Genetic markers of drug hypersensitivity in pediatrics: current state and promise

Elzagallaai, Abdelbaset A; Rieder, Michael J.

doi:10.1080/17512433.2022.2100345

Cited by 3 publications

(3 citation statements)

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“…94 Only a few drugs have been investigated using this model because genetic associations of DHRs with sufficient strength have only been established with a few drugs, namely, abacavir, carbamazepine and allopurinol (Figure 3). 5…”

Section: The Altered Peptide Repertoire Hypothesismentioning

confidence: 99%

“…2 In contrast to type A ADRs, type B are always referred to as dose-independent and unpredictable but this is absolutely incorrect as a certain threshold of drug/metabolite(s) concentration is required to elicit the reaction 3 and many of these reactions can now be predicted by pharmacogenomic and in vitro testing. [4][5][6][7][8][9] The third traditional characteristic of type B ADRs is being off-target and unrelated to the drug pharmacology. This is partially true but not always as DHRs to vaccines, some biologicals and immune check points inhibitors are indeed related to the intended drug target.…”

Section: Introductionmentioning

confidence: 99%

“…Drug hypersensitivity reactions (DHRs) are traditionally classified as type B or idiosyncratic adverse drug reactions (ADRs) and defined as “objectively reproducible symptoms of signs initiated by exposure to a defined stimulus at a dose tolerated by normal subjects.” 1 It is an umbrella term that covers cases when the involvement of an immunologic mechanism is demonstrated (drug allergy) or when an immunologic mechanism cannot be proven (nonallergic hypersensitivity) 2 . In contrast to type A ADRs, type B are always referred to as dose‐independent and unpredictable but this is absolutely incorrect as a certain threshold of drug/metabolite(s) concentration is required to elicit the reaction 3 and many of these reactions can now be predicted by pharmacogenomic and in vitro testing 4–9 . The third traditional characteristic of type B ADRs is being off‐target and unrelated to the drug pharmacology.…”

Section: Introductionmentioning

confidence: 99%

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Pathophysiology of drug hypersensitivity

Elzagallaai

Rieder

2023

Brit J Clinical Pharma

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Drug hypersensitivity reactions (DHRs) are type B adverse drug reactions (ADRs) traditionally defined as unpredictable, dose independent and not related to the drug pharmacology. DHRs, also called drug allergy if the immune system involvement is confirmed, represent around one‐sixth of all ADRs and can cause major clinical problems due to their vague clinical presentation and irregular time course. Understanding the underlying pathophysiology of DHRs is very important for their diagnosis and management. Multiple layers of evidence exist pointing to the involvement of the immune system in DHRs. Recent data have led to a paradigm shift in our understanding of the exact pathophysiology of these reactions. Numerous hypotheses proposing explanation on how a low molecular weight drug molecule can elicit an immune reaction have been proposed. In addition to the classical “hapten” hypothesis, the reactive metabolite hypothesis, the pharmacological interaction with the immune system (p‐i) concept, the danger/injury hypothesis and the altered peptide repertoire hypothesis have been proposed. We here introduce the inflammasome activation hypothesis and the cross‐reactivity hypothesis as additional models explaining the pathophysiology of DHRs. Available data supporting these hypotheses are briefly summarized and discussed. We also introduced the cross‐reactivity model, which may provide a platform to appreciate the potential role played by other factors leading to the activation of the immune system. We believe that although the drug in question could be the trigger of the reaction, the components of the immune system mediating the reaction do not act in isolation but rather are affected by the proinflammatory milieu occurring at the time of the reaction. This review attempts to summarize the available evidence to further illustrate the pathophysiology of DHRs.

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Section: The Altered Peptide Repertoire Hypothesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pathophysiology of drug hypersensitivity

Elzagallaai

Rieder

2023

Brit J Clinical Pharma

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Novel insights into molecular and cellular aspects of delayed drug hypersensitivity reactions

Elzagallaai,

Rieder

2023

Expert Review of Clinical Pharmacology

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Drug fever—an immune-mediated delayed type hypersensitivity reaction to Vinca alkaloids in pediatric oncology patients, possibly mediated by cysteinyl leukotrienes

Kidon,

Haj Yahia,

Abebe-Campino

et al. 2024

Front. Allergy

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BackgroundDrug hypersensitivity reactions are common in pediatric hemato-oncology patients due to multiple factors including immune compromise and pharmacological complexities. Fever can signify severe delayed-type hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS). The etiology of fever as an isolated hypersensitivity reaction to chemotherapeutic agents not fully understood. Here, we report three children with intracranial neoplasms experiencing recurrent febrile reactions following Vinca alkaloid-based chemotherapy, mitigated by cysteinyl leukotriene receptor antagonist therapy.MethodsWe present a series of pediatric patients with diverse intracranial neoplasms who developed recurrent fever episodes after multiple courses of Vinca alkaloid-based chemotherapy. Treatment involved prophylactic and post-chemotherapy administration of a cysteinyl leukotriene receptor antagonist to prevent fever episodes and enable completion of chemotherapy regimens without protocol modifications or desensitization.ResultsAll three patients experienced fever consistent with delayed-type hypersensitivity reactions to Vinca alkaloids. Prophylactic use of the leukotriene antagonist Montelukast successfully prevented fever recurrence, allowing uninterrupted completion of chemotherapy courses.ConclusionOur findings suggest that Montelukast, a leukotriene antagonist, may be beneficial in managing fever as a delayed-type hypersensitivity reaction to Vinca alkaloids in pediatric patients. Further research is warranted to elucidate the underlying mechanisms and leukotriene pathways involved in drug-induced fever reactions.

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Genetic markers of drug hypersensitivity in pediatrics: current state and promise

Cited by 3 publications

References 179 publications

Pathophysiology of drug hypersensitivity

Pathophysiology of drug hypersensitivity

Novel insights into molecular and cellular aspects of delayed drug hypersensitivity reactions

Drug fever—an immune-mediated delayed type hypersensitivity reaction to Vinca alkaloids in pediatric oncology patients, possibly mediated by cysteinyl leukotrienes

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