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Background. Drug patch tests (DPTs) with medicaments suspected of causing an allergic reaction represent a method of diagnostic testing that is low risk; DPTs can reproduce delayed hypersensitivity to drugs, and entail only a moderate re-exposure of patients to potential offending drugs. We assessed the non-irritating concentrations of DPTs and determined the amounts of active ingredient (AI) contained in the drugs used in the tests. Objectives. The objectives were to assess the non-irritating concentration of DPTs and determine the amounts of active ingredient (AI) contained in the drugs used in the tests. Methods. From a retrospective, single-centre study of all patients investigated during a 6-year period with a drug eruption, each potentially responsible drug was tested with the commercially available preparation diluted to 30% in water, petrolatum, or alcohol. Data collection was performed with a customized computer database. For each type of DPT studied, the numbers of positive and negative test results were recorded. The amount of AI contained in the DPT (as a percentage) was then calculated after weighing of each tablet. Results. Of the 5558 DPTs studied, all were non-irritant. The average concentration of AI was 9.8%; 25% of DPTs had an AI concentration of <2%, and 25% had an AI concentration of >16%. The AI concentration ranged from 0.05% (digoxin) to 30% (paracetamol lyophilisate). Conclusion. These data provide thresholds for the non-irritating concentration of AI of 68 different drugs, and thresholds for the non-irritating dilution for 82 drugs, and will help to standardize DPT methods. [ABSTRACT FROM AUTHOR]

Purpose: Fluindione is an oral vitamin K antagonist (indanedione derivative) exclusively marketed in France and Luxembourg, known to have immuno-allergic adverse effects such as hepatitis, fever or interstitial nephritis. A few cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with fluindione. The aim of the present study was to investigate fluindione-induced DRESS cases reported in France and to describe their characteristics. Methods: We searched for potential cases of DRESS with fluindione reported in the French pharmacovigilance database since 2000. Results: Thirty-six cases of DRESS were included and concerned 17 women and 19 men. The mean age was 65 years (median: 68 years, range: 28-95 years). Kidneys and liver were the most frequent organs involved. Thirty-five cases were serious. In 5 cases, the effect was life-threatening. Most of the patients recovered. Fluindione was the only medicine suspected in 26 cases. Skin patch tests, performed in 10 cases, were positive with fluindione in 9 cases. Conclusions: Fluindione is not known to be a frequent cause of DRESS. However, the number of reports found is probably underestimated. The seriousness of DRESS, as all immuno-allergic adverse effects, contraindicates fluindione reintroduction. Coumarinic derivatives are the alternatives in patients who need oral anticoagulant treatment. [ABSTRACT FROM AUTHOR]

Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA2LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD®) has been established under FileMaker® Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA2LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA2LEN–ENDA–DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments. [ABSTRACT FROM AUTHOR]

Abstract: Patch testing with the suspected compound has been reported to be helpful in determining the cause of a cutaneous adverse drug reaction (CADR) and in studying the pathophysiological mechanisms involved. The main advantages of drug patch tests are that they can be done with no hospital surveillance because they induce only rarely adverse reactions and that any commercialized form of a drug can be used. In contrast, intradermal tests can be performed only with injectable forms or with a pure and sterile form of the drug. It is advised to perform drug patch tests during the 6 months following the CADR as we do not know whether positive results will persist. Due to the possibility that a low concentration might yield false negative results, drug patch tests have to be performed with rather high concentrations of the commercialized form of the drug, mostly diluted at 30% in petrolatum and/or in water. For some drugs and severe CADR, it is necessary to tests with lower concentrations or in other vehicles. Drug patch tests are positive in ca. 32–50% of patients who have developed a CADR. The clinical relevance of drug patch tests depends on the clinical features of the CADR (valuable in testing generalized eczema, systemic contact dermatitis, maculopapular rash, acute generalized exanthematous pustulosis, fixed drug eruption) and on the involved drug. As false positive results can be observed, it is always necessary to consider the relevance of any positive drug patch test. Their specificity and their negative predictive value have not been yet determined. [Copyright &y& Elsevier]

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Acute generalized exanthematous pustulosis (AGEP) is a rare, usually drug‐induced, acute pustular rash. Despite the lack of strong data supporting the effectiveness of topical or systemic corticosteroids in this drug reaction, they are widely used. More generally, there is no consensus on the diagnostic modalities and the management of patients with AGEP. We aimed to provide European expert recommendations for the diagnosis and management or patients with AGEP. Members of the ToxiTEN group of the European Reference Network (ERN)‐skin, all dermatologists and/or allergologists with expertise in drug reactions, elaborated these recommendations based on their own experience and on a review of the literature. Recommendations were separated into the following categories: professionals involved, assessment of the diagnosis of AGEP, management of the patient and allergological work‐up after the acute phase. Consensus was obtained among experts for the list of professionals involved for the diagnosis and management of AGEP, including the minimum diagnostic work‐up, the setting of management, the treatments, the modalities and the timing of allergological work‐up and follow‐up. European experts in drug allergies propose herein consensus on the diagnosis and management of patients with AGEP. A multidisciplinary approach is warranted, including dermatologists, allergologists and pharmacovigilance services. [ABSTRACT FROM AUTHOR]

Background: The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome represents a severe form of drug hypersensitivity reaction characterized by significant morbidity, mortality, and long-term sequelae, coupled with limited therapeutic avenues. Accurate identification of the causative drug(s) is paramount for acute management, exploration of safe therapeutic alternatives, and prevention of future occurrences. However, the absence of a standardized diagnostic test and a specific causality algorithm tailored to DRESS poses a significant challenge in its clinical management. Methods: We conducted a retrospective case–control study involving 37 DRESS patients to validate a novel causality algorithm, the ALDRESS, designed explicitly for this syndrome, comparing it against the current standard algorithm, SEFV. Results: The ALDRESS algorithm showcased superior performance, exhibiting an 85.7% sensitivity and 93% specificity with comparable negative predictive values (80.6% vs. 97%). Notably, the ALDRESS algorithm yielded a substantially higher positive predictive value (75%) compared to SEFV (51.40%), achieving an overall accuracy rate of 92%. Conclusions: Our findings underscore the efficacy of the ALDRESS algorithm in accurately attributing causality to drugs implicated in DRESS syndrome. However, further validation studies involving larger, diverse cohorts are warranted to consolidate its clinical utility and broaden its applicability. This study lays the groundwork for a refined causality assessment tool, promising advancements in the diagnosis and management of DRESS syndrome. [ABSTRACT FROM AUTHOR]

Acute generalized exanthematous pustulosis (AGEP) is a rare severe cutaneous reaction. In over 90% of patients it is an adverse reaction to drugs. Delayed-type (type IV) hypersensitivity seems to play an important role in its pathophysiology. Positive patch tests have ranged from 18% to 75%, with 93 culprit drugs identified. Our case involves an 87-year-old female patient, treated for a periprosthetic joint infection with ceftriaxone and daptomycin, who developed acute generalized exanthematous pustulosis. Clinical diagnosis was confirmed by skin biopsy. Patch testing performed 5 months later confirmed sensitization to ceftriaxone. Patch testing is useful to identify the cause of AGEP when the responsible drug is unclear. [ABSTRACT FROM AUTHOR]

