ABSTRACT
Background: COVID-19-Convalescent Plasma (CCP) showed beneficial effects when given early in the treatment course or when it contains high-titre of neutralizing antibodies. Here we present a long-term follow up of patients of the multicentric national randomized CAPSID trial that investigated the effect of CCP in hospitalized COVID-19 patients. CCP donors were also included in the follow up and severed as a control group of patients with mild to moderate disease. Method(s): Patients and donors were invited to participate in the long-term follow up. Data on long-term overall survival (OS) were available for n=52 patients (control group: n=22, high titre CCP: n=16, low-titre CCP: n=14) and n=113 donors. Structured interview and a quality of life (QoL) assessment by questionnaires (FACIT fatigue, FACIT dyspnea and EQ-ED- 5DL) were performed. Visits took place online or on site. Laboratory tests included neutralizing antibody testing by PRNT and inflammation markers. Data are given as median with IQR. Medical events were assessed and graded according to CTCAE. For donors the median follow up time was 517 (483-553) days after the first plasmapheresis and for patients 395 (371-417) days after randomization. Result(s): Medical events during follow up were reported in 27% of donors and 16% of patients (p=0.164) with grade 3 or higher in 9% of donors and 22% of patients. More patients than donors reported a decrease in their socioeconomic status and reported more frequently about GI, pulmonal, pain symptoms or alopecia (p<0.02), but no difference in neurologic symptoms including anosmia was observed. Post COVID-Scale was worse in patients with a trend for better outcome in the CCP group (p=0.089). The trend for better OS in the CCP group became more pronounced during the long-term follow up (p=0.08) and OS remained significantly better in the high dose CCP group (p=0.01). All QoL scores showed a consistent trend towards better outcomes of the CCP group. Conclusion(s): To our knowledge, this is the first long-term follow up from a randomized trial of CCP. CCP-donors with mild to moderate COVID- 19 had a significant smaller long-term disease burden than patients with severe disease. The addition of CCP added to standard treatment in severe COVID-19 showed a trend to better OS and QoL. We had previously reported significant better outcomes in the high-titre CCP subgroup (until day 60). This was even more pronounced during the long-term follow up (> 1 year).
ABSTRACT
This paper proposes a framework for the systematic adaptation and digitalisation of engineering product development courses in the event of a crisis. Applicants can use resources of the framework to identify crisis-related boundary conditions that impact the delivery of education and are assisted in determining the necessary level of course digitalisation to respond to the crisis. Furthermore, the framework comprehends a review of modern educational teaching objectives, as well as a table containing tools and methodologies linked to educational targets. These can be used to enhance course design to keep students independently of their learning profiles engaged in study activities and to uphold an excellent knowledge acquisition in a volatile environment. An exemplary application of the framework on a CAD course in a higher education context guides the educator through the processes. © Proceedings of the 24th International Conference on Engineering and Product Design Education: Disrupt, Innovate, Regenerate and Transform, E and PDE 2022. All rights reserved.
ABSTRACT
Background: Several observational studies suggested efficacy of COVID-19 convalescent plasma (CCP) but the results of several randomized clinical trials of CCP are not consistent. The trials differ in treatment schedules in terms of timing, volume and antibody content of CCP as well as enrolled patient populations and endpoints. The CAPSID was designed at the beginning of the pandemic and assessed the efficacy of neutralizing antibody containing high-dose COVID-19 convalescent plasma (CCP) in hospitalized patients with severe COVID-19. Methods: Patients (n=105) in 13 hospitals in Germany were randomized to either receive standard treatment and three units of CCP on days 1, 3 and 5 (total dose 846 ml) (n=53) or standard treatment alone (n=52). Patients in the control group with progress on day 14 could receive CCP (crossover group;n=7) on days 15, 17 and 19. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria of severe COVID-19 on day 21. For Cross over patients a propensity matching with patients of the plasma group was performed. Results: Neutralizing antibodies were present at baseline in 18.2% of CCP and 19.2% of control group patients. In the ITT analysis the primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group (p=0.32). The CCP group showed a trend for shorter times to clinical improvement (40 days, p=0.27) and discharge from hospital (20 days, p=0.24). Among those in the CCP group who received a higher or lower cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% and 32.1% of patients The high titer group showed significantly shorter intervals to clinical improvement or hospital discharge and a better overall survival (p=0.02). None of the patients in the crossover group (CG) achieved clinical improvement and survived. Comparing the CG to 14 CCP patients matched by baseline characteristics resulted in worse OS in the CG group (p=0.02) while comparison with 6 day 14 matched patients showed equal OS. Interpretation: CCP added to standard treatment did not result in a significant difference in the primary and secondary outcomes. A pre-defined subgroup analysis showed a signal of benefit for CCP among those who received a larger amount of neutralizing antibodies. A progress on day 14 is an indicator for poor outcome in COVID-19. Late administration of CCP is not supported by our results.
