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Importance: Passive antibody transfer is a longstanding treatment strategy for infectious diseases that involve the respiratory system. In this context, human convalescent plasma has been used to treat coronavirus disease 2019 (COVID-19), but the efficacy remains uncertain. Objective: To explore potential signals of efficacy of COVID-19 convalescent plasma. Design: Open-label, Expanded Access Program (EAP) for the treatment of COVID-19 patients with human convalescent plasma. Setting: Multicenter, including 2,807 acute care facilities in the US and territories. Participants: Adult participants enrolled and transfused under the purview of the US Convalescent Plasma EAP program between April 4 and July 4, 2020 who were hospitalized with (or at risk of) severe or life threatening acute COVID-19 respiratory syndrome. Intervention: Transfusion of at least one unit of human COVID-19 convalescent plasma using standard transfusion guidelines at any time during hospitalization. Convalescent plasma was donated by recently-recovered COVID-19 survivors, and the antibody levels in the units collected were unknown at the time of transfusion. Main Outcomes and Measures: Seven and thirty-day mortality. Results: The 35,322 transfused patients had heterogeneous demographic and clinical characteristics. This cohort included a high proportion of critically-ill patients, with 52.3% in the intensive care unit (ICU) and 27.5% receiving mechanical ventilation at the time of plasma transfusion. The seven-day mortality rate was 8.7% [95% CI 8.3%-9.2%] in patients transfused within 3 days of COVID-19 diagnosis but 11.9% [11.4%-12.2%] in patients transfused 4 or more days after diagnosis (p<0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p<0.0001). Importantly, a gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma. For patients who received high IgG plasma (>18.45 S/Co), seven-day mortality was 8.9% (6.8%, 11.7%); for recipients of medium IgG plasma (4.62 to 18.45 S/Co) mortality was 11.6% (10.3%, 13.1%); and for recipients of low IgG plasma (<4.62 S/Co) mortality was 13.7% (11.1%, 16.8%) (p=0.048). This unadjusted dose-response relationship with IgG was also observed in thirty-day mortality (p=0.021). The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units. Conclusions and Relevance: The relationships between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients. This information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma. Trial Registration: ClinicalTrials.gov Identifier: NCT04338360

BACKGROUND.Convalescent plasma is the only antibody-based therapy currently available for patients with coronavirus disease 2019 . It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19.METHODS. Thus, we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma in 5000 hospitalized adults with severe or life-threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA expanded access program for COVID-19 convalescent plasma. RESULTS.The incidence of all serious adverse events (SAEs), including mortality rate (0.3%), in the first 4 hours after transfusion was <1%. Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n = 4), transfusion-associated circulatory overload (n = 7), transfusion-related acute lung injury (n = 11), and severe allergic transfusion reactions (n = 3). However, only 2 of 36 SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The 7-day mortality rate was 14.9%. CONCLUSION.Given the deadly nature of COVID-19 and the large population of critically ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19. TRIAL REGISTRATION. ClinicalTrials.gov NCT04338360.

Background: Convalescent plasma is the only antibody based therapy currently available for COVID-19 patients. It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19. Methods: Thus, we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma in 5,000 hospitalized adults with severe or life-threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA Expanded Access Program for COVID-19 convalescent plasma. Results: The incidence of all serious adverse events (SAEs) in the first four hours after transfusion was <1%, including mortality rate (0.3%). Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n=4), transfusion-associated circulatory overload (TACO; n=7), transfusion-related acute lung injury (TRALI; n=11), and severe allergic transfusion reactions (n=3).However, only 2 (of 36) SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The seven-day mortality rate was 14.9%. Conclusion:Given the deadly nature of COVID-19 and the large population of criticallyill patients included in these analyses, the mortality rate does not appear excessive.These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19.

To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from 10 randomized clinical trials (RCT), 20 matched-control studies, two dose-response studies, and 96 case-reports or case-series. Studies published between January 1, 2020 – January 16, 2021 were identified through a systematic search of online PubMed and MEDLINE databases. Random-effects analyses of RCT and matched-control data demonstrated that COVID-19 patients transfused with convalescent plasma exhibited a lower mortality rate compared to patients receiving standard treatments. Additional analyses showed that early transfusion (within 3 days of hospital admission) of higher-titer plasma is associated with lower patient mortality. These data provide evidence favoring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized COVID-19 patients.