国际传染病学杂志发表《羟氯喹、阿奇霉素和联合用药治疗新型冠状病毒肺炎住院患者》

这篇7月1日发表在国际传染病学杂志上的文章表明,单独使用羟氯喹和联合阿奇霉素治疗可以降低一半CCP病毒肺炎的死亡率。这项由亨利福特医疗系统发表的大型多医院联合研究和此前其他团队发表文章的区别主要在于药物剂量、用药时机和基础疾病的筛查不同。此研究使用的药物计量为:羟氯喹用量第一天每天两次,每次400毫克; 第二天每天两次,每次200毫克; 第三天每天两次,每次200毫克; 第三天每天两次,每次200毫克; 第三天每天两次,每次200毫克。阿奇霉素的剂量为500毫克每日一次,第1天随后250毫克每日一次,连续4天。

翻译:【Naomi】校对:【Michelle】

战友之间玫瑰园小队出品

图片来源:https://isid.org

原文链接

中英文对照全文:

Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19

羟氯喹、阿奇霉素和联合用药治疗新型冠状病毒肺炎住院患者

Published: July 01, 2020

发表时间: 2020年7月1日

Samia Arshad
Paul Kilgore
Zohra S. Chaudhry
Gordon Jacobsen
Dee Dee Wang
Kylie Huitsing
Indira Brar
George J. Alangaden
Mayur S. Ramesh
John E. McKinnon
William O’Neill
Marcus Zervos

Henry Ford COVID-19 Task Force

Highlights 精彩内容

As of May27, 2020 there are over 1,678,843 confirmed cases of COVID-19 claiming more than 100,000 lives in the Unites States. Currently there is no known effective therapy or vaccine. 

截至2020年5月27日,在美国有超过1,678,843例确诊的新型冠状病毒肺炎感染病例,夺走了超过10万人的生命。目前还没有已知有效的治疗方法或疫苗。

According to a protocol-based treatment algorithm, among hospitalized patients, use of hydroxychloroquine alone and in combination with azithromycin was associated with a significant reduction in-hospital mortality compared to not receiving hydroxychloroquine. 

根据一个基于协议的治疗算法,在住院患者中,单独使用羟氯喹和与阿奇霉素联合使用,与不使用羟氯喹相比,能显著降低住院死亡率。

Findings of this observational study provide crucial data on experience with hydroxychloroquine therapy, providing necessary interim guidance for COVID-19 therapeutic practice. 

本观察性研究的发现为羟氯喹治疗的经验提供了重要的数据,为新型冠状病毒肺炎治疗实践提供了必要的临时指导。

Abstract  摘要

Significance 重要性

The United States is in an acceleration phase of the COVID-19 pandemic. Currently there is no known effective therapy or vaccine for treatment of SARS-CoV-2, highlighting urgency around identifying effective therapies. 

美国正处于新型冠状病毒肺炎流感大流行的加速阶段。目前还没有已知的治疗 SARS-CoV-2的有效疗法或疫苗,这突出表明急需确定有效的治疗方法。

Objective 目标

The purpose of this study was to evaluate the role of hydroxychloroquine therapy alone and in combination with azithromycin in hospitalized patients positive for COVID-19. 

本研究的目的是评估羟氯喹单独和联合阿奇霉素治疗住院新型冠状病毒肺炎阳性患者的作用

Design 设计

Multi-center retrospective observational study 多中心回顾观察性研究

Setting 环境

The Henry Ford Health System (HFHS) in Southeast Michigan: large six hospital integrated health system; the largest of hospitals is an 802-bed quaternary academic teaching hospital in urban Detroit, Michigan. 

位于密执安州东南部的亨利 · 福特医疗系统: 六家大型医院的综合医疗系统; 最大的医院是位于密执安州底特律市的一家拥有802张病床的第四级学术教学医院。

Participants 参加者

Consecutive patients hospitalized with a COVID-related admission in the health system from March 10,2020 to May 2,2020 were included. Only the first admission was included for patients with multiple admissions. All patients evaluated were 18 years of age and older and were treated as inpatients for at least 48  hours unless expired within 24  hours. 

从2020年3月10日到2020年5月2日,与COVID相关的按次序入院的病人被纳入此研究。对于多次入院的患者,只采用第一次入院数据。所有接受评估的患者年龄在18岁或18岁以上,而且已经接受了至少48小时的住院治疗,除非在24小时内已死亡。

Exposure 接受的治疗方式

Receipt of hydroxychloroquine alone, hydroxychloroquine in combination with azithromycin, azithromycin alone, or neither. 