Table of contents: Poster walk 11: miscellaneous drug hypersensitivity 2 (P92–P94, P96–P101) P92 16 years of experience with proton pump inhibitors (PPIs) Javier Dionicio Elera, Cosmin Boteanu, Maria Aranzazu Jimenez Blanco, Rosario Gonzalez‐Mendiola, Irene Carrasco García, Antonio Alvarez, Jose Julio Laguna Martinez P93 Allergy evaluation of quinolone induced adverse reactions Jaume Martí Garrido, Carla Torán Barona, Carolina Perales Chorda, Ramón López Salgueiro, Miguel Díaz Palacios, Dolores Hernández Fernández De Rojas P94 Bupropion‐induced acute urticaria and angioedema, a case report Emre Ali Acar, Ayse Aktas, Aylin Türel Ermertcan, Peyker Temiz P96 Delayed type hypersensitivity and study of cross‐reactivity between proton‐pump inhibitors Chien‐Yio Lin, Chung‐Yee Rosaline Hui, Ya‐Ching Chang, Chih‐Hsun Yang, Wen‐Hung Chung P97 Diagnostic work‐up in suspected hypersensitivity to proton‐pump inhibitors: looking at cross‐reactivity Fabrícia Carolino, Diana Silva, Eunice Dias De Castro, Josefina R. Cernadas P98 Management of infusion‐related hypersensitivity reactions to enzyme replacement therapy for lysosomal diseases Luis Felipe Ensina, Carolina Aranda, Ines Camelo Nunes, Alex Lacerda, Ana Maria Martins, Ekaterini Goudouris, Marcia Ribeiro, José Francisco Da Silva Franco, Leandra Queiroz, Dirceu Solé P99 Management of insulin allergy with continuous subcutaneous insulin infusion Ceyda Tunakan Dalgiç, Aytül Zerrin Sin, Fatma Düsünür Günsen, Gökten Bulut, Fatma Ömür Ardeniz, Okan Gülbahar, Emine Nihal Mete Gökmen, Ali Kokuludag P100 Off‐label use of icatibant for management of serious angioedema associated with angiotensin inhibitors Ana M. Montoro De Francisco, Talía Mª De Vicente Jiménez, Adriana M. Mendoza Parra, Angella M. Burgos Pimentel, Amelia García Luque P101 Thiocolchicoside anaphylaxis: an unusual suspect? Luis Amaral, Fabricia Carolino, Leonor Carneiro Leão, Eunice Castro, Josefina Cernadas Poster walk 12: betalactam hypersensitivity (P102–P111) P102 A curious delayed reading: a case report of a β‐lactam allergy in a child Nicole Pinto, Joana Belo, João Marques, Pedro Carreiro‐Martins, Paula Leiria‐Pinto P103 Betalactam‐induced hypersensitivity: a 10‐years' experience Amel Chaabane, Haifa Ben Romdhane, Nadia Ben Fredj, Zohra Chadly, Naceur A. Boughattas, Karim Aouam P104 Cefazolin hypersensitivity: towards optimized diagnosis Astrid P. Uyttebroek, Chris H. Bridts, Antonino Romano, Didier G. Ebo, Vito Sabato P105 Clavulanic acid allergy: two cases report Anabela Lopes, Joana Cosme, Rita Aguiar, Tatiana Lourenço, Maria‐João Paes, Amélia Spínola‐Santos, Manuel Pereira‐Barbosa P106 Diagnosis of betalactam allergy in an allergy department Cíntia Rito Cruz, Rute Pereira Dos Reis, Elza Tomaz, Ana Paula Pires, Filipe Inácio P107 Diagnostic work‐up of 410 patients with suspicion of betalactam antibiotic hypersensitivity Filipe Benito‐Garcia, Inês Mota, Magna Correia, Ângela Gaspar, Marta Chambel, Susana Piedade, Mário Morais‐Almeida P108 Immediate selective hypersensitivity reactions to clavulanic acid Alla Nakonechna, Yurij Antipkin, Tetiana Umanets, Fernando Pineda, Francisca Arribas, Volodymyr Lapshyn P109 Prevalence and incidence of penicillin hypersensitivity reactions in Colombia Pablo Andrés Miranda, Bautista De La Cruz Hoyos P110 Selective sensitization to amoxicilin and clavulanic acid Jose Julio Laguna Martinez, Aranzazu Jimenez Blanco, Javier Dionicio Elera, Cosmin Boteanu, Rosario Gonzalez‐Mendiola, Marta Del Pozo P111 Infliximab‐specific T cells are detectable also in treated patients who have not developed anti‐drug antibodies Alessandra Vultaggio, Francesca Nencini, Sara Pratesi, Andrea Matucci, Enrico Maggi Poster walk 13: biologicals, local anesthetics, others (P112–P118) P112 A case report of allergic immediate systemic reaction to adalimumab and certolizumab Ceyda Tunakan Dalgiç, Fatma Düsünür Günsen, Gökten Bulut, Fatma Ömür Ardeniz, Okan Gülbahar, Emine Nihal Mete Gökmen, Aytül Zerrin Sin, Ali Kokuludag P113 Allergy to local anesthetics: negative predictive value of skin tests Ivana Cegec, Danica Juricic Nahal, Viktorija Erdeljic Turk, Matea Radacic Aumiler, Ksenija Makar Ausperger, Iva Kraljickovic, Iveta Simic P114 Cutaneous adverse reactions of molecular targeted agents: a retrospective analysis in 150 patients in our department Yukie Yamaguchi, Tomoya Watanabe, Megumi Satoh, Tomohiko Tanegashima, Kayoko Oda, Hidefumi Wada, Michiko Aihara P115 Generalized paralysis induced by local lidocaine injection Jaechun Jason Lee, Jay Chol Choi, Hwa Young Lee P116 Hypersensitivity to local anaesthetics: a 10 year review Rosa‐Anita Rodrigues Fernandes, Emília Faria, Joana Pita, Nuno Sousa, Carmelita Ribeiro, Isabel Carrapatoso, Ana Todo Bom P117 Local anaesthetics: a rare culprit in hypersensitivity reactions Ana Rodolfo, Eunice Dias‐Castro, Josefina Cernadas P118 Stevens–Johnson syndrome in clinical practice: a variant of clinical course Marina Voronova Poster walk 14: RCM (P119–P128) P119 13 cases of severe anaphylactic reactions due to radiocontrast media Jaume Martí Garrido, Ramon Lopez Salgueiro, Diana Kury Valle, Verónica Pacheco Coronel, Carolina Perales Chordá, Dolores Hernandez Fernandez De Rojas P120 Anaphylactic shock after administration of iodinated contrast medium during cardiac catheterization Roselle Catherine Yu Madamba, Marta Ferrer, Maria Jose Goikoetxea, Carmen D'Amelio, Amalia Bernad, Olga Vega, Gabriel Gastaminza P121 Anaphylactic shock and cardiac arrest induced by gadolinium‐based contrast agents Beatriz Pola Bibián, Marina Lluncor Salazar, Gemma Vilà Nadal, Ana María Fiandor Roman, Javier Dominguez Ortega, Miguel Gonzalez Muñoz, Santiago Quirce Gancedo, Maria Rosario Cabañas Moreno P122 Anaphylaxis to gadobenate and cross‐reactivity to other gadolinium‐based contrast agents in two patients Kathrin Scherer Hofmeier P123 Anaphylaxis to glatiramer acetate in a patient with multiple sclerosis Fabrícia Carolino, Vladyslava Barzylovych, Josefina R. Cernadas P124 Delayed hypersensitivity reaction to radiocontrast media Fabrícia Carolino, Diana Silva, Leonor Leão, Josefina R. Cernadas P125 Drug reaction with eosinophilia and systemic symptoms induced by iodixanol Gemma Vilà‐Nadal, Beatriz Pola, Marina Lluncor, Ana Fiandor, Teresa Bellón, Javier Domínguez, Santiago Quirce P126 Electronic consultation support system for radiocontrast media hypersensitivity changes clinician's behavior Min‐Suk Yang, Sun‐Sin Kim, Sae‐Hoon Kim, Hye‐Ryun Kang, Heung‐Woo Park, Sang‐Heon Cho, Kyung‐Up Min, Yoon‐Seok Chang P127 Hypersensitivity reactions to iodinated contrast media: skin testing and follow‐up Danica Juricic Nahal, Ivana Cegec, Viktorija Erdeljic Turk, Iva Kraljickovic, Matea Radacic Aumiler, Ksenija Makar Ausperger, Iveta Simic P128 Would iodine allergy exist? Clémence Delahaye, Jenny Flabbee, Julie Waton, Olivia Bauvin, Annick Barbaud Poster walk 15: MPE/type 4 (P129–P137) P129 Delayed hypersensitivity cutaneous reactions: a case/control study from a tunisian database Karim Aouam, Najah Ben Fadhel, Zohra Chadly, Nadia Ben Fredj, Naceur A. Boughattas, Amel Chaabane P130 Delayed hypersensitivity reactions to cephalosporins: a review of seven cases Joana Cosme, Anabela Lopes, Amélia Spínola‐Santos, Manuel Pereira‐Barbosa P131 Diclofenac induced allergic contact dermatitis: case series of four patients Sandra Jerkovic Gulin, Anca Chiriac P132 Late‐onset maculopapular rash to irbesartan Bárbara Kong Cardoso, Elza Tomaz, Regina Viseu, Filipe Inácio P133 Nonimmediate hypersensitivity reactions to betalactams: a retrospective analysis Ana Moreira, Susana Cadinha, Ana Castro Neves, Patricia Barreira, Daniela Malheiro, J. P. Moreira Da Silva P134 Occupational airborne contact dermatitis to omeprazole Ružica Jurakic‐Toncic, Suzana Ljubojevic, Petra Turcic P135 Ornidazole‐induced fixed drug eruption confirmed by positive patch test on a residual pigmented lesion Liesbeth Gilissen, Sara Huygens, An Goossens P136 Repeated delayed reaction induced by amoxicillin and amoxicillin clavulanate Inmaculada Andreu, Ramon Lopez‐Salgueiro, Alicia Martinez Romero, Pau Gomez Cabezas P137 Systemic photosensitivity from fenofibrate in a patient photo‐sensitized to ketoprofen Liesbeth Gilissen, An Goossens Poster walk 16: HLA genetics (P138–P146) P138 A copy number variation in ALOX5 and PTGER1 is associated with nonsteroidal anti‐inflammatory drugs induced urticaria and/or angioedema Pedro Ayuso Parejo, Maria Del Carmen Plaza‐Serón, Inmaculada Doña, Natalia Blanca López, Carlos Flores, Luisa Galindo, Ana Molina, James Richard Perkins, Jose Antonio Cornejo‐García, José Augusto García‐Agúndez, Elena García‐Martín, Paloma Campo, María Gabriela Canto, Miguel Blanca P139 Association of galectin‐3 (LGALS3) single nucleotide polymorphisms with non‐steroidal anti‐inflammatory drugs‐induced urticaria/angioedema José Antonio Cornejo‐Garcia, Inmaculada Doña, Rosa María Guéant‐Rodríguez, Natalia Blanca‐López, María Carmen Plaza‐Serón, Raquel Jurado‐Escobar, Esther Barrionuevo, María Salas, María Luisa Galindo, Gabriela Canto, Miguel Blanca, Jean‐Louis Guéant P140 Detection of T cell responses to ticlopidine using peripheral blood mononuclear cells from HLA‐A*33:03+ healthy donors Toru Usui, Arun Tailor, Lee Faulkner, John Farrell, Ana Alfirevic, B. Kevin Park, Dean J. Naisbitt P141 Epistasis approaches to identify novel genes potentially involved in NSAIDs hypersensitivity James Richard Perkins, Jose Antonio Cornejo García, Oswaldo Trelles, Inmaculada Doña, Esther Barrionuevo, María Salas, María Auxiliadora Guerrero, Miguel Blanca, Alex Upton P142 Genetic predisposition of cold medicine related SJS/TEN with severe ocular complications Mayumi Ueta, Hiromi Sawai, Chie Sotozono, Katushi Tokunaga, Shigeru Kinoshita P143 HLA‐B*13:01 and dapsone induced hypersensitivity in Thai population Chonlaphat Chonlaphat Sukasem, Patompong Satapornpong, Therdpong Tempark, Pawinee Rerknimitr, Kulprapat Pairayayutakul, Jettanong Klaewsongkram P144 HLA‐B*15:02 alleles and lamotrigine‐induced cutaneous adverse drug reactions in Thai Chonlaphat Sukasem, N. Koomdee, T. Jantararoungtong, S. Santon, A. Puangpetch, U. Intusoma, W. Tassaneeyakul, V. Theeramoke P145 HLA‐B*38:01 and HLA‐A*24:02 allele frequencies in Spanish patients with lamotrigine‐induced SCARs Teresa Bellón, Elena Ramirez, Alberto Manuel Borobia, Hoi Tong, Jose Luis Castañer, Francisco José De Abajo P146 Overrepresentation of a class II HLA haplotype in severe hypersensitivity type I reactions to carboplatin Violeta Régnier Galvao, Rebecca Pavlos, Elizabeth Mckinnon, Kristina Williams, Alicia Beeghly‐Fadiel, Alec Redwood, Elizabeth Phillips, Mariana Castells Poster walk 17: in vivo diagnosis + sIgE (P147–P154) P147 Absence of specific Ig‐e against beta‐lactams 9 months after an allergic reaction to amoxicillin‐clavulanic acid Elisa Boni, Marina Russello, Marina Mauro P148 Drug provocation tests in suspected opioid allergy Kok Loong Ue, Krzysztof Rutkowski P149 Improvement to the specific IgE cut‐off in the assess of β‐lactamic allergy Victor Soriano Gomis, Jorge Frances Ferre, Angel Esteban Rodriguez, Vicente Cantó Reig, Javier Fernandez Sanchez P150 Initial false negative specific IgE to gelatin in a patient with gelatin‐induced anaphylaxis Christine Breynaert, Erna Van Hoeyveld, Rik Schrijvers P151 Inmediate reactions to beta‐lactam antibiotics: pattern of skin test response over the time Jose Julio Laguna Martinez, Rosario Gonzalez Mendiola, Javier Dionicio Elera, Cosmin Boteanu, Aranzazu Jimenez Blanco, Marta Del Pozo, Raquel Fuentes Irigoyen P152 New fluorescent dendrimeric antigens for the evaluation of dendritic cell maturation as a test to detect allergy reactions to amoxicillin Daniel Collado, Yolanda Vida, Francisco Najera, Ezequiel Perez‐Inestrosa, Pablo Mesa‐Antunez, Cristobalina Mayorga, María José Torres, Miguel Blanca P153 Positive skin test or positive specific IgE to penicillin does not predict penicillin allergy Line K. Tannert, Charlotte G. Mortz, Per Stahl Skov, Carsten Bindslev‐Jensen P154 Significance of skin testing and in vitro‐analysis of neuromuscular blocking agents in diagnosis of perioperative drug hypersensitivity: evaluation of a negative control population Wolfgang Pfützner, Hannah Dörnbach, Johanna Visse, Michele Rauber, Christian Möbs Poster walk 18: in vitro/ex vivo (P155–P158, P160–P164) P155 Diagnostic value of the lymphocyte toxicity assay (LTA) and the in vitro platelet toxicity assay (IPTA) for β‐lactam allergy Abdelbaset A. Elzagallaai, Lindsey Chow, Awatif M. Abuzgaia, Michael J. Rieder P156 Enzyme linked immunospot assay used in the diagnosis of severe cutaneous adverse reactions to antimicrobials Alec Redwood, Jason Trubiano, Rebecca Pavlos, Emily Woolnough, Kaija Stautins, Christina Cheng, Elizabeth Phillips P157 Evaluation of in vitro diagnostic methods for identifying the culprit drugs in drug hypersensitivity Kenichi Kato, Hiroaki Azukizawa, Takaaki Hanafusa, Ichiro Katayama P158 Ex‐vivo expanded skin‐infiltrating T cells from severe drug eruptions are reactive with causative drugs: a possible novel method for determination of causative drugs Toshiharu Fujiyama, Hideo Hashizume, Takatsune Umayahara, Taisuke Ito, Yoshiki Tokura P160 In vitro release of IL‐2, IL‐5 and IL‐13 in diagnosis of patients with delayed‐type nickel hypersensitivity Mira Silar, Mihaela Zidarn, Helena Rupnik, Peter Korosec P161 Single cell analysis of drug responsive T cells; identification of candidate drug reactive T cell receptors in abacavir and carbamazepine hypersensitivity Alec James Redwood, Kaija Strautins, Katie White, Abha Chopra, Katherine Konvinse, Shay Leary, Rebecca Pavlos, Simon Mallal, Elizabeth Phillips P162 Specificity and sensitivity of LTT in DRESS: analysis of agreement with the Spanish pharmacovigilance system probability algorithm Rosario Cabañas, Elena Ramirez, Ana María Fiandor, Teresa Bellón P163 The role of interleukin‐22 in β‐lactam hypersensitivity Andrew Sullivan, Paul Whitaker, Daniel Peckham, B. Kevin Park, Dean J. Naisbitt P164 Vancomycin‐specific T cell responses and teicoplanin cross‐reactivity Wei Yann Haw, Marta E. Polak, Carolann Mcguire, Michael R. Ardern‐Jones Poster walk 19: BAT and biomarkers (P165–P173) P165 A combination of early biomarkers useful for the prediction of severe ADRs Yumi Aoyama, Tetsuo Shiohara P166 Basophil activation test in the diagnostic approach of reactions during general anaesthesia Ana Moreira, Susana Cadinha, Patrícia Barreira, Ana Castro Neves, Daniela Malheiro, Sara Correia, J. P. Moreira Da Silva P167 IL‐10 can be related to successful desensitization Asli Gelincik, Semra Demir, Fatma Sen, Hamza Ugur Bozbey, Muge Olgac, Derya Unal, Raif Coskun, Bahauddin Colakoglu, Suna Buyuozturk, Esin Çatin‐Aktas, Gunnur Deniz P168 Immediate reactions to proton pump inhibitors: value of basophil activation test Maria Salas, Jose Julio Laguna, Esther Barrionuevo, J. Dionicio, Tahia Fernandez, R. Gonzalez‐Mendiola, I. Olazabal, Maria Dolores Ruiz, Miguel Blanca, Cristobalina Mayorga, Maria José Torres P169 Improvement of the elevated tryptase criterion to discriminate IgE from non‐IgE mediated allergic reactions Gabriel Gastaminza, Alberto Lafuente, Carmen D'Amelio, Amalia Bernad, Olga Vega, Roselle Catherine Madamba, M. Jose Goikoetxea, Marta Ferrer, Jorge Núñez P170 Low expression of Tim‐3 could serve as a biomarker for control and diagnose maculopapular exanthema induced by drugs Tahia Diana Fernández, Inmaculada Doña, Francisca Palomares, Rubén Fernández, Maria Salas, Esther Barrionuevo, Maria Isabel Sanchez, Miguel Blanca, Maria José Torres, Cristobalina Mayorga P171 Role of basophil activation test using two different activation markers for the diagnosis of allergy to fluoroquinolones Esther Barrionuevo, Tahía Fernandez, Arturo Ruiz, Adriana Ariza, Maria Salas, Inmaculada Doña, Ana Molina, Miguel Blanca, Maria Jose Torres, Cristobalina Mayorga P172 The importance of basophil activation test in anaphylaxis due to celecoxib Amalia Bernad Alonso, Carmen D'Amelio Garófalo, Olga Vega Matute, Marta Ferrer Puga, María José Goikoetxea Lapresa, Roselle Catherine Yu Madamba, Gabriel Gastaminza Lasarte P173 The role of basophil activation test in the diagnosis of immediate type drug hypersensitivity to betalactam antibiotics Antonia Thinnes, Hans F. Merk, Jens Malte Baron, Martin Leverkus, Galina Balakirski Poster walk 20: TCR recognition, cellular (P174–P183) P174 Characterisation of the effect of co‐inhibitory signalling on the activation of drug‐derived antigen‐specific T‐cells Andrew Gibson, Monday Ogese, Lee Faulkner, B. Kevin Park, Dean J. Naisbitt P175 Characterization of drug hapten‐specific T cell responses in piperacillin hypersensitive patients Zaid Al‐Attar, Fiazia Yaseen, Xiaoli Meng, Rozalind Jenkins, Paul Whitaker, Daniel Peckham, Lee Faulkner, John Farrel, Kevin Park, Dean Naisbitt P176 Characterization of the response of T‐cells to telaprevir and its metabolite in normal volunteers Zaid Al‐Attar, Khetam Alhilali, Yanni Xue, John Farrell, Lee Faulkner, Kevin Park, Dean Naisbitt P177 Characterization of the T cell receptor signatures of drug‐responsive T cells Patricia Illing, Nicole Mifsud, Heidi Fettke, Jeffrey Lai, Rebecca Ho, Patrick Kwan, Anthony Purcell P178 Defining the signals between hepatocytes and immune cells in idiosyncratic drug‐induced liver injury (DILI) Monday O. Ogese, Lee Faulkner, B. Kevin Park, Catherine Betts, Dean J. Naisbitt P179 Development of novel chemicals that do not bind to HLA‐B*57:01 or activate CD8 + T‐cells through modification of the 6‐amino cyclopropyl group of abacavir Paul Thomson, John Farrell, Mohammad Alhaidari, Neill Berry, Paul M. O'Neill, B. Kevin Park, Dean J. Naisbitt P180 Generation and characterization of dapsone‐ and nitroso‐dapsone‐specific T‐cell clones using lymphocytes from healthy volunteers Abdulaziz Alzahrani, Monday O. Ogese, John Farrell, Lee Faulkner, Andrew Gibson, Arun Tailor, B. Kevin Park, Dean J. Naisbitt P181 Identification of benzylpenicillin‐hapten peptides responsible for naïve T‐cell activation and immunization of allergic patients to penicillin Marie Eliane Azoury, Lucia Fili, Rami Bechara, Noémie Scornet, Cathy Nhim, Richard Weaver, Nancy Claude, Delphine Joseph, Bernard Maillere, Paola Parronchi, Marc Pallardy P182 Massive expansion of clonotypic and polycytotoxic CD8+ T cells in toxic epidermal necrolysis Axel Patrice Villani, Aurore Rozières, Benoît Bensaïd, Mathilde Tardieu, Floriane Albert, Virginie Mutez, Tugba Baysal, Marc Pallardy, Janet Maryanski, Jean‐François Nicolas, Osami Kanagawa, Marc Vocanson P183 Pharmaco‐immunological synapse of HLA‐drug‐TCR in SCAR Shuen‐Iu Hung Poster walk 21: new in vitro methods, haptens, etc. (P184–P194) P184 Amoxicillin‐clavulanate forms distinct multiple haptenic structures on human serum albumin in patients Xiaoli Meng, Arun Tailor, Caroline J. Harrison, Rosalind E. Jenkins, Paul Whitaker, Neil S. French, Dean J. Naisbitt, B. Kevin Park P185 Dendrimeric antigens for studying the influence of penicillin determinants orientation on IgE recognition Maria Isabel Montañez, Cristobalina Mayorga, Francisco Najera, Adriana Ariza, Tahia D. Fernandez, Maria Salas, Angela Martin‐Serrano, Miguel Blanca, Ezequiel Perez‐Inestrosa, Maria Jose Torres P186 Dendrimeric antigens on solid supports: designed materials for IgE quantification Yolanda Vida, Maria Isabel Montañez, Noemi Molina, Daniel Collado, Francisco Najera, Adriana Ariza, Maria Jose Torres, Cristobalina Mayorga, Ezequiel Perez‐Inestrosa P187 Development of a screening assay for drug hypersensitivity using naïve T cells from donors with seven different HLA class I risk alleles Lee Faulkner, Sally Wood, Ana Alfirevic, Munir Pirmohamed, Dean J. Naisbitt, B. Kevin Park P188 Different patterns of recognition of structures derived from amoxicillin by IgE antibodies from patients with immediate hypersensitivity reactions to betalactams Adriana Ariza, Cristobalina Mayorga, María Isabel Montañez, María Salas, Inmaculada Doña, Ángela Martín‐Serrano, Ezequiel Pérez‐Inestrosa, Dolores Pérez‐Sala, Miguel Blanca, Antonio E. Guzmán, María José Torres P189 High‐resolution typing of HLA polymorphism and T‐cell receptor repertoire for severe adverse drug reactions based on the cost‐effective next‐generation sequencing approaches Tai‐Ming Ko, Yuan‐Tsong Chen, Jer‐Yuarn Wu P190 Identification and fate of intracellular proteins haptenated by amoxicillin Francisco J. Sánchez‐Gómez, Juan M. González‐Morena, Yolanda Vida, Ezequiel Pérez‐Inestrosa, Miguel Blanca, María J. Torres, Dolores Pérez‐Sala P191 In vitro detection of terbinafine protein adducts Arun Tailor, Toru Usui, Yanni Xue, Xiaoli Meng, Dean J. Naisbitt, B. Kevin Park P192 MicroRNAs dysregulation in PBMCs from drug hypersensitivity patients during drug challenge in vitro Alejandra Monroy Arreola, Jesus Agustin Badillo Corona, Silvia Mendez Flores, Judith Dominguez Cherit, Dean J. Naisbitt, Noe Valentin Duran Figueroa, Jose Luis Castrejon Flores P193 NSAIDs‐exacerbated cutaneous disease: high throughput gene expression profiling José Antonio Cornejo‐García, James Perkins, Natalia Blanca‐López, Diana Pérez‐Alzate, Raquel Jurado‐Escobar, Inmaculada Doña, Gador Bogas, María J. Torres, Gabriela Canto, Miguel Blanca P194 Utility of skin tests in non‐immediate reactions to amoxicillin Luis Mario Tubella Marti, Fernando Pineda De La Losa, Francisca Arribas Poves, Jaime Tubella Lopez, Teodora Lopez Santiago [ABSTRACT FROM AUTHOR]

