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1.
Biomedicines ; 10(4):858, 2022.
Article in English | MDPI | ID: covidwho-1776131

ABSTRACT

In December 2019, the first case of COVID-19 was reported and since then several groups have already published that the virus can be present in the testis. To study the influence of SARS-CoV-2 which cause a dysregulation of the androgen receptor (AR) level, thereby leading to fertility problems and inducing germ cell testicular changes in patients after the infection. Formalin-Fixed-Paraffin-Embedded (FFPE) testicular samples from patients who died with or as a result of COVID-19 (n = 32) with controls (n = 6), inflammatory changes (n = 9), seminoma with/without metastasis (n = 11) compared with healthy biopsy samples (n = 3) were analyzed and compared via qRT-PCR for the expression of miR-371a-3p. An immunohistochemical analysis (IHC) and ELISA were performed in order to highlight the miR-371a-3p targeting the AR. Serum samples of patients with mild or severe COVID-19 symptoms (n = 34) were analyzed for miR-371a-3p expression. In 70% of the analyzed postmortem testicular tissue samples, a significant upregulation of the miR-371a-3p was detected, and 75% of the samples showed a reduced spermatogenesis. In serum samples, the upregulation of the miR-371a-3p was also detectable. The upregulation of the miR-371a-3p is responsible for the downregulation of the AR in SARS-CoV-2-positive patients, resulting in decreased spermatogenesis. Since the dysregulation of the AR is associated with infertility, further studies have to confirm if the identified dysregulation is regressive after a declining infection.

2.
Mod Pathol ; 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1773954

ABSTRACT

The rate of SARS-CoV-2 infections in vaccinees has become a relevant serious issue. This study aimed to determine the causes of death, histological organ alteration, and viral spread in relation to demographic, clinical-pathological, viral variants, and vaccine types for deceased individuals with proven SARS-CoV-2 infection after vaccination who died between January and November 2021. Twenty-nine consecutively collected cases were analyzed and compared to 141 nonvaccinated control cases. Autopsies were performed on 16 partially and 13 fully vaccinated individuals. Most patients were elderly and suffered from several relevant comorbidities. Real-time RT-PCR (RT-qPCR) identified a significantly increased rate of generalized viral dissemination within organ systems in vaccinated cases versus nonvaccinated cases (45% vs. 16%, respectively; P = 0.008) mainly with Ct-values of higher than 25 in non-respiratory samples. However, vaccinated cases also showed high viral loads, reaching Ct-values below 10, especially in the upper airways and lungs. This was accompanied by high rates of pulmonal bacterial or mycotic superinfections and the occurrence of immunocompromising factors, such as malignancies, immunosuppressive drug intake, or decreased immunoglobulin levels. All these findings were particularly accentuated in partially vaccinated patients compared to fully vaccinated individuals. The virus dissemination observed in our case study may indicate that patients with an impaired immune system have a decreased ability to eliminate the virus. However, the potential role of antibody-dependent enhancement must also be ruled out in future studies. Fatal cases of COVID-19 in vaccinees were rare and often associated with severe comorbidities or other immunosuppressive conditions.

