • Authors: Paul Engeroff; Flurin Caviezel, Federico Storni, Franziska Thoms, Monique Vogel, Martin F. Bachmann
      Abstract: The goal of allergen-specific immunotherapy is the induction of protective immune responses in the absence of anaphylactic reactions. We have previously shown that Fel d 1, the major cat allergen, displayed in a repetitive fashion on virus-like particles (VLPs) may fulfill these criteria. Specifically, Fel d 1 on VLPs induced strongly increased IgG responses compared to the free allergen in mice while anaphylactic reactions were essentially abolished. Here we extend these findings to human mast cells and offer a mechanistic explanation for the reduced anaphylactic activity. By performing allergen binding studies and cellular activation assays, we demonstrate that the inability of Fel d 1 displayed on VLPs to activate mast cells is based on a biophysical as well as a biochemical mechanism. Firstly, Fel d 1 on VLPs showed a strongly impaired ability to bind to surface-bound IgE as assessed by Surface Plasmon Resonance (SPR) as well as flow cytometry. Secondly, despite residual binding, repetitively displayed allergen on VLPs failed to cause mast cell activation.These findings indicate that repetitively displaying allergens on VLPs increases their immunogenicity while reducing their potential to cause anaphylactic reactions by essentially eliminating IgE-mediated activation of mast cells.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-08T18:34:18.870268-05:
      DOI: 10.1111/all.13268
  • Local IL-25 contributes to Th2-biased inflammatory profiles in nasal
    • Authors: H.-Y. Hong; F.-H. Chen, Y.-Q. Sun, X.-T. Hu, Y. Wei, Y.-P. Fan, J. Zhang, D.-H. Wang, R. Xu, H.-B. Li, J.-B. Shi
      Abstract: BackgroundIL-25 has been proposed to play a key role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aims to evaluate the association of IL-25 with the Th2-biased inflammatory profiles in CRSwNP.MethodsNasal polyp (NP) tissues and control uncinate process tissues were collected from 92 patients with CRSwNP, 20 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 16 normal control subjects. IL-25 expression was examined using immunohistochemistry and immunofluorescence staining, flow cytometry, RT-qPCR, and ELISA. The inflammatory profiles and clinical characteristics of 2 NP subtypes (IL-25high and IL-25low) were evaluated, and the effects of IL-25 on Th2 cytokine production in cultured dispersed polyp cells were examined in vitro.ResultsThe mRNA and protein levels of IL-25 were significantly increased in the polyp tissues compared with the control uncinate process tissues. The IL-25high subtype showed greater computed tomography scores, endoscopic scores, and Th2 response. Exposure to IL-25 activated type 2 innate lymphoid cells and Th2 cells in NP simultaneously which further increased Th2 cytokine production in vitro.ConclusionsLocal IL-25 plays a crucial role in promoting Th2-biased inflammatory profiles in NP, and may serve as a promising therapeutic target in CRSwNP patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-03T12:55:22.909768-05:
      DOI: 10.1111/all.13267
  • Challenges in the implementation of EAACI Guidelines on Allergen
           Immunotherapy: A global perspective on the regulation of allergen products
    • Authors: A. Bonertz; G. Roberts, M. Hoefnagel, M. Timon, J. Slater, R. Rabin, J. Bridgewater, C. Pini, O. Pfaar, C. Akdis, J. Goldstein, L. K. Poulsen, R. van Ree, C. Rhyner, D. Barber, O. Palomares, A. Sheikh, R. Pawankar, D. Hamerlijnk, L. Klimek, I. Agache, E. Angier, T. Casale, M. Fernandez-Rivas, S. Halken, M. Jutel, S. Lau, G. Pajno, G. Sturm, E. Maria Varga, R. Gerth Wijk, S. Bonini, A. Muraro, S. Vieths
      Abstract: Regulatory approaches for allergen immunotherapy (AIT) products and the availability of high quality AIT products are inherently linked to each other. While allergen products are available in many countries across the globe, their regulation is very heterogeneous. First, we describe the regulatory systems applicable for AIT products in the European Union (EU) and in the United States (US). For Europe, a depiction of the different types of relevant procedures, as well as the committees involved is provided and the fundamental role of national agencies of the EU member states in this complex and unique network is highlighted. Furthermore, the regulatory agencies from Australia, Canada, Japan, Russia, and Switzerland provided information on the system implemented in their countries for the regulation of allergen products. While AIT products are commonly classified as biological medicinal products, they are made available by varying types of procedures, most commonly by either obtaining a marketing authorisation or by being distributed as named patient products. Exemptions from marketing authorisations in exceptional cases, as well as import of allergen products from other countries, are additional tools applied by countries to ensure availability of needed AIT products. Several challenges for AIT products are apparent from this analysis and will require further consideration.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-03T12:45:20.306224-05:
      DOI: 10.1111/all.13266
  • Assessment of eosinophilic airway inflammation as a contribution to the
           diagnosis of occupational asthma
    • Authors: Carolina Beretta; Catherine Rifflart, Geneviève Evrard, Jacques Jamart, Joël Thimpont, Olivier Vandenplas
      Abstract: BackgroundAscertaining the presence of asthma through the assessment of nonspecific bronchial hyperresponsiveness (NSBH) is a key step in the diagnosis of occupational asthma (OA). We aimed at investigating whether indices of airway inflammation including fractional exhaled nitric oxide (FeNO) and sputum eosinophils would be useful adjuncts to the measurement of NSBH in diagnosing OA defined as a positive specific inhalation challenge (SIC).MethodsThe study included 240 consecutive subjects with a suspicion of OA who completed a SIC, of whom 133 showed a positive response. The sensitivity, specificity, and predictive values of NSBH, and FeNO, as well as sputum eosinophil counts assessed at baseline of the SIC were determined.ResultsA concentration of histamine inducing a 20% decline in FEV1 (PC20) ≤16 mg/mL showed a sensitivity of 87% and a specificity of 36%. A FeNO level ≥25 ppb and a sputum eosinophil count ≥ 2% provided lower sensitivity rates (47% and 39%, respectively) than the PC20 value. Eight of the 17 subjects without baseline NSBH despite a positive SIC showed a sputum eosinophil count ≥2%, a FeNO level ≥25 ppb or both outcomes. Combining either a PC20 value ≤16mg/mL or a FeNO ≥25 ppb increased the sensitivity to 91%. Using either a PC20 ≤16mg/mL or a sputum eosinophil count ≥1% increased the sensitivity to 94%.ConclusionAdding the assessment of FeNO level and sputum eosinophils to NSBH improves the identification of subjects who may have OA and require further objective testing before excluding the possibility of OA.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-03T12:40:19.836433-05:
      DOI: 10.1111/all.13265
  • Blood and Nasal Epigenetics Correlate to Allergic Rhinitis Symptom
           Development in the Environmental Exposure Unit
    • Authors: Michelle L. North; Meaghan J. Jones, Julia L. MacIsaac, Alexander M. Morin, Lisa M. Steacy, Alexander Gregor, Michael S. Kobor, Anne K. Ellis
      Abstract: BackgroundEpigenetic alterations may represent new therapeutic targets and/or biomarkers of allergic rhinitis (AR). Our aim was to examine genome-wide epigenetic changes induced by controlled pollen exposure in the Environmental Exposure Unit (EEU).Methods38 AR-sufferers and 8 non-allergic controls were exposed to grass pollen for 3h on two consecutive days. We interrogated DNA methylation at baseline and 3h in peripheral blood mononuclear cells (PBMCs) using the Infinium Methylation 450K array. We corrected for demographics, cell composition, and multiple testing (Benjamini-Hochberg), and verified hits using bisulfite PCR-pyrosequencing and qPCR. To extend these findings to a clinically relevant tissue, we investigated DNA methylation and gene expression of mucin 4 (MUC4), in nasal brushings from a separate validation cohort exposed to birch pollen.ResultsIn PBMCs of allergic rhinitis participants, 42 sites showed significant DNA methylation changes of 2% or greater. DNA methylation changes in tryptase gamma 1 (TPSG1), schlafen 12 (SLFN12) and MUC4 in response to exposure were validated by pyrosequencing. SLFN12 DNA methylation significantly correlated with symptoms (p
      PubDate: 2017-07-29T09:50:33.932439-05:
      DOI: 10.1111/all.13263
  • EAACI Guidelines on Allergen Immunotherapy: Hymenoptera venom allergy
    • Authors: Gunter J Sturm; Eva-Maria Varga, Graham Roberts, Holger Mosbech, M. Beatrice Bilò, Cezmi A Akdis, Darío Antolín-Amérigo, Ewa Cichocka-Jarosz, Radoslaw Gawlik, Thilo Jakob, Mitja Kosnik, Joanna Lange, Ervin Mingomataj, Dimitris I Mitsias, Markus Ollert, Joanna N.G. Oude Elberink, Oliver Pfaar, Constantinos Pitsios, Valerio Pravettoni, Franziska Ruëff, Betül Ayşe Sin, Ioana Agache, Elizabeth Angier, Stefania Arasi, Moises A Calderón, Montserrat Fernandez-Rivas, Susanne Halken, Marek Jutel, Susanne Lau, Giovanni B Pajno, Ronald van Ree, Dermot Ryan, Otto Spranger, Roy Gerth van Wijk, Sangeeta Dhami, Hadar Zaman, Aziz Sheikh, Antonella Muraro
      Abstract: Hymenoptera venom allergy is a potentially life-threatening allergic reaction following a honeybee, vespid or ant sting. Systemic allergic sting reactions have been reported in up to 7.5% of adults and up to 3.4% of children. They can be mild and restricted to the skin or moderate-to-severe with a risk of life-threatening anaphylaxis. Patients should carry an emergency kit containing an adrenaline autoinjector, H1-antihistamines, and corticosteroids depending on the severity of their previous sting reaction(s). The only treatment to prevent further systemic sting reactions is venom immunotherapy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Venom Immunotherapy as part of the EAACI Guidelines on Allergen Immunotherapy initiative. The guideline aims to provide evidence-based recommendations for the use of venom immunotherapy, has been informed by a formal systematic review and meta-analysis and produced using the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included representation from a range of stakeholders. Venom immunotherapy is indicated in venom allergic children and adults to prevent further moderate to severe systemic sting reactions. Venom immunotherapy is also recommended in adults with only generalized skin reactions as it results in significant improvements in quality of life compared to carrying an adrenaline auto-injector. This guideline aims to give practical advice on performing venom immunotherapy. Key sections cover general considerations before initiating venom immunotherapy, evidence-based clinical recommendations, risk factors for adverse events and for relapse of systemic sting reaction, and a summary of gaps in the evidence.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-27T03:05:35.002498-05:
      DOI: 10.1111/all.13262
  • ADAM10 and Notch1 on murine dendritic cells control the development of
           type 2 immunity and IgE production
    • Authors: Sheela R. Damle; Rebecca K. Martin, Chelsea L. Cockburn, Joseph C. Lownik, Jason A. Carlyon, Allen D. Smith, Daniel H. Conrad
      Abstract: BackgroundAllergy and allergic asthma are significant health burdens in developed countries and are increasing in prevalence. Dendritic cells (DCs) initiate immune responses to common aeroallergens and ADAM10 has been demonstrated to be important for the development of adaptive responses. This study's objective was to understand the role of ADAM10 on DCs in the development of allergic and anaphylactic responses.MethodsIn this study we used mouse models of allergic airway inflammation (house dust mice and Alternaria alternata) and OVA-induced models of active anaphylaxis to determine the DC-specific function of ADAM10 and Notch signaling. To examine TH1 and TH17 immunity infection with Anaplasma phagocytophilum and Citrobacter rodentium were used.ResultsMice, which have ADAM10 deleted from DCs, have dramatic reductions in IgE production and do not develop significant TH2 immune responses. Further, ADAM10DC-/- mice are resistant to IgE-mediated anaphylaxis. This response is selective for TH2 immunity as TH1 and TH17 immunity are largely unaffected. Notch1, a known ADAM10 substrate, when knocked out of DCs (Notch1DC-/-) demonstrated a similar reduction in anaphylaxis and IgE. Without ADAM10 and Notch1 signaling, DCs were unable to make cytokines that stimulate TH2 cells and cytokines. Anaphylaxis and allergic lung inflammation were restored in ADAM10DC-/- with the overexpression of the Notch1-intracellular domain, confirming the role of Notch signaling.ConclusionsTargeting ADAM10 and Notch1 on DCs represent a novel strategy for modulating TH2 immune responses and IgE production.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-26T03:12:45.294422-05:
      DOI: 10.1111/all.13261
  • House dust mites as potential carriers for IgE sensitisation to bacterial
    • Authors: Sheron Dzoro; Irene Mittermann, Yvonne Resch, Susanne Vrtala, Marion Nehr, Alexander M. Hirschl, Gustav Wikberg, Lena Lundeberg, Catharina Johansson, Annika Scheynius, Rudolf Valenta
      Abstract: BackgroundIgE-reactivity to antigens from gram-positive and negative bacteria is common in patients suffering from respiratory and skin manifestations of allergy, but the routes and mechanisms of sensitisation are not fully understood. The analysis of the genome, transcriptome and microbiome of house dust mites (HDM) has shown that S. aureus and E. coli species are abundant bacteria within the HDM microbiome. Therefore, our aim was to investigate if HDM are carriers of bacterial antigens leading to IgE sensitisation in patients suffering from atopic dermatitis.MethodsPlasma samples from AD patients (n=179) were analysed for IgE-reactivity to a comprehensive panel of micro-arrayed HDM allergen molecules and to S. aureus and E. coli by IgE immunoblotting. Antibodies specific for S. aureus and E. coli antigens were tested for reactivity to nitrocellulose-blotted extract from purified HDM bodies and the IgE-reactive antigens were detected by IgE-immunoblot inhibition experiments. IgE antibodies directed to bacterial antigens in HDM were quantified by IgE ImmunoCAP™ inhibition experiments.ResultsIgE-reactivity to bacterial antigens was significantly more frequent in AD patients sensitised to HDM than in AD patients without HDM sensitisation. S. aureus and E. coli antigens were detected in immune-blotted HDM extract and the presence of IgE-reactive antigens in HDM was demonstrated by qualitative and quantitative IgE inhibition experiments.ConclusionHDM may serve as carriers of bacteria responsible for the induction of IgE sensitisation to microbial antigens.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-25T03:45:19.982048-05:
      DOI: 10.1111/all.13260
  • Asthma in the Elderly and Late-onset Adult Asthma
    • Authors: Ryan M. Dunn; Paula J. Busse, Michael E. Wechsler
      Abstract: Elderly asthmatics are at a higher risk for morbidity and mortality from their asthma than younger patients. There are important age-related physiologic and immunologic changes that complicate the presentation, diagnosis and management of asthma in the aged population. Evidence suggests that elderly asthmatics are more likely to be under-diagnosed and under-treated. Additionally, elderly patients with asthma have highest rates of morbidity and mortality from their disease than younger patients. The underlying airway inflammation of asthma in this age group likely differs from younger patients and is felt to be non-Type 2 mediated. While elderly patients are underrepresented in clinical trials, subgroup analysis of large clinical trials suggests they may be less likely to respond to traditional asthma therapies (i.e., corticosteroids). As the armamentarium of pharmacologic asthma therapies expands, it will be critical to include elderly asthmatics in large clinical trials so that therapy may be better tailored to this at-risk and growing population.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-19T10:15:36.971033-05:
      DOI: 10.1111/all.13258
  • The potential of anti-infectives and immunomodulators as therapies for
           asthma and asthma exacerbations
    • Authors: Michael R Edwards; Ross P Walton, David J Jackson, Wojciech Feleszko, Chrysanthi Skevaki, Tuomas Jartti, Heidi Makrinoti, Alexandra Nikonova, Igor Shilovskiy, Jurgen Schwarze, Sebastian L. Johnston, Musa Khaitov
      Abstract: Asthma is responsible for approximately 25,000 deaths annually in Europe despite available medicines that maintain asthma control and reduce asthma exacerbations. Better treatments are urgently needed for the control of chronic asthma and reduction of asthma exacerbations, the major cause of asthma mortality. Much research spanning>20 years shows a strong association between microorganisms including pathogens in asthma onset, severity and exacerbation, yet with the exception of antibiotics, few treatments are available that specifically target the offending pathogens. Recent insights into the microbiome suggest that modulating commensal organisms within the gut or lung may also be a possible way to treat/prevent asthma. The European Academy of Allergy & Clinical Immunology Task Force on Anti-infectives in Asthma was initiated to investigate the potential of anti-infectives and immunomodulators in asthma. This review provides a concise summary of the current literature and aims to identify and address key questions that concern the use of anti-infectives and both microbe and host based immunomodulators and their feasibility for use in asthma.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-19T10:15:34.019993-05:
      DOI: 10.1111/all.13257
  • Computational validation of the recently proposed pollen season definition
    • Authors: K. Karatzas; M. Riga, U. Berger, M. Werchan, O. Pfaar, K.Ch. Bergmann
      Abstract: In a recently published paper (Pfaar et al., 2016), a Task Force of the Immunotherapy and Aerobiology and Pollution Interest Groups of the EAACI suggested specific criteria for the definition of pollen exposure times for three types of pollen events: (a) Pollen Season (PS) start and end, (b) high pollen season (or Peak Pollen Period-PPP) start and end, and (c) high pollen days. Species addressed included Birch, Grasses, Cypress, Olive, and Ragweed. Two important questions arise from the aforementioned definitions: (i) do they lead to a narrow (thus well defined) time interval identifying start and end event dates (robustness of the criteria) and (ii) if slightly altered, will they result to a narrow (thus again well defined) fluctuation of start and end event dates (sensitivity of the criteria)' In an effort to provide with responses to aforementioned questions, we analyzed Poaceae pollen count data coming from Germany (up to 40 pollen monitoring stations, years 2012-2016). The analysis addressed all pollen events for the first question, and focused on the PS and PPP start and end events for the second question.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:29:39.437808-05:
      DOI: 10.1111/all.13255
  • Long term effects: Galectin-1 and specific immunotherapy for allergic
           responses in the intestine
    • Authors: Li-Tao Yang; Qing Shu, Xiang-Qian Luo, Zhi-Qiang Liu, Shu-Qi Qiu, Jiang-Qi Liu, Hai-Jian Guo, Lin-Jing Li, Mao-Gang Li, Da-Bo Liu, Li-Xin Xia, Zhi-Gang Liu, Ping-Chang Yang
      Abstract: Background and aimsMast cell activation interferes with the effects of allergen-specific immunotherapy (SIT). Galectin-1 (Gal-1) is capable of regulating immune cells’ functions. This study tests the hypothesis that administration of Gal-1 promotes and prolongs the efficacy of SIT via suppressing mast cell activation.MethodsAn intestinal allergy mouse model was developed. The co-administration of SIT and Gal-1 on suppression of the allergic responses, prevention of mast cell activation, and generation of antigen-specific regulatory T cells (Treg) in the intestine were observed in sensitized mice.ResultsThe coadministration of Gal-1 and SIT markedly suppressed the allergic responses in the mouse intestine vs. the use of either SIT alone or Gal-1 alone. The Gal-1 binds to the IgE/FcɛRI complexes on the surface of mast cells to prevent mast cell activation during SIT. Gal-1 promoted the SIT-generated allergen-specific Tregs in the intestine of sensitized mice. Coadministration of Gal-1 and SIT significantly enhanced the efficacy of immunotherapy in suppressing allergic responses in the intestine, which lasted for at least for 12 months.ConclusionsLong term effects of specific immunotherapy on intestinal allergy can be achieved with Gal-1/SIT therapy by inhibiting mast cell activation and facilitating Treg development.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:29:33.724806-05:
      DOI: 10.1111/all.13256
  • Health Economic Analysis of Allergen Immunotherapy (AIT) for the
           Management of Allergic Rhinitis, Asthma, Food Allergy and Venom Allergy: A
           Systematic Overview
    • Authors: Miqdad Asaria; Sangeeta Dhami, Ronald van Ree, Roy Gerth van Wijk, Antonella Muraro, Graham Roberts, Aziz Sheikh
      Abstract: BackgroundThe European Academy of Allergy and Clinical Immunology (EAACI) is developing guidelines for allergen immunotherapy (AIT) for the management of allergic rhinitis, allergic asthma, IgE-mediated food allergy and venom allergy. To inform the development of clinical recommendations, we undertook systematic reviews to critically assess evidence on the effectiveness, safety and cost-effectiveness of AIT for these conditions. This paper focusses on synthesizing data and gaps in the evidence on the cost-effectiveness of AIT for these conditions.MethodsWe produced summaries of evidence in each domain and then synthesized findings on health economic data identified from four recent systematic reviews on allergic rhinitis, asthma, food allergy and venom allergy, respectively. The quality of these studies were independently assessed using the Critical Appraisal Skills Programme (CASP) tool for health economic evaluations.Results23 studies satisfied our inclusion criteria. Of these, 19 studies investigated the cost-effectiveness of AIT in allergic rhinitis, of which seven were based on data from randomized controlled trials with economic evaluations conducted from a health system perspective. This body of evidence suggested that sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) would be considered cost-effective using the (English) National Institute for Health and Clinical Excellence (NICE) cost-effectiveness threshold of £20,000/quality adjusted life year (QALY). However, the quality of the studies and the general lack of attention to characterizing uncertainty and handling missing data should be taken into account when interpreting these results. For asthma, there were three eligible studies, all of which had significant methodological limitations; these suggested that SLIT, when used in patients with both asthma and allergic rhinitis, may be cost-effective with an incremental cost-effectiveness ratio (ICER) of £10,726 per QALY. We found one economic modelling study for venom allergy which, despite being based largely on expert opinion and plausible assumptions, suggested that AIT for bee and wasp venom allergy is only likely to be cost-effective for very high risk groups who may be exposed to multiple exposures to venom/year (e.g., bee keepers). We found no eligible studies investigating the cost-effectiveness of AIT for food allergy.ConclusionsOverall the evidence to support the cost-effectiveness of AIT is limited and of low methodological quality, but suggests that AIT may be cost-effective for people with allergic rhinitis with or without asthma and in high risk subgroups for venom allergy. We were unable to draw any conclusions on the cost-effectiveness of AIT for food allergy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:29:30.320786-05:
      DOI: 10.1111/all.13254
  • Therapeutic effect of capsaicin nasal treatment in patients with mixed
           rhinitis unresponsive to intranasal steroids
    • Authors: Laura Van Gerven; B Steelant, Y. A. Alpizar, Karel Talavera, Peter W Hellings
      Abstract: Literature is convincing regarding the efficacy of capsaicin nasal treatment in idiopathic rhinitis (IR). However, up to 50% of IR patients do not meet the strict inclusion criteria of the trials conducted so far. As a consequence, the efficacy of capsaicin is unknown in a significant number of IR patients that do not meet the strict inclusion/exclusion criteria (1)(2). ‘Mixed rhinitis’ (MR) patients have more than one major etiologic factor involved in the mucosal pathology. We have no idea about the efficacy of capsaicin nasal spray in these patients nor about the time interval to seek a second application. We report here that capsaicin nasal spray is effective in a broader group of IR than the purely selected ones described before, that subjective nasal hyperreactivity is a good predictor of positive outcome and that the time interval for seeking a second treatment is likely to be shorter in MR patients than in the strictly selected IR patients.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-16T08:05:25.013486-05:
      DOI: 10.1111/all.13245
  • Evidence of an abnormal epithelial barrier in active, untreated and
           corticosteroid-treated eosinophilic esophagitis
    • Authors: Dagmar Simon; Basile Page, Monique Vogel, Christian Bussmann, Carine Blanchard, Alex Straumann, Hans-Uwe Simon
      Abstract: BackgroundEosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated disease characterized by symptoms related to esophageal dysfunction and an eosinophil-predominant inflammation. This study has aimed to investigate whether the recently observed sensitization to Candida albicans in EoE patients is owing to pre-existing disease and its underlying abnormal epithelial barrier or, alternatively, is linked to corticosteroid (CS) therapy.MethodsMedical histories, as well as serum and tissue samples of 60 EoE patients (15 CS-naive, 45 with current or previous CS therapy) and 20 controls, stored in the Swiss Eosinophilic Esophagitis Database (SEED) and Biobank, were analyzed. We applied ImmunoCAP to measure IgE levels and immunofluorescence techniques to examine epithelial barrier components.ResultsEoE patients had higher total IgE levels and were more frequently sensitized to Candida albicans than controls. In EoE tissue specimens, increased numbers of eosinophils and mast cells, a higher expression levels of thymic stromal lymphopoietin (TSLP), cathelicidin, proteases, i.e. the kallikreins (KLK)-5 and KLK-7, were observed as compared with controls, while reduced expression of lympho-epithelial Kazal-type-related inhibitor (LEKTI), filaggrin, E-cadherin, claudin, occludin, demoglein-1 was found, independent of CS therapy. In CS-treated EoE, significantly lower numbers of CD1a+ cells and cathelicidin expression were noted as compared to CS-naive EoE.ConclusionThis study provides further evidence that EoE is associated with an abnormal epithelial barrier and postulates that CS therapy, by reducing innate immune mechanisms, may promote Candida albicans colonization and likely subsequent sensitization.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-16T08:05:22.863863-05:
      DOI: 10.1111/all.13244
  • A comparative study on basophil activation test, histamine release assay
           and passive sensitization histamine release assay in the diagnosis of
           peanut allergy
    • Authors: Lau Fabricius Larsen; Nanna Juel-Berg, Kirsten Skamstrup Hansen, E. N. Clare Mills, Ronald Ree, Lars K. Poulsen, Bettina M. Jensen
