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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.

2.
Graefes Arch Clin Exp Ophthalmol ; 260(5): 1789-1797, 2022 May.
Article in English | MEDLINE | ID: covidwho-1787813

ABSTRACT

PURPOSE: To detect SARS-CoV-2 RNA in post-mortem human eyes. Ocular symptoms are common in patients with COVID-19. In some cases, they can occur before the onset of respiratory and other symptoms. Accordingly, SARS-CoV-2 RNA has been detected in conjunctival samples and tear film of patients suffering from COVID-19. However, the detection and clinical relevance of intravitreal SARS-CoV-2 RNA still remain unclear due to so far contradictory reports in the literature. METHODS: In our study 20 patients with confirmed diagnosis of COVID-19 were evaluated post-mortem to assess the conjunctival and intraocular presence of SARS-CoV-2 RNA using sterile pulmonary and conjunctival swabs as well as intravitreal biopsies (IVB) via needle puncture. SARS-CoV-2 PCR and whole genome sequencing from the samples of the deceased patients were performed. Medical history and comorbidities of all subjects were recorded and analyzed for correlations with viral data. RESULTS: SARS-CoV-2 RNA was detected in 10 conjunctival (50%) and 6 vitreal (30%) samples. SARS-CoV-2 whole genome sequencing showed the distribution of cases largely reflecting the frequency of circulating lineages in the Munich area at the time of examination with no preponderance of specific variants. Especially there was no association between the presence of SARS-CoV-2 RNA in IVBs and infection with the variant of concern (VOC) alpha. Viral load in bronchial samples correlated positively with load in conjunctiva but not the vitreous. CONCLUSION: SARS-CoV-2 RNA can be detected post mortem in conjunctival tissues and IVBs. This is relevant to the planning of ophthalmologic surgical procedures in COVID-19 patients, such as pars plana vitrectomy or corneal transplantation. Furthermore, not only during surgery but also in an outpatient setting it is important to emphasize the need for personal protection in order to avoid infection and spreading of SARS-CoV-2. Prospective studies are needed, especially to determine the clinical relevance of conjunctival and intravitreal SARS-CoV-2 detection concerning intraocular affection in active COVID-19 state and in post-COVID syndrome.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , Conjunctiva , Humans , RNA, Viral/genetics , SARS-CoV-2/genetics , Tears/chemistry
3.
Nat Commun ; 13(1): 1589, 2022 03 24.
Article in English | MEDLINE | ID: covidwho-1764177

ABSTRACT

Progressive respiratory failure and hyperinflammatory response is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. Despite mounting evidence of disruption of the hypothalamus-pituitary-adrenal axis in COVID-19, relatively little is known about the tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to adrenal glands and associated changes. Here we demonstrate adrenal viral tropism and replication in COVID-19 patients. Adrenal glands showed inflammation accompanied by inflammatory cell death. Histopathologic analysis revealed widespread microthrombosis and severe adrenal injury. In addition, activation of the glycerophospholipid metabolism and reduction of cortisone intensities were characteristic for COVID-19 specimens. In conclusion, our autopsy series suggests that SARS-CoV-2 facilitates the induction of adrenalitis. Given the central role of adrenal glands in immunoregulation and taking into account the significant adrenal injury observed, monitoring of developing adrenal insufficiency might be essential in acute SARS-CoV-2 infection and during recovery.


