Abstract

BACKGROUND Outpatient monoclonal antibodies are no longer effective and antiviral treatments for COVID-19 disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma is promising, clinical trials among outpatients have shown mixed results. METHODS We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching MEDLINE, Embase, MedRxiv, World Health Organization, Cochrane Library, and Web of Science from January 2020 to September 2022. RESULTS Five included studies from four countries enrolled and transfused 2,620 adult patients. Comorbidities were present in 1,795 (69%). The virus neutralizing antibody dilutional titer levels ranged from 8 to 14,580 in diverse assays. 160 (12.2%) of 1315 control patients were hospitalized, versus 111 (8.5%) of 1305 COVID-19 convalescent plasma treated patients, yielding a 3.7% (95%CI: 1.3%-6.0%; p=.001) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titer with a 7.6% absolute risk reduction (95%CI: 4.0%-11.1%; p=.0001) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving COVID-19 convalescent plasma with antibody titers below the median titer. CONCLUSIONS Among outpatients with COVID-19, treatment with COVID-19 convalescent plasma reduced the rate of all-cause hospitalization and may be most effective when given within 5 days of symptom onset and when antibody titer is higher.

Abstract

BACKGROUND Convalescent plasma may reduce mortality in patients 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 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; and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, and the Epistemonikos COVID-19 L*OVE Platform. We searched monthly until 03 March 2022. SELECTION CRITERIA We included randomised controlled trials (RCTs) evaluating convalescent plasma for COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. To assess bias in included studies we used RoB 2. We used the GRADE approach to rate the certainty of evidence for the following outcomes: all-cause mortality at 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, grade 3 or 4 adverse events, and serious adverse events. MAIN RESULTS In this fourth review update version, we included 33 RCTs with 24,861 participants, of whom 11,432 received convalescent plasma. Of these, nine studies are single-centre studies and 24 are multi-centre studies. Fourteen studies took place in America, eight in Europe, three in South-East Asia, two in Africa, two in western Pacific and three in eastern Mediterranean regions and one in multiple regions. We identified a further 49 ongoing studies evaluating convalescent plasma, and 33 studies reporting as being completed. Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease 29 RCTs investigated the use of convalescent plasma for 22,728 participants with moderate to severe disease. 23 RCTs with 22,020 participants compared convalescent plasma to placebo or standard care alone, five compared to standard plasma and one compared to human immunoglobulin. We evaluate subgroups on detection of antibodies detection, symptom onset, country income groups and several co-morbidities in the full text. Convalescent plasma versus placebo or standard care alone Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.03; 220 per 1000; 21 RCTs, 19,021 participants; high-certainty evidence). It has little to no impact on need for invasive mechanical ventilation, or death (RR 1.03, 95% CI 0.97 to 1.11; 296 per 1000; 6 RCTs, 14,477 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; 665 per 1000; 6 RCTs, 12,721 participants; high-certainty evidence). Convalescent plasma may have little to no impact on quality of life (MD 1.00, 95% CI -2.14 to 4.14; 1 RCT, 483 participants; low-certainty evidence). Convalescent plasma may have little to no impact on the risk of grades 3 and 4 adverse events (RR 1.17, 95% CI 0.96 to 1.42; 212 per 1000; 6 RCTs, 2392 participants; low-certainty evidence). It has probably little to no effect on the risk of serious adverse events (RR 1.14, 95% CI 0.91 to 1.44; 135 per 1000; 6 RCTs, 3901 participants; moderate-certainty evidence). Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces or increases all-cause mortality at up to day 28 (RR 0.73, 95% CI 0.45 to 1.19; 129 per 1000; 4 RCTs, 484 participants; very low-certainty evidence). We are uncertain whether convalescent plasma reduces or increases the need for invasive mechanical ventilation, or death (RR 5.59, 95% CI 0.29 to 108.38; 311 per 1000; 1 study, 34 participants; very low-certainty evidence) and whether it reduces or increases the risk of serious adverse events (RR 0.80, 95% CI 0.55 to 1.15; 236 per 1000; 3 RCTs, 327 participants; very low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus human immunoglobulin Convalescent plasma may have little to no effect on all-cause mortality at up to day 28 (RR 1.07, 95% CI 0.76 to 1.50; 464 per 1000; 1 study, 190 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Individuals with a confirmed diagnosis of SARS-CoV-2 infection and mild disease We identified two RCTs reporting on 536 participants, comparing convalescent plasma to placebo or standard care alone, and two RCTs reporting on 1597 participants with mild disease, comparing convalescent plasma to standard plasma. Convalescent plasma versus placebo or standard care alone We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (odds ratio (OR) 0.36, 95% CI 0.09 to 1.46; 8 per 1000; 2 RCTs, 536 participants; very low-certainty evidence). It may have little to no effect on admission to hospital or death within 28 days (RR 1.05, 95% CI 0.60 to 1.84; 117 per 1000; 1 RCT, 376 participants; low-certainty evidence), on time to COVID-19 symptom resolution (hazard ratio (HR) 1.05, 95% CI 0.85 to 1.30; 483 per 1000; 1 RCT, 376 participants; low-certainty evidence), on the risk of grades 3 and 4 adverse events (RR 1.29, 95% CI 0.75 to 2.19; 144 per 1000; 1 RCT, 376 participants; low-certainty evidence) and the risk of serious adverse events (RR 1.14, 95% CI 0.66 to 1.94; 133 per 1000; 1 RCT, 376 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. Convalescent plasma versus standard plasma We are uncertain whether convalescent plasma reduces all-cause mortality at up to day 28 (OR 0.30, 95% CI 0.05 to 1.75; 2 per 1000; 2 RCTs, 1597 participants; very low-certainty evidence). It probably reduces admission to hospital or death within 28 days (RR 0.49, 95% CI 0.31 to 0.75; 36 per 1000; 2 RCTs, 1595 participants; moderate-certainty evidence). Convalescent plasma may have little to no effect on initial symptom resolution at up to day 28 (RR 1.12, 95% CI 0.98 to 1.27; 1 RCT, 416 participants; low-certainty evidence). We did not identify any study reporting other key outcomes. This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence. AUTHORS' CONCLUSIONS For the comparison of convalescent plasma versus placebo or standard care alone, our certainty in the evidence that convalescent plasma for individuals with moderate to severe disease does not reduce mortality and has little to no impact on clinical improvement or worsening is high. It probably has little to no effect on SAEs. For individuals with mild disease, we have low certainty evidence for our primary outcomes. There are 49 ongoing studies, and 33 studies reported as complete in a trials registry. Publication of ongoing studies might resolve some of the uncertainties around convalescent plasma therapy for people with asymptomatic or mild disease.

Abstract

BACKGROUND While early evidence concluded a lack of clinical benefit of convalescent plasma therapy (CPT) in COVID-19 management, recent trials demonstrate the therapeutic potential of CPT in ambulatory care. CPT may also potentiate thromboembolic events given the presence of coagulation factors and the prothrombotic state of COVID-19. OBJECTIVE The present study aims to assess and compare the clinical efficacy and the risk of venous/arterial thromboembolism (VTE, ATE) of CPT in ambulatory vs hospitalized COVID-19 patients. METHODS MEDLINE, Embase, and Cochrane CENTRAL were searched from December 2019 to December 2022 for randomized controlled trials that investigated the use of CPT against placebo or standard of care in adult COVID-19 patients. The primary outcome was non-mortality disease progression. Secondary outcomes include VTE, ATE, 28-day mortality, clinical improvement, length of hospitalization (LOH), sepsis/fever, and major adverse cardiovascular events (MACE). RESULTS Twenty randomized controlled trials, with 21340 patients, were included. CPT significantly reduced non-mortality disease progression in ambulatory patients (OR 0.72, 0.56-0.92, P = 0.009) but not in hospitalized patients (1.03, 0.94-1.12, P = 0.58). The risk of VTE and ATE did not differ between the CPT and the control group (1.15, 0.81 to 1.64, P = 0.44; 1.01, 0.37 to 2.79, P = 0.98). No conclusive differences between CPT and control were noted in 28-day mortality, clinical improvement, LOH, risk of sepsis/fever, and MACE. CONCLUSIONS In conclusion, treatment of COVID-19 with CPT prevents the progression of COVID-19 in the ambulatory care. It is not associated with an increased risk of VTE, ATE, or other adverse events.

Abstract

The aim of this review was to update evidence for benefit of convalescent plasma transfusion (CPT) in patients with coronavirus disease 2019 (COVID-19). Databases were searched for randomized controlled trials (RCT) comparing CPT plus standard treatment versus standard treatment only in adults with COVID-19. Primary outcome measures were mortality and need for invasive mechanical ventilation (IMV). Twenty-Six RCT involving 19,816 patients were included in meta-analysis for mortality. Quantitative synthesis showed no statistically significant benefit of adding CPT to standard treatment (RR = 0.97, 95% CI = 0.92 to 1.02) with unimportant heterogeneity (Q(25) = 26.48, p = .38, I(2) = 0.00%). Trim-and-fill-adjusted effect size was unimportantly changed and level of evidence was graded as high. Trial sequential analysis (TSA) indicated information size was adequate and CPT was futile. Seventeen trials involving 16,083 patients were included in meta-analysis for need of IMV. There was no statistically significant effect of CPT (RR = 1.02, 95% CI = 0.95 to 1.10) with unimportant heterogeneity (Q(16) = 9.43, p = .89, I(2) = 3.30%). Trim-and-fill-adjusted effect size was trivially changed and level of evidence was graded as high. TSA showed information size was adequate and indicated futility of CPT. It is concluded with high level of certainty that CPT added to standard treatment of COVID-19 is not associated with reduced mortality or need of IMV compared with standard treatment alone. In view of these findings, further trials on efficacy of CPT in COVID-19 patients are probably not needed.