      Abstract: BackgroundAllergy can be diagnosed using basophil tests. Several methods measuring basophil activation are available. This study aimed at comparing basophil activation test (BAT), histamine release assay (HR) and passive sensitization histamine release assay (passive HR) in the diagnosis of peanut allergy.MethodsBAT, HR, and passive HR were performed on eleven peanut allergic and fourteen non-allergic subjects. Blood was incubated with peanut extract or anti-IgE and tests performed as follows: BAT - CD63-upregulation assessed by flow cytometry; HR - released histamine quantified by a glass fiber-based fluorometric method; Passive HR - IgE-stripped donor basophils were incubated with participants’ serum and histamine release quantified as HR.ResultsCDsens, a measure of basophil allergen sensitivity, was significantly higher for BAT (80.1 ± 17.4) compared to HR (23.4 ± 10.31) and passive HR (11.1 ± 2.0). BAT, HR, and passive HR had a clinical sensitivity of 100%, 100%, and 82%, and specificity of 100%, 100%, and 100%, respectively when excluding inconclusive results. BAT identified 11 of 11 allergic patients, HR 10 and passive HR 9. Likewise, BAT recognized 12 of 14 non-allergic subjects, HR 10 and passive HR 13. However, the tests’ diagnostic performances were not statistically different. Interestingly, non-releasers in HR but not in BAT had lower basophil count compared to releasers (249 vs. 630 counts/min).ConclusionBAT displayed a significant higher CDsens compared to HR and passive HR. The basophil tests’ diagnostic performances were not significantly different. Still, BAT could diagnose subjects with low basophil number in contrast to HR.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-07T08:15:29.642544-05:
      DOI: 10.1111/all.13243
  • Vitamin D supplementation in primary allergy prevention: systematic review
           of randomized and non-randomized studies
    • Authors: Juan José Yepes-Nuñez; Jan L. Brożek, Alessandro Fiocchi, Ruby Pawankar, Carlos Cuello-García, Yuan Zhang, Gian Paolo Morgano, Arnav Agarwal, Shreyas Gandhi, Luigi Terracciano, Holger J. Schünemann
      Abstract: BackgroundTo date, a systematic review of the evidence regarding the association between Vitamin D and allergic diseases development has not yet been undertaken.ObjectiveTo review the efficacy and safety of Vitamin D supplementation when compared to no supplementation in pregnant women, breastfeeding women, infants and children for the prevention of allergies.MethodsThree databases were searched through 30 January 2016 including randomized (RCT) and non-randomized studies (NRS). Two reviewers independently extracted data and assessed the certainty in the body of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.ResultsAmong the 1932 articles identified, one RCT and four NRS were eligible. Very low certainty in the body of evidence across examined studies suggests that Vitamin D supplementation for pregnant women, breastfeeding women and infants may not decrease the risk of developing allergic diseases such as atopic dermatitis (in pregnant women), allergic rhinitis (in pregnant women, and infants), asthma and/or wheezing (in pregnant women, breastfeeding women, and infants), or food allergies (in pregnant women). We found no studies of primary prevention of allergic diseases in children.ConclusionLimited information is available addressing primary prevention of allergic diseases after Vitamin D supplementation and its potential impact remains uncertain.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-04T13:10:37.198216-05:
      DOI: 10.1111/all.13241
  • Estimating the causal effect of body mass index on hay fever, asthma, and
           lung function using Mendelian randomization
    • Authors: Tea Skaaby; Amy E. Taylor, Betina H. Thuesen, Rikke K. Jacobsen, Nele Friedrich, Line Tang Møllehave, Susanne Hansen, Sofus C. Larsen, Uwe Völker, Matthias Nauck, Henry Völzke, Torben Hansen, Oluf Pedersen, Torben Jørgensen, Lavinia Paternoster, Marcus Munafò, Niels Grarup, Allan Linneberg
      Abstract: BackgroundObservational studies have shown that body mass index (BMI) is positively associated with asthma. However, observational data are prone to confounding and reverse causation. In Mendelian randomization, genetic variants are used as un-confounded markers of exposures to examine causal effects. We examined the causal effect of BMI on asthma, hay fever, allergic sensitization, serum total immunoglobulin E (IgE), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC).MethodsWe included 490,497 participants in the observational and 162,124 participants in the genetic analyses. A genetic risk score (GRS) was created using 26 BMI-associated single nucleotide polymorphisms (SNPs). Results were pooled in meta-analyses and expressed as odds ratios (ORs) or β-estimates with 95% confidence interval (CI).ResultsThe GRS was significantly associated with asthma (OR=1.009; 95% CI: 1.004, 1.013), but not with hay fever (OR= 0.998; 95% CI: 0.994, 1.002), or allergic sensitization (OR=0.999; 95% CI: 0.986, 1.012) per BMI-increasing allele. The GRS was significantly associated with decrease in FEV1: β=-0.0012 (95% CI: -0.0019, -0.0006) and FVC: β=-0.0022 (95% CI: -0.0031, -0.0014) per BMI-increasing allele. Effect sizes estimated by instrumental variable analyses were OR=1.07 (95% CI: 1.03, 1.10) for asthma, a 9 ml decrease in FEV1 (95% CI: 2.0-15 ml decrease), and a 16 ml decrease in FVC (95% CI: 7.0-24 ml decrease) per 1 kg/m2 higher BMI.ConclusionsThe results support the conclusion that increasing BMI is causally related to higher prevalence of asthma and decreased lung function, but not with hay fever or biomarkers of allergy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-04T13:10:29.03563-05:0
      DOI: 10.1111/all.13242
  • Ultra-short-course booster is effective in recurrent grass
           pollen–induced allergic rhinitis
    • Authors: O. Pfaar; S. Lang, U. Pieper-Fürst, A. Astvatsatourov, F. Gerich, L. Klimek, M. F. Kramer, Y. Reydelet, K. Shah-Hosseini, R. Mösges
      Abstract: BackgroundA relevant proportion of allergic rhinitis (AR) patients experience recurrent symptoms after successfully completing allergen immunotherapy (AIT). This prospective, controlled, non-interventional study used internationally standardised instruments to determine the clinical effects of a preseasonal, ultra-short-course booster AIT on clinical outcome parameters.MethodsThis two-arm study included patients aged ≥12 years with recurrent grass pollen–induced seasonal AR who had completed a successful course of any grass pollen AIT at least five years before enrolment. Overall, 56 patients received one preseasonal short-course booster AIT using tyrosine-absorbed grass pollen allergoids containing the adjuvant monophosphoryl lipid A (MPL®); 51 control patients received symptomatic medication. The combined symptom and medication score (CSMS) was recorded in the (peak) grass pollen season. Furthermore, concomitant (antiallergic) medication use, the patients'state of health, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) results, and safety/tolerability of the treatment were assessed.ResultsThe CSMS in the peak grass pollen season was significantly lower in the booster AIT group (Δ=38.4%, P
      PubDate: 2017-07-04T02:20:41.796844-05:
      DOI: 10.1111/all.13240
  • Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in
           atopic dermatitis
    • Authors: Masutaka Furue; Kazuhiko Yamamura, Makiko Kido-Nakahara, Takeshi Nakahara, Yoshinori Fukui
      Abstract: Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder associated with skin barrier dysfunction. The lesional skin of AD exhibits T helper 2 (TH2)-deviated immune reactions. Interleukin-31 (IL-31), preferentially produced from TH2 cells, is a potent pruritogenic cytokine, and its systemic and local administration induces scratching behavior in rodents, dogs and monkeys. Recent clinical trials have revealed that administration of an anti-IL-31 receptor antibody significantly alleviates pruritus in patients with AD. In this review, we summarize recent topics related to IL-31 and its receptor with special references to atopic itch.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-03T02:26:52.735656-05:
      DOI: 10.1111/all.13239
  • Meat allergy associated with α-Gal – Closing diagnostic gaps by
           anti-α-Gal IgE immune profiling
    • Authors: U. Jappe; S. Minge, B. Kreft, A. Ludwig, B. Przybilla, A. Walker, R. Varga, P. Seidel, T. Biedermann, W. Anemüller, A. Kromminga, F. Ruëff, H. Merk, N. Wagner, R. Treudler, M. Worm, I. Waldmann, J. Saloga, W. M. Becker, T. Goldmann, T. A. Platts-Mills, A. Homann
      Abstract: BackgroundGlycoproteins and glycolipids of some mammalian species contain the disaccharide galactosyl-α-(1,3)-galactose (α-Gal). It is known that α-Gal is immunogenic in humans and causes glycan-specific IgG and also IgE responses with clinical relevance. α-Gal is part of the IgE-reactive monoclonal therapeutic antibody cetuximab and is associated with delayed anaphylaxis to red meat. In this study, different alpha-Gal-containing analytes are examined in singleplex and multiplex assays to resolve individual sensitization patterns with IgE against α-Gal.MethodsThree serum groups, α-Gal-associated meat allergy (MA) patients, idiopathic anaphylaxis (IA) patients with suspected meat allergy and non-meat-allergic healthy control individuals (HC), were analyzed via singleplex allergy diagnostics and a newly established immunoblot diagnostic system. The new dot blot detection system resolved individual IgE sensitization profiles for α-Gal-containing analytes cetuximab, bovine thyroglobulin and HSA-conjugated α-Gal.ResultsSingleplex allergy diagnostics using the α-Gal-analytes cetuximab and bovine thyroglobulin confirms the history of meat allergy patients in 91% and 88% of the cases, respectively. A novel dot-blot-based assay system for the detection of IgE against α-Gal reveals individual IgE sensitization profiles for α-Gal-containing analytes. An α-Gal-associated IgE cross-reactivity profile (IgE against cetuximab, bovine thyroglobulin and HSA-α-Gal) was identified, which is associated with meat allergy.ConclusionsDetection of individual sensitization patterns with different α-Gal-containing analytes provides the basis for an individual allergy diagnosis for α-Gal sensitized patients. Higher amounts of α-Gal in pork and beef innards compared to muscle meat as indicated by a higher staining intensity are a plausible explanation for the difference in allergic symptom severity.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-03T02:20:24.596553-05:
      DOI: 10.1111/all.13238
  • Omalizumab prevents anaphylaxis and improves symptoms in systemic
           mastocytosis; efficacy and safety observations
    • Authors: Sigurd Broesby-Olsen; Hanne Vestergaard, Charlotte Gotthard Mortz, Britt Jensen, Troels Havelund, Anne Pernille Hermann, Frank Siebenhaar, Michael Boe Møller, Thomas Kielsgaard Kristensen, Carsten Bindslev-Jensen,
      Abstract: BackgroundPatients with systemic mastocytosis (SM) may suffer from mast cell (MC) mediator-related symptoms insufficiently controlled by conventional therapy. Omalizumab is an established treatment in other MC-driven diseases, but experiences in SM are limited.ObjectiveTo assess the efficacy and safety of omalizumab in SM.MethodsIn our patient cohort we evaluated all SM patients treated with omalizumab. A physician global assessment of type and severity of symptoms was performed at baseline, at 3 and 6 months and at latest follow-up. Quality-of-life was assessed by visual analogue scale. S-tryptase and KIT D816V allele burden were monitored.ResultsA total of 14 adult SM patients (10 ISM, 2 BMM, 1 SSM and 1 ASM-AHN) received omalizumab with a median duration of 17 months (range: 1-73 months). One patient was excluded due to concomitant cytoreductive therapy. In the remaining 13 patients we observed a significant reduction of symptoms, with complete symptom control in five (38.5%), major response in three (23.1%) and a partial response in three (23.1%) patients, whereas two patients (15.4%) withdrew due to subjective side-effects at first dose. The treatment was most effective for recurrent anaphylaxis and skin symptoms, less for gastrointestinal, musculoskeletal and neuropsychiatric symptoms. Patient-reported quality-of-life showed significant improvement. No significant changes in s-tryptase/KIT D816V allele burden were observed. No severe adverse events were recorded.ConclusionsOmalizumab appears to be a promising treatment option in SM, effectively preventing anaphylaxis and improving chronic MC mediator-related symptoms, insufficiently controlled by conventional therapy. Controlled studies are needed to substantiate findings.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-29T14:55:18.685173-05:
      DOI: 10.1111/all.13237
  • Immediate moxifloxacin hypersensitivity: is there more than currently
           meets the eye'
    • Authors: Athina L Van Gasse; Vito Sabato, A P Uyttebroek, Jessy Elst, Margaretha A Faber, Margo M Hagendorens, Christel Mertens, Chris H Bridts, Luc S De Clerck, Didier G Ebo
      Abstract: Immediate drug hypersensitivity reactions (IDHR) to moxifloxacin constitute a pathomechanistic conundrum and a diagnostic challenge. Our objective was to study whether simultaneous phenotyping and quantification of histamine release might add to our knowledge about the basophil activation properties of moxifloxacin and constitute a reliable diagnostic aid. Fifteen patients with an IDHR to moxifloxacin and 9 moxifloxacin challenged controls were selected. All had a basophil activation test (BAT) with moxifloxacin. Flow cytometric analysis of basophil responses implied labeling for CD63, CD203c and intracellular histamine. Unlike tolerant challenged controls, basophilic upregulation of CD203c in response to moxifloxacin was observed in 7/15 patients. Only 2 of these 7 patients demonstrated appearance of CD63 and release of histamine. In the remainder 8 patients no basophil responses were demonstrable. In conclusion, immediate hypersensitivity to moxifloxacin might involve mechanisms difficult to capture by traditional CD63/CD203c-based BAT. Deciphering the complexity of quinolone IDHR seems mandatory.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-28T11:31:28.045139-05:
      DOI: 10.1111/all.13236
  • Delayed type hypersensitivity reactions induced by proton pump inhibitors:
           a clinical and in vitro T cell reactivity study
    • Authors: Chien-yio Lin; Chuang-Wei Wang, Chung-Yee Rosaline Hui, Ya-Ching Chang, Chih-Hsun Yang, Chi-Yuan Cheng, Wen-Wen Chen, Wei-Ming Ke, Wen-Hung Chung
