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3.
Am J Respir Cell Mol Biol ; 65(3): 300-308, 2021 09.
Article in English | MEDLINE | ID: covidwho-1381187

ABSTRACT

Endothelial dysfunction is implicated in the thrombotic events reported in patients with coronavirus disease (COVID-19), but the underlying molecular mechanisms are unknown. Circulating levels of the coagulation cascade activator PAI-1 are substantially higher in patients with COVID-19 with severe respiratory dysfunction than in patients with bacterial sepsis and acute respiratory distress syndrome. Indeed, the elevation of PAI-1 is recognized as an early marker of endothelial dysfunction. Here, we report that the rSARS-CoV-2-S1 (recombinant severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] viral envelope spike) glycoprotein stimulated robust production of PAI-1 by human pulmonary microvascular endothelial cells (HPMECs). We examined the role of protein degradation in this SARS-CoV-2-S1 induction of PAI-1 and found that the proteasomal degradation inhibitor bortezomib inhibited SARS-CoV-2-S1-mediated changes in PAI-1. Our data further show that bortezomib upregulated KLF2, a shear-stress-regulated transcription factor that suppresses PAI-1 expression. Aging and metabolic disorders are known to increase mortality and morbidity in patients with COVID-19. We therefore examined the role of ZMPSTE24 (zinc metallopeptidase STE24), a metalloprotease with a demonstrated role in host defense against RNA viruses that is decreased in older individuals and in metabolic syndrome, in the induction of PAI-1 in HPMECs by SARS-CoV-2-S1. Indeed, overexpression of ZMPSTE24 blunted enhancement of PAI-1 production in spike protein-exposed HPMECs. In addition, we found that membrane expression of the SARS-CoV-2 entry receptor ACE2 was reduced by ZMPSTE24-mediated cleavage and shedding of the ACE2 ectodomain, leading to accumulation of ACE2 decoy fragments that may bind SARS-CoV-2. These data indicate that decreases in ZMPSTE24 with age and comorbidities may increase vulnerability to vascular endothelial injury by SARS-CoV-2 viruses and that enhanced production of endothelial PAI-1 might play role in prothrombotic events in patients with COVID-19.


Subject(s)
COVID-19/virology , Endothelial Cells/pathology , Membrane Proteins/metabolism , Metalloendopeptidases/metabolism , Plasminogen Activator Inhibitor 1/metabolism , Pulmonary Artery/pathology , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/metabolism , Aging , COVID-19/metabolism , Cells, Cultured , Endothelial Cells/metabolism , Endothelial Cells/virology , Humans , Membrane Proteins/genetics , Metalloendopeptidases/genetics , Plasminogen Activator Inhibitor 1/genetics , Proteolysis , Pulmonary Artery/metabolism , Pulmonary Artery/virology , Spike Glycoprotein, Coronavirus/genetics
4.
Lancet Infect Dis ; 20(10): 1135-1140, 2020 10.
Article in English | MEDLINE | ID: covidwho-1377877

ABSTRACT

BACKGROUND: COVID-19 is characterised by respiratory symptoms, which deteriorate into respiratory failure in a substantial proportion of cases, requiring intensive care in up to a third of patients admitted to hospital. Analysis of the pathological features in the lung tissues of patients who have died with COVID-19 could help us to understand the disease pathogenesis and clinical outcomes. METHODS: We systematically analysed lung tissue samples from 38 patients who died from COVID-19 in two hospitals in northern Italy between Feb 29 and March 24, 2020. The most representative areas identified at macroscopic examination were selected, and tissue blocks (median seven, range five to nine) were taken from each lung and fixed in 10% buffered formalin for at least 48 h. Tissues were assessed with use of haematoxylin and eosin staining, immunohistochemical staining for inflammatory infiltrate and cellular components (including staining with antibodies against CD68, CD3, CD45, CD61, TTF1, p40, and Ki-67), and electron microscopy to identify virion localisation. FINDINGS: All cases showed features of the exudative and proliferative phases of diffuse alveolar damage, which included capillary congestion (in all cases), necrosis of pneumocytes (in all cases), hyaline membranes (in 33 cases), interstitial and intra-alveolar oedema (in 37 cases), type 2 pneumocyte hyperplasia (in all cases), squamous metaplasia with atypia (in 21 cases), and platelet-fibrin thrombi (in 33 cases). The inflammatory infiltrate, observed in all cases, was largely composed of macrophages in the alveolar lumina (in 24 cases) and lymphocytes in the interstitium (in 31 cases). Electron microscopy revealed that viral particles were predominantly located in the pneumocytes. INTERPRETATION: The predominant pattern of lung lesions in patients with COVID-19 patients is diffuse alveolar damage, as described in patients infected with severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses. Hyaline membrane formation and pneumocyte atypical hyperplasia are frequent. Importantly, the presence of platelet-fibrin thrombi in small arterial vessels is consistent with coagulopathy, which appears to be common in patients with COVID-19 and should be one of the main targets of therapy. FUNDING: None.


