Plasma with high titers of anti-SARS-Cov2 antibodies improves outcome of COVID-19 in patients with hematological malignancy and cancer in a randomized controlled trial

Background. Patients with hematological malignancy or other cancers as well as immunosuppression bear a high risk for severe COVID-19. Monoclonal antibodies (mAb) are efficient at early stages of the disease but may lose potency with new variants. Trials on plasma from convalescent donors in unselected patients have not shown clinical benefit. No randomized trials focussing on patients with underlying disease have been published. Methods. We conducted an open-label, multicenter, randomized controlled trial to evaluate efficacy of plasma (CVP - convalescent or after vaccination) in patients with COVID-19 at high risk for adverse outcome in Germany. We assessed the effect of high-titer CVP (2 units from different donors, 238-337 ml each, on subsequent days). Patients with hematological or other malignancy (group 1), immunosuppression (group 2), age >50 and <=75 years and lymphopenia and/or high D-dimers (group 3) or age >75 years (group 4) who were hospitalized with confirmed SARS-CoV-2 infection and with an oxygen saturation <=94% were included. Primary outcome measure was time to clinical improvement on a seven-point ordinal scale, secondary outcome was mortality (Janssen et al. Trials 2020 Oct 6;21(1):828). Results. Overall, 133 patients were randomized, 68 received CVP with an additional 10 patients as a crossover on day 10. Median age (range) was 68 years (39-95) in the CVP group and 70 (38-90) in controls. For the entire cohort, no significant difference was seen in time to improvement (median days: CVP 12.5 vs. control 18;HR 1.24 (95% confidence interval (CI) 0.83-1.85), p=0.29). Subgroup analysis (group 1+2) revealed shortened time to improvement (median days CVP 13 vs. control 32;HR 2.03 (95%CI 1.17-3.6), p=0.01) and mortality was reduced (mortality CVP n=6 (18%) vs. control n=10 (29%). No significant differences in time to improvement were observed in group 3 or 4 (HR 0.72 (95%CI 0.41-1.28), p=0.26). No relevant adverse events were observed. Conclusion. CVP improves time to clinical improvement and mortality for COVID-19 patients with underlying hematological disease/cancer or other reasons of impaired immune response. Even with new variants, high-titer CVP may offer a widely available and inexpensive therapy option in high-risk groups. Funding. BMBF FKZ 01KI20152;EudraCT 2020-001632-10.

Modeling Access Differences to Reduce Disparity in Resource Allocation

Motivated by COVID-19 vaccine allocation, where vulnerable subpopulations are simultaneously more impacted in terms of health and more disadvantaged in terms of access to the vaccine, we formalize and study the problem of resource allocation when there are inherent access differences that correlate with advantage and disadvantage. We identify reducing resource disparity as a key goal in this context and show its role as a proxy to more nuanced downstream impacts. We develop a concrete access model that helps quantify how a given allocation translates to resource flow for the advantaged vs. the disadvantaged, based on the access gap between them. We then provide a methodology for access-aware allocation. Intuitively, the resulting allocation leverages more vaccines in locations with higher vulnerable populations to mitigate the access gap and reduce overall disparity. Surprisingly, knowledge of the access gap is often not needed to perform access-aware allocation. To support this formalism, we provide empirical evidence for our access model and show that access-aware allocation can significantly reduce resource disparity and thus improve downstream outcomes. We demonstrate this at various scales, including at county, state, national, and global levels. © 2022 Owner/Author.

A RANDOMIZED CONTROLLED CLINICAL TRIAL DEMONSTRATES THAT PLASMA FROM CONVALESCENT AND VACCINATED DONORS IMPROVES OUTCOME OF COVID-19 IN PATIENTS WITH HEMATOLOGICAL DISEASE, CANCER OR IMMUNOSUPPRESSION