单独使用羟氯喹、羟氯喹联合阿奇霉素、单独使用阿奇霉素或两者都不用

Main Outcome 主要成果

The primary outcome was in-hospital mortality 

住院死亡率

Results 结果

Of 2,541 patients, with a median total hospitalization time of 6 days (IQR: 4-10 days), median age was 64 years (IQR:53-76 years), 51% male, 56% African American, with median time to follow-up of 28.5 days (IQR:3-53). Overall in-hospital mortality was 18.1% (95% CI:16.6%-19.7%); by treatment: hydroxychloroquine + azithromycin, 157/783 (20.1% [95% CI: 17.3%-23.0%]), hydroxychloroquine alone, 162/1202 (13.5% [95% CI: 11.6%-15.5%]), azithromycin alone, 33/147 (22.4% [95% CI: 16.0%-30.1%]), and neither drug, 108/409 (26.4% [95% CI: 22.2%-31.0%])​. Primary cause of mortality was respiratory failure (88%); no patient had documented torsades de pointes. From Cox regression modeling, predictors of mortality were age>65 years (HR:2.6 [95% CI:1.9-3.3]), white race (HR:1.7 [95% CI:1.4-2.1]), CKD (HR:1.7 [95%CI:1.4-2.1]), reduced O2 saturation level on admission (HR:1.5 [95%CI:1.1-2.1]), and ventilator use during admission (HR: 2.2 [95%CI:1.4-3.3]). Hydroxychloroquine provided a 66% hazard ratio reduction, and hydroxychloroquine + azithromycin 71% compared to neither treatment (p < 0.001). 

在2,541名患者当中,中位总住院时间为6天(四分位间距 [IQR]:4-10天),中位年龄为64岁(IQR:53-76岁),51%为男性,56%为非裔美国人,中位随访时间为28.5天(IQR:3-53)。院内总死亡率为18.1%(95% 置信区间 [CI]:16.6%-19.7%);不同治疗方式的死亡率:羟氯喹+阿奇霉素,157/783(20.1% [95% CI:17.3%-23.0%]),单用羟氯喹,162/1202(13.5% [95% CI:11.6%-15.5%]),单用阿奇霉素,33/147(22.4% [95%CI:16.0%-30.1%]),两种药物均不使用,108/409(26.4% [95%CI:22.2%-31.0%])。死亡的主要原因是呼吸衰竭(88%);没有患者有记录在案的心肌梗死。从Cox回归模型来看,能预测死亡率的预测因素包括年龄>65岁(风险比:2.6 [95% CI:1.9-3.3])、白人种族(风险比:1.7 [95% CI:1.4-2.1])、慢性肾病CKD(风险比:1. 7 [95% CI:1.4-2.1])、入院时血氧饱和度降低(风险比:1.5 [95% CI:1.1-2.1])、入院时使用呼吸机(风险比:2.2 [95% CI:1.4-3.3])。与两种治疗相比,羟氯喹降低了66%的风险比,羟氯喹+阿奇霉素降低了71%的风险比(p值<0.001)。

Conclusions and Relevance 结论和相关性

In this multi-hospital assessment, when controlling for COVID-19 risk factors, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality. Prospective trials are needed to examine this impact. 

在这个多医院的评估中,当控制新型冠状病毒肺炎的危险因素时,单独使用羟氯喹和联合阿奇霉素治疗可以降低新型冠状病毒肺炎相关的死亡率。需要进行前瞻性试验来研究这种影响。

Keywords 关键词

hydroxychloroquine 羟氯喹

mortality 死亡率

COVID-19 

SARS-COV-2

coronavirus 冠状病毒

therapy 治疗

Introduction 引言

As of May 27, 2020, there were over 1,678,843 confirmed cases of COVID-19 claiming more than 100,000 lives in the Unites States. (Cases in the U.S, 2020) Currently there is no known effective therapy or vaccine. The urgent need for therapeutic agents has resulted in repurposing and redeployment of experimental agents (McCreary and Pogue, 2020, Sanders et al., 2020).

截至2020年5月27日,美国有超过1,678,843例COVID-19确诊病例,夺去了超过10万人的生命。(美国病例,2020年)目前还没有已知的有效疗法或疫苗。对治疗剂的迫切需求导致了实验剂的重新利用和重新部署(McCreary和Pogue,2020;Sanders等人,2020)。

