Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis

Abstract

Background: The safety and efficacy of convalescent plasma in severe coronavirus disease 2019 (COVID-19) remain uncertain. To support a guideline on COVID-19 management, we conducted a systematic review and meta-analysis of convalescent plasma in COVID-19 and other severe respiratory viral infections.

Methods: In March 2020, we searched international and Chinese biomedical literature databases, clinical trial registries and prepublication sources for randomized controlled trials (RCTs) and nonrandomized studies comparing patients receiving and not receiving convalescent plasma. We included patients with acute coronavirus, influenza and Ebola virus infections. We conducted a meta-analysis using random-effects models and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Results: Of 1099 unique records, 6 studies were eligible, and none of these included patients with COVID-19. One nonrandomized study (n = 40) on convalescent plasma in severe acute respiratory syndrome coronavirus (SARS-CoV) provided uninformative results regarding mortality (relative risk [RR] 0.10, 95% confidence interval [CI] CI 0.01 to 1.70). Pooled estimates from 4 RCTs on influenza (n = 572) showed no convincing effects on deaths (4 RCTs, RR 0.94, 95% CI 0.49 to 1.81), complete recovery (2 RCTs, odds ratio 1.04, 95% CI 0.69 to 1.64) or length of stay (3 RCTs, mean difference -1.62, 95% CI -3.82 to 0.58, d). The quality of evidence was very low for all efficacy outcomes. Convalescent plasma caused few or no serious adverse events in influenza RCTs (RR 0.85, 95% CI 0.56 to 1.29, low-quality evidence).

Interpretation: Studies of non-COVID-19 severe respiratory viral infections provide indirect, very low-quality evidence that raises the possibility that convalescent plasma has minimal or no benefit in the treatment of COVID-19 and low-quality evidence that it does not cause serious adverse events.

Figure 1:

Potential mechanisms of action of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in coronavirus disease 2019 (COVID-19). This figure illustrates the normal entry of SARS-CoV-2 in a host cell, in which membrane fusion is mediated by the interaction between the SARS-CoV-2 spike glycoprotein (red) and the angiotensin-converting enzyme 2 (ACE2) receptor (green) on the host cell, either through the cytoplasmic or endosomal route. Antibodies directed against the receptor-binding domain (RBD) of the spike protein can interfere with its interaction with the ACE2 receptor and prevent viral entry in the host cell (panel A). Antibodies directed against epitopes outside the RBD can also exert antiviral functions through other mechanisms (panels B, C and D). The relative importance of these various functions in rescuing patients from an active SARS-CoV-2 infection is unknown. Importantly, neutralization assays generally used to qualify hyperimmune products measure only 1 of the 4 mechanisms depicted here and do not necessarily correlate with the others.

Figure 2:

Study selection flow chart. Note: NRS = nonrandomized study, RCT = randomized controlled trial, SARS-CoV = severe acute respiratory syndrome coronavirus.

Figure 3:

Efficacy of convalescent plasma on mortality in acute viral respiratory infections. Weights are from random-effects analysis. Note: CI = confidence interval, RR = relative risk, SARS = severe acute respiratory syndrome.

Figure 4:

Efficacy of convalescent plasma in recovery from acute viral respiratory illness. Weights are from random-effects analysis. Note: CI = confidence interval, ES = effect size.

Figure 5:

Efficacy of convalescent plasma in reducing length of hospital stay. Weights are from random-effects analysis. Note: CI = confidence interval, MD = mean difference, SD = standard deviation.

Figure 6:

Safety of convalescent plasma. Weights are from random-effects analysis. Note: CI = confidence interval, RR = relative risk.