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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
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.
... Se reconoce un patrón de daño hepático predominantemente colestásico, dado por elevación de bilirrubinas y fosfatasa alcalina (4) . Esta nueva entidad clínica, denominada colangiopatía por COVID-19 (4,5) , es más frecuente en pacientes críticos (6,7) , y se caracteriza por una lesión grave del tracto biliar. Se proponen diversos mecanismos fisio-ratorio agudo grave de tipo 2 (SARS-CoV-2), confirmada por resultados de laboratorio positivos (reacción en cadena de la polimerasa [PCR] positiva o antígeno positivo) y que fueron evaluados en la consulta ambulatoria del servicio de gastroenterología y hepatología. ...
... patológicos como microtrombosis a nivel de los ductos biliares, colangitis esclerosante del paciente críticamente enfermo y lesión directa causada por el virus. La frecuencia de esta entidad parece ser más alta en pacientes que presentan casos graves de COVID-19 (6,7) . ...
Introduction:
Post-COVID-19 cholangiopathy is a novel condition characterized by biliary tract sclerosis and elevated alkaline phosphatase levels in critically ill patients. This case series aims to describe the experience of a Latin American reference hospital in managing this condition.
Methods:
This case series includes patients with confirmed coronavirus disease 2019 (COVID-19) who exhibited subsequent elevation of alkaline phosphatase levels exceeding three times the normal value. The patients also had documented bile duct abnormalities observed through cholangioresonance or endoscopic retrograde cholangiopancreatography (ERCP). The clinical presentation, imaging findings, complications, and treatment approaches are described.
Results:
Eight patients (56.5 ± 9.2 years old, 62.5% male) were included in the study. All patients had previously experienced severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pneumonia and required mechanical ventilation. Four patients (50%) received sedoanalgesia with ketamine, and all eight patients (100%) received propofol. All patients developed infections, such as cholangitis or liver abscesses, caused by gram-negative bacteria. The peak alkaline phosphatase level during follow-up averaged 1646.12 ± 611.3. Imaging findings revealed intrahepatic (100%) and extrahepatic (87.5%) bile duct dilation. In 75% of cases, bile molds with a black appearance were extracted. Seven patients experienced recurrent cholangitis, and three patients were referred for pre-liver transplant consultation.
Conclusions:
Post-COVID-19 cholangiopathy is characterized by severe cholestasis, intra- and extrahepatic bile duct dilation, formation of bile molds, and recurrent cholangitis. In our study, a possible association between sepsis caused by gram-negative bacteria and the use of sedative medications is hypothesized. Further studies are necessary to establish the most appropriate management strategies for these patients, as they currently face unfavorable long-term morbidity and mortality outcomes.
... Arterial blockage and venous thromboembolism are caused by COVID-19-associated hypercoagulability [20]. SARS-CoV-2 infection has been linked to various neurological events, including hemorrhagic lesions in the central nervous system. ...
Brain arteriovenous malformations (AVMs) are usually asymptomatic. They can cause intense pain or bleeding or lead to other serious medical problems. We present a rare case of a woman who presented with a severe headache and was brought to the emergency service for an intracerebral hemorrhage due to a ruptured AVM. During the surgery, a sellar mass was identified that was also resected. AVM showed vasculitis, endarteritis, endothelial damage, leukocyte plug, and damage to the vessel wall with fragmentation of the collagen and actin filaments. The sellar mass showed a non-functioning pituitary adenoma with hemorrhagic foci and necrosis as well as a proteinaceous vs. lipid material deposition with minimal vascular changes such as endothelial hyperplasia with minimal vasculitis and hyperplasia of reticular stellate cells, with positive glial fibrillary acidic protein (GFAP), which expressed low expression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), IL6, IL10, IL17, tumor necrosis factor-alpha (TNFa), HIF1a, factor VIII (FVIII), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and VEGF receptor 2 (VEGFR2). The patient's polymerase chain reaction COVID-19 test was positive, and she died three days after the surgery procedure. In our knowledge of COVID-19 brain lesions and in the literature review, this was a rare case of a double pathology associated with COVID-19 infection characterized by rupture of the AVM with hemorrhages and brain infarcts associated with endarteritis, vessel wall injuries, and pituitary apoplexy.
