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Pascal Demoly - One of the best experts on this subject based on the ideXlab platform.
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Multiple Drug Hypersensitivity syndrome.
Current opinion in allergy and clinical immunology, 2013Co-Authors: Anca Mirela Chiriac, Pascal DemolyAbstract:Purpose of reviewThe multiple Drug Hypersensitivity syndrome (MDH) is a distinct clinical entity, different from cross-reactivity and flare-up reactions. Following its initial description in 1989 by Sullivan et al., several authors have addressed the issues surrounding this peculiar form of Drug hyp
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Provocation tests in diagnosing Drug Hypersensitivity.
Current pharmaceutical design, 2008Co-Authors: Philippe Bousquet, Francesco Gaeta, L. Bousquet-rouanet, Jean-yves Lefrant, Pascal Demoly, Antonino RomanoAbstract:A position paper by the European Network for Drug Allergy (ENDA), the European Academy of Allergology and Clinical Immunology (EAACI) interest group on Drug Hypersensitivity, defines Drug provocation tests (DPTs) as "the controlled administration of a Drug in order to diagnose Drug Hypersensitivity reactions". The DPT is widely considered to be the "gold standard" to establish or exclude the diagnosis of Hypersensitivity to a certain substance, as it not only reproduces Hypersensitivity symptoms, but also any other adverse clinical manifestation, irrespective of the mechanism. The DPT can be harmful and thus should only be considered after balancing the risk-benefit ratio in the individual patient. The ENDA position paper specifies two main indications for DPTs with the suspected compounds: 1. to exclude Hypersensitivity in non-suggestive histories of Drug Hypersensitivity and in patients with non-specific symptoms, such as vagal symptoms under local anesthesia; 2. to establish a firm diagnosis in suggestive histories of Drug Hypersensitivity with negative, non-conclusive, or non-available allergologic tests. A positive DPT result optimizes allergen avoidance, while a negative one allows a false label of Drug Hypersensitivity to be removed. For these reasons, DPTs are often carried out to exclude a diagnosis of Hypersensitivity to beta-lactams when other allergologic tests are negative. DPTs are also performed when the sensitivity of allergologic tests for evaluating allergic reactions to certain Drugs, such as non-beta-lactam antibiotics, heparins, and glucocorticoids, is limited. On the other hand, DPTs are also performed to diagnose Hypersensitivity reactions to nonsteroidal anti-inflammatory Drugs in subjects with the cross-reactive pattern, because both skin tests and in vitro diagnostic methods are ineffective in such patients.
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Comparison of pharmacovigilance algorithms in Drug Hypersensitivity reactions.
European journal of clinical pharmacology, 2005Co-Authors: S. Benahmed, Marie-christine Picot, Dominique Hillaire-buys, J.-p. Blayac, P Dujols, Pascal DemolyAbstract:Background A firm diagnosis of Drug Hypersensitivity, because it may re-induce the reaction, is seldom confirmed. Causality assessment algorithms are therefore of interest.
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Accuracy of a pharmacovigilance algorithm in diagnosing Drug Hypersensitivity reactions
Archives of internal medicine, 2005Co-Authors: S. Benahmed, Marie-christine Picot, Francine Dumas, Pascal DemolyAbstract:Background: This study was performed to evaluate the diagnostic accuracy of a pharmacovigilance algorithm in patients with 1 or more histories suggestive of Drug Hypersensitivity. Methods: We performed a retrospective analysis of a clinic case series. We analyzed patients with suspected clinical reactions of Drug Hypersensitivity. Patients with severe skin reactions were excluded. Patients with history of Drug allergy were subjected to additional testing to validate this history. Following a detailed clinical history,skintestswereperformed.Ifskintestswerenotavailable or validated, Drug provocation tests were conducted. Assessment of causality was established by an investigatorunawareofDrugtestingresultsusingapharmacovigilance algorithm that was then compared with the final diagnosis. Results: A total of 677 consecutive patients with 1001 reactions were analyzed. No score could be given because of the absence of 1 of the criteria required for 204 reactions (20.4%). For 720 reactions (71.9%), a dubious causality assessment score was given. Drug Hypersensitivity was confirmed by Drug testing in 175 reactions (17.5%) and eliminated in 826 reactions (82.5%). Sensitivity of the algorithm was 10.3% and specificity was 76.9%. Although there were 1.7% false-positive scores, there were no false-negative scores. The logistic regression that was performed to look for independent clinical risk factors linked to the Drug Hypersensitivity diagnosis found 3 parameters: likely causality assessment score, Drug reintroduction in clinical history, and delay between reaction and last Drug intake of less than 1 hour. Conclusion: A pharmacovigilance algorithm is not accurate for the diagnosis of Drug Hypersensitivity reactions and cannot replace Drug allergy testing. Arch Intern Med. 2005;165:1500-1505
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Drug Hypersensitivity: Clinical Manifestations and Diagnosis
Allergy Frontiers: Clinical Manifestations, 1Co-Authors: Pascal Demoly, Antonino RomanoAbstract:Drug Hypersensitivity, including the allergic type, is one of the side effects of Drugs and is a daily worry for the clinician. Even though urticarial and maculopapular eruptions are the most frequent manifestations, there are many clinical forms, mirroring many distinct pathophysiological events. The diagnosis of Drug Hypersensitivity often relies on clinical histories, skin tests, patch tests, and a few validated in vitro tests, such as serum specific IgE assays, which are available only for a few Drugs. The sensitivity of these tests is not 100%; in selected cases, therefore, provocation tests are necessary. However, new diagnostic tools, such as the basophil activation test and the lymphocyte activation test, have been developed and are under validation. Their routine use could increase the sensitivity of diagnostic work-ups, thus reducing the need for Drug provocation tests.
