Systematic review finds convalescent plasma does not reduce mortality in COVID-19

Rationale Convalescent plasma (CP) may reduce mortality in people with viral respiratory diseases, and is being investigated as a potential therapy for coronavirus disease 2019 (COVID‐19). A thorough understanding of the current body of evidence regarding the benefits and risks of this intervention is required. Objectives To assess the effectiveness and safety of convalescent plasma transfusion in the treatment of people with COVID‐19. Search methods To identify completed and ongoing studies, we searched CENTRAL, MEDLINE, Embase, the Epistemonikos COVID‐19 L*OVE Platform, and clinical trial registries to October 2024. Eligibility criteria We included randomised controlled trials (RCTs) evaluating convalescent plasma for people with COVID‐19, irrespective of disease severity, age, gender, or ethnicity. We excluded studies investigating other coronavirus diseases or standard immunoglobulin. Outcomes We used the GRADE approach to rate the certainty of evidence for the following outcomes: all‐cause mortality (up to day 28), worsening and improvement of clinical status (for individuals with moderate to severe disease), hospital admission or death, COVID‐19 symptoms resolution (for individuals with mild disease), quality of life (QoL), grade 3/4 adverse events, and serious adverse events. Risk of bias We used RoB 2 to assess bias in included studies. Synthesis methods We followed standard Cochrane methodology. Included studies We included 48 RCTs (24,518 participants), 15 of which were added in this update. We also identified 36 new ongoing studies and 33 completed studies awaiting classification. Synthesis of results Individuals with a confirmed diagnosis of COVID‐19 and moderate to severe disease Forty‐two RCTs investigated the use of CP for 21,393 participants with moderate to severe disease. Of these, 36 RCTs (20,798 participants) compared CP to placebo or standard care, five (604 participants) to standard plasma, and one (190 participants) to human immunoglobulin. In the full review, we performed subgroup analyses by antibody detection, time since symptom onset, country income level, and key comorbidities. Convalescent plasma versus placebo or standard care alone CP does not reduce all‐cause mortality at up to day 28 (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.90 to 1.03; 31 RCTs, 20,798 participants; high‐certainty evidence). It has little to no impact on the need for invasive mechanical ventilation, or death (RR 1.03, 95% CI 0.98 to 1.08; 8 RCTs, 15,189 participants; high‐certainty evidence) and has no impact on whether participants are discharged from hospital (RR 1.00, 95% CI 0.97 to 1.02; 9 RCTs, 13,930 participants; high‐certainty evidence). CP may have little to no impact on QoL (MD 1.00, 95% CI −2.14 to 4.14; 1 RCT, 483 participants; low‐certainty evidence). CP may have little to no impact on the risk of grade 3/4 adverse events (RR 1.17, 95% CI 0.96 to 1.42; 6 RCTs, 2392 participants; low‐certainty evidence). It probably has little to no effect on the risk of serious adverse events (RR 1.19, 95% CI 1.02 to 1.38; 11 studies, 5298 participants; moderate‐certainty evidence). Convalescent plasma versus standard plasma The evidence is uncertain about whether CP reduces all‐cause mortality at up to day 28 (RR 0.77, 95% CI 0.53 to 1.10; 5 RCTs, 604 participants; very low‐certainty evidence) and whether it increases the need for invasive mechanical ventilation, or death (RR 5.59, 95% CI 0.29 to 108.38; 1 study, 34 participants; very low‐certainty evidence). The evidence is uncertain about whether convalescent plasma reduces or increases the risk of grade 3/4 adverse events (1 RCT, 248 participants). The evidence is also uncertain about whether CP reduces the risk of serious adverse events (RR 0.82, 95% CI 0.57 to 1.17; 4 RCTs, 447 participants; very low‐certainty evidence). No studies in this comparison reported clinical improvement or QoL. Individuals with a confirmed diagnosis of SARS‐CoV‐2 infection and mild disease Six RCTs investigated the use of CP for 2761 participants with mild disease. Four RCTs (1164 participants) compared CP to placebo or standard care alone, and two (1597 participants) to standard plasma. Convalescent plasma versus placebo or standard care alone The evidence is uncertain about whether CP reduces all‐cause mortality at up to day 28 (odds ratio (OR) 1.24, 95% CI 0.33 to 4.60; 3 RCTs, 1004 participants; very low‐certainty evidence) and admission to hospital or death within 28 days (RR 0.45, 95% CI 0.04 to 4.81; 2 RCTs, 493 participants; very low‐certainty evidence). It may have little to no impact on time to COVID‐19 symptom resolution (hazard ratio (HR) 1.05, 95% CI 0.85 to 1.30; 1 RCT, 376 participants) and on the risk of grade 3/4 adverse events (RR 1.29, 95% CI 0.75 to 2.19; 1 RCT, 376 participants), both with low‐certainty evidence. The evidence is uncertain about whether CP has an impact on the risk of serious adverse events (RR 0.84, 95% CI 0.56 to 1.26; 2 RCTs, 494 participants; very low‐certainty evidence). No studies in this comparison reported other critical outcomes. Convalescent plasma versus standard plasma The evidence is uncertain about whether CP reduces all‐cause mortality at up to day 28 (RR 0.41, 95% CI 0.05 to 3.06; 2 RCTs, 1597 participants; very low‐certainty evidence). It probably reduces admission to hospital or death within 28 days (RR 0.50, 95% CI 0.32 to 0.78; 2 RCTs, 1597 participants; moderate‐certainty evidence). CP may have little to no effect on initial symptom resolution at up to day 28 (RR 1.12, 95% CI 0.82 to 1.54; 1 RCT, 416 participants; low‐certainty evidence). Neither study in this comparison reported other critical outcomes. Authors' conclusions Compared with placebo or standard care, high‐certainty evidence shows that CP does not reduce mortality in individuals with moderate to severe disease and has little to no effect on clinical improvement or worsening. CP probably has little to no effect on serious adverse events. Publication of ongoing studies might resolve some of the uncertainties around CP therapy for people with asymptomatic or mild disease. This review was previously a living systematic review, from the first version published in 2020 until our last search in October 2024. The research question is no longer a priority for decision‐making, new studies are less frequently published, and research that might impact the conclusions of the review is no longer emerging. Funding The European Commission, Belgium SUPorting high quality evaluation of COVID‐19 convalescent plasma thrOughouT Europe (SUPPORT‐E, grant number 101015756) supported this review. Registration Protocol registered with the Center for Open Science on 17 April 2020 (DOI: 10.17605/OSF.IO/DWF53). Access the 2023 version of this review here: DOI: 10.1002/14651858.CD013600.pub6. PICOs PICOs Population Intervention Comparison Outcome