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1.
Virchows Arch ; 2022 Apr 01.
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.

3.
Frontiers in immunology ; 13, 2022.
Article in English | EuropePMC | ID: covidwho-1710866

ABSTRACT

Complement plays an important role in the direct defense to pathogens, but can also activate immune cells and the release of pro-inflammatory cytokines. However, in critically ill patients with COVID-19 the immune system is inadequately activated leading to severe acute respiratory syndrome (SARS) and acute kidney injury, which is associated with higher mortality. Therefore, we characterized local complement deposition as a sign of activation in both lungs and kidneys from patients with severe COVID-19. Using immunohistochemistry we investigated deposition of complement factors C1q, MASP-2, factor D (CFD), C3c, C3d and C5b-9 as well as myeloperoxidase (MPO) positive neutrophils and SARS-CoV-2 virus particles in lungs and kidneys from 38 patients who died from COVID-19. In addition, tissue damage was analyzed using semi-quantitative scores followed by correlation with complement deposition. Autopsy material from non-COVID patients who died from cardiovascular causes, cerebral hemorrhage and pulmonary embolism served as control (n=8). Lung injury in samples from COVID-19 patients was significantly more pronounced compared to controls with formation of hyaline membranes, thrombi and edema. In addition, in the kidney tubular injury was higher in these patients and correlated with lung injury (r=0.361*). In autopsy samples SARS-CoV-2 spike protein was detected in 22% of the lungs of COVID-19 patients but was lacking in kidneys. Complement activation was significantly stronger in lung samples from patients with COVID-19 via the lectin and alternative pathway as indicated by deposition of MASP-2, CFD, C3d and C5b9. Deposits in the lung were predominantly detected along the alveolar septa, the hyaline membranes and in the alveolar lumina. In the kidney, complement was significantly more deposited in patients with COVID-19 in peritubular capillaries and tubular basement membranes. Renal COVID-19-induced complement activation occurred via the lectin pathway, while activation of the alternative pathway was similar in both groups. Furthermore, MPO-positive neutrophils were found in significantly higher numbers in lungs and kidneys of COVID-19 patients and correlated with local MASP-2 deposition. In conclusion, in patients who died from SARS-CoV-2 infection complement was activated in both lungs and kidneys indicating that complement might be involved in systemic worsening of the inflammatory response. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury in COVID-19.

4.
von Stillfried, Saskia, Bülow, Roman David, Röhrig, Rainer, Boor, Peter, Böcker, Jana, Schmidt, Jens, Tholen, Pauline, Majeed, Raphael, Wienströer, Jan, Weis, Joachim, Bremer, Juliane, Knüchel, Ruth, Breitbach, Anna, Cacchi, Claudio, Freeborn, Benita, Wucherpfennig, Sophie, Spring, Oliver, Braun, Georg, Römmele, Christoph, Märkl, Bruno, Claus, Rainer, Dhillon, Christine, Schaller, Tina, Sipos, Eva, Hirschbühl, Klaus, Wittmann, Michael, Kling, Elisabeth, Kröncke, Thomas, Heppner, Frank L.; Meinhardt, Jenny, Radbruch, Helena, Streit, Simon, Horst, David, Elezkurtaj, Sefer, Quaas, Alexander, Göbel, Heike, Hansen, Torsten, Titze, Ulf, Lorenzen, Johann, Reuter, Thomas, Woloszyn, Jaroslaw, Baretton, Gustavo, Hilsenbeck, Julia, Meinhardt, Matthias, Pablik, Jessica, Sommer, Linna, Holotiuk, Olaf, Meinel, Meike, Mahlke, Nina, Esposito, Irene, Crudele, Graziano, Seidl, Maximilian, Amann, Kerstin U.; Coras, Roland, Hartmann, Arndt, Eichhorn, Philip, Haller, Florian, Lange, Fabienne, Schmid, Kurt Werner, Ingenwerth, Marc, Rawitzer, Josefine, Theegarten, Dirk, Birngruber, Christoph G.; Wild, Peter, Gradhand, Elise, Smith, Kevin, Werner, Martin, Schilling, Oliver, Acker, Till, Gattenlöhner, Stefan, Stadelmann, Christine, Metz, Imke, Franz, Jonas, Stork, Lidia, Thomas, Carolina, Zechel, Sabrina, Ströbel, Philipp, Wickenhauser, Claudia, Fathke, Christine, Harder, Anja, Ondruschka, Benjamin, Dietz, Eric, Edler, Carolin, Fitzek, Antonia, Fröb, Daniela, Heinemann, Axel, Heinrich, Fabian, Klein, Anke, Kniep, Inga, Lohner, Larissa, Möbius, Dustin, Püschel, Klaus, Schädler, Julia, Schröder, Ann-Sophie, Sperhake, Jan-Peter, Aepfelbacher, Martin, Fischer, Nicole, Lütgehetmann, Marc, Pfefferle, Susanne, Glatzel, Markus, Krasemann, Susanne, Matschke, Jakob, Jonigk, Danny, Werlein, Christopher, Schirmacher, Peter, Domke, Lisa Maria, Hartmann, Laura, Klein, Isabel Madeleine, Schwab, Constantin, Röcken, Christoph, Friemann, Johannes, Langer, Dorothea, Roth, Wilfried, Strobl, Stephanie, Rudelius, Martina, Stock, Konrad Friedrich, Weichert, Wilko, Delbridge, Claire, Kasajima, Atsuko, Kuhn, Peer-Hendrik, Slotta-Huspenina, Julia, Weirich, Gregor, Barth, Peter, Wardelmann, Eva, Evert, Katja, Büttner, Andreas, Manhart, Johannes, Nigbur, Stefan, Bittmann, Iris, Fend, Falko, Bösmüller, Hans, Granai, Massimo, Klingel, Karin, Warm, Verena, Steinestel, Konrad, Umathum, Vincent Gottfried, Rosenwald, Andreas, Kurz, Florian, Vogt, Niklas.
The Lancet Regional Health - Europe ; : 100330, 2022.
Article in English | ScienceDirect | ID: covidwho-1693139

