免疫球蛋白治疗新冠肺炎患者的疗效调研！

Background

The benefit of IVIG (Intravenous Immunoglobulin) therapy for COVID-19 remains controversial. We performed a meta-analysis to investigate the efficacy of IVIG treatment in patients with COVID-19.

调查背景

静脉注射免疫球蛋白（IVIG）治疗新冠肺炎的益处仍存在争议。我们进行了一项汇聚分析，以调查IVIG治疗新冠肺炎患者的疗效。

Methods

We searched articles from Web of Science, PubMed, Embase, the Cochrane Library, MedRxiv between 1 January 2020 and February 17, 2021. We selected randomized clinical trials and observational studies with a control group to assess the efficiency of IVIG in treating patients with COVID-19. Subjects were divided into ‘non-severe’, ‘severe’ and ‘critical’ three subgroups based on the information of the study and the World Health Organization (WHO) definition of severity. We pooled the data of mortality and other outcomes using either a fixed-effect model or a random-effects model.

方法

我们搜索了2020年1月1日至2021 2月17日期间来自科学网、PubMed、Embase、Cochrane图书馆、MedRxiv的文章。我们选择随机临床试验和观察性研究作为对照组，以评估IVIG治疗新冠肺炎患者的疗效。根据研究信息和世界卫生组织（WHO）对严重程度的定义，受试者被分为“非严重”、“严重”和“严重”三个亚组。我们使用固定效应模型或随机效应模型汇总了死亡率和其他结果的数据。

Results

Our meta-analysis retrieved 4 clinical trials and 3 cohort studies including 825 hospitalized patients. The severity of COVID-19 is associated with the efficiency of IVIG. In critical subgroup, IVIG could reduce the mortality compared with the control group [RR = 0.57 (0.42–0.79, I2 = 025%). But there was no significant difference in the severe or non-severe subgroups.

后果

我们的汇聚分析检索了4项临床试验和3项队列研究，包括825名住院患者。新冠肺炎的严重程度与IVIG的效率相关。与对照组相比，在危重亚组中，IVIG可以降低死亡率[RR=0.57（0.42–0.79，I2=025%）。但在重症或非重症亚组中没有显著差异。

Conclusion

IVIG has demonstrated clinical efficacy on critical ill patients with COVID-19. There may be a relationship between the efficacy of IVIG and the COVID-19 disease severity. Well-designed clinical trials to identify the clinical and biochemical characteristics in COVID-19 patients’ population that could benefit from IVIG are warranted in the future.

结论

IVIG已证明对新冠肺炎危重患者的临床疗效。IVIG的疗效可能与新冠肺炎的严重程度有关。未来需要进行精心设计的临床试验，以确定新冠肺炎患者人群中可能受益于IVIG的临床和生化特征。

1.Introduction

In 2019, a novel coronavirus disease (COVID-19) which caused by the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has aroused an outbreak worldwide. COVID-19 has been diagnosed in 110.7 million cases and over 2.4 million deaths since the start of the pandemic [1]. The high infection rate and mortality pose an unprecedented challenge to clinicians. Numerous clinical trials, retrospective studies and observational studies about SARS-Cov-2 disease are underway, and we found some effective antiviral agents against the infection but the lack of standardized therapy makes the condition worse. In parallel with the development of new antiviral agents and vaccines in this disease, it is necessary to research the efficacy of existing therapeutic such as Intravenous immunoglobulin (IVIG).

1. 介绍

2019年，由严重急性呼吸综合征冠状病毒2型（SARS-Cov-2）引起的新型冠状病毒病（新冠肺炎）在全球范围内爆发。自疫情爆发以来，新冠肺炎已被诊断出1.107亿病例，240多万人死亡[1]。高感染率和高死亡率给临床医生带来了前所未有的挑战。关于SARS-Cov-2疾病的大量临床试验、回顾性研究和观察性研究正在进行中，我们发现了一些有效的抗病毒药物，但缺乏标准化治疗使病情恶化。在开发新的抗病毒药物和疫苗治疗该疾病的同时，有必要研究现有治疗药物的疗效，如静脉免疫球蛋白（IVIG）。

IVIG is a kind of blood product from healthy donors containing a polyclonal IgG antibody. Known for its anti-inflammatory reactions, it has been used to treat patients with inflammatory diseases including Kawasaki diseases, multiple sclerosis and so on [2]. The SARS-Cov-2 virus is a member of coronavirus family. Based on the experience of treating previous coronavirus diseases such as severe acute respiratory syndrome (SARS) [3], Middle East respiratory syndrome (MERS) [4] and swine-origin influenza virus (SOIV) H1N1 [5], though no sufficient clinical data, it might be believed that IVIG could be used in COVID-19 patients and be one of worthwhile therapeutic options. The controversy over the efficacy of IVIG for improving in clinical symptoms and mortality, nevertheless, has been occurring with the increasing number of COVID-19 patients [6], [7], [8]. There still exist types of studies which have evaluated the efficiency of IVIG in patients with COVID-19 so far [9], [10]. A meta-analysis to review these evidences is greatly essential for the use of IVIG for COVID-19. We performed a meta-analysis by selecting literature from five databases to synthesize the results of well-done randomized clinical trial (RCTs) and observational studies to tested the significance of IVIG therapy and give some advice for clinical treatment.