      Abstract: BackgroundProton pump inhibitors (PPI) has been known to induce type I hypersensitivity reactions. However, severe delayed type hypersensitivity reactions (DHR) induced by PPI, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS), are rarely reported. We conducted a study of a large series of PPI-related DHR, followed up their tolerability to alternative anti-ulcer agents, and investigated the T cell reactivity to PPI in PPI-related DHR patients.MethodsWe retrospectively analyzed patients with PPI-related DHR from multiple medical centers in Taiwan during the study period January 2003 to April 2016. We analyzed the causative PPI, clinical manifestations, organ involvement, treatment, and complications. We also followed up the potential risk of cross-hypersensitivity or tolerability to other PPI after their hypersensitivity episodes. Drug lymphocyte activation test (LAT) was conducted by measuring granulysin and interferon-γ to confirm the causalities.ResultsThere were 69 cases of PPI-related DHR, including SJS/TEN (n=27) and DRESS (n=10). The LAT by measuring granulysin showed a sensitivity of 59.3% and specificity of 96.4%. Esomeprazole was the most commonly involved in PPI-related DHR (51%). Thirteen patients allergic to one kind of PPI could tolerate other structurally different PPI without cross-hypersensitivity reactions, whereas three patients developed cross-hypersensitivity reactions to alternative structurally similar PPI. The cross-reactivity to structurally similar PPI was also observed in LAT assay.ConclusionsPPIs have the potential to induce life-threatening DHR. In patients when PPI is necessary for treatment, switching to structurally different alternatives should be considered.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-28T11:31:24.405618-05:
      DOI: 10.1111/all.13235
  • Fibroblast-derived exosomes promote epithelial cell proliferation through
           TGF-β2 signaling pathway in severe asthma
    • Authors: Ikhlass haj-Salem; Sophie Plante, Abdelilah S. Gounni, Mahmoud Rouabhia, Jamila Chakir
      Abstract: BackgroundBronchial fibroblasts play a key role in airway remodeling in asthma. They regulate epithelial cell functions such as proliferation through growth factors, cytokines, chemokines and exosomes. The role of exosomes in the communication between epithelial cells and fibroblasts by vehiculing these mediators in asthma remains to be determined.ObjectiveTo evaluate the role of exosomes released by bronchial fibroblasts on epithelial cell proliferation in severe asthma.MethodsExosomes were obtained from culture media of primary bronchial fibroblasts and characterized using Western blot, electron microscopy and flow cytometry. Uptake profile of fluorescent-labeled exosomes in epithelial cells was assessed by flow cytometry. Exosome cytokine content was analysed by Cytokine Arrays. Bronchial epithelial cell proliferation was evaluated by BrdU incorporation test. Exosomes biogenesis/release was blocked by using sphingomyelinase inhibitor. Plasmid transfection was used to modulate TGF-β2 gene expression.ResultsWe showed that bronchial fibroblasts secreted exosomes, which were internalized by bronchial epithelial cells. Exosomes of severe asthmatic subjects’ fibroblasts showed a lower level of TGF-β2 and significantly increased the epithelial cells proliferation of both healthy and severe asthmatic subjects compared to healthy controls’ exosomes. Overexpression of TGF-β2 in severe asthmatics’ fibroblasts induced enhanced TGF-β2 in exosomes leading to a reduced proliferation of epithelial cells, whereas knockdown of TGF-β2 enhanced epithelial cell proliferation.ConclusionOur study shows that exosomes are involved in fine-tuning intercellular communication in asthma. Exosomes of severe eosinophilic asthmatics’ fibroblasts can contribute to airway remodeling, at least in part, by modulating epithelial cell proliferation observed in severe asthma.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-26T01:42:31.525685-05:
      DOI: 10.1111/all.13234
  • Cytomegalovirus DNA is highly prevalent in the blood of patients with
           asthma and is associated with age and asthma traits
    • Authors: Marek L. Kowalski; Aleksandra Wardzynska, Miroslawa Studzinska, Malgorzata Pawelczyk, Zbigniew Jan Lesnikowski, Edyta Paradowska
      Abstract: CMV IgG antibodies have been associated with inflammageing and immunosenescence. We aimed to assess the presence of CMV DNA in the blood of adult and elderly patients with bronchial asthma to establish potential association of CMV DNAemia with asthma and asthma characteristics. Eighty-five elderly asthmatics, 74 younger asthma patients and 114 age-matched controls were recruited. The CMV DNA was detected using commercial artus assay in 10.7% of asthma patients, but was negative in all control individuals. The secondary assay identified CMV DNA in 41.5% of asthmatics and 13.3% of control subjects (p
      PubDate: 2017-06-22T21:20:28.258004-05:
      DOI: 10.1111/all.13233
  • Atopic dermatitis is associated with anxiety, depression, and suicidal
           ideation, but not with hospitalization or suicide
    • Authors: Jacob P. Thyssen; Carsten R. Hamann, Allan Linneberg, Thomas Meinertz Dantoft, Lone Skov, Gunnar H. Gislason, Jashin J. Wu, Alexander Egeberg
      Abstract: BackgroundAtopic dermatitis (AD) has been linked with psychiatric disease in adults. However, the exact relationship and its consequences have been insufficiently studied. Our aim in this study was to assess the association between depression, anxiety and AD in adults, and examine the risk of hospitalization and suicide.MethodsWe utilized questionnaire data from a large general population study with data on social habits and psychiatric symptoms to compare prevalences of depression, anxiety, suicidal ideation, and anxiety attacks, in adults with and without a history of AD. Additionally we used nationwide hospital/clinic registry and prescription data to examine the risk of anxiety and depression in Danish adults with mild and moderate-severe AD, as well as the risk of hospitalization and suicide.ResultsIn the general population study, those with AD reported clinician-diagnosed depression and anxiety more often than non-AD subjects, and had an increased prevalence of suicidal ideation and depressive symptoms. In the health registry study, moderate-severe AD patients had increased risk of antidepressant and anxiolytic medication use, while patients with mild AD only had increased risk of anxiolytic medication use. There was no increased risk of hospitalization or outpatient contacts due to depression or anxiety, or risk of suicide in AD patients.ConclusionsDepression, anxiety, and suicidal ideation are more common among AD individuals, but do not to lead to psychiatric consultations, hospitalization, or suicide.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-20T13:16:04.878-05:00
      DOI: 10.1111/all.13231
  • A prospective microbiome-wide association study of food sensitization and
           food allergy in early childhood
    • Authors: Jessica H. Savage; Kathleen A. Lee-Sarwar, Joanne Sordillo, Supinda Bunyavanich, Yanjiao Zhou, George O'Connor, Megan Sandel, Leonard Bacharier, Robert Zeiger, Erica Sodergren, George M Weinstock, Diane R. Gold, Scott T. Weiss, Augusto A. Litonjua
      Abstract: BackgroundAlterations in the intestinal microbiome are prospectively associated with the development of asthma; less is known regarding the role of microbiome alterations in food allergy development.MethodsIntestinal microbiome samples were collected at age 3-6 months in children participating in the follow-up phase of an interventional trial of high dose Vitamin D given during pregnancy. At age 3, sensitization to foods (milk, egg, peanut, soy, wheat, walnut) was assessed. Food allergy was defined as caretaker report of healthcare provider-diagnosed allergy to the above foods prior to age 3 with evidence of IgE sensitization. Analysis was performed using Phyloseq and DESeq2; p-values were adjusted for multiple comparisons.ResultsComplete data were available for 225 children; there were 87 cases of food sensitization and 14 cases of food allergy. Microbial diversity measures did not differ between food sensitization and food allergy cases and controls. The genera Haemophilus (log2 fold change -2.15, p=0.003), Dialister (log2 fold change -2.22, p=0.009), Dorea (log2 fold change -1.65, p=0.02) and Clostridium (log2 fold change -1.47, p=0.002) were underrepresented among subjects with food sensitization. The genera Citrobacter (log2 fold change -3.41, p=0.03), Oscillospira (log2 fold change -2.80, p=0.03), Lactococcus (log2 fold change -3.19, p=0.05) and Dorea (log2 fold change -3.00, p=0.05) were underrepresented among subjects with food allergy.ConclusionsThe temporal association between bacterial colonization and food sensitization and allergy suggests that the microbiome may have a causal role in the development of food allergy. Our findings have therapeutic implications for the prevention and treatment of food allergy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-20T13:16:01.451215-05:
      DOI: 10.1111/all.13232
  • Is the atopic march related to confounding by genetics and early life
           environment' A systematic review of sibship and twin data
    • Authors: Sabria J. Khan; Shyamali C. Dharmage, Melanie C. Matheson, Lyle C. Gurrin
      Abstract: A popular hypothesis known as the atopic march proposes a set of sequential allergy and respiratory disorders in early childhood contributes enormously to the burden of disease in developed countries. Although the concept of the atopic march has been refined and strengthened by many cross-sectional and longitudinal studies linking eczema as the initial manifestation with progression to hay fever and then asthma, there is yet no definitive proof that the atopic march is the primary causal factor in childhood allergic disease. This debate is mainly related to the controversy around potential confounding of these associations by genetic and environmental factors. Family studies are ideally suited to unravelling the role of these factors. While multiple reviews have synthesised evidence from studies investigating this question, no review to date has explored specific evidence generated by twin and sibling studies to understand the aetiology of atopic march diseases. Our aim was to conduct a systematic review of twin and sibling studies that examine the allergic phenotypes that form the atopic march, to determine whether such analyses of data from these studies attempt to control for the effect confounding by shared factors, and to report estimates the magnitude of associations between multiple phenotypes. Our review suggests that (1) genetics play a bigger role predisposing eczema to hay fever and eczema to asthma than environmental factors; and (2) the link between eczema, and asthma and hay fever is independent of shared early life environmental factors and genetics.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-15T05:15:22.798184-05:
      DOI: 10.1111/all.13228
  • Validation of International consensus equation for acute serum total
           tryptase in mast cell activation: A perioperative perspective
    • Authors: Richard L Baretto; Sarah Beck, Jane Heslegrave, Cathryn Melchior, Omar Mohamed, Anjali Ekbote, Aarnoud P Huissoon, Mamidipudi T Krishna
      Abstract: IntroductionThere is no standardised method for assessing serum total mast cell tryptase (MCT) in anaphylaxis. The consensus equation (peak MCT should be>1.2x baseline tryptase+2mg/L) has been proposed to interpret acute MCT in mast cell activation syndrome (MCAS).AimTo validate consensus equation in a setting of perioperative anaphylaxis.MethodsAnalyses of suspected perioperative anaphylaxis during general anaesthesia (GA). Anaphylaxis was defined as per World Allergy Organisation (WAO) criteria. Timed serial MCT measurements were mapped against the consensus equation and receiver operating characteristic (ROC) curves produced.Results82 patients (60 females, mean age 56.5 years ± SD17.2) underwent investigation. 60 (73%) patients fulfilled WAO criteria for anaphylaxis and 22 patients did not (controls). Aetiology: 59% IgE-mediated anaphylaxis, 2% non-IgE mediated anaphylaxis, 12% anaphylaxis of unknown cause, and 27% deemed non-anaphylaxis. IgE-mediated anaphylaxis included - NMBA (35%), antibiotics (46%), chlorhexidine (8%), patent blue dye (8%) and others (8%). An acute MCT with a comparable baseline was available in 71/82 (87%) patients (60-anaphylaxis and 11-controls).The median (IQR) time from reaction to peak MCT was 1.34 (0.82-2.51) hours. Analyses confirmed that a rise in acute MCT greater than that defined by the equation had a sensitivity, specificity, positive predictive value (PPV) and negative (N) PV of 78%, 91%, 98%, and 44% respectively. The magnitude of increase in acute MCT above the threshold predicted by consensus equation was higher in the anaphylaxis group compared to controls (P=0.0001).ConclusionThis equation has a high specificity, PPV with a moderate NPV and sensitivity in perioperative anaphylaxis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-13T14:35:19.144206-05:
      DOI: 10.1111/all.13226
  • Transfer of innovation on allergic rhinitis and asthma multimorbidity in
           the elderly (MACVIA-ARIA) - Reference Site Twinning (EIP on AHA)
