SARS-CoV-2及其他β-冠状病毒相关呼吸系统疾病治疗措施的安全性系统评价与Meta分析

Safety of Treatments Recommended by Guidelines for SARS-CoV-2 and Otherβ-coronaviruses Associated Respiratory Diseases:A Systematic Review and Meta-analysis

目的评估指南推荐疗法治疗严重急性呼吸综合征冠状病毒2(SARS-CoV-2)和其他β冠状病毒相关呼吸道疾病的安全性。方法系统检索PubMed、Embase、Web of Science、Cochrane library、SinoMed、中国知网、万方数据库2003—2020年6月公开发表的关于β-冠状病毒治疗措施的随机对照试验(RCT)、类试验和队列研究。双人独立筛选文献、提取资料,并对符合入选标准的文献采用Cochrane偏倚评价工具进行质量评价后,使用Stata 14.0版软件进行Meta分析。结果最终纳入59项研究,共计9598例。其中49项研究关于SARS-CoV-2,包括27项RCT,19项队列和3项类试验,9项研究关于SARS-CoV,1项队列关于中东呼吸综合征冠状病毒(MERS-CoV)。所有研究中显著性结果如下:在SARS-CoV-2患者中,两项关于洛匹那韦/利托那韦的队列和一项关于大剂量羟氯喹或氯喹的RCT比标准治疗有更多的整体不良反应事件发生[RR=2.68,95%CI(1.48,4.85),I^(2)=34.3%,采用建议分级评估、开发和评价准则(GRADE)评级为:低;RR=3.43,95%CI(1.55,7.58),GRADE评级:中]。而在一项RCT和一项非随机对照试验中,应用洛匹那韦/利托那韦和皮质类固醇激素相比标准治疗发生急性呼吸窘迫综合征的发生率更低[RR=0.46,95%CI(0.25,0.86),GRADE评级:低;RR=0.65,95%CI(0.44,0.98),GRADE评级:极低]。两项应用瑞德昔韦治疗10 d的RCT[RR=0.94,95%CI(0.80,1.11),I^(2)=28.8%,GRADE评级:中]和11项应用中药治疗的RCT[RR=0.77,95%CI(0.53,1.10),I^(2)=0.0%,GRADE评级:低]的安全性与标准治疗相比差异无统计学意义。在SARS-CoV患者中,6项应用中药治疗的RCT相比标准治疗的总体不良反应发生率更低[RR=0.38,95%CI(0.21,0.71),I^(2)=0.0%,GRADE评级:低]。结论洛匹那韦/利托那韦和大剂量羟基氯喹或氯喹治疗SARS-CoV-2的总体不良反应发生率更高,而瑞德西韦和中药相对安全。

Objective The pandemic of COVID-19 has brought unprecedented disaster to humans.This study was aimed to evaluate the safety of treatments for SARS-CoV-2 and otherβ-coronaviruses.Methods We meta-analyzed random controlled trials(RCTs),cohort studies and quasi-random controlled trials(quasi-RCTs)investigating treatments for fiveβ-coronaviruses with data from PubMed,Embase,Web of Science,Cochrane library,SinoMed,China National Knowledge Infrastructure and WanFang Database.Results From 2003 to June 2020,a total of 59 studies involving 9598 participants met the inclusion criteria,with 49 studies included 27 RCTs,19 cohort studies and three quasi-RCTs on SARS-CoV-2,nine studies on SARS-CoV,and one cohort study on MERS-CoV.Within the included literature,the following results were of significance.Compared with standard of care(SOC)for patients with SARS-CoV-2,two cohort studies conducting lopinavir/ritonavir(LPV/RIT)treatment[RR=2.68,95%CI(1.48,4.85),I^(2)=34.3%,low quality]and one RCT delivering high dose hydroxychloroquine or chloroquine(CQ)[RR=3.43,95%CI(1.55,7.58),moderate quality]reported more overall adverse events(OAEs).Nevertheless,in an RCT and a non-randomized RCT,LPV/RIT/corticosteroids groups had less incidences of acute respiratory distress syndrome(ARDS)than those of SOC[RR=0.46,95%CI(0.25,0.86)low quality;RR=0.65,95%CI(0.44,0.98),very low quality,respectively].Two RCTs implementing 10-day remdesivir treatment[RR=0.94,95%CI(0.80,1.11),I^(2)=28.8%,moderate quality]and 11 RCTs employing traditional Chinese medicine(TCM)[RR=0.77,95%CI(0.53,1.10),I^(2)=0.0%,low quality]demonstrated no significant difference from SOC.Compared with SOC for patients with SARS-CoV,six RCTs with TCM treatment reported lower OAEs[RR=0.38%,95%CI(0.21,0.71),I^(2)=0.0%,low quality].Conclusion Overall,LPV/RIT and high dose CQ showed OAE issues treating SARS-CoV-2,while remdesivir and TCM seemed safe considering all considered safety outcomes.