Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 13 de 13
Filter
1.
Dtsch Arztebl Int ; (Forthcoming)2022 Jun 24.
Article in English | MEDLINE | ID: covidwho-1963370

ABSTRACT

BACKGROUND: The COVID-19 pandemic is the third worldwide coronavirus-associated disease outbreak in the past 20 years. Lung involvement, with acute respiratory distress syndrome (ARDS) in severe cases, is the main clinical feature of this disease; the cardiovascular system, the central nervous system, and the gastrointestinal tract can also be affected. The pathophysiology of both pulmonary and extrapulmonary organ damage was almost completely unknown when the pandemic began. METHODS: This review is based on pertinent publications retrieved by a selective search concerning the structural changes and pathophysiology of COVID-19, with a focus on imaging techniques. RESULTS: Immunohistochemical, electron-microscopic and molecular pathological analyses of tissues obtained by autopsy have improved our understanding of COVID-19 pathophysiology, including molecular regulatory mechanisms. Intussusceptive angiogenesis (IA) has been found to be a prominent pattern of damage in the affected organs of COVID-19 patients. In IA, an existing vessel changes by invagination of the endothelium and formation of an intraluminal septum, ultimately giving rise to two new lumina. This alters hemodynamics within the vessel, leading to a loss of laminar flow and its replacement by turbulent, inhomogeneous flow. IA, which arises because of ischemia due to thrombosis, is itself a risk factor for the generation of further microthrombi; these have been detected in the lungs, heart, liver, kidneys, brain, and placenta of COVID-19 patients. CONCLUSION: Studies of autopsy material from various tissues of COVID-19 patients have revealed ultrastructural evidence of altered microvascularity, IA, and multifocal thrombi. These changes may contribute to the pathophysiology of post-acute interstitial fibrotic organ changes as well as to the clinical picture of long COVID.

2.
Front Immunol ; 13: 879157, 2022.
Article in English | MEDLINE | ID: covidwho-1933664

ABSTRACT

During the COVID-19 pandemic, vaccination is the most important countermeasure. Pharmacovigilance concerns however emerged with very rare, but potentially disastrous thrombotic complications following vaccination with ChAdOx1. Platelet factor-4 antibody mediated vaccine-induced immune thrombotic thrombocytopenia (VITT) was described as an underlying mechanism of these thrombotic events. Recent work moreover suggests that mechanisms of immunothrombosis including neutrophil extracellular trap (NET) formation might be critical for thrombogenesis during VITT. In this study, we investigated blood and thrombus specimens of a female patient who suffered severe stroke due to VITT after vaccination with ChAdOx1 in comparison to 13 control stroke patients with similar clinical characteristics. We analyzed cerebral thrombi using histological examination, staining of complement factors, NET-markers, DNase and LL-37. In blood samples at the hyper-acute phase of stroke and 7 days later, we determined cell-free DNA, myeloperoxidase-histone complexes, DNase activity, myeloperoxidase activity, LL-37 and inflammatory cytokines. NET markers were identified in thrombi of all patients. Interestingly, the thrombus of the VITT-patient exclusively revealed complement factors and high amounts of DNase and LL-37. High DNase activity was also measured in blood, implying a disturbed NET-regulation. Furthermore, serum of the VITT-patient inhibited reactive oxygen species-dependent NET-release by phorbol-myristate-acetate to a lesser degree compared to controls, indicating either less efficient NET-inhibition or enhanced NET-induction in the blood of the VITT-patient. Additionally, the changes in specific cytokines over time were emphasized in the VITT-patient as well. In conclusion, insufficient resolution of NETs, e.g. by endogenous DNases or protection of NETs against degradation by embedded factors like the antimicrobial peptide LL-37 might thus be an important factor in the pathology of VITT besides increased NET-formation. On the basis of these findings, we discuss the potential implications of the mechanisms of disturbed NETs-degradation for diagnostic and therapeutic approaches in VITT-related thrombogenesis, other auto-immune disorders and beyond.


