HLA-B*58: 01 carrier status of Hmong in Minnesota: first in Hmong genotyping for prevalence of this biomarker of risk for severe cutaneous adverse reactions caused by allopurinol.

Allopurinol, a common medication to treat gout, is associated with severe cutaneous adverse reactions, and the occurrence is highly predicted by an individual's HLA-B*58:01 carrier status. Guidelines endorse preemptive testing in select Asian populations before initiating allopurinol. The Hmong, an Asian subpopulation originally from China who now live dispersed around the world, have a 2.5-fold higher risk of gout when compared to non-Hmong in Minnesota. Given the concern for severe cutaneous adverse reactions when prescribing allopurinol, we quantified the carrier status of HLA-B*58:01 in Hmong from two independent cohorts in Minnesota. Using a community-based participatory research approach, HLA-B*58:01 carrier status was determined in 49 US-born Hmong without a history of gout or allopurinol use. Further, 47 Hmong patients undergoing clinical evaluation to receive gout pharmacotherapy were also tested. The frequency of HLA-B*58:01 positive carrier status in these two cohorts were compared to published data from a Han Chinese (n = 2910) and a Korean cohort (n = 485) using a Fisher's exact test with a Bonferroni-corrected P-value <0.025 for significance. With one uninterpretable result, we identified two out of 95 people (2.1%) who carried HLA-B*58:01. This 2.1% incidence in these Hmong adults is notably lower than Han Chinese (19.6%, P < 0.0001) and Korean (12.2%, P = 0.0016) populations. Though commonly understood to be of Chinese descent, the lower prevalence within the Hmong underscores the risk of generalizing genotypic findings from Chinese to Asian subpopulations. We suggest no change to the current guidelines recommending which populations should be tested for HLA-B*58:01 before allopurinol use until further validation.

Quality of Documentation of Contrast Agent Allergies in Electronic Health Records.

PURPOSE: To describe and appraise contrast agent allergy documentation in the electronic health record (EHR). METHODS: We systematically identified medical imaging drugs and class terms in an integrated EHR allergy repository for patients seen at a large health care system between 2000 and 2013. Structured and free-text contrast allergy records were normalized and categorized by inciting agent and nature of adverse reaction. Allergen records were evaluated by their level of specificity. Reaction records were evaluated by whether the reaction was known or unknown and whether known reactions would be categorized as allergic-like or physiologic. RESULTS: Among 2.7 million patients, we identified 36,144 patients (1.3%) with at least one of 40,669 contrast allergy records associated with 49,000 reactions. Contrast allergens were more likely than other allergens to be entered as free text (15.2% versus 6.3%; odds ratio 2.69, 95% confidence interval 2.61-2.76). There were 1,305 unique contrast allergen records, which we grouped into 141 concepts. Most contrast allergen records were ambiguous contrast concepts (69.1%), rather than imaging modality-specific class terms (19.4%) or specific contrast agents (11.5%). Contrast reactions were occasionally entered as free text (24.8%), which together with structured entries were grouped into 183 concepts. A known reaction was documented in 71.8% of cases; however, 12.2% were non-allergic-like reactions. CONCLUSION: Contrast allergy records in EHRs are diverse and commonly low quality. Continued EHR enhancements and training are needed to support contrast allergy documentation to facilitate improved patient care and medical research.

Hypersensitivity and Cardiovascular Risks Related to Allopurinol and Febuxostat Therapy in Asians: A Population-Based Cohort Study and Meta-Analysis.

