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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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... Lungs from such patients show widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries as was previously shown (35)(36)(37). ...
... This can be a limitation to the performance of autopsy examinations (44). HP studies among patients dying from COVID-19 were scarce during the first months of the pandemic given the worldwide paucity of available N95 respirators and other personnel protective equipment (36,45), but more autopsy studies have been performed over the last months (36,38). ...
... This can be a limitation to the performance of autopsy examinations (44). HP studies among patients dying from COVID-19 were scarce during the first months of the pandemic given the worldwide paucity of available N95 respirators and other personnel protective equipment (36,45), but more autopsy studies have been performed over the last months (36,38). ...
Article
Background and objective: A thorough understanding of the pathogenic mechanisms elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still requires further research. Until recently, only a restricted number of autopsies have been performed, therefore limiting the accurate knowledge of the lung injury associated with SARS-CoV-2. A multidisciplinary European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group of Forensic and Post-mortem Microbiology-ESGFOR team conducted a non-systematic narrative literature review among coronavirus 2019 disease (COVID-19) pneumonia cases assessing the histopathological (HP) effects of positive airways pressure. HP lung features were recorded and compared between mechanically ventilated (>24 hours) and control (ventilation <24 hours) patients. A logistic regression analysis was performed to identify associations between mechanical ventilation (MV) and HP findings. Methods: A PubMed and MEDLINE search was conducted in order to identify studies published between March 1st 2020 and June 30th 2021. Key content and findings: Seventy patients (median age: 69 years) from 24 studies were analysed, among whom 38 (54.2%) underwent MV longer than 24 hours. Overall, main HP features were: diffuse alveolar damage (DAD) in 53 (75.7%), fibrosis (interstitial/intra-alveolar) in 43 (61.4%), vascular damage-including thrombosis/emboli- in 41 (58.5%), and endotheliitis in only 8 (11.4%) patients. Association of DAD, fibrosis and vascular damage was detected in 30 (42.8%) patients. Multivariate analysis, adjusted by age and gender, identified MV >24 hours as an independent variable associated with DAD (OR =5.40, 95% CI: 1.48-19.62), fibrosis (OR =3.88, 95% CI: 1.25-12.08), vascular damage (OR =5.49, 95% CI: 1.78-16.95) and association of DAD plus fibrosis plus vascular damage (OR =6.99, 95% CI: 2.04-23.97). Conclusions: We identified that patients mechanically ventilated >24 hours had a significantly higher rate of pulmonary injury on histopathology independently of age and gender. Our findings emphasize the importance of maintaining a protective ventilator strategy when subjects with COVID-19 pneumonia undergo intubation.
... 50 Further, a clinical autopsy on 67 patients who died of COVID-19 revealed that the consistently detectable virus was rare in the brain and olfactory bulbs. 51 In another study, SARS-CoV-2 was significantly rare in the brain tissue compared to other organs, assuming the low expression level of ACE2 receptors in brain tissues. 52 Although an increased MRI signal to the olfactory cortex may imply that viral infection has occurred, 53 ...
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The coronavirus disease 2019 (COVID-19), induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a multi-organ and multi-system disease with high morbidity and mortality in severe cases due to respiratory failure and severe cardiovascular events. However, the various manifestations of neurological and psychiatric (N/P) systems of COVID-19 should not be neglected. Some clinical studies have reported a high risk of N/P disorders in COVID-19 and post-COVID-19 patients and that their outcomes were positively associated with the disease severity. These clinical manifestations could attribute to direct SARS-CoV-2 invasion into the central nervous system (CNS), which is often complicated by systemic hypoxia, the dysfunctional activity of the renin-angiotensin system and other relevant pathological changes. These changes may remain long term and may even lead to persistent post-COVID consequences on the CNS, such as memory, attention and focus issues, persistent headaches, lingering loss of smell and taste, enduring muscle aches and chronic fatigue. Mild confusion and coma are serious adverse outcomes of neuropatho-logical manifestations in COVID-19 patients, which could be diversiform and vary at different stages of the clinical course. Although lab investigations and neuro-imaging findings may help quantify the disease's risk, progress and prognosis, large-scale and persistent multicenter clinical cohort studies are needed to evaluate the impact of COVID-19 on the N/P systems. However, we used "Boolean Operators" to search for relevant research articles, reviews and clinical trials from PubMed and the ClinicalTrials dataset for " COVID-19 sequelae of N/P systems during post-COVID periods" with the time frame from December 2019 to April 2022, only found 42 in 254,716 COVID-19-related articles and 2 of 7931 clinical trials involved N/P sequelae during post-COVID periods. Due to the increasing number of infected cases and the incessant mutation characteristics of this virus, diagnostic and therapeutic guidelines for N/P manifestations should be further refined.
... Emerging reports from patients suffering from COVID-19 note the effect of the virus on multiple organs and associated vasculature, especially the vasculature around the brain [124]. Particularly concerning the central nervous system (CNS), stroke, delirium, lethal clot formation, and rare cases of encephalitis are reported. ...
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The recent pandemic, Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has devastated humanity and is continuing to threaten us. Due to the high transmissibility of this pathogen, researchers are still trying to cope with the treatment and prevention of this disease. Few of them were successful in finding cure for COVID-19 by including repurposed drugs in the treatment. In such pandemic situations, when it is nearly impossible to design and implement a new drug target, previously designed antiviral drugs could help against novel viruses, referred to as drug repurposing/redirecting/repositioning or re-profiling. This review describes the current landscape of the repurposing of antiviral drugs for COVID-19 and the impact of these drugs on our nervous system. In some cases, specific antiviral therapy has been notably associated with neurological toxicity, characterized by peripheral neuropathy, neurocognitive and neuropsychiatric effects within the central nervous system (CNS).
... 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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Objectives: Immunopathology of ongoing COVID-19 global pandemic is not limited solely to pulmonary tissue, but is often associated with multi-organ complications, mechanisms of which are intensely being investigated. In this regard, the interplay between immune, stromal cells and cytokines in pulmonary and extrapulmonary infected tissues, especially in young adults (median age 46 years, range 30-53 years) without comorbidities, remains poorly characterised. Methods: We profiled lung, heart and intestinal autopsy samples from five SARS-CoV-2-infected cases for 18-20 targets to detect immune, cytokine and stromal cell status at subcellular resolution by a novel IHC-based deep-phenotyping technique, iSPOT (immunoSpatial histoPhenOmics using TSA-IHC), to assess spatial and functional patterns of immune response in situ, in lethal COVID-19 infection. Results: SARS-CoV-2-infected autopsy samples exhibit skewed counts of immune populations in all samples with organ-specific dysfunctions. Lung and ileal tissue reveal altered architecture with marked loss of tissue integrity, while lung and heart tissue show severe hyperinflammation marked by elevated TNF-α in heart tissue and additionally IL-6, IFN-γ and IL-10 cytokines in lung samples. Conclusion: With resurgence of infection in younger populations, single-cell cytokine localisation in immune and stromal structures provides important mechanistic insights into organ-specific immunopathology of naïve SARS-CoV-2 infection in the absence of other comorbidities.
... 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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