Subject(s)
COVID-19 , Extracellular Traps , Purpura, Thrombocytopenic, Idiopathic , Stroke , Thrombocytopenia , Thrombosis , Vaccines , Deoxyribonuclease I/metabolism , Deoxyribonucleases , Female , Humans , Neutrophils , Pandemics , Peroxidase/metabolism , Platelet Factor 4/metabolism , Purpura, Thrombocytopenic, Idiopathic/metabolism , Stroke/etiology , Stroke/metabolism , Thrombocytopenia/chemically induced , Thrombocytopenia/metabolism , Thrombosis/etiology , Thrombosis/metabolism , Vaccines/metabolism
3.
Virchows Arch ; 481(2): 139-159, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1787815

ABSTRACT

The use of autopsies in medicine has been declining. The COVID-19 pandemic has documented and rejuvenated the importance of autopsies as a tool of modern medicine. In this review, we discuss the various autopsy techniques, the applicability of modern analytical methods to understand the pathophysiology of COVID-19, the major pathological organ findings, limitations or current studies, and open questions. This article summarizes published literature and the consented experience of the nationwide network of clinical, neuro-, and forensic pathologists from 27 German autopsy centers with more than 1200 COVID-19 autopsies. The autopsy tissues revealed that SARS-CoV-2 can be found in virtually all human organs and tissues, and the majority of cells. Autopsies have revealed the organ and tissue tropism of SARS-CoV-2, and the morphological features of COVID-19. This is characterized by diffuse alveolar damage, combined with angiocentric disease, which in turn is characterized by endothelial dysfunction, vascular inflammation, (micro-) thrombosis, vasoconstriction, and intussusceptive angiogenesis. These findings explained the increased pulmonary resistance in COVID-19 and supported the recommendations for antithrombotic treatment in COVID-19. In contrast, in extra-respiratory organs, pathological changes are often nonspecific and unclear to which extent these changes are due to direct infection vs. indirect/secondary mechanisms of organ injury, or a combination thereof. Ongoing research using autopsies aims at answering questions on disease mechanisms, e.g., focusing on variants of concern, and future challenges, such as post-COVID conditions. Autopsies are an invaluable tool in medicine and national and international interdisciplinary collaborative autopsy-based research initiatives are essential.


Subject(s)
COVID-19 , Autopsy , Humans , Lung/pathology , Pandemics , SARS-CoV-2
5.
Mol Med Rep ; 25(4)2022 04.
Article in English | MEDLINE | ID: covidwho-1715860

ABSTRACT

In addition to the angiotensin­converting enzyme 2 (ACE2), a number of host cell entry mediators have been identified for severe acute respiratory syndrome coronavirus­2 (SARS­CoV­2), including transmembrane protease serine 4 (TMPRSS4). The authors have recently demonstrated the upregulation of TMPRSS4 in 11 different cancers, as well as its specific expression within the central nervous system using in silico tools. The present study aimed to expand the initial observations and, using immunohistochemistry, TMPRSS4 protein expression in the gastrointestinal (GI) tract and lungs was further mapped. Immunohistochemistry was performed on tissue arrays and lung tissues of patients with non­small cell lung cancer with concurrent coronavirus disease 2019 (COVID­19) infection using TMPRSS4 antibody. The results revealed that TMPRSS4 was abundantly expressed in the oesophagus, stomach, small intestine, jejunum, ileum, colon, liver and pancreas. Moreover, the extensive TMPRSS4 protein expression in the lungs of a deceased patient with COVID­19 with chronic obstructive pulmonary disease and bronchial carcinoma, as well in the adjacent normal tissue, was demonstrated for the first time, at least to the best of our knowledge. On the whole, the immunohistochemistry data of the present study suggest that TMPRSS4 may be implicated in the broader (pulmonary and extra­pulmonary) COVID­19 symptomatology; thus, it may be responsible for the tropism of this coronavirus both in the GI tract and lungs.


Subject(s)
COVID-19/pathology , Gastrointestinal Tract/pathology , Lung Neoplasms/pathology , Lung/pathology , Membrane Proteins/metabolism , Serine Endopeptidases/metabolism , Aged , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/virology , Gastrointestinal Tract/virology , Humans , Immunohistochemistry , Lung/virology , Lung Neoplasms/complications , Male , Membrane Proteins/analysis , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/analysis , Virus Internalization
6.
Int J Mol Sci ; 23(3)2022 Jan 29.
Article in English | MEDLINE | ID: covidwho-1667195

ABSTRACT

(1) Background: In COVID-19 survivors there is an increased prevalence of pulmonary fibrosis of which the underlying molecular mechanisms are poorly understood; (2) Methods: In this multicentric study, n = 12 patients who succumbed to COVID-19 due to progressive respiratory failure were assigned to an early and late group (death within ≤7 and >7 days of hospitalization, respectively) and compared to n = 11 healthy controls; mRNA and protein expression as well as biological pathway analysis were performed to gain insights into the evolution of pulmonary fibrogenesis in COVID-19; (3) Results: Median duration of hospitalization until death was 3 (IQR25-75, 3-3.75) and 14 (12.5-14) days in the early and late group, respectively. Fifty-eight out of 770 analyzed genes showed a significantly altered expression signature in COVID-19 compared to controls in a time-dependent manner. The entire study group showed an increased expression of BST2 and IL1R1, independent of hospitalization time. In the early group there was increased activity of inflammation-related genes and pathways, while fibrosis-related genes (particularly PDGFRB) and pathways dominated in the late group; (4) Conclusions: After the first week of hospitalization, there is a shift from pro-inflammatory to fibrogenic activity in severe COVID-19. IL1R1 and PDGFRB may serve as potential therapeutic targets in future studies.