Subject(s)
COVID-19 , Autopsy , Humans , Research , SARS-CoV-2 , Tropism
4.
Infection ; 2022 Feb 18.
Article in English | MEDLINE | ID: covidwho-1703033

ABSTRACT

PURPOSE: Duodenal involvement in COVID-19 is poorly studied. Aim was to describe clinical and histopathological characteristics of critically ill COVID-19 patients suffering from severe duodenitis that causes a significant bleeding and/or gastrointestinal dysmotility. METHODS: In 51 critically ill patients suffering from SARS-CoV-2 pneumonia, severe upper intestinal bleeding and/or gastric feeding intolerance were indications for upper gastrointestinal endoscopy. Duodenitis was diagnosed according to macroscopic signs and mucosal biopsies. Immunohistochemistry was performed to detect viral specific protein and ACE2. In situ hybridization was applied to confirm viral replication. RESULTS: Nine of 51 critically ill patients (18%) suffering from SARS-CoV-2 pneumonia had developed upper GI bleeding complications and/or high gastric reflux. Five of them presented with minor and four (44%) with severe duodenitis. In two patients, erosions had caused severe gastrointestinal bleeding requiring PRBC transfusions. Immunohistochemical staining for SARS-CoV-2 spike protein was positive inside duodenal enterocytes in three of four patients suffering from severe duodenitis. Viral replication could be confirmed by in situ hybridization. CONCLUSION: Our data suggest that about 8% of critically ill COVID-19 patients may develop a severe duodenitis presumably associated with a direct infection of the duodenal enterocytes by SARS-CoV-2. Clinical consequences from severe bleeding and/or upper gastrointestinal dysmotility seem to be underestimated.

5.
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.
Cell Rep ; 38(7): 110387, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1654154

ABSTRACT

SARS-CoV-2 variants of concern (VOCs) display enhanced transmissibility and resistance to antibody neutralization. Comparing the early 2020 isolate EU-1 to the VOCs Alpha, Beta, and Gamma in mice transgenic for human ACE2 reveals that VOCs induce a broadened scope of symptoms, expand systemic infection to the gastrointestinal tract, elicit the depletion of natural killer cells, and trigger variant-specific cytokine production patterns. Gamma infections result in accelerated disease progression associated with increased immune activation and inflammation. All four SARS-CoV-2 variants induce pDC depletion in the lungs, paralleled by reduced interferon responses. Remarkably, VOCs also use the murine ACE2 receptor for infection to replicate in the lungs of wild-type animals, which induce cellular and innate immune responses that apparently curtail the spread of overt disease. VOCs thus display distinct intrinsic pathogenic properties with broadened tissue and host range. The enhanced pathogenicity of VOCs and their potential for reverse zoonotic transmission pose challenges to clinical and pandemic management.


Subject(s)
COVID-19/virology , Disease Models, Animal , SARS-CoV-2/physiology , SARS-CoV-2/pathogenicity , Animals , COVID-19/immunology , Cytokines/metabolism , Host Specificity , Immunity, Cellular , Immunity, Innate , Lung/immunology , Lung/virology , Mice , Species Specificity , Viral Load , Viral Tropism , Virulence , Virus Replication
7.
Infection ; 2021 Oct 30.
Article in English | MEDLINE | ID: covidwho-1491465

ABSTRACT

PURPOSE: To investigate the expression of the receptor protein ACE-2 alongside the urinary tract, urinary shedding and urinary stability of SARS-CoV-2 RNA. METHODS: Immunohistochemical staining was performed on tissue from urological surgery of 10 patients. Further, patients treated for coronavirus disease (COVID-19) at specialized care-units of a university hospital were assessed for detection of SARS-CoV-2 RNA in urinary samples via PCR, disease severity (WHO score), inflammatory response of patients. Finally, the stability of SARS-CoV-2 RNA in urine was analyzed. RESULTS: High ACE-2 expression (3/3) was observed in the tubules of the kidney and prostate glands, moderate expression in urothelial cells of the bladder (0-2/3) and no expression in kidney glomeruli, muscularis of the bladder and stroma of the prostate (0/3). SARS-CoV-2 RNA was detected in 5/199 urine samples from 64 patients. Viral RNA was detected in the first urinary sample of sequential samples. Viral RNA load from other specimen as nasopharyngeal swabs (NPS) or endotracheal aspirates revealed higher levels than from urine. Detection of SARS-CoV-2 RNA in urine was not associated with impaired WHO score (median 5, range 3-8 vs median 4, range 1-8, p = 0.314), peak white blood cell count (median 24.1 × 1000/ml, range 5.19-48.1 versus median 11.9 × 1000/ml, range 2.9-60.3, p = 0.307), peak CRP (median 20.7 mg/dl, 4.2-40.2 versus median 11.9 mg/dl, range 0.1-51.9, p = 0.316) or peak IL-6 levels (median: 1442 ng/ml, range 26.7-3918 versus median 140 ng/ml, range 3.0-11,041, p = 0.099). SARS-CoV-2 RNA was stable under different storage conditions and after freeze-thaw cycles. CONCLUSIONS: SARS-CoV-2 RNA in the urine of COVID-19 patients occurs infrequently. The viral RNA load and dynamics of SARS-CoV-2 RNA shedding suggest no relevant route of transmission through the urinary tract.

