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Pathophysiology of SARS-CoV-2: Targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience

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Abstract

BACKGROUND Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe, disproportionately affecting New York City. A comprehensive, integrative autopsy series that advances the mechanistic discussion surrounding this disease process is still lacking. METHODS Autopsies were performed at the Mount Sinai Hospital on 67 COVID-19 positive patients and data from the clinical records were obtained from the Mount Sinai Data Warehouse. The experimental design included a comprehensive microscopic examination carried out by a team of expert pathologists, along with transmission electron microscopy, immunohistochemistry, RNA in situ hybridization, as well as immunology and serology assays. RESULTS Laboratory results of our COVID-19 cohort show elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8 and TNFα. Autopsies revealed large pulmonary emboli in four cases. We report microthrombi in multiple organ systems including the brain, as well as conspicuous hemophagocytosis and a secondary hemophagocytic lymphohistiocytosis-like syndrome in many of our patients. We provide electron microscopic, immunofluorescent and immunohistochemical evidence of the presence of the virus and the ACE2 receptor in our samples. CONCLUSIONS We report a comprehensive autopsy series of 67 COVID-19 positive patients revealing that this disease, so far conceptualized as a primarily respiratory viral illness, also causes endothelial dysfunction, a hypercoagulable state, and an imbalance of both the innate and adaptive immune responses. Novel findings reported here include an endothelial phenotype of ACE2 in selected organs, which correlates with clotting abnormalities and thrombotic microangiopathy, addressing the prominent coagulopathy and neuropsychiatric symptoms. Another original observation is that of macrophage activation syndrome, with hemophagocytosis and a hemophagocytic lymphohistiocytosis-like disorder, underlying the microangiopathy and excessive cytokine release. We discuss the involvement of critical regulatory pathways.
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... Most histopathological analyses of SARS-CoV-2 cases in the literature are from aged cohorts (> 65 years) with comorbidities where single-to-few immune cell types have been profiled to describe clinical presentations. 14, 15 Rendeiro et al. 16 recently published an extensive in situ characterisation of SARS-CoV-2 pulmonary infection by imaging mass cytometry in an old age cohort (mean age of 62 years) with a partial overlapping panel of markers. We observe similar changes in tissue architecture with marked elevation in tissue cytokines indicating that, in lethal infection, SARS-CoV-2 pathology has a dominant effect on both age-related frailty and comorbid conditions. ...
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... Moreover, 60% of patients had evidence of a patchy epicardial mononuclear infiltrate with a predominance of CD4 T cells compared to CD8 T cells. Small vessel thrombi were observed in three cases, and one had hemophagocytosis within an area of epicardial inflammation [6]. ...
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... Lastly, microthrombosis is another well-known stimulus for vascular growth [37], accounting for both the increased capillary density and the impaired microcirculatory flow in our series. In this regard, post-mortem studies from COVID-19 patients revealed regular presence of widespread microthrombosis, capillary congestion, and areas of increased capillary density in different organ systems [38][39][40][41]. ...
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