ABSTRACT

Summary Background Autopsies are an important tool in medicine, dissecting disease pathophysiology and causes of death. In COVID-19, autopsies revealed e.g., the effects on pulmonary (micro)vasculature or the nervous system, systemic viral spread, or the interplay with the immune system. To facilitate multicentre autopsy-based studies and provide a central hub supporting autopsy centres, researchers, and data analyses and reporting, in April 2020 the German COVID-19 Autopsy Registry (DeRegCOVID) was launched. Methods The electronic registry uses a web-based electronic case report form. Participation is voluntary and biomaterial remains at the respective site (decentralized biobanking). As of October 2021, the registry included N=1129 autopsy cases, with 69271 single data points including information on 18674 available biospecimens gathered from 29 German sites. Findings In the N=1095 eligible records, the male-to-female ratio was 1·8:1, with peaks at 65-69 and 80-84 years in males and >85 years in females. The analysis of the chain of events directly leading to death revealed COVID-19 as the underlying cause of death in 86% of the autopsy cases, whereas in 14% COVID-19 was a concomitant disease. The most common immediate cause of death was diffuse alveolar damage, followed by multi-organ failure. The registry supports several scientific projects, public outreach and provides reports to the federal health authorities, leading to legislative adaptation of the German Infection Protection Act, facilitating the performance of autopsies during pandemics. Interpretation A national autopsy registry can provide multicentre quantitative information on COVID-19 deaths on a national level, supporting medical research, political decision-making and public discussion. Funding German Federal Ministries of Education and Research and Health. Hintergrund: Obduktionen sind ein wichtiges Instrument in der Medizin, um die Pathophysiologie von Krankheiten und Todesursachen zu untersuchen. Im Rahmen von COVID-19 wurden durch Obduktionen z.B. die Auswirkungen auf die pulmonale Mikrovaskulatur, das Nervensystem, die systemische Virusausbreitung, und das Zusammenspiel mit dem Immunsystem untersucht. Um multizentrische, auf Obduktionen basierende Studien zu erleichtern und eine zentrale Anlaufstelle zu schaffen, die Obduktionszentren, Forscher sowie Datenanalysen und -berichte unterstützt, wurde im April 2020 das deutsche COVID-19-Autopsieregister (DeRegCOVID) ins Leben gerufen. Methoden: Das elektronische Register verwendet ein webbasiertes elektronisches Fallberichtsformular. Die Teilnahme ist freiwillig und das Biomaterial verbleibt am jeweiligen Standort (dezentrales Biobanking). Im Oktober 2021 umfasste das Register N=1129 Obduktionsfälle mit 69271 einzelnen Datenpunkten, die Informationen über 18674 verfügbare Bioproben enthielten, die von 29 deutschen Standorten gesammelt wurden. Ergebnisse: In den N=1095 ausgewerteten Datensätzen betrug das Verhältnis von Männern zu Frauen 1,8:1 mit Spitzenwerten bei 65-69 und 80-84 Jahren bei Männern und >85 Jahren bei Frauen. Die Analyse der Sequenz der unmittelbar zum Tod führenden Ereignisse ergab, dass in 86 % der Obduktionsfälle COVID-19 die zugrunde liegende Todesursache war, während in 14 % der Fälle COVID-19 eine Begleiterkrankung war. Die häufigste unmittelbare Todesursache war der diffuse Alveolarschaden, gefolgt von Multiorganversagen. Das Register unterstützt mehrere wissenschaftliche Projekte, die Öffentlichkeitsarbeit und liefert Berichte an die Bundesgesundheitsbehörden, was zu einer Anpassung des deutschen Infektionsschutzgesetzes führte und die Durchführung von Obduktionen in Pandemien erleichtert. Interpretation: Ein nationales Obduktionsregister kann multizentrische quantitative Informationen über COVID-19-Todesfälle auf nationaler Ebene liefern und damit die medizinische Forschung, die politische Entscheidungsfindung und die öffentliche Diskussion unterstützen. Finanzierung: Bundesministerien für Bildung und Forschung und für Gesundheit.

