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1.
Virchows Arch ; 2022 Jan 06.
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.

2.
Cell ; 2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1588146

ABSTRACT

Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.

3.
Cell Stem Cell ; 2021 Dec 25.
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.

4.
Cell ; 184(26): 6243-6261.e27, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1536467

ABSTRACT

COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.


Subject(s)
COVID-19/pathology , COVID-19/virology , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/virology , Macrophages/pathology , Macrophages/virology , SARS-CoV-2/physiology , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , COVID-19/diagnostic imaging , Cell Communication , Cohort Studies , Fibroblasts/pathology , Gene Expression Regulation , Humans , Idiopathic Pulmonary Fibrosis/diagnostic imaging , Idiopathic Pulmonary Fibrosis/genetics , Mesenchymal Stem Cells/pathology , Phenotype , Proteome/metabolism , Receptors, Cell Surface/metabolism , Respiratory Distress Syndrome/diagnostic imaging , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Tomography, X-Ray Computed , Transcription, Genetic
5.
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.

6.
Pathologe ; 2021 Oct 29.
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.

7.
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
8.
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
9.
Pathologe ; 42(2): 208-215, 2021 Mar.
Article in German | MEDLINE | ID: covidwho-1235730

ABSTRACT

BACKGROUND: Analyses for the presence of SARS-CoV­2 in the tissues of COVID-19 patients is important in order to improve our understanding of the disease pathophysiology for interpretation of diagnostic histopathological findings in autopsies, biopsies, or surgical specimens and to assess the potential for occupational infectious hazard. MATERIAL AND METHODS: In this review we identified 136 published studies in PubMed's curated literature database LitCovid on SARS-CoV­2 detection methods in tissues and evaluated them regarding sources of error, specificity, and sensitivity of the methods, taking into account our own experience. RESULTS: Currently, no sufficiently specific histomorphological alterations or diagnostic features for COVID-19 are known. Therefore, three approaches for SARS-CoV­2 detection are used: RNA, proteins/antigens, or morphological detection by electron microscopy. In the preanalytical phase, the dominant source of error is tissue quality, especially the different intervals between sample collection and processing or fixation (and its duration) and specifically the interval between death and sample collection in autopsies. However, this information is found in less than half of the studies (e.g., in only 42% of autopsy studies). Our own experience and first studies prove the significantly higher sensitivity and specificity of RNA-based detection methods compared to antigen or protein detection by immunohistochemistry or immunofluorescence. Detection by electron microscopy is time consuming and difficult to interpret. CONCLUSIONS: Different methods are available for the detection of SARS-CoV­2 in tissue. Currently, RNA detection by RT-PCR is the method of choice. However, extensive validation studies and method harmonization are not available and are absolutely necessary.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , RNA, Viral , Sensitivity and Specificity
10.
Pathologe ; 42(2): 216-223, 2021 Mar.
Article in German | MEDLINE | ID: covidwho-1235725

ABSTRACT

BACKGROUND: Autopsy is an important tool for understanding the pathogenesis of diseases, including COVID-19. MATERIAL AND METHODS: On 15 April 2020, together with the German Society of Pathology and the Federal Association of German Pathologists, the German Registry of COVID-19 Autopsies (DeRegCOVID) was launched ( www.DeRegCOVID.ukaachen.de ). Building on this, the German Network for Autopsies in Pandemics (DEFEAT PANDEMIcs) was established on 1 September 2020. RESULTS: The main goal of DeRegCOVID is to collect and distribute de facto anonymized data on potentially all autopsies of people who have died from COVID-19 in Germany in order to meet the need for centralized, coordinated, and structured data collection and reporting during the pandemic. The success of the registry strongly depends on the willingness of the respective centers to report the data, which has developed very positively so far and requires special thanks to all participating centers. The rights to own data and biomaterials (stored decentrally) remain with each respective center. The DEFEAT PANDEMIcs network expands on this and aims to strengthen harmonization and standardization as well as nationwide implementation and cooperation in the field of pandemic autopsies. CONCLUSIONS: The extraordinary cooperation in the field of autopsies in Germany during the COVID-19 pandemic is impressively demonstrated by the establishment of DeRegCOVID, the merger of the registry of neuropathology (CNS-COVID19) with DeRegCOVID and the establishment of the autopsy network DEFEAT PANDEMIcs. It gives a strong signal for the necessity, readiness, and expertise to jointly help manage current and future pandemics by autopsy-derived knowledge.