3.
Crit Care ; 26(1): 83, 2022 03 28.
Article in English | MEDLINE | ID: covidwho-1765459

ABSTRACT

BACKGROUND: In severe cases, SARS-CoV-2 infection leads to acute respiratory distress syndrome (ARDS), often treated by extracorporeal membrane oxygenation (ECMO). During ECMO therapy, anticoagulation is crucial to prevent device-associated thrombosis and device failure, however, it is associated with bleeding complications. In COVID-19, additional pathologies, such as endotheliitis, may further increase the risk of bleeding complications. To assess the frequency of bleeding events, we analyzed data from the German COVID-19 autopsy registry (DeRegCOVID). METHODS: The electronic registry uses a web-based electronic case report form. In November 2021, the registry included N = 1129 confirmed COVID-19 autopsy cases, with data on 63 ECMO autopsy cases and 1066 non-ECMO autopsy cases, contributed from 29 German sites. FINDINGS: The registry data showed that ECMO was used in younger male patients and bleeding events occurred much more frequently in ECMO cases compared to non-ECMO cases (56% and 9%, respectively). Similarly, intracranial bleeding (ICB) was documented in 21% of ECMO cases and 3% of non-ECMO cases and was classified as the immediate or underlying cause of death in 78% of ECMO cases and 37% of non-ECMO cases. In ECMO cases, the three most common immediate causes of death were multi-organ failure, ARDS and ICB, and in non-ECMO cases ARDS, multi-organ failure and pulmonary bacterial ± fungal superinfection, ordered by descending frequency. INTERPRETATION: Our study suggests the potential value of autopsies and a joint interdisciplinary multicenter (national) approach in addressing fatal complications in COVID-19.


Subject(s)
COVID-19 , Extracorporeal Membrane Oxygenation , Respiratory Distress Syndrome , Respiratory Insufficiency , COVID-19/complications , COVID-19/therapy , Extracorporeal Membrane Oxygenation/adverse effects , Humans , Intracranial Hemorrhages/complications , Intracranial Hemorrhages/epidemiology , Male , Respiratory Distress Syndrome/therapy , Respiratory Insufficiency/etiology , Respiratory Insufficiency/therapy , SARS-CoV-2
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.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-321642

ABSTRACT

Background: A number of histopathological reports showed the presence of widespread thrombosis and associated morphology in pulmonary vessels of patients with COVID-19. Later, we identified vascular occlusions with neutrophils and neutrophil extracellular traps (NETs), as major components, in autopsy tissue from patients with COVID-19.Methods: We, here investigated 109 lung specimens from 17 patients with COVID-19 and compared them with 11 lung specimens from two patients who succumbed to pulmonary embolism and acute cardiac. Healthy lung specimens from four patients served as controls. We studied these autopsy lung specimens using immunohistochemistry and native endogenous fluorescence.Findings: We present a label-free imaging technique using native endogenous fluorescence that enables the visualization of occluded vessels. We demonstrate that native endogenous fluorescence identified occluded vessels in tissue specimens from patients with COVID-19.Interpretation: Label-free detection of occluded vessels enabled the detection of affected occluded vessels in lung specimens of patients with COVID-19 where the occluding components showed varying contents of neutrophil-derived materials.Funding Statement: Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-StiftungDeclaration of Interests: All authors have no conflicts of interests to declare.Ethics Approval Statement: An institutional approval from each local Ethical Committee was obtained (permit #193_13B;permit # 174_20B;EK 092/20;EK 119/20;EK 460/20).

8.
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
9.
Virchows Arch ; 480(3): 519-528, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1611405

ABSTRACT

Confronted with an emerging infectious disease at the beginning of the COVID-19 pandemic, the medical community faced concerns regarding the safety of autopsies on those who died of the disease. This attitude has changed, and autopsies are now recognized as indispensable tools for understanding COVID-19, but the true risk of infection to autopsy staff is nevertheless still debated. To clarify the rate of SARS-CoV-2 contamination in personal protective equipment (PPE), swabs were taken at nine points in the PPE of one physician and one assistant after each of 11 full autopsies performed at four centers. Swabs were also obtained from three minimally invasive autopsies (MIAs) conducted at a fifth center. Lung/bronchus swabs of the deceased served as positive controls, and SARS-CoV-2 RNA was detected by real-time RT-PCR. In 9 of 11 full autopsies, PPE samples tested RNA positive through PCR, accounting for 41 of the 198 PPE samples taken (21%). The main contaminated items of the PPE were gloves (64% positive), aprons (50% positive), and the tops of shoes (36% positive) while the fronts of safety goggles, for example, were positive in only 4.5% of the samples, and all the face masks were negative. In MIAs, viral RNA was observed in one sample from a glove but not in other swabs. Infectious virus isolation in cell culture was performed on RNA-positive swabs from the full autopsies. Of all the RNA-positive PPE samples, 21% of the glove samples, taken in 3 of 11 full autopsies, tested positive for infectious virus. In conclusion, PPE was contaminated with viral RNA in 82% of autopsies. In 27% of autopsies, PPE was found to be contaminated even with infectious virus, representing a potential risk of infection to autopsy staff. Adequate PPE and hygiene measures, including appropriate waste deposition, are therefore essential to ensure a safe work environment.


