ABSTRACT
Coronavirus disease 2019 (COVID-19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions Here, we utilize imaging mass cytometry (IMC) to characterize the cutaneous immune response in maculopapular drug rashes (MDR), including those associated with COVID-19 infection (COVID MDR). For comparison skin from healthy controls and patients with drug rash with eosinophilia and systemic symptoms (DRESS) was analyzed. Results demonstrated that COVID MDR are characterized by a more prominent infiltration of cytotoxic CD8+ T cells and highly activated, phenotypically shifted monocyte/macrophage (Mo/Mac) clusters in comparison to MDR and DRESS. RNA sequencing transcriptome of the affected skin also demonstrated a more robust cytotoxic response in lesional COVID MDR skin Serum proteomic profiling of COVID MDR patients revealed up-regulation of various inflammatory mediators (IL-4, IL-5, IL-8, IL-18, IL-6, TNF and IFN-γ), eosinophil and Mo/Mac -attracting chemokines MCP-2, MCP- 3, MCP-4 and CCL11. Analyses of cytokine networks demonstrated a relatively milder cytokine storm in DRESS compared to COVID MDR while MDR did not exhibit such features. Our results suggest that a massive systemic cytokine storm promotes activation of Mo/Mac and cytotoxic CD8+ T cells, which impacts MDR development in severely ill COVID-19 patients.