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Risk factors of allopurinol-induced severe cutaneous adverse reactions in a Thai population

Saksit N, Tassaneeyakul W, Nakkam N, Konyoung P, Khunarkornsiri U, Chumworathayi P, et al.

Pharmacogenet Genomics, 2017 07;27(7):255-263.
PMID: 28509689 DOI: 10.1097/FPC.0000000000000285

BACKGROUND: Allopurinol is one of the most common causes of severe cutaneous adverse drug reactions (SCARs) including drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). This study identified the risk factors associated with the development of allopurinol-induced SCARs in a Thai population.
PATIENTS AND METHODS: Eighty-six allopurinol-induced SCARs (i.e. 19 DRESS and 67 SJS/TEN) and 182 allopurinol-tolerant patients were enrolled in the study. The HLA-B*58:01 allele was determined. Clinical and medicinal data were collected.
RESULTS: Results from multivariate analysis showed that only the HLA-B*58:01 and female sex were identified as risk factors of allopurinol-induced SCARs in this Thai population. Patients who carried the HLA-B*58:01 allele were at a higher risk of allopurinol-induced DRESS [odds ratio (OR)=149.2, 95% confidence interval (CI)=24.0-∞, P<1.00×10]. Similar results were observed in allopurinol-induced SJS/TEN (OR=175.0, 95% CI=44.3-690.9, P=1.69×10). The risk of allopurinol-induced SCARs in women was higher than that in men (OR=4.6, 95% CI=1.4-15.6, P=1.44×10). The overall mortality rate of allopurinol-induced SCARs was 11.39% and a higher mortality rate was observed in elderly women.
CONCLUSION: Among the risk factors identified, the HLA-B*58:01 allele had the greatest impact on the development of both phenotypes of allopurinol-induced SCARs in this studied Thai population. In case HLA-B*58:01 genotyping cannot be accessed, close monitoring of allopurinol usage, especially in elderly women with impaired renal function, is necessary to reduce the mortality rate of these life-threatening SCARs.
Fulltext Diagnostic procedures & practices in drug allergy/hypersensitivity: a survey of 13 Asian countries

Tang MM, Fok JS, Thong BY, Yun J, Li PH, Kang HR, et al.

Asia Pac Allergy, 2020 Oct;10(4):e36.
PMID: 33178561 DOI: 10.5415/apallergy.2020.10.e36

Background: The issues and challenges in the diagnosis of drug allergy/hypersensitivity among children and adults in Asia are likely to be different from non-Asian countries.
Objective: To study the diagnostic modalities used in the evaluation and management of drug allergy/drug hypersensitivity reactions (DHRs) among member societies of the Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI).
Methods: A questionnaire comprising 41 questions was circulated electronically to member societies and individual members of APAAACI between January 23, 2020 and March 6, 2020.
Results: Twenty-six respondents from 15 member societies and 1 individual member responded. European DHR guidelines were most commonly used. Skin prick and intradermal testing was used by 100%, with only 60% having access to commercial penicillin skin test reagents. In vitro-speciﬁc IgE tests were used by 75%, and basophil activation test by 56.3% for immediate DHR. Patch tests were used by 75% in contrast to lymphocyte transformation tests by 25% for nonimmediate DHR. Drug provocation tests were used by 68.8%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (93.3%). Human leukocyte antigen (HLA) genotype testing was mandatory among 25% respondents before new carbamazepine prescriptions, and 8.3% for allopurinol prescriptions.
Conclusions: There was increased use of skin testing for iodinated contrast media hypersensitivity and patch testing for nonimmediate DHR. HLA genotype testing prior to new carbamazepine, allopurinol and abacavir prescriptions remain variable despite strong associations for severe cutaneous adverse reactions with Asian ethnicity. Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across APAAACI member societies.
Drug hypersensitivity reactions in Asia: regional issues and challenges

Thong BY, Lucas M, Kang HR, Chang YS, Li PH, Tang MM, et al.