Background: Beta-lactam (BL) antibiotics are among the most prescribed groups of drugs worldwide and have been implicated in a variety of allergic reactions. There is a paucity of literature regarding patient adherence to prescribed instructions following comprehensive allergy assessments. Objective: The objective was to follow up the clinical course of BL allergy in patients who underwent thorough allergological investigation for suspected BL allergy at a tertiary hospital and ascertain patients' compliance with the provided written instructions. Materials: An observational study in patients referred for suspected BL allergy who underwent a comprehensive allergy workup (in vivo ± in vitro tests, DPT in culprit and/or alternative BL) and who subsequently received written instructions was conducted. Data on the nature of the reported drug hypersensitivity reaction, the culprit BL drug, the allergological workup, and the detailed instructions provided in a written drug allergy report were collected retrospectively. Patients' compliance with the instructions was recorded by a telephone survey using a pre-defined questionnaire. Results: Among the 212 patients meeting the inclusion criteria, 87 patients (72.4% women; mean age 50.1 years; age range 6–84 years) responded to the telephone survey and were included in this study. Surprisingly, 45 out of 87 (51.7%) patients did not adhere to the written instructions. The primary factor contributing to non-compliance was the fear of re-occurrence of a drug-induced allergic reaction (personal and/or triggered by their treating physician reluctance), accounting for 77.7% of cases. The analysis demonstrated that the initial reaction's severity and type, as well as the outcomes of skin testing, did not correlate with compliance to instructions (p > 0.05). Surprisingly enough, a drug provocation test (DPT), irrespectively of the result, emerged as a negative predictor for adherence, with only 40.6% of DPT patients complying compared to 77.8% of those who did not undergo DPT (p = 0.005; odds ratio = 0.195; 95% confidence interval: 0.058–0.655). Variables such as performing DPT with alternative or incriminated drugs or the result of the DPT (positive–negative) were not associated with patient compliance. Conversely, the type of instructions provided exhibited a noteworthy correlation with compliance. Patients who were explicitly instructed to entirely avoid all BL antibiotics demonstrated markedly higher adherence rates (83.3%) compared to those who were advised to have a partial or complete release of BLs (31.8% and 58.1%, respectively; p < 0.05). Notably, among compliant patients who received either the original culprit drug or the alternative (32 out of 87, 36.7%), no allergic reactions were reported. In contrast, among the 12 patients with written avoidance of all BLs, subsequent BL intake led to immediate reactions (Grade I and IV) in 2 patients (16.6%). Conclusions: A notable disparity in patient adherence to written instructions prohibiting or releasing beta-lactams was demonstrated. Less than half of the patients ultimately complied with the provided instructions, underscoring the need for tailored patients' education and strategies to improve adherence in the management of suspected BL allergy. [ABSTRACT FROM AUTHOR]

