Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK.
Jon J van Rood Center for Clinical Transfusion Research, Sanquin/Leiden University Medical Center, Leiden, Netherlands.
Cochrane Database Syst Rev. 2023 Jan 26;1(1):CD015167. doi: 10.1002/14651858.CD015167.pub2.
BACKGROUND: Hyperimmune immunoglobulin (hIVIG) contains polyclonal antibodies, which can be prepared from large amounts of pooled convalescent plasma or prepared from animal sources through immunisation. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). This review was previously part of a parent review addressing convalescent plasma and hIVIG for people with COVID-19 and was split to address hIVIG and convalescent plasma separately. OBJECTIVES: To assess the benefits and harms of hIVIG therapy for 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 Research Database, the Cochrane COVID-19 Study Register, the Epistemonikos COVID-19 L*OVE Platform and Medline and Embase from 1 January 2019 onwards. We carried out searches on 31 March 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated hIVIG 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 that evaluated standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used RoB 2. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all-cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), quality of life, adverse events, and serious adverse events. MAIN RESULTS: We included five RCTs with 947 participants, of whom 688 received hIVIG prepared from humans, 18 received heterologous swine glyco-humanised polyclonal antibody, and 241 received equine-derived processed and purified F(ab') fragments. All participants were hospitalised with moderate-to-severe disease, most participants were not vaccinated (only 12 participants were vaccinated). The studies were conducted before or during the emergence of several SARS-CoV-2 variants of concern. There are no data for people with COVID-19 with no symptoms (asymptomatic) or people with mild COVID-19. We identified a further 10 ongoing studies evaluating hIVIG. Benefits of hIVIG prepared from humans We included data on one RCT (579 participants) that assessed the benefits and harms of hIVIG 0.4 g/kg compared to saline placebo. hIVIG may have little to no impact on all-cause mortality at 28 days (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.43 to 1.44; absolute effect 77 per 1000 with placebo versus 61 per 1000 (33 to 111) with hIVIG; low-certainty evidence). The evidence is very uncertain about the effect on worsening of clinical status at day 7 (RR 0.85, 95% CI 0.58 to 1.23; very low-certainty evidence). It probably has little to no impact on improvement of clinical status on day 28 (RR 1.02, 95% CI 0.97 to 1.08; moderate-certainty evidence). We did not identify any studies that reported quality-of-life outcomes, so we do not know if hIVIG has any impact on quality of life. Harms of hIVIG prepared from humans hIVIG may have little to no impact on adverse events at any grade on day 1 (RR 0.98, 95% CI 0.81 to 1.18; 431 per 1000; 1 study 579 participants; low-certainty evidence). Patients receiving hIVIG probably experience more adverse events at grade 3-4 severity than patients who receive placebo (RR 4.09, 95% CI 1.39 to 12.01; moderate-certainty evidence). hIVIG may have little to no impact on the composite outcome of serious adverse events or death up to day 28 (RR 0.72, 95% CI 0.45 to 1.14; moderate-certainty evidence). We also identified additional results on the benefits and harms of other dose ranges of hIVIG, not included in the summary of findings table, but summarised in additional tables. Benefits of animal-derived polyclonal antibodies We included data on one RCT (241 participants) to assess the benefits and harms of receptor-binding domain-specific polyclonal F(ab´) fragments of equine antibodies (EpAbs) compared to saline placebo. EpAbs may reduce all-cause mortality at 28 days (RR 0.60, 95% CI 0.26 to 1.37; absolute effect 114 per 1000 with placebo versus 68 per 1000 (30 to 156) ; low-certainty evidence). EpAbs may reduce worsening of clinical status up to day 28 (RR 0.67, 95% CI 0.38 to 1.18; absolute effect 203 per 1000 with placebo versus 136 per 1000 (77 to 240); low-certainty evidence). It may have some effect on improvement of clinical status on day 28 (RR 1.06, 95% CI 0.96 to 1.17; low-certainty evidence). We did not identify any studies that reported quality-of-life outcomes, so we do not know if EpAbs have any impact on quality of life. Harms of animal-derived polyclonal antibodies EpAbs may have little to no impact on the number of adverse events at any grade up to 28 days (RR 0.99, 95% CI 0.74 to 1.31; low-certainty evidence). Adverse events at grade 3-4 severity were not reported. Individuals receiving EpAbs may experience fewer serious adverse events than patients receiving placebo (RR 0.67, 95% CI 0.38 to 1.19; low-certainty evidence). We also identified additional results on the benefits and harms of other animal-derived polyclonal antibody doses, not included in the summary of findings table, but summarised in additional tables. AUTHORS' CONCLUSIONS: We included data from five RCTs that evaluated hIVIG compared to standard therapy, with participants with moderate-to-severe disease. As the studies evaluated different preparations (from humans or from various animals) and doses, we could not pool them. hIVIG prepared from humans may have little to no impact on mortality, and clinical improvement and worsening. hIVIG may increase grade 3-4 adverse events. Studies did not evaluate quality of life. RBD-specific polyclonal F(ab´) fragments of equine antibodies may reduce mortality and serious adverse events, and may reduce clinical worsening. However, the studies were conducted before or during the emergence of several SARS-CoV-2 variants of concern and prior to widespread vaccine rollout. As no studies evaluated hIVIG for participants with asymptomatic infection or mild disease, benefits for these individuals remains uncertain. This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence.
背景: 免疫球蛋白(hIVIG)含有多克隆抗体,可从大量恢复期血浆或通过免疫动物来源制备。它们被作为治疗 2019 年冠状病毒病(COVID-19)的潜在疗法进行研究。本综述之前是针对 COVID-19 患者恢复期血浆和 hIVIG 的综述的一部分,现已拆分以分别评估 hIVIG 和恢复期血浆。
目的:评估 hIVIG 治疗 COVID-19 患者的益处和危害,并通过使用实时系统评价方法保持证据的时效性。
检索方法:为了确定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 研究数据库、Cochrane COVID-19 研究注册、Epistemonikos COVID-19 L*OVE 平台和 Medline 和 Embase 数据库,检索时间为 2019 年 1 月 1 日起。我们于 2022 年 3 月 31 日进行了检索。
入选标准:我们纳入了评估 COVID-19 中 hIVIG 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。我们排除了包括其他冠状病毒疾病(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。
数据收集和分析:我们遵循了标准的 Cochrane 方法。使用 RoB 2 评估纳入研究的偏倚。我们使用 GRADE 方法评估了以下结局的证据确定性:全因死亡率、中度至重度疾病个体的临床状况改善和恶化、生活质量、不良事件和严重不良事件。
主要结果:我们纳入了五项 RCT,共 947 名参与者,其中 688 名接受了来自人类的 hIVIG 治疗,18 名接受了异源猪糖基化人源化多克隆抗体治疗,241 名接受了马源处理和纯化的 F(ab') 片段治疗。所有参与者均患有中重度疾病,大多数参与者未接种疫苗(仅 12 名参与者接种了疫苗)。这些研究是在几种 SARS-CoV-2 关注变异株出现之前或期间进行的。没有关于无症状(无症状)或 COVID-19 轻症患者的研究数据。我们还确定了另外 10 项正在评估 hIVIG 的研究。
人类来源的 hIVIG 的益处:我们纳入了一项 RCT(579 名参与者)的数据,评估了 hIVIG 0.4 g/kg 与生理盐水安慰剂相比的益处和危害。hIVIG 可能对 28 天的全因死亡率影响不大(风险比(RR)0.79,95%置信区间(CI)0.43 至 1.44;安慰剂组每 1000 名中有 77 名,hIVIG 组每 1000 名中有 61 名(33 至 111);低确定性证据)。证据非常不确定 hIVIG 对第 7 天临床状况恶化的影响(RR 0.85,95%CI 0.58 至 1.23;极低确定性证据)。hIVIG 可能对第 28 天的临床状况改善影响不大(RR 1.02,95%CI 0.97 至 1.08;中等确定性证据)。我们没有发现任何报告生活质量结局的研究,因此我们不知道 hIVIG 是否对生活质量有影响。
人类来源的 hIVIG 的危害:hIVIG 可能对第 1 天任何等级的不良事件影响不大(RR 0.98,95%CI 0.81 至 1.18;431 例/1000 例;1 项研究 579 名参与者;低确定性证据)。与接受安慰剂的患者相比,接受 hIVIG 的患者可能经历更多 3-4 级严重程度的不良事件(RR 4.09,95%CI 1.39 至 12.01;中等确定性证据)。hIVIG 可能对第 28 天的严重不良事件或死亡复合结局影响不大(RR 0.72,95%CI 0.45 至 1.14;中等确定性证据)。我们还在其他剂量范围内的 hIVIG 的益处和危害的额外结果,未包含在汇总表中,但在额外表格中进行了总结。
动物源性多克隆抗体的益处:我们纳入了一项 RCT(241 名参与者)的数据,评估了受体结合域特异性多克隆 F(ab´) 片段的马源抗体(EpAbs)与生理盐水安慰剂相比的益处和危害。EpAbs 可能降低 28 天的全因死亡率(RR 0.60,95%CI 0.26 至 1.37;安慰剂组每 1000 名中有 114 名,EpAbs 组每 1000 名中有 68 名(30 至 156);低确定性证据)。EpAbs 可能降低第 28 天的临床状况恶化(RR 0.67,95%CI 0.38 至 1.18;安慰剂组每 1000 名中有 203 名,EpAbs 组每 1000 名中有 136 名(77 至 240);低确定性证据)。它可能对第 28 天的临床状况改善有一定的影响(RR 1.06,95%CI 0.96 至 1.17;低确定性证据)。我们没有发现任何报告生活质量结局的研究,因此我们不知道 EpAbs 是否对生活质量有影响。
动物源性多克隆抗体的危害:EpAbs 对 28 天内任何等级的不良事件数量可能影响不大(RR 0.99,95%CI 0.74 至 1.31;低确定性证据)。未报告 3-4 级严重程度的不良事件。与接受安慰剂的患者相比,接受 EpAbs 的患者可能经历较少的严重不良事件(RR 0.67,95%CI 0.38 至 1.19;低确定性证据)。我们还在其他剂量范围内的 EpAbs 的益处和危害的额外结果,未包含在汇总表中,但在额外表格中进行了总结。
作者结论:我们纳入了五项评估 hIVIG 与标准治疗相比的 RCT 数据,参与者均患有中重度疾病。由于研究评估了不同的制剂(来自人类或来自各种动物)和剂量,我们无法对其进行合并。来自人类的 hIVIG 可能对死亡率以及临床改善和恶化没有影响。hIVIG 可能会增加 3-4 级不良事件的发生。研究未评估生活质量。RBD 特异性多克隆 F(ab´) 片段的马源抗体可能降低死亡率和严重不良事件,并且可能减少临床恶化。然而,这些研究是在几种 SARS-CoV-2 关注变异株出现之前或期间进行的,没有研究评估 hIVIG 对无症状感染或轻症患者的疗效,因此这些患者的获益仍不确定。这是一项实时系统评价。我们每月检索新证据,并在发现相关新证据时更新综述。
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