6.
Front Immunol ; 11: 594849, 2020.
Article in English | MEDLINE | ID: covidwho-1083385

ABSTRACT

Most patients who became critically ill following infection with COVID-19 develop severe acute respiratory syndrome (SARS) attributed to a maladaptive or inadequate immune response. The complement system is an important component of the innate immune system that is involved in the opsonization of viruses but also in triggering further immune cell responses. Complement activation was seen in plasma adsorber material that clogged during the treatment of critically ill patients with COVID-19. Apart from the lung, the kidney is the second most common organ affected by COVID-19. Using immunohistochemistry for complement factors C1q, MASP-2, C3c, C3d, C4d, and C5b-9 we investigated the involvement of the complement system in six kidney biopsies with acute kidney failure in different clinical settings and three kidneys from autopsy material of patients with COVID-19. Renal tissue was analyzed for signs of renal injury by detection of thrombus formation using CD61, endothelial cell rarefaction using the marker E-26 transformation specific-related gene (ERG-) and proliferation using proliferating cell nuclear antigen (PCNA)-staining. SARS-CoV-2 was detected by in situ hybridization and immunohistochemistry. Biopsies from patients with hemolytic uremic syndrome (HUS, n = 5), severe acute tubular injury (ATI, n = 7), zero biopsies with disseminated intravascular coagulation (DIC, n = 7) and 1 year protocol biopsies from renal transplants (Ctrl, n = 7) served as controls. In the material clogging plasma adsorbers used for extracorporeal therapy of patients with COVID-19 C3 was the dominant protein but collectin 11 and MASP-2 were also identified. SARS-CoV-2 was sporadically present in varying numbers in some biopsies from patients with COVID-19. The highest frequency of CD61-positive platelets was found in peritubular capillaries and arteries of COVID-19 infected renal specimens as compared to all controls. Apart from COVID-19 specimens, MASP-2 was detected in glomeruli with DIC and ATI. In contrast, the classical pathway (i.e. C1q) was hardly seen in COVID-19 biopsies. Both C3 cleavage products C3c and C3d were strongly detected in renal arteries but also occurs in glomerular capillaries of COVID-19 biopsies, while tubular C3d was stronger than C3c in biopsies from COVID-19 patients. The membrane attack complex C5b-9, demonstrating terminal pathway activation, was predominantly deposited in COVID-19 biopsies in peritubular capillaries, renal arterioles, and tubular basement membrane with similar or even higher frequency compared to controls. In conclusion, various complement pathways were activated in COVID-19 kidneys, the lectin pathway mainly in peritubular capillaries and in part the classical pathway in renal arteries whereas the alternative pathway seem to be crucial for tubular complement activation. Therefore, activation of the complement system might be involved in the worsening of renal injury. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury.