Subject(s)
Coronavirus Infections/pathology , Lung/pathology , Pneumonia, Viral/pathology , Adult , Aged , Aged, 80 and over , Autopsy , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Female , Humans , Hyaline Membrane Disease , Inflammation , Italy/epidemiology , Lung/blood supply , Lung/ultrastructure , Lung/virology , Male , Middle Aged , Neutrophil Infiltration , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Pulmonary Alveoli/blood supply , Pulmonary Alveoli/pathology , Pulmonary Alveoli/ultrastructure , Pulmonary Alveoli/virology , Pulmonary Artery/pathology , SARS-CoV-2 , Thrombosis
5.
Int J Mol Sci ; 22(16)2021 Aug 22.
Article in English | MEDLINE | ID: covidwho-1367850

ABSTRACT

SARS-CoV-2 primarily infects epithelial airway cells that express the host entry receptor angiotensin-converting enzyme 2 (ACE2), which binds to the S1 spike protein on the surface of the virus. To delineate the impact of S1 spike protein interaction with the ACE2 receptor, we incubated the S1 spike protein with human pulmonary arterial endothelial cells (HPAEC). HPAEC treatment with the S1 spike protein caused disruption of endothelial barrier function, increased levels of numerous inflammatory molecules (VCAM-1, ICAM-1, IL-1ß, CCL5, CXCL10), elevated mitochondrial reactive oxygen species (ROS), and a mild rise in glycolytic reserve capacity. Because low oxygen tension (hypoxia) is associated with severe cases of COVID-19, we also evaluated treatment with hemoglobin (HbA) as a potential countermeasure in hypoxic and normal oxygen environments in analyses with the S1 spike protein. We found hypoxia downregulated the expression of the ACE2 receptor and increased the critical oxygen homeostatic signaling protein, hypoxia-inducible factor (HIF-1α); however, treatment of the cells with HbA yielded no apparent change in the levels of ACE2 or HIF-1α. Use of quantitative proteomics revealed that S1 spike protein-treated cells have few differentially regulated proteins in hypoxic conditions, consistent with the finding that ACE2 serves as the host viral receptor and is reduced in hypoxia. However, in normoxic conditions, we found perturbed abundance of proteins in signaling pathways related to lysosomes, extracellular matrix receptor interaction, focal adhesion, and pyrimidine metabolism. We conclude that the spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in HPAEC, and that treatment with HbA failed to reverse the vast majority of these spike protein-induced changes.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Endothelial Cells/metabolism , Hemoglobins/metabolism , Spike Glycoprotein, Coronavirus/metabolism , COVID-19/virology , Cell Hypoxia , Cell Survival , Cells, Cultured , Endothelial Cells/virology , Endothelium, Vascular/cytology , Endothelium, Vascular/pathology , Humans , Protein Subunits/metabolism , Pulmonary Artery/cytology , Pulmonary Artery/pathology , Reactive Oxygen Species/metabolism , Recombinant Proteins/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity
6.
SLAS Discov ; 26(9): 1079-1090, 2021 10.
Article in English | MEDLINE | ID: covidwho-1314244

