Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption

BACKGROUND: Lymphocyte transformation test (LTT) is a safety and reproducible test to assess activation of drug-specific T cells in vitro; however, there are several practical concerns such as the time of testing and the influence of treatment. Our aim was to define the right timing to perform LTT for determining the causative agent in various types of drug reactions. METHODS: Lymphocyte transformation test was performed at different time points during the evolution of three types of drug reactions, maculo-papular type of drug eruptions (MP), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug-induced hypersensitivity syndrome/drug rash and eosinophilia with systemic symptoms (DIHS/DRESS). RESULTS: Positive LTT reactions were obtained when the test was performed at the acute stage but not the recovery stage in MP and SJS/TEN, while positive LTT reactions were obtained at the recovery stage but not the acute stage in DIHS/DRESS, regardless of treatment with systemic prednisolone. CONCLUSIONS: Lymphocyte transformation test is a reliable method to define the causative agent, when LTT is performed at the right timing depending on the type of drug reactions. Lymphocyte transformation test should be performed within 1 week after the onset of skin rashes in patients with MP and SJS/TEN; and 5-8 weeks after in patients with DIHS/DRESS, respectively.     

The thymus and activation-regulated chemokine (TARC) level in serum at an early stage of a drug eruption is a prognostic biomarker of severity of systemic inflammation

Background

In severe drug eruptions, precise evaluation of disease severity at an early stage is needed to start appropriate treatment. It is not always easy to diagnose these conditions at their early stage. In addition, there are no reported prognostic biomarkers of disease severity in drug eruptions. The aim of this study was to test whether the thymus and activation-regulated chemokine (TARC) level in serum at an early stage of a drug eruption can serve as a prognostic biomarker of systemic inflammation.

An infant with γ-globulin-induced hypersensitivity syndrome who developed Evans' syndrome after a second γ-globulin treatment

One month after treatment with γ-globulin for Kawasaki disease, an 18-month-old girl developed Evans' syndrome in addition to drug-induced hypersensitivity syndrome (DIHS) after a second γ-globulin treatment. She suffered from hyperbilirubinemia, hemolytic anemia, and thrombocytopenia. The findings and her clinical course involved plasma exchange and treatment with prednisolone, with good results. Peripheral lymphocyte stimulation tests indicated that γ-globulin was the likeliest cause of the DIHS. A real-time polymerase chain reaction test showed the human herpes virus (HHV)-6 genome in peripheral blood. We demonstrated that a primary infection or infection reactivation by the HHV-6 virus was involved in the development of γ-globulin-induced hypersensitivity and Evans' syndrome.     

药物超敏反应综合征一例

患者女,35岁,农民,因全身皮肤瘙痒10余天、红斑丘疹5天入院。1月前曾因“溃疡性结肠炎”口服“柳氮磺胺吡啶”等治疗。用药20余天后出现全身皮肤瘙痒,5天后瘙痒加重,并逐渐出现颜面部、躯干、四肢近端红斑丘疹,伴有腹痛、腹泻,鼻涕样粘液便5-10次/日,便后腹泻稍缓解,有恶心感,呕出非咖啡样胃内容物一次。既往体健,无重大疾病及药物食物过敏史。     

药物超敏反应综合征并人类免疫缺陷病毒感染1例及文献复习

目的 提高临床医师对药物超敏反应综合征和人类免疫缺陷病毒（HIV）感染者/艾滋病病人药疹的认识,减少误诊。方法回顾性分析2021年11月于兰州大学第二医院住院的1例药物超敏反应综合征伴HIV感染者的临床资料,并行文献复习。结果 病人因“全身出红斑伴痒20 d”入院,入院前有复杂的用药史,入院后反复发热,查体面部水肿、淋巴结肿大、脾大,辅助检查提示嗜酸性粒细胞明显升高、HIV抗体筛查阳性,明确诊断为药物超敏反应综合征,予以糖皮质激素联合人免疫球蛋白为主的治疗,病情缓解。结论 药物超敏反应综合征是一种病毒激活相关的重症药疹,典型特征为发热、皮疹、面部水肿、嗜酸性粒细胞升高、淋巴结肿大、肝酶异常和病情反复,系统使用糖皮质激素联合人免疫球蛋白治疗有效。HIV感染可参与该病的发生发展。     

DRESS syndrome

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, initially recognized as a serious form of cutaneous drug adverse reaction, is now viewed as a drug-related syndrome that can cause life-threatening organ dysfunctions. Characteristic features include a long time interval from first drug exposure to symptom onset and a prolonged course, often with flares, even after discontinuation of the causal drug. The pathophysiology of DRESS syndrome remains incompletely understood but involves reactivation of herpes viruses (HHV-6, HHV-7, EBV, and CMV), against which the body mounts a strong immune response. The culprit drugs may not only affect epigenetic control mechanisms, thereby promoting viral reactivation, but also induce an antiviral T-cell response by interacting with the major histocompatibility complex receptor in individuals with genetic susceptibility factors. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a potentially life-threatening form of cutaneous drug adverse reaction. The severity of this syndrome is related to the systemic manifestations, which can result in multiorgan failure. DRESS syndrome is characterized by highly specific features, most notably regarding the timing of the manifestations. New insights into the underlying pathophysiological mechanisms indicate a role for immunogenetic susceptibility factors and for reactivation of human herpes viruses (HHVs), chiefly HHV-6. We report a typical case of DRESS syndrome and discuss recent data about this condition.     

Genotype–phenotype association between HLA and carbamazepine-induced hypersensitivity reactions: Strength and clinical correlations

BackgroundIncreasing studies reported genetic susceptibility to drug hypersensitivity reactions, as exemplified by the HLA-A*31:01 and HLA-B*15:02 association with carbamazepine (CBZ)-induced hypersensitivity reactions, such as maculopapular exanthema (MPE), drug rash with eosinophilia and systemic symptoms (DRESS), and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).ObjectiveTo carry out a comprehensive analysis on the clinical spectrum and HLA genotype–phenotype correlations in CBZ-induced hypersensitivity reactions.MethodsWe analyzed the clinical information of 194 patients with CBZ hypersensitivity (51 MPE, 23 DRESS, 112 SJS/TEN, and 8 cases with other phenotypes), and 152 CBZ-tolerant controls. All are Han Chinese. We examined the HLA-A/HLA-B genotypes, gene dosage, and drug dosage effects.ResultsCBZ-SJS/TEN showed the strongest association with the HLA-B*15:02 allele (Pc = 5.8 × 10⁻⁴³; odds ratio (OR) (95% CI) = 97.6(42.0–226.8)), in which HLA-B*15:02 was identified in all patients (25/25) with SJS/TEN with >5% body surface area (BSA) skin detachment, but lost its 100% association (85.1%, 74/87) in SJS with <5% BSA detachment. In contrast, HLA-B*40:01 showed negative association with CBZ-induced SJS/TEN ((Pc = 8.3 × 10⁻⁵; OR (95% CI) = 0.22(0.1–0.4)). By comparison, CBZ-induced MPE/DRESS had no association with HLA-B*15:02, but linked to HLA-A*31:01 (Pc = 2.7 × 10⁻³; OR (95% CI) = 6.86(2.4–19.9), and HLA-B*51:01 (Pc = 0.01; OR (95% CI) = 4.56(2.0–10.5)). No gene dosage or CBZ dosage effects was observed.ConclusionThis study reported the different strength of HLA association with CBZ hypersensitivity in Han Chinese. With the increasing application of pharmacogenetic markers, the HLA genotype–phenotype correlations and the results of the test need to be carefully interpreted for CBZ-induced hypersensitivity reactions.