The safety of newer xanthine oxidase inhibitor febuxostat compared to allopurinol remains unclear. To compare the risks of allopurinol hypersensitivity and febuxostat hypersensitivity and cardiovascular diseases (CVDs) in Asians, we conducted a population-based cohort study enrolling patients receiving allopurinol or febuxostat from Chang Gung Memorial Hospital Health System across Taiwan during 2012-2016 and further performed a meta-analysis incorporating two recent studies. Among the 61,539 users, a corresponding 12,007 and 5,680 patients were identified as new users. The overall incidence of febuxostat hypersensitivity was significantly lower than allopurinol hypersensitivity (0.2 vs. 2.7 per 1,000 new users; P < 0.001). There were 33 allopurinol-hypersensitivity reactions (including 18 severe cutaneous adverse drug reactions), and only one patient developed febuxostat-maculopapular exanthema. Moreover, febuxostat did not statistically increase the risk of CVD (hazard ratio (HR), 1.16; P = 0.152) and related death (HR, 1.49; P = 0.496) compared to allopurinol. The result of the meta-analysis also showed a consistent result. In conclusion, the incidence and severity of febuxostat-hypersensitivity are lower than with allopurinol. Febuxostat did not show an increased risk of CVD and related death.

Genetic risk factors for antiepileptic drug-induced hypersensitivity reactions in Israeli populations.

The human leukocyte antigen (HLA) alleles B*15:02 and A*31:01 have been identified as predictive markers of adverse cutaneous effects of carbamazepine and phenytoin in Asian and North European populations, respectively. Our aim was to estimate the distribution of these alleles in Jewish and Arab populations in Israel. The HLA-B*15:02 and HLA-A*31:01 carrier rate was estimated based on data from the Hadassah Bone Marrow Registry. Data on Stevens-Johnson syndrome (SJS)- and toxic epidermal necrolysis (TEN)-related hospitalizations were obtained from the Israeli Ministry of Health (MOH) registries and from four Israeli medical centers. Of 83,705 Jewish and Arab-Muslim donors, 81 individuals of known origin carried the HLA-B*15:02. Among them, 66 were Jews of India-Cochin descent. Of the Cochin Jewish donors, 12.7% were B*15:02 carriers. HLA-A*31:01 carrier incidence among Arab and Jewish Israeli populations (3.5% and 2.2%, respectively) was within the range reported in other countries. We did not identify SJS- or TEN-related hospitalizations of Jews of Indian descent. Yet, this population should be considered at greater risk for antiepileptic drug-induced SJS and TEN. Until further data on actual risk are available, such patients should be typed for HLA-B before treatment with carbamazepine or phenytoin.

A multiplex allele-specific real-time polymerase chain reaction assay for HLA-B*13:01 genotyping in four Chinese populations.

Human leukocyte antigen HLA-B*13:01 is identified currently as a marker of individual susceptibility to drug-induced hypersensitivity reaction, such as dapsone-induced hypersensitivity reactions (DIHRs) and trichloroethylene-induced dermatitis. Therefore, screening for the HLA-B*13:01 allele can assist clinics in identifying patients at risk of developing DIHRs. By combining the allele-specific primers with TaqMan probes, we established a single tube, triplex real-time PCR to detect HLA-B*13:01. The reliability of this assay was validated by the comparison of genotyping results with those by sequence-based typing (SBT). With this assay, the distribution of HLA-B*13:01 in a total of 350 blood samples from four ethnic groups: Han, Tibetan, Uighur, and Buyei were determined. A 100% concordance was observed between the results with the established real-time PCR and SBT in 100 samples. The detection limit of this assay was 0.016 ng genomic DNA. The prevalence of HLA-B*13:01 carriers were 11%, 8%, 1%, and 2% in the Buyei (n = 100), Northern Han (n = 100), Tibetan (n = 100), and Uighur (n = 50) populations, respectively. The multiplex real-time PCR assay provided a fast and reliable method for accurate detection of HLA-B*13:01 allele prior to dapsone administration in clinical practice and onset of the reaction after exposure to trichloroethylene.

Identifying opportunities in EHR to improve the quality of antibiotic allergy data.