ABSTRACT

The recent renascence of phenotypic drug discovery (PDD) is catalyzed by its ability to identify first-in-class drugs and deliver results when the exact molecular mechanism is partially obscure. Acute respiratory distress syndrome (ARDS) is a severe, life-threatening condition with a high mortality rate that has increased in frequency due to the COVID-19 pandemic. Despite decades of laboratory and clinical study, no efficient pharmacological therapy for ARDS has been found. An increase in endothelial permeability is the primary event in ARDS onset, causing the development of pulmonary edema that leads to respiratory failure. Currently, the detailed molecular mechanisms regulating endothelial permeability are poorly understood. Therefore, the use of the PDD approach in the search for efficient ARDS treatment can be more productive than classic target-based drug discovery (TDD), but its use requires a new cell-based assay compatible with high-throughput (HTS) and high-content (HCS) screening. Here we report the development of a new plate-based image cytometry method to measure endothelial barrier function. The incorporation of image cytometry in combination with digital image analysis substantially decreases assay variability and increases the signal window. This new method simultaneously allows for rapid measurement of cell monolayer permeability and cytological analysis. The time-course of permeability increase in human pulmonary artery endothelial cells (HPAECs) in response to the thrombin and tumor necrosis factor α treatment correlates with previously published data obtained by transendothelial resistance (TER) measurements. Furthermore, the proposed image cytometry method can be easily adapted for HTS/HCS applications.


Subject(s)
COVID-19/diagnostic imaging , High-Throughput Screening Assays/methods , Image Cytometry/methods , Respiratory Distress Syndrome/diagnostic imaging , COVID-19/diagnosis , COVID-19/virology , Cell Membrane Permeability/genetics , Drug Discovery , Endothelial Cells/ultrastructure , Endothelial Cells/virology , Humans , Image Processing, Computer-Assisted , Pandemics/prevention & control , Phenotype , Pulmonary Artery/diagnostic imaging , Pulmonary Artery/pathology , Pulmonary Artery/virology , Pulmonary Edema/diagnosis , Pulmonary Edema/diagnostic imaging , Pulmonary Edema/virology , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/virology , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/diagnostic imaging , Respiratory Insufficiency/virology , SARS-CoV-2/pathogenicity , Thrombin/pharmacology , Tumor Necrosis Factor-alpha/pharmacology
8.
J Intern Med ; 290(3): 655-665, 2021 09.
Article in English | MEDLINE | ID: covidwho-1297793

ABSTRACT

IMPORTANCE: Assessment of the causative association between the COVID-19 and cause of death has been hampered by limited availability of systematically performed autopsies. We aimed to present autopsy-confirmed causes of death in patients who died with COVID-19 and to assess the association between thrombosis and diffuse alveolar damage consistent with COVID-19 (DAD). METHODS: Consecutive forensic (n = 60) and clinical (n = 42) autopsies with positive post-mortem SARS-CoV-2 PCR in lungs (age 73 ± 14 years, 50% men) were included. The cause of death analysis was based on a review of medical records and histological reports. Thrombotic phenomena in lungs were defined as pulmonary thromboembolism (PE), thrombosis in pulmonary artery branches or microangiopathy in capillary vessels. RESULTS: COVID-19 caused or contributed to death in 71% of clinical and 83% of forensic autopsies, in whom significant DAD was observed. Of the patients with COVID-19 as the primary cause of death, only 19% had no thrombotic phenomena in the lungs, as opposed to 38% amongst those with COVID-19 as a contributing cause of death and 54% amongst patients whose death was not related to COVID-19 (p = 0.002). PE was observed in 5 patients. Two patients fulfilled the criteria for lymphocyte myocarditis. CONCLUSIONS: Vast majority of all PCR-positive fatalities, including out-of-hospital deaths, during the SARS-CoV-2 pandemic were related to DAD caused by COVID-19. Pulmonary artery thrombosis and microangiopathy in pulmonary tissue were common and associated with the presence of DAD, whilst venous PE was rarely observed. Histology-confirmed lymphocyte myocarditis was a rare finding.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Cause of Death , Pulmonary Alveoli/pathology , Pulmonary Embolism/pathology , Thromboembolism/pathology , Aged , Autopsy , Capillaries/pathology , Female , Humans , Lymphocytes , Male , Middle Aged , Myocarditis/pathology , Pandemics , Polymerase Chain Reaction , Pulmonary Artery/pathology , SARS-CoV-2 , Thrombotic Microangiopathies/pathology
9.
Medicina (Kaunas) ; 57(4)2021 Mar 24.
Article in English | MEDLINE | ID: covidwho-1154448