    • Authors: J Bousquet; I Agache, M R Aliberti, R Angles, I Annesi-Maesano, J M Anto, S Arnavielhe, E Asayag, E Bacci, A Bedbrook, C Bachert, I Baroni, B A Barreto, M Bedolla-Barajas, K C Bergmann, L Bertorello, M Bewick, T Bieber, S Birov, C Bindslev-Jensen, A Blua, M Bochenska Marciniak, I Bogus-Buczynska, S Bosnic-Anticevich, I Bosse, R Bourret, C Bucca, R Buonaiuto, D Caiazza, D Caillot, D P Caimmi, P Camargos, G Canfora, V Cardona, A M Carriazo, C Cartier, G Castellano, N H Chavannes, M M Ciaravolo, C Cingi, A Ciceran, L Colas, E Colgan, J Coll, D Conforti, J Correira de Sousa, R M Cortés-Grimaldo, F Corti, E Costa, A L Courbis, E Cousein, A A Cruz, A Custovic, B Cvetkovski, C Dario, M da Silva, Y Dauvilliers, F De Blay, T Dedeu, G De Feo, B De Martino, P Demoly, G De Vries, S Di Capua Ercolano, N Di Carluccio, M Doulapsi, G Dray, R Dubakiene, E Eller, R Emuzyte, J M Espinoza-Contreras, A Estrada-Cardona, J Farrell, J Ferrero, W J Fokkens, J Fonseca, J F Fontaine, S Forti, J L Gálvez-Romero, C I García-Cobas, M H Garcia Cruz, B Gemicioğlu, R Gerth van Wijk, M Guidacci, J Gómez-Vera, N A Guldemond, Z Gutter, T Haahtela, J Hajjam, P W Hellings, L Hernández-Velázquez, M Illario, J C Ivancevich, E Jares, G Joos, J Just, O Kalayci, A F Kalyoncu, J Karjalainen, T Keil, N Khaltaev, L Klimek, V Kritikos, I Kull, P Kuna, V Kvedariene, V Kolek, E Krzych-Fałta, M Kupczyk, P Lacwik, D Larenas-Linnemann, D Laune, D Lauri, J Lavrut, M Lessa, G Levato, L Lewis, I Lieten, A Lipiec, R Louis, J A Luna-Pech, A Magnan, J Malva, J F Maspero, J J Matta-Campos, O Mayora, M A Medina-Ávalos, E Melén, E Menditto, J Millot-Keurinck, G Moda, M Morais-Almeida, R Mösges, A Mota-Pinto, J Mullol, A Muraro, R Murray, M Noguès, M Nalin, L Napoli, H Neffen, R E O'Hehir, G Onorato, S Palkonen, N G Papadopoulos, G Passalacqua, J L Pépin, A M Pereira, M Persico, O Pfaar, A C Pozzi, E Prokopakis, F Raciborski, J Rimmer, J A Rizzo, C Robalo-Cordeiro, M Rodríguez-González, G Rolla, R E Roller-Wirnsberger, A Romano, M Romano, J Salimäki, B Samolinski, F S Serpa, S Shamai, M Sierra, M Sova, M Sorlini, C Stellato, R Stelmach, T Strandberg, V Stroetmann, R Stukas, A Szylling, R Tan, V Tibaldi, A Todo-Bom, S Toppila-Salmi, P Tomazic, U Trama, M Triggiani, A Valero, E Valovirta, A Valiulis, M van Eerd, T Vasankari, A Vatrella, M T Ventura, M T Verissimo, F Viart, S Williams, M Wagenmann, C Wanscher, M Westman, M Wickman, I Young, A Yorgancioglu, E Zernotti, T Zurbierber, A Zurkuhlen, B De Oliviera, A Senn
      Abstract: The overarching goals of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) are to enable European citizens to lead healthy, active and independent lives while ageing. The EIP on AHA includes 74 Reference Sites. The aim of this study is to transfer innovation from an App developed by the MACVIA-France EIP on AHA reference site (Allergy Diary) to other reference sites. The phenotypic characteristics of rhinitis and asthma multimorbidity in adults and the elderly will be compared using validated information and communication technology (ICT) tools (i.e. the Allergy Diary and CARAT: Control of Allergic Rhinitis and Asthma Test) in 22 Reference Sites or regions across Europe. This will improve understanding, assessment of burden, diagnosis and management of rhinitis in the elderly by comparison with an adult population. Specific objectives will: (i) assess the percentage of adults and elderly who are able to use the Allergy Diary, (ii) study phenotypic characteristics and treatment over a period of one year of rhinitis and asthma multimorbidity at baseline (cross-sectional study) and (iii) follow-up using visual analogue scale (VAS). This part of the study may provide some insight into the differences between the elderly and adults in terms of response to treatment and practice. Finally (iv) work productivity will be examined in adults.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-10T09:50:20.718726-05:
      DOI: 10.1111/all.13218
  • Spontaneous food allergy in Was-/- mice occurs independent of
           FcεRI-mediated mast cell activation
    • Authors: Willem S. Lexmond; Jeremy A. Goettel, Benjamin F. Sallis, Katelyn McCann, Edmond H. H. M. Rings, Erika Jensen-Jarolim, Samuel Nurko, Scott B. Snapper, Edda Fiebiger
      Abstract: BackgroundFood allergies are a growing health problem and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome (WAS) and defined whether spontaneous disease in Was-/- mice recapitulates the pathology of a conventional disease model and/or human food allergy.MethodsComparative ImmunoCAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was-/- mice was compared to an adjuvant-based model in wild-type mice (WT-OVA/alum). Intestinal and systemic anaphylaxis was assessed and the role of the high affinity IgE Fc receptor (FcεRI) in allergic sensitization was evaluated using Was-/-Fcer1a-/- mice.ResultsPolysensitization to food was detected in both WAS and food allergic patients which was recapitulated in the Was-/- model. Oral administration of OVA in Was-/- mice induced low titers of OVA-specific IgE compared to the WT-OVA/alum model. Irrespectively, 79% of Was-/- mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was-/- mice (95%) with a mortality rate>50%. Spontaneous sensitization and intestinal allergy occurred independent of FcεRI expression on mast cells and basophils.ConclusionsWas-/- mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/FcεRI activation cascade will not affect sensitization to food.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-10T09:30:21.088787-05:
      DOI: 10.1111/all.13219
  • Mechanisms of exercise-induced bronchoconstriction in athletes: current
           perspectives and future challenges
    • Authors: Mariana Couto; Marcin Kurowski, André Moreira, Dominique M.A. Bullens, Kai-Håkon Carlsen, Luís Delgado, Marek L. Kowalski, Sven F. Seys
      Abstract: The evidence of exercise-induced bronchoconstriction (EIB) without asthma (EIBwA) occurring in athletes led to speculate about different endotypes inducing respiratory symptoms within athletes. Classical postulated mechanisms for bronchial obstruction in this population include the osmotic and the thermal hypotheses. More recently, the presence of epithelial injury and inflammation in the airways of athletes was demonstrated. In addition, neuronal activation has been suggested as a potential modulator of bronchoconstriction. Investigation of these emerging mechanisms are of major importance since EIB is a significant problem for both recreational and competitive athletes and is the most common chronic condition among Olympic athletes, with obvious implications for their competing performance, health and quality of life. Hereby we summarize the latest achievements in this area and identify the current gaps of knowledge so that future research heads towards better defining the etiologic factors and mechanisms involved in development of EIB in elite athletes as well as essential aspects to ultimately propose preventive and therapeutic measures.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-09T12:42:02.935532-05:
      DOI: 10.1111/all.13224
  • Functional and phenotypic analysis of basophils allows determining
           distinct subtypes in patients with chronic urticaria
    • Authors: Michèle Myriam Rauber; Julia Pickert, Lily Holiangu, Christian Möbs, Wolfgang Pfützner
      Abstract: BackgroundChronic urticaria (CU) is a frequent skin disease characterized by relapsing appearance of pruritic hives. While clinical symptoms are due to the release of histamine by cutaneous mast cells, the underlying pathophysiology is still unknown. However, previous studies indicate that basophils might be of relevance. Besides, the occurrence of autoantibodies against IgE or its receptor, FcεRI, and the therapeutic efficacy of anti-IgE antibodies imply that IgE-mediated mechanisms also play an important role in CU.MethodsReactivity of CU patients’ peripheral blood basophils (n=60) to specific anti-FcεRI and IgE-independent fMLP stimulation was determined by basophil activation test in comparison to patients suffering from IgE-mediated allergic rhinitis (n=10) and healthy controls (n=10). In addition, immunoglobulin receptor (FcεRI, FcγRII) expression and surface bound antibodies (IgE, IgG) were quantified on basophils. Furthermore, the autoreactive capacity of CU sera was evaluated and urticaria-related symptoms were assessed by both UCT and CU-Q2oL.ResultsStimulating CU patients’ basophils via FcεRI, we identified three distinct immunological phenotypes. One subgroup of patients' basophils reacted to FcεRI stimulation, whereas the others had anti-FcεRI non-reactive basophils. Among the latter a subgroup with pronounced basopenia was identified. Of note, this group was characterized by augmented serum-induced basophil activation, increased levels of autoantibodies against thyroid peroxidase and also exhibited the strongest disease impact on their quality of life.ConclusionsCU patients can be categorized into three immunological subgroups based on their basophil reactivity and frequency. These phenotypes are associated with different clinical characteristics, pointing to basophils as important players in CU pathophysiology.This article is protected by copyright. All rights reserved.
      PubDate: 2017-06-05T22:43:37.265921-05:
      DOI: 10.1111/all.13215
  • Sublingual immunotherapy provides long-term relief in allergic rhinitis
           and reduces the risk of asthma: a retrospective, real-world database
    • Authors: S Zielen; P Devillier, J Heinrich, H Richter, U Wahn
      Abstract: BackgroundAllergy immunotherapy (AIT) is the only treatment for allergic rhinitis (AR) and/or allergic asthma (AA) with long-term efficacy. However, there are few real-life data on the progression of AR and/or AA in patients receiving AIT.ObjectivesTo assess the real-world, long-term efficacy of grass-pollen sublingual immunotherapy (SLIT) tablets in AR and their impact on asthma onset and progression.MethodsIn a retrospective analysis of a German longitudinal prescription database, AR patients treated with grass pollen SLIT tablets were compared with a control group not having received AIT. Multiple regression was used to compare changes over time in rescue symptomatic AR medication use after treatment cessation, asthma medication use, and the time to asthma onset in the two groups.ResultsAfter applying all selection criteria, 2851 SLIT and 71275 Control patients were selected for the study.After treatment cessation, AR medication use was 18.8 percentage points lower (after adjustment for covariates, and relative to the pre-treatment period) in SLIT tablet group than in the non AIT group (p
      PubDate: 2017-05-31T07:17:18.788984-05:
      DOI: 10.1111/all.13213
  • Allergen immunotherapy for allergic rhinoconjunctivitis: a systematic
           review and meta-analysis
    • Authors: Sangeeta Dhami; Ulugbek Nurmatov, Stefania Arasi, Tahir Khan, Miqdad Asaria, Hadar Zaman, Arnav Agarwal, Gopal Netuveli, Graham Roberts, Oliver Pfaar, Antonella Muraro, Ignacio J. Ansotegui, Moises Calderon, Cemal Cingi, Stephen Durham, Ronald Gerth van Wijk, Susanne Halken, Eckard Hamelmann, Peter Hellings, Lars Jacobsen, Edward Knol, Desiree Larenas Linnemann, Sandra Lin, Paraskevi Maggina, Ralph Mösges, Hanneke Oude Elberink, Giovanni Pajno, Ruby Panwankar, Elide Pastorello, Martin Penagos, Constantinos Pitsios, Giuseppina Rotiroti, Frans Timmermans, Olympia Tsilochristou, Eva-Maria Varga, Carsten Schmidt-Weber, Jamie Wilkinson, Andrew Williams, Margitta Worm, Luo Zhang, Aziz Sheikh
      Abstract: BackgroundThe European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis. In order to inform the development of clinical recommendations, we undertook a systematic review to assess the effectiveness, cost-effectiveness and safety of AIT in the management of allergic rhinoconjunctivitisMethodsWe searched 15 international biomedical databases for published, in progress and unpublished evidence. Studies were independently screened by two reviewers against pre-defined eligibility criteria and critically appraised using established instruments. Our primary outcomes of interest were symptom, medication and combined symptom and medication scores. Secondary outcomes of interest included cost-effectiveness and safety. Data were descriptively summarized and then quantitatively synthesized using random-effects meta-analyses.ResultsWe identified 5932 studies of which 160 studies satisfied our eligibility criteria. There was a substantial body of evidence demonstrating significant reductions in standardized mean differences (SMD) of symptom (SMD -0.53, 95%CI -0.63, -0.42), medication (SMD -0.37, 95%CI -0.49, -0.26) and combined symptom and medication (SMD -0.49, 95%CI -0.69, -0.30) scores whilst on treatment that were robust to pre-specified sensitivity analyses. There was in comparison a more modest body of evidence on effectiveness post-discontinuation of AIT, this suggesting a benefit in relation to symptom scores.ConclusionsAIT is effective in improving symptom, medication and combined symptom and medication scores in patients with allergic rhinoconjunctivitis whilst on treatment, and there is some evidence suggesting that these benefits are maintained in relation to symptom scores after discontinuation of therapy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-05-11T10:05:39.858587-05:
      DOI: 10.1111/all.13201
  • Effect of anti-IgE in occupational asthma caused by exposure to low
           molecular weight agents
    • Authors: M Ollé-Monge; M J Cruz, S Gomez-Ollés, I Ojanguren, J Vanoirbeek, X Muñoz
      Abstract: BackgroundThe role of immunoglobulin (Ig)-E in occupational asthma (OA) due to low molecular weight (LMW) agents is not well established compared to classical atopic asthma. In the present study we evaluate whether anti-IgE monoclonal antibody (mAb) has an effect in a mouse model of OA, using persulfate salts.MethodsOn days 1 and 8, BALB/C mice were dermally sensitized with 5% ammonium persulfate (AP) or dimethyl sulfoxide (DMSO). On days 15, 18 and 21 animals were injected intraperitoneally with anti-IgE mAb or PBS 6 hours before challenge with AP or saline. Airway hyperresponsiveness (AHR) using a methacholine test, airway inflammation in bronchoalveolar lavage (BAL) and lung tissue and total free IgE in serum samples were analyzed 24, 48 and 96 hours after the last challenge.ResultsAnti-IgE mAb treatment almost completely neutralized free serum IgE. In AP sensitized and challenged mice, anti-IgE mAb treatment abolished AHR 24h and 48h after the last challenge and significantly reduced the total number of eosinophils and neutrophils 48h and 96h after the last AP challenge compared with non-treated mice. Levels of interleukin (IL)-13 in BAL were also significantly decreased after anti-IgE administration 24h and 48h after the last AP challenge. Histological analysis of the lung sections from anti-IgE-treated mice revealed normal inflammatory patterns similar to control groups 48h after the last challenge.ConclusionsAnti-IgE-treated mice showed a significant improvement in asthma features related to the AHR and airway inflammation. Anti-IgE mAb has positive effects in OA induced by persulfate salts.This article is protected by copyright. All rights reserved.