... Internalization and transport of the virus through the cerebral endothelium, where the expression of SARS-CoV-2 docking proteins is unknown, would be required to cross the intact BBB. Immunoreactivity to ACE2 was found in the brain arteries of a patient who died from repeated ischemic infarctions but the precise cellular location remains unknown [27]. Entry via additional putative SARS-CoV-2 receptors, such as NRP1 and BSG, which are more broadly expressed in the cerebral vasculature, cannot be ruled out. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19), induced a global pandemic with a diverse array of clinical manifestations. While the acute phase of the pandemic may be waning, the intricacies of COVID-19′s impact on neurological health remain a crucial area of investigation. Early recognition of the spectrum of COVID-19 symptoms, ranging from mild fever and cough to life-threatening respiratory distress and multi-organ failure, underscored the significance of neurological complications, including anosmia, seizures, stroke, disorientation, encephalopathy, and paralysis. Notably, patients requiring intensive care unit (ICU) admission due to neurological challenges or due to them exhibiting neurological abnormalities in the ICU have shown increased mortality rates. COVID-19 can lead to a range of neurological complications such as anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, seizures, etc., in affected patients. This review elucidates the burgeoning landscape of neurological sequelae associated with SARS-CoV-2 infection and explores the underlying neurobiological mechanisms driving these diverse manifestations. A meticulous examination of potential neuroinvasion routes by SARS-CoV-2 underscores the intricate interplay between the virus and the nervous system. Moreover, we dissect the diverse neurological manifestations emphasizing the necessity of a multifaceted approach to understanding the disease’s neurological footprint. In addition to elucidating the pathophysiological underpinnings, this review surveys current therapeutic modalities and delineates prospective avenues for neuro-COVID research. By integrating epidemiological, clinical, and diagnostic parameters, we endeavor to foster a comprehensive analysis of the nexus between COVID-19 and neurological health, thereby laying the groundwork for targeted therapeutic interventions and long-term management strategies.
... COVID-19'daki sitokinlerin patern ve dağılımı, ateş, akut faz yüksekliği (CRP, serum amiloid A, ferritin) gibi klinik bulgular MAS ve HLH durumuna benzerlik göstermektedir (Henderson et al., 2020;Kabeerdoss & Danda, 2020). COVID-19 hastalarının otopsi sonuçlarında lenf nodları, dalak, kemik iliği, kalp ve karaciğerde hemofagositik histiyositler saptamıştır (Bryce et al., 2020). ...
... • Another evidence of corona virus affecting brain tissue was given by Mary Fowkers team who showed the presence of Corona virus in the brain tissue itself by Electron Microscopy. (Brain tissue obtained by post mortems in 67 people who had died of COVID-19 as posted in a reprint in late may) [25]. • SARS-COV-2 RNA has been recently isolated from the central Nervous system of the COVID- 19 patients which provides the evidence of neurotropic nature of COVID-19 virus [8,26]. ...
COVID-19 disease is caused by Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2). In most of the cases the patients present with typical symptoms of fever, cough, dyspnea, sore throat etc. The involvement of central nervous system by SARS-CoV-2 resulting in encephalopathy, encephalitis and neuropsychiatric symptoms such as anxiety, depression, panic attack and post traumatic symptoms have been described in the literature. But the clinical presentation of Psychosis as a neuropsychiatric manifestation in COVID-19 patients has been described in very few literatures. Our aim of the study was to find out the incidence of Psychosis in COVID-19 patients and its association with elevated levels of inflammatory markers such as IL-6, CRP etc, and with that of elevated coagulation parameter such as D-dimer values. Severity of Pneumonia (by HRCT thorax), neuropsychiatric presentation of Psychosis and the various interventions received by the COVID-19 patients with Psychosis were also studied. Out of 2752 COVID-19 cases new onset COVID Psychosis was seen only in 36 cases with an incidence of 1.308%. Out of these, 30 cases were aged > 60 years (83.3%) with male predominance (n=25)(69.44%) Psychotic manifestations such as delusion, hallucinations and mania were seen in 34 (94%), 32(88.8%) and 28 (77.7%) cases respectively.
As detailed in the first part of this review, post-infectious vasculitides are a wide and complex category, including several clinical, microbiological and neuroradiological patterns. In order to raise the suspicion for diagnosis, the knowledge of two different neuroradiological issues is needed, i.e. the knowledge of neuroimaging pattern of infections and the one of neuroimaging pattern of vasculitis.