Werner J. Pichler - One of the best experts on this subject based on the ideXlab platform.
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Multiple Drug Hypersensitivity.
International archives of allergy and immunology, 2017Co-Authors: Werner J. Pichler, Yuttana Srinoulprasert, James Yun, Oliver HausmannAbstract:Multiple Drug Hypersensitivity (MDH) is a syndrome that develops as a consequence of massive T-cell stimulations and is characterized by long-lasting Drug Hypersensitivity reactions (DHR) to different Drugs. The initial symptoms are mostly severe exanthems or Drug rash with eosinophilia and systemic symptoms (DRESS). Subsequent symptoms due to another Drug often appear in the following weeks, overlapping with the first DHR, or months to years later after resolution of the initial presentation. The second DHR includes exanthema, erythroderma, DRESS, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hepatitis, and agranulocytosis. The eliciting Drugs can be identified by positive skin or in vitro tests. The Drugs involved in starting the MDH are the same as for DRESS, and they are usually given in rather high doses. Fixed Drug combination therapies like sulfamethoxazole/trimethoprim or piperacillin/tazobactam are frequently involved in MDH, and 30-40% of patients with severe DHR to combination therapy show T-cell reactions to both components. The Drug-induced T-cell stimulation appears to be due to the p-i mechanism. Importantly, a permanent T-cell activation characterized by PD-1+/CD38+ expression on CD4+/CD25low T cells can be found in the circulation of patients with MDH for many years. In conclusion, MDH is a Drug-elicited syndrome characterized by a long-lasting hyperresponsiveness to multiple, structurally unrelated Drugs with clinically diverse symptoms.
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T-cell-mediated Drug Hypersensitivity: immune mechanisms and their clinical relevance
Asia Pacific allergy, 2016Co-Authors: James Yun, Fenfen Cai, Frederick J. Lee, Werner J. PichlerAbstract:T-cell-mediated Drug Hypersensitivity represents a significant proportion of immune mediated Drug Hypersensitivity reactions. In the recent years, there has been an increase in understanding the immune mechanisms behind T-cell-mediated Drug Hypersensitivity. According to hapten mechanism, Drug specific T-cell response is stimulated by Drug-protein conjugate presented on major histocompatibility complex (MHC) as it is presented as a new antigenic determinant. On the other hand, p-i concept suggests that a Drug can stimulate T cells via noncovalent direct interaction with T-cell receptor and/or peptide-MHC. The Drug binding site is quite variable and this leads to several different mechanisms within p-i concept. Altered peptide repertoire can be regarded as an 'atypical' subset of p-i concept since the mode of the Drug binding and the binding site are essentially identical to p-i concept. However, the intracellular binding of abacavir to HLA-B(*)57:01 additionally results in alteration in peptide repertoire. Furthermore the T-cell response to altered peptide repertoire model is only shown for abacavir and HLA-B(*)57:01 and therefore it may not be generalised to other Drug Hypersensitivity. Danger hypothesis has been postulated to play an important role in Drug Hypersensitivity by providing signal 2 but its experimental data is lacking at this point in time. Furthermore, the recently described allo-immune response suggests that danger signal may be unnecessary. Finally, in view of these new understanding, the classification and the definition of type B adverse Drug reaction should be revised.
