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1.
JAMA Cardiol ; 2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1575887

ABSTRACT

Importance: Myocardial injury is a common feature of patients with SARS-CoV-2 infection. However, the cardiac inflammatory processes associated with SARS-CoV-2 infection are not completely understood. Objective: To investigate the inflammatory cardiac phenotype associated with SARS-CoV-2 infection compared with viral myocarditis, immune-mediated myocarditis, and noninflammatory cardiomyopathy by integrating histologic, transcriptomic, and proteomic profiling. Design, Setting, and Participants: This case series was a cooperative study between the Ludwig Maximilian University Hospital Munich and the Cardiopathology Referral Center at the University of Tübingen in Germany. A cohort of 19 patients with suspected myocarditis was examined; of those, 5 patients were hospitalized with SARS-CoV-2 infection between March and May 2020. Cardiac tissue specimens from those 5 patients were compared with specimens from 5 patients with immune-mediated myocarditis, 4 patients with non-SARS-CoV-2 viral myocarditis, and 5 patients with noninflammatory cardiomyopathy, collected from January to August 2019. Exposures: Endomyocardial biopsy. Main Outcomes and Measures: The inflammatory cardiac phenotypes were measured by immunohistologic analysis, RNA exome capture sequencing, and mass spectrometry-based proteomic analysis of endomyocardial biopsy specimens. Results: Among 19 participants, the median age was 58 years (range, 37-76 years), and 15 individuals (79%) were male. Data on race and ethnicity were not collected. The abundance of CD163+ macrophages was generally higher in the cardiac tissue of patients with myocarditis, whereas lymphocyte counts were lower in the tissue of patients with SARS-CoV-2 infection vs patients with non-SARS-CoV-2 virus-associated and immune-mediated myocarditis. Among those with SARS-CoV-2 infection, components of the complement cascade, including C1q subunits (transcriptomic analysis: 2.5-fold to 3.6-fold increase; proteomic analysis: 2.0-fold to 3.4-fold increase) and serine/cysteine proteinase inhibitor clade G member 1 (transcriptomic analysis: 1.7-fold increase; proteomic analysis: 2.6-fold increase), belonged to the most commonly upregulated transcripts and differentially abundant proteins. In cardiac macrophages, the abundance of C1q was highest in SARS-CoV-2 infection. Assessment of important signaling cascades identified an upregulation of the serine/threonine mitogen-activated protein kinase pathways. Conclusions and Relevance: This case series found that the cardiac immune signature varied in inflammatory conditions with different etiologic characteristics. Future studies are needed to examine the role of these immune pathways in myocardial inflammation.

2.
JCI Insight ; 6(18)2021 09 22.
Article in English | MEDLINE | ID: covidwho-1435144

ABSTRACT

Neutrophils provide a critical line of defense in immune responses to various pathogens, inflicting self-damage upon transition to a hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing to lung injury and acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19). Here, we use state-of-the art mass spectrometry-based proteomics and transcriptomic and correlative analyses as well as functional in vitro and in vivo studies to dissect how neutrophils contribute to the progression to severe COVID-19. We identify a reinforcing loop of both systemic and neutrophil intrinsic IL-8 (CXCL8/IL-8) dysregulation, which initiates and perpetuates neutrophil-driven immunopathology. This positive feedback loop of systemic and neutrophil autocrine IL-8 production leads to an activated, prothrombotic neutrophil phenotype characterized by degranulation and neutrophil extracellular trap (NET) formation. In severe COVID-19, neutrophils directly initiate the coagulation and complement cascade, highlighting a link to the immunothrombotic state observed in these patients. Targeting the IL-8-CXCR-1/-2 axis interferes with this vicious cycle and attenuates neutrophil activation, degranulation, NETosis, and IL-8 release. Finally, we show that blocking IL-8-like signaling reduces severe acute respiratory distress syndrome of coronavirus 2 (SARS-CoV-2) spike protein-induced, human ACE2-dependent pulmonary microthrombosis in mice. In summary, our data provide comprehensive insights into the activation mechanisms of neutrophils in COVID-19 and uncover a self-sustaining neutrophil-IL-8 axis as a promising therapeutic target in severe SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , Interleukin-8/metabolism , Lung/immunology , Neutrophils/immunology , SARS-CoV-2 , Thrombosis/etiology , Animals , COVID-19/complications , COVID-19/pathology , Humans , Lung/pathology , Mice , Neutrophil Activation , Neutrophils/pathology , Phenotype , Thrombosis/pathology
3.
Dtsch Med Wochenschr ; 146(13-14): 891-893, 2021 Jul.
Article in German | MEDLINE | ID: covidwho-1307352