The main aim of this second part is to summarize the neuroradiological features of post-infectious vasculitides focusing on imaging of vessels and consequences of vessel involvement, continuing the discussion proposed in the first part about neuroimaging of infections. In some cases, the two neuroradiological issues are both simultaneously present in the same patient, but in other cases only the second one can be depicted due to the latency between infection and vasculitis.
Beyond general features of cerebral vascular involvement in post-infectious vasculitides, some well-studied and homogenous diseases, as treponemal vasculitis, Varicella Zoster Virus (VZV) arteriopathy, neuroborreliosis, SARS-CoV2-related endotheliopathy are described in detail, being not rare and sometimes underdiagnosed. The main clinical and neuroradiological features of these conditions are deeply addressed, providing diagnostic clues and pictorial examples.
Although some general features are common in clinical presentation and neuroimaging of post-infectious vasculitides, there are few neuroimaging clues pointing out a specific microbial agent as causative. The main step is to raise the diagnostic suspicion in order to start the dedicated investigation pathway and treatment.
Background: Even If Specific mechanisms are not completely understood, several studies highlightedSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) ability to alter vascular homeostasis.In the literature, multiple reports of microscopic pulmonary findings of vascular structures in patientsdeceased by or with SARS-Cov-2 infection are available. Nevertheless, the scientific literature lacks asystematic analysis of these findings. Methods: the authors realized a systematic review of the literature inorder to identify common microscopic patterns representative of pulmonary vascular damage: useful datafor pathologists in clinical and forensic settings. The research yielded 23 articles (79 total cases). Quali/quantitative analysis was carried out. Conclusion: the review allowed to identify vascular thrombosis(especially in lesser caliber vessels) as common microscopic pattern. The recurrence of this pattern wasconfirmed by scientific literature data which demonstrate SARS-CoV-2 ability to interfere with coagulationcascade. Other meaningful microscopic findings were also discussed, even if their low frequency in studypopulation did not allow to define them as common
COVID-19 has recently been one of the greatest challenges of public health services worldwide. SARS-CoV-19 affects not only the respiratory, but also other systems, including the brain. It causes strokes, meningitis, encephalopathy, encephalitis, etc. Due to the multifactorial nature and complexity of COVID-19 pathogenesis, studying its impact on brain tissue is relevant. The aim of the work is to study the cytometric parameters of neurons in the parietal-occipital lobe of the cerebral cortex in patients who died due to COVID-19. Materials and Methods. For histomorphological examination, autopsies of the parietal-occipital lobe of the cerebral cortex were fixed in 10 % neutral formalin and embedded in paraffin. Cross sections (5–6 μm) were stained with hematoxylin-eosin. Histologic specimens were studied under a light microscope. Morphometric measurements of the nucleus and cytoplasm area of neurons of the parietal-occipital lobe of the cerebral cortex were performed on the images. The nuclear-cytoplasmic ratio was calculated. The results of the histomorphological study were analyzed along with the medical history. For comparison, autopsies of the parietal-occipital lobe of the cerebral cortex from patients who died from cerebral infarction were used. Results. Nucleus and cytoplasm areas of neurons in the pyramidal and ganglionic layers of the cerebral cortex were measured. In the cerebral cortex, COVID-19 mainly affects the microvasculature vessels, disrupting their permeability and causing hemorrhages. Damage to the neurons of the cerebral cortex is less pronounced and does not have any specific pathomorphological picture, which corresponds to the pattern of long-term ischemic effects on the gray matter.
The SARS-CoV-2 coronavirus (COVID-19) induced infection can be associated with a coagulopathy, findings consistent with infection induced inflammatory changes as observed in patients with disseminated intravascular coagulopathy (DIC). The lack of prior immunity to COVID-19 has resulted in large numbers of infected patients across the globe and uncertainty regarding management of the complications that arise in the course of this viral illness. The lungs are the target organ for COVID-19; patients develop acute lung injury which can progress to respiratory failure, although multiorgan failure can also occur. The initial coagulopathy of COVID-19 presents with prominent elevation of D-dimer and fibrin/fibrinogen degradation products, while abnormalities in prothrombin time, partial thromboplastin time, and platelet counts are relatively uncommon in initial presentations. Coagulation test screening, including the measurement of D-dimer and fibrinogen levels, is suggested. COVID-19 associated coagulopathy should be managed as it would be for any critically ill patient, following the established practice of using thromboembolic prophylaxis for critically ill hospitalized patients, and standard supportive care measures for those with sepsis-induced coagulopathy or DIC. Although D-dimer, sepsis physiology, and consumptive coagulopathy are indicators of mortality, current data do not suggest the use of full intensity anticoagulation doses unless otherwise clinically indicated. Even though there is an associated coagulopathy with COVID-19, bleeding manifestations, even in those with DIC, have not been reported. If bleeding does occur, standard guidelines for the management of DIC and bleeding should be followed.