Subject(s)
COVID-19 , Pandemics , Autopsy , Humans , Registries , SARS-CoV-2
11.
Microb Biotechnol ; 14(4): 1627-1641, 2021 07.
Article in English | MEDLINE | ID: covidwho-1228701

ABSTRACT

Virus detection methods are important to cope with the SARS-CoV-2 pandemics. Apart from the lung, SARS-CoV-2 was detected in multiple organs in severe cases. Less is known on organ tropism in patients developing mild or no symptoms, and some of such patients might be missed in symptom-indicated swab testing. Here, we tested and validated several approaches and selected the most reliable RT-PCR protocol for the detection of SARS-CoV-2 RNA in patients' routine diagnostic formalin-fixed and paraffin-embedded (FFPE) specimens available in pathology, to assess (i) organ tropism in samples from COVID-19-positive patients, (ii) unrecognized cases in selected tissues from negative or not-tested patients during a pandemic peak, and (iii) retrospectively, pre-pandemic lung samples. We identified SARS-CoV-2 RNA in seven samples from confirmed COVID-19 patients, in two gastric biopsies, one small bowel and one colon resection, one lung biopsy, one pleural resection and one pleural effusion specimen, while all other specimens were negative. In the pandemic peak cohort, we identified one previously unrecognized COVID-19 case in tonsillectomy samples. All pre-pandemic lung samples were negative. In conclusion, SARS-CoV-2 RNA detection in FFPE pathology specimens can potentially improve surveillance of COVID-19, allow retrospective studies, and advance our understanding of SARS-CoV-2 organ tropism and effects.


Subject(s)
COVID-19 , RNA, Viral/isolation & purification , SARS-CoV-2 , COVID-19/diagnosis , Diagnostic Tests, Routine , Humans , Pandemics , Retrospective Studies
12.
Pathologe ; 42(Suppl 1): 81-88, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1152000

ABSTRACT

BACKGROUND: Analyses for the presence of SARS-CoV­2 in the tissues of COVID-19 patients is important in order to improve our understanding of the disease pathophysiology for interpretation of diagnostic histopathological findings in autopsies, biopsies, or surgical specimens and to assess the potential for occupational infectious hazard. MATERIAL AND METHODS: In this review we identified 136 published studies in PubMed's curated literature database LitCovid on SARS-CoV­2 detection methods in tissues and evaluated them regarding sources of error, specificity, and sensitivity of the methods, taking into account our own experience. RESULTS: Currently, no sufficiently specific histomorphological alterations or diagnostic features for COVID-19 are known. Therefore, three approaches for SARS-CoV­2 detection are used: RNA, proteins/antigens, or morphological detection by electron microscopy. In the preanalytical phase, the dominant source of error is tissue quality, especially the different intervals between sample collection and processing or fixation (and its duration) and specifically the interval between death and sample collection in autopsies. However, this information is found in less than half of the studies (e.g., in only 42% of autopsy studies). Our own experience and first studies prove the significantly higher sensitivity and specificity of RNA-based detection methods compared to antigen or protein detection by immunohistochemistry or immunofluorescence. Detection by electron microscopy is time consuming and difficult to interpret. CONCLUSIONS: Different methods are available for the detection of SARS-CoV­2 in tissue. Currently, RNA detection by RT-PCR is the method of choice. However, extensive validation studies and method harmonization are not available and are absolutely necessary.


Subject(s)
COVID-19 , SARS-CoV-2 , Autopsy , Humans , RNA, Viral , Sensitivity and Specificity
13.
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
14.
EMBO Mol Med ; 12(8): e12885, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-607957

ABSTRACT

The WHO declared the global outbreak of SARS-CoV-2 a pandemic on March 11, 2020, and "call(ed) on all countries to exchange country experiences and practices in a transparent and timely way" (http://www.euro.who.int/en/health-topics/health-emergencies/pages/news/news/2020/03/who-announces-covid-19-outbreak-a-pandemic). To date, many medical societies have announced their intention to collect and analyze data from COVID-19 patients and some large-scale prospective data collections are already running, such as the LEOSS registry (Lean European Open Survey on SARS-CoV-2 Infected Patients) or the CAPACITYCOVID registry (registry of patients with COVID-19 including cardiovascular risk and complications). The necessity to mobilize and harmonize basic and applied research worldwide is of utmost importance (Sansonetti, 2020).


Subject(s)
Autopsy , Betacoronavirus , Coronavirus Infections/pathology , Pandemics , Pneumonia, Viral/pathology , Registries , COVID-19 , Coronavirus Infections/mortality , Data Collection , Germany/epidemiology , Global Health , Humans , International Cooperation , Pneumonia, Viral/mortality , Research , SARS-CoV-2
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