ABSTRACT

Background: Establishing the diagnosis of COVID-19 and Pneumocystisjirovecii pulmonary coinfection is difficult due to clinical and radiological similarities that exist between the two disorders. For the moment, fungal coinfections are underestimated in COVID-19 patients. Case presentation: We report the case of a 52-year-old male patient, who presented to the emergency department for severe dyspnea and died 17 h later. The RT-PCR test performed at his admission was negative for SARS-CoV-2. Retesting of lung fragments collected during autopsy revealed a positive result for SARS-CoV-2. Histopathological examination showed preexisting lesions, due to comorbidities, as well as recent lesions: massive lung thromboses, alveolar exudate rich in foam cells, suprapleural and intra-alveolar Pneumocystisjirovecii cystic forms, and bilateral adrenal hemorrhage. Conclusion: COVID-19 and P.jirovecii coinfection should be considered, particularly in critically ill patients, and we recommend the systematic search for P. jirovecii in respiratory samples.


Subject(s)
COVID-19/pathology , Lung/pathology , Pneumonia, Pneumocystis/pathology , Respiratory Insufficiency/pathology , Thrombosis/pathology , Acute Kidney Injury/complications , Acute-On-Chronic Liver Failure/complications , Adrenal Gland Diseases/complications , Adrenal Gland Diseases/pathology , Autopsy , COVID-19/complications , Coinfection/pathology , Exudates and Transudates , Fatal Outcome , Fibrosis , Foam Cells/pathology , Hemorrhage/complications , Hemorrhage/pathology , Humans , Hypertension/complications , Liver Diseases, Alcoholic/complications , Male , Middle Aged , Myocardial Ischemia/complications , Pneumonia, Pneumocystis/complications , Pulmonary Artery/pathology , Pulmonary Veins/pathology , Respiratory Insufficiency/etiology , SARS-CoV-2 , Thrombosis/etiology
10.
Jpn J Radiol ; 39(6): 589-597, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1144386

ABSTRACT

PURPOSE: To describe the prognostic value of pulmonary artery (PA) trunk enlargement on the admission of in-hospital patients with severe COVID-19 infection by unenhanced CT image. MATERIALS AND METHODS: In-hospital patients confirmed COVID-19 from January 18, 2020, to March 7, 2020, were retrospectively enrolled. PA trunk diameters on admission and death events were collected to calculate the optimum cutoff using a receiver operating characteristic curve. According to the cutoff, the subjects on admission were divided into two groups. Then the in-hospital various parameters were compared between the two groups to assess the predictive value of PA trunk diameter. RESULTS: In the 180 enrolled in-hospital patients (46.99 ± 14.95 years; 93 (51.7%) female, 14 patients (7.8%) died during their hospitalization. The optimum cutoff PA trunk diameter to predict in-hospital mortality was > 29 mm with a sensitivity of 92.59% and a specificity of 91.11%. Kaplan-Meier survival curves for PA trunk diameter on admission showed that a PA trunk diameter > 29 mm was a significant predictor of subsequent death (log-rank < 0.001, median survival time of PA > 29 mm was 28 days). CONCLUSION: PA trunk enlargement can be a useful predictive factor for distinguishing between mild and severe COVID-19 disease progression.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Pulmonary Artery/pathology , Adult , COVID-19/diagnostic imaging , Dilatation, Pathologic/diagnostic imaging , Female , Hospital Mortality , Hospitalization , Humans , Male , Middle Aged , Prognosis , Pulmonary Artery/diagnostic imaging , ROC Curve , Retrospective Studies , SARS-CoV-2 , Tomography, X-Ray Computed/methods
11.
Biomed Res Int ; 2021: 8851736, 2021.
Article in English | MEDLINE | ID: covidwho-1140379

