ABSTRACT
Background: In acute COVID-19 infection, growing evidence hints towards a broad activation of plasma cells and the presence of pathologic autoantibodies (abs). A systematic screening for abs confrmed induction of diverse functional abs by SARS-CoV-2 infection (1, 2). Immune-mediated thrombosis, involving platelet activation, has been identifed as one of the key pathogenic mechanisms in COVID-19 and is linked to morbidity and mortality (3). As natural abs against G protein-coupled receptors, functional abs against the thrombin receptor type-1 (PAR-1) might predispose for increased activation of the coagulation system present in COVID-19 infection. Objectives: The aim of this study is to identify the diagnostic value of anti-PAR1 antibodies and their capacity to predict the outcome of COVID-19 infection. Methods: 82 serum samples from 55 individuals with COVID-19 derived from three different hospitals in Schleswig-Holstein, Germany, and 88 single time point samples from healthy controls were subjected to ELISA-based quantifcation of anti-PAR-1 abs (CellTrend GmbH Luckenwalde, Germany). The levels of anti-AT1R abs were compared with clinical and laboratory parameters. Results: COVID-19 patients revealed markedly increased levels of circulating anti-PAR1 abs in hospitalized patients particularly in those required intensive care treatment in comparison to controls (p < 0.0001, Figure 1a). Anti-PAR1 ab levels were highest in patients with fatal outcome (p = 0.006, Figure 1a). Receiver operating characteristic (ROC) analysis of PAR1 abs levels in COVID-19 patients revealed a sensitivity of 84.00% and a specifcity 79.25% for patients requiring intensive care unit (ICU) treatment and a sensitivity of 87.50 % and a specifcity 84.51 % to distinguish fatal vs. non-fatal disease outcome (Figure 1b). We found correlation of circulating anti-PAR1 abs with D dimers. Conclusion: The increased anti-PAR1 abs, their prediction to identify patients requiring ICU and fatal outcome, and the correlation with markers for blood clotting suggest a role for antibodies against PAR1 in the disease development of blood clotting in COVID-19.
ABSTRACT
Background and Aim Obesity and type 2 diabetes (T2D) show an increased risk for a severe COVID-19 disease. Treatment with DPP4 inhibitor (DPP4i) results in reduced mortality and better clinical outcome. Here, we aimed to identify potential mechanisms for the observed DPP4i effect in COVID-19. Methods We compared T2D subjects with (cases) and without (controls) DPP4i treatment (N=69), as well as patients hospitalised for severe COVID-19 and healthy controls (N=34) with regard to serum concentrations of soluble frizzle receptor protein 5 (sFRP5) using univariate statistics. Furthermore, we isolated pre-adipocytes, mature adipocytes and macrophages from adipose tissue biopsies (N=100) and performed western-blotting for sFRP5 and Wnt5a expression. Results In T2D patients, we identified a significant increase of the anti-inflammatory adipokine sFRP5 in relation to DPP4 inhibition. sFRP5 is a specific antagonist to Wnt5a, a glycopeptide secreted by adipose tissue macrophages acting proinflammatory in various diseases. We therefore examined sFRP5 levels in patients hospitalised for severe COVID-19 and found significant lower levels compared to healthy controls. Since sFRP5 might consequently be a molecular link for the beneficial effects of DPP4i in COVID-19, we further aimed to identify the exact source of sFRP5 in adipose tissue on cellular level. Results from western-blotting in adipose tissues showed a sFRP5 expression specifically in mature adipocytes of subcutaneous and omental adipose tissue. Conclusion In summary, our data suggest that DPP4i increase serum levels of anti-inflammatory sFRP5 which might be beneficial in COVID-19, reflecting a state of sFRP5 deficiency.
