Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases
Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases
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DOI：
10.1016/j.trsl.2020.04.007
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发表时间：
2020-06-01
影响因子：
7.8
通讯作者：
Laurence, Jeffrey
中科院分区：
文献类型：
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作者：
Magro, Cynthia;Mulvey, J. Justin;Laurence, Jeffrey
急性呼吸衰竭和全身性凝血病是严重急性呼吸窘迫综合征相关冠状病毒2（2019冠状病毒病（COVID-19）的病原体）感染的发病率和死亡率的关键方面。我们检查了5例严重COVID-19患者的皮肤和肺组织，其特征为呼吸衰竭（n= 5）和紫癜性皮疹（n = 3）。COVID-19肺炎主要是一种少炎性间隔毛细血管损伤，伴有显著的间隔毛细血管壁和管腔纤维蛋白沉积以及中性粒细胞对肺泡间隔的渗透。未观察到病毒性细胞病变，弥漫性肺泡损伤（DAD）伴透明膜、炎症和II型肺细胞增生（经典急性呼吸窘迫综合征的标志）并不突出。这些肺部发现伴随微血管中末端补体成分C5 b-9（膜攻击复合物）、C4d和甘露糖结合凝集素（MBL）相关丝氨酸蛋白酶（MASP）2的显著沉积，与补体途径的持续全身激活一致。紫癜性皮肤病变同样显示出少炎性血栓形成性血管病变，在严重受累和正常外观的皮肤中均有C5 b-9和C4d沉积。此外，在2例受检病例的肺泡间隔和皮肤微血管中存在COVID-19刺突糖蛋白与C4d和C5 b-9的共定位。总之，至少有一部分持续的严重COVID-19可能定义了一种由补体途径激活和相关促凝血状态介导的灾难性微血管损伤综合征。它为进一步探索补体在COVID-19中的病理生理重要性提供了基础，并可能为特定干预提供靶点。
Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3). COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention.