Publications by authors named "Jacob Nattermann"

139 Publications

COVID-19 mortality in cirrhosis is determined by cirrhosis-associated comorbidities and extrahepatic organ failure: Results from the multinational LEOSS registry.

United European Gastroenterol J 2022 May 28;10(4):409-424. Epub 2022 Apr 28.

Department of Internal Medicine III, University Hospital RWTH Aachen, RWTH Aachen University, Aachen, Germany.

Background And Objective: International registries have reported high mortality rates in patients with liver disease and COVID-19. However, the extent to which comorbidities contribute to excess COVID-19 mortality in cirrhosis is controversial.

Methods: We used the multinational Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) to identify patients with cirrhosis documented between March 2020 and March 2021, when the wild-type and alpha variant were predominant. We compared symptoms, disease progression and mortality after propensity score matching (PSM) for age, sex, obesity, smoking status, and concomitant diseases. Mortality was also compared with that of patients with spontaneous bacterial peritonitis (SBP) without SARS-CoV-2 infection, a common bacterial infection and well-described precipitator of acute-on-chronic liver failure.

Results: Among 7096 patients with SARS-CoV-2 infection eligible for analysis, 70 (0.99%) had cirrhosis, and all were hospitalized. Risk factors for severe COVID-19, such as diabetes, renal disease, and cardiovascular disease were more frequent in patients with cirrhosis. Case fatality rate in patients with cirrhosis was 31.4% with the highest odds of death in patients older than 65 years (43.6% mortality; odds ratio [OR] 4.02; p = 0.018), Child-Pugh class C (57.1%; OR 4.00; p = 0.026), and failure of two or more organs (81.8%; OR 19.93; p = 0.001). After PSM for demographics and comorbidity, the COVID-19 case fatality of patients with cirrhosis did not significantly differ from that of matched patients without cirrhosis (28.8% vs. 26.1%; p = 0.644) and was similar to the 28-day mortality in a comparison group of patients with cirrhosis and SBP (33.3% vs. 31.5%; p = 1.000).

Conclusions: In immunologically naïve patients with cirrhosis, mortality from wild-type SARS-CoV-2 and the alpha variant is high and is largely determined by cirrhosis-associated comorbidities and extrahepatic organ failure.
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http://dx.doi.org/10.1002/ueg2.12232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103364PMC
May 2022

Natural Killer Cell-Mediated Antibody-Dependent Cellular Cytotoxicity Against SARS-CoV-2 After Natural Infection Is More Potent Than After Vaccination.

J Infect Dis 2022 May;225(10):1688-1693

Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.

We compared the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific antibodies to induce natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in patients with natural infection and vaccinated persons. Analyzing plasma samples from 39 coronavirus disease 2019 (COVID-19) patients and 11 vaccinated individuals, significant induction of ADCC could be observed over a period of more than 3 months in both vaccinated and recovered individuals. Although plasma antibody concentrations were lower in recovered patients, we found antibodies elicited by natural infection induced a significantly stronger ADCC response compared to those induced by vaccination, which may affect protection conferred by vaccination.
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http://dx.doi.org/10.1093/infdis/jiac060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8992321PMC
May 2022

Mitochondrial dysfunction contributes to impaired cytokine production of CD56 bright NK cells from HIV(+) individuals under effective antiviral therapy.

J Infect Dis 2022 Mar 21. Epub 2022 Mar 21.

Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.

HIV infection is associated with impaired NK cell activity, which is only incompletely restored under antiretroviral therapy. Analysing the bioenergetics profiles of oxygen consumption, we observed several parameters were significantly reduced in HIV(+) NK cells, indicating a mitochondrial defect. Accordingly, we found HIV(+) CD56 bright NK cells to display a decreased mitochondrial membrane potential and mitochondrial mass. Both parameters were positively correlated with IFNγ production of NK cells. Finally, we demonstrated that stimulation of HIV(+) NK cells with MitoTEMPO, mitochondria-targeting antioxidant, significantly improved IFNγ production. In conclusion, we identified mitochondrial dysfunction as a mechanism that contributes to impaired NK cell function.
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http://dx.doi.org/10.1093/infdis/jiac103DOI Listing
March 2022

Liver Fibrosis-From Mechanisms of Injury to Modulation of Disease.

Front Med (Lausanne) 2021 11;8:814496. Epub 2022 Jan 11.

Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital RWTH Aachen, Aachen, Germany.

The Transregional Collaborative Research Center "Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease" (referred to as SFB/TRR57) was funded for 13 years (2009-2021) by the German Research Council (DFG). This consortium was hosted by the Medical Schools of the RWTH Aachen University and Bonn University in Germany. The SFB/TRR57 implemented combined basic and clinical research to achieve detailed knowledge in three selected key questions: (i) What are the relevant mechanisms and signal pathways required for initiating organ fibrosis? (ii) Which immunological mechanisms and molecules contribute to organ fibrosis? and (iii) How can organ fibrosis be modulated, e.g., by interventional strategies including imaging and pharmacological approaches? In this review we will summarize the liver-related key findings of this consortium gained within the last 12 years on these three aspects of liver fibrogenesis. We will highlight the role of cell death and cell cycle pathways as well as nutritional and iron-related mechanisms for liver fibrosis initiation. Moreover, we will define and characterize the major immune cell compartments relevant for liver fibrogenesis, and finally point to potential signaling pathways and pharmacological targets that turned out to be suitable to develop novel approaches for improved therapy and diagnosis of liver fibrosis. In summary, this review will provide a comprehensive overview about the knowledge on liver fibrogenesis and its potential therapy gained by the SFB/TRR57 consortium within the last decade. The kidney-related research results obtained by the same consortium are highlighted in an article published back-to-back in Frontiers in Medicine.
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http://dx.doi.org/10.3389/fmed.2021.814496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8787129PMC
January 2022

Impact of regular additional endobiliary radiofrequency ablation on survival of patients with advanced extrahepatic cholangiocarcinoma under systemic chemotherapy.

Sci Rep 2022 01 19;12(1):1011. Epub 2022 Jan 19.

Department of Internal Medicine I, University Hospital of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

Prognosis of patients with advanced extrahepatic cholangiocarcinoma (eCCA) is poor. The current standard first-line treatment is systemic chemotherapy (CT) with gemcitabine and a platinum derivate. Additionally, endobiliary radiofrequency ablation (eRFA) can be applied to treat biliary obstructions. This study aimed to evaluate the additional benefit of scheduled regular eRFA in a real-life patient cohort with advanced extrahepatic cholangiocarcinoma under standard systemic CT. All patients with irresectable eCCA treated at University Hospital Bonn between 2010 and 2020 were eligible for inclusion. Patients were stratified according to treatment: standard CT (n = 26) vs. combination of eRFA with standard CT (n = 40). Overall survival (OS), progression free survival (PFS), feasibility and toxicity were retrospectively analyzed using univariate and multivariate approaches. Combined eRFA and CT resulted in significantly longer median OS (17.3 vs. 8.6 months, p = 0.004) and PFS (12.9 vs. 5.7 months, p = 0.045) compared to the CT only group. While groups did not differ regarding age, sex, tumor stage and chemotherapy treatment regimen, mean MELD was even higher (10.1 vs. 6.7, p = 0.015) in the eRFA + CT group. The survival benefit of concomitant eRFA was more evident in the subgroup with locally advanced tumors. Severe hematological toxicities (CTCAE grades 3 - 5) did not differ significantly between the groups. However, therapy-related cholangitis occurred more often in the combined treatment group (p = 0.031). Combination of eRFA and systemic CT was feasible, well-tolerated and could significantly prolong survival compared to standard CT alone. Thus, eRFA should be considered during therapeutic decision making in advanced eCCA.
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http://dx.doi.org/10.1038/s41598-021-04297-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770452PMC
January 2022

Complement activation induces excessive T cell cytotoxicity in severe COVID-19.

Cell 2022 02 28;185(3):493-512.e25. Epub 2021 Dec 28.

Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Center for Infection Research (HZI), Würzburg, Germany.

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.
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http://dx.doi.org/10.1016/j.cell.2021.12.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712270PMC
February 2022

The Different Immune Profiles of Normal Colonic Mucosa in Cancer-Free Lynch Syndrome Carriers and Lynch Syndrome Colorectal Cancer Patients.

Gastroenterology 2022 03 2;162(3):907-919.e10. Epub 2021 Dec 2.

Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background & Aims: Owing to the high load of immunogenic frameshift neoantigens, tumors arising in individuals with Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, are characterized by a pronounced immune infiltration. However, the immune status of normal colorectal mucosa in LS is not well characterized. We assessed the immune infiltrate in tumor-distant normal colorectal mucosa from LS CRC patients, sporadic microsatellite-unstable (MSI) and microsatellite-stable (MSS) CRC patients, and cancer-free LS carriers.

Methods: CD3-positive, FOXP3-positive, and CD8-positive T cells were quantified in, respectively, 219, 233, and 201 formalin-fixed paraffin-embedded (FFPE) normal colonic mucosa tissue sections from CRC patients and cancer-free LS carriers and 26, 22, and 19 LS CRCs. CD3-positive T cells were also quantified in an independent cohort of 97 FFPE normal rectal mucosa tissue sections from LS carriers enrolled in the CAPP2 clinical trial. The expression of 770 immune-relevant genes was analyzed in a subset of samples with the use of the NanoString nCounter platform.

Results: LS normal mucosa specimens showed significantly elevated CD3-, FOXP3-, and CD8-positive T-cell densities compared with non-LS control specimens. Gene expression profiling and cluster analysis revealed distinct immune profiles in LS carrier mucosa with and without cancer manifestation. Long-term follow-up of LS carriers within the CAPP2 trial found a correlation between mucosal T-cell infiltrate and time to subsequent tumor occurrence.

