scholarly journals Genotyping for HLA Risk Alleles to Prevent Drug Hypersensitivity Reactions: Impact Analysis

2021 ◽  
Vol 15 (1) ◽  
pp. 4
Author(s):  
Lisanne E. N. Manson ◽  
Wilbert B. van den Hout ◽  
Henk-Jan Guchelaar
Keyword(s):  
The Netherlands ◽  
Impact Analysis ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Cost Effective ◽  
Gene Interaction ◽  
Hypersensitivity Reactions ◽  
Drug Label ◽  
Risk Alleles ◽  
Drug Hypersensitivity Reactions

Human Leukocyte Antigen (HLA) variants can be a risk factor for developing potentially fatal drug hypersensitivity reactions. Our aim was to estimate the potential impact of genotyping for the HLA risk alleles incorporated in the Dutch Pharmacogenetics Working Group (DPWG) guidelines in The Netherlands. We estimated the number of hypersensitivity reactions and associated deaths that can be avoided annually by genotyping for these HLA risk alleles. Additionally, the cost-effectiveness was estimated. Nationwide implementation of genotyping HLA risk alleles before initiating drugs with an actionable drug–gene interaction can potentially save the life of seven allopurinol initiators and two flucloxacillin initiators each year in The Netherlands. Besides these deaths, 28 cases of abacavir hypersensitivity, 24 cases of allopurinol induced SCARs, 6 cases of carbamazepine induced DRESS and 22 cases of flucloxacillin induced DILI can be prevented. Genotyping HLA-B*5701 in abacavir initiators has a number needed to genotype of 31 to prevent one case of abacavir hypersensitivity and is cost-saving. Genotyping HLA-B*5801 in allopurinol initiators has a number needed to genotype of 1149 to prevent one case of SCAR but is still cost-effective. Genotyping before initiating antiepileptic drugs or flucloxacillin is not cost-effective. Our results confirm the need for mandatory testing of HLA-B*5701 in abacavir initiators, as indicated in the drug label, and show genotyping of HLA-B*5801 in allopurinol initiators should be considered.

scholarly journals HLA Associations and Clinical Implications in T-Cell Mediated Drug Hypersensitivity Reactions: An Updated Review

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Chi-Yuan Cheng ◽  
Shih-Chi Su ◽  
Chi-Hua Chen ◽  
Wei-Li Chen ◽  
Shin-Tarng Deng ◽  
...  
Keyword(s):  
T Cell ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Hypersensitivity Syndrome ◽  
Stevens Johnson Syndrome ◽  
Hypersensitivity Reactions ◽  
Genetic Associations ◽  
Drug Induced ◽  
Hla Alleles ◽  
Drug Hypersensitivity Reactions

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.

scholarly journals Novel Concepts for Drug Hypersensitivity Based on the Use of Long-Time Scale Molecular Dynamic Simulation

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Takahiro Murai ◽  
Norihito Kawashita ◽  
Yu-Shi Tian ◽  
Tatsuya Takagi
Keyword(s):  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Md Simulations ◽  
Hypersensitivity Reactions ◽  
Drug Induced ◽  
Leukocyte Antigen ◽  
Cell Clones ◽  
Drug Hypersensitivity Reactions ◽  
Long Time ◽  
Underlying Mechanisms

The discovery that several drug hypersensitivity reactions (DHRs) are associated with specific human leukocyte antigen (HLA) alleles has attracted increasing research interest. However, the underlying mechanisms of these HLA-induced DHRs remain unclear, especially for drug-induced immediate activation of T-cell clones (TCCs). Recently, a novel hypothesis involving partial detachment between self-peptide(s) and the HLA molecule (altered peptide-HLA (pHLA) model) has been proposed to explain these phenomena. In order to clarify this hypothesis, we performed long-timescale molecular dynamics (MD) simulations. We focused on HLA-B⁎57:01-restricted abacavir hypersensitivity reactions (AHRs), one of the most famous DHRs. One of the simulation results showed that this altered-pHLA model might be driven by an increase in the distance not only between HLA and self-peptides but also between the α1 and α2 helices of HLA. Our findings provide novel insights into abacavir-induced immediate activation of TCCs and these findings might also be applied to other DHRs, such as HLA-B⁎58:01-restricted allopurinol hypersensitivity reactions.