Objective: Local anesthetics are broadly used in various health care settings with high probability of lifetime exposure. The main aim of this study was to determine the characteristics and risk factors of the patients presenting to our allergy outpatient clinic due to suspected hypersensitivity to local anesthetics. Materials and Methods: We retrospectively evaluated the clinical data and test results obtained from patients who had presented to our allergy outpatient clinic for allergological work-up of local anesthetics from 2015 to 2020. Results: A total of 289 subjects were included. The most common referral reason was a history of non-local anesthetic drug hypersensitivity reaction (65.7%, n=190). Twenty-five out of 289 (8.65%) patients had positivity for at least one of the tested drugs in skin prick test/ intradermal test/ subcutaneous drug provocation test. Of these 25 patients, 4 (16%) had a history of DHR to LA and 9 (36%) had a history of multiple drug hypersensitivity (MDH). Allergy to local anesthetics was observed in only 13 (18.6%) of 70 patients with a history of local anesthetic hypersensitivity reaction. Patients with atopy were 5.3 times more likely to have local anesthetic hypersensitivity (odds ratio: 5.254; 95% CI: 1.316-20.974; p=0.019). Cross-reactivity among amide-local anesthetics without a distinct predictive pattern has also been demonstrated in 3 patients. Conclusion: Most patients who report local anesthetic allergy can tolerate local anesthetics without having a hypersensitivity reaction. Atopic status is associated with increased risk of a hypersensitivity reaction to local anesthetics. Atopic patients are candidates for performing allergy tests to local anesthetics to enable appropriate counseling. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions are a serious concern in clinical practice because they can be severe and result in lifelong sequelae. An accurate diagnosis and identification of the culprit drug is essential to prevent future reactions as well as for the identification of safe treatment alternatives. Nonetheless, the diagnosis can be challenging. In vivo and in vitro tests can be helpful, although none are conclusive; therefore, the tests are not usually performed in isolation but as part of a diagnostic algorithm. In addition, some in vitro tests are only available in research laboratories, and standardization has not been fully accomplished. Collaborating research is needed to improve drug hypersensitivity reaction diagnosis. In this review, we update the current available in vivo and in vitro tools with their pros and cons and propose an algorithm to integrate them into clinical practice. [ABSTRACT FROM AUTHOR]

The list of drugs patients may be exposed to during the perioperative and postoperative periods is potentially extensive. It includes induction agents, neuromuscular blocking drugs (NMBDs), opioids, antibiotics, sugammadex, colloids, local anesthetics, polypeptides, antifibrinolytic agents, heparin and related anticoagulants, blue dyes, chlorhexidine, and a range of other agents depending on several factors related to individual patients' clinical condition and progress in the postoperative recovery period. To avoid poor or ultrarapid metabolizers to a particular drug (for example tramadol and codeine) or possible adverse drug reactions (ADRs), some drugs may need to be avoided during or after surgery. This will be the case for patients with a history of anaphylaxis or other adverse events/intolerances to a known drug. Other drugs may be ceased for a period before surgery, e.g., anticoagulants that increase the chance of bleeding; diuretics for patients with acute renal failure; antihypertensives relative to kidney injury after major vascular surgery; and serotonergic drugs that together with some opioids may rarely induce serotonin toxicity. Studies of germline variations shown by genotyping and phenotyping to identify a predisposition of genetic factors to ADRs offer an increasingly important approach to individualize drug therapy. Studies of associations of human leukocyte antigen (HLA) genes with some serious delayed immune-mediated reactions are ongoing and variations of drug-metabolizing cytochrome CYP450 enzymes, P-glycoprotein, and catechol-O-methyltransferase show promise for the assessment of ADRs and non-responses to drugs, particularly opioids and other analgesics. Surveys of ADRs from an increasing number of institutions often cover small numbers of patients, are retrospective in nature, fail to clearly identify culprit drugs, and do not adequately distinguish immune-mediated from non-immune-mediated anaphylactoid reactions. From the many surveys undertaken, the large list of agents identified during and after anesthesia and surgery are examined for their ADR involvement. Drugs are classified into those most often involved, (NMBD and antibiotics); drugs that are becoming more frequently implicated, namely antibiotics (particularly teicoplanin), and blue dyes; those becoming less frequently involved; and drugs more rarely involved in perioperative, and postoperative adverse reactions but still important and necessary to keep in mind for the occasional potential sensitive patient. Clinicians should be aware of the similarities between drug-induced true allergic type I IgE/FcεRI- and pseudoallergic MRGPRX2-mediated ADRs, the clinical features of each, and their distinguishing characteristics. Procedures for identifying MRGPRX2 agonists and diagnosing and distinguishing pseudoallergic from allergic reaction mechanisms are discussed. [ABSTRACT FROM AUTHOR]

Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Beta-lactams (BLs) are the main suspected culprits in drug hypersensitivity in children. Oral drug challenges are the gold standard for drug hypersensitivity diagnosis and to delabel BL hypersensitivity. In studies that enrolled patients with adverse drug events that occurred >6 h after medication administration, drug hypersensitivities were generally less prevalent. [Extracted from the article]

Background: Mislabeling of drug allergic histories causes avoidable negative impacts on patients and healthcare system. Although multidisciplinary adverse drug reaction (ADR) services to verify and de-label drug allergic histories have been operated in particular hospitals in Thailand, their performances have not been reported. This research aimed to examine the effectiveness of verification of drug allergic history and de-labeling (VD) services of the physician-led multidisciplinary ADR clinic. Methods: This research was a retrospective descriptive study. Medical charts of patients with at least one drug allergic history who received VD services at the multidisciplinary clinic between January 2017 to December 2018, were reviewed. Data on the history of drug allergy, VD services, and results were analyzed and presented using descriptive statistics. Results: Seventy patients' charts were reviewed, and 171 unconfirmed drug allergic histories were identified. 79.53% of the reported reactions involved skin and soft tissues. The most found adverse skin reactions were maculopapular rash, pruritic and erythematous rash, and angioedema. The remaining 20.47% were systemic reactions which included drug reaction with eosinophilia and systemic symptoms (DRESS), anaphylaxis, and nausea/vomiting was the most prevalent. Antituberculosis, beta-lactam antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs) were the most reported suspected drugs. Drug allergic history reviewing by physicians or pharmacists could confirm and de-label for 3 and 20 reactions, respectively. Seven and one reactions were confirmed by enzyme‐linked immunospot assay and patch test, respectively. The provocation tests with the suspected or alternative drug were conducted in 64 reactions. Twelve reactions were confirmed, and 45 reactions were de-labeled. Totally, 65/171 (38.01%) allergic histories were successfully de-labeled, 23/171 (13.45%) were confirmed, and 83/171 (48.53%) were inconclusive. Conclusions: More than half of drug allergic histories were successfully confirmed or de-labeled by the multidisciplinary ADR team. The collaborative activities of various healthcare professionals, consisting of physicians, nurse, and pharmacists as presented in the study were effective in VD services and should be implemented in other healthcare settings. [ABSTRACT FROM AUTHOR]

Background: Drug patch testing has been proposed as a helpful investigation upon suspecting drug allergy. We evaluated the value of drug patch testing in Cutaneous Adverse Drug Reactions (CADRs). Methods: All patients with a diagnosis of CADRs were patch tested with suspected drugs. Results: Of 122 patients with CADRs, 44.3% had at least one positive result after drug patch testing, P value = 0.312. Drug rash with eosinophilia and systemic symptom (DRESS) rendered the highest positive patch testing at 53.9%, followed by a maculopapular rash (MP) at 49.0%, fixed drug eruption (FDE) at 48.3%, lichenoid drug eruption and Stevens‐Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) at 25.0% each. Lichenoid drug eruption had the longest mean onset of almost 2.5 years. One hundred and twenty‐eight drugs and herbal medicines were tested. About 32.8% of these drugs gave a positive result, P value = 0.041. Nonsteroidal anti‐inflammatory drugs (NSAIDs) were the most common positive drug especially for fixed drug eruption (FDE), followed by antiretroviral and antibiotics, which were the most common positive drugs for MP. While anti‐Tuberculosis (anti‐TB) drugs and antihypertensives together with lipid‐lowering drugs were the most common for DRESS and lichenoid eruption, respectively. Subgroup analysis among HIV patients showed a 61.5% positive patch test. The median CD4 count in the positive group was 43.5 cells/mm3. Conclusion: We recommend drug patch testing as a safe method to identify the culprit drug in CADRs, especially DRESS, MP, and FDE. In HIV patients, the positive test was associated with low CD4 count and copositive reaction. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions are classified into immediate and delayed types, according to the onset time. In contrast to the immediate type, delayed drug hypersensitivity mainly involves T lymphocyte recognition of the drug antigens and cell activation. The clinical presentations of such hypersensitivity are various and range from mild reactions (e.g., maculopapular exanthema (MPE) and fixed drug eruption (FDE)), to drug-induced liver injury (DILI) and severe cutaneous adverse reactions (SCARs) (e.g., Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP)). The common culprits of delayed drug hypersensitivity include anti-epileptics, antibiotics, anti-gout agents, anti-viral drugs, etc. Delayed drug hypersensitivity is proposed to be initiated by different models of molecular recognition, composed of drug/metabolite antigen and endogenous peptide, HLA presentation, and T cell receptor (TCR) interaction. Increasing the genetic variants of HLA loci and drug metabolic enzymes has been identified to be responsible for delayed drug hypersensitivity. Furthermore, preferential TCR clonotypes, and the activation of cytotoxic proteins/cytokines/chemokines, are also involved in the pathogenesis of delayed drug hypersensitivity. This review provides a summary of the current understanding of the molecular recognition, genetic susceptibility, and immune mediators of delayed drug hypersensitivity. [ABSTRACT FROM AUTHOR]

