Study population and setting
The US government authorized an expanded access program (EAP) nationally using an open-label protocol for patients 18 years and older hospitalized with confirmed severe COVID-19 to assess mortality rates after administering convalescent plasma donated from COVID survivors. The Mayo Clinic served as the main research body. A total of 1,959 sites registered, and 1,809 sites had at least one patient receive a transfusion from April 4 to July 4 2020. Across all study sites, 47,047 patients enrolled, of whom 36,226 received COVID-19 convalescent plasma. Compatible plasma was transfused intravenously in units of ~200mL, and additional units administered if justified based on clinical indication. Each site reported participant demographic characteristics, clinical presentation and medications received, and the number of days since COVID-19 diagnosis at the time of receiving convalescent plasma. For those who died, the date of death was reported; those without a reported death were assumed alive. A subset of participants had residual specimens saved for blood banking quality assurance; when available these were tested for SARS-CoV-2 neutralizing antibody levels. Analysis was stratified by month of transfusion – April, May, or June, 2020 – due to a marked temporal reduction in overall mortality from COVID-19 from May to July. All analyses were limited to patients who received a single unit of convalescent plasma from a single donor. This study sought to answer the following two questions: (1) was mortality lower with a shorter time to transfusion from diagnosis of COVID-19; and (2) was mortality lower with transfusion of a higher antibody titer unit of convalescent plasma. Analysis was conducted by calculating unadjusted mortality by month of transfusion and using Cox regression models to adjust for month of transfusion, gender, race, age, and clinical condition on presentation, mechanical ventilation, and receipt of hydroxychloroquine, remdesivir, or steroids prior to transfusion.
Summary of Main Findings
Of the 36,226 who received convalescent plasma, 35,322 patients were included in the analysis of time to transfusion from hospitalization and death and 3082 in the analysis of antibody titer. Overall all-cause 7 and 30-day mortality among individuals who received convalescent plasma within 3 days of hospitalization declined from 13.4% and 30.4% in April, 2020 to 6.1% and 20.2%, respectively, in June, 2020. Multiple changes in patient population, time to hospitalization, and care occurred over this time including shifts in age, gender, weight, race, clinical status, and use of remdesivir, an agent with demonstrated improved outcomes in two RCTs. For example, 49.9% of patients were receiving mechanical ventilation prior to convalescent plasma infusion in April compared to 16.4% in June while 4.7% of patients in April received remdesivir compared to 46.3% in June.
Analysis 1: Since April, there was a difference in the 7 and 30-day all-cause mortality for patients who received transfusion within 3 days of COVID-19 diagnosis compared to 4 or more days from COVID-19 diagnosis. Seven-day mortality was 8.7% and 11.9% for within 3 days and 4 or more days, respectively, while 30-day mortality was 21.6% and 26.7% for within 3 days and 4 or more days, respectively. Improved survival with earlier transfusion held over time-period and with adjusted modeling to account for age, sex, disease severity, and receipt of hydroxychloroquine, remdesivir, or steroids prior to transfusion. There were notable changes in transfusion practice with 22.7% of transfusions within 3 days of COVID-19 diagnosis in April compared to 54.3% in June.
Analysis 2: Among a subset of participants with available antibody titers (n=3082), there was evidence of a dose-response relationship between low-, medium-, or high-levels of neutralizing antibodies and mortality. For low and high titer transfusions, mortality was 13.7% and 8.9% at 7 days and 29.9% and 22.3% at 30 days, respectively. The difference in mortality by antibody titer held with stratification by transfusion month and days from diagnosis to transfusion. In addition, there appeared to be a consistent dose response in mortality from low, medium, and high antibody units. Notably, there were considerable differences in the populations receiving low and high titer transfusion; for example, during April, 11% of transfusions were high titer compared to 19% in June.
The study team collected several potential clinical confounders, including disease severity at the time of transfusion and patient age that were included in an adjusted analysis and may have reduced some of the confounding in their estimates. Including the antibody titer analysis added a comparison that may have been less prone to confounding over time and by facility than the time from COVID-19 diagnosis analysis. However, even antibody titers changed over time, with a higher proportion of high titer units during the overall lower mortality month of June.
The study did not include a comparator group that did not receive convalescent plasma which would have provided a much more robust control group to assess therapeutic benefit. In the absence of this, the researchers sought to test if patients who received convalescent plasma earlier in the disease course and with a higher dose of neutralizing antibodies had lower mortality; however, data on the timing of transfusion in the course of the illness are presented relative to COVID-19 diagnosis rather than relative to disease onset or day of hospitalization. If the time from onset of symptoms to diagnosis varied over the course of the pandemic, this could be another source of variation between time periods in the study. Substantial differences in patients receiving earlier or later convalescent plasma or higher titer plasma may have caused the observed differences, including disease severity a characteristic that used very broad categories. It appears that the cut-offs for ‘low’ and ‘high’ antibody titers were determined after the analysis started; setting those thresholds a priori would have improved the methods. The endpoint for the study was either death or no report of death rather than recovery; it’s unclear if the patients who did not die actually recovered within 30 days. Given the multiple possible confounders over time, adjusting for these in the analysis are important, but the variables adjusted for in the analysis were limited; it is plausible that patients with longer delay to intervention were those who had more severe disease. There was also no information provided on why these patients chose to receive the treatment such that the potential for selection bias could not be assessed. Finally, patients who received the intervention after 4 days had to survive that long to receive the intervention, leaving the potential for further bias.
A randomized clinical trial of plasma therapy in China and one in the Netherlands demonstrated no significant clinical benefit 28 days post onset of illness; however, these studies had limited statistical power to detect a meaningful difference. This study adds value because of the large number of patients enrolled, and showed no major safety concerns in this large group of patients. This is the first report on mortality outcomes from the national Expanded Access Program for convalescent plasma therapy from COVID-survivor donors.
This review was posted on: 25 August 2020