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Cutaneous and systemic hyperinflammation drives maculopapular drug exanthema in severely ill COVID-19 patients


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 is associated with 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 up-regulation 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

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 is associated with 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 up-regulation 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Intensive Care Medicine
04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
07 Faculty of Science > Department of Quantitative Biomedicine
04 Faculty of Medicine > Swiss Institute of Allergy and Asthma Research
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Immunology and Allergy
Life Sciences > Immunology
Language:English
Date:1 February 2022
Deposited On:25 Jun 2021 09:45
Last Modified:01 Oct 2022 22:23
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0105-4538
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/all.14983
PubMed ID:34157151
  • Content: Published Version
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)