Kyung-Up Min

Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans

BACKGROUND Although the US FDA recommends screening for HLA-B*1502 allele in most of Asian ancestry before initiating carbamazepine therapy, the HLA associations with carbamazepine hypersensitivity in non-Chinese Asian populations remain unclear. This study investigated the association between the HLA class I genotype and carbamazepine-induced severe cutaneous adverse reaction (SCAR) in Koreans. METHODS Twenty-four patients who had developed carbamazepine-induced SCAR (7 Stevens-Johnson syndrome (SJS), 17 drug hypersensitivity syndrome (HSS)), 50 carbamazepine-tolerant controls from the Korean Pharmacogenetic Adverse Drug Reaction Research Network and data of 485 Korean general population from a previously published study were recruited. HLA-A, -B, and -C genotyping was performed by direct DNA sequence analysis. RESULTS Only one of the seven SJS patients was positive for the B*1502 allele, but the frequency of B*1511 was much higher in the patients with CBZ-SJS than in the CBZ-tolerant control patients (P=0.011, P(c)=not significant; OR=18.0(2.3-141.2)). The frequencies of A*3101 in carbamazepine-induced HSS and SCAR were significantly higher than those in carbamazepine-tolerant controls (P(c)=0.011, OR=8.8(2.5-30.7) and P(c)=0.013, OR=7.3(2.3-22.5), respectively). The frequencies of B*1511 in carbamazepine-SJS and A*3101 in carbamazepine-HSS/SCAR were significantly higher than those in the general population. CONCLUSIONS HLA-B*1502 does not seem to be an effective predictive marker for carbamazepine-induced SCAR, while HLA-B*1511 and A*3101 was associated with carbamazepine-induced SJS and HSS/SCAR respectively in the Korean population.

Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans.

Recent investigations suggest genetic susceptibility of allopurinol-induced severe cutaneous adverse reactions (SCARs). However, the strength of association was variable according to phenotypes and ethnic backgrounds. To explore genetic markers for allopurinol-induced SCARs in Koreans, we genotyped human leukocyte antigen (HLA) class I alleles of 25 cases of allopurinol-induced SCARs (20 cases of drug-induced hypersensitivity syndrome and five cases of Stevens–Johnson syndrome/toxic epidermal necrolysis) and 57 patients tolerant to allopurinol. Frequencies of B*5801 [92.0 vs. 10.5%, Pc=2.45×10−11, odds ratio (OR)=97.8], Cw*0302 (92.0 vs. 12.3%, Pc=9.39×10−11, OR=82.1), and A*3303 (88.0 vs. 26.3%, Pc=3.31×10−6, OR=20.5) were significantly higher in SCARs compared with tolerant controls. In contrast, A*0201 was not found in SCARs patients despite relatively high frequency in tolerant controls (29.8%). We found strong positive association of HLA-B*5801 and negative association of HLA-A*0201 with the development of allopurinol-induced SCARs in the Korean population.