ABSTRACT

PURPOSE: This study is aimed at assessing the prevalence of pulmonary artery filling defects (PAFDs) consistent with pulmonary artery embolism (PAE) in patients with SARS-CoV-2 infection and at investigating possible radiological or clinical predictors. MATERIALS AND METHODS: Computed Tomography Pulmonary Angiographies (CTPAs) from 43 consecutive patients with a confirmed COVID-19 infection were retrospectively reviewed, taking into consideration the revised Geneva score and the D-dimer value for each patient. Filling defects within the pulmonary arteries were recorded along with pleural and parenchymal findings such as ground glass opacities, consolidation, crazy paving, linear consolidation, and pleural effusion. All these variables were compared between patients with and without PAFD. The predictive performance of statistically different parameters was investigated using the receiver operating characteristics (ROC). RESULTS: Pulmonary embolism was diagnosed in 15/43 patients (35%), whereas CTPA and parenchymal changes related to pulmonary COVID-19 disease were evident in 39/43 patients (91%). The revised Geneva score and the mean D-dimer value obtained using two consecutive measurements were significantly higher in patients with PAFD. The ROC analysis demonstrated that a mean D-dimer value is the parameter with the higher predictivity (AUC 0.831) that is a cut-off value > 1800 µg/l which predicts the probability of PAFD with a sensitivity and specificity of 70% and 78%, respectively. CONCLUSIONS: This single centre retrospective report shows a high prevalence of pulmonary artery filling defects revealed using CTPA in COVID-19 patients and demonstrates that the mean value of multiple D-dimer measurements may represent a predicting factor of this complication.


Subject(s)
COVID-19/diagnostic imaging , Computed Tomography Angiography/methods , Pulmonary Artery/diagnostic imaging , Adult , Aged , COVID-19/metabolism , COVID-19/virology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Lung/diagnostic imaging , Lung/pathology , Male , Middle Aged , Prevalence , Pulmonary Artery/pathology , Pulmonary Artery/virology , Pulmonary Embolism/diagnosis , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/virology , ROC Curve , Retrospective Studies , SARS-CoV-2/isolation & purification , Sensitivity and Specificity
12.
Interact Cardiovasc Thorac Surg ; 33(1): 150-152, 2021 06 28.
Article in English | MEDLINE | ID: covidwho-1118995

ABSTRACT

We report a rare case of solitary peripheral pulmonary artery aneurysm in a patient who was evaluated for haemoptysis. Incidentally, his total antibodies were positive for Coronavirus 2019 infection. Patient underwent right lower lobectomy uneventfully. Peripheral pulmonary artery aneurysms arising from segmental or intrapulmonary branches are extremely rare. Untreated, the majority end fatally due to sudden rupture and exsanguination. The purpose of this article is to report our rare case and review the pertinent literature.


Subject(s)
Aneurysm/pathology , Pulmonary Artery/pathology , Adult , Aneurysm/diagnostic imaging , Aneurysm/surgery , Humans , Male , Pulmonary Artery/diagnostic imaging , Pulmonary Artery/surgery , Tomography, X-Ray Computed
13.
Eur J Radiol ; 134: 109442, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1060223