Frequent mislabelled causal relationship between drug hypersensitivity reactions and culprit drugs reinforces the need for an accurate diagnosis. The systematic reviews and meta-analyses of in vitro assays published so far focused on immediate reactions and the most severe delayed reactions, while the most frequent drug-induced delayed reactions—nonsevere exanthemas—have been underestimated. We aim to fill this gap. A systematic review of studies on in vitro assays used in the diagnosis of nonsevere drug-induced delayed reactions was conducted following the methodology of Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies Statement. The EMBASE and PubMed databases were searched. We have included 33 studies from which we extracted the data, then performed meta-analysis where possible, or synthesised the evidence narratively. The quality of the analysed studies was assessed with the QUADAS-2 tool. The tests identified the most frequently were lymphocyte transformation test (LTT), ELISpot, and ELISA. In the meta-analysis carried out for LTT in reactions induce by beta-lactams, the pool estimate of sensitivity and specificity amounted to 49.1% (95% CI: 14.0%, 85.0%) and 94.6% (95% CI: 81.7%, 98.6%), respectively. The studies showed heterogeneity in study design and laboratory settings, which resulted in a wide range of specificity and sensitivity of testing. [ABSTRACT FROM AUTHOR]

Oral drug provocation tests (DPT) are the basic diagnostic tool for the detection of hypersensitivity to non-opioid analgesics and for selecting a safe alternative for a patient. They are of great practical importance due to their common use, but the data on the follow-up of patients after negative DPT are still very scarce. We examined the further fate of 164 such adult patients after negative NSAID or paracetamol tests and analyzed which excipients in the studied drugs they could be exposed to after the diagnostic workup. A structured medical interview was performed 32.9 months (mean) after the provocation tests. Of the 164 patients, 131 (79.9%) retook the tested drug and 12 developed another hypersensitivity reaction, giving the estimated negative predictive value of 90.8%. These reactions were induced by acetylsalicylic acid, paracetamol, meloxicam, and diclofenac, and were clinically similar to the initial ones (most commonly urticaria and angioedema). There are 93 generics of these drugs on the local market, containing a total of 33 excipients for which hypersensitivity reactions have been reported. All available generics contain such excipients. Thirty-one patients (20.1%) did not take the previously tested drug again, most often because it was not needed or because they were afraid of another reaction. DPT with analgesics has a high diagnostic performance. A minority of patients had relapsed after reexposure. One of the underestimated reasons for this may be drug excipients provoking a reaction, so it is advisable to use exactly the same medical product that has been negatively tested. Many patients avoid reexposure to a given drug, despite negative tests, therefore very reliable patient education in connection with DPT is highly needed. [ABSTRACT FROM AUTHOR]

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Background: The lymphocyte transformation test (LTT) is an in vitro assay used to diagnose drug induced hypersensitivity reactions by detecting the activation and expansion of drug-specific memory T cells to the suspected implicated drug. Traditionally radiolabelled thymidine (3H-thymidine) has been used but requires the handling and disposal of radioactive materials. Objective: To examine safe alternatives to 3H-thymidine, test assay modifications for improved assay sensitivity and evaluate the modified LTT in patients with DRESS and AGEP. Methods: Four proliferation detection assays (BRDU, CyQUANT™, MTT and XTT) were screened for LTT sensitivity. XTT the most sensitive and practical was selected for further evaluation Modifications like autologous serum (AS) and regulatory T cell depletion (T-REG) were tested for improved assay sensitivity. Finally, an initial evaluation of the XTT–LTT was performed in 8 patients with DRESS and 2 with AGEP including cytokine testing. Results: Of the non-radioactive alternatives we tested, XTT a colorimetric assay was the most sensitive and practical to move to evaluation. The addition of AS increased background signal. Depletion of T-REGs improved sensitivity but cell sorting time and risk of contamination limited benefit. Of eight patients diagnosed with DRESS and 2 with AGEP tested with XTT–LTT assay results showed our assay matched clinical findings of implicated drugs in 8/10 patients when using a stimulation index (SI) ≥ 2 and 8/10 with analysis by ANOVA. All ten patients were correctly diagnosed by either analysis. Conclusion: XTT appears to be a safe, viable alternative to 3H-thymidine, with high sensitivity and allowing direct cytokine quantification on specific patient cells. [ABSTRACT FROM AUTHOR]

What is Known and Objective: Allopurinol‐induced drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but serious and potentially life‐threatening drug hypersensitivity syndrome. In this study, we aimed to investigate the clinical features, treatment outcomes, and prognostic factors of allopurinol‐induced DRESS. Methods: Case reports of allopurinol‐induced DRESS published by China from January 2000 to August 2021 were retrieved from CNKI, Wan Fang, VIP, and PubMed databases for analysis. Results and Discussion: This study included 52 patients, consisting of 41 (78.8%) males and 11 (21.2%) females (M:F = 3.7:1). The mean of age was 56.1 ± 17.1 years (range: 18–86 years). The mean of latency periods was 24.6 ± 15.0 days (range:1‐63 days). Most patients presented with fever, cutaneous eruption, eosinophilia, lymphadenopathy, and facial edema. 36/52 (69.2%) patients showed two or more internal organs involved. Liver and kidney injuries were the most common visceral manifestation. Pulmonary involvement (34.6%), cardiac involvement (25.0%) and gastrointestinal involvement (21.2%) were relatively less known but severe complications. 2/52 (3.8%) patients showed nervous system involved, presenting as leukoencephalopathy or peripheral neuropathy. 2/52 (3.8%) patients presented with secondary hemophagocytic lymphohistiocytosis.1/52 (1.9%) patient developed pure red cell aplasia and 1/52 (1.9%) patient developed painless thyroiditis. HLA*B 58:01 allele was tested in 18/52 (34.6%) patients. 16/18 (88.9%) cases were positive. 48/52 (92.3%) patients were treated with systemic corticosteroids. 16/52 (30.8%) patients were cured, 23/52 (44.2%) patients received partial recovery, and 13/52 (25.0%) patients were died. Septic shock, gastrointestinal bleeding and multiple organ failure were the leading causes of death. Advanced age, underlying cardiovascular disease, chronic kidney disease and high dose of allopurinol, infection and internal organ involvement (including kidney, heart, lung and gastrointestinal tract) were risk factors for death. What is New and Conclusion: We explored clinical features, treatment outcomes and prognostic factors of 52 allopurinol‐induced DRESS cases in China. Ethnicity, especially Han Chinese, and positive HLA‐B*58:01 allele are the clearest risk factors so far. Advanced age, underlying cardiovascular disease, chronic kidney disease and high dose of allopurinol, infection and internal organ involvement (including kidney, heart, lung and gastrointestinal tract) were associated with poorer outcomes. Early identification and discontinuation of the causative drug are crucial to the management of DRESS. For patients with severe disease, corticosteroids are recommended as the first‐line therapy. However, further studies are needed to address diagnostic criteria of DRESS for early diagnosis, as well as to develop standardized corticosteroid treatment regimens. [ABSTRACT FROM AUTHOR]

One of the most severe forms of cutaneous adverse drug reactions is "drug reaction with eosinophilia and systemic symptoms" (DRESS), hence subsequent avoidance of the causal drug is imperative. However, attribution of drug culpability in DRESS is challenging and standard skin allergy tests are not recommended due to patient safety reasons. Whilst incidence of DRESS is relatively low, between 1:1000 and 1:10 000 drug exposures, antibiotics are a commoner cause of DRESS and absence of confirmatory diagnostic test can result in unnecessary avoidance of efficacious treatment. We therefore sought to identify potential biomarkers for development of a diagnostic test in antibiotic-associated DRESS. Peripheral blood mononuclear cells from a "discovery" cohort (n  = 5) challenged to causative antibiotic or control were analyzed for transcriptomic profile. A panel of genes was then tested in a validation cohort (n  = 6) and compared with tolerant controls and other inflammatory conditions which can clinically mimic DRESS. A scoring system to identify presence of drug hypersensitivity was developed based on gene expression alterations of this panel. The DRESS transcriptomic panel identified antibiotic-DRESS cases in a validation cohort but was not altered in other inflammatory conditions. Machine learning or differential expression selection of a biomarker panel consisting of 6 genes (STAC, GPR183, CD40, CISH, CD4, and CCL8) showed high sensitivity and specificity (100% and 85.7%–100%, respectively) for identification of the culprit drug in these cohorts of antibiotic-associated DRESS. Further work is required to determine whether the same panel can be repeated for larger cohorts, different medications, and other T-cell-mediated drug hypersensitivity reactions. [ABSTRACT FROM AUTHOR]

The literature on positive patch test results in drug reaction with eosinophilia and systemic symptoms (DRESS) is reviewed. One hundred and five drugs were identified that have together caused 536 positive patch tests in 437 DRESS patients. By far, the most reactions (n = 145) were caused by carbamazepine, followed by amoxicillin, isoniazid, phenytoin, ethambutol, fluindione, phenobarbital, rifampicin, and ceftriaxone; 43 drugs each caused a single case only. The drug classes causing the highest number of reactions were anticonvulsants (39%), beta-lactam antibiotics (20%), antituberculosis agents (11%), non-beta-lactam antibiotics (6%), and iodinated contrast media (5%). The sensitivity of patch testing (percentage of positive reactions) is high for anticonvulsants (notably carbamazepine), beta-lactam antibiotics (notably amoxicillin), and, possibly, iodinated contrast media. Allopurinol and sulfasalazine frequently cause DRESS but never give positive patch tests. Patch testing in DRESS appears to be safe, although mild recurrence of DRESS symptoms, mostly skin reactions, may not be rare. Multiple drug hypersensitivity was found to occur in 16% of all patients, but it is argued that the true frequency is higher. Clinical aspects of DRESS, including diagnosing the disease and identifying culprit drugs (patch tests, intradermal tests, in vitro tests, challenge tests) are also provided, emphasizing the role of patch testing. [ABSTRACT FROM AUTHOR]