Hydroxychloroquine, an antimalarial and immunomodulatory agent and a safer analogue of chloroquine, has demonstrated antiviral activity against SARS-CoV-2. (Wang et al., 2020a, Liu et al., 2020, Yao et al., 2020, The cardiotoxicity of antimalarials – WHO, 2017) It is postulated to exert a direct antiviral activity by increasing intracellular pH resulting in decreased phago-lysosome fusion, impairing viral receptor glycosylation. In addition, it has immune-modulating effect by inhibiting toll-like receptor signaling, decreasing production of cytokines especially IL-1 and IL-6. (Savarino et al., 2003) Prior data also suggests a potential anti-thrombotic effect (Jung et al., 2010). Azithromycin, a macrolide antibiotic has in vitro antiviral properties such as decreased viral replication, blocking entrance into host cells, and a potential immunomodulating effect. (Tran et al., 2019) An in vitro study demonstrated synergistic activity of the combination of hydroxychloroquine and azithromycin against SARS-CoV-2. (Andreani et al., 2020) A small non-randomized, open-label trial from France reported higher frequency of SARS-CoV-2 clearance after six days of treatment with hydroxychloroquine alone or hydroxychloroquine in combination with azithromycin versus untreated control group (70% vs 12.5%; P < 0.001). (Gautret et al., 2020a). Other early studies of hydroxychloroquine have reported conflicting results (Gao et al., 2020, Gautret et al., 2020b, Jun et al., 2020, Tang et al., 2020, Chen et al., 2020, Yu et al., 2020, Geleris et al., 2020, Rosenberg et al., 2020, Magagnoli et al., 2020, Million et al., 2020). The US FDA as of June 15, 2020 has revoked the prior emergency use authorization (EUA) to use hydroxychloroquine and chloroquine to treat COVID-19 in certain hospitalized patients when clinical trial data is unavailable or participation is not feasible (Anon, 2020).

羟氯喹是一种抗疟药和免疫调节剂,也是氯喹的一种较安全的类似物,已显示出对SARS-CoV-2的抗病毒活性(Wang等,2020a;Liu等,2020;Yao等,2020,《抗疟药的心脏毒性—WHO,2017》)。据推测,它通过增加细胞内pH值导致吞噬体-溶酶体融合减少,损害病毒受体糖基化,直接发挥抗病毒活性。此外,它还具有免疫调节作用,通过抑制toll样受体信号传导,减少细胞因子的产生,尤其是 IL-1 和 IL-6(Savarino等,2003)。之前的数据也表明其具有潜在的抗血栓作用(Jung等,2010)。阿奇霉素是一种大环内酯类抗生素,具有体外抗病毒特性,如减少病毒复制,阻断进入宿主细胞,以及潜在的免疫调节作用(Tran等,2019) 。一项体外研究表明,羟氯喹和阿奇霉素联合使用对SARS-CoV-2具有协同活性(Andreani等,2020) 。来自法国的一项小型非随机、开放标签试验报导,单用羟氯喹或羟氯喹联合阿奇霉素治疗6天后,SARS-CoV-2清除频率高于未治疗的对照组(70%比12.5%;p值<0.001)(Gautret等,2020a)。羟氯喹的其它早期研究报告了相互矛盾的结果(Gao等,2020;Gautret等,2020b;Jun等,2020;Tang等,2020;Chen等,2020;Yu等,2020;Geleris等,2020;Rosenberg等,2020;Magagnoli等,2020;Million等,2020)。美国FDA截至2020年6月15日已经撤销了之前的紧急用户许可证(EUA),当无法获得临床试验资料或无法参与临床试验时,可以使用羟氯喹和氯喹治疗某些住院患者的COVID-19(Anon,2020)。

Currently, randomized trials of hydroxychloroquine for treatment and chemoprophylaxis are underway. (Antiviral Therapy, 2020, Outcomes Related to COVID-19, 2020, Trial of Treatments for COVID-19 in Hospitalized Adults, 2020, Pagliano et al., 2020) Based on these early reports, hydroxychloroquine alone and in combination with azithromycin was incorporated into our institutional clinical guidelines for the treatment of hospitalized patients with COVID-19. We examined the association between hydroxychloroquine use and mortality in a large cohort of hospitalized COVID-19 patients.

目前,羟氯喹治疗和化学预防的随机试验正在进行(抗病毒治疗,2020,COVID-19相关结果,2020,COVID-19在Hospi-talized成人中的治疗试验,2020,Pagliano等,2020)。这些早期报导,羟氯喹单药和与阿奇霉素联合使用被纳入我院临床指南,用于治疗住院COVID-19患者。我们在一个大型的住院COVID-19患者队列中研究了羟氯喹的使用与死亡率之间的关系。

Methods 方法

SETTING 环境设置

This is a comparative retrospective cohort study evaluating clinical outcomes of all consecutive patients hospitalized at the Henry Ford Health System (HFHS) in Southeast Michigan being treated for COVID-19. The organization is a large six hospital integrated health system; the largest of hospitals is an 802-bed quaternary academic teaching hospital in urban Detroit, Michigan. Approval for this study was granted by the Henry Ford Hospital IRB (#13897). 