      PubDate: 2017-04-25T01:46:09.580547-05:
      DOI: 10.1111/all.13190
  • Aspergillus fumigatus in cystic fibrosis: An update on immune interactions
           and molecular diagnostics in allergic bronchopulmonary aspergillosis
    • Authors: A. Carsin; T. Romain, S. Ranque, M. Reynaud-Gaubert, J.-C. Dubus, J.-L. Mège, J. Vitte
      Pages: 1632 - 1642
      Abstract: A wide spectrum of pathological conditions may result from the interaction of Aspergillus fumigatus and the immune system of its human host. Allergic bronchopulmonary aspergillosis is one of the most severe A. fumigatus-related diseases due to possible evolution toward pleuropulmonary fibrosis and respiratory failure. Allergic bronchopulmonary aspergillosis occurs almost exclusively in cystic fibrosis or asthmatic patients. An estimated 8%-10% of patients with cystic fibrosis experience this condition. The diagnosis of allergic bronchopulmonary aspergillosis relies on criteria first established in 1977. Progress in the understanding of host-pathogen interactions in A. fumigatus and patients with cystic fibrosis and the ongoing validation of novel laboratory tools concur to update and improve the diagnosis of allergic bronchopulmonary aspergillosis.
      PubDate: 2017-06-09T04:35:33.020267-05:
      DOI: 10.1111/all.13204
  • Comparing immediate-type food allergy in humans and companion
           animals—revealing unmet needs
    • Authors: I. Pali-Schöll; M. De Lucia, H. Jackson, J. Janda, R. S. Mueller, E. Jensen-Jarolim
      Pages: 1643 - 1656
      Abstract: Adverse food reactions occur in human as well as veterinary patients. Systematic comparison may lead to improved recommendations for prevention and treatment in both. In this position paper, we summarize the current knowledge on immediate-type food allergy vs other food adverse reactions in companion animals, and compare this to the human situation. While the prevalence of food allergy in humans has been well studied for some allergens, this remains to be investigated for animal patients, where owner-reported as well as veterinarian-diagnosed food adverse reactions are on the increase. The characteristics of the disease in humans vs dogs, cats, and horses are most often caused by similar, but sometimes species-dependent different pathophysiological mechanisms, prompting the specific clinical symptoms, diagnoses, and treatments. Furthermore, little is known about the allergen molecules causative for type I food allergy in animals, which, like in human patients, could represent predictive biomarkers for risk evaluation. The definite diagnosis of food allergy relies—as in humans—on elimination diet and provocation tests. Besides allergen avoidance in daily practice, novel treatment options and tolerization strategies are underway. Taken together, numerous knowledge gaps were identified in veterinary food allergy, which need to be filled by systematic comparative studies.
      PubDate: 2017-05-22T02:30:56.840172-05:
      DOI: 10.1111/all.13179
  • Non-allergic rhinitis: Position paper of the European Academy of Allergy
           and Clinical Immunology
    • Authors: P. W. Hellings; L. Klimek, C. Cingi, I. Agache, C. Akdis, C. Bachert, J. Bousquet, P. Demoly, P. Gevaert, V. Hox, C. Hupin, L. Kalogjera, F. Manole, R. Mösges, J. Mullol, N. B. Muluk, A. Muraro, N. Papadopoulos, R. Pawankar, C. Rondon, M. Rundenko, S. F. Seys, E. Toskala, L. Van Gerven, L. Zhang, N. Zhang, W. J. Fokkens
      Pages: 1657 - 1665
      Abstract: This EAACI position paper aims at providing a state-of-the-art overview on nonallergic rhinitis (NAR). A significant number of patients suffering from persistent rhinitis are defined as nonallergic noninfectious rhinitis (NANIR) patients, often denominated in short as having NAR. NAR is defined as a symptomatic inflammation of the nasal mucosa with the presence of a minimum of two nasal symptoms such as nasal obstruction, rhinorrhea, sneezing, and/or itchy nose, without clinical evidence of endonasal infection and without systemic signs of sensitization to inhalant allergens. Symptoms of NAR may have a wide range of severity and be either continuously present and/or induced by exposure to unspecific triggers, also called nasal hyperresponsiveness (NHR). NHR represents a clinical feature of both AR and NAR patients. NAR involves different subgroups: drug-induced rhinitis, (nonallergic) occupational rhinitis, hormonal rhinitis (including pregnancy rhinitis), gustatory rhinitis, senile rhinitis, and idiopathic rhinitis (IR). NAR should be distinguished from those rhinitis patients with an allergic reaction confined to the nasal mucosa, also called “entopy” or local allergic rhinitis (LAR). We here provide an overview of the current consensus on phenotypes of NAR, recommendations for diagnosis, a treatment algorithm, and defining the unmet needs in this neglected area of research.
      PubDate: 2017-06-02T02:45:30.554564-05:
      DOI: 10.1111/all.13200
  • BTK inhibition is a potent approach to block IgE-mediated histamine
           release in human basophils
    • Authors: D. Smiljkovic; K. Blatt, G. Stefanzl, Y. Dorofeeva, C. Skrabs, M. Focke-Tejkl, W. R. Sperr, U. Jaeger, R. Valenta, P. Valent
      Pages: 1666 - 1676
      Abstract: BackgroundRecent data suggest that Bruton's tyrosine kinase (BTK) is an emerging therapeutic target in IgE receptor (IgER)-cross-linked basophils.MethodsWe examined the effects of four BTK inhibitors (ibrutinib, dasatinib, AVL-292, and CNX-774) on IgE-dependent activation and histamine release in blood basophils obtained from allergic patients (n=11) and nonallergic donors (n=5). In addition, we examined the effects of these drugs on the growth of the human basophil cell line KU812 and the human mast cell line HMC-1.ResultsAll four BTK blockers were found to inhibit anti-IgE-induced histamine release from basophils in nonallergic subjects and allergen-induced histamine liberation from basophils in allergic donors. Drug effects on allergen-induced histamine release were dose dependent, with IC50 values ranging between 0.001 and 0.5 μmol/L, and the following rank order of potency: ibrutinib>AVL-292>dasatinib>CNX-774. The basophil-targeting effect of ibrutinib was confirmed by demonstrating that IgE-dependent histamine release in ex vivo blood basophils is largely suppressed in a leukemia patient treated with ibrutinib. Dasatinib and ibrutinib were also found to counteract anti-IgE-induced and allergen-induced upregulation of CD13, CD63, CD164, and CD203c on basophils, whereas AVL-292 and CNX-774 showed no significant effects. Whereas dasatinib and CNX-774 were found to inhibit the growth of HMC-1 cells and KU812 cells, no substantial effects were seen with ibrutinib or AVL-292.ConclusionsBTK-targeting drugs are potent inhibitors of IgE-dependent histamine release in human basophils. The clinical value of BTK inhibition in the context of allergic diseases remains to be determined.
      PubDate: 2017-04-20T03:43:55.451794-05:
      DOI: 10.1111/all.13166
  • Natural tolerance development in cow's milk allergic children: IgE and
           IgG4 epitope binding
    • Authors: J. C. Caubet; J. Lin, B. Ahrens, G. Gimenez, L. Bardina, B. Niggemann, H. A. Sampson, K. Beyer
      Pages: 1677 - 1685
      Abstract: BackgroundAlthough most of cow's milk (CM) allergic children will outgrow their allergy, the pathomechanism of the natural development of tolerance remains poorly understood. It has been suggested that the balance between milk-specific IgE and IgG4 plays a major role.ObjectiveWe aimed to investigate differences in IgE and IgG4 antibody binding to CM epitopes between patients with persistent CM allergy (CMA) and those that naturally became tolerant.MethodsSera from 35 children with proven CMA (median age at inclusion of 10 months) were analyzed retrospectively; 22 patients have become tolerant (median age at tolerance acquisition of 51 months) during the study period as confirmed by a negative oral food challenge. IgE and IgG4 binding to sequential epitopes derived from five major CM proteins were measured with a peptide microarray-based immunoassay.ResultsAt baselines, greater intensity and broader diversity of IgE and IgG4 binding have been found in children with persistent CMA beyond 5 years of age compared to patients with transient CMA. Moreover, children with transient CMA had IgE and IgG4 antibodies that more often recognized the same epitopes, compared to those with persistent CMA. From baseline to the time of tolerance development, both IgE and IgG4 binding intensity decreased significantly, particularly in areas of α-s- and β-casein (P
      PubDate: 2017-06-09T04:35:49.619164-05:
      DOI: 10.1111/all.13167
  • AhR mediates an anti-inflammatory feedback mechanism in human Langerhans
           cells involving FcεRI and IDO
    • Authors: S. Koch; T. J. Stroisch, J. Vorac, N. Herrmann, N. Leib, S. Schnautz, H. Kirins, I. Förster, H. Weighardt, T. Bieber
      Pages: 1686 - 1693
      Abstract: BackgroundAryl hydrocarbon receptor (AhR), an important regulator of immune responses, is activated by UVB irradiation in the skin. Langerhans cells (LC) in the epidermis of patients with atopic dermatitis (AD) carry the high-affinity receptor for IgE, FcεRI, and are crucially involved in the pathogenesis of AD by inducing inflammatory responses and regulating tolerogenic processes.ObjectivesWe investigated AhR and AhR repressor (AhRR) expression and functional consequences of AhR activation in human ex vivo skin cells and in in vitro-generated LC.MethodsEpidermal cells from healthy skin were analyzed for their expression of AhR and AhRR. LC generated from CD34+ hematopoietic stem cells (CD34LC) were treated with the UV photoproduct and AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ). Cell surface receptors, transcription factors, and the tolerogenic tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) were analyzed using flow cytometry and quantitative PCR.ResultsEpidermal LC and CD34LC express AhR and AhRR. AhR was also found in keratinocytes, which lack AhRR. AhR activation of LC by FICZ caused downregulation of FcεRI in CD34LC without affecting their maturation. AhR-mediated regulation of FcεRI did not involve any known transcription factors related to this receptor. Furthermore, we could show upregulation of IDO mediated by AhR engagement.ConclusionsOur study shows that AhR activation by FICZ reduces FcεRI and upregulates IDO expression in LC. This AhR-mediated anti-inflammatory feedback mechanism may dampen the allergen-induced inflammation in AD.