Background: Mild non‐immediate reactions (NIR) to beta‐lactams (βLs) are the most common manifestation of adverse drug reactions in children, and the drug provocation test (DPT) remains the gold standard for diagnosis. However, there are still controversies about the protocol that should be used, especially regarding the administration of doses and the DPT length. Objective: This study aimed to evaluate a pediatric population with a history of mild NIR to amoxicillin (AMX) or to amoxicillin‐clavulanic acid (AMX/CL) who underwent a diagnostic workup including a DPT with the culprit drug, to understand if a graded DPT or, instead, a single full dose could be the most appropriate way of administration in clinical practice. Methods: The data of children were retrospectively analyzed for a 5‐year period, with demographic and clinical characteristics collected. We reported the allergy workup and the results of the DPT performed with the administration of incremental doses and a prolonged DPT at home for a total of 5 days. Results: Three hundred fifty‐four patients were included. Overall, 23/354 (6.5%) DPTs were positive: 11/23 patients showed a reaction after 2–8 h after the last dose on the 1st or 2nd day (1 reacted 30 min after the last dose), 1/23 reacted with urticaria 30 min after the first dose, 11/23 reacted at home on the 5th day of the DPT. Conclusion: This paper indirectly suggests that a single therapeutic dose administered on the 1st day of a DPT could be safe in the diagnostic workup of mild NIR to AMX/CL. Moreover, this could be less time‐consuming as patients would spend less time in the hospital, also considering the public health restrictions imposed during the COVID‐19 pandemic. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions (DHRs) represent a great challenge to clinicians due to their unpredictability and severity, notably being potentially fatal. Genetic markers for DHRs have been emerging as potential valuable clinical tools for prediction and diagnosis of DHRs. Dedicated pediatric studies in this field are scarce and many published studies lack key data in this regard. This review briefly covers the current status of the use and validation of genetic markers for drug hypersensitivity in pediatrics. Classification, epidemiology and pathophysiology of DHRs are also briefly described. We searched PubMed, Ovid Medline, Web of Science, Scopus and Google Scholar literature databases for all relevant articles published from their date of commencement to March 2022. We summarized the current existing evidence and discussed the role and potential of pharmacogenomic testing in management of DHRs in pediatrics. Several genetic markers for DHRs in children have been identified and proven to be useful tools for prediction, diagnosis, and management of these adverse reactions. However, data in pediatric populations is still limited and confined to specific drugs in specific ethnic groups. Further research is needed to identify and validate more genetic markers to help guide drug therapy in children. [ABSTRACT FROM AUTHOR]

Chemotherapeutic drugs have been widely used in the treatment of cancer disease for about 70 years. The development of new treatments has not hindered their use, and oncologists still prescribe them routinely, alone or in combination with other antineoplastic agents. However, all chemotherapeutic agents can induce hypersensitivity reactions (HSRs), with different incidences depending on the culprit drug. These reactions are the third leading cause of fatal drug‐induced anaphylaxis in the United States. In Europe, deaths related to chemotherapy have also been reported. In particular, most reactions are caused by platinum compounds, taxanes, epipodophyllotoxins and asparaginase. Despite their prevalence and relevance, the ideal pathways for diagnosis, treatment and prevention of these reactions are still unclear, and practice remains considerably heterogeneous with vast differences from center to center. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology organized a task force to provide data and recommendations regarding the allergological work‐up in this field of drug hypersensitivity reactions. This position paper aims to provide consensus on the investigation of HSRs to chemotherapeutic drugs and give practical recommendations for clinicians that treat these patients, such as oncologists, allergologists and internists. Key sections cover risk factors, pathogenesis, symptoms, the role of skin tests, in vitro tests, indications and contraindications of drug provocation tests and desensitization of neoplastic patients with allergic reactions to chemotherapeutic drugs. Statements, recommendations and unmet needs were discussed and proposed at the end of each section. [ABSTRACT FROM AUTHOR]

Background: Patch tests (PTs) with two readings have been used for decades to identify the culprit drug in nonimmediate cutaneous adverse drug reactions (NICADRs), followed more recently by late reading of intradermal tests (IDTs). Some teams tend to perform PTs with only one reading before IDTs or even directly perform IDTs. Objectives: To evaluate the relevance of a late PT reading on day 4 (D4) in NICADRs. Methods: We retrospectively selected patients who had a PT for an NICADR between July 2014 and March 2020. Results: During the study period, 328 patients had a PT with available results. Among the 75 positive‐PT patients with available data for the two readings, 41 (54.7%) had positive results on D2 and D4 and 34 (45.3%) had negative results on D2 but positive results on D4. No patient had positive results on D2 and negative results on D4. Conclusion: This study shows that a D4 reading enhanced the PT‐positive results. A positive PT result allows for reducing the number of IDTs, which are more difficult and costly to perform. Our series suggests that a late PT reading at D4 should be performed for exploring NICADRs. [ABSTRACT FROM AUTHOR]

Background: Cutaneous drug eruptions are common side-effects. The imputation score combining intrinsic (chronology, clinical and paraclinical signs) and extrinsic criteria used in Pharmacovigilance Centres is insufficient alone to identify with certainty a responsible drug. Objective: To evaluate the imputation score before and after performing skin testing in patients with cutaneous drug eruptions. Patients/Methods: A single-centre retrospective study was performed on 339 patients tested between 2001–2006. Imputation scores were calculated before and after skin tests for each cutaneous drug eruption according to the clinical type of skin eruption and the type of drug. Results: Among 121 patients meeting inclusion criteria, 46% showed an increase of the imputation score as shown by 25/41 cases of maculo-papular exanthema, 4/11 cases of acute generalized exanthematous pustulosis and 17/41 cases of urticaria/anaphylaxis. The imputation score increased in 25/70 cases of the tested antibiotic drugs, in 14/56 cases of cardiovascular drugs, and it increased in 19 patients (34%) with I1 or I2 imputation scores before skin testing and in 29 (52%) with an I3 imputation score before skin testing. Conclusions: Drug skin testing appeared useful in investigating cutaneous drug eruptions in routine practice, including not only drugs with a high imputation score (I3) but also those with a lower score (I1, I2). Drug skin testing should lead to oral rechallenge of drugs with negative tests in order to determine which drugs may be used safely. [ABSTRACT FROM AUTHOR]

Background: Drug reaction with eosinophilia and systemic symptoms syndrome is a rare but severe and potentially life-threatening hypersensitivity reaction, with significant morbidity and mortality. The clinical presentation of drug reaction with eosinophilia and systemic symptoms may include extensive skin rash, fever, lymphadenopathy, internal organ involvement, eosinophilia, and atypical lymphocytosis, most commonly due to drug-induced reaction. Our case is a rare occurrence of drug reaction with eosinophilia and systemic symptoms syndrome in the setting of oxacillin therapy.Case Presentation: A 55-year-old Caucasian male presented to the emergency department on account of acute onset, 2-day history of generalized pruritic rash with associated fever, occurring 3 weeks after commencing therapy with intravenous oxacillin for methicillin-sensitive Staphylococcus aureus bacteremia. He had no known drug allergies. Two days prior to hospitalization, he had a telehealth visit with the infectious diseases specialist on account of his rash, and was recommended to use oral diphenhydramine. However, with the onset of fever and persistence of his rash, he was advised to discontinue the oxacillin and present to the emergency department. On examination, he was febrile at 101.2 °F and had a generalized blanchable maculopapular and morbilliform rash involving the face, trunk, upper and lower extremities, but sparing the palms, soles, and oral mucosa. He had palpable nontender lymph nodes in the cervical and inguinal regions bilaterally. Laboratory studies revealed atypical lymphocytosis, eosinophilia, neutrophilia, and elevated serum transaminases. He was started on intravenous diphenhydramine and admitted to the in-patient medical service. On the second day of hospitalization, his fever resolved. However, his rash was persistent and generalized, as well as elevated transaminases and an abnormal cell count on the second day of hospitalization. To complete his 6-week course of antibiotics for methicillin-sensitive Staphylococcus aureus bacteremia, he was switched to an alternative therapy with cefazolin, and he was scheduled for weekly follow-up assessments following hospital discharge.Conclusions: Healthcare providers should increasingly be aware of the significant morbidity and mortality attributable to drug reaction with eosinophilia and systemic symptoms syndrome and the potential medications which may incite such life-threatening reactions. Early recognition of drug reaction with eosinophilia and systemic symptoms syndrome and prompt institution of management strategies can promote improved clinical outcomes. Enhanced patient-provider communication strategies should be implemented to better prepare patients for the likelihood of such drug reactions, with the goal of improving patient-centered care and adherence with treatment strategies. [ABSTRACT FROM AUTHOR]

Delayed-type drug hypersensitivity reactions (dtDHR) are immune-mediated reactions with skin and visceral manifestations ranging from mild to severe. Clinical care is negatively impacted by a limited understanding of disease pathogenesis. Though T cells are believed to orchestrate disease, the type of T cell and the location and mechanism of T cell activation remain unknown. Resident memory T cells (TRM) are a unique T cell population potentially well situated to act as key mediators in disease pathogenesis, but significant obstacles to defining, identifying, and testing TRM in dtDHR preclude definitive conclusions at this time. Deeper mechanistic interrogation to address these unanswered questions is necessary, as involvement of TRM in disease has significant implications for prediction, diagnosis, and treatment of disease. [ABSTRACT FROM AUTHOR]

Introduction: Beta-lactams (BLs) are one of the most frequent causes of drug hypersensitivity reactions (HRs), and cephalosporins are a widely used subclass of BLs, especially in children. The aim of this study was to evaluate the clinical features and diagnostic test results of pediatric patients evaluated for suspected cephalosporin allergy. Methods: This study included patients who presented to our pediatric allergy clinic with a history of reactions attributed to cephalosporins between January 1, 2011, and December 31, 2019, and whose diagnostic tests were completed for the diagnosis. Results: This study included 120 pediatric patients and 69 (57.5%) of them were girls. The median age was 38.63 (interquartile range 10.5–85.7) months. Reactions occurring within 1 h of drug intake were reported in 33 patients (27.5%). Reactions were maculopapular rash in 55 (45.8%) patients, urticaria and/or angioedema in 49 (40.8%), anaphylaxis in 11 (9.2%), severe cutaneous drug reaction in 4 (3.3%), and fixed drug reaction in 1 patient (0.83%). The most frequently suspected agent was cefixime in 41 patients (34.2%). In total, 30 (25%) patients were diagnosed as having cephalosporin hypersensitivity. Confirmation of HRs was also significantly more frequent among patients who were older (p: 0.000), who had taken the drug parenterally (p: 0.000) and with immediate reactions (p: 0.000). Conclusion: Cephalosporin allergy has been confirmed in approximately one-fourth of the patients evaluated for suspected cephalosporin allergy. Confirmation of HRs was significantly more common among patients who were older, had immediate reactions, and had taken the drug parenterally. [ABSTRACT FROM AUTHOR]

