ABSTRACT
Background: COVID-19, an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes acute respiratory symptoms and is reported to affect the vascular system, which may be underlying the systemic symptoms observed in affected patients. However, severe cases were reported to be associated with reduced erythrocyte (RBCs) turnover, low hemoglobin (Hb) levels along with increased total bilirubin and ferritin serum concentrations. Moreover, expansion of erythroid progenitors in peripheral blood together with hypoxia, anemia, and coagulopathies highly correlates with severity and mortality. We demonstrate that SARS-CoV-2 directly infects erythroid precursor cells, impairs Hb homeostasis and aggravates COVID19 disease. Method(s): RBC precursors derived from peripheral CD34+ blood stem cells of healthy donors were infected in vitro with SARS-CoV-2 alpha variant and differentiated into RBCs. Hb and iron metabolism in more than 20 hospitalized Covid-19 patients and controls were analyzed in plasma-reduced whole blood samples using different approaches. Result(s): RBC precursors express ACE2 receptor, CD26 and CD147 at day 5 of differentiation, which makes them susceptible to SARS-CoV-2 infection, but virus is not able o replicate in these cell. qPCR analysis of differentiated RBCs revealed increased HAMP mRNA expression levels, encoding for hepcidin, which inhibits iron uptake. Furthermore, we found significantly changes in spin state of the iron in Hb as well as the tertiary structure shown by the formation of disulfide bridges in samples of COVID-19 patients. In addition, COVID-19 patients showed impaired Hb biosynthesis, enhanced formation of zinc-protoporphyrine IX, heme-CO2, and CO-Hb as well as degradation of Fe-heme. Moreover, significant iron dysmetablolism with high serum ferritin and low iron and transferrin levels occurred, explaining disturbances of oxygen-binding capacity observed in severely ill COVID-19 patients. Conclusion(s): Our data identify RBC precursors as a direct target of SARSCoV- 2 and suggest that SARS-CoV-2 induced dysregulation in Hb- and iron-metabolism contributes to the severe systemic course of COVID-19. Because changes in Hb structure may also be significantly involved in the development of Long-COVID symptoms such as fatigue and exhaustion, our findings may open the door for new diagnostic and therapeutic strategies for both intensive care COVID-19 patients and Long-COVID patients.
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
Plasma from recovered donors with COVID-19 (COVID-19 convalescent plasma, CCP) has been considered as a treatment option for patients with COVID-19. Several case reports and case-control studies with evidence of therapeutic effect were published during the initial phase of the pandemic. Results of several randomized trials are now available. The studies differed in terms of patient populations, which ranged from outpatients to critically ill patients, and primary endpoints. Also, the standard of care varied widely within the clinical trials. Most notably, the investigational drug differed significantly in terms of treatment regimen, volume, and antibody content. In the following we will discuss the results of the randomized trials published to date. From the results published to date, we can infer efficacy of CCP that contains high titers of neutralizing antibodies and is administered early in the course of the disease. COVID-19 convalescent plasma is not yet a routine treatment and should not be administered outside of a clinical trial. Newly designed studies should focus on early use of CCP containing high levels of neutralizing antibody and control important concomitant medications.