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classification of Drug Hypersensitivity into allergic p i and pseudo allergic forms
International Archives of Allergy and Immunology, 2016Co-Authors: Werner J. Pichler, Oliver HausmannAbstract:Drug Hypersensitivity reactions (DHR) are clinically and functionally heterogeneous. Different subclassifications based on timing of symptom appearance or type of immune mechanism have been proposed.
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Drug Hypersensitivity flare up reactions cross reactivity and multiple Drug Hypersensitivity
Journal of Dermatology, 2011Co-Authors: Werner J. Pichler, Barbara Daubner, Tom KawabataAbstract:In Drug Hypersensitivity, change of Drug treatment and continuation with a new Drug may result in reappearance of Drug Hypersensitivity symptoms. This is not uncommon in patients with chronic infections requiring continued and long-lasting antibiotic treatments. For the clinician, the question arises whether these symptoms are due to cross-reactivity, are due to a new sensitization or are a reflection of a multiple Drug Hypersensitivity syndrome. Based on the p-i concept (pharmacological interaction with immune receptors), we propose that the efficient stimulation of T cells by a Drug is the sum of Drug-T-cell receptor affinity and readiness of the T cell to react, and therefore not constant. It heavily depends on the state of underlying immune activation. Consequently, Drug Hypersensitivity diseases, which go along with massive immune stimulations and often high serum cytokine values, are themselves risk factors for further Drug Hypersensitivity. The immune stimulation during Drug Hypersensitivity may, similar to generalized virus infections, lower the threshold of T-cell reactivity to Drugs and cause rapid appearance of Drug Hypersensitivity symptoms to the second Drug. We call the second Hypersensitivity reaction a "flare-up" reaction; this is clinically important, as in most cases the second Drug may be tolerated again, if the cofactors are missing. Moreover, the second treatment is often too short to cause a relevant sensitization.
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Drug Hypersensitivity: Flare‐up reactions, cross‐reactivity and multiple Drug Hypersensitivity
The Journal of dermatology, 2011Co-Authors: Werner J. Pichler, Barbara Daubner, T. T. KawabataAbstract:In Drug Hypersensitivity, change of Drug treatment and continuation with a new Drug may result in reappearance of Drug Hypersensitivity symptoms. This is not uncommon in patients with chronic infections requiring continued and long-lasting antibiotic treatments. For the clinician, the question arises whether these symptoms are due to cross-reactivity, are due to a new sensitization or are a reflection of a multiple Drug Hypersensitivity syndrome. Based on the p-i concept (pharmacological interaction with immune receptors), we propose that the efficient stimulation of T cells by a Drug is the sum of Drug-T-cell receptor affinity and readiness of the T cell to react, and therefore not constant. It heavily depends on the state of underlying immune activation. Consequently, Drug Hypersensitivity diseases, which go along with massive immune stimulations and often high serum cytokine values, are themselves risk factors for further Drug Hypersensitivity. The immune stimulation during Drug Hypersensitivity may, similar to generalized virus infections, lower the threshold of T-cell reactivity to Drugs and cause rapid appearance of Drug Hypersensitivity symptoms to the second Drug. We call the second Hypersensitivity reaction a "flare-up" reaction; this is clinically important, as in most cases the second Drug may be tolerated again, if the cofactors are missing. Moreover, the second treatment is often too short to cause a relevant sensitization.
Dean J. Naisbitt - One of the best experts on this subject based on the ideXlab platform.
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Immune dysregulation increases the incidence of delayed-type Drug Hypersensitivity reactions.
Allergy, 2019Co-Authors: Dean J. Naisbitt, Xiaoli Meng, Monday O. Ogese, Anna Olsson-brown, Andrew Gibson, Arun Tailor, Paul J. ThomsonAbstract:Delayed-type, T cell-mediated, Drug Hypersensitivity reactions are a serious unwanted manifestation of Drug exposure that develops in a small percentage of the human population. Drugs and Drug metabolites are known to interact directly and indirectly (through irreversible protein binding and processing to the derived adducts) with HLA proteins that present the Drug-peptide complex to T cells. Multiple forms of Drug Hypersensitivity are strongly linked to expression of a single HLA allele, and there is increasing evidence that Drugs and peptides interact selectively with the protein encoded by the HLA allele. Despite this, many individuals expressing HLA risk alleles do not develop Hypersensitivity when exposed to culprit Drugs suggesting a nonlinear, multifactorial relationship in which HLA risk alleles are one factor. This has prompted a search for additional susceptibility factors. Herein, we argue that immune regulatory pathways are one key determinant of susceptibility. As expression and activity of these pathways are influenced by disease, environmental and patient factors, it is currently impossible to predict whether Drug exposure will result in a health benefit, Hypersensitivity or both. Thus, a concerted effort is required to investigate how immune dysregulation influences susceptibility towards Drug Hypersensitivity.