Background: Lymphocyte transformation test (LTT) has been widely used to evaluate non‐immediate drug hypersensitivity reactions (NIDHRs). However, the lack of standardization and the low sensitivity have limited its routine diagnostic use. The drug presentation by dendritic cells (DCs) and the assessment of proliferation on effector cells have shown promising results. Flow‐cytometry‐based methods can help apply these improvements. We aimed to assess the added value of using drug‐primed‐DCs and the determination of the proliferative response of different lymphocyte subpopulations in NIDHRs. Methods: Patients with confirmed NIDHR were evaluated by both conventional (C‐LTT) and with drug‐primed‐DCs LTT (dDC‐LTT)analysing the proliferative response in T cells and other effector cell subpopulations by using the fluorescent molecule, carboxyfluorescein diacetate succinimidyl ester (CFSE). Results: The C‐LTT showed a significantly lower sensitivity (29.4%) compared with dDC‐LTT (61.8%), which was confirmed analysing each particular clinical entity: SJS‐TEN (62.5% vs 87.5%), MPE (15% vs 47.4%) and AGEP (33% vs 80%). When including the effector cell subpopulations involved in each clinical entity, CD3++CD4+Th1 or CD3++NK cells in SJS‐TEN, CD3++CD4+Th1+NK cells in MPE and CD3++NK cells in AGEP, we could significantly increase the sensitivity of the in vitro test to 100%, 68.4% and 100%, respectively, with an overall sensitivity of 87% and 85% of specificity in NIDHR. Conclusions: The use of a flow‐cytometry‐based test, DCs as drug presenting cells, and focusing on effector cell subpopulations for each clinical entity significantly improved the drug‐specific proliferative response in NIDHRs with a unique cellular in vitro test. [ABSTRACT FROM AUTHOR]

Background: Patients with a penicillin allergy label tend to have worse clinical outcomes and increased healthcare use. Drug provocation tests (DPT) are the gold‐standard in the diagnostic workup of penicillin allergy, but safety concerns may hinder their performance. We aimed to assess the frequency of severe reactions following a DPT in patients with reported allergy to penicillins or other β‐lactams. Methods: We performed a systematic review, searching MEDLINE, Scopus, and Web of Science. We included primary studies assessing participants with a penicillin allergy label who underwent a DPT. We performed a Bayesian meta‐analysis to estimate the pooled frequency of severe reactions to penicillin DPTs. Sources of heterogeneity were explored by subgroup and metaregression analyses. Results: We included 112 primary studies which included a total of 26,595 participants. The pooled frequency of severe reactions was estimated at 0.06% (95% credible interval [95% CrI] = 0.01%–0.13%; I2 = 57.9%). Most severe reactions (80/93; 86.0%) consisted of anaphylaxis. Compared to studies where the index reaction was immediate, we observed a lower frequency of severe reactions for studies assessing non‐immediate index reactions (OR = 0.05; 95% CrI = 0‐0.31). Patients reporting anaphylaxis as their index reaction were found to be at increased risk of developing severe reactions (OR = 13.5; 95% CrI = 7.7–21.5; I2 = 0.3%). Performance of direct DPTs in low‐risk patients or testing with the suspected culprit drug were not associated with clinically relevant increased risk of severe reactions. Conclusions: In patients with a penicillin allergy label, severe reactions resulting from DPTs are rare. Therefore, except for patients with potentially life‐threatening index reactions or patients with positive skin tests—who were mostly not assessed in this analysis ‐, the safety of DPTs supports their performance in the diagnostic assessment of penicillin allergy. [ABSTRACT FROM AUTHOR]

Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation. Additional factors outside of HLA contributing to risk of severe T-cell-mediated DHRs include variation in drug metabolism, T-cell receptor (TCR) specificity, and, most recently, HLA-presented immunopeptidome-processing efficiencies via endoplasmic reticulum aminopeptidase (ERAP). Active research continues toward identification of other highly polymorphic factors likely to impose risk. These include those previously associated with T-cell-mediated HLA-associated infectious or auto-immune disease such as Killer cell immunoglobulin-like receptors (KIR), epistatically linked with HLA class I to regulate NK- and T-cell-mediated cytotoxic degranulation, and co-inhibitory signaling pathways for which therapeutic blockade in cancer immunotherapy is now associated with an increased incidence of DHRs. As such, the field now recognizes that susceptibility is not simply a static product of genetics but that individuals may experience dynamic risk, skewed toward immune activation through therapeutic interventions and epigenetic modifications driven by ecological exposures. This review provides an updated overview of current and proposed genetic factors thought to predispose risk for severe T-cell-mediated DHRs. [ABSTRACT FROM AUTHOR]

Severe cutaneous adverse reactions (SCARs) [Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic syndrome (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed eruption (GBFE)] are severe drug reactions that often require hospitalization and could be fatal. BRAF and MEK inhibitors (BRAF/MEKi) are a standard of care in patients with BRAF‐mutated metastatic melanomas. These agents are administered until disease progression or unacceptable toxicity occurs. This review has focus on BRAF/MEKi‐induced SCARs. A systematic search of the following terms: 'vemurafenib', 'cobimetinib', 'dabrafenib', 'trametinib', 'encorafenib', 'binimetinib', 'Acute Generalized Exanthematous Pustulosis', 'Stevens Johnson syndrome', 'Toxic Epidermal Necrolysis', 'Generalized Bullous Fixed Eruption' 'Drug Hypersensitivity Syndrome', and 'DRESS' in simple combination (every drug with each disease) and all in combination, was performed on MEDLINE, EMBASE, Web of Knowledge and The Cochrane Library repositories, with no restriction on language, for original studies. One hundred sixty‐eight original articles were found, 26 (retrospective series, case reports and conference abstracts) were selected, and 21 were included in the qualitative synthesis. A total of 31 SCAR cases (23 DRESS and 8 SJS/TEN – 1 SJS and 7 TEN –) were identified. Vemurafenib was the culprit drug in all but one case, which was dabrafenib‐induced. Mean time to SCAR onset from drug intake was 15.5 and 11.4 days, for SJS/TEN and DRESS, respectively. For the DRESS cases, hepatic involvement occurred in 96% and renal alterations in 87% of patients. Overall, BRAF/MEKi‐induced SCARs are rare. Among them, vemurafenib is the drug that requires more close monitoring for SCARs. Prior immunotherapy can favour SCARs. Vemurafenib DRESS is likely to occur within the first fifteen days of treatment accompanied by hepatic and renal involvement. Following vemurafenib‐induced SCAR resolution, switching to dabrafenib seems to be a safe alternative for these patients' treatment. [ABSTRACT FROM AUTHOR]

Our objective was to describe and discuss management of recent cases of drug hypersensitivity in children reported in a pharmacovigilance center. Two pediatric allergy units conducted a collaborative retrospective analysis of 101 adverse drug reactions reported to a regional pharmacovigilance center between January 2016 and July 2019. Time lapse between hypersensitivity reaction onset and allergy consultation varied from 1 month to 12 years. Sixty-two patients (61.4%) presented with immediate reactions, 11 (10.9%) with non-immediate reactions, and 28 (27.7%) had reactions impossible to classify through medical interview. Overall, 92 children (91%) were explored for simultaneously administered drugs. All 113 prick tests were negative, and 2 were uncertain. Among 108 intradermal tests, 2 were positive to penicillin and to an iodinated contrast medium, 105 were negative, and 1 was uncertain. Overall, 129 drug provocation tests were proposed. Nine provocation tests among 80 were positive (11.25%): 6 to penicillin, 1 to sulfonamide antibiotics, and 2 to non-steroidal anti-inflammatory drugs; the remaining 71 were negative. No severe reaction was observed during these tests. Finally, drug allergy was only retained in 11 reported cases (10.9%).Conclusion: These pharmacovigilance reports show the difficulty in defining drug allergy in children only by anamnesis, and that explorations, particularly provocation tests, should take place at a reasonable time lapse after drug hypersensitivity reaction onset. What is Known: • True drug allergy is rarely observed in children. • Absence of full workup leads to falsely labeling children as "allergic." What is New: • Short time lapse between hypersensitivity onset and consultation improves classification of pediatric allergy. • Timely allergy consultations are essential, and tests are useful to confirm or exclude pediatric allergy. [ABSTRACT FROM AUTHOR]

β-Lactams which include penicillins, cephalosporins, carbapenems, and monobactams are the most common antibiotic classes reported to cause allergic reactions to drugs. This review is mainly about published studies assessing the cross-reactivity among β-lactams in penicillin- or cephalosporin-allergic subjects by carrying out diagnostic tests with alternative β-lactams and, if appropriate, graded challenges. Several studies demonstrated that cross-reactivity connected with the β-lactam ring, causing positive responses to allergy tests with all β-lactams, is infrequent in subjects with an IgE-mediated allergy and anecdotal in those with a T-cell-mediated allergy. Identities or similarities of β-lactam side-chain structures are mainly responsible for cross-reactivity among these antibiotics. For example, in aminopenicillin-allergic subjects, cross-reactivity with aminocephalosporins could possibly be over 30%. On the other hand, in a few prospective studies of penicillin-allergic individuals, less than 1% of cases show a cross-reactivity between penicillins and both aztreonam and carbapenems. Particular patterns of allergy-test positivity observed in some studies that assessed cross-reactivity among β-lactams seem to indicate that prior exposures may be responsible for coexisting sensitivities. Therefore, pre-treatment skin tests with the related β-lactams are suggested before administering them via graded challenges to β-lactam-allergic patients who need alternative β-lactams. [ABSTRACT FROM AUTHOR]

A correct diagnosis of drug hypersensitivity reactions (DHRs) is very important for both the patient and health system. However, DHRs diagnosis is complex, time consuming, requires trained personnel, is not standardized for many drugs, involves procedures not exempt of risk, and in most cases lacks standardized in vivo and in vitro tests. Thus, there is an urgent need for improving the different approaches to diagnose patients with suspected DHRs. In this review, we have analyzed the advances performed in immediate and nonimmediate DHRs diagnosis during the last two years and obtained several conclusions: the significant heterogeneity in current practice among centers illustrates the need to re‐evaluate, update, and standardize in vivo tests and protocols for the diagnosis and management of patients with suspected drug allergy. Regarding in vitro tests, the latest studies have focused on increasing their sensitivity or on establishing the sensitivity and specificity for the tests performed with new drugs. There seems to be a consensus about combining in vivo and in vitro tests as the best way to increase the diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Background: A drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe T cell mediated hypersensitivity reaction. Relapses of symptoms in the recovery phase are frequent and linked to the reduction of the corticosteroid treatment, to viral reactivations or to the exposure to new drugs. Here, we analyzed, how often the exposure to new drugs leads to new sensitization or drug-related relapses without detectable sensitization. Methods: 46 patients with DRESS treated in the allergy division of the Inselspital, Bern University Hospital, were retrospectively assessed. Drug-related relapses were analyzed in terms of frequency and whether a possible sensitization evaluated by skin tests and/or lymphocyte transformation tests (LTT) to the new drugs was detectable. Furthermore, drug tolerance was evaluated in a subset of patients. Results: 56 relapses were observed in 27 of 46 patients with DRESS (58.7%). 33 (58.9%) of these relapses were associated with the use of new drugs, 30 drug-related relapses were evaluated by patch test and/or lymphocyte transformation test. In 8/30 (26.7%) drug-related relapses, a sensitization to the new drug was demonstrated, suggesting the emergence of a multiple drug hypersensitivity syndrome (MDH). 14 patients experienced 22 drug-related relapses without any detectable sensitization and only 1/6 patients developed new symptoms upon reexposure. Conclusion: Patients with DRESS frequently suffered from drug related relapses. Half of the patients with drug-related relapses developed a MDH with proven sensitizations not only to the DRESS inducing drugs, but also to newly applied drugs. When not sensitized, drugs involved in drug related relapses could be reintroduced, if needed. Here, we propose a procedure for drug testing and future management of drug-related relapses in DRESS. [ABSTRACT FROM AUTHOR]