Conclusions: LS carriers show elevated mucosal T-cell infiltration even in the absence of cancer. The normal mucosa immune profile may be a temporary or permanent tumor risk modifier in LS carriers.
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http://dx.doi.org/10.1053/j.gastro.2021.11.029DOI Listing
March 2022

Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19.

Immunity 2021 11 4;54(11):2650-2669.e14. Epub 2021 Sep 4.

Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.
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http://dx.doi.org/10.1016/j.immuni.2021.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416549PMC
November 2021

Hepatocellular Carcinoma Prevention by Aspirin: Are Platelets the Link?

Hepatol Commun 2021 12 7;5(12):2151-2152. Epub 2021 Jul 7.

Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany.

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http://dx.doi.org/10.1002/hep4.1769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631088PMC
December 2021

Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X.

Int J Cancer 2022 01 14;150(1):56-66. Epub 2021 Sep 14.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX.
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http://dx.doi.org/10.1002/ijc.33790DOI Listing
January 2022

Cardiac MRI in Patients with Prolonged Cardiorespiratory Symptoms after Mild to Moderate COVID-19.

Radiology 2021 12 10;301(3):E419-E425. Epub 2021 Aug 10.

From the Department of Diagnostic and Interventional Radiology (D. Kravchenko, A.I., N.M., M.R., A.F., C.C.P., D. Kuetting, U.I.A., J.A.L.), Quantitative Imaging Laboratory Bonn (D. Kravchenko, A.I., N.M., M.R., A.F., D. Kuetting, J.A.L.), Department of Internal Medicine II-Cardiology (S.Z.), Department of Internal Medicine III-Oncology (A.H.), Department of Anesthesiology (M.V.), and Department of Internal Medicine I (J.N.), University Hospital Bonn, Venusberg Campus 1, 53127 Bonn, Germany; and the Department of Cardiothoracic and Vascular Surgery, University Hospital Mainz, Mainz, Germany (G.D.D.).

Background Myocardial injury and inflammation at cardiac MRI in patients with COVID-19 have been described in recent publications. Concurrently, a chronic COVID-19 syndrome (CCS) after SARS-CoV-2 infection has been observed and manifests with symptoms such as fatigue and exertional dyspnea. Purpose To explore the relationship between CCS and myocardial injury and inflammation as an underlying cause of the persistent complaints in previously healthy individuals. Materials and Methods In this prospective study from January 2021 to April 2021, study participants without known cardiac or pulmonary diseases prior to SARS-CoV-2 infection who had persistent CCS symptoms such as fatigue or exertional dyspnea after convalescence and healthy control participants underwent cardiac MRI. The cardiac MRI protocol included evaluating the T1 and T2 relaxation times, extracellular volume, T2 signal intensity ratio, and late gadolinium enhancement (LGE). Student tests, Mann-Whitney tests, and χ tests were used for statistical analysis. Results Forty-one participants with CCS (mean age, 39 years ± 13 [standard deviation]; 18 men) and 42 control participants (mean age, 39 years ± 16; 26 men) were evaluated. The median time between the initial incidence of mild to moderate COVID-19 not requiring hospitalization and undergoing cardiac MRI was 103 days (interquartile range, 88-158 days). Troponin T levels were normal. Parameters indicating myocardial inflammation and edema were comparable between participants with CCS and control participants (T1 relaxation times: 978 msec ± 23 vs 971 msec ± 25 [ = .17]; T2 relaxation times: 53 msec ± 2 vs 52 msec ± 2 [ = .47]; T2 signal intensity ratios: 1.6 ± 0.2 vs 1.6 ± 0.3 [ = .10]). Visible myocardial edema was present in none of the participants. Three of 41 (7%) participants with CCS demonstrated nonischemic LGE, whereas no participants in the control group demonstrated nonischemic LGE (0 of 42 [0%]; = .07). None of the participants fulfilled the 2018 Lake Louise criteria for the diagnosis of myocarditis. Conclusion Individuals with chronic COVID-19 syndrome who did not undergo hospitalization for COVID-19 did not demonstrate signs of active myocardial injury or inflammation at cardiac MRI. © RSNA, 2021 See also the editorial by Lima and Bluemke in this issue.
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http://dx.doi.org/10.1148/radiol.2021211162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369880PMC
December 2021

Early detection of duodenal cancer by upper gastrointestinal-endoscopy in Lynch syndrome.

Int J Cancer 2021 12 7;149(12):2052-2062. Epub 2021 Aug 7.

Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.