Subject(s)
COVID-19/genetics , COVID-19/metabolism , Pulmonary Fibrosis/pathology , Aged , COVID-19/mortality , Female , Hospital Mortality/trends , Hospitalization , Humans , Lung/pathology , Male , Middle Aged , Pulmonary Fibrosis/metabolism , Respiratory Insufficiency/pathology , SARS-CoV-2/pathogenicity
7.
Elife ; 102021 12 21.
Article in English | MEDLINE | ID: covidwho-1597375

ABSTRACT

For the first time, we have used phase-contrast X-ray tomography to characterize the three-dimensional (3d) structure of cardiac tissue from patients who succumbed to Covid-19. By extending conventional histopathological examination by a third dimension, the delicate pathological changes of the vascular system of severe Covid-19 progressions can be analyzed, fully quantified and compared to other types of viral myocarditis and controls. To this end, cardiac samples with a cross-section of 3.5mm were scanned at a laboratory setup as well as at a parallel beam setup at a synchrotron radiation facility the synchrotron in a parallel beam configuration. The vascular network was segmented by a deep learning architecture suitable for 3d datasets (V-net), trained by sparse manual annotations. Pathological alterations of vessels, concerning the variation of diameters and the amount of small holes, were observed, indicative of elevated occurrence of intussusceptive angiogenesis, also confirmed by high-resolution cone beam X-ray tomography and scanning electron microscopy. Furthermore, we implemented a fully automated analysis of the tissue structure in the form of shape measures based on the structure tensor. The corresponding distributions show that the histopathology of Covid-19 differs from both influenza and typical coxsackie virus myocarditis.


Subject(s)
COVID-19/complications , Myocarditis/pathology , Myocarditis/virology , Myocardium/pathology , SARS-CoV-2/isolation & purification , Artificial Intelligence , COVID-19/pathology , Heart/diagnostic imaging , Heart/virology , Humans , Imaging, Three-Dimensional , Myocarditis/diagnostic imaging , Myocarditis/etiology , Synchrotrons , Tomography, X-Ray Computed
9.
Cells ; 10(8)2021 07 27.
Article in English | MEDLINE | ID: covidwho-1335012

ABSTRACT

Multiorgan tropism of SARS-CoV-2 has previously been shown for several major organs. We have comprehensively analyzed 25 different formalin-fixed paraffin-embedded (FFPE) tissues/organs from autopsies of fatal COVID-19 cases (n = 8), using histopathological assessment, detection of SARS-CoV-2 RNA using polymerase chain reaction and RNA in situ hybridization, viral protein using immunohistochemistry, and virus particles using transmission electron microscopy. SARS-CoV-2 RNA was mainly localized in epithelial cells across all organs. Next to lung, trachea, kidney, heart, or liver, viral RNA was also found in tonsils, salivary glands, oropharynx, thyroid, adrenal gland, testicles, prostate, ovaries, small bowel, lymph nodes, skin and skeletal muscle. Viral RNA was predominantly found in cells expressing ACE2, TMPRSS2, or both. The SARS-CoV-2 replicating RNA was also detected in these organs. Immunohistochemistry and electron microscopy were not suitable for reliable and specific SARS-CoV-2 detection in autopsies. These findings were validated using in situ hybridization on external COVID-19 autopsy samples (n = 9). Apart from the lung, correlation of viral detection and histopathological assessment did not reveal any specific alterations that could be attributed to SARS-CoV-2. In summary, SARS-CoV-2 and its replication could be observed across all organ systems, which co-localizes with ACE2 and TMPRSS2 mainly in epithelial but also in mesenchymal and endothelial cells. Apart from the respiratory tract, no specific (histo-)morphologic alterations could be assigned to the SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/metabolism , Endothelial Cells/metabolism , RNA, Viral/analysis , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Aged , Autopsy , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Endothelial Cells/pathology , Endothelial Cells/virology , Female , Gene Expression Regulation , Humans , Male , Middle Aged , Organ Specificity , Tropism
10.
Pathologe ; 42(2): 164-171, 2021 Mar.
Article in German | MEDLINE | ID: covidwho-1235729

