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 (preprint)

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 TNF. 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.

Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region (preprint)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The percentage of infected individuals who seroconvert is still an open question. In addition, it has been shown in some individuals that viral genome can still be detected at considerable time post symptom resolution. Here we investigated both seroconversion and PCR-positivity in a large cohort of convalescent serum donors in New York City. Methods: Individuals with confirmed or suspected SARS-CoV-2 infection were screened via PCR for presence of viral genome and via enzyme-linked immunosorbent assay for presence of anti SARS-CoV-2 spike antibodies. Results: All but three confirmed SARS-CoV-2 patients seroconverted to the SARS-CoV-2 spike while only 37.4% of suspected SARS-CoV-2 patients seroconverted. PCR-positivity was detected up to 28 days from symptom resolution. Conclusions: Here we show that the vast majority of confirmed COVID19 patients seroconvert, potentially providing immunity to reinfection. We also report that in a large proportion of individuals, viral genome can be detected via PCR in the upper respiratory tract for weeks post symptom resolution, but it is unclear if this signal represents infectious virus.

Introductions and early spread of SARS-CoV-2 in the New York City area (preprint)

New York City (NYC) has emerged as one of the epicenters of the current SARS-CoV2 pandemic. To identify the early events underlying the rapid spread of the virus in the NYC metropolitan area, we sequenced the virus causing COVID19 in patients seeking care at the Mount Sinai Health System. Phylogenetic analysis of 84 distinct SARS-CoV2 genomes indicates multiple, independent but isolated introductions mainly from Europe and other parts of the United States. Moreover, we find evidence for community transmission of SARS-CoV2 as suggested by clusters of related viruses found in patients living in different neighborhoods of the city.