BACKGROUND: Antimicrobial resistance is a growing, global public health crisis, due in large part to the overuse and misuse of antibiotics. Understanding medication allergy data and allergy reactions that are documented in electronic health records (EHRs) can help to identify opportunities to improve the quality of documentation of beta-lactam allergies, thus potentially reducing the prescribing of alternative antibiotics. METHODS: Medication allergies and allergy reactions recorded in the EHR for 319 051 patients seen across 32 community health centers were reviewed. Patients with a beta-lactam allergy recorded in their EHR were identified. Free text, as well as standardized allergy and allergy reaction fields, were analyzed. RESULTS: Among patients, 9.1% (n = 29 095) had evidence of a beta-lactam allergy recorded in their EHR. Women, white, and non-Hispanic patients were more likely to have a documented allergy compared to men, black, and Hispanic patients. Among all patients with a documented beta-lactam allergy, 36.2% had an empty or missing allergy reaction description in their EHR. CONCLUSIONS: Findings suggest that current EHR documentation practices among the health centers reviewed do not provide enough information on allergic reactions to allow providers to discern between true allergies and common, but anticipated, drug side effects. Improved EHR documentation guidance, training that reinforces the use of standardized data and more detailed recording of allergic reactions, combined with initiatives to address patient barriers including health literacy, may help to improve the accuracy of drug allergies in patients' records. These initiatives, combined with antimicrobial stewardship programs, can help to reduce inappropriate prescribing of alternative antibiotics when beta-lactam antibiotics are first-line and can be tolerated.

Safety and outcomes of test doses for the evaluation of adverse drug reactions: a 5-year retrospective review.

BACKGROUND: Graded challenges are the criterion standard for evaluating adverse drug reactions (ADR). Evidence-based guidelines regarding the optimal number of steps for challenges are lacking. OBJECTIVE: To determine the safety and outcomes of 1- or 2-step test doses among patients with ADRs seen by the allergy/immunology consult service and to compare the outcomes of 1- or 2-step test doses with multistep challenges performed during the same time period. METHODS: We conducted a retrospective chart review of all 1- or 2-step test doses and multistep challenges at a single academic center between 2008 and 2013. Patient demographics, symptoms of initial ADRs, and outcomes of test doses and multistep challenges were reviewed. ADRs were classified by type and were graded by severity. Outcomes of 1- or 2-step test doses were compared with multistep challenges. RESULTS: We identified 456 patients who underwent 497 one- or 2-step test doses (mean age, 51 years; 67.5% female patients). The most common drugs that prompted test doses were ß-lactams (62%). The majority of patients (n = 444 [89%]) did not experience any ADRs during test doses. ADRs that occurred during test doses (n = 53 [11%]) were most commonly non-immune-mediated (45%) or IgE-mediated (32%), with grade 1 or 2 severity (100%). Forty-nine percent of ADRs during test doses did not receive any treatment. The ADR rate during multistep challenges (10/82 [12%]) was similar to test doses. CONCLUSION: One- or 2-step test doses were safe for evaluation of ADRs. Multistep challenges did not confer added safety. Furthermore, 1- or 2-step test doses did not raise concern for induction of tolerance.

Genotyping for severe drug hypersensitivity.

Over the past decade, there have been significant advances in our understanding of the immunopathogenesis and pharmacogenomics of severe immunologically-mediated adverse drug reactions. Such T-cell-mediated adverse drug reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug-induced liver disease (DILI) and other drug hypersensitivity syndromes have more recently been shown to be mediated through interactions with various class I and II HLA alleles. Key examples have included the associations of HLA-B*15:02 and carbamazepine induced SJS/TEN in Southeast Asian populations and HLA-B*57:01 and abacavir hypersensitivity. HLA-B*57:01 screening to prevent abacavir hypersensitivity exemplifies a successful translational roadmap from pharmacogenomic discovery through to widespread clinical implementation. Ultimately, our increased understanding of the interaction between drugs and the MHC could be used to inform drug design and drive pre-clinical toxicity programs to improve drug safety.

Hypersensitivity reactions to etoposide phosphate.

Etoposide phosphate is a prodrug of intravenous etoposide recommended for use in patients with demonstrated allergy to etoposide. We have previously published a case series comprising six patients who were successfully treated with etoposide phosphate following preceding etoposide hypersensitivity. In this new paper we now present the cases of two patients who had allergic reactions to both etoposide and etoposide phosphate. As such, we suggest that whilst most patients with etoposide hypersensitivity can safely be treated with etoposide phosphate, a small number are at risk of an additional allergic reaction to etoposide phosphate. Patients being treated for the first time with etoposide phosphate after etoposide allergy should receive their first dose under medical supervision.