The drug allergy "label" may have a lifetime of consequences for a child. Many children with alleged drug allergies are proven to be tolerant to the culprit medication when challenged. The field of drug hypersensitivity is a recently evolving field of research, but studies on its epidemiology and diagnostic tools are lacking in children. Clinical history is significant in the diagnosis and classification of drug hypersensitivity in children. Diagnostic tools have been evaluated in a limited number of children; therefore, the guidelines are mainly in line with those for adults. Here, we review the clinical characteristics, main drugs, risk factors, and diagnosis of drug hypersensitivity to aid in its accurate diagnosis in children. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti‐inflammatory drugs (NSAIDs), the medications most commonly used for treating pain and inflammation, are the main triggers of drug hypersensitivity reactions. The latest classification of NSAIDs hypersensitivity by the European Academy of Allergy and Clinical Immunology (EAACI) differentiates between cross‐hypersensitivity reactions (CRs), associated with COX‐1 inhibition, and selective reactions, associated with immunological mechanisms. Three phenotypes fill into the first group: NSAIDs‐exacerbated respiratory disease, NSAIDs‐exacerbated cutaneous disease and NSAIDs‐induced urticaria/angioedema. Two phenotypes fill into the second one: single‐NSAID‐induced urticaria/angioedema/anaphylaxis and single‐NSAID‐induced delayed reactions. Diagnosis of NSAIDs hypersensitivity is hampered by different factors, including the lack of validated in vitro biomarkers and the uselessness of skin tests. The advances achieved over recent years recommend a re‐evaluation of the EAACI classification, as it does not consider other phenotypes such as blended reactions (coexistence of cutaneous and respiratory symptoms) or food‐dependent NSAID‐induced anaphylaxis. In addition, it does not regard the natural evolution of phenotypes and their potential interconversion, the development of tolerance over time or the role of atopy. Here, we address these topics. A state of the art on the underlying mechanisms and on the approaches for biomarkers discovery is also provided, including genetic studies and available information on transcriptomics and metabolomics. [ABSTRACT FROM AUTHOR]

Background: A drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe T cell mediated hypersensitivity reaction. Relapses of symptoms in the recovery phase are frequent and linked to the reduction of the corticosteroid treatment, to viral reactivations or to the exposure to new drugs. Here, we analyzed, how often the exposure to new drugs leads to new sensitization or drug‐related relapses without detectable sensitization. Methods: 46 patients with DRESS treated in the allergy division of the Inselspital, Bern University Hospital, were retrospectively assessed. Drug‐related relapses were analyzed in terms of frequency and whether a possible sensitization evaluated by skin tests and/or lymphocyte transformation tests (LTT) to the new drugs was detectable. Furthermore, drug tolerance was evaluated in a subset of patients. Results: 56 relapses were observed in 27 of 46 patients with DRESS (58.7%). 33 (58.9%) of these relapses were associated with the use of new drugs, 30 drug‐related relapses were evaluated by patch test and/or lymphocyte transformation test. In 8/30 (26.7%) drug‐related relapses, a sensitization to the new drug was demonstrated, suggesting the emergence of a multiple drug hypersensitivity syndrome (MDH). 14 patients experienced 22 drug‐related relapses without any detectable sensitization and only 1/6 patients developed new symptoms upon reexposure. Conclusion: Patients with DRESS frequently suffered from drug related relapses. Half of the patients with drug‐related relapses developed a MDH with proven sensitizations not only to the DRESS inducing drugs, but also to newly applied drugs. When not sensitized, drugs involved in drug related relapses could be reintroduced, if needed. Here, we propose a procedure for drug testing and future management of drug‐related relapses in DRESS. [ABSTRACT FROM AUTHOR]

Within the broad category of adverse drug reactions in children, there has been a recent focus specifically on the evaluation of children with antibiotic allergy, in particular, beta-lactam allergy. The potential consequences of being labeled beta-lactam allergy are increasingly recognized. Appropriate evaluation of children with suspected reactions to antibiotics is essential as it is increasingly being recognized that the label of "penicillin allergy" is associated with adverse health and economic outcomes. This review will focus on the 3 main classes of antibiotics reported to cause allergic reactions in children: beta lactams (penicillin derivatives and cephalosporins), macrolides, and sulfonamides. This article is a narrative review of the prevalence, diagnosis, and management of different types of antibiotic allergies in children. Our review reveals that antibiotic allergy is often overreported and not appropriately diagnosed in the pediatric age groups. There is a recent shift in the diagnostic paradigm from the use of skin tests and if negative challenges to the use of challenge only in the pediatric age group. Larger studies to establish the usefulness and safety of this new approach as well as updated guidelines are needed. [ABSTRACT FROM AUTHOR]

Comments on cutaneous adverse drug reactions. What causes adverse drug reactions; The diagnosis of drug allergy and the identification of the offending agent being a clinical exercise; Mention of a study by A. Barbaud and colleagues of inpatients with adverse reactions to confirm that a drug reaction did occur; The use of skin patch testing; The necessity for standardization of allergens; The suggestion that skin testing for systemic drug allergy is experimental.

Drug Hypersensitivity Reactions: Response Patterns, Drug Involved, and Temporal Variations in a Large Series of Patients. Once the culprit drug has been identified, the most common treatment is drug avoidance. Keywords: drug; adverse reaction; hypersensitivity; diagnosis; management EN drug adverse reaction hypersensitivity diagnosis management 1 3 3 06/23/21 20210617 NES 210617 Adverse drugs reactions occur in 10-15% of hospitalized patients and cause 3-6% of hospital admissions, constituting adn important public health issue ([3]). Therefore, an update on drug pharmacology, DHR classifications and mechanisms, and development of new tools and protocols to improve diagnosis and management is essential. [Extracted from the article]

Case report, fixed drug eruption, fluconazole, drug patch testing Keywords: case report; drug patch testing; fixed drug eruption; fluconazole EN case report drug patch testing fixed drug eruption fluconazole 350 352 3 04/07/21 20210501 NES 210501 Fluconazole, a triazole antifungal agent, is commonly used in the treatment of vulvovaginal candidiasis.1 Whilst fluconazole is rarely associated with fixed drug eruptions (FDE), some cases have been reported in the literature.1,2 In FDE, patch testing has reported utility,3 and is conventionally performed on residual pigmented lesional sites.4 In this case report of bullous FDE induced by fluconazole, we report on the value of multi-site lesional patch testing in safely establishing the diagnosis. Bullous fixed drug eruption induced by fluconazole: Importance of multi-site lesional patch testing. [Extracted from the article]

Keywords: allergy diagnosis; drug allergy; IgE; immunologic tests; T cells EN allergy diagnosis drug allergy IgE immunologic tests T cells 985 987 3 04/14/21 20210401 NES 210401 Abbreviations AX amoxicillin CLV clavulanic acid COVID-19 coronavirus disease 2019 DHR drug hypersensitivity reaction DPT drug provocation test DRESS drug reaction with eosinophilia and systemic symptoms ELISpot, enzyme-linked immunospot LTT lymphocyte transformation test MPE maculopapular exanthema Drug hypersensitivity reactions (DHRs) represent a global threat to healthcare systems due to their incidence, with a significant increase over last years.1 DHR figures are overestimated in the general population since <40% of cases initially labelled as allergic can be confirmed as such when evaluated in an allergy unit.2 Achieving an accurate diagnosis is complex and time-consuming; besides, tests must be tailored to specific clinical manifestations and underlying mechanisms and will depend on the culprit drugs. Allergy diagnosis, drug allergy, IgE, immunologic tests, T cells Rapid drug desensitization for platinum-based chemotherapy drugs significantly increases peripheral blood IL-10 levels. [Extracted from the article]

Introduction: Drug allergy is an important public health problem that causes 0.4–10.3% of hospital admissions in children. The epidemiology, clinical spectrum, diagnosis, and management of drug hypersensitivity reactions (DHRs) differ in pediatric and adult patients. However, the same algorithms used in adults have often been applied in the pediatric population due to a lack of evidence in the literature. Areas covered: In this review, we aimed to discuss recent developments in the area of pediatric DHRs based on the growing body of literature advancing our understanding of the epidemiology, clinical aspects, and diagnostic approaches to DHRs in children. Expert opinion: Misdiagnosis, under-diagnosis, and self-diagnosis are common problems related to drug allergies in children. Viral infections are particularly frequent in children and make diagnosis difficult. Identifying true DHR is a key step in the management of drug allergy in children. Therefore, a complete allergy work-up with standardized drug allergy tests is necessary. In order to eliminate non-standardized tests, future studies including larger numbers of children should be conducted to determine more accurate standardized tests for diagnosing DHRs in the pediatric population. [ABSTRACT FROM AUTHOR]

Background: The epidemiology of multiple drug intolerance syndrome (MDIS) and multiple drug allergy syndrome (MDAS) is poorly characterized. We used electronic health record (EHR) data to describe prevalences of MDIS and MDAS and to examine associations with anxiety and depression. Methods: Patients with ≥3 outpatient encounters at Partners HealthCare System from 2008 to 2015 were included. Patients with MDIS had intolerances to ≥3 drug classes, and patients with MDAS had hypersensitivities to ≥2 drug classes. Psychiatric conditions and comorbidities were defined from the EHR and used in multivariable logistic regression models to assess the relation between anxiety/depression and MDIS/MDAS. Results: Of 746 888 patients, 47 634 (6.4%) had MDIS and 8615 (1.2%) had MDAS; 3171 (0.4%) had both. Anxiety (adjusted odds ratio [aOR] 1.72 [1.65, 1.80]), depression (aOR 1.46 [1.41, 1.52]), and both anxiety and depression (aOR 1.97 [1.86, 2.08]) were associated with increased odds of MDIS. Depression was associated with increased odds of MDAS (aOR 1.41 [1.28, 1.56]), but there were no clear associations with anxiety (aOR 1.13 [0.99, 1.30]) nor both depression and anxiety (aOR 1.13 [0.92, 1.38]). Conclusion: While 6% of patients had MDIS, only 1% had MDAS. MDIS was associated with both anxiety and depression; patients with both anxiety and depression had an almost twofold increased odds of MDIS. MDAS was associated with a 40% increased odds of depression, but there was no significant association with anxiety. Psychological assessments may be useful in the evaluation and treatment of patients with MDIS and MDAS; physiologic causes for MDAS warrant further investigation. In this study, we used electronic health record data from 746 888 patients in a large US healthcare system to determine the prevalence of multiple drug intolerance syndrome (MDIS, 6%) and multiple drug allergy syndrome (MDAS, 1%). Patients with both MDIS and MDAS comprised 0.4% of the population (upper left). Common drug classes for MDIS and MDAS were penicillins, opiates, sulfonamides, and nonsteroidal antiinflammatory drugs (upper right). We assessed the association between MDIS and MDAS and anxiety and depression while adjusting for confounding variables (bottom right). MDIS was associated with both depression and anxiety; patients with both depression and anxiety had a twofold increased odds of MDIS. MDAS was associated with a 40% increased odds of depression, but there was no consistent relationship with anxiety. [ABSTRACT FROM AUTHOR]