Cutaneous and systemic hyperinflammation drives maculopapular drug exanthema in severely ill COVID-19 patients.
Cutaneous and systemic hyperinflammation drives maculopapular drug exanthema in severely ill COVID-19 patients.
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DOI：
10.1111/all.14983
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发表时间：
2022-03
期刊：
影响因子：
12.4
通讯作者：
Brüggen MC
中科院分区：
文献类型：
--
作者：
Mitamura Y;Schulz D;Oro S;Li N;Kolm I;Lang C;Ziadlou R;Tan G;Bodenmiller B;Steiger P;Marzano A;de Prost N;Caudin O;Levesque M;Stoffel C;Schmid-Grendelmeier P;Maverakis E;Akdis CA;Brüggen MC
冠状病毒病- 2019 （COVID - 19）与皮肤表现有关，其中一些是药物超敏反应的结果，如黄斑丘疹（MDR）。本研究的目的是调查COVID - 19是否会影响耐多药的发展。对耐多药耐多药（COVID - MDR）的COVID - 19患者（基于鼻咽PCR阳性）、健康对照、非COVID - 19相关的伴有嗜酸性粒细胞增多和全身症状（DRESS）的药物皮疹患者和耐多药患者的血液和皮肤样本进行分析。我们利用成像细胞计数术（IMC）来表征皮肤活检中的细胞浸润。此外，对皮肤活检样本进行RNA测序转录组和血清的高通量多重蛋白质组分析。IMC通过聚类分析揭示了COVID - MDR中更突出的、表型转移的细胞毒性CD8+ T细胞群和高度激活的单核/巨噬细胞（Mo/Mac）集群。RNA测序转录组在COVID - MDR皮肤中显示出更强的细胞毒性反应。但在耐多药诊断时，皮肤活检未检出严重急性呼吸综合征冠状病毒2型。COVID - MDR患者的血清蛋白质组学分析显示，多种炎症介质（IL‐4、IL‐5、IL‐6、TNF和IFN‐γ）、嗜酸性粒细胞和Mo/Mac -吸引趋化因子（MCP‐2、MCP‐3、MCP‐4和CCL11）上调。蛋白质组学分析显示，与DRESS中观察到的相对温和的细胞因子风暴相比，COVID - MDR中存在大规模的系统性细胞因子风暴，而MDR没有表现出这些特征。在严重的COVID - 19患者中，系统性细胞因子风暴可能促进Mo/Mac和细胞毒性CD8+ T细胞的激活，这反过来可能影响耐多药的发展。影像细胞术、RNA测序和血清蛋白质组学的结合揭示了COVID - 19相关黄斑丘疹皮肤免疫反应的特征。COVID - MDR的特征是更突出的细胞毒性CD8+ T细胞浸润和高度活化的单核细胞/巨噬细胞集群。血清蛋白质组学（92种炎症生物标志物）显示，在COVID - MDR中存在大量的细胞因子风暴，而在DRESS中存在相对温和的高炎症。缩写：COVID - 19，冠状病毒病19；DERSS、药物反应伴嗜酸性粒细胞增多和全身症状；MDR，黄斑丘疹
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. 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. 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. 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. 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
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