LTT and HLA testing as diagnostic tools in Spanish vancomycin-induced DRESS cases: A case-control study

Abstract

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe T-cell-mediated off-target adverse reaction. DRESS cases caused by vancomycin have often been reported. The HLA-A*32:01 allele has been associated with genetic susceptibility to vancomycin-induced DRESS in US citizens of European descent. We have analyzed the association of the HLA-A*32:01 allele in 14 Spanish DRESS cases in which vancomycin was suspected as the culprit drug, and the lymphocyte transformation test (LTT) as an in vitro assay to evaluate vancomycin sensitization. The results were compared to vancomycin-tolerant control donors. LTT was performed in 12 DRESS cases with PBMCs from resolution samples available and in a group of 12 tolerant donors. ROC curves determined that LTT is a suitable tool to identify patients sensitized to vancomycin (AUC = 0.9646; p < 0.0001). When a stimulation index >3 was regarded as a positive result, contingency tables determined 91% sensitivity, 91.67% specificity, 91% positive predictive value, and 91.67% negative predictive value (p = 0.0001, Fisher’s exact test). The HLA A*32:01 allele was determined by an allele-specific PCR assay in 14 cases and 25 tolerant controls. Among the DRESS cases, five carriers were identified (35.7%), while it was detected in only one (4%) of the tolerant donors, [odds ratio (OR) = 13.33; 95% CI: 1.364–130.3; p = 0.016]. The strength of the association increased when only cases with positive LTT to vancomycin were considered (OR = 24.0; 95% CI: 2.28–252.6; p = 4.0 × 10−3). Our results confirm the association of the risk allele HLA-A*32:01 with vancomycin-induced DRESS in Spanish cases, and support LTT as a reliable tool to determine vancomycin sensitization.

Tools for Etiologic Diagnosis of Drug-Induced Allergic Conditions

“…It has been calculated as 20% for HLA-A*32:01 in North American patients of European descent with vancomycin-induced DRESS [ 203 ]. However, considering the prevalence of the disease among European patients and the average carriage rate of HLA-A*32:01 at 5%, a lower PPV is likely more realistic [ 221 ] and consistent with the results recently reported in Spanish patients [ 164 ].…”

“…In this study, higher sensitivity (S) and specificity (Sp) values were found for determined groups such as anticonvulsants (S 100%, Sp 100%), anti-TB drugs (S 87.5%, Sp 100%), and beta-lactam antibiotics (S 73%, Sp 100%). A recent study determined 91% sensitivity, 91.67% specificity, 91% PPV, and 91.67% NPV for the LTT with vancomycin performed in 14 vancomycin-induced DRESS cases and 12 vancomycin-tolerant control donors [ 164 ].…”

Current understanding of genetic associations with delayed hypersensitivity reactions induced by antibiotics and anti-osteoporotic drugs

“…HLA-A*32:01 is associated with vancomycin-induced DRESS in European population ( Konvinse et al, 2019 ). Bellon et al (2022) also revealed the association between HLA-A*32:01 and vancomycin-induced DRESS in Spanish population. Recently, we reported the association between HLA-A*32:01, HLA-B*07:05, HLA-B:40:06, HLA-B*67:01 and vancomycin-induced DRESS in Taiwanese population ( Wang et al, 2022c ).…”

“…Moreover, HLA-B*13:01 testing is recommended for Chinese patients with leprosy before initiating dapsone therapy ( Liu et al, 2019 ). Owing to the relatively high frequency of HLA-A*32:01 in European population, genetic examination before vancomycin treatment can be effective to prevent vancomycin-induced DRESS ( Rwandamuriye et al, 2019 ; Bellon et al, 2022 ). Hama et al (2022) reported that the frequency of HLA-A*32:01 is 6.8% in European population and 20% of whom developed vancomycin-induced DRESS.…”

Severe Cutaneous Adverse Drug Reactions at a Tertiary Care Center in Saudi Arabia

“…A strong HLA − A ∗ 32 : 01 association was previously reported in patients with European background living in North America who developed vancomycin-induced DRESS [ 26 ]. In a Spanish study on 14 patients with DRESS, HLA − A ∗ 32 : 01 was found in 36% of cases [ 27 ]. Furthermore, the lymphocyte transformation test (LTT) showed high sensitivity and specificity in cases of vancomycin-induced DRESS.…”