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.

Infection with the new pandemic pathogen Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) can cause a wide range of disease varying from mild cold-like symptoms to complicated pneumonia, severe inflammatory response, and death. 1 Although available data has been limited, recent case reports of concurrent infections with influenza virus, 2 human metapneumovirus (hMPV) 3 and seasonal coronaviruses such as CoV-HKU-1 4 in adults and children with SARS-CoV-2 infection have suggested that coinfection may influence morbidity and mortality. A recent study from Kim et al, 5 found that co-infections were frequent in their patient population in Northern California; more than 20% of 116 SARS-CoV-2 positive specimens also contained one or more additional respiratory pathogens, most often rhinovirus/enterovirus, respiratory syncytial virus, and non-SARS Coronaviridae.Conversely, 7.5% of their specimens positive for a non-SARS-CoV-2 respiratory pathogen were also positive for SARS-CoV-2. 5 In addition, a study from Wuhan examining 8274 patients with 2745 confirmed SARS-CoV-2 cases, revealed that 5.8% of SARS-CoV-2 infected and 18.4% of non-SARS-CoV-2-infected patients had co-infections. 6 To determine whether co-infections with other respiratory pathogens represent a significant subset of SARS-CoV-2 infections in our patient population, we reviewed results from our laboratory, which performs diagnostic testing for 8 inpatient and associated outpatient facilities in the greater New York City metropolitan area. tested 16,408 patients for SARS-CoV-2 by real-time reverse transcription polymerase chain reaction amplification (RT-PCR, cobas® 6800 system, RocheDiagnostics); of those, 2,049 were also tested with the multiplex FilmArray® Respiratory Panel (RPPCR2, BioMerieux) or Cepheid Xpert® Xpress Flu/RSV (Flu/RSV). Our findings are notable for high rates of SARS-CoV-2 positivity (54.8 %) during that time period, and very low rates of co-infection with other non-SARS-CoV-2 pathogens. Specific data for the detection of other respiratory pathogens in our SARS-CoV-2 positive patients is presented in Table I, and compared to findings for patients in whom SARS-CoV-2 was not detected.This article is protected by copyright. All rights reserved.otherwise modified disease course. However, our results are in keeping with a recent paper from Spain showing that hospitalized SARS-CoV-2 patients with pneumonia were infrequently co-infected with other respiratory viruses. 7

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 and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.

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The urgent need to implement and rapidly expand testing for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has led to the development of multiple assays. How these tests perform relative to one another is poorly understood. We evaluated the concordance between the Roche Diagnostics cobas 6800 SARS-CoV-2 test and a laboratory-developed test (LDT) real-time reverse transcription-polymerase chain reaction based on a modified Centers for Disease Control and Prevention protocol, for the detection of SARS-CoV-2 in samples submitted to the Clinical Laboratories of the Mount Sinai Health System. A total of 1006 nasopharyngeal swabs in universal transport medium from persons under investigation were tested for SARS-CoV-2 as part of routine clinical care using the cobas SARS-CoV-2 test with subsequent evaluation by the LDT. Cycle threshold values were analyzed and interpreted as either positive ("detected" or "presumptive positive"), negative (not detected), inconclusive, or invalid. Statistical analysis was performed using GraphPad Prism 8. The cobas SARS-CoV-2 test reported 706 positive and 300 negative results. The LDT reported 640 positive, 323 negative, 34 inconclusive, and 9 invalid results. When excluding inconclusive and invalid results, the overall percent agreement between the two platforms was 95.8%. Cohen's κ coefficient was 0.904 (95% confidence interval, 0.875-0.933), suggesting almost perfect agreement between both platforms. An overall discordance rate of 4.2% between the two systems may reflect differences in primer sequences, assay limit of detection, or other factors, highlighting the importance of comparing the performance of different testing platforms. K E Y W O R D S coronavirus, RNA extraction, SARS Elisabet Pujadas and Nnaemeka Ibeh contributed equally to this work.