      PubDate: 2017-05-10T03:10:31.419472-05:
      DOI: 10.1111/all.13170
  • RNase 7 downregulates TH2 cytokine production by activated human T cells
    • Authors: V. Kopfnagel; S. Wagenknecht, L. Brand, J. Zeitvogel, J. Harder, K. Hofmann, M. Kleine, T. Werfel
      Pages: 1694 - 1703
      Abstract: BackgroundThe antimicrobial peptide (AMP) RNase 7 is constitutively expressed in the epidermis of healthy human skin and has been found to be upregulated in chronic inflammatory skin diseases such as atopic dermatitis and psoriasis. Activated T cells in lesional skin of patients with atopic dermatitis (AD) and psoriasis (PSO) might be directly exposed to RNase 7. In addition to their antimicrobial activity, immunoregulatory functions have been published for several AMPs. In this study, we investigated immunoregulatory effects of the antimicrobial peptide RNase 7 on activated T cells.MethodsIsolated human CD3+T cells were stimulated with RNase 7 and screened for possible effects by mRNA microarray analysis. The results of the mRNA microarray were confirmed in isolated CD4+T cells and in polarized TH2 cells using skin-derived native RNase 7 and a recombinant ribonuclease-inactive RNase 7 mutant. Activation of GATA3 was analysed by electrophoretic mobility shift assay.ResultsTreatment of activated human CD4+T cells and TH2 cells with RNase 7 selectively reduced the expression of TH2 cytokines (IL-13, IL-4 and IL-5). Experiments with a ribonuclease-inactive recombinant RNase 7 mutant showed that RNase 7 ribonuclease activity is dispensable for the observed regulatory effect. We further demonstrate that CD4+T cells from AD patients revealed a significantly less pronounced downregulation of IL-13 in response to RNase 7 compared to healthy control. Finally, we show that GATA3 activation was diminished upon cultivation of T cells with RNase 7.ConclusionOur data indicate that RNase 7 has immunomodulatory functions on TH2 cells and decreases the production of TH2 cytokines in the skin.
      PubDate: 2017-06-21T03:31:31.075857-05:
      DOI: 10.1111/all.13173
  • Protease-activated receptor-2 suppresses interleukin (IL)-10 expression in
           B cells via upregulating Bcl2L12 in patients with allergic rhinitis
    • Authors: J.-M. Xue; L.-T. Yang, G. Yang, X.-R. Geng, Z.-Q. Liu, S. Wang, H.-L. Zhao, Z.-G. Liu, C.-Q. Zhao, P.-C. Yang
      Pages: 1704 - 1712
      Abstract: Background and aimsThe function of interleukin (IL)-10-producing B cells (B10 cell) is compromised in patients with allergic diseases. Protease-activated receptor (PAR)-2 has immunoregulatory functions. This study aimed to elucidate the role of PAR2 in the suppression of IL-10 expression in peripheral B cells.MethodsPeripheral blood B cells were collected from patients with allergic rhinitis (AR). A correlation between the expression of Bcl2-like protein 12 (Bcl2L12) and IL-10 in the B cells was analyzed. An AR mouse model was developed.ResultsWe observed that the expression of IL-10 was lower in the peripheral B cells from patients with airway allergy. A negative correlation was identified between the expression of IL-10 and PAR2 in B cells. Activation of PAR2 of B cells increased the expression of Bcl2L12 and suppression of LPS-induced IL-10 expression, which were inhibited by knocking down the Bcl2L12 gene. Treating B cells from AR patients with Bcl2L12-shRNA-carrying liposomes reversed the capability of IL-10 expression and the immunosuppressive function. Administration of Bcl2L12 shRNA-carrying liposomes attenuated experimental AR in mice.ConclusionsActivation of PAR2 inhibits the expression of IL-10 in B cells, which can be reversed by treating B cells with Bcl2L12 shRNA-carrying liposomes. The data suggest that regulation of Bcl2L12 may be a novel approach in the treatment for AR.
      PubDate: 2017-05-23T00:25:31.388668-05:
      DOI: 10.1111/all.13186
  • Topical corticosteroid phobia in atopic dermatitis: International
           feasibility study of the TOPICOP score
    • Authors: J.-F. Stalder; H. Aubert, E. Anthoine, M. Futamura, D. Marcoux, M.-A. Morren, M. Trzeciak, Z. Szalai, K. Veres, M. Deleuran, C. Vestergaard, F. Boralevi, C.-Y. Chu, L. De Raeve, Å. Svensson, R. Fölster-Holst, M. Buchner, R. Takaoka, V. Aoki, P. Chernyshov, L. Chernyshova, D. F. Murrell, C. Zhao, C. D. Mckinster, L. Von Kobyletzky, L. Eichenfield, C. Totri, P. Lio, J. Seneschal, L. Moret, S. Barbarot
      Pages: 1713 - 1719
      Abstract: BackgroundAdherence to topical corticosteroids (TCS) is essential for the effective treatment of atopic dermatitis but can be limited by concerns about their use. This study examined the feasibility of applying the validated TOPICOP score for assessing TCS phobia across different countries.MethodsThis was a prospective multicentre feasibility study conducted in 21 hospitals in 17 countries. Patients>3 months of age with atopic dermatitis or their parents or legal representatives completed a validated translation of the TOPICOP questionnaire in the country's native language. Respondents also completed questionnaires collecting opinions about the feasibility and acceptability of the TOPICOP questionnaire.ResultsA total of 1564 participants in 15 countries were included in the analysis. 81% of respondents considered the questions clear or very clear, and 79% reported that it took less than 5 minutes to complete. Each of the individual items in the TOPICOP questionnaire was considered to be not at all difficult to answer by 49% to 74% of participants. The mean global TOPICOP score was 44.7%±20.5. Mean TOPICOP subscores were 37.0±22.8% for knowledge and beliefs, 54.7±27.8% for fears and 50.1±29.1% for behaviours. Global scores and subscores differed between countries, although the subscores did not always vary in parallel, suggesting different levels of TCS phobia and different drivers for each country.ConclusionsThe TOPICOP score can be feasibly applied across countries and may therefore be useful for obtaining qualitative and quantitative data from international studies and for adapting patient education and treatment.
      PubDate: 2017-05-22T01:51:02.891248-05:
      DOI: 10.1111/all.13189
  • Der f 35: An MD-2-like house dust mite allergen that cross-reacts with Der
           f 2 and Pso o 2
    • Authors: T. Fujimura; T. Aki, T. Isobe, A. Matsuoka, T. Hayashi, K. Ono, S. Kawamoto
      Pages: 1728 - 1736
      Abstract: BackgroundDermatophagoides farinae is a source of airborne house dust mite (HDM) allergens. We elucidated IgE-reactive allergens from D. farinae by two-dimensional immunoblotting-based allergenome analysis, and identified one new allergen, named Der f 35, that possesses IgE-binding capacity comparable to that of Der f 2. The aim of this study was to clarify the allergenic capacity of new HDM allergen Der f 35.MethodsWe cloned der f 35 from D. farinae mRNA and produced recombinant Der f 35 in Escherichia coli. The IgE-binding capacity of Der f 35 and its cross-reactivity with group 2 allergens from D. farinae and Psoroptes ovis were determined by enzyme-linked immunosorbent assay (ELISA) and ELISA inhibition assays, respectively.ResultsThe deduced amino acid sequence for der f 35, which possesses the MD-2-related lipid-recognition domain, showed higher identity with group 2 allergens from P. ovis (61.5%) and Blomia tropicalis (50.7%) than with Der f 2 (40.8%). Der f 35 showed IgE-binding frequencies of 77.5% (31/40) for the native form upon allergenome analysis and 51.4% (18/35) for recombinant structure by ELISA. Der f 35 showed cross-reactivity with Der f 2 and Pso o 2 in reaction with HDM-allergic patients' IgE by ELISA inhibition assay.ConclusionDer f 35 is a candidate major allergen from D. farinae, which is more similar to group 2 allergens from sheep scab mite and storage mites. Der f 35 could be responsible for the cross-reactivity among group 2 mite allergens.
      PubDate: 2017-05-23T00:30:36.14906-05:0
      DOI: 10.1111/all.13192
  • Prospective evaluation of the diagnostic value of sensitive KIT D816V
    • Authors: T. Kristensen; H. Vestergaard, C. Bindslev-Jensen, C. G. Mortz, H. F. Kjaer, M. Ollert, M. B. Møller, S. Broesby-Olsen,
      Pages: 1737 - 1743
      Abstract: BackgroundSensitive KIT D816V mutation analysis of blood has been proposed to guide bone marrow (BM) investigation in suspected systemic mastocytosis (SM). The aim of this prospective study was for the first time to compare the D816V status of the “screening blood sample” used to guide BM biopsy in suspected SM to the outcome of the subsequent BM investigation.MethodsFifty-eight adult patients with suspected SM were included. The outcome of sensitive KIT D816V analysis of blood was compared to the result of the BM investigation.ResultsScreening blood samples from 44 of 58 patients tested D816V-positive. In 43 of these, SM was subsequently diagnosed in the BM investigation. One patient with a D816V-positive screening sample was diagnosed with monoclonal MC activation syndrome. Screening blood samples from 14 patients tested D816V-negative. SM was subsequently diagnosed in five of these, whereas nine patients did not fulfill any diagnostic SM criteria (excluding tryptase criterion). Of the 48 SM patients, 90% tested D816V-positive. Thirteen SM patients presented with Hymenoptera venom-induced anaphylaxis, no skin lesions, and baseline serum tryptase ≤20 ng/mL. Of these, 92% tested D816V-positive in the screening blood sample.ConclusionThis prospective study demonstrates that a D816V-positive result in a screening blood sample identifies SM among patients with hymenoptera venom-induced anaphylaxis in whom the diagnosis would most probably have been missed, with potential severe implications. The observed false-negative screening results also underline that BM investigation is mandatory in all adult patients with clear signs of, or highly suspected SM, regardless of the KIT mutation status.
      PubDate: 2017-05-16T02:55:26.902896-05:
      DOI: 10.1111/all.13187
  • Altered fatty acid metabolism and reduced stearoyl-coenzyme a desaturase
           activity in asthma
    • Authors: N. Rodriguez-Perez; E. Schiavi, R. Frei, R. Ferstl, P. Wawrzyniak, S. Smolinska, M. Sokolowska, N.A. Sievi, M. Kohler, P. Schmid-Grendelmeier, D. Michalovich, K.D. Simpson, E.M. Hessel, M. Jutel, M. Martin-Fontecha, O. Palomares, C.A. Akdis, L. O'Mahony
      Pages: 1744 - 1752
      Abstract: BackgroundFatty acids and lipid mediator signaling play an important role in the pathogenesis of asthma, yet this area remains largely underexplored. The aims of this study were (i) to examine fatty acid levels and their metabolism in obese and nonobese asthma patients and (ii) to determine the functional effects of altered fatty acid metabolism in experimental models.MethodsMedium- and long-chain fatty acid levels were quantified in serum from 161 human volunteers by LC/MS. Changes in stearoyl-coenzyme A desaturase (SCD) expression and activity were evaluated in the ovalbumin (OVA) and house dust mite (HDM) murine models. Primary human bronchial epithelial cells from asthma patients and controls were evaluated for SCD expression and activity.ResultsThe serum desaturation index (an indirect measure of SCD) was significantly reduced in nonobese asthma patients and in the OVA murine model. SCD1 gene expression was significantly reduced within the lungs following OVA or HDM challenge. Inhibition of SCD in mice promoted airway hyper-responsiveness. SCD1 expression was suppressed in bronchial epithelial cells from asthma patients. IL-4 and IL-13 reduced epithelial cell SCD1 expression. Inhibition of SCD reduced surfactant protein C expression and suppressed rhinovirus-induced IP-10 secretion, which was associated with increased viral titers.ConclusionsThis is the first study to demonstrate decreased fatty acid desaturase activity in humans with asthma. Experimental models in mice and human epithelial cells suggest that inhibition of desaturase activity leads to airway hyper-responsiveness and reduced antiviral defense. SCD may represent a new target for therapeutic intervention in asthma patients.
      PubDate: 2017-05-10T03:15:27.266652-05:
      DOI: 10.1111/all.13180
  • Serum periostin relates to type-2 inflammation and lung function in
           asthma: Data from the large population-based cohort Swedish GA(2)LEN
    • Authors: A. James; C. Janson, A. Malinovschi, C. Holweg, K. Alving, J. Ono, S. Ohta, A. Ek, R. Middelveld, B. Dahlén, B. Forsberg, K. Izuhara, S.-E. Dahlén
      Pages: 1753 - 1760
      Abstract: BackgroundPeriostin has been suggested as a novel, phenotype-specific biomarker for asthma driven by type 2 inflammation. However, large studies examining relationships between circulating periostin and patient characteristics are lacking and the suitability of periostin as a biomarker in asthma remains unclear.AimTo examine circulating periostin in healthy controls and subjects with asthma from the general population with different severity and treatment profiles, both with and without chronic rhinosinusitis (CRS), in relation to other biomarkers and clinical characteristics.MethodsSerum periostin was examined by ELISA in 1100 subjects aged 17-76 from the Swedish Global Allergy and Asthma European Network (GA(2)LEN) study, which included 463 asthmatics with/without chronic rhinosinusitis (CRS), 98 individuals with CRS only, and 206 healthy controls. Clinical tests included measurement of lung function, Fraction of exhaled NO (FeNO), IgE, urinary eosinophil-derived neurotoxin (U-EDN), and serum eosinophil cationic protein (S-ECP), as well as completion of questionnaires regarding respiratory symptoms, medication, and quality of life.ResultsAlthough median periostin values showed no differences when comparing disease groups with healthy controls, multiple regression analyses revealed that periostin was positively associated with higher FeNO, U-EDN, and total IgE. In patients with asthma, an inverse relationship with lung function was also observed. Current smoking was associated with decreased periostin levels, whereas increased age and lower body mass index (BMI) related to higher periostin levels in subjects both with and without asthma.ConclusionWe confirm associations between periostin and markers of type 2 inflammation, as well as lung function, and identify novel constitutional factors of importance to the use of periostin as a phenotype-specific biomarker in asthma.
