Valk Sarah J, Piechotta Vanessa, Chai Khai Li, Doree Carolyn, Monsef Ina, Wood Erica M, Lamikanra Abigail, Kimber Catherine, McQuilten Zoe, So-Osman Cynthia, Estcourt Lise J, Skoetz Nicole
Jon J van Rood Center for Clinical Transfusion Research, Sanquin/Leiden University Medical Center, Leiden, Netherlands.
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.
Cochrane Database Syst Rev. 2020 May 14;5(5):CD013600. doi: 10.1002/14651858.CD013600.
BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with respiratory virus diseases, and are currently being investigated in trials as a 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 assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19. SEARCH METHODS: The protocol was pre-published with the Center for Open Science and can be accessed here: osf.io/dwf53 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 trials registries to identify ongoing studies and results of completed studies on 23 April 2020 for case-series, cohort, prospectively planned, and randomised controlled trials (RCTs). SELECTION CRITERIA: We followed standard Cochrane methodology and performed all steps regarding study selection in duplicate by two independent review authors (in contrast to the recommendations of the Cochrane Rapid Reviews Methods Group). We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of 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 immunoglobulins. DATA COLLECTION AND ANALYSIS: We followed recommendations of the Cochrane Rapid Reviews Methods Group regarding data extraction and assessment. To assess bias in included studies, we used the assessment criteria tool for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events, and serious adverse events. MAIN RESULTS: We included eight studies (seven case-series, one prospectively planned, single-arm intervention study) with 32 participants, and identified a further 48 ongoing studies evaluating convalescent plasma (47 studies) or hyperimmune immunoglobulin (one study), of which 22 are randomised. Overall risk of bias of the eight included studies was high, due to: study design; small number of participants; poor reporting within studies; and varied type of participants with different severities of disease, comorbidities, and types of previous or concurrent treatments, including antivirals, antifungals or antibiotics, corticosteroids, hydroxychloroquine and respiratory support. We rated all outcomes as very low certainty, and we were unable to summarise numerical data in any meaningful way. As we identified case-series studies only, we reported results narratively. Effectiveness of convalescent plasma for people with COVID-19 The following reported outcomes could all be related to the underlying natural history of the disease or other concomitant treatment, rather than convalescent plasma. All-cause mortality at hospital discharge All studies reported mortality. All participants were alive at the end of the reporting period, but not all participants had been discharged from hospital by the end of the study (15 participants discharged, 6 still hospitalised, 11 unclear). Follow-up ranged from 3 days to 37 days post-transfusion. We do not know whether convalescent plasma therapy affects mortality (very low-certainty evidence). Improvement of clinical symptoms (assessed by respiratory support) Six studies, including 28 participants, reported the level of respiratory support required; most participants required respiratory support at baseline. All studies reported improvement in clinical symptoms in at least some participants. We do not know whether convalescent plasma improves clinical symptoms (very low-certainty evidence). Time to discharge from hospital Six studies reported time to discharge from hospital for at least some participants, which ranged from four to 35 days after convalescent plasma therapy. Admission on the intensive care unit (ICU) Six studies included patients who were critically ill. At final follow-up the majority of these patients were no longer on the ICU or no longer required mechanical ventilation. Length of stay on the ICU Only one study (1 participant) reported length of stay on the ICU. The individual was discharged from the ICU 11 days after plasma transfusion. Safety of convalescent plasma for people with COVID-19 Grade 3 or 4 adverse events The studies did not report the grade of adverse events after convalescent plasma transfusion. Two studies reported data relating to participants who had experienced adverse events, that were presumably grade 3 or 4. One case study reported a participant who had moderate fever (38.9 °C). Another study (3 participants) reported a case of severe anaphylactic shock. Four studies reported the absence of moderate or severe adverse events (19 participants). We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence). Serious adverse events One study (3 participants) reported one serious adverse event. As described above, this individual had severe anaphylactic shock after receiving convalescent plasma. Six studies reported that no serious adverse events occurred. We are very uncertain whether or not convalescent plasma therapy affects the risk of serious adverse events (very low-certainty evidence). AUTHORS' CONCLUSIONS: We identified eight studies (seven case-series and one prospectively planned single-arm intervention study) with a total of 32 participants (range 1 to 10). Most studies assessed the risks of the intervention; reporting two adverse events (potentially grade 3 or 4), one of which was a serious adverse event. We are very uncertain whether convalescent plasma is effective for people admitted to hospital with COVID-19 as studies reported results inconsistently, making it difficult to compare results and to draw conclusions. We identified very low-certainty evidence on the effectiveness and safety of convalescent plasma therapy for people with COVID-19; all studies were at high risk of bias and reporting quality was low. No RCTs or controlled non-randomised studies evaluating benefits and harms of convalescent plasma have been completed. There are 47 ongoing studies evaluating convalescent plasma, of which 22 are RCTs, and one trial evaluating hyperimmune immunoglobulin. We will update this review as a living systematic review, based on monthly searches in the above mentioned databases and registries. These updates are likely to show different results to those reported here.