IVIG是一种来自健康供体的血液制品，含有多克隆IgG抗体。以其抗炎反应而闻名，它已被用于治疗炎症性疾病，包括川崎病、多发性硬化症等[2]。SARS-Cov-2病毒是冠状病毒家族的一员。根据以往治疗冠状病毒疾病的经验，如严重急性呼吸综合征（SARS）[3]、中东呼吸综合征[4]和猪源性流感病毒（SOIV）H1N1[5]，虽然没有足够的临床数据，但可以相信IVIG可以用于新冠肺炎患者，是值得选择的治疗方法之一。然而，随着新冠肺炎患者数量的增加，IVIG在改善临床症状和死亡率方面的功效一直存在争议[6]、[7]、[8]。迄今为止，仍有一些类型的研究评估了IVIG对新冠肺炎患者的疗效[9]，[10]。对这些证据进行荟萃分析对新冠肺炎IVIG的使用至关重要。我们通过从五个数据库中选择文献进行了荟萃分析，综合了做得好的随机临床试验（RCT）和观察研究的结果，以测试IVIG治疗的意义，并为临床治疗提供一些建议。

Two reviewers (Yun Li and Xuan Cheng) searched Web of Science, PubMed, Embase, the Cochrane Library, MedRxiv for clinical trials and observational studies. A combination of search terminologies (“Coronavirus Disease 2019” OR “COVID-19” OR “SARS-Cov-2” OR “2019-nCoV Diseases” OR “COVID 19 Virus Infection”) AND (“IVIG” OR “immunoglobulin” OR “IVIG”). Search were down on February 17, 2021. The search was imposed restriction on the date between 1.1 2020 to 2.17 2021. No restriction on the geographical location or language of the studies.

2. 方法

该荟萃分析在《系统审查和荟萃分析首选报告项目》（PRISMA-P）声明中进行了描述[11]。本研究的方案已在国际前瞻性系统评价登记册（PROSPERO，CRD42021238498）中登记。

2. Methods

This meta-analysis was described by the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA-P) statement [11]. The protocol for this study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42021238498).

2.1. Search strategy

Two reviewers (Yun Li and Xuan Cheng) searched Web of Science, PubMed, Embase, the Cochrane Library, MedRxiv for clinical trials and observational studies. A combination of search terminologies (“Coronavirus Disease 2019” OR “COVID-19” OR “SARS-Cov-2” OR “2019-nCoV Diseases” OR “COVID 19 Virus Infection”) AND (“IVIG” OR “immunoglobulin” OR “IVIG”). Search were down on February 17, 2021. The search was imposed restriction on the date between 1.1 2020 to 2.17 2021. No restriction on the geographical location or language of the studies.

2.2. Selection criteria

Inclusion criteria included:

(1) Study types: Clinical trials and observational studies which patients were divided into treatment group using IVIG and the control group not using IVIG.

(2) Patients: Patients with lab-confirmed COVID-19, aged 18 years and above.

(3) Outcome: The primary outcome measure was defined as mortality. The secondary outcome measures were mechanical ventilation need, length of hospital stay (day) and length of Intensive Care Unit (ICU) stay (day).

Exclusion criteria included:

(1) Studies with insufficient data;

(2) Studies with no control group;

(3) Review articles, viewpoints, editorials, and expert opinion.

2.1搜索策略

两位审稿人（Yun Li和Zhuan Cheng）在科学网、PubMed、Embase、Cochrane图书馆、MedRxiv上搜索临床试验和观察研究。搜索术语的组合（“2019年冠状病毒病”或“新冠肺炎”或“SARS-Cov-2”或“2019-nCoV疾病”或“新冠肺炎病毒感染”）和（“IVIG”或“免疫球蛋白”或“IVIG”）。搜索于2021 2月17日停止。搜索日期限制在2020年1月1日至2021 2月17日。对研究的地理位置或语言没有限制。

2.2.选择标准

入选标准包括：

（1） 研究类型：临床试验和观察性研究，将患者分为使用IVIG的治疗组和不使用IVIG对照组。

（2） 患者：实验室确认的新冠肺炎患者，年龄18岁及以上。

（3） 结果：主要结果指标定义为死亡率。