Neurologic sequelae can be devastating complications of respiratory viral infections. We report the presence of virus in neural and capillary endothelial cells in frontal lobe tissue obtained at postmortem examination from a patient infected with Severe Acute Respiratory Syndrome Coronavirus‐2. Our observations of virus in neural tissue, in conjunction with clinical correlates of worsening neurologic symptoms, pave the way to a closer understanding of the pathogenic mechanisms underlying CNS involvement.
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Endothelial cell infection and endotheliitis in COVID-19
Data on pathologic changes of the 2019 novel coronavirus disease (COVID-19) are scarce. To gain knowledge about the pathology that may contribute to disease progression and fatality, we performed postmortem needle core biopsies of lung, liver, and heart in four patients who died of COVID-19 pneumonia. The patients’ ages ranged from 59 to 81, including three males and one female. Each patient had at least one underlying disease, including immunocompromised status (chronic lymphocytic leukemia and renal transplantation) or other conditions (cirrhosis, hypertension, and diabetes). Time from disease onset to death ranged from 15 to 52 days. All patients had elevated white blood cell counts, with significant rise toward the end, and all had lymphocytopenia except for the patient with leukemia. Histologically, the main findings are in the lungs, including injury to the alveolar epithelial cells, hyaline membrane formation, and hyperplasia of type II pneumocytes, all components of diffuse alveolar damage. Consolidation by fibroblastic proliferation with extracellular matrix and fibrin forming clusters in airspaces is evident. In one patient, the consolidation consists of abundant intra-alveolar neutrophilic infiltration, consistent with superimposed bacterial bronchopneumonia. The liver exhibits mild lobular infiltration by small lymphocytes, and centrilobular sinusoidal dilation. Patchy necrosis is also seen. The heart shows only focal mild fibrosis and mild myocardial hypertrophy, changes likely related to the underlying conditions. In conclusion, the postmortem examinations show advanced diffuse alveolar damage, as well as superimposed bacterial pneumonia in some patients. Changes in the liver and heart are likely secondary or related to the underlying diseases.
Introduction
COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of thrombotic complications are however not available.
Methods
We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital.
Results
We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications.
Conclusion
The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.
In the midst of the coronavirus disease 2019 (COVID-19) pandemic, we are seeing widespread disease burden affecting patients of all ages across the globe. However, much remains to be understood as clinicians, epidemiologists, and researchers alike are working to describe and characterize the disease process while caring for patients at the frontlines. We describe the case of a 6-month-old infant admitted and diagnosed with classic Kawasaki disease, who also screened positive for COVID-19 in the setting of fever and minimal respiratory symptoms. The patient was treated per treatment guidelines, with intravenous immunoglobulin and high-dose aspirin, and subsequently defervesced with resolution of her clinical symptoms. The patient's initial echocardiogram was normal, and she was discharged within 48 hours of completion of her intravenous immunoglobulin infusion, with instruction to quarantine at home for 14 days from the date of her positive test results for COVID-19. Further study of the clinical presentation of pediatric COVID-19 and the potential association with Kawasaki disease is warranted, as are the indications for COVID-19 testing in the febrile infant.
The pandemic outbreak of coronavirus disease 2019 (COVID-19) is rapidly spreading all over the world. Reports from China showed that about 20% of patients developed severe disease, resulting in a fatality of 4%. In the past two months, we clinical immunologists participated in multi-rounds of MDT (multidiscipline team) discussion on the anti-inflammation management of critical ill COVID-19 patients, with our colleagues dispatched from Chinese leading PUMC Hospital to Wuhan to admit and treat the most severe patients. Here, from the perspective of clinical immunologists, we will discuss the clinical and immunological characteristics of severe patients, and summarize the current evidence and share our experience in anti-inflammation treatment, including glucocorticoids, IL-6 antagonist, JAK inhibitors and choloroquine/hydrocholoroquine, of patients with severe COVID-19 that may have an impaired immune system.
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