Utility of Patch Testing, LTT, and HLA Genotyping in Identifying Culprit Drugs and Diagnosing Multiple Drug Hypersensitivity in Definite DRESS: A 10-Year Cohort Study.

Abstract

Background/aim: We evaluated the role of lymphocyte transformation test (LTT), patch testing (PT), and human leukocyte antigen (HLA) genotyping in identifying culprit drugs in Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and assessed long-term outcomes.

Methods: DRESS was diagnosed using Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) criteria; only definite cases (score > 5) were included. Severe DRESS was defined as ≥ 1 major organ involvement with clinical and laboratory abnormalities, and RegiSCAR scores supported severity assessment. Patients were grouped by single- or multiple drug exposure. Drug causality was assessed using the WHO-UMC criteria. LTT, PT, and/or HLA genotyping were performed for "possible" culprit drugs. Multiple drug hypersensitivity syndrome (MDHS) was defined as hypersensitivity to ≥ 2 unrelated drugs confirmed by testing. Hypersensitivity to a single drug was classified as single-drug hypersensitivity (SDH). Long-term follow-up assessed autoimmune diseases and neo-sensitization to unrelated drugs.

Results: Fifty patients with definite DRESS (median age 49 years; 50% were female) were included, and six (12%) had severe disease. Compared with non-severe cases (mild/moderate), severe cases had higher median RegiSCAR scores (8 [7-8] vs. 6 [6-7]; p = 0.012) and more frequent facial edema (p < 0.001) and lymphadenopathy (p = 0.029). MDHS was more common in severe cases (83% vs. 11%; p = 0.001), and HLA risk alleles were more prevalent (p = 0.016), including HLA-B*58:01, HLA-A*31:01, and HLA-B*13:02, associated with allopurinol, carbamazepine, and levofloxacin-induced DRESS, respectively. Among 20 patients with multiple drug exposures, 10 were diagnosed with MDHS: 5 simultaneous, 2 sequential, and 4 long-interval; one patient exhibited both simultaneous and long-interval reactions. Compared with SDH, MDHS patients had higher median RegiSCAR scores (7 [6-8] vs. 6 [6-8]; p < 0.001) and a higher prevalence of HLA risk alleles (p = 0.038), including HLA-B*58:01 (allopurinol), HLA-A*31:01 (carbamazepine), HLA-B*13:02 (levofloxacin) and HLA-A*24:02 (lamotrigine). Long-term complications occurred in eight patients: four developed autoimmune diseases, and four had neo-sensitization leading to subsequent DRESS, considered long-interval MDHS.

Conclusion: PT and LTT effectively identified culprit drugs in DRESS, particularly in multiple drug exposure. MDHS was more frequent in severe DRESS and associated with a higher prevalence of drug-related HLA risk alleles; however, no single HLA marker defined MDHS. Long-term follow-up was essential to detect autoimmune sequelae and neo-sensitization, and to guide safe drug evaluation and reintroduction.