Cutaneous and systemic hyperinflammation drives maculopapular drug exanthema in severely ill COVID‐19 patients. Issue 2 (19th July 2021) - Mitamura, Yasutaka
Abstract: Background: Coronavirus disease‐2019 (COVID‐19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions such as maculopapular drug rashes (MDR). The aim of this study was to investigate whether COVID‐19 may impact the development of the MDR. Methods: Blood and skin samples from COVID‐19 patients (based on a positive nasopharyngeal PCR) suffering from MDR (COVID‐MDR), healthy controls, non‐COVID‐19—related patients with drug rash with eosinophilia and systemic symptoms (DRESS), and MDR were analyzed. We utilized imaging mass cytometry (IMC) to characterize the cellular infiltrate in skin biopsies. Furthermore, RNA sequencing transcriptome of skin biopsy samples and high‐throughput multiplexed proteomic profiling of serum were performed. Results: IMC revealed by clustering analyses a more prominent, phenotypically shifted cytotoxic CD8 + T cell population and highly activated monocyte/macrophage (Mo/Mac) clusters in COVID‐MDR. The RNA sequencing transcriptome demonstrated a more robust cytotoxic response in COVID‐MDR skin. However, severe acute respiratory syndrome coronavirus 2 was not detected in skin biopsies at the time point of MDR diagnosis. Serum proteomic profiling of COVID‐MDR patients revealed upregulation of various inflammatory mediators (IL‐4, IL‐5, IL‐6, TNF, and IFN‐γ), eosinophil and Mo/Mac ‐attracting chemokines (MCP‐2, MCP‐3, MCP‐4 and CCL11). Proteomics analyses demonstrated a massive systemic cytokine storm in COVID‐MDR compared with the relatively milder cytokine storm observed in DRESS, while MDR did not exhibit such features. Conclusion: A systemic cytokine storm may promote activation of Mo/Mac and cytotoxic CD8 + T cells in severe COVID‐19 patients, which in turn may impact the development of MDR. Abstract : The combination of imaging mass cytometry, RNA sequencing, and serum proteomics reveals the characteristics in the cutaneous immune response of COVID‐19‐associated maculopapular drug rashes. COVID‐MDR is characterized by a more prominent infiltration of cytotoxic CD8+ T cells and highly activated monocyte/macrophage clusters. Serum proteomics (92 inflammatory biomarkers) reveals a massive cytokine storm in COVID‐MDR and relatively milder hyper‐inflammation in DRESS. Abbreviations: COVID‐19, coronavirus disease 19; DERSS, drug reaction with eosinophilia and systemic symptoms; MDR, maculopapular drug rashes