ABSTRACT
Introduction: More than 2.5 million people in Europe are diagnosed with inflammatory bowel diseases (IBD). IBD affects the quality of life, but also has important consequences for health systems. It remains unknown if variations in IBD care and education differs across Europe and to help address this question, we conducted this European Variation In IBD PracticE suRvey (VIPER) to study potential differences. Aims & Methods: This trainee-initiated survey, run through SurveyMonkey ®, consisted of 47 questions inquiring basic demographics, IBD training and clinical care. The survey was distributed through social media and national GI societies from December 2020 - January 2021. Results were compared according to GDP per capita, for which countries were divided into 2 groups (low/high income, according to the World Bank). Differences between groups were calculated using the chi2 statistic. Results: The online survey was completed by 1268 participants from 39 European countries. Most of the participants are specialists (65.3 %), followed by fellows in training (>/< 3 years, 19.1%, 15.6 %). Majority of the responders are working in academic institutions (50.4 %), others in public/ district hospitals (33.3 %) or private practices (16.3 %). Despite significant differences in access to IBD-specific training between high (56.4%) and low (38.5%) GDP countries (p<0.001), majority of clinicians feels comfortable in treating IBD (77.2% vs 72.0%, p=0.04). GDP was not a factor that dictated confidence in treating patients. IBD patients seen per week, IBD boards and especially IBD specific training were factors increasing confidence in managing IBD patients. Interestingly, a difference in availability of dedicated IBD units could be observed (58.5% vs 39.7%, p<0.001), as well as an inequality in multidisciplinary meetings (72.6% vs 40.2%, p<0.001), which often take place on a weekly basis (53.0%). In high GDP countries, IBD nurses are more common (86.2%) than in low GDP countries (36.0%, p<0.001), which is mirrored by differences in nurse-led IBD clinics (40.6% vs 13.8%, p<0.001). IBD dieticians (32.4% vs 16.6%) and psychologists (16.7% vs 7.5%) are mainly present in high GDP countries (p<0.001). In the current COVID era, telemedicine is available in 58.4% vs 21.4% of the high/low GDP countries respectively (p<0.001), as well as urgent flare clinics (58.6% vs 38.7%, p<0.001) and endoscopy within 24 hours if needed (83.0% vs 86.7% p=0.1). Treat-to-target approaches are implemented everywhere (85.0%), though access to biologicals and small molecules differs significantly. Almost all (94.7%) use faecal calprotectin for routine monitoring, whereas half also use intestinal ultrasound (47.9%). Conclusion: A lot of variability in IBD practice exists across Europe, with marked differences between high vs low GDP countries. Further work is required to help address some of these inequalities, aiming to improve and standardise IBD care across Europe.
ABSTRACT
Aims Dipeptidylpeptidase is a key regulator of the incretin system. Initially, it's soluble form (sDPP-4) was described as an adipokine mediating metabolic inflammation. This is recently questioned in mechanistic rodent studies. To further clarify sDPP-4's role in physiology and metabolic diseases, we examined sDPP-4 in a large human cohort and during weight-loss interventions. Like ACE2, sDPP-4 serves as a binding partner for certain corona-like viruses enabling virus entry. As metabolic diseases are major risk factors for the COVID-19 pandemic, we additionally examined sDPP-4 in patients suffering severe Sars-CoV-2 infection. Methods sDPP-4 serum concentrations were measured using ELISA and related to various metabolic variables. Using a case-control-design, sDPP-4 was assessed in acute COVID-19 and sepsis infection. Results sDPP-4 increased with body weight, insulin resistance and hypertriglyceridemia but reduced in type 2 diabetes and arterial hypertension. Altered serum concentrations appeared with impaired liver and kidney but not cardiac function. No association to systemic inflammation was observed. Having found increased sDPP-4 in obesity, surgical (gastric bypass/sleeve gastrectomy) and non-surgical weight-loss interventions revealed a significant association of sDPP-4 with the improvement of liver function but neither with changes in body weight nor fat mass. Complementary, the case control study revealed reduced sDPP-4 concentrations specific for COVID-19 infection. Conclusions We suggest that sDPP-4 is rather related to hepatic abnormalities in obesity than primarily functioning as an adipokine. sDPP-4 is implicated in glucose and lipid metabolism, but not fundamentally in systemic inflammation. Additional to ACE-2, sDPP-4 might also have a regulatory role in COVID-19 infection.