8.
J Thromb Haemost ; 19(2): 574-581, 2021 02.
Article in English | MEDLINE | ID: covidwho-939789

ABSTRACT

OBJECTIVE: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe pneumonia, but also thrombotic complications and non-pulmonary organ failure. Recent studies suggest intravascular neutrophil activation and subsequent immune cell-triggered immunothrombosis as a central pathomechanism linking the heterogenous clinical picture of coronavirus disease 2019 (COVID-19). We sought to study whether immunothrombosis is a pathognomonic factor in COVID-19 or a general feature of (viral) pneumonia, as well as to better understand its upstream regulation. APPROACH AND RESULTS: By comparing histopathological specimens of SARS-CoV-2 with influenza-affected lungs, we show that vascular neutrophil recruitment, NETosis, and subsequent immunothrombosis are typical features of severe COVID-19, but less prominent in influenza pneumonia. Activated neutrophils were typically found in physical association with monocytes. To explore this further, we combined clinical data of COVID-19 cases with comprehensive immune cell phenotyping and bronchoalveolar lavage fluid scRNA-seq data. We show that a HLADRlow CD9low monocyte population expands in severe COVID-19, which releases neutrophil chemokines in the lungs, and might in turn explain neutrophil expansion and pulmonary recruitment in the late stages of severe COVID-19. CONCLUSIONS: Our data underline an innate immune cell axis causing vascular inflammation and immunothrombosis in severe SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Immunity, Innate , Influenza, Human/immunology , Lung/immunology , Neutrophils/immunology , Thrombosis/immunology , Vasculitis/immunology , COVID-19/diagnosis , COVID-19/virology , Diagnosis, Differential , Host-Pathogen Interactions , Humans , Influenza, Human/diagnosis , Influenza, Human/virology , Lung/pathology , Lung/virology , Neutrophils/virology , Predictive Value of Tests , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Thrombosis/virology , Vasculitis/virology
9.
Circulation ; 142(12): 1176-1189, 2020 09 22.
Article in English | MEDLINE | ID: covidwho-696368

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19. METHODS: A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction-confirmed COVID-19 and n=24 non-COVID-19 controls). We performed histopathologic assessment of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well. RESULTS: We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non-COVID-19 pneumonia. Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability. CONCLUSIONS: Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.


Subject(s)
Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Respiratory Insufficiency/etiology , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/etiology , Blood Platelets/cytology , Blood Platelets/metabolism , Blood Platelets/pathology , COVID-19 , Case-Control Studies , Coronavirus Infections/complications , Coronavirus Infections/pathology , Coronavirus Infections/virology , Extracellular Traps/metabolism , Humans , Kidney/pathology , Lung/pathology , Neutrophils/cytology , Neutrophils/metabolism , Neutrophils/pathology , Pandemics , Phenotype , Platelet Activation , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Respiratory Insufficiency/diagnosis , SARS-CoV-2 , Severity of Illness Index , Thrombosis/complications , Thrombosis/diagnosis
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