Subject(s)
COVID-19 , Personal Protective Equipment , Autopsy , COVID-19/prevention & control , Humans , Pandemics/prevention & control , RNA, Viral/genetics , SARS-CoV-2
10.
Cell Stem Cell ; 29(2): 217-231.e8, 2022 02 03.
Article in English | MEDLINE | ID: covidwho-1586459

ABSTRACT

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/complications , Fibrosis , Humans , Kidney , Organoids/pathology
11.
Virchows Arch ; 479(1): 97-108, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1574264

ABSTRACT

Between April and June 2020, i.e., during the first wave of pandemic coronavirus disease 2019 (COVID-19), 55 patients underwent long-term treatment in the intensive care unit at the University Hospital of Regensburg. Most of them were transferred from smaller hospitals, often due to the need for an extracorporeal membrane oxygenation system. Autopsy was performed in 8/17 COVID-19-proven patients after long-term treatment (mean: 33.6 days). Autopsy revealed that the typical pathological changes occurring during the early stages of the disease (e.g., thrombosis, endothelitis, capillaritis) are less prevalent at this stage, while severe diffuse alveolar damage and especially coinfection with different fungal species were the most conspicuous finding. In addition, signs of macrophage activation syndrome was detected in 7 of 8 patients. Thus, fungal infections were a leading cause of death in our cohort of severely ill patients and may alter clinical management of patients, particularly in long-term periods of treatment.


Subject(s)
COVID-19/microbiology , Coinfection , Lung Diseases, Fungal/microbiology , Lung/microbiology , Multiple Organ Failure/microbiology , Adult , Aged , COVID-19/drug therapy , COVID-19/mortality , COVID-19/pathology , COVID-19/therapy , Cause of Death , Extracorporeal Membrane Oxygenation , Female , Humans , Intensive Care Units , Lung/pathology , Lung/virology , Lung Diseases, Fungal/mortality , Lung Diseases, Fungal/pathology , Macrophage Activation Syndrome/microbiology , Macrophage Activation Syndrome/pathology , Male , Middle Aged , Multiple Organ Failure/mortality , Multiple Organ Failure/pathology , Multiple Organ Failure/virology , Risk Factors , Time Factors , Treatment Outcome
12.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-295175