Small bowel cancer (SBC) is the malignancy with the highest standardized incidence ratio in Lynch syndrome (LS) patients. Of all SBCs, about 50% are duodenal cancers (DCs), therefore being accessible by esophago-gastro-duodenoscopy (EGD) for surveillance. We asked whether early detection of DC is possible for LS patients undergoing surveillance by EGD and if surveillance should be limited to specific subgroups. Data for LS patients with DC were retrieved from the registry of the German Consortium for Familial Intestinal Cancer. Patients undergoing active surveillance by EGDs (surveillance group) were compared to those who did not (nonsurveillance group) regarding tumor stage at diagnosis. Union for International Cancer Control stages I-IIA were defined as early stage disease and IIB-IV as advanced stage disease. Statistical analysis was performed using Fisher's exact test. Among 2015 patients with pathogenic variants in any mismatch-repair-gene, 47 patients with 49 DCs were identified. In 10% of cases, patients were under 35 years at diagnosis; family and personal tumor history did not correlate with DC diagnosis. Pathogenic germline variants in MSH6, PMS2 or EPCAM were present in 10% of patients. Statistical analysis could be performed on 13 DC patients in the surveillance group and 14 in the nonsurveillance group. Early detection was possible for 71% of patients in the surveillance group and 29% of patients in the nonsurveillance group (P = .021). Early detection of DC by EGD in LS patients is feasible regardless of family history, mutational status and should start no later than 25 years of age.
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http://dx.doi.org/10.1002/ijc.33753DOI Listing
December 2021

[Postoperative dumping-syndrome with relevant impairment of glucose homeostasis - relief by continuous glucose monitoring and individual therapy with GLP-1 receptor agonists].

Z Gastroenterol 2021 Jun 15;59(6):556-559. Epub 2021 Jun 15.

Innere Medizin, Krankenhaus St. Marienwörth, Bad Kreuznach, Germany.

Dumping syndromes are a common side effect after partial or total gastric resection. The symptoms may be diverse, with vasomotoric reactions, collapse tendencies and digestive disorders (early dumping) as well as blood sugar derailment as a result of too fast absorption of glucose (late dumping).Entrenched therapy concepts, including personalized nutritional concepts and the use of medication as octreotide or diazoxide, will not always lead to the desired results. It is then, that individual therapy concepts have to be found to restore the patient's quality of life, as shown in this case study.
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http://dx.doi.org/10.1055/a-1324-4136DOI Listing
June 2021

A genetic variant in toll-like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis.

Liver Int 2021 09 27;41(9):2139-2148. Epub 2021 Jun 27.

Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany.

Background & Aims: Bacterial translocation drives liver disease progression. We investigated whether functional genetic variants in toll-like receptor 5 (TLR5), the receptor for bacterial flagellin, affect the risk for hepatocellular carcinoma (HCC).

Methods: Healthy controls (n = 212), patients with alcohol abuse without liver disease (n = 382), and patients from a discovery cohort of alcohol-associated cirrhosis (n = 372 including 79 HCC cases), a validation cohort of alcohol-associated cirrhosis (n = 355 including 132 HCC cases), and a cohort of cirrhosis due to nonalcoholic steatohepatitis (NASH) (n = 145 including 62 HCC cases) were genotyped for the TLR5 rs5744174 and rs5744168 polymorphisms. Chemokine levels were measured by ELISA in patients' sera and supernatants of flagellin-stimulated healthy monocytes.

Results: Frequency of the TLR5 rs5744174 TT genotype was similar in healthy controls (33%), controls with alcohol abuse (34%), and patients with alcohol-associated cirrhosis in the discovery (28%), validation (33%), and NASH cohort (31%). The TT genotype was enriched in patients with versus without HCC in the discovery, validation, and NASH cohort (41% vs 25%; 39% vs 29%; 40% vs 24%; p < .05 each). This genotype remained a risk factor for HCC (OR = 1.9; p = .01) after multivariate correction for age, gender, diabetes, and carriage of the PNPLA3 148M variant. Interleukin-8 induction in monocytes from healthy controls and serum levels of interleukin-8 and CXCL1 from cirrhotic patients with the TT genotype were significantly increased versus C allele carriers.

Conclusion: The TLR5 rs5744174 polymorphism, affecting immune response to flagellin, is linked to occurrence of HCC in cirrhosis caused by steatohepatitis.
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http://dx.doi.org/10.1111/liv.14980DOI Listing
September 2021

Swarm Learning for decentralized and confidential clinical machine learning.

Nature 2021 06 26;594(7862):265-270. Epub 2021 May 26.

Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.

Fast and reliable detection of patients with severe and heterogeneous illnesses is a major goal of precision medicine. Patients with leukaemia can be identified using machine learning on the basis of their blood transcriptomes. However, there is an increasing divide between what is technically possible and what is allowed, because of privacy legislation. Here, to facilitate the integration of any medical data from any data owner worldwide without violating privacy laws, we introduce Swarm Learning-a decentralized machine-learning approach that unites edge computing, blockchain-based peer-to-peer networking and coordination while maintaining confidentiality without the need for a central coordinator, thereby going beyond federated learning. To illustrate the feasibility of using Swarm Learning to develop disease classifiers using distributed data, we chose four use cases of heterogeneous diseases (COVID-19, tuberculosis, leukaemia and lung pathologies). With more than 16,400 blood transcriptomes derived from 127 clinical studies with non-uniform distributions of cases and controls and substantial study biases, as well as more than 95,000 chest X-ray images, we show that Swarm Learning classifiers outperform those developed at individual sites. In addition, Swarm Learning completely fulfils local confidentiality regulations by design. We believe that this approach will notably accelerate the introduction of precision medicine.
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http://dx.doi.org/10.1038/s41586-021-03583-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189907PMC
June 2021

Reconvalescent plasma/camostat mesylate in early SARS-CoV-2 Q-PCR positive high-risk individuals (RES-Q-HR): a structured summary of a study protocol for a randomized controlled trial.

