One-year follow-up of the CAPSID randomized trial for high-dose convalescent plasma in severe COVID-19 patients

Abstract

BACKGROUNDResults of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported, but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP.METHODSOf 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP donors (n = 113) with asymptomatic to moderate COVID-19 were included as a reference group.RESULTSThe median follow-up of patients was 396 days, and the estimated 1-year survival was 78.7% in the CCP group and 60.2% in the control (P = 0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared with the control group (91.5% versus 60.2%, P = 0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase in neutralizing antibodies after vaccination between the CCP and control groups.CONCLUSIONThe trial demonstrated a trend toward better outcome in the CCP group without reaching statistical significance. A predefined subgroup analysis showed a significantly better outcome (long-term survival, time to discharge from ICU, and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared with the control group. A substantial long-term disease burden remains after severe COVID-19.Trial registrationEudraCT 2020-001310-38 and ClinicalTrials.gov NCT04433910.FundingBundesministerium für Gesundheit (German Federal Ministry of Health).

Keywords: COVID-19; Immunotherapy; Therapeutics.

Figure 1. Patient and donor enrollment in the CAPSID trial and the extended follow-up.

Figure 2. Overall survival.

Kaplan-Meier cumulative estimates of probability of overall survival are shown. In all panels, a “+” indicates a censored patient. (A) Overall survival of donors (dotted magenta line), control (solid green line), and CCP group (dotted red line). P = 0.083 (log-rank test) for CCP versus control group. (B) Overall survival compared in the CCP subgroup that received a low cumulative amount of neutralizing antibodies (solid red line), the CCP subgroup that received a high cumulative amount of neutralizing antibodies (solid blue line), and the control group (solid green line). P = 0.011 for high amount versus control and P = 0.032 for high amount versus low amount (log-rank test). (C) Overall survival by amount of donor symptoms in control group (solid green line) patients transfused with CCP from donors with ≤3 symptoms (dotted red line) or transfused from CCP donors with >3 symptoms (dotted blue line). P = 0.061 for CCP donors with >3 symptoms versus control (log-rank test).

Figure 3. Long-term occurrence of secondary outcomes by amount of transfused neutralizing units.

Kaplan-Meier cumulative estimates of probability are shown. In all panels, a “+” indicates a censored patient. (A) The key secondary outcome time to clinical improvement compared in the CCP subgroup that received a low cumulative amount of neutralizing units (red), the CCP subgroup that received a high cumulative amount of neutralizing units (blue), and the control group (green line). P = 0.088 (log-rank test; high amount vs. control group). (B) Time to first negative PCR compared in the CCP subgroup that received a low cumulative amount of neutralizing units (red), the CCP subgroup that received a high cumulative amount of neutralizing units (blue), and the control group (green line). P = 0.019 (log-rank test, high amount vs. control group). (C) Probability of discharge from ICU compared in the CCP subgroup that received a low cumulative amount of neutralizing units (red), the CCP subgroup that received a high cumulative amount of neutralizing units (blue), and the control group (green line). P = 0.025 (log-rank test, high amount group vs. control group). (D) Probability of discharge from hospital compared in the CCP subgroup that received a low cumulative amount of neutralizing units (red), the CCP subgroup that received a high cumulative amount of neutralizing units (blue), and the control group (green line). P = 0.017 (log-rank test, high amount vs. control group).

Figure 4. Post–COVID-19 scale and socioeconomic status.

(A) Relative proportion of donors (upper row), CAPSID trial patients (second row) (P < 0.0001 by Fisher´s exact test), patients stratified by randomization group (CCP group and control groups) (middle rows) (P = 0.089), and patients who received a high or low amount of neutralizing units (lower rows) (P = 0.1304) according to the post–COVID-19 scale from grade 0 to grade 4. (B) Relative proportion of donors (upper row), CAPSID trial patients (second row), and patients stratified by randomization group (CCP group and control groups) (middle rows) and patients who received a high or low amount of neutralizing units (lower rows) (P = 0.4171) according to their change in socioeconomic status (increased, unchanged, decreased).

Figure 5. Quality of life score.

Data given as median and interquartile ranges. (A) EQ-5D-5L visual scale: Donors (n = 107) versus patients (n = 46) (****P < 0.0001), control group (n = 19) versus CCP group (n = 27) (P = 0.355), and control group versus CCP that received a high cumulative amount of neutralizing units (n = 16) (P = 0.730). No test was performed for the group that received a low cumulative amount of neutralizing units (n = 11). Cross walk score: donors (n = 105) versus patients (n = 47) (****P < 0.0001), control group (n = 19) versus CCP group (n = 28) (P = 0.280), and control group versus CCP subgroup that received a high cumulative amount of neutralizing units (n = 16) (P = 0.702). No test was performed for the group that received a low cumulative amount of neutralizing units (n = 12). (B) FACIT Dyspnea score 1: Donors (n = 107) versus patients (n = 48) (****P < 0.0001), control group (n = 19) versus CCP group (n = 29) (P = 0.196), and control group versus CCP subgroup that received a high cumulative amount of neutralizing units (n = 16) (P = 0.518). No test was performed for the group that received a low cumulative amount of neutralizing units (n = 13). FACIT Dyspnea score 2: Donors (n = 107) versus patients (n = 46) (****P < 0.0001), control group (n = 18) versus CCP group (n = 28) (P = 0.15), and control group versus CCP subgroup that received a high cumulative amount of neutralizing units (n = 15) (P = 0.446). No test was performed for the group that received a low cumulative amount of neutralizing units (n = 13). (C) FACIT Fatigue score: Donors (n = 105) versus patients (n = 47) (**P = 0.004), control group (n = 19) versus CCP group (n = 28) (P = 0.306), and control group versus CCP subgroup that received a high cumulative amount of neutralizing units (n = 15) (P = 0.492). No test was performed for the group that received a low cumulative amount of neutralizing units (n = 13). The Mann-Whitney test was used for calculation of P values.

Figure 6. Neutralizing anti–SARS-CoV-2 antibodies (PRNT50) at baseline and last follow-up.

(A) Neutralizing antibodies of all study participants as available. Follow-up data of patients (n = 25) and donors (n = 95). Baseline values donors (n = 97) versus patients (n = 48): *P = 0.045. (B) Neutralizing antibodies of vaccinated study participants during follow-up with available baseline and follow-up data. Patients (n = 21) baseline versus follow-up values: ****P < 0.0001. Donors (n = 76) baseline versus follow up values: ****P < 0.0001. Follow-up values patients versus donors: ***P = 0.0005. (C) Vaccinated patients with available baseline and follow-up data by randomization group (CCP [n = 16] and control group [n = 5]). Baseline versus follow-up in CCP patients: ****P < 0.0001. No test was performed for control because of the low patient number. Horizontal lines indicate the median and interquartile ranges. The Mann-Whitney test was used for calculation of P values for unpaired analysis and Wilcoxon’s matched-pair test for comparison of matched pairs.