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome patients are at risk for fungal infections, especially aspergillosis and mucormycosis. COVID-19-associated pulmonary aspergillosis (CAPA) is differentiated in a pulmonary form and Aspergillus tracheobronchitis (ATB). During the first wave of the pandemic, bronchoscopy for diagnosing Aspergillus superinfections was rarely performed in COVID-19 patients, so that detailed on data on ATB in CAPA patients is scarce. We analyzed prevalence and mortality of tracheobronchitis in patients with CAPA.Methods: We conducted a retrospective, single-centre study at the 14-bed intensive care unit (ICU) of the Department I of Internal Medicine of the University Hospital of Cologne, Germany from March 2020 to February 2021. CAPA patients were identified by twice weekly analysis of tracheal aspirates for Aspergillus growth, Aspergillus DNA (PCR) and galactomannan combined with serum galactomannan testing. In case of positive results, bronchoscopy with the examination of trachea and lower airways and bronchoalveolar lavage followed.Findings: A total of 69 COVID-19 patients were admitted to the ICU, with 17 patients developing probable CAPA. All CAPA patients received bronchoscopy resulting in a clinical diagnosis of tracheobronchitis in 8 patients with signs of tracheal lesions, pseudomembranes or vulnerable bloody trachea. Seven bronchoalveolar lavages revealed culture and eight PCR positivity for Aspergillus fumigatus. In 7 of 8 tracheobronchitis patients, bronchoalveolar lavage samples tested positive for galactomannan antigen optical density index of >0.5. The overall mortality of CAPA patients was 52.9% and the overall mortality of ATB patients was 75%.Interpretation: Our data indicate a substantial prevalence of tracheobronchitis in this single-center cohort of CAPA patients. To facilitate early diagnosis bronchoscopic tracheal examination is crucial as computed tomography lacks diagnostic accuracy to enable timely initiation of therapy.Funding Information: This work was in part supported by the German Registry of COVID-19 Autopsies (www.DeRegCOVID.ukaachen.de), funded by the Federal Ministry of Health (ZMVI1-2520COR201), and the project DEFEAT PANDEMICs, funded by the Federal Ministry of Education and Research (01KX2021).Declaration of Interests: PK reports grants or contracts from German Federal Ministry of Research and Education and the State of North Rhine-Westphalia;Consulting fees Ambu GmbH, Gilead Sciences, Noxxon N.V. and Pfizer Pharma;Honoraria for lectures from Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, medupdate GmbH, MedMedia, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicación Científica SC and University Hospital and LMU Munich;Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Pfizer Pharma;A pending patent currently reviewed at the German Patent and Trade Mark Office;Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. SvS none. JGB reports scientific grants and travel expenses from Kite/Gilead outside the submitted work. FF has a clinician scientist position supported by the deans office, medical faculty, University of Cologne. JSG none. FP none. BB reports honoraria, travel expenses and advisory role from/for Astellas, Celgene, Johnson & Johnson, Kite/Gilead, MSD, Novartis, Pfizer, Takeda and financing of scientific research by Astellas, Celgene, Kite/Gilead, MSD and Takeda outside the submitted work. DAE received honoraria from Sanofi and TAKEDA outside the submitted work. ASV reports travel grants from Gilead Sciences outside the submitted work. OK reports payment or honoraria for lectures, presentations or speakers bureaus by Gilead and Pfizer and receipt of equipment, materials, drugs, medical writing, gifts or other services by Pfizer MSD, Basilea, Gilead, Virotech and Wako Fujifilm outside the submitted work. PB none. MK reports payment or honoraria for lectures, presentations or speakers bureaus by Gilead, MSD and Pfizer outside the submitted work. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis;Consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, PSI, Scynexis, Seres;Honoraria for lectures from Abbott, Al 344 Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Pfizer;Payment for expert testimony from Cidara;Participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI, Shionogi;A pending patent currently reviewed at the German Patent and Trade Mark Office;Other interests from DGHO, DGI, ECMM, ISHAM, MSG-ERC, Wiley outside the submitted work.Ethics Approval Statement: Patients with CAPA were included in the FungiScope® global registry for emerging invasive fungal infections (https://www.clinicaltrials.gov;National Clinical Trials identifier NCT01731353), which was approved by the local ethics committee of the University of Cologne, Cologne, Germany (identifier 05-102).