Trials 2021 May 17;22(1):343. Epub 2021 May 17.

Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty Heinrich-Heine-University Duesseldorf, Moorenstr. 5, D-40225, Duesseldorf, Germany.

Objectives: Currently, there are no approved treatments for early disease stages of COVID-19 and few strategies to prevent disease progression after infection with SARS-CoV-2. The objective of this study is to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate administered within 72 h of diagnosis of SARS-CoV-2 infection in adult individuals with pre-existing risk factors at higher risk of getting seriously ill with COVID-19. Camostat mesylate acts as an inhibitor of the host cell serine protease TMPRSS2 and prevents the virus from entering the cell. CP represents another antiviral strategy in terms of passive immunization. The working hypothesis to be tested in the RES-Q-HR study is that the early use of CP or camostat mesylate reduces the likelihood of disease progression to (modified) WHO stages 4b-8 in SARS-CoV-2-positive adult patients at high risk of moderate or severe COVID-19 progression.

Trial Design: This study is a 4-arm (parallel group), multicenter, randomized (2:2:1:1 ratio), partly double-blind, controlled trial to evaluate the safety and efficacy of convalescent plasma (CP) or camostat mesylate with control or placebo in adult patients diagnosed with SARS-CoV-2 infection and high risk for progression to moderate/severe COVID-19. Superiority of the intervention arms will be tested.

Participants: The trial is conducted at 10-15 tertiary care centers in Germany. Individuals aged 18 years or above with ability to provide written informed consent with SARS-CoV-2 infection, confirmed by PCR within 3 days or less before enrolment and the presence of at least one SARS-CoV-2 symptom (such as fever, cough, shortness of breath, sore throat, headache, fatigue, smell/and or taste disorder, diarrhea, abdominal symptoms, exanthema) and symptom duration of not more than 3 days. Further inclusion criteria comprise: Presence of at least one of the following criteria indicating increased risk for severe COVID-19: Age > 75 years Chronic obstructive pulmonary disease (COPD) and/or pulmonary fibrosis BMI > 40 kg/m Age > 65 years with at least one other risk factor (BMI > 35 kg/m, coronary artery disease (CAD), chronic kidney disease (CKD) with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) BMI > 35 kg/m with at least one other risk factor (CAD, CKD with GFR < 60 ml/min but ≥ 30 ml/min, diabetes mellitus, active tumor disease) Exclusion criteria: 1. Age < 18 years 2. Unable to give informed consent 3. Pregnant women or breastfeeding mothers 4. Previous transfusion reaction or other contraindication to a plasma transfusion 5. Known hypersensitivity to camostat mesylate and/or severe pancreatitis 6. Volume stress due to CP administration would be intolerable 7. Known IgA deficiency 8. Life expectancy < 6 months 9. Duration SARS-CoV-2 typical symptoms > 3 days 10. SARS-CoV-2 PCR detection older than 3 days 11. SARS-CoV-2 associated clinical condition ≥ WHO stage 3 (patients hospitalized for other reasons than COVID-19 may be included if they fulfill all inclusion and none of the exclusion criteria) 12. Previously or currently hospitalized due to SARS-CoV-2 13. Previous antiviral therapy for SARS-CoV-2 14. ALT or AST > 5 x ULN at screening 15. Liver cirrhosis > Child A (patients with Child B/C cirrhosis are excluded from the trial) 16. Chronic kidney disease with GFR < 30 ml/min 17. Concurrent or planned anticancer treatment during trial period 18. Accommodation in an institution due to legal orders (§40(4) AMG). 19. Any psycho-social condition hampering compliance with the study protocol. 20. Evidence of current drug or alcohol abuse 21. Use of other investigational treatment within 5 half-lives of enrolment is prohibited 22. Previous use of convalescent plasma for COVID-19 23. Concomitant proven influenza A infection 24. Patients with organ or bone marrow transplant in the three months prior to screening visit INTERVENTION AND COMPARATOR: Participants will be randomized to the following 4 groups: 1) Convalescent plasma (CP), 2 units at screening/baseline visit (day 0) or day 1; CP is defined by the presence of neutralizing anti-SARS-CoV-2 antibodies with titers ≥ 1:160; individuals with body weight ≥ 150 kg will receive a third unit of plasma on day 3 2) Camostat mesylate (200 mg per capsule, one capsule taken each in the morning, afternoon and evening on days 1-7) 3) Standard of care (SOC, control for CP) 4) Placebo (identical in appearance to camostat mesylate capsules, one capsule taken each morning, afternoon and evening on days 1-7; for camostat mesylate control group) Participants will be monitored after screening/baseline on day 3, day 5, day 8, and day 14. On day 28 and day 56, telephone visits and on day 90, another outpatient visit are scheduled. Adverse events and serious adverse events will be monitored and reported until the end of the study. An independent data safety monitoring committee will review trial progression and safety.