Human Leukocyte Antigen Associations in Drug Hypersensitivity Reactions

2018 ◽  
Vol 38 (4) ◽  
pp. 669-677 ◽  
Author(s):  
Ryan J. Schutte ◽  
Yonghu Sun ◽  
Danmeng Li ◽  
Furen Zhang ◽  
David A. Ostrov
Keyword(s):  
Human Leukocyte Antigen ◽  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Hypersensitivity Reactions ◽  
Leukocyte Antigen ◽  
Drug Hypersensitivity Reactions

scholarly journals Hypersensitivity reactions to IL-1 and IL-6 inhibitors are linked to common HLA-DRB1*15 alleles

2020 ◽  
Author(s):  
Jill Hollenbach ◽  
Michael Ombrello ◽  
Adriana Tremoulet ◽  
Jaime S Rosa Duque ◽  
Gilbert T Chua ◽  
...  
Keyword(s):  
Drug Hypersensitivity ◽  
Human Leukocyte ◽  
Hypersensitivity Reactions ◽  
Diffuse Lung Disease ◽  
Entire Cohort ◽  
Systemic Jia ◽  
Inflammatory Conditions ◽  
Drug Hypersensitivity Reactions ◽  
Hla Dqa1 ◽  
Hla Genotype

In Saper et al (2019), we described systemic JIA patients who developed a high-fatality diffuse lung disease (DLD) while on IL-1 or IL-6 inhibitors. We observed severe delayed drug hypersensitivity reactions (DHR) in a significant subset. Because alleles of the human leukocyte antigen (HLA) loci can mediate DHR, we investigated HLA genotype association with these DHR. We typed subjects treated with these inhibitors: 34 sJIA/DHR/DLD, 11 sJIA/DHR without DLD, 18 drug-tolerant sJIA, and 19 Kawasaki disease (KD) patients in an anti-IL-1(anakinra) trial. We also accessed genotypes from a large sJIA case/control cohort. We first compared White subjects with sJIA/DHR to 550 ancestry-matched sJIA subjects. We found striking enrichments of HLA-DRB1*15:01, HLA-DQA1*01:02, and DQB1*06:02, alleles in near-complete linkage (White individuals). HLA-DRB1*15:01 (as haplotype proxy) was increased in White sJIA subjects with DHR/DLD versus sJIA drug-tolerant controls and was observed upon inclusion of sJIA+DHR-only and KD+DHR White subjects. In our entire cohort regardless of ancestry, 75% carried HLA-DRB1*15:01 or the structurally related DRB1*15:03 and DRB1*15:06, which were absent among drug-tolerant subjects (p=5 x 10-13; Odds Ratio lower bound=20.11). Patients who harbor HLA-DRB1*15 alleles are at high risk of developing DHR to anti-IL-1/IL-6. Our data also suggest DHR maybe a trigger/enhancer of DLD in sJIA patients and support performing prospective HLA screening in sJIA, its adult-onset counterpart, and other inflammatory conditions where these drugs are used, such as KD.

Skin testing and drug challenge in the evaluation of drug hypersensitivity reactions

2021 ◽  
Vol 42 (1) ◽  
pp. 16-21 ◽  
Author(s):  
Anna R. Wolfson ◽  
Aleena Banerji
Keyword(s):  
Negative Impact ◽  
Skin Testing ◽  
Drug Hypersensitivity ◽  
Clinical History ◽  
Hypersensitivity Reactions ◽  
Causative Drug ◽  
Care Assessment ◽  
Drug Hypersensitivity Reactions ◽  
Drug Challenge ◽  
Drug Challenges

Immediate hypersensitivity to drugs is characterized by symptoms such as hives, swelling, and wheezing. To prevent a negative impact on care, assessment by an allergist is important. Evaluation requires a clear clinical history, but it is often lacking or vague, which makes a diagnosis difficult. Allergists instead can use skin testing and drug challenge to evaluate drug hypersensitivity reactions, which help the patient and provider understand the causative drug(s) and, more importantly, enables the use of the exonerated drug(s). Although penicillin skin testing is standardized, well described, and widely used, skin testing for most other drugs requires the use of a nonirritating skin testing concentration that can have a low negative predictive value. Drug challenges are the criterion standard for confirming tolerance. The allergist must obtain an in-depth clinical history and then follow with skin testing and/or drug challenges when indicated to determine which drugs can be de-labelled and which should be avoided. In this review, we focused on the evaluation of drug hypersensitivity reactions to antibiotics, perioperative agents, biologics, and chemotherapeutics.