Background: Therapy options are limited for COVID-19 patients with hematological disease, cancer, immunosuppression or adanced age. Een though no benefit was obsered for conalescent plasma in unselected patients with COVID-19, retrospectie data suggest that it could be effectie in patients unable to mount a sufficient immune response upon SARS-CoV-2 infection. Plasma from accinated donors has not been systematically assessed for COVID-19 treatment. Aims: We conducted a randomized clinical trial to address plasma efficacy in patients at high risk for an aderse outcome. Methods: COVID-19 patients with confirmed SARS-CoV-2 infections and oxygen saturation <=94% were randomized (NCT05200754). Patients receied conalescent or accinated SARS-CoV-2 plasma in two bags (238 - 337 ml plasma each) from different donors on day 1 and 2 (PLASMA) or standard of care (CONTROL). Randomization was stratified according to four clinical patient groups, hematological/solid cancer (group-1), treatment or disease associated immunosuppression (group 2), high risk disease by standard parameters (group-3) or age >=75 years (group-4). Mechanically entilated patients were not eligible. Plasma was obtained from donors with high leel neutralizing actiity (titer >=1:80) either after SARS-CoV-2 infection (conalescent) or after accination with at least two doses of mRNA accines (accinated). Crossoer for the control group was allowed at day 10. The primary endpoint was time to improement as two points on a seen-point ordinal scale or lie discharge from the Hospital (IMPROVEMENT) with prespecified analyses of subgroups (Janssen M, et al. Trials 2020 Oct 6;21(1):828). Results: A total of 133 patients were randomized with 68 receiing PLASMA with a median age of 68 years (range 36-95) or CONTROL (n=65, of which n=10 (15.4%) crossed oer at day 10) with a median age of 70 years (range 38-90). The distribution of the four predefined groups was group-1, n=53;group-2, n=18;group-3, n=35;and group-4, n=27. The intention to treat analysis reealed a non-significant shorter time to IMPROVEMENT for patients in PLASMA (median 12.5 days, 95%-CI [10;16]) compared to patients in CONTROL (median 18 days, 95%-CI [11;28] ), hazard ratio 1.24, 95% confidence interal [0.83;1.85], p=0.29). Oerall, 27 patients died (PLASMA, n=12;CONTROL, n=15;p=0.80). Predefined subgroup analysis reealed a clinically significant benefit in patients with hematological malignancies, other cancers or immunosuppression (group-1, group-2, n=71). With a median time to improement of 13 days (95%-CI [9;19]) for PLASMA and 32 days (95%-CI [17;57]) for CONTROL(HR 2.03, 95%-CI [1.17;3.6], p=0.01). A sensitiity analysis reealed that IMPROVEMENT appeared to be seen een earlier with accinated (median 10 days, 95%-CI [8;14]) compared to conalescent SARS-CoV-2 plasma (median 13 days, 95%-CI [6;38]) and CONTROL. Within group-1 and group-2, six patients in PLASMA (18.2%) and 10 in CONTROL (28.6%) died. No significant differences in improement were obsered in group-3 and group-4 with a HR of 0.72 (95%-CI [0.41;1.28], p=0.26). Within group-3 and group-4, six patients in PLASMA (18.8%) and fie in CONTROL (16.7%) died. No preiously unknown side effects of plasma therapy emerged within the trial. Summary/Conclusion: Plasma from conalescent and particularly accinated donors improed outcome of COVID-19 patients with an underlying hematological disease /cancer or other reasons of impaired immune response. Plasma did not improe outcome in immune-competent patients with other risk factors and/or older age. (Figure Presented).

Challenges and Successes in Synchronous Cohort-Based International Education

To increase enrollment, universities have expanded their offerings to international graduate students beyond residential studies. Advances in teaching and learning technology have played a key role in enabling remote instruction to these students. In particular, synchronous instruction and engagement with peers within a cohort have been shown to improve the educational experience and lead to high persistence rates. It has previously been reported that instructional technology can be used to teach a full master's degree program in electrical and computer engineering to international graduate students in a synchronous fashion. To increase engagement, students study in the program as cohorts and collaborate in the classroom and in completing a significant engineering project. This technology platform allows a single instructor to teach live to multiple classrooms (before COVID-19) and a large number of students at home (during COVID-19). This technology facilitates in-class assessment, proctored examinations, and project-based collaboration. In this paper, we address some of the challenges in this domain based on our experience of teaching in this modality for over 10 semesters. We review how we have performed in-class assessments, conducted remote exams for student cohorts, and implemented group-based design project courses. We discuss our use of technology to support our educational objectives while overcoming limitations. We believe that our experiences are valuable to other instructors and institutions as they shift toward remote instruction due to ongoing public health concerns related to COVID-19 and a broader need to provide alternative modes of graduate instruction. © American Society for Engineering Education, 2021

Use of remdesivir in a kidney transplant recipient suffering from covid-19 pneumonia

Introduction: Due to limited experience in the management of COVID-19 infection in the posttransplant population [1,2] we want to report a case of a kidney transplant recipient infected with SARS-CoV-2, undergoing a therapy with Remdesivir. Methods: The 38-year old kidney transplant recipient, who received a renal allograft in 10/2019 (unknown underlying kidney disease) was admitted to the emergency department with a history of intermittent fever, beginning oliguria, low blood pressure and somnolence. The laboratory results revealed a slight increase of acute phase reactants, hyponatremia and a low CD4+ T cell count. Results: A naso-and oropharyngeal swab specimen tested positive for SARSCoV-2;a chest CT scan revealed only minor changes. The patient was started on empirical broad-spectrum antibiotics. Maintenance immunosuppressive agents (mycophenolate mofetil and tacrolimus) were discontinued and hydrocortisone was initiated as a continuous i.v. infusion. Further, valganciclovir and prophylactic anticoagulation with low molecular weight heparin were initiated and ivIG were administered as supportive treatment. About 10 days after admission, the patient had persistent fever and gradually developed dyspnea. A second chest CT scan showed bilateral basal infiltrates with ground glass opacity. Oxygen was administered at 5-7 l/min. Due to acute clinical deterioration and the high risk of progression and significant mortality of SARS-CoV-2 pneumonia [3], a 5-day course of antiviral treatment with Remdesivir in emergency use was started. The patient improved with normalization of inflammatory parameters and fever disappeared. As of today day 25 after admission, the patient has normal blood gas analysis without oxygen supply, normal graft function, and had no rejection episode or CMV reactivation. Conclusion: Despite a few reported cases of COVID-19 infection in the transplant population additional data are needed to optimize management of this patient group [4]. This case report shows the delayed development of SARS-CoV-2 pneumonia in a kidney transplant recipient. The clinical improvement after a 5 day Remdesivir therapy underlines the encouraging results observed with use of Remdesivir in other patients [5].