背景:康复期血浆和高效免疫球蛋白可能降低呼吸道病毒疾病患者的死亡率,目前正在试验中作为2019冠状病毒病(COVID-19)的一种潜在治疗方法进行研究。需要全面了解当前有关其益处和风险的证据。 目的:评估康复期血浆或高效免疫球蛋白输血治疗COVID-19患者是否有效和安全。 检索方法:该方案已在开放科学中心预先发表,可在此处访问:osf.io/dwf53。我们检索了世界卫生组织(WHO)的COVID-19全球研究数据库、MEDLINE、Embase、Cochrane COVID-19研究注册库、疾病控制与预防中心COVID-19研究文章数据库以及试验注册库,以识别2020年4月23日正在进行的研究以及已完成研究的结果,包括病例系列研究、队列研究、前瞻性计划研究和随机对照试验(RCT)。 选择标准:我们遵循标准的Cochrane方法,由两名独立的综述作者重复进行研究选择的所有步骤(与Cochrane快速综述方法组的建议相反)。我们纳入了评估康复期血浆或高效免疫球蛋白治疗COVID-19患者的研究,无论疾病严重程度、年龄、性别或种族如何。我们排除了包括患有其他冠状病毒疾病(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。 数据收集与分析:我们遵循Cochrane快速综述方法组关于数据提取和评估的建议。为了评估纳入研究中的偏倚,我们使用了Cochrane儿童癌症提供的观察性研究评估标准工具。我们使用GRADE方法对以下结局的证据确定性进行评级:出院时的全因死亡率、临床症状改善情况(输血后7天、15天和30天)、3级和4级不良事件以及严重不良事件。 主要结果:我们纳入了八项研究(七项病例系列研究、一项前瞻性计划的单臂干预研究),共32名参与者,并识别出另外48项正在进行的评估康复期血浆(47项研究)或高效免疫球蛋白(一项研究)的研究,其中22项为随机研究。由于以下原因,纳入的八项研究的总体偏倚风险较高:研究设计;参与者数量少;研究内报告不充分;以及参与者类型多样,包括疾病严重程度、合并症以及既往或同时进行的不同治疗类型,包括抗病毒药物、抗真菌药物或抗生素、皮质类固醇、羟氯喹和呼吸支持。我们将所有结局的证据确定性评为非常低,并且无法以任何有意义的方式汇总数值数据。由于我们仅识别出病例系列研究,因此我们以叙述方式报告结果。 康复期血浆对COVID-19患者的有效性 以下报告的结局可能都与疾病的潜在自然史或其他伴随治疗有关,而非康复期血浆。 出院时的全因死亡率 所有研究均报告了死亡率。在报告期结束时所有参与者均存活,但并非所有参与者在研究结束时都已出院(15名参与者出院,6名仍住院,11名情况不明)。输血后的随访时间为3天至37天。我们不知道康复期血浆疗法是否会影响死亡率(证据确定性非常低)。 临床症状改善情况(通过呼吸支持评估) 六项研究,包括28名参与者,报告了所需的呼吸支持水平;大多数参与者在基线时需要呼吸支持。所有研究均报告至少部分参与者的临床症状有所改善。我们不知道康复期血浆是否能改善临床症状(证据确定性非常低)。 出院时间 六项研究报告了至少部分参与者的出院时间,康复期血浆治疗后为4天至35天。 入住重症监护病房(ICU) 六项研究纳入了危重症患者。在最终随访时,这些患者中的大多数不再在ICU或不再需要机械通气。 在ICU的住院时间 仅有一项研究(1名参与者)报告了在ICU的住院时间。该个体在输血后11天从ICU出院。 康复期血浆对COVID-19患者的安全性 3级或4级不良事件 研究未报告康复期血浆输血后的不良事件分级。两项研究报告了与经历不良事件的参与者相关的数据,推测可能为3级或4级。一项病例研究报告了一名中度发热(38.9°C)的参与者。另一项研究(3名参与者)报告了一例严重过敏性休克。四项研究报告未发生中度或严重不良事件(19名参与者)。我们非常不确定康复期血浆疗法是否会影响中度至重度不良事件的风险(证据确定性非常低)。 严重不良事件 一项研究(3名参与者)报告了一项严重不良事件。如上所述,该个体在接受康复期血浆后发生了严重过敏性休克。六项研究报告未发生严重不良事件。我们非常不确定康复期血浆疗法是否会影响严重不良事件的风险(证据确定性非常低)。 作者结论:我们识别出八项研究(七项病例系列研究和一项前瞻性计划的单臂干预研究),共32名参与者(范围为1至10名)。大多数研究评估了干预措施的风险;报告了两起不良事件(可能为3级或4级),其中一起为严重不良事件。我们非常不确定康复期血浆对COVID-19住院患者是否有效,因为研究报告结果不一致,难以比较结果并得出结论。我们识别出关于康复期血浆疗法对COVID-19患者有效性和安全性的证据确定性非常低;所有研究的偏倚风险都很高,报告质量也很低。尚无评估康复期血浆利弊的RCT或对照非随机研究完成。有47项正在进行的评估康复期血浆的研究,其中22项为RCT,还有一项评估高效免疫球蛋白的试验。我们将根据每月在上述数据库和注册库中的检索结果,作为动态系统综述更新本综述。这些更新可能会显示与本文报道不同的结果。
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