ABSTRACT

During COVID 19 pandemic patients typically present with respiratory symptoms. However, in a significant number of patients the gastrointestinal tract is also involved in the disease. Up to 20 % of patients suffering from gastrointestinal symptoms. New insights in pathophysiological aspects might open new therapeutic concepts. This up-date includes current data regarding epidemiology of gastrointestinal symptoms in COVID 19, its role for prognosis and specific risks in relation to immunosuppressive therapies and underlying diseases.


Subject(s)
COVID-19/complications , Gastrointestinal Diseases/etiology , Liver Diseases/virology , Pancreatic Diseases/virology , SARS-CoV-2/physiology , Gastrointestinal Diseases/epidemiology , Gastrointestinal Diseases/therapy , Humans , Prevalence , Prognosis , Risk Factors , SARS-CoV-2/pathogenicity
4.
Eur Respir J ; 58(1)2021 Jul.
Article in English | MEDLINE | ID: covidwho-1105685

ABSTRACT

A fraction of COVID-19 patients progress to a severe disease manifestation with respiratory failure and the necessity of mechanical ventilation. Identifying patients at risk is critical for optimised care and early therapeutic interventions. We investigated the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding relative to disease severity.We analysed nasopharyngeal and tracheal shedding of SARS-CoV-2 in 92 patients with diagnosed COVID-19. Upon admission, standardised nasopharyngeal swab or sputum samples were collected. If patients were mechanically ventilated, endotracheal aspirate samples were additionally obtained. Viral shedding was quantified by real-time PCR detection of SARS-CoV-2 RNA.45% (41 out of 92) of COVID-19 patients had a severe disease course with the need for mechanical ventilation (severe group). At week 1, the initial viral shedding determined from nasopharyngeal swabs showed no significant difference between nonsevere and severe cases. At week 2, a difference could be observed as the viral shedding remained elevated in severely ill patients. A time-course of C-reactive protein, interleukin-6 and procalcitonin revealed an even more protracted inflammatory response following the delayed drop of virus shedding load in severely ill patients. A significant proportion (47.8%) of patients showed evidence of prolonged viral shedding (>17 days), which was associated with severe disease courses (73.2%).We report that viral shedding does not differ significantly between severe and nonsevere COVID-19 cases upon admission to the hospital. Elevated SARS-CoV-2 shedding in the second week of hospitalisation, a systemic inflammatory reaction peaking between the second and third week, and prolonged viral shedding are associated with a more severe disease course.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , RNA, Viral , Respiratory System , Severity of Illness Index , Virus Shedding
6.
J Am Soc Nephrol ; 31(2): 257-278, 2020 02.
Article in English | MEDLINE | ID: covidwho-992926

ABSTRACT

BACKGROUND: Mononuclear phagocytes (MPs), including macrophages, monocytes, and dendritic cells (DCs), are phagocytic cells with important roles in immunity. The developmental origin of kidney DCs has been highly debated because of the large phenotypic overlap between macrophages and DCs in this tissue. METHODS: We used fate mapping, RNA sequencing, flow cytometry, confocal microscopy, and histo-cytometry to assess the origin and phenotypic and functional properties of renal DCs in healthy kidney and of DCs after cisplatin and ischemia reperfusion-induced kidney injury. RESULTS: Adult kidney contains at least four subsets of MPs with prominent Clec9a-expression history indicating a DC origin. We demonstrate that these populations are phenotypically, functionally, and transcriptionally distinct from each other. We also show these kidney MPs exhibit unique age-dependent developmental heterogeneity. Kidneys from newborn mice contain a prominent population of embryonic-derived MHCIInegF4/80hiCD11blow macrophages that express T cell Ig and mucin domain containing 4 (TIM-4) and MER receptor tyrosine kinase (MERTK). These macrophages are replaced within a few weeks after birth by phenotypically similar cells that express MHCII but lack TIM-4 and MERTK. MHCII+F4/80hi cells exhibit prominent Clec9a-expression history in adulthood but not early life, indicating additional age-dependent developmental heterogeneity. In AKI, MHCIInegF4/80hi cells reappear in adult kidneys as a result of MHCII downregulation by resident MHCII+F4/80hi cells, possibly in response to prostaglandin E2 (PGE2). RNA sequencing further suggests MHCII+F4/80hi cells help coordinate the recruitment of inflammatory cells during renal injury. CONCLUSIONS: Distinct developmental programs contribute to renal DC and macrophage populations throughout life, which could have important implications for therapies targeting these cells.