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implications of hla allele associations for the study of type iv Drug Hypersensitivity reactions
Expert Opinion on Drug Metabolism & Toxicology, 2018Co-Authors: Andrew Sullivan, J. C. Waddington, Joel Watkinson, B K Park, Dean J. NaisbittAbstract:ABSTRACTIntroduction: Type IV Drug Hypersensitivity remains an important clinical problem and an obstacle to the development of new Drugs. Several forms of Drug Hypersensitivity are associated with...
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Immunological Mechanisms of Drug Hypersensitivity
Current pharmaceutical design, 2017Co-Authors: Xiaoli Meng, Adriana Ariza, J. C. Waddington, Kevin Park, Dean J. NaisbittAbstract:Drug Hypersensitivity reactions (DHRs) are adverse Drug reactions that may be divided into several categories; namely pharmacologic intolerance, idiosyncratic reactions, pseudo-allergic reactions and allergic reactions. Drug allergic reactions are those DHRs that are mediated by either antibodies or Drug-specific T cells. They vary in terms of severity, time-to-onset of clinical manifestations and target organ. Skin is most commonly implicated in Drug Hypersensitivity reactions; however, it is now apparent that reactions targeting internal organs fall under the definition of Drug Hypersensitivity. Multiple hypotheses have been proposed to explain the diverse immune mechanisms involved and the heterogeneous clinical presentation. The discovery of human leukocyte antigen (HLA) risk alleles for some DHRs has provided insights in the pathogenesis of these reactions. In this review we summarize immune cells involved in DHRs, discuss the possible immunological mechanisms of DHRs, with an emphasis on the IgE-mediated immediate reactions and T cell-dependent delayed type reactions.
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Towards the development of mechanism-based biomarkers to diagnose Drug Hypersensitivity
Toxicology Research, 2015Co-Authors: Noé V. Durán-figueroa, Dean J. Naisbitt, Jesús A. Badillo-corona, José L. Castrejón-floresAbstract:Drug Hypersensitivity reactions or Drug allergy is a form of serious adverse Drug reaction with an immunological aetiology to otherwise safe and effective therapeutic agents. The use of certain classes of Drugs (e.g., antibiotics, anti-convulsants and anti-retrovirals) is associated with a particular high frequency of reactions. The skin is the organ most commonly targeted in Drug Hypersensitivity reactions; however, other organs can be damaged in isolation or as part of a generalized Hypersensitivity syndrome. Diverse epidemiological studies have been performed in order to estimate the incidence of Drug Hypersensitivity, but due to the heterogeneous presentation, different immunological mechanisms involved and the lack of simple and cost-effective in vitro tests to confirm a clinical diagnosis, the real incidence remains elusive. Furthermore, lack of knowledge relating to the way in which Drugs interact with immune cells has hindered attempts to develop such tests. Nonetheless, during the last thirty years several groups have demonstrated that Drug-responsive lymphocytes play a key role in the pathogenesis of most forms of this iatrogenic disease. This present review focus on (1) the cellular mechanism involved in Drug Hypersensitivity and (2) the biomarkers used to diagnose Drug Hypersensitivity. In addition, using our increasing knowledge of post-transcriptional immune regulators, such as microRNAs, we explored the possibility of identifying novel Drug Hypersensitivity biomarkers and their possible application in assays to diagnose Drug Hypersensitivity reactions in susceptible patients.
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In vitro diagnosis of delayed-type Drug Hypersensitivity: mechanistic aspects and unmet needs.
Immunology and allergy clinics of North America, 2014Co-Authors: Dean J. Naisbitt, Ryan Nattrass, Monday O. OgeseAbstract:Abstract Several laboratories use the lymphocyte transformation test for the diagnosis of delayed-type Drug Hypersensitivity reactions. Recently, the availability of multiple readouts has improved our ability to diagnose reactions. It is important to note that most published studies characterizing the usefulness of diagnostic tests utilize blood samples from well-defined test and control patient groups. The purpose of this article is to briefly summarize the cellular and chemical basis of delayed-type Drug Hypersensitivity reactions and to review in vitro assays that are available for Drug Hypersensitivity diagnosis.