Subject(s)
Acute Kidney Injury/immunology , Acute Kidney Injury/virology , COVID-19/complications , COVID-19/immunology , Complement Activation/physiology , Adult , Aged , Female , Humans , Male , Middle Aged , SARS-CoV-2
7.
J Nephrol ; 33(6): 1369-1372, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-746136

ABSTRACT

SARS-CoV-2 is characterized by a multiorgan tropism including the kidneys. Recent autopsy series indicated that SARS-CoV-2 can infect both tubular and glomerular cells. Whereas tubular cell infiltration may contribute to acute kidney injury, data on a potential clinical correlative to glomerular affection is rare. We describe the first case of nephrotic syndrome in the context of COVID-19 in a renal transplant recipient. A 35 year old male patient received a kidney allograft for primary focal segmental glomerulosclerosis (FSGS). Three months posttransplant a recurrence of podocytopathy was successfully managed by plasma exchange, ivIG, and a conversion from tacrolimus to belatacept (initial proteinuria > 6 g/l decreased to 169 mg/l). Six weeks later he was tested positive for SARS-CoV-2 and developed a second increase of proteinuria (5.6 g/l). Renal allograft biopsy revealed diffuse podocyte effacement and was positive for SARS-CoV-2 in RNA in-situ hybridation indicating a SARS-CoV-2 associated recurrence of podocytopathy. Noteworthy, nephrotic proteinuria resolved spontaneously after recovering from COVID-19. The present case expands the spectrum of renal involvement in COVID-19 from acute tubular injury to podocytopathy in renal transplant recipients. Thus, it may be wise to test for SARS-CoV-2 prior to initiation of immunosuppression in new onset glomerulopathy during the pandemic.


Subject(s)
COVID-19/complications , Kidney Glomerulus/pathology , Nephrologists/standards , Nephrotic Syndrome/etiology , Adult , Biopsy , COVID-19/epidemiology , Humans , Male , Nephrotic Syndrome/diagnosis , Pandemics , Recurrence
8.
Am J Transplant ; 20(11): 3210-3215, 2020 11.
Article in English | MEDLINE | ID: covidwho-703598

ABSTRACT

The optimal management in transplant recipients with coronavirus disease 2019 (COVID-19) remains uncertain. The main concern is the ability of immunosuppressed patients to generate sufficient immunity for antiviral protection. Here, we report on immune monitoring facilitating a successful outcome of severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated pneumonia, meningoencephalitis, gastroenteritis, and acute kidney and pancreas graft failure in a pancreas-kidney transplant recipient. Despite the very low numbers of circulating B, NK, and T cells identified in follow-up, a strong SARS-CoV-2 reactive T cell response was observed. Importantly, we detected T cells reactive to Spike, Membrane, and Nucleocapsid proteins of SARS-CoV-2 with majority of T cells showing polyfunctional proinflammatory Th1 phenotype at all analyzed time points. Antibodies against Spike protein were also detected with increasing titers in follow-up. Neutralization tests confirmed their antiviral protection. A correlation between cellular and humoral immunity was observed underscoring the specificity of demonstrated data. We conclude that analyzing the kinetics of nonspecific and SARS-CoV-2-reactive cellular and humoral immunity can facilitate the clinical decision on immunosuppression adjustment and allow successful outcome as demonstrated in the current clinical case. Although the antiviral protection of the detected SARS-CoV-2-reactive T cells requires further evaluation, our data prove an ability mounting a strong SARS-CoV-2-reactive T cell response with functional capacity in immunosuppressed patients.


Subject(s)
Antibodies, Viral/immunology , COVID-19/epidemiology , Immunity, Humoral , Kidney Transplantation , Monitoring, Immunologic/methods , Pancreas Transplantation/methods , SARS-CoV-2/immunology , COVID-19/virology , Clinical Decision-Making , Comorbidity , Graft Rejection/epidemiology , Graft Rejection/immunology , Humans , Immunocompromised Host , Pandemics
9.
EBioMedicine ; 58: 102925, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-701831

ABSTRACT

BACKGROUND: Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood. METHODS: Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry. PATIENT FINDINGS: Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage. INTERPRETATION: These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage. FUNDING: Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung.


Subject(s)
Coronavirus Infections/pathology , Extracellular Traps/metabolism , Microvessels/pathology , Neutrophils/metabolism , Pneumonia, Viral/pathology , Thrombosis/metabolism , COVID-19 , Cells, Cultured , Coronavirus Infections/complications , Coronavirus Infections/metabolism , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Humans , Microvessels/metabolism , Neutrophils/pathology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , Thrombosis/etiology , Thrombosis/pathology
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