Abstract

BACKGROUND Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required.  OBJECTIVES To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19. SEARCH METHODS We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 19 August 2020. SELECTION CRITERIA We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' 2.0 tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, mortality (time to event), improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events (AEs), and serious adverse events (SAEs). MAIN RESULTS This is the second living update of our review. We included 19 studies (2 RCTs, 8 controlled NRSIs, 9 non-controlled NRSIs) with 38,160 participants, of whom 36,081 received convalescent plasma. Two completed RCTs are awaiting assessment (published after 19 August 2020). We identified a further 138 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 73 are randomised (3 reported in a study registry as already being completed, but without results). We did not identify any completed studies evaluating hyperimmune immunoglobulin. We did not include data from controlled NRSIs in data synthesis because of critical risk of bias. The overall certainty of evidence was low to very low, due to study limitations and results including both potential benefits and harms.  Effectiveness of convalescent plasma for people with COVID-19  We included results from two RCTs (both stopped early) with 189 participants, of whom 95 received convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. We are uncertain whether convalescent plasma decreases all-cause mortality at hospital discharge (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.22 to 1.34; 1 RCT, 86 participants; low-certainty evidence).  We are uncertain whether convalescent plasma decreases mortality (time to event) (hazard ratio (HR) 0.64, 95% CI 0.33 to 1.25; 2 RCTs, 189 participants; low-certainty evidence). Convalescent plasma may result in little to no difference in improvement of clinical symptoms (i.e. need for respiratory support) at seven days (RR 0.98, 95% CI 0.30 to 3.19; 1 RCT, 103 participants; low-certainty evidence). Convalescent plasma may increase improvement of clinical symptoms at up to 15 days (RR 1.34, 95% CI 0.85 to 2.11; 2 RCTs, 189 participants; low-certainty evidence), and at up to 30 days (RR 1.13, 95% CI 0.88 to 1.43; 2 studies, 188 participants; low-certainty evidence).  No studies repo ted on quality of life.  Safety of convalescent plasma for people with COVID-19 We included results from two RCTs, eight controlled NRSIs and nine non-controlled NRSIs assessing safety of convalescent plasma. Reporting of safety data and duration of follow-up was variable. The controlled studies reported on AEs and SAEs only in participants receiving convalescent plasma. Some, but not all, studies included death as a SAE.  The studies did not report the grade of AEs. Fourteen studies (566 participants) reported on AEs of possible grade 3 or 4 severity. The majority of these AEs were allergic or respiratory events. We are very uncertain whether convalescent plasma therapy affects the risk of moderate to severe AEs (very low-certainty evidence).  17 studies (35,944 participants) assessed SAEs for 20,622 of its participants. The majority of participants were from one non-controlled NRSI (20,000 participants), which reported on SAEs within the first four hours and within an additional seven days after transfusion. There were 63 deaths, 12 were possibly and one was probably related to transfusion. There were 146 SAEs within four hours and 1136 SAEs within seven days post-transfusion. These were predominantly allergic or respiratory, thrombotic or thromboembolic and cardiac events. We are uncertain whether convalescent plasma therapy results in a clinically relevant increased risk of SAEs (low-certainty evidence). AUTHORS' CONCLUSIONS We are uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. There was limited information regarding grade 3 and 4 AEs to determine the effect of convalescent plasma therapy on clinically relevant SAEs. In the absence of a control group, we are unable to assess the relative safety of convalescent plasma therapy.  While major efforts to conduct research on COVID-19 are being made, recruiting the anticipated number of participants into these studies is problematic. The early termination of the first two RCTs investigating convalescent plasma, and the lack of data from 20 studies that have completed or were due to complete at the time of this update illustrate these challenges. Well-designed studies should be prioritised. Moreover, studies should report outcomes in the same way, and should consider the importance of maintaining comparability in terms of co-interventions administered in all study arms.  There are 138 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 73 are RCTs (three already completed). This is the second living update of the review, and we will continue to update this review periodically. Future updates may show different results to those reported here.