Population pharmacokinetic and pharmacogenetic analysis of nevirapine in hypersensitive and tolerant HIV-infected patients from Malawi.

We modeled nevirapine (NVP) pharmacokinetics in HIV-infected Malawian patients to assess the relationship between drug exposure and patient characteristics, genetic polymorphisms, and development of hypersensitivity reaction (HSR). One thousand one hundred seventeen patients were prospectively recruited and followed for 26 weeks with multiple or single serum samples obtained in a subset of patients for NVP quantification. Single nucleotide polymorphisms (SNPs) within CYP2B6 and CYP3A4 genes were typed. Nonlinear mixed effects modeling was utilized to assess the influence of patient characteristics and host genetics on NVP apparent oral clearance (CL/F) and to explore the relationship between NVP CL/F and HSR. Published haplotype distributions were used to simulate NVP concentrations in Caucasians versus Africans. One hundred eighty patients (101 female) were included in the model; 25 experienced HSR. No associations between patient demographics or HSR and NVP CL/F were evident. A significant relationship between CYP2B6 c.983T>C and CYP2B6 c.516G>T and NVP CL/F was observed (P < 0.01). NVP CL/F was reduced by 23% and 36% in patients with CYP2B6 983TT/516TT and 983TC/516GG or GT, respectively, compared to the reference genotype. Simulated exposures suggested similar proportions (13 to 17%) of patients with subtherapeutic NVP among Caucasians and an African population. Influence of CYP2B6 polymorphisms on NVP CL/F in this population is in agreement with other reports. Our data indicate a lack of association between NVP exposure and HSR. Based on these data, dose optimization based solely on ethnicity (without individual gene testing) is unlikely to impact on risk of treatment failure or toxicity even in an African population with high carriage of poor metabolizer mutations.

Stratification of the risk of serious allergic cutaneous reactions with therapeutic management of trigeminal neuralgia.

Patients with the HLA-B*1502 allele have a high risk of serious allergic cutaneous reactions from antiepileptic drugs used in the management of trigeminal neuralgia. Awareness of this uncommon but potentially fatal reaction will help to avoid the use of these drugs in patients from racial groups at high risk.

Genetic and ethnic risk factors associated with drug hypersensitivity.

PURPOSE OF REVIEW: The purpose of this article is to review the recent findings of studies reporting on the genetic and ethnic factors associated with hypersensitivity reactions to common drugs such as acetyl salicylic acid/NSAIDs, antibiotics, antituberculus medications, and other drugs including carbamazepine (CBZ), abacarvir, and allopurinol that can cause severe hypersensitivity reactions. RECENT FINDINGS: Aspirin hypersensitivity has recently been associated with a variety of genetic polymorphisms associated with leukotriene overproduction, eosinophil infiltration, and histamine-related genes. Recently, beta-lactam antibiotic hypersensitivity has been reported to be associated with interleukin (IL)-4 and IL-13 receptors in Italian, Chinese, and French populations. Moreover, a significant association of CYP2E1 in the Chinese, NAT2 in Koreans and glutathione S-transferase genotypes in Caucasians has been reported with antituberculus drug-induced hepatitis. The association of the HLA-B*1502 allele with CBZ-induced Stevens-Johnson syndrome in Asian population has also recently been observed. SUMMARY: Aspirin hypersensitivity has been associated with various genetic polymorphisms. Human leukocyte antigen (HLA)-related markers and a variety of genetic polymorphisms of leukotriene-related genes, eosinophil-related genes, and genes associated with immune function have been described according to ethnicity. The genetic mechanisms of antibiotic hypersensitivity have been reported in Italian, French, and Chinese populations in addition to antibiotics-induced cutaneous reactions in the Korean population. Most prior genetic studies on antituberculus drug-induced hepatitis have focused on a few drug-metabolizing enzymes such as cytochrome P450 and N-acetyltransferase 2. HLA-related markers associated with CBZ, lamotrigine, and abacavir-induced severe hypersensitivity reactions have been described.