13.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-294937

ABSTRACT

Background: The rate of SARS-CoV-2 breakthrough infections in vaccinees is becoming an increasingly serious issue. Objective: To determine the causes of death, histological organ alteration, and viral spread in relation to demographic, clinical-pathological, viral variants, and vaccine types. Design: Comprehensive retrospective observational cohort study. Setting: Consecutive cases from four German academic medical centers. Patients: Deceased with proven SARS-CoV-2 infection after vaccination who died between January and November 2021. Collections of 29 vaccinees which were analyzed and compared to 141 nonvaccinated control cases. Results: Autopsies were performed on 16 partially and 13 fully vaccinated individuals. Most patients were elderly and suffered from several relevant comorbidities. Real-time RT-PCR (RT-qPCR) identified a significantly increased rate of generalized viral dissemination within the organism in vaccinated cases versus nonvaccinated cases (45% vs. 16%, respectively;P = 0.008). Vaccinated cases also showed high viral loads, reaching Ct values below 10, especially in the upper airways and lungs. This was accompanied by high rates of pulmonal bacterial or mycotic superinfections and the occurrence of immunocompromising factors such as malignancies, immunosuppressive drug intake, or decreased immunoglobulin levels. All these findings were particularly accentuated in partially vaccinated patients compared to fully vaccinated individuals. A fatal course after vaccination occurred in only 14% of all COVID-19 deceased in Augsburg. Limitations: Restricted number of cases Conclusions: Fatal cases of COVID-19 in vaccinees were rare and often associated with severe comorbidities or other immunosuppressive conditions. Interestingly, we observed striking virus dissemination in our case study, which may indicate a decreased ability to eliminate the virus in patients with an impaired immune system. However, the potential role of antibody-dependent enhancement must also be ruled out in future studies.

14.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293536

ABSTRACT

Background: The rate of SARS-CoV-2 breakthrough infections in vaccinees is becoming an increasingly serious issue. Objective: To determine the causes of death, histological organ alteration, and viral spread in relation to demographic, clinical-pathological, viral variants, and vaccine types. Design: Comprehensive retrospective observational cohort study. Setting: Consecutive cases from four German academic medical centers. Patients: Deceased with proven SARS-CoV-2 infection after vaccination who died between January and November 2021. Collections of 29 vaccinees which were analyzed and compared to 141 nonvaccinated control cases. Results: Autopsies were performed on 16 partially and 13 fully vaccinated individuals. Most patients were elderly and suffered from several relevant comorbidities. Real-time RT-PCR (RT-qPCR) identified a significantly increased rate of generalized viral dissemination within the organism in vaccinated cases versus nonvaccinated cases (45% vs. 16%, respectively;P = 0.008). Vaccinated cases also showed high viral loads, reaching Ct values below 10, especially in the upper airways and lungs. This was accompanied by high rates of pulmonal bacterial or mycotic superinfections and the occurrence of immunocompromising factors such as malignancies, immunosuppressive drug intake, or decreased immunoglobulin levels. All these findings were particularly accentuated in partially vaccinated patients compared to fully vaccinated individuals. A fatal course after vaccination occurred in only 14% of all COVID-19 deceased in Augsburg. Limitations: Restricted number of cases Conclusions: Fatal cases of COVID-19 in vaccinees were rare and often associated with severe comorbidities or other immunosuppressive conditions. Interestingly, we observed striking virus dissemination in our case study, which may indicate a decreased ability to eliminate the virus in patients with an impaired immune system. However, the potential role of antibody-dependent enhancement must also be ruled out in future studies.

15.
J Am Soc Nephrol ; 32(2): 357-374, 2021 02.
Article in English | MEDLINE | ID: covidwho-1496662

ABSTRACT

BACKGROUND: Injury to kidney podocytes often results in chronic glomerular disease and consecutive nephron malfunction. For most glomerular diseases, targeted therapies are lacking. Thus, it is important to identify novel signaling pathways contributing to glomerular disease. Neurotrophic tyrosine kinase receptor 3 (TrkC) is expressed in podocytes and the protein transmits signals to the podocyte actin cytoskeleton. METHODS: Nephron-specific TrkC knockout (TrkC-KO) and nephron-specific TrkC-overexpressing (TrkC-OE) mice were generated to dissect the role of TrkC in nephron development and maintenance. RESULTS: Both TrkC-KO and TrkC-OE mice exhibited enlarged glomeruli, mesangial proliferation, basement membrane thickening, albuminuria, podocyte loss, and aspects of FSGS during aging. Igf1 receptor (Igf1R)-associated gene expression was dysregulated in TrkC-KO mouse glomeruli. Phosphoproteins associated with insulin, erb-b2 receptor tyrosine kinase (Erbb), and Toll-like receptor signaling were enriched in lysates of podocytes treated with the TrkC ligand neurotrophin-3 (Nt-3). Activation of TrkC by Nt-3 resulted in phosphorylation of the Igf1R on activating tyrosine residues in podocytes. Igf1R phosphorylation was increased in TrkC-OE mouse kidneys while it was decreased in TrkC-KO kidneys. Furthermore, TrkC expression was elevated in glomerular tissue of patients with diabetic kidney disease compared with control glomerular tissue. CONCLUSIONS: Our results show that TrkC is essential for maintaining glomerular integrity. Furthermore, TrkC modulates Igf-related signaling in podocytes.


