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Human leukocyte antigen (HLA) alleles have been implicated as risk factors for immune-mediated adverse drug reactions. The authors recently reported a strong association between HLA-A*32:01 and vancomycin-induced drug reaction with eosinophilia and systemic symptoms. Identification of individuals with the risk allele before or shortly after the initiation of vancomycin therapy is of great clinical importance to prevent morbidity and mortality, and improve drug safety and antibiotic treatment options. A prerequisite to the success of pharmacogenetic screening tests is the development of simple, robust, cost-effective single HLA allele test that can be implemented in routine diagnostic laboratories. In this study, the authors developed a simple, real-time allele-specific PCR for typing the HLA-A*32:01 allele. Four-hundred and fifty-eight DNA samples including 30 HLA-A*32:01-positive samples were typed by allele-specific PCR. Compared with American Society for Histocompatibility and Immunogenetics-accredited, sequence-based, high-resolution, full-allelic HLA typing, this assay demonstrates 100% accuracy, 100% sensitivity (95% CI, 88.43% to 100%), and 100% specificity (95% CI, 99.14% to 100%). The lowest limit of detection of this assay using PowerUp SYBR Green is 10 ng of template DNA. The assay demonstrates a sensitivity and specificity to differentiate the HLA-A*32:01 allele from closely related non-HLA-A*32 alleles and may be used in clinical settings to identify individuals with the risk allele before or during the course of vancomycin therapy.
Copyright © 2019 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.
© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.
BACKGROUND - Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell-mediated adverse drug reactions, which has led to preventive screening strategies for some drugs.
OBJECTIVE - We sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS.
METHODS - Probable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele.
RESULTS - Twenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01-positive group indicated that 19.2% had DRESS and did so within 4 weeks.
CONCLUSIONS - HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics.
Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Antibiotics are the commonest cause of life-threatening immune-mediated drug reactions that are considered off-target, including anaphylaxis, and organ-specific and severe cutaneous adverse reactions. However, many antibiotic reactions documented as allergies were unknown or not remembered by the patient, cutaneous reactions unrelated to drug hypersensitivity, drug-infection interactions, or drug intolerances. Although such reactions pose negligible risk to patients, they currently represent a global threat to public health. Antibiotic allergy labels result in displacement of first-line therapies for antibiotic prophylaxis and treatment. A penicillin allergy label, in particular, is associated with increased use of broad-spectrum and non-β-lactam antibiotics, which results in increased adverse events and antibiotic resistance. Most patients labelled as allergic to penicillins are not allergic when appropriately stratified for risk, tested, and re-challenged. Given the public health importance of penicillin allergy, this Review provides a global update on antibiotic allergy epidemiology, classification, mechanisms, and management.
Copyright © 2019 Elsevier Ltd. All rights reserved.
BACKGROUND - The most common immediate hypersensitivity to macrogols is associated with polyethylene glycol (PEG) 3350; however, the epidemiology, mechanisms, and cross-reactivity are poorly understood. Thousands of medications contain either PEGs or structurally similar polysorbates.
OBJECTIVE - Our objective was to better understand the mechanism, cross-reactivity, and scope of PEG hypersensitivity.
METHODS - Two cases with a past history of immediate hypersensitivity to PEG-containing medications were used to study potential mechanisms and cross-reactivity of immediate reactions to PEG 3350. Skin testing and oral challenges with PEG and polysorbate-containing agents were employed to determine clinical reactivity and cross-reactivity between the 2 allergens. Enzyme-linked immunosorbent assay and electrochemiluminescent immunoassay were used to detect anti-PEG specific IgG and IgE, respectively, using PEGylated protein or PEG alone as antigens in 2 cases and 6 PEG 3350 tolerant controls. We searched US Food and Drug Administration (FDA) adverse event reports for immediate reactions to PEG 3350 to determine the potential scope of this problem in the United States.
RESULTS - Skin and provocation testing demonstrated symptomatic reactivity in both cases to PEG 3350 and polysorbate 80. Plasma samples were positive for anti-PEG specific IgE and IgG antibodies only in cases and binding increased directly proportional to the molecular weight of PEG tested. FDA adverse event reports revealed 53 additional cases of possible PEG 3350 anaphylaxis.
CONCLUSIONS - Immediate hypersensitivity to PEG 3350 with cross-reactive polysorbate 80 hypersensitivity may be underrecognized in clinical practice and can be detected with clinical skin testing. Our studies raise the possibility of an IgE-mediated type I hypersensitivity mechanism in some cases.
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Transmaternal exposure to tobacco, microbes, nutrients, and other environmental factors shapes the fetal immune system through epigenetic processes. The gastric microbe Helicobacter pylori represents an ancestral constituent of the human microbiota that causes gastric disorders on the one hand and is inversely associated with allergies and chronic inflammatory conditions on the other.
OBJECTIVE - Here we investigate the consequences of transmaternal exposure to H pylori in utero and/or during lactation for susceptibility to viral and bacterial infection, predisposition to allergic airway inflammation, and development of immune cell populations in the lungs and lymphoid organs.
METHODS - We use experimental models of house dust mite- or ovalbumin-induced airway inflammation and influenza A virus or Citrobacter rodentium infection along with metagenomics analyses, multicolor flow cytometry, and bisulfite pyrosequencing, to study the effects of H pylori on allergy severity and immunologic and microbiome correlates thereof.
RESULTS - Perinatal exposure to H pylori extract or its immunomodulator vacuolating cytotoxin confers robust protective effects against allergic airway inflammation not only in first- but also second-generation offspring but does not increase susceptibility to viral or bacterial infection. Immune correlates of allergy protection include skewing of regulatory over effector T cells, expansion of regulatory T-cell subsets expressing CXCR3 or retinoic acid-related orphan receptor γt, and demethylation of the forkhead box P3 (FOXP3) locus. The composition and diversity of the gastrointestinal microbiota is measurably affected by perinatal H pylori exposure.
CONCLUSION - We conclude that exposure to H pylori has consequences not only for the carrier but also for subsequent generations that can be exploited for interventional purposes.
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
OBJECTIVE - To assess drug reactions (ADRs) encountered by practicing urologists for contrast instilled into the urinary collecting system, and to describe current practice patterns regarding contrast administration into the urinary tract for patients with known contrast allergies.
METHODS - Endourological Society members were e-mailed a web-based survey about their prior experience with contrast-related ADRs and practices for contrast administration into the urinary tract among patients with known intravenous contrast allergies. Chi-squared analysis was used to compare management patterns between patients with established allergies and those without.
RESULTS - An estimated 2300-2500 e-mails were reached, resulting in an estimated response rate of 6.3%-8%. Over 75% of respondents were fellowship trained. Average time in practice was 16 years, and respondents performed a mean of 6.7 urologic contrast studies per week. Among respondents, 32.6%, 14.7%, and 4.0% had treated at least 1 patient with a mild, moderate, or severe reaction, respectively. Contrast-related ADRs were most commonly associated with retrograde pyelogram (50%). For patients with known contrast allergies, 5.4% pursue additional work-up before administering contrast in the urinary tract. Pretreatment with antihistamine or steroids is used by 24.8% and 23.4%, respectively. When performing retrograde pyelograms for such patients, urologists are more likely to use dilute contrast (P = .003), but otherwise do not significantly alter technique.
CONCLUSION - Contrast ADRs are encountered not infrequently among practicing urologists. There is notable practice variation in the management of patients with known contrast allergies, though the overall perceived risk of contrast use in these patients is low, provided good technique is used.
Copyright © 2018 Elsevier Inc. All rights reserved.