Potential Biomarker Identification by RNA-Seq Analysis in Antibiotic-Related Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A Pilot Study.

One of the most severe forms of cutaneous adverse drug reactions is "drug reaction with eosinophilia and systemic symptoms" (DRESS), hence subsequent avoidance of the causal drug is imperative. However, attribution of drug culpability in DRESS is challenging and standard skin allergy tests are not recommended due to patient safety reasons. Whilst incidence of DRESS is relatively low, between 1:1000 and 1:10 000 drug exposures, antibiotics are a commoner cause of DRESS and absence of confirmatory diagnostic test can result in unnecessary avoidance of efficacious treatment. We therefore sought to identify potential biomarkers for development of a diagnostic test in antibiotic-associated DRESS. Peripheral blood mononuclear cells from a "discovery" cohort (n = 5) challenged to causative antibiotic or control were analyzed for transcriptomic profile. A panel of genes was then tested in a validation cohort (n = 6) and compared with tolerant controls and other inflammatory conditions which can clinically mimic DRESS. A scoring system to identify presence of drug hypersensitivity was developed based on gene expression alterations of this panel. The DRESS transcriptomic panel identified antibiotic-DRESS cases in a validation cohort but was not altered in other inflammatory conditions. Machine learning or differential expression selection of a biomarker panel consisting of 6 genes (STAC, GPR183, CD40, CISH, CD4, and CCL8) showed high sensitivity and specificity (100% and 85.7%-100%, respectively) for identification of the culprit drug in these cohorts of antibiotic-associated DRESS. Further work is required to determine whether the same panel can be repeated for larger cohorts, different medications, and other T-cell-mediated drug hypersensitivity reactions.

In vitro rapid diagnostic tests for severe drug hypersensitivity reactions in children.

BACKGROUND: Previous reports have demonstrated the utility of T-cell proliferation and cytokine release assays as in vitro diagnostic tests for drug causation in drug hypersensitivity reactions (DHR). However, data from pediatric populations are scarce compared with data in adults. OBJECTIVE: To compare the lymphocyte proliferation assay (LPA) with combination cytokine assays in the pediatric population and to identify its potential use in the acute and postrecovery phases. METHODS: A total of 18 in vitro tests were undertaken ex vivo to compare drug-specific proliferation and cytokine release (interferon-γ [IFN-γ] and interleukin-4 [IL-4]). The study included 16 patients with DHR: 7 children tested in the acute phase, 7 tested after recovery, and 2 tested during both the acute and postrecovery phases. RESULTS: The sensitivity of the LPA was better during the acute stage of DHR in children. Cytokine assays revealed a higher frequency of positive drug-specific responses compared with LPA in both the acute (LPA, 77.8%; IFN-γ, 88.9%; IL-4, 100%) and postrecovery phases (LPA, 33.3%; IFN-γ, 66.7%; IL-4, 66.7%). Combination cytokine assays (IFN-γ and IL-4) produced higher positive drug-specific responses in identifying culprit drugs compared with LPA in both the acute and postrecovery phases. CONCLUSION: In vitro drug-induced T-cell proliferation and cytokine release assays are useful for identification of the causative drug in children with DHR. Cytokine assays (IFN-γ and IL-4) were better than LPA, but when combined, they offer even greater utility in the diagnosis of acute and postrecovery DHR. Cytokine detection is rapid and does not involve radioactivity. These novel in vitro assays may offer a significant advancement in our future management of DHR in children.

Skin cancer excision performance in Scottish primary and secondary care: a retrospective analysis.

BACKGROUND: In contrast with most published evidence, studies from north-east Scotland suggest that GPs may be as good at treating skin cancers in primary care as secondary care specialists. AIM: To compare the quality of skin cancer excisions of GPs and secondary care skin specialists in east and south-east Scotland. DESIGN AND SETTING: A retrospective analysis of reports from GPs in Lothian, Fife, and Tayside regions. METHOD: Skin cancer histopathology reports from GPs in Lothian, Fife, and Tayside regions in 2010 were compared with reports from skin specialists in November 2010. The histopathology reports were rated for completeness and adequacy of excision. RESULTS: A total of 944 histopathology reports were analysed. In 1 year, GPs biopsied or excised 380 skin cancers. In 1 month, dermatologists biopsied or excised 385 skin cancers, and plastic surgeons 179 skin cancers. 'High risk' basal cell carcinomas (BCC) comprised 63.0% of BCC excised by GPs. For all skin cancer types, GPs excised smaller lesions, and had a lower rate of complete excisions compared with skin specialists. A statistical difference was demonstrated for BCC excisions only. CONCLUSION: GPs in east and south-east Scotland excise a number of skin cancers including malignant melanoma (MM), squamous cell carcinoma (SCC) and high-risk BCC. Despite removing smaller lesions, less commonly on difficult surgical sites of the head and neck, GP excision rates are lower for all skin cancers, and statistically inferior for BCC, compared with secondary care, supporting the development of guidelines in Scotland similar to those in other UK regions. Poorer GP excision rates may have serious consequences for patients with high-risk lesions.