Subject(s)
Kidney Diseases/metabolism , Nephrons/metabolism , Receptor, IGF Type 1/metabolism , Receptor, trkC/metabolism , Animals , Case-Control Studies , Disease Models, Animal , Humans , Kidney Diseases/etiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphoproteins/metabolism , Podocytes/metabolism , Signal Transduction/physiology
16.
Der Pathologe ; : 1-5, 2021.
Article in German | EuropePMC | ID: covidwho-1490241

ABSTRACT

Hintergrund Obduktionen sind ein wichtiges Instrument zum Verständnis neuartiger Krankheiten, einschließlich COVID-19. Material und Methoden Das Deutsche Register für COVID-19-Obduktionen (DeRegCOVID) wurde bereits im April 2020 eingerichtet und gestartet. DeRegCOVID dient als elektronisches Rückgrat des Deutschen Netzwerks für Obduktionen bei Pandemien (DEFEAT PANDEMIcs), das im September 2020 angelaufen ist. Ergebnisse Die Ergebnisse von DeRegCOVID und DEFEAT PANDEMIcs zeichnen sich durch eine beispiellose Zusammenarbeit von mehr als 35 universitären und außeruniversitären Obduktionszentren aus, die pathologische, neuropathologische und rechtsmedizinische Institute vernetzen. DeRegCOVID hat sich weiterentwickelt, an neue Herausforderungen angepasst und enthält derzeit den international größten Obduktionsdatensatz. Nach nur kurzer Laufzeit sind mehr als 80 Publikationen entstanden, die zum Verständnis der Pathogenese von COVID-19 beigetragen haben, z. B. durch die Entdeckung von thromboembolischen Ereignissen, Multiorgantropismus und Neuro-COVID-19. Die Obduktionszentren haben umfangreiche Aufklärungsarbeit geleistet und über den wissenschaftlichen Erkenntnisgewinn hinaus PolitikerInnen und der breiten Öffentlichkeit die wesentliche Rolle der Obduktion bei der Pandemiebekämpfung erläutert. Um die obduktionsgetriebene Forschung weiterzuentwickeln, wurde als Fortsetzung von DEFEAT PANDEMIcs das Nationale Obduktionsnetzwerk (NATON) konzipiert. Schlussfolgerungen Das Register und das Netzwerk, an dem sich alle interessierten Zentren beteiligen können, haben den Wert der vernetzten medizinischen Forschung und den hohen Stellenwert der Obduktion für die Medizin unter Beweis gestellt.

17.
Pathologe ; 42(Suppl 2): 129-134, 2021 Dec.
Article in German | MEDLINE | ID: covidwho-1491093

ABSTRACT

BACKGROUND: Autopsies are an important tool for understanding novel diseases, including COVID-19. MATERIALS AND METHODS: The German Registry of COVID-19 Autopsies (DeRegCOVID) was established and launched in April 2020. DeRegCOVID acts as the electronic backbone of the German Network for Autopsies in Pandemics (DEFEAT PANDEMIcs), which started in September 2020. RESULTS: The results of DeRegCOVID and DEFEAT PANDEMIcs are characterized by an unprecedented collaboration of more than 35 university and non-university autopsy centers linking pathological, neuropathological, and forensic medicine institutes. DeRegCOVID has evolved, adapted to new challenges, and currently contains the largest international autopsy dataset. After only a short period of operation, more than 80 publications have been produced, which have contributed to the understanding of the pathogenesis of COVID-19, e.g., through the discovery of thromboembolic events, multiorgan tropism, and NeuroCovid-19. The autopsy centers have carried out extensive educational work and, beyond the scientific gain in knowledge, have explained to politicians and the general public the essential role of autopsies in pandemic management. To further develop autopsy-driven research, a continuation of DEFEAT PANDEMIcs was conceived, the National Autopsy Network (NATON). CONCLUSIONS: The registry and network, in which all interested centers can participate, have demonstrated the value of networked medical research and the high value of autopsy for medicine.