Main Outcomes: The primary endpoint of the study is the cumulative number of individuals who progress to or beyond category 4b on the modified WHO COVID-19 ordinal scale (defined as hospitalization with COVID-19 pneumonia and additional oxygen demand via nasal cannula or mask) within 28 days after randomization.

Randomization: Participants will be randomized using the Alea-Tool ( aleaclinical.com ) in a 2:2:1:1 ratio to the treatment arms (1) CP, (2) camostat mesylate, (3) standard of care (SoC), and (4) placebo matching camostat mesylate. Randomization will be stratified by study center.

Blinding (masking): The camostat mesylate treatment arm and the respective placebo will be blinded for participants, caregivers, and those assessing outcomes. The treatment arms convalescent plasma and standard of care will not be blinded and thus are open-labeled, unblinded.

Numbers To Be Randomized (sample Size): Overall, n = 994 participants will be randomized to the following groups: n = 331 to convalescent plasma (CP), n = 331 to camostat mesylate, n = 166 to standard of care (SoC), and n = 166 to placebo matching camostat mesylate.

Trial Status: The RES-Q-HR protocol (V04F) was approved on the 18 December 2020 by the local ethics committee and by the regulatory institutions PEI/BfARM on the 2 December 2020. The trial was opened for recruitment on 26 December 2020; the first patient was enrolled on 7 January 2021 and randomized on 8 January 2021. Recruitment shall be completed by June 2021. The current protocol version RES-Q HR V05F is from 4 January 2021, which was approved on the 18 January 2021.

Trial Registration: EudraCT Number 2020-004695-18 . Registered on September 29, 2020. ClinicalTrial.gov NCT04681430 . Registered on December 23, 2020, prior to the start of the enrollment (which was opened on December 26, 2020).

Full Protocol: The full protocol (V05F) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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http://dx.doi.org/10.1186/s13063-021-05181-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127198PMC
May 2021

Cardiac MRI in Suspected Acute COVID-19 Myocarditis.

Radiol Cardiothorac Imaging 2021 Apr 4;3(2):e200628. Epub 2021 Mar 4.

Department of Diagnostic and Interventional Radiology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany (J.A.L., A.I., N.M., M.R., A.F., D.D., U.A.); Quantitative Imaging Lab Bonn (QILaB) (J.A.L., A.I., N.M., M.R., A.F., D.D.); Department of Internal Medicine II - Cardiology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany (C.O., S.Z.); Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany (M.M., S.S., C.B., C.P.S., J.N.); Department of Internal Medicine III-Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany (A.H.); Department of Anesthesiology, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany (M.V.); Department of Cardiac Surgery, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany (G.D.D.).

COVID-19; coronavirus; myocarditis; cardiac MRI; T1 mapping; T2 mapping.
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http://dx.doi.org/10.1148/ryct.2021200628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098091PMC
April 2021

Advances in the pharmacological management of bacterial peritonitis.

Expert Opin Pharmacother 2021 Aug 21;22(12):1567-1578. Epub 2021 Apr 21.

Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany.

Bacterial peritonitis is an infection with high mortality if not treated immediately. In the absence of an intraabdominal source of infection, bacterial peritonitis may arise in patients with liver cirrhosis, in patients on peritoneal dialysis (PD) for end-stage renal disease or in patients with tuberculosis. In patients with cirrhosis, bacterial peritonitis may trigger acute on chronic liver failure with substantial mortality despite optimal treatment. In patients on PD, peritonitis may make continuation of PD impossible, necessitating the switch to hemodialysis. Recovery from peritonitis and prevention of complications depend on timely pharmacological management. Challenges are the broad microbiological spectrum with growing rates of antimicrobial resistance, the underlying chronic liver or kidney failure and high rates of relapse. The authors provide a review of predisposing conditions, diagnosis, and prevention of bacterial peritonitis with a particular focus on the pharmacological management. Diagnosis of the type of bacterial peritonitis is essential to pharmacological management. In patients with spontaneous bacterial peritonitis, broad-spectrum antibiotics should be given intravenously in conjunction with albumin. In patients on PD, antibiotic therapy should be preferably applied intraperitoneally with empirical coverage of gram-positive and gram-negative bacteria. Secondary peritonitis usually requires surgical or interventional treatment.
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http://dx.doi.org/10.1080/14656566.2021.1915288DOI Listing
August 2021

N-protein presents early in blood, dried blood and saliva during asymptomatic and symptomatic SARS-CoV-2 infection.