ABSTRACT

PURPOSE: The vascular enlargement (VE) pattern differs from previously described imaging patterns for pneumonia. This study aimed to investigate the incidence, computed tomography (CT) characteristics, and diagnostic value of the VE pattern in coronavirus disease 2019 (COVID-19). METHOD: The CT data of 106 patients with COVID-19 from January 19 to February 29, 2020, and 52 patients with influenza virus pneumonia (IVP) from January 2018 to February 2020 were retrospectively collected. The incidences of the VE pattern between the two groups were compared. The CT manifestations of COVID-19 were analyzed with a particular focus on the VE pattern's specific CT signs, dynamic changes, and relationships with lesion size and disease severity. RESULTS: Peripheral and multilobar ground-glass opacities (GGOs) or mixed GGOs with various sizes and morphologies were typical features of COVID-19 on initial CT. The VE pattern was more common in COVID-19 (88/106, 83.02 %) than in IVP (10/52, 19.23 %) on initial CT (P < 0.001). Three special VE-pattern-specific CT signs, including central vascular sign, ginkgo leaf sign, and comb sign, were identified. Four types of dynamic changes in the VE pattern were observed on initial and follow-up CT, which were closely associated with the evolution of lesions and the time interval from the onset of symptoms to initial CT scan. The VE pattern in COVID-19 was more commonly seen in larger lesions and patients with severe-critical type (all P < 0.001). CONCLUSIONS: The VE pattern is a valuable CT sign for differentiating COVID-19 from IVP, which correlates with more extensive or serious disease. A good understanding of the CT characteristics of the VE pattern may contribute to the early and accurate diagnosis of COVID-19 and prediction of the evolution of lesions.


Subject(s)
COVID-19/diagnostic imaging , Lung/diagnostic imaging , Pneumonia/diagnostic imaging , Pulmonary Artery/pathology , Pulmonary Veins/diagnostic imaging , Pulmonary Veins/pathology , Tomography, X-Ray Computed/methods , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/pathology , Child , Diagnosis, Differential , Female , Humans , Influenza, Human/diagnostic imaging , Influenza, Human/pathology , Lung/blood supply , Lung/pathology , Male , Middle Aged , Pneumonia/pathology , Pulmonary Artery/diagnostic imaging , Retrospective Studies , SARS-CoV-2 , Young Adult
14.
S Afr Med J ; 110(12): 1195-1200, 2020 10 19.
Article in English | MEDLINE | ID: covidwho-994151

ABSTRACT

BACKGROUND: An outbreak of a novel coronavirus in China in late 2019 has resulted in a global pandemic. The virus (SARS-CoV-2) causes a severe acute respiratory syndrome and had been responsible for >14 000 deaths in South Africa (SA) at the time of writing, 30 August 2020. Autopsies in our setting have not been prioritised owing to the infective risks for staff, resulting in a lack of information on the histopathology of the disease in the SA setting. Postmortem biopsies are relatively quick and easy to perform and reduce the infective risk posed by full autopsies. OBJECTIVES: To determine whether postmortem biopsies of lung tissue could be used to determine cause of death in lieu of full autopsies in patients dying from COVID-19. METHODS: We performed postmortem biopsies of lung tissue on 4 patients with SARS-CoV-2 confirmed by reverse transcriptase polymerase chain reaction who died in the Tygerberg Hospital (Cape Town, SA) intensive care unit (ICU) in June - July 2020, in order to determine their cause of death. The biopsies were performed in the ICU with the necessary personal protective equipment within 2 hours after death. Clinical information was obtained from the hospital records and the histopathology was reviewed by two consultant histopathologists. Microbiology and electron microscopy were also performed on this tissue. RESULTS: All 4 patients were aged >50 years and had multiple comorbidities. Pulmonary pathology was present in only 3 cases, and the findings were surprisingly heterogeneous. One case demonstrated several findings including diffuse alveolar damage, extensive fibrin thrombi in pulmonary arteries with pulmonary infarction, organising pneumonia and bronchopneumonia. Other findings included type 2 pneumocyte hyperplasia, intra-alveolar macrophages and squamous metaplasia. An organising pneumonia was present in 2 other cases, although these findings were not deemed to be severe enough to be the cause of death. Fibrin thrombi were present in pulmonary arteries of 3 cases. One case showed no significant acute pulmonary pathology. The cause of death could only be determined in 1 case. CONCLUSIONS: The pulmonary findings we observed are in keeping with those described in the international literature. However, the pathology was surprisingly heterogeneous between cases, and was only deemed severe enough to be the cause of death in 1 of 4 cases. While lung-targeted, standardised postmortem biopsies may be safe, easy to perform and provide useful insights into the disease, they are not suitable to replace full autopsies in determining cause of death.