Wen-hung Chung - One of the best experts on this subject based on the ideXlab platform.
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The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity.
Frontiers in immunology, 2021Co-Authors: Yun-shiuan Olivia Hsu, Chuang-wei Wang, Shuen-iu Hung, Yu-fen Lin, Wen-cheng Chang, Kun-yun Yeh, Wen-hung ChungAbstract:The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug Hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and Drug reaction with eosinophilia and systemic symptoms/Drug-induced Hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit Drug Hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe Hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce Hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of Drug Hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type Drug Hypersensitivity in the hope of identifying potential pharmacologic targets.
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An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity
Hindawi Limited, 2018Co-Authors: Chun-bing Chen, Riichiro Abe, Ren-you Pan, Chuang-wei Wang, Shuen-iu Hung, Yi-giien Tsai, Wen-hung ChungAbstract:Drug Hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, Drug reactions with eosinophilia and systemic symptoms (DRESS)/Drug-induced Hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some Drug Hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding Drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually Drug, phenotype, and ethnic specific. The Drug presentation models that explain how small Drug antigens might interact with HLA and T cell receptor (TCR) molecules in Drug Hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of Drug Hypersensitivity involving different Drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for Drug Hypersensitivity
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HLA Associations and Clinical Implications in T-cell Mediated Drug Hypersensitivity Reactions: An Updated Review
Journal of immunology research, 2014Co-Authors: Chi-yuan Cheng, Chi-hua Chen, Wei-li Chen, Shin-tarng Deng, Wen-hung ChungAbstract:T-cell mediated Drug Hypersensitivity reactions may range from mild rash to severe fatal reactions. Among them, Drug reaction with eosinophilia and systemic symptoms (DRESS) or Drug-induced Hypersensitivity syndrome (DIHS), Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN), are some of the most life-threatening severe cutaneous adverse reactions (SCARs). Recent advances in pharmacogenetic studies show strong genetic associations between human leukocyte antigen (HLA) alleles and susceptibility to Drug Hypersensitivity. This review summarizes the literature on recent progresses in pharmacogenetic studies and clinical application of pharmacogenetic screening based on associations between SCARs and specific HLA alleles to avoid serious conditions associated with Drug Hypersensitivity.
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Human leukocyte antigens and Drug Hypersensitivity.
Current opinion in allergy and clinical immunology, 2007Co-Authors: Wen-hung Chung, Shuen-iu Hung, Yuan-tsong ChenAbstract:Purpose of reviewThe present article reviews the recent literature on the identification of human leukocyte antigen (HLA) alleles as major susceptible genes for Drug Hypersensitivity and discusses the clinical implications.Recent findingsSeveral recent studies have reported strong genetic associatio
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Genetics of Severe Drug Hypersensitivity Reactions in Han Chinese
Drug Hypersensitivity, 2007Co-Authors: Shuen-iu Hung, Wen-hung Chung, Yuan-tsong ChenAbstract:Drug Hypersensitivity, an immune-related idiosyncratic adverse reaction, was historically referred to as being unpredictable. However, recent studies in Han Chinese have revealed that several types
Ana Dioun Broyles - One of the best experts on this subject based on the ideXlab platform.
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Pediatric Drug Hypersensitivity
Current Allergy and Asthma Reports, 2019Co-Authors: Christine R. F. Rukasin, Allison E. Norton, Ana Dioun BroylesAbstract:Purpose of Review Pediatric Drug Hypersensitivity is a rapidly evolving field. The purpose of this paper is to review the current state of pediatric Drug Hypersensitivity and highlight new developments in diagnosis and management. Recent Findings This paper will discuss the safety and use of risk stratification to proceed directly to oral challenge without prior skin testing for β-lactam reactions. We review unique aspects of pediatric Drug challenges and desensitizations. Summary It is important to accurately diagnose pediatric Drug Hypersensitivity reactions through a detailed history, physical examination, and available diagnostic testing. Understanding of the underlying mechanism leads to appropriate classification which is necessary to direct management. The decision to perform Drug challenge, desensitization, or recommend avoidance of a medication can have a significant impact on a patient’s treatment. Utilization of weight-based dose and infusion rate adjustments for current Drug challenge and desensitization protocols optimize success.
