Severe COVID-19: A multifaceted viral vasculopathy syndrome

Cynthia M. Magro, Justin Mulvey, Jeffrey Kubiak, Sheridan Mikhail, David Suster, A. Neil Crowson, Jeffrey Laurence, Gerard Nuovo

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


The objective of this study was to elucidate the pathophysiology that underlies severe COVID-19 by assessing the histopathology and the in situ detection of infectious SARS-CoV-2 and viral capsid proteins along with the cellular target(s) and host response from twelve autopsies. There were three key findings: 1) high copy infectious virus was limited mostly to the alveolar macrophages and endothelial cells of the septal capillaries; 2) viral spike protein without viral RNA localized to ACE2+ endothelial cells in microvessels that were most abundant in the subcutaneous fat and brain; 3) although both infectious virus and docked viral spike protein was associated with complement activation, only the endocytosed pseudovirions induced a marked up-regulation of the key COVID-19 associated proteins IL6, TNF alpha, IL1 beta, p38, IL8, and caspase 3. Importantly, this microvasculitis was associated with characteristic findings on hematoxylin and eosin examination that included endothelial degeneration and resultant basement membrane zone disruption and reduplication. It is concluded that serious COVID-19 infection has two distinct mechanisms: 1) a microangiopathy of pulmonary capillaries associated with a high infectious viral load where endothelial cell death releases pseudovirions into the circulation, and 2) the pseudovirions dock on ACE2+ endothelial cells most prevalent in the skin/subcutaneous fat and brain that activates the complement pathway/coagulation cascade resulting in a systemic procoagulant state as well as the expression of cytokines that produce the cytokine storm. The data predicts a favorable response to therapies based on either removal of circulating viral proteins and/or blunting of the endothelial-induced response.

Original languageEnglish (US)
Article number151645
JournalAnnals of Diagnostic Pathology
StatePublished - Feb 2021
Externally publishedYes


  • COVID-19
  • Complement
  • Endothelialitis
  • In situ
  • Spike protein

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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