Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Transfusion Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
Cochrane Database Syst Rev. 2023 Feb 1;2(2):CD013600. doi: 10.1002/14651858.CD013600.pub5.
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.
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.
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.
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.
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.
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.
恢复期血浆可能降低病毒性呼吸道疾病患者的死亡率，目前正在研究其作为 2019 年冠状病毒病（COVID-19）潜在治疗方法的作用。需要全面了解这一干预措施的现有证据的益处和风险。
评估 COVID-19 患者使用恢复期血浆输注治疗的有效性和安全性；并通过使用动态系统综述方法保持证据的时效性。
为了识别已完成和正在进行的研究，我们检索了世界卫生组织（WHO）COVID-19 全球冠状病毒病研究数据库、MEDLINE、Embase、Cochrane COVID-19 研究注册中心和 Epistemonikos COVID-19 L*OVE 平台。我们每月检索一次，直到 2022 年 3 月 3 日。
我们纳入了评估 COVID-19 恢复期血浆的随机对照试验（RCT），无论疾病严重程度、年龄、性别或种族如何。我们排除了包含其他冠状病毒疾病（严重急性呼吸综合征（SARS）或中东呼吸综合征（MERS））人群的研究，以及评估标准免疫球蛋白的研究。
我们遵循标准的 Cochrane 方法。对于纳入的研究，我们使用 RoB 2 评估偏倚。我们使用 GRADE 方法评估以下结局的证据确定性：至第 28 天的全因死亡率、中度至重度疾病患者的临床状况改善或恶化、住院或死亡、轻度疾病患者的 COVID-19 症状缓解、生活质量、3 级或 4 级不良事件和严重不良事件。
在本次第四次综述更新版本中，我们纳入了 33 项 RCT，共 24861 名参与者，其中 11432 名接受了恢复期血浆治疗。其中，9 项研究为单中心研究，24 项为多中心研究。14 项研究发生在美国，8 项在欧洲，3 项在东南亚，2 项在非洲，2 项在西太平洋地区，3 项在东地中海地区，1 项在多个地区。我们还确定了另外 49 项正在评估恢复期血浆的研究，以及 33 项报告已完成的研究。纳入了确诊 COVID-19 和中度至重度疾病的患者，29 项 RCT 对 22728 名中度至重度疾病患者使用恢复期血浆进行了研究。23 项 RCT 对 22020 名患者比较了恢复期血浆与安慰剂或标准治疗单独使用，5 项比较了恢复期血浆与标准血浆，1 项比较了恢复期血浆与人类免疫球蛋白。我们在全文中评估了基于抗体检测、症状发作、国家收入群体和几种合并症的亚组。
与安慰剂或标准治疗单独使用相比，恢复期血浆并不能降低至第 28 天的全因死亡率（风险比（RR）0.98，95%置信区间（CI）0.92 至 1.03；每 1000 人 220 例；21 项 RCT，19021 名参与者；高确定性证据）。它对需要有创机械通气或死亡的影响较小（RR 1.03，95%CI 0.97 至 1.11；每 1000 人 296 例；6 项 RCT，14477 名参与者；高确定性证据），对住院患者出院的影响较小（RR 1.00，95%CI 0.97 至 1.02；6 项 RCT，12721 名参与者；高确定性证据）。恢复期血浆可能对生活质量的影响较小（MD 1.00，95%CI -2.14 至 4.14；1 项 RCT，483 名参与者；低确定性证据）。恢复期血浆对 3 级和 4 级不良事件的风险可能影响较小（RR 1.17，95%CI 0.96 至 1.42；212 例每 1000 人；6 项 RCT，2392 名参与者；低确定性证据）。它对严重不良事件的风险可能影响较小（RR 1.14，95%CI 0.91 至 1.44；6 项 RCT，3901 名参与者；中等确定性证据）。
我们不确定恢复期血浆是否能降低或增加至第 28 天的全因死亡率（RR 0.73，95%CI 0.45 至 1.19；每 1000 人 129 例；4 项 RCT，484 名参与者；非常低确定性证据）。我们不确定恢复期血浆是否能降低或增加需要有创机械通气或死亡的风险（RR 5.59，95%CI 0.29 至 108.38；311 例每 1000 人；1 项研究，34 名参与者；非常低确定性证据），以及是否能降低或增加严重不良事件的风险（RR 0.80，95%CI 0.55 至 1.15；3 项 RCT，327 名参与者；非常低确定性证据）。我们没有发现报告其他关键结局的研究。
与人类免疫球蛋白相比，恢复期血浆可能对至第 28 天的全因死亡率影响较小（RR 1.07，95%CI 0.76 至 1.50；每 1000 人 464 例；1 项研究，190 名参与者；低确定性证据）。我们没有发现报告其他关键结局的研究。
确诊 SARS-CoV-2 感染和轻症患者：我们确定了两项比较恢复期血浆与安慰剂或标准治疗的 RCT，共纳入 536 名参与者，以及两项比较恢复期血浆与标准血浆的 RCT，共纳入 1597 名轻症患者。
我们不确定恢复期血浆是否能降低至第 28 天的全因死亡率（OR 0.36，95%CI 0.09 至 1.46；8 例每 1000 人；2 项 RCT，536 名参与者；非常低确定性证据）。它可能对 28 天内住院或死亡的风险影响较小（RR 1.05，95%CI 0.60 至 1.84；117 例每 1000 人；1 项 RCT，376 名参与者；低确定性证据），对 COVID-19 症状缓解的时间影响较小（HR 1.05，95%CI 0.85 至 1.30；483 例每 1000 人；1 项 RCT，376 名参与者；低确定性证据），对 3 级和 4 级不良事件的风险影响较小（RR 1.29，95%CI 0.75 至 2.19；144 例每 1000 人；1 项 RCT，376 名参与者；低确定性证据），以及对严重不良事件的风险影响较小（RR 1.14，95%CI 0.66 至 1.94；133 例每 1000 人；1 项 RCT，376 名参与者；低确定性证据）。我们没有发现报告其他关键结局的研究。
我们不确定恢复期血浆是否能降低至第 28 天的全因死亡率（OR 0.30，95%CI 0.05 至 1.75；2 例每 1000 人；2 项 RCT，1597 名参与者；非常低