Subject(s)
Biopsy , COVID-19/pathology , Lung Injury/pathology , Lung/pathology , Pulmonary Artery/pathology , Pulmonary Edema/pathology , Pulmonary Infarction/pathology , Thrombosis/pathology , Aged , Alveolar Epithelial Cells/pathology , Autopsy , C-Reactive Protein/metabolism , COVID-19/blood , COVID-19/mortality , Cause of Death , Comorbidity , Diabetes Mellitus, Type 2/epidemiology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Giant Cells/pathology , Humans , Hypertension/epidemiology , Lymphocytes/pathology , Macrophages, Alveolar/pathology , Male , Middle Aged , Obesity/epidemiology , Procalcitonin/blood , SARS-CoV-2 , South Africa , Tertiary Care Centers
15.
Vascul Pharmacol ; 137: 106823, 2021 04.
Article in English | MEDLINE | ID: covidwho-939340

ABSTRACT

Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. So far, 60 million people have been infected with SARS-CoV-2, and 1.4 million people have died because of COVID-19 worldwide, causing serious health, economical, and sociological problems. However, the mechanism of the effect of SARS-CoV-2 on human host cells has not been defined. The present study reports that the SARS-CoV-2 spike protein alone without the rest of the viral components is sufficient to elicit cell signaling in lung vascular cells. The treatment of human pulmonary artery smooth muscle cells or human pulmonary artery endothelial cells with recombinant SARS-CoV-2 spike protein S1 subunit (Val16 - Gln690) at 10 ng/ml (0.13 nM) caused an activation of MEK phosphorylation. The activation kinetics was transient with a peak at 10 min. The recombinant protein that contains only the ACE2 receptor-binding domain of the SARS-CoV-2 spike protein S1 subunit (Arg319 - Phe541), on the other hand, did not cause this activation. Consistent with the activation of cell growth signaling in lung vascular cells by the SARS-CoV-2 spike protein, pulmonary vascular walls were found to be thickened in COVID-19 patients. Thus, SARS-CoV-2 spike protein-mediated cell growth signaling may participate in adverse cardiovascular/pulmonary outcomes, and this mechanism may provide new therapeutic targets to combat COVID-19.


Subject(s)
COVID-19/metabolism , Endothelial Cells/metabolism , Lung/blood supply , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , COVID-19/virology , Cells, Cultured , Endothelial Cells/pathology , Endothelial Cells/virology , Host-Pathogen Interactions , Humans , Kinetics , Mitogen-Activated Protein Kinase Kinases/metabolism , Muscle, Smooth, Vascular/pathology , Muscle, Smooth, Vascular/virology , Myocytes, Smooth Muscle/pathology , Myocytes, Smooth Muscle/virology , Phosphorylation , Protein Interaction Domains and Motifs , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Pulmonary Artery/virology , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Signal Transduction
16.
PLoS One ; 15(10): e0240078, 2020.
Article in English | MEDLINE | ID: covidwho-814641