Immediate Hypersensitivity Reaction to Gadolinium-based MR Contrast Media

PURPOSE To determine the incidence and risk factors of immediate hypersensitivity reactions to gadolinium-based magnetic resonance (MR) contrast agents. MATERIALS AND METHODS Institutional review board approval and a waiver of informed consent were obtained. A retrospective study of patients who had been given gadolinium-based MR contrast media between August 2004 and July 2010 was performed by reviewing their electronic medical records. In addition to data on immediate hypersensitivity reaction, the kinds of MR contrast media and demographic data including age, sex, and comorbidity were collected. To compare the groups, the χ(2) test, Fisher exact test, χ(2) test for trend, Student t test, analysis of variance test, and multiple logistic regression test were performed. RESULTS A total of 112 immediate hypersensitivity reactions (0.079% of 141 623 total doses) were identified in 102 patients (0.121% of 84 367 total patients). Among the six evaluated MR contrast media, gadodiamide had the lowest rate (0.013%) of immediate hypersensitivity reactions, while gadobenate dimeglumine had the highest rate (0.22%). The rate for immediate hypersensitivity reactions was significantly higher in female patients (odds ratio = 1.687; 95% confidence interval: 1.143, 2.491) and in patients with allergies and asthma (odds ratio = 2.829; 95% confidence interval: 1.427, 5.610). Patients with a previous history of immediate hypersensitivity reactions had a higher rate of recurrence after reexposure to MR contrast media (30%) compared with the incidence rate in total patients (P < .0001). The incidence of immediate hypersensitivity reactions increased depending on the number of times patients were exposed to MR contrast media (P for trend = .036). The most common symptom was urticaria (91.1%), and anaphylaxis occurred in 11 cases (9.8%). The mortality rate was 0.0007% because of one fatality. CONCLUSION The incidence of immediate hypersensitivity reactions to MR contrast media was 0.079%, and the recurrence rate of hypersensitivity reactions was 30% in patients with previous reactions.

High prevalence of current asthma and active smoking effect among the elderly

Background Although asthma is a common cause of morbidity in adults, relatively few objectively measured population studies of asthma prevalence in adult populations have been conducted.

Epidemiologic and clinical features of anaphylaxis in Korea

BACKGROUND Little is known about the characteristics of anaphylaxis in Korea or even in Asia. OBJECTIVE To evaluate the incidence of anaphylaxis and the clinical features of patients with anaphylaxis in a Korean tertiary care hospital. METHODS We performed a retrospective review from January 1, 2000, through July 31, 2006, of 138 patients with anaphylaxis, including inpatients, outpatients, and emergency department visitors, in the Seoul National University Hospital. RESULTS Among 978,146 patients, 138 (0.014%) had anaphylaxis. Two cardiopulmonary resuscitations were performed and 1 death occurred. The total mortality rate of anaphylactic patients was 0.0001%. The causes of anaphylaxes were drug (35.3%), food (21.3%), food-dependent exercise-induced (13.2%), idiopathic (13.2%), insect stings (11.8%), exercise induced (2.9%), blood products (1.5%), and latex (0.7%). Radiocontrast media and buckwheat were the leading causes of drug and food anaphylaxis, respectively. The organs most frequently involved in the anaphylaxis were cutaneous (95.7%), cardiovascular (76.8%), and respiratory (74.6%). The most common manifestations were dyspnea (71.3%), urticaria (81.9%), and angioedema (69.4%). Three of 138 patients (2.2%) had biphasic reactions. CONCLUSIONS The incidence, mortality rate, and clinical features of Korean patients with anaphylaxis were similar to rates for patients from other countries, despite some differences in causative agents.

HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency

BACKGROUND Although allopurinol is a very effective urate-lowering drug for complicated hyperuricemia, in some patients, it can induce severe cutaneous adverse reactions (SCARs). Recent investigations suggest that HLA-B*5801 is a very strong marker for allopurinol-induced SCARs, especially in the population with a high frequency of HLA-B*5801. Korea is one of the countries with a high frequency of HLA-B*5801 which is the only subtype of HLA-B58 in the Korean population. Objective. This study was conducted to find out the incidence of allopurinol-induced hypersensitivity on patients with chronic renal insufficiency (CRI) according to HLA-B58 and the clinical implications of HLA-B58 as a risk marker for the development of allopurinol-induced hypersensitivity. METHODS We retrospectively reviewed the medical records of patients with CRI who took allopurinol and carried out serologic human leukocyte antigen (HLA) typing for kidney transplantation between January 2003 and May 2010. RESULTS Among a total of 448 patients with CRI, 16 (3.6%) patients experienced allopurinol hypersensitivity. Nine of these patients (2.0%) were diagnosed with SCARs (two Stevens-Johnson syndrome and seven allopurinol hypersensitivity syndrome) and seven patients (1.6%) had simple maculopapular rashes. The HLA-B58 allele was present in all patients with allopurinol-induced SCARs, while the frequency of HLA-B58 was only 9.5% in allopurinol-tolerant patients (P < 0.05). The incidence of allopurinol-induced SCARs in CRI shows a wide disparity according to HLA-B58 [18% in HLA-B58 (+) versus 0% in HLA-B58 (-)]. Among patients without HLA-B58, most (98.2%) of the CRI patients were tolerant to allopurinol and only 1.8% experienced simple rashes after taking allopurinol. CONCLUSIONS In this study, the incidence of allopurinol-induced SCARs was considerably high in CRI patients with HLA-B58. This finding indicates that the presence of HLA-B58 may increase the risk of allopurinol-induced SCARs. Screening tests for HLA-B58 in CRI patients will be clinically helpful in preventing severe allopurinol hypersensitivity reactions.

Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to predict response

Background:  Recent findings have raised new interests about the use of anticholinergics, especially tiotropium, for the treatment of asthma. This study was performed to determine whether an additional improvement in lung function is obtained when tiotropium is administrated in addition to conventional therapies in severe asthmatics, and to identify factors capable of predicting the response to tiotropium, using a pharmacogenetic approach.

Allergen-specific conventional immunotherapy decreases immunoglobulin E-mediated basophil histamine releasability

Background Allergen‐specific immunotherapy has proven to be clinically effective in the treatment of patients with atopic asthma; however, the mechanisms are still unclear. Several noted immunological changes include an increase of the allergen‐specific IgG antibody, a reduction in the allergen‐specific IgE antibody subsequent to transient increase, an allergen‐specific T cell shift in cytokine production from Th2 to Th1, and a decrease in quantity and activity of basophils and mast cells.

Prevalence of childhood asthma based on questionnaires and methacholine bronchial provocation test in Korea

Background In most epidemiological survey studies, only subjective symptoms and past medical history of asthma have been used as diagnostic criteria. Even though a questionnaire survey can be performed in a large population study at low cost, limitations such as lack of objectivity and poor predictability in non‐specific bronchial hyperresponsiveness cannot be avoided.

Association between polymorphisms in prostanoid receptor genes and aspirin-intolerant asthma.

Background Genetic predisposition is linked to the pathogenesis of aspirin-intolerant asthma. Most candidate gene approaches have focused on leukotriene-related pathways, whereas there have been relatively few studies evaluating the effects of polymorphisms in prostanoid receptor genes on the development of aspirin-intolerant asthma. Therefore, we investigated the potential association between prostanoid receptor gene polymorphisms and the aspirin-intolerant asthma phenotype. Methods We screened for genetic variations in the prostanoid receptor genes PTGER1, PTGER2, PTGER3, PTGER4, PTGDR, PTGIR, PTGFR, and TBXA2R using direct sequencing, and selected 32 tagging single nucleotide polymorphisms among the 77 polymorphisms with frequencies >0.02 based on linkage disequilibrium for genotyping. We compared the genotype distributions and allele frequencies of three participant groups (108 patients with aspirin-intolerant asthma, 93 patients with aspirin-tolerant asthma, and 140 normal controls). Results Through association analyses studies of the 32 single nucleotide polymorphisms, the following single nucleotide polymorphisms were found to have significant associations with the aspirin-intolerant asthma phenotype: −616C>G (P=0.038) and −166G>A (P=0.023) in PTGER2; −1709T>A (P=0.043) in PTGER3; −1254A>G (P=0.018) in PTGER4; 1915T>C (P=0.015) in PTGIR; and −4684C>T (P=0.027), and 795T>C (P=0.032) in TBXA2R. In the haplotype analysis of each gene, the frequency of PTGIR ht3[G-G-C-C], which includes 1915T>C, differed significantly between the aspirin-intolerant asthma patients and aspirin-tolerant asthma patients (P=0.015). Conclusion These findings suggest that genetic polymorphisms in PTGER2, PTGER3, PTGER4, PTGIR, and TBXA2R play important roles in the pathogenesis of aspirin-intolerant asthma.