Nat Commun 2021 03 26;12(1):1931. Epub 2021 Mar 26.

Quanterix Corporation, Billerica, MA, USA.

The COVID-19 pandemic continues to have an unprecedented impact on societies and economies worldwide. There remains an ongoing need for high-performance SARS-CoV-2 tests which may be broadly deployed for infection monitoring. Here we report a highly sensitive single molecule array (Simoa) immunoassay in development for detection of SARS-CoV-2 nucleocapsid protein (N-protein) in venous and capillary blood and saliva. In all matrices in the studies conducted to date we observe >98% negative percent agreement and >90% positive percent agreement with molecular testing for days 1-7 in symptomatic, asymptomatic, and pre-symptomatic PCR+ individuals. N-protein load decreases as anti-SARS-CoV-2 spike-IgG increases, and N-protein levels correlate with RT-PCR Ct-values in saliva, and between matched saliva and capillary blood samples. This Simoa SARS-CoV-2 N-protein assay effectively detects SARS-CoV-2 infection via measurement of antigen levels in blood or saliva, using non-invasive, swab-independent collection methods, offering potential for at home and point of care sample collection.
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http://dx.doi.org/10.1038/s41467-021-22072-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997897PMC
March 2021

Renal replacement therapy as bridging-to-recovery in refractory hepatorenal syndrome.

Z Gastroenterol 2021 Apr 25;59(4):331-335. Epub 2021 Feb 25.

Department of Internal Medicine I, University Hospital Bonn, Venusberg Campus 1, Bonn, Germany.

A 50-year-old female patient with cirrhosis due to alcoholic steatohepatitis was referred to our department because of recurrent hepatorenal syndrome (HRS) and hepatic hydrothorax. Clinically, severe anasarca was the leading problem. In contrast to previous episodes, HRS did not respond to standard treatment including terlipressin.Given the severe, refractory hyperhydration, we finally initiated renal replacement therapy (RRT). Subsequently, RRT was performed without severe side effects for more than 100 days. In the meantime, liver function remarkably improved, most probably due to the prolonged abstinence from alcohol. Finally, RRT could be stopped. Since then, our patient has remained in good clinical condition for more than 6 months, with well-compensated Child-Pugh stage A cirrhosis and only mild chronic kidney disease stage III.In conclusion, this case highlights that RRT may be considered in individual cases as bridging therapy in refractory HRS until the liver regenerates due to the absence of damaging mechanisms.
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http://dx.doi.org/10.1055/a-1369-9859DOI Listing
April 2021

SIV-induced terminally differentiated adaptive NK cells in lymph nodes associated with enhanced MHC-E restricted activity.

Nat Commun 2021 02 24;12(1):1282. Epub 2021 Feb 24.

Institut Pasteur, Unité HIV, Inflammation et Persistance, Paris, France.

Natural killer (NK) cells play a critical understudied role during HIV infection in tissues. In a natural host of SIV, the African green monkey (AGM), NK cells mediate a strong control of SIVagm infection in secondary lymphoid tissues. We demonstrate that SIVagm infection induces the expansion of terminally differentiated NKG2a NK cells in secondary lymphoid organs displaying an adaptive transcriptional profile and increased MHC-E-restricted cytotoxicity in response to SIV Env peptides while expressing little IFN-γ. Such NK cell differentiation was lacking in SIVmac-infected macaques. Adaptive NK cells displayed no increased NKG2C expression. This study reveals a previously unknown profile of NK cell adaptation to a viral infection, thus accelerating strategies toward NK-cell directed therapies and viral control in tissues.
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http://dx.doi.org/10.1038/s41467-021-21402-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904927PMC
February 2021

Solid organ transplantation is not a risk factor for COVID-19 disease outcome.

Transpl Int 2021 02 10;34(2):378-381. Epub 2021 Jan 10.

Department of Internal Medicine I, Department of Gastroenterology, Hepatology, Nephrology, Infectiology, Endocrinology and Diabetology, University Hospital Bonn, Bonn, Germany.

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http://dx.doi.org/10.1111/tri.13795DOI Listing
February 2021

Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients.

Genome Med 2021 01 13;13(1). Epub 2021 Jan 13.

PRECISE Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany.

Background: The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system.

Methods: In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings.

Results: Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host.

Conclusions: Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.
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http://dx.doi.org/10.1186/s13073-020-00823-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805430PMC
January 2021

Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status.

Cancers (Basel) 2020 Dec 11;12(12). Epub 2020 Dec 11.

Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany.

Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic or germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic variants (PV) in 60 patients (28 families) and one PV in two patients from one family. Sixty-eight percent ( = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 ± 13 years vs. 44 ± 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% ( = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant.
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http://dx.doi.org/10.3390/cancers12123726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763201PMC
December 2020

Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19.

Immunity 2020 12 26;53(6):1296-1314.e9. Epub 2020 Nov 26.

Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, 24105 Kiel, Germany.

Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is needed for understanding skewed immune responses and defining predictors of outcome. Here, we performed a longitudinal multi-omics study using a two-center cohort of 14 patients. We analyzed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of interferon-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling. Megakaryocyte- and erythroid-cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond adaptive immune cells and provides an entry point toward developing biomarkers and targeted treatments of patients with COVID-19.
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http://dx.doi.org/10.1016/j.immuni.2020.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689306PMC
December 2020

Transpapillary tissue sampling of biliary strictures: balloon dilatation prior to forceps biopsy improves sensitivity and accuracy.

Sci Rep 2020 10 15;10(1):17423. Epub 2020 Oct 15.

Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

The early and definitive diagnosis of malignant bile duct stenoses is essential for a timely and adequate therapy. However, tissue sampling with transpapillary brush cytology (BC) or forceps biopsy (FB) remains challenging. With this study, we aimed to compare the effectiveness and safety of different tissue sampling modalities (BC, FB without/after previous balloon dilatation). Standardized database research identified all patients, who underwent endoscopic retrograde cholangiography with BC and/or FB for indeterminate bile duct stenosis between January 2010 and April 2018 and with a definitive diagnosis. 218 patients were enrolled (149 cases with malignant and 69 with benign disease). FB had a significant higher sensitivity than BC (43% vs. 16%, p < 0.01). Prior balloon dilatation of the stenosis improved the sensitivity of FB from 41 to 71% (p = 0.03), the NPV from 36 to 81% (p < 0.01) and the accuracy from 55 to 87% (p < 0.01). The complication rates did not differ significantly between the modalities. In our center FB turned out to be the diagnostically more effective procedure. Balloon dilatation of the stenosis before FB had a significant diagnostic benefit and was not associated with a higher complication rate.
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http://dx.doi.org/10.1038/s41598-020-74451-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566456PMC
October 2020

First results of the "Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS)".

Infection 2021 Feb 1;49(1):63-73. Epub 2020 Oct 1.

Department I for Internal Medicine, University Hospital of Cologne, University of Cologne, Cologne, Germany.

Purpose: Knowledge regarding patients' clinical condition at severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is sparse. Data in the international, multicenter Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort study may enhance the understanding of COVID-19.

Methods: Sociodemographic and clinical characteristics of SARS-CoV-2-infected patients, enrolled in the LEOSS cohort study between March 16, 2020, and May 14, 2020, were analyzed. Associations between baseline characteristics and clinical stages at diagnosis (uncomplicated vs. complicated) were assessed using logistic regression models.

Results: We included 2155 patients, 59.7% (1,287/2,155) were male; the most common age category was 66-85 years (39.6%; 500/2,155). The primary COVID-19 diagnosis was made in 35.0% (755/2,155) during complicated clinical stages. A significant univariate association between age; sex; body mass index; smoking; diabetes; cardiovascular, pulmonary, neurological, and kidney diseases; ACE inhibitor therapy; statin intake and an increased risk for complicated clinical stages of COVID-19 at diagnosis was found. Multivariable analysis revealed that advanced age [46-65 years: adjusted odds ratio (aOR): 1.73, 95% CI 1.25-2.42, p = 0.001; 66-85 years: aOR 1.93, 95% CI 1.36-2.74, p < 0.001; > 85 years: aOR 2.38, 95% CI 1.49-3.81, p < 0.001 vs. individuals aged 26-45 years], male sex (aOR 1.23, 95% CI 1.01-1.50, p = 0.040), cardiovascular disease (aOR 1.37, 95% CI 1.09-1.72, p = 0.007), and diabetes (aOR 1.33, 95% CI 1.04-1.69, p = 0.023) were associated with complicated stages of COVID-19 at diagnosis.

Conclusion: The LEOSS cohort identified age, cardiovascular disease, diabetes and male sex as risk factors for complicated disease stages at SARS-CoV-2 diagnosis, thus confirming previous data. Further data regarding outcomes of the natural course of COVID-19 and the influence of treatment are required.
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http://dx.doi.org/10.1007/s15010-020-01499-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527665PMC
February 2021

Value of upper gastrointestinal endoscopy for gastric cancer surveillance in patients with Lynch syndrome.

Int J Cancer 2021 01 13;148(1):106-114. Epub 2020 Oct 13.

Department of Hematology and Oncology, Klinikum Hochsauerland, Meschede, Germany.

In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from the registry of the German Consortium for Familial Intestinal Cancer. In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty-nine GC events were observed in 47 patients. MLH1 (n = 21) and MSH2 (n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early-stage disease (UICC I) than GCs detected through symptoms (83% vs 25%; P = .0231). Thirty-two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28-66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30.
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http://dx.doi.org/10.1002/ijc.33294DOI Listing
January 2021

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment.

Cell 2020 09 5;182(6):1419-1440.e23. Epub 2020 Aug 5.

Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Lung Research (DZL).

Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRCD11c inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DR monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.
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http://dx.doi.org/10.1016/j.cell.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405822PMC
September 2020
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