Undressing drug reactions, one cell at a time

Allergic reactions to medications are an important issue in clinical practice; these can range from minor transient rashes to life-threatening symptoms. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) represent severe drug reactions that require immediate systemic treatment. However, the pathophysiology of DiHS/DRESS is not well understood, and treatment is aimed at alleviating clinical symptoms, usually through systemic immunosuppression. Treatment of DiHS/DRESS can be a challenge when it is not responsive to these immunosuppressive agents.

Kim et al. describe such a treatment-refractory case of DiHS/DRESS induced by the antibiotics sulfamethoxazole and trimethoprim, in which a single-cell transcriptomic profiling approach led to clinical resolution. After unsuccessful treatment with prednisone, cyclosporine, and mycophenolate, the authors obtained a skin biopsy from the patient and performed single-cell RNA sequencing (scRNA-seq) on the resulting individual cells. They found enrichment of the interleukin-2 receptor gamma, Janus kinase 3 (JAK3), and signal transducer and activator of transcription (STAT1) pathways among lymphocyte clusters in the affected skin tissues; these pathways were similarly up-regulated among peripheral circulating T lymphocytes. Additionally, human herpesvirus 6b signatures were up-regulated in select circulating CD4⁺ T cells. These data suggested several possible pharmacological interventions, and the authors ultimately decided to use tofacitinib (a JAK1/JAK3 inhibitor) along with valganciclovir (an antiviral drug), which led to resolution of skin inflammation.

This work highlights the potential for using advanced single-cell sequencing approaches to better understand the diversity of pathways involved in a specific patient’s disease process and to identify new treatment approaches with available therapeutics. The findings that JAK-STAT inhibition and antiviral treatments might be beneficial in DiHS/DRESS will need to be confirmed in larger cohorts. Although such individualized single-cell analyses as described here are currently resource-intensive and not optimized for widespread clinical use, advances in both sequencing and computational technologies will likely make such analyses clinically feasible and cost-effective in the near future.

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