ABSTRACT
Background: COVID-19 antibody (Ab) induced procoagulant platelets (PLTs) were recently identified and associated with a higher risk of thromboembolic events in patients infected with SARS-CoV-2. However, the underlying mechanisms leading to procoagulant PLTs in COVID-19 remain elusive. Aims: In this study the mechanisms of COVID-19 Ab induced procoagulant PLT formation as well as the contribution of this PLT subpopulation in thrombus formation were investigated. Methods: Washed PLTs were incubated with IgG fractions from severe COVID-19 ICU or non-COVID-19 ICU patients and analyzed for changes in the expression of caspase 3 using immunoblot as well as CD62P (P-selectin) and phosphatidylserine (PS) via double staining in flow cytometry. To investigate the impact of procoagulant PLTs on thrombus formation, collagen coated microfluidic channels were perfused with whole blood after incubation with IgG antibodies from COVID-19 or control patients. Results: ICU COVID-19 IgG induced a significant increase in caspase 3 cleavage and formation of CD62P/PS positive procoagulant PLTs compared to the ICU control group (31.63%±3.86 vs. 4.04%±1.16, P = 0.0007). Remarkably, incubation of PLTs with ICU COVID-19 IgG resulted in increased thrombus formation (mean % surface area covered [SAC]±SEM: 13.95±1.55 vs. 2.86±1.10, P = 0.0070) and was significantly inhibited by PLT FcγRIIA blockade (16.49±1.02 vs. 5.84±1.93, P = 0.0090). Most importantly and of potential therapeutic relevance, Ab induced procoagulant PLTs and increased thrombus formation were markedly reduced in the presence of Iloprost, a prostacyclin analogue and elevator of intracellular cAMP (41.36%±3.60 vs. 22.22%±3.92, P = 0.0156 and 14.63±2.31 vs. 3.85±0.95, P = 0.0079, respectively). Conclusions: Our findings indicate that COVID-19 Abs induce procoagulant PLTs and increased thrombus formation in a FcγRIIA dependent pathway. As these changes were inhibited via Iloprost, upregulation of cAMP in PLTs might be a promising future therapeutic approach for the complex coagulopathy observed in critical ill COVID-19 patients. (Figure Presented) .
ABSTRACT
Background : The pathophysiology of COVID-19-associated coagulopathy is to be complex and multifactorial. In this study, we hypothesized that the coagulopathy in COVID-19 is accompanied by immune mediated procoagulant platelets with subsequent alteration of the coagulation system. Aims : We aimed to further analyze the role of platelets (PLTs) leading to increased thromboembolic events in patients with severe COVID-19. Methods : Blood samples from COVID-19 intensive care unit (ICU) patients were analyzed for procoagulant markers. Flow cytometry was used to investigate depolarization of mitochondrial inner transmembrane potential (ΔΨm), intracellular Ca2+ concentration, and phosphatidylserine (PS) externalization. Results : PLTs from COVID-19 patients ( n = 21) showed significantly higher ΔΨm depolarization (1.39 ± 0.07 vs. 0.99 ± 0.06, P = 0.0005), Ca2+ concentration (2.73 ± 0.31 vs. 1.00 ± 0.05, P < 0.0001) and PS externalization (2.05 ± 0.48 vs. 0.86 ± 0.11, P = 0.0236), compared to healthy control (HC), respectively. Most importantly, PS exposure was associated with SOFA score (sequential organ failure assessment, r = 0.5635, P = 0.0078) and plasma levels of D-Dimer ( r = 0.4473, P = 0.0420). Finally, patients with thromboembolic events had higher PS externalization compared to those without thrombosis (2.85 ± 0.75 vs. 0.99 ± 0.20, P = 0.0340). Sera from COVID-19 patients also induced significant increase in procoagulant markers (ΔΨm depolarization (1.52 ± 0.117 vs. 0.958 ± 0.082, P = 0.0086), Ca2+ concentration (1.372 ± 0.074 vs. 0.984 ± 0.055, P = 0.0036) and PS externalization (1.624 ± 0.126 vs. 0.969 ± 0.100, P = 0.0051)) compared to sera from HC. Interestingly, immunoglobulin G (IgG) fractions from COVID-19 patients induced an Fc gamma receptor IIA dependent platelet apoptosis (ΔΨm depolarization (2.23 ± 0.25 vs. 1.22 ± 0.12, P = 0.0216), Ca2+ concentration (1.80 ± 0.15 vs. 0.58 ± 0.04) and PS externalization (9.59 ± 1.52 vs. 2.12 ± 0.20, P = 0.0371)). Conclusions : Our study shows that COVID-19 patients had increased IgG-mediated procoagulant platelets. The strong correlations between procoagulant PLTs and increased D-Dimer levels as well as the incidence of thromboembolic complications may indicate that procoagulant platelets potentially contribute to sustained increased thromboembolic risk in COVID-19 ICU patients.