Cutaneous and systemic hyperinflammation drives maculopapular drug exanthema in severely ill COVID-19 patients.
Yasutaka Mitamura, Daniel Schulz, Saskia Oro, Nick Li, Isabel Kolm, Claudia Lang, Reihane Ziadlou, Ge Tan, Bernd Bodenmiller, Peter Steiger, Angelo Marzano, Nicolas de Prost, Olivier Caudin, Mitchell Levesque, Corinne Stoffel, Peter Schmid-Grendelmeier, Emanual Maverakis, Cezmi A Akdis, Marie-Charlotte Brüggen
Author Information
Yasutaka Mitamura: Swiss Institute for Allergy Research (SIAF) Davos, Davos, Switzerland. ORCID
Daniel Schulz: Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Saskia Oro: Department of Dermatology, Henri Mondor Hospital, Paris, France.
Nick Li: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Isabel Kolm: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Claudia Lang: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Reihane Ziadlou: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Ge Tan: Swiss Institute for Allergy Research (SIAF) Davos, Davos, Switzerland. ORCID
Bernd Bodenmiller: Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Peter Steiger: Faculty of Medicine, University Zurich, Zurich, Switzerland.
Angelo Marzano: Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Nicolas de Prost: Department of Dermatology, Henri Mondor Hospital, Paris, France.
Olivier Caudin: Department of Dermatology, Henri Mondor Hospital, Paris, France.
Mitchell Levesque: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Corinne Stoffel: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
Peter Schmid-Grendelmeier: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. ORCID
Emanual Maverakis: Department of Dermatology, University of California, Davis, Sacramento, CA, USA.
Cezmi A Akdis: Swiss Institute for Allergy Research (SIAF) Davos, Davos, Switzerland. ORCID
Marie-Charlotte Brüggen: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. ORCID
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.