Clinical Phenotypes of Severe Cutaneous Drug Hypersensitivity Reactions

2019 ◽  
Vol 25 (36) ◽  
pp. 3840-3854 ◽  
Author(s):  
Hakan Guvenir ◽  
Tugba Arikoglu ◽  
Emine Vezir ◽  
Emine Dibek Misirlioglu
Keyword(s):  
Adverse Drug Reactions ◽  
Drug Hypersensitivity ◽  
Stevens Johnson Syndrome ◽  
Facial Oedema ◽  
Hypersensitivity Reactions ◽  
Drug Reactions ◽  
Cutaneous Manifestations ◽  
Clinical Phenotypes ◽  
Drug Eruptions ◽  
Drug Hypersensitivity Reactions

Drug hypersensitivity reactions are clinically heterogenous ranging from mild to severe. Most drug hypersensitivity reactions are accompanied by cutaneous manifestations. Fever, mucous membrane involvement, large blisters, facial oedema, pustulosis and visceral involvement are clinical features that lead to suspicion of severe adverse drug reactions. Severe cutaneous adverse drug reactions (SCARs) include Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis. Serum sickness like reactions, drug induced vasculitis and generalized bullous fixed drug eruptions are less severe clinical entities. SCARs are uncommon but associated with significant morbidity and mortality. Physician should be aware of specific red flags and danger signs to immediately identify these reactions. Immediate drug withdrawal is mandatory. Early diagnosis and appropriate treatment significantly affect the prognosis of the disease. The purpose of our review is to discuss clinical phenotypes of severe cutaneous drug hypersensitivity reactions.

Early Biomarkers for Severe Drug Hypersensitivity Reactions

2019 ◽  
Vol 25 (36) ◽  
pp. 3829-3839 ◽  
Author(s):  
Adriana Ariza ◽  
Maria J. Torres ◽  
Carmen Moreno-Aguilar ◽  
Rubén Fernández-Santamaría ◽  
Tahia D. Fernández
Keyword(s):  
Drug Exposure ◽  
Drug Hypersensitivity ◽  
Clinical Manifestations ◽  
Skin Tests ◽  
Time Interval ◽  
Hypersensitivity Reactions ◽  
Early Biomarkers ◽  
Immunological Mechanisms ◽  
Drug Hypersensitivity Reactions ◽  
Delayed Reactions

Drug hypersensitivity reactions (DHRs) are typically classified into immediate and delayed reactions based on the time interval between drug exposure and onset of symptoms. Clinical manifestations range from mild to severe and life-threatening reactions. The most severe clinical entities are anaphylaxis and anaphylactic shock for immediate reactions, and severe cutaneous adverse reactions such as Steven Johnson Syndrome and Toxic Epidermal Necrolysis for delayed reactions. The diagnosis is complex and challenging, as drug provocation tests and even skin tests can be very risky procedures, which makes them not recommended. Therefore, it is necessary to search for useful early biomarkers to manage the diagnosis of these reactions. These biomarkers could be useful to determine the clinical entity, but not to identify the culprit drug. Some of the currently available biomarkers are few genetic associations of drug allergy with polymorphisms of human leukocyte antigen (HLA), the detection of inflammatory and lipid mediators in serum, or the detection of cytokines, chemokines, and cytotoxic markers in skin biopsies. In this literature review, it has been summarize the immunological mechanisms involved in severe reactions, both immediate and delayed, and different early biomarkers: those currently used for the diagnosis of these reactions as well as possible early biomarkers that could be useful with further studies to standardize their clinical use.

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