Subject(s)
COVID-19 , Autopsy , Forensic Medicine , Humans , Pandemics , SARS-CoV-2
18.
Am J Clin Pathol ; 157(1): 54-63, 2022 01 06.
Article in English | MEDLINE | ID: covidwho-1379433

ABSTRACT

OBJECTIVES: Respiratory failure is the major cause of death in coronavirus disease 2019 (COVID-19). Autopsy-based reports describe diffuse alveolar damage (DAD), organizing pneumonia, and fibrotic change, but data on early pathologic changes and during progression of the disease are rare. METHODS: We prospectively enrolled three patients with COVID-19 and performed full clinical evaluation, including high-resolution computed tomography. We took transbronchial biopsy (TBB) specimens at different time points and autopsy tissue samples for histopathologic and ultrastructural evaluation after the patients' death. RESULTS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed by reverse transcription polymerase chain reaction and/or fluorescence in situ hybridization in all TBBs. Lung histology showed reactive pneumocytes and capillary congestion in one patient who died shortly after hospital admission with detectable virus in one of two lung autopsy samples. SARS-CoV-2 was detected in two of two autopsy samples from another patient with a fulminant course and very short latency between biopsy and autopsy, showing widespread organizing DAD. In a third patient with a prolonged course, autopsy samples showed extensive fibrosis without detectable virus. CONCLUSIONS: We report the course of COVID-19 in paired biopsy specimens and autopsies, illustrating vascular, organizing, and fibrotic patterns of COVID-19-induced lung injury. Our results suggest an early spread of SARS-CoV-2 from the upper airways to the lung periphery with diminishing viral load during disease.


Subject(s)
COVID-19 , SARS-CoV-2 , Autopsy , Biopsy , Humans , In Situ Hybridization, Fluorescence , Lung
19.
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
20.
Pathologe ; 42(2): 197-207, 2021 Mar.
Article in German | MEDLINE | ID: covidwho-1235733

ABSTRACT

BACKGROUND: The COVID-19 pandemic represents a so far unknown challenge for the medical community. Autopsies are important for studying this disease, but their safety was challenged at the beginning of the pandemic. OBJECTIVES: To determine whether COVID-19 autopsies can be performed under existing legal conditions and which safety standards are required. MATERIALS AND METHODS: The autopsy procedure undertaken in five institutions in Germany, Austria, and Switzerland is detailed with respect to legal and safety standards. RESULTS: In all institutions the autopsies were performed in technically feasible rooms. The personal equipment consisted of functional clothing including a disposable gown and apron, a surgical cap, eye protection, FFP­3 masks, and two pairs of gloves. In four institutions, complete autopsies were performed; in one institution the ultrasound-guided biopsy within the postmortal imaging and biopsy program. The latter does not allow the appreciation of gross organ pathology; however, it is able to retrieve standardized biopsies for diagnostic and research purposes. Several scientific articles in highly ranked journals resulted from these autopsies and allowed deep insights into organ damage and conclusions to better understand the pathomechanisms. Viral RNA was frequently detectable in the COVID-19 deceased, but the issue of infectivity remains unresolved and it is questionable if Ct values are greater than 30. CONCLUSIONS: With appropriate safeguards, autopsies of people who have died from COVID-19 can be performed safely and are highly relevant to medical research.


Subject(s)
COVID-19 , Pandemics , Austria , Autopsy , Germany , Humans , SARS-CoV-2 , Switzerland
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