Subject(s)
Dendritic Cells/immunology , Kidney/immunology , Macrophages/immunology , Nephritis/immunology , Acute Kidney Injury/immunology , Age Factors , Animals , CD11b Antigen/analysis , CX3C Chemokine Receptor 1/analysis , Calcium-Binding Proteins/analysis , Cisplatin/pharmacology , Histocompatibility Antigens Class II/analysis , Kidney/drug effects , Kidney/metabolism , Lectins, C-Type/analysis , Mice , Mice, Inbred C57BL , Receptors, G-Protein-Coupled/analysis , Receptors, Immunologic/analysis
7.
Dig Dis ; 39(5): 540-548, 2021.
Article in English | MEDLINE | ID: covidwho-729441

ABSTRACT

BACKGROUND: The COVID-19-pandemic poses challenges to the medical system and especially to endoscopic staff and patients. National, European and International societies provided recommendations on how to safely perform endoscopic procedures during the current pandemic. Until now, the effect of the current pandemic on tertiary endoscopy centers has not been reported. OBJECTIVE: The aim of this was to analyze the influence of the early SARS-CoV2-pandemic on endoscopic care and work flow in 2 European tertiary endoscopy units. METHODS: Data from 2 tertiary endoscopy units (Katowice and Munich) were retrospectively collected during the early pandemic and compared to an equivalent pre-pandemic period. Data include procedures, complications, benchmarks, and influence on endoscopy training. RESULTS: During the early pandemic, we noted a highly significant decrease (49.1%) in the overall number of all endoscopies with a significant increase in therapeutic procedures. Besides, there were no significant differences in the number of urgent endoscopic retrograde cholangiopancreatography or interventional endoscopic ultrasound procedures. The exceptional situation reduced endoscopic procedures performed by trainees significantly. CONCLUSIONS: The SARS-CoV2-pandemic halved the endoscopy service of 2 tertiary centers while maintaining an urgent therapeutic service. Recommended personal safety measures in endoscopy proved to be efficient and safe in preventing SARS-CoV2 infection of staff or spreading. Unnecessarily, the SARS-CoV2 pandemic prevented routine endoscopy training.


Subject(s)
COVID-19 , Infection Control , Pandemics , Adult , Aged , Endoscopy , Female , Humans , Male , Middle Aged , RNA, Viral , Retrospective Studies , SARS-CoV-2
8.
Dtsch Med Wochenschr ; 145(15): 1033-1038, 2020 Jul.
Article in German | MEDLINE | ID: covidwho-691080

ABSTRACT

COVID 19, caused by SARS-CoV2, a new variant of coronaviruses, typically presents with respiratory symptoms. However, in a significat number of patients different organs are involved in the disease, often including gastrointestinal symptoms. These could include loss of appetite, vomiting, abdominal pain and diarrhea, with diarrhea being associated with a more severe course of COVID-19. Because viral RNA can be detected in fecal samples, some implications for clinical routine in diagnostic and therapeutic procedures are grown. Until yet, no clear evidence is given regarding fecal-oral transmission of SARS-CoV2.


Subject(s)
Coronavirus Infections , Gastrointestinal Diseases , Pandemics , Pneumonia, Viral , Anorexia , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Diarrhea , Gastrointestinal Diseases/epidemiology , Gastrointestinal Diseases/therapy , Gastrointestinal Diseases/virology , Humans , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , SARS-CoV-2 , Vomiting
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