Asia Pac Allergy, 2020 Jan;10(1):e8.
PMID: 32099830 DOI: 10.5415/apallergy.2020.10.e8

There are geographical, regional, and ethnic differences in the phenotypes and endotypes of patients with drug hypersensitivity reactions (DHRs) in different parts of the world. In Asia, aspects of drug hypersensitivity of regional importance include IgE-mediated allergies and T-cell-mediated reactions, including severe cutaneous adverse reactions (SCARs), to beta-lactam antibiotics, antituberculous drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) and radiocontrast agents. Delabeling of low-risk penicillin allergy using direct oral provocation tests without skin tests have been found to be useful where the drug plausibility of the index reaction is low. Genetic risk associations of relevance to Asia include human leucocyte antigen (HLA)-B*1502 with carbamazepine SCAR, and HLA-B*5801 with allopurinol SCAR in some Asian ethnic groups. There remains a lack of safe and accurate diagnostic tests for antituberculous drug allergy, other than relatively high-risk desensitization regimes to first-line antituberculous therapy. NSAID hypersensitivity is common among both adults and children in Asia, with regional differences in phenotype especially among adults. Low dose aspirin desensitization is an important therapeutic modality in individuals with cross-reactive NSAID hypersensitivity and coronary artery disease following percutaneous coronary intervention. Skin testing allows patients with radiocontrast media hypersensitivity to confirm the suspected agent and test for alternatives, especially when contrasted scans are needed for future monitoring of disease relapse or progression, especially cancers.
Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians

Wang CW, Tassaneeyakul W, Chen CB, Chen WT, Teng YC, Huang CY, et al.

J Allergy Clin Immunol, 2021 04;147(4):1402-1412.
PMID: 32791162 DOI: 10.1016/j.jaci.2020.08.003

BACKGROUND: Co-trimoxazole, a sulfonamide antibiotic, is used to treat a variety of infections worldwide, and it remains a common first-line medicine for prophylaxis against Pneumocystis jiroveci pneumonia. However, it can cause severe cutaneous adverse reaction (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. The pathomechanism of co-trimoxazole-induced SCAR remains unclear.
OBJECTIVE: We aimed to investigate the genetic predisposition of co-trimoxazole-induced SCAR.
METHODS: We conducted a multicountry case-control association study that included 151 patients with of co-trimoxazole-induced SCAR and 4631 population controls from Taiwan, Thailand, and Malaysia, as well as 138 tolerant controls from Taiwan. Whole-genome sequencing was performed for the patients and population controls from Taiwan; it further validated the results from Thailand and Malaysia.
RESULTS: The whole-genome sequencing study (43 case patients vs 507 controls) discovered that the single-nucleotide polymorphism rs41554616, which is located between the HLA-B and MICA loci, had the strongest association with co-trimoxazole-induced SCAR (P = 8.2 × 10-9; odds ratio [OR] = 7.7). There were weak associations of variants in co-trimoxazole-related metabolizing enzymes (CYP2D6, GSTP1, GCLC, N-acetyltransferase [NAT2], and CYP2C8). A replication study using HLA genotyping revealed that HLA-B∗13:01 was strongly associated with co-trimoxazole-induced SCAR (the combined sample comprised 91 case patients vs 2545 controls [P = 7.2 × 10-21; OR = 8.7]). A strong HLA association was also observed in the case patients from Thailand (P = 3.2 × 10-5; OR = 3.6) and Malaysia (P = .002; OR = 12.8), respectively. A meta-analysis and phenotype stratification study further indicated a strong association between HLA-B∗13:01 and co-trimoxazole-induced drug reaction with eosinophilia and systemic symptoms (P = 4.2 × 10-23; OR = 40.1).
CONCLUSION: This study identified HLA-B∗13:01 as an important genetic factor associated with co-trimoxazole-induced SCAR in Asians.