Beta lactam allergy in children from two ethnically different populations.

BACKGROUND: The effects of ethnicity on beta lactam allergy have not been reported. The Negev Desert in Southern Israel is inhabited by two ethnically distinct populations: Jews and Bedouin Muslims. Approximately 60% of the pediatric population of the area is Jewish. Whereas most Jews live in Westernized urban centers, Bedouins are in the process of transition from semi-nomadic conditions to a sedentary lifestyle and the majority of them now live in towns and villages. We sought to determine the rate and characteristics of physician-reported beta lactam allergy in Jewish and Bedouin children. METHODS: The medical records of all children registered in five primary community clinics were reviewed and screened for allergy to beta lactam antibiotics. RESULTS: A total of 26,655 medical records were reviewed: of 11,069 Jewish children and 15,586 Bedouin children. Beta lactam allergy was registered in 344 records (1.3%), and was more frequent in Jewish (n= 226, 2.1%) than in Bedouin children (n= 118, 0.8%, P < 0.0001). Beta lactam allergy was more common in boys in both populations (P < 0.01). The clinical features of the reaction that led to the diagnosis of beta lactam allergy were not significantly different between the two ethnic populations, although the specific antibiotics prescribed and the diagnoses for which they were prescribed were different in the two ethnic populations. CONCLUSIONS: We concluded in this study that pediatric beta lactam allergy was registered more frequently in Jewish than in Bedouin children, and in boys more than in girls.

Oxaliplatin-induced allergic reaction in patients with colorectal cancer in Japan.

BACKGROUND: Oxaliplatin is a platinum compound that is clinically effective for colorectal cancer (CRC), in combination with 5-fluorouracil (5-FU) and leucovorin (LV), and it is widely used for metastatic disease and for the adjuvant treatment of stage III CRC. With the increasing use of oxaliplatin in Japan, serious adverse events have been experienced other than hematologic and neurologic toxicities. METHODS: In order to clarify the clinical features of allergic reactions to oxaliplatin, we retrospectively investigated CRC patients who had received oxaliplatin-based chemotherapies. RESULTS: One hundred and twenty-five CRC patients who had been treated with FOLFOX regimens (containing oxaliplatin, 5-FU, and LV) were examined, and 21 patients (17%) were found to have developed allergic reactions. Sixteen patients (13%) had grade 1/2 adverse events, classified according to the common terminology criteria for adverse events (CTC-AE) version 3.0 and 5 (4%) had grade 3/4 adverse events. The allergic reaction appeared after a median number of nine cycles (range, 2-15 cycles). Previous chemotherapy included 5-FU/LV, CPT-11, and S-1. All of the patients with allergic reactions recovered completely when treated with antiallergy drugs. Oxaliplatin was reintroduced in 11 patients, with the use of prophylactic agents; allergic reaction to the reintroduction was not observed in 8 patients and grade 1/2 allergic reactions developed in 3 patients. No correlation was identified between allergic reaction and patients' background characteristics such as sex, history of allergy, and profile of other adverse events. CONCLUSION: Allergic reactions to oxaliplatin remain an important issue for patients being able to safely continue effective chemotherapies; further analysis will be needed to establish methods for the prediction and prophylaxis of such reactions.

Current trends in screening across ethnicities for hypersensitivity to abacavir.

Abacavir is a potent nucleoside analog reverse transcriptase inhibitor approved for the treatment of HIV infection. Approximately 5-8% of Caucasian patients receiving abacavir develop a hypersensitivity reaction, characterized by rash, fever and, occasionally, multisystemic involvement. Rechallenge with the drug can be fatal. The discovery of the mechanisms involved in this hypersensitivity reaction and the identification of tools for its prediction are the subject of this review. The most relevant finding is the recognition of a strong association between one specific haplotype at the HLA complex type I, HLA-B*5701, and the abacavir hypersensitivity reaction. The heterogeneity in the prevalence of HLA-B*5701 across distinct ethnicities accounts for differences in the risk of abacavir hypersensitivity reactions in distinct populations.