      PubDate: 2017-05-22T01:40:41.26461-05:0
      DOI: 10.1111/all.13181
  • Clinical, functional and inflammatory characteristics in patients with
           paucigranulocytic stable asthma: Comparison with different sputum
    • Authors: P. Ntontsi; S. Loukides, P. Bakakos, K. Kostikas, G. Papatheodorou, E. Papathanassiou, G. Hillas, N. Koulouris, S. Papiris, A. I. Papaioannou
      Pages: 1761 - 1767
      Abstract: BackgroundAccording to induced sputum cell count, four different asthma phenotypes have been recognized (eosinophilic, neutrophilic, mixed and paucigranulocytic). The aim of this study was to detect functional and inflammatory characteristics of patients with paucigranulocytic asthma.MethodsA total of 240 asthmatic patients were categorized into the four phenotypes according to cell counts in induced sputum. All patients underwent pulmonary function tests, and measurement of fraction of exhaled nitric oxide (FeNO). The levels of IL-8, IL-13 and eosinophilic cationic protein (ECP) were also measured in sputum supernatant. Treatment, asthma control and the presence of severe refractory asthma (SRA) were also recorded.ResultsPatients were categorized into the four phenotypes as follows: eosinophilic (40%), mixed (6.7%), neutrophilic (5.4%) and paucigranulocytic (47.9%). Although asthma control test did not differ between groups (P=.288), patients with paucigranulocytic asthma had better lung function (FEV1 % pred) [median (IQR): 71.5 (59.0-88.75) vs 69.0 (59.0-77.6) vs 68.0 (60.0-85.5) vs 80.5 (69.7-95.0), P=.009] for eosinophilic, mixed, neutrophilic and paucigranulocytic asthma, respectively, P=.009). SRA occurred more frequently in the eosinophilic and mixed phenotype (41.6% and 43.7%, respectively) and less frequently in the neutrophilic and paucigranulocytic phenotype (25% and 21.7%, respectively, P=.01). FeNO, ECP and IL-8 were all low in the paucigranulocytic, whereas as expected FeNO and ECP were higher in eosinophilic and mixed asthma, while IL-8 was higher in patients with neutrophilic and mixed asthma (P
      PubDate: 2017-05-11T03:35:39.028199-05:
      DOI: 10.1111/all.13184
  • Children with atopic dermatitis and frequent emollient use have increased
    • Authors: L. E. K. Overgaard; K. M. Main, H. Frederiksen, S. Stender, P. B. Szecsi, H. C. Williams, J. P. Thyssen
      Pages: 1768 - 1777
      Abstract: BackgroundParabens may be added to cosmetic and personal care products for preservation purposes. Low-molecular weight (LMW) phthalate diesters function as plasticizers, fixatives or solvents in such products, but may also be found in small quantities as contaminants from plastic containers.ObjectiveTo evaluate the association between emollient use, atopic dermatitis and FLG mutations, respectively, with urinary concentrations of phthalate metabolites and parabens in Danish children.MethodsEight hundred and forty-five Danish children 4-9 years of age were studied. Urinary concentrations of phthalate metabolites and parabens were determined, and children were genotyped for common FLG loss-of-function mutations. Information about atopic dermatitis and use of emollients was obtained from questionnaires completed by parents.ResultsThe prevalence of atopic dermatitis was 16.1%. Phthalate metabolite and paraben levels were generally higher in children with frequent use of emollients compared to uncommon users, reaching statistical significance for some LMW phthalates and parabens. While there was no association with common FLG mutations, children with atopic dermatitis had significantly higher urinary levels of one LMW phthalate and two parabens, respectively, when compared to children without atopic dermatitis.ConclusionEmollient use and atopic dermatitis were associated with modestly increased internal LMW phthalate and paraben exposure in 4-9 year old children. It is unknown whether the difference is explained by increased use of the specific emollients that are used to treat pruritic and inflamed skin, and/or whether the impaired skin barrier allows chemicals to penetrate more easily. Moreover, the putative toxicological burden is unknown.
      PubDate: 2017-04-04T23:40:27.475567-05:
      DOI: 10.1111/all.13157
  • Transcriptome analysis of severely active chronic spontaneous urticaria
           shows an overall immunological skin involvement
    • Authors: A. Giménez-Arnau; L. Curto-Barredo, L. Nonell, E. Puigdecanet, J. Yelamos, R. Gimeno, S. Rüberg, L. Santamaria-Babi, R.M. Pujol
      Pages: 1778 - 1790
      Abstract: BackgroundThe knowledge about chronic spontaneous urticaria (CSU) phenotypes is based on its clinical characteristics, associated comorbidities, course of the disease, and its response to the available effective drugs. Genotype expression and its further correlation with CSU phenotypes are still unknown. We describe the cutaneous transcriptome of patients suffering a severely active CSU refractory to antihistamine treatment.MethodsThrough the bioinformatic analysis of the whole Human Genome with Oligo Microarrays and quantitative real-time polymerase chain reaction (qPCR), relevant genes expressed in nonlesional (NLS-CSU) and lesional skin (LS-CSU) and peripheral blood were identified in 20 patients suffering from severely active CSU and 10 healthy controls (HCs).ResultsFrom 39 genes differentially expressed in NLS-CSU when compared with HCs, 31 (79.48%) were confirmed by qPCR corresponding to genes involved in epidermal homeostasis and dermal repair. From the analysis comparing LS-CSU with NLS-CSU, a selection of 142 genes was studied with qPCR, and 103 (72.53%) were confirmed. Differentially expressed genes in the phenomenon of wheal development are involved in a variety of biological functions as, epidermal differentiation, intracellular signal function, transcriptional factors cell cycle differentiation, inflammation, or coagulation. Differentially expressed genes that uniformly increase or decrease along the skin worsening until the wheal appearance is shown.ConclusionThe skin of CSU patients with a severely active disease shows an overall immunological skin involvement showing a peculiar gene profile.
      PubDate: 2017-05-26T04:15:56.833487-05:
      DOI: 10.1111/all.13183
  • Birth decade affects the sensitization pattern and asthma risk in Finnish
           adult population
    • Authors: S. Toppila-Salmi; A. Luukkainen, R. Lemmetyinen, J. Karjalainen, H. Huhtala, R. Renkonen, D. Y. Wang, M. J. Mäkelä, J. Pekkanen
      Pages: 1791 - 1795
      Abstract: We have previously shown that sensitizations to several types of allergens distinguish subjects with and without adult-onset asthma in Finland. The aim was to analyze how age affects sensitization and asthma risk. We used previous population-based case-control data (N=456) from Finnish adult asthma patients with one or two matched controls. Asthma was diagnosed based on a typical history of asthmatic symptoms and lung function tests. Allergic sensitization was determined by skin prick test (SPT) to 17 aeroallergens. Information on demographics was obtained by a questionnaire. Sensitization to more than one allergen type and the number of positive SPT reactions associated with younger age and asthma. Atopic subjects aged 65 and above were characterized by sensitization to only one to two allergens, with very few animal danders and without an association with asthma. Multiple sensitizations and animal dander sensitization are more common among Finnish asthmatic adults aged under 56 than among older asthmatics. Cohort studies are needed to understand timing of host-environmental interactions behind this.
      PubDate: 2017-05-22T01:50:37.723894-05:
      DOI: 10.1111/all.13194
  • The relationship between nasopharyngeal CCL5 and microbiota on disease
           severity among infants with bronchiolitis
    • Authors: K. Hasegawa; J. M. Mansbach, N. J. Ajami, J. F Petrosino, R. J. Freishtat, S. J. Teach, P. A. Piedra, C. A. Camargo 
      Pages: 1796 - 1800
      Abstract: Emerging evidence suggests that the airway microbiota plays an important role in viral bronchiolitis pathobiology. However, little is known about the combined role of airway microbiota and CCL5 in infants with bronchiolitis. In this multicenter prospective cohort study of 1005 infants (age
      PubDate: 2017-04-12T02:55:37.028652-05:
      DOI: 10.1111/all.13160
  • Serum levels of 9α,11β-PGF2 and apolipoprotein A1 achieve high
           predictive power as biomarkers of anaphylaxis
    • Authors: M. Wittenberg; M. Nassiri, W. Francuzik, K. Lehmann, M. Babina, M. Worm
      Pages: 1801 - 1805
      Abstract: Anaphylaxis is a life-threatening hypersensitivity reaction. To identify biomarkers for the condition, we assessed serum levels of apolipoprotein (Apo)A and ApoE. We found a reduction of both lipoproteins in anaphylactic mice as well as in orally challenged food allergic patients. We then compared patients after acute anaphylaxis with several control groups (nonallergic, history of allergen-triggered anaphylaxis, acute cardiovascular/febrile reactions). In this unpaired setting, ApoE levels were unaltered, while ApoA1 was reduced in the anaphylactic group. Although unable to discriminate between anaphylaxis and cardiovascular/febrile reactions, ROC curve analysis revealed a reasonably high area under the curve (AUC) of 0.91 for ApoA1. Serum 9α,11ß-PGF2, recently identified as a suitable biomarker for anaphylaxis, outperformed ApoA1 with AUC=0.95. Intriguingly however its power further increased upon combination of both mediators reaching AUC=1. Our data suggest that ApoA1 combined with 9α,11ß-PGF2 represents a useful composite biomarker of anaphylaxis, achieving superior diagnostic power over either factor alone.
      PubDate: 2017-05-10T03:15:35.268974-05:
      DOI: 10.1111/all.13176
  • Identification of a polygalacturonase (Cup s 2) as the major CCD-bearing
           allergen in Cupressus sempervirens pollen
    • Authors: Y. Shahali; J.-P. Sutra, C. Hilger, K. Swiontek, I. Haddad, J. Vinh, L. Guilloux, D. Charpin, H. Sénéchal, P. Poncet
      Pages: 1806 - 1810
      Abstract: As IgE glyco-epitopes, also referred to as cross-reactive carbohydrate determinants (CCDs), can share significant structural homologies between different plants, they are prone to extensive cross-reactivity among allergen pollen extracts. Here, cypress pollen allergens, especially a polygalacturonase (PG), were further characterized using double one-dimensional electrophoresis (D1-DE). The presence of specific IgE directed against CCDs was investigated by bromelain IgE inhibition and concanavalin A binding assays using sera of cypress pollen-sensitized patients. Our results showed that IgE reactivity to CCDs in Cupressus sempervirens pollen extracts is mainly related to bromelain-type epitopes of a newly identified cypress PG. This glycoprotein has been further characterized through an immunoproteomic approach and officially indexed as Cup s 2 by the WHO/IUIS allergen nomenclature. Cup s 2 could thus be associated with the increased prevalence of IgE reactivity to cypress pollen extracts because of CCD interference.
      PubDate: 2017-05-22T01:12:37.425806-05:
      DOI: 10.1111/all.13191
  • Predictive value of serum sST2 in preschool wheezers for development of
           asthma with high FeNO
    • Authors: M. E. Ketelaar; K. D. Kant, F. N. Dijk, E. M. Klaassen, N. S. Grotenboer, M. C. Nawijn, E. Dompeling, G. H. Koppelman
      Pages: 1811 - 1815
      Abstract: Wheezing is common in childhood. However, current prediction models of pediatric asthma have only modest accuracy. Novel biomarkers and definition of subphenotypes may improve asthma prediction. Interleukin-1-receptor-like-1 (IL1RL1 or ST2) is a well-replicated asthma gene and associates with eosinophilia. We investigated whether serum sST2 predicts asthma and asthma with elevated exhaled NO (FeNO), compared to the commonly used Asthma Prediction Index (API). Using logistic regression modeling, we found that serum sST2 levels in 2-3 years-old wheezers do not predict doctors’ diagnosed asthma at age 6 years. Instead, sST2 predicts a subphenotype of asthma characterized by increased levels of FeNO, a marker for eosinophilic airway inflammation. Herein, sST2 improved the predictive value of the API (AUC=0.70, 95% CI 0.56-0.84), but had also significant predictive value on its own (AUC=0.65, 95% CI 0.52-0.79). Our study indicates that sST2 in preschool wheezers has predictive value for the development of eosinophilic airway inflammation in asthmatic children at school age.
      PubDate: 2017-05-23T00:30:24.564335-05:
      DOI: 10.1111/all.13193
  • Minimal impact of extensive heating of hen's egg and cow's milk in a food
           matrix on threshold dose-distribution curves
    • Authors: B. C. Remington; J. Westerhout, D. E. Campbell, P. J. Turner
      Pages: 1816 - 1819
      Abstract: We analyzed reaction threshold data from 352 children undergoing open food challenges to hen's egg or cow's milk, either fresh or extensively heated into a muffin. There was no significant shift in dose-distribution curves due to the baking process, implying that existing threshold data for these allergens can be applied to allergen risk management, even when these allergens are heat-processed into baked foods.
      PubDate: 2017-05-26T04:15:39.723282-05:
      DOI: 10.1111/all.13198
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