ABSTRACT

Viral respiratory diseases constitute the most common reasons for hospitalization with more than half of all acute illnesses worldwide. Progressive respiratory failure with pronounced diffuse alveolar damage has been identified as the primary cause of death in COVID-19. COVID-19 pneumonia shares common histopathological hallmarks with influenza (H1N1)-related ARDS, like diffuse alveolar damage (DAD) with edema, hemorrhage, and intra-alveolar fibrin deposition. The lungs with COVID-19 pneumonia revealed perivascular inflammation, an endothelial injury, microangiopathy, and an aberrant blood vessel neoformation by intussusceptive angiogenesis. While this pronounced angiocentric inflammation is likely be found - to varying degrees - in numerous other organs, e.g., the heart, COVID-19 is hypothesized to be not just a pulmonary, but rather a systemic "vascular disease."


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Heart , Humans , Lung , SARS-CoV-2
11.
Pathologe ; 42(2): 164-171, 2021 Mar.
Article in German | MEDLINE | ID: covidwho-1070829

ABSTRACT

Viral respiratory diseases constitute the most common reasons for hospitalization with more than half of all acute illnesses worldwide. Progressive respiratory failure with pronounced diffuse alveolar damage has been identified as the primary cause of death in COVID-19. COVID-19 pneumonia shares common histopathological hallmarks with influenza (H1N1)-related ARDS, like diffuse alveolar damage (DAD) with edema, hemorrhage, and intra-alveolar fibrin deposition. The lungs with COVID-19 pneumonia revealed perivascular inflammation, an endothelial injury, microangiopathy, and an aberrant blood vessel neoformation by intussusceptive angiogenesis. While this pronounced angiocentric inflammation is likely be found - to varying degrees - in numerous other organs, e.g., the heart, COVID-19 is hypothesized to be not just a pulmonary, but rather a systemic "vascular disease."


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Heart , Humans , Lung , SARS-CoV-2
12.
Elife ; 92020 08 20.
Article in English | MEDLINE | ID: covidwho-724355

ABSTRACT

We present a three-dimensional (3D) approach for virtual histology and histopathology based on multi-scale phase contrast x-ray tomography, and use this to investigate the parenchymal architecture of unstained lung tissue from patients who succumbed to Covid-19. Based on this first proof-of-concept study, we propose multi-scale phase contrast x-ray tomography as a tool to unravel the pathophysiology of Covid-19, extending conventional histology by a third dimension and allowing for full quantification of tissue remodeling. By combining parallel and cone beam geometry, autopsy samples with a maximum cross section of 8 mm are scanned and reconstructed at a resolution and image quality, which allows for the segmentation of individual cells. Using the zoom capability of the cone beam geometry, regions-of-interest are reconstructed with a minimum voxel size of 167 nm. We exemplify the capability of this approach by 3D visualization of diffuse alveolar damage (DAD) with its prominent hyaline membrane formation, by mapping the 3D distribution and density of lymphocytes infiltrating the tissue, and by providing histograms of characteristic distances from tissue interior to the closest air compartment.


Subject(s)
Betacoronavirus/pathogenicity , Clinical Laboratory Techniques , Coronavirus Infections/diagnostic imaging , Imaging, Three-Dimensional , Lung/diagnostic imaging , Pneumonia, Viral/diagnostic imaging , Tomography, X-Ray Computed , Adult , Aged , Aged, 80 and over , Autopsy , Biopsy , COVID-19 , COVID-19 Testing , Coronavirus Infections/diagnosis , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Host Microbial Interactions , Humans , Lung/pathology , Lung/virology , Male , Middle Aged , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Predictive Value of Tests , Proof of Concept Study , SARS-CoV-2 , Young Adult
13.
N Engl J Med ; 383(2): 120-128, 2020 07 09.
Article in English | MEDLINE | ID: covidwho-327378

ABSTRACT

BACKGROUND: Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19. METHODS: We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro-computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression. RESULTS: In patients who died from Covid-19-associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth - predominantly through a mechanism of intussusceptive angiogenesis - was 2.7 times as high as that in the lungs from patients with influenza (P<0.001). CONCLUSIONS: In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.).


Subject(s)
Coronavirus Infections/pathology , Endothelium, Vascular/pathology , Neovascularization, Pathologic , Pneumonia, Viral/pathology , Thrombosis/virology , Aged , Aged, 80 and over , Autopsy , Betacoronavirus , COVID-19 , Coronavirus Infections/mortality , Endothelium, Vascular/virology , Female , Humans , Influenza A Virus, H1N1 Subtype , Influenza, Human/mortality , Influenza, Human/pathology , Lung/pathology , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Respiratory Insufficiency , SARS-CoV-2
SELECTION OF CITATIONS
SEARCH DETAIL