ABSTRACT

BACKGROUND: To evaluate chest-computed-tomography (CT) scans in coronavirus-disease-2019 (COVID-19) patients for signs of organizing pneumonia (OP) and microinfarction as surrogate for microscopic thromboembolic events. METHODS: Real-time polymerase-chain-reaction (RT-PCR)-confirmed COVID-19 patients undergoing chest-CT (non-enhanced, enhanced, pulmonary-angiography [CT-PA]) from March-April 2020 were retrospectively included (COVID-19-cohort). As control-groups served 175 patients from 2020 (cohort-2020) and 157 patients from 2019 (cohort-2019) undergoing CT-PA for pulmonary embolism (PE) during the respective time frame at our institution. Two independent readers assessed for presence and location of PE in all three cohorts. In COVID-19 patients additionally parenchymal changes typical of COVID-19 pneumonia, infarct pneumonia and OP were assessed. Inter-reader agreement and prevalence of PE in different cohorts were calculated. RESULTS: From 68 COVID-19 patients (42 female [61.8%], median age 59 years [range 32-89]) undergoing chest-CT 38 obtained CT-PA. Inter-reader-agreement was good (k = 0.781). On CT-PA, 13.2% of COVID-19 patients presented with PE whereas in the control-groups prevalence of PE was 9.1% and 8.9%, respectively (p = 0.452). Up to 50% of COVID-19 patients showed changes typical for OP. 21.1% of COVID-19 patients suspected with PE showed subpleural wedge-shaped consolidation resembling infarct pneumonia, while only 13.2% showed visible filling defects of the pulmonary artery branches on CT-PA. CONCLUSION: Despite the reported hypercoagulability in critically ill patients with COVID-19, we did not encounter higher prevalence of PE in our patient cohort compared to the control cohorts. However, patients with suspected PE showed a higher prevalence of lung changes, resembling patterns of infarct pneumonia or OP and CT-signs of pulmonary-artery hypertension.


Subject(s)
Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Pulmonary Artery/pathology , Pulmonary Infarction/diagnostic imaging , Thromboembolism/diagnostic imaging , Adult , Aged , Aged, 80 and over , COVID-19 , Coronavirus Infections/diagnostic imaging , Female , Humans , Lung/blood supply , Lung/pathology , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnostic imaging , Retrospective Studies , Tomography, X-Ray Computed
18.
Cardiovasc Pathol ; 49: 107263, 2020.
Article in English | MEDLINE | ID: covidwho-650406

ABSTRACT

Since its recognition in December 2019, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has rapidly spread globally causing a pandemic that represents the greatest medical challenge in decades. The aim of the study was to evaluate the spectrum of cardiopulmonary pathology of COVID-19 based on (non-minimal invasive) autopsies performed on 14 COVID-19 decedents. Bilateral diffuse alveolar damage (DAD) was found in all patients. Superimposed acute bronchopneumonia was present in 11 of 14 (78.6%) patients and was considered the major cause of death in 2 patients. A key finding was the presence of thrombotic/thromboembolic vascular occlusions. We classified 5 types of pulmonary thrombi: 1. capillary microthrombi (11/14, 78.6%); 2. partially organized thrombi in mid-sized pulmonary arteries with complete vessel occlusion; 3. non-organized thrombi in mid-sized pulmonary arteries that did not completely fill out the vessel lumen and probably represented thromboemboli rather than thrombosis; 4. bone marrow emboli (1/14, 7.1%); and 5. septic pulmonary thromboemboli (1/14, 7.1%). Pulmonary thrombi in mid-sized arteries were noted in 5 of 14 (35.7%) patients, causing pulmonary infarction and/or pulmonary hemorrhage. All patients had evidence of chronic cardiac disease, including myocardial hypertrophy (13/14, 92.9%), mild to marked coronary artery atherosclerosis (14/14, 100%) and focal myocardial fibrosis (3/14, 21.4%). Acute myocardial infarction was found as concurrent cause of death in 3 (21.4%) patients, and significant cardiac hypertrophy (heart weight 750 g) was present in 1 (7.1%) patient with ATTR-positive cardiac amyloidosis. The autopsy findings confirm that COVID-19 is a systemic disease, with major involvement of the lungs, that increases the risk of cardiac and vascular complications including acute myocardial injury and thrombotic/thromboembolic events. Secondary acute bronchopneumonia is a common complication in patients with COVID-19 and may be the major cause of death.


Subject(s)
Bronchopneumonia/pathology , Coronavirus Infections/complications , Coronavirus Infections/pathology , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Pulmonary Artery/pathology , Thrombosis/pathology , Aged , Aged, 80 and over , Autopsy , Betacoronavirus , Bronchopneumonia/virology , COVID-19 , Female , Humans , Incidence , Male , Middle Aged , Pandemics , Pulmonary Embolism/pathology , Pulmonary Embolism/virology , SARS-CoV-2 , Thrombosis/virology
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