这是一项比较回顾性队列研究,评估所有在密执安州东南部的亨利福特医疗系统住院接受新型冠状病毒肺炎治疗的患者的临床结果。本组织是一个大型的六家医院综合卫生系统; 最大的医院是密执安州底特律市一家拥有802张床位的第四级学术教学医院。亨利·福特医院的 IRB 批准了这项研究(# 13897)

PATIENTS 病人

Patients with a COVID-related admission in the health system from March 10, 2020 to May 2, 2020 were included. Only the first admission was included for patients with multiple admissions. All patients were hospitalized though our emergency department. A COVID-related admission was defined as hospitalization during which the patient had a positive SARS-CoV-2 test. Diagnosis with SARS-CoV-2 was confirmed by a positive reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay from a nasopharyngeal sample. All patients evaluated were 18 years of age and older and were treated as inpatients for at least 48 hours unless they expired within the time period. The primary objective was to assess treatment experience with hydroxychloroquine versus hydroxychloroquine + azithromycin, azithromycin alone, and other treatments for COVID-19. Treatments were protocol driven, uniform in all hospitals and established by a system-wide interdisciplinary COVID-19 Task Force. Hydroxychloroquine was dosed as 400 mg twice daily for 2 doses on day 1, followed by 200 mg twice daily on days 2-5. Azithromycin was dosed as 500 mg once daily on day 1 followed by 250 mg once daily for the next 4 days. The combination of hydroxychloroquine + azithromycin was reserved for selected patients with severe COVID-19 and with minimal cardiac risk factors. An electrocardiogram (ECK) based algorithm was utilized for hydroxychloroquine use. QTc>500 ms was considered an elevated cardiac risk and consequently hydroxychloroquine was reserved for patients with severe disease with telemetry monitoring and serial QTc checks. The clinical guidelines included adjunctive immunomodulatory therapy with corticosteroids and tocilizumab. 

研究对象包括2020年3月10日至2020年5月2日在卫生系统接受 COVID相关治疗的患者。对于多次入院的患者,只采用第一次入院数据。所有的病人都通过我们的急诊室住院了。COVID相关入院被定义为住院期间有一次阳性 SARS-CoV-2检验的患者。经逆转录聚合酶链反应(RT-PCR)检测,确诊为 SARS-CoV-2。所有接受评估的患者年龄均在18岁或18岁以上,而且已经接受了至少48小时的住院治疗,除非在24小时内已死亡。主要目的是评估羟氯喹与羟氯喹 + 阿奇霉素、阿奇霉素单独使用以及其他治疗新型冠状病毒肺炎的疗效。治疗是由协议驱动的,在所有医院都是用统一的协议,并且由一个全系统跨学科的新型冠状病毒肺炎工作组建立。羟氯喹用量第一天每天两次,每次400毫克; 第二天每天两次,每次200毫克; 第三天每天两次,每次200毫克; 第三天每天两次,每次200毫克; 第三天每天两次,每次200毫克。阿奇霉素的剂量为500毫克每日一次,第1天随后250毫克每日一次,连续4天。联合使用羟氯喹 + 阿奇霉素治疗某些有严重新型冠状病毒肺炎并且心脏危险因素很小的患者。一个基于心电图(ECK)的算法被用于羟氯喹。大于500ms 被认为是心脏风险增加的,因此,对于有遥测监测和连续 QTc 检查的严重疾病患者保留羟氯喹。临床指南包括皮质类固醇和西利珠单抗辅助免疫调节治疗

DATA SOURCES 数据

The data source for analysis of patient information was derived from electronic medical records in the Electronic Information System. Study variables collected on each patient included the following; 1) patient demographics: age, gender, race, body mass index (BMI) on admission, stratified into four categories: <18.5; 18.5-24.9; 25.0-29.9 and ≥ 30; 2) clinical characteristics: admission date, discharge date, length of stay (LOS), comorbidities including: cardiovascular disease (CVD), chronic lung disease, chronic kidney disease (CKD), hypertension, asthma, chronic obstructive pulmonary disease (COPD), diabetes mellitus, immunodeficiency, and cancer (defined as active or past/resolved). Additionally, intensive care unit (ICU) status and ventilator use at any point during admission, minimum O2 saturation level collected on day of admission in the emergency department, and the maximal modified Sequential Organ Failure Assessment (mSOFA) score on admission were also collected. The mSOFA score is predictive of ICU mortality utilizing similar accuracy to the full SOFA score without substantial lab testing (ABG, LFTs) to complete. (Grissom et al., 2010) The duration and dosages of all therapies for COVID-19 were collected.

分析患者信息的数据源来自于电子信息系统中的电子病历。对每位患者收集的研究变量包括以下内容;1)患者人口学资料:年龄、性别、种族、入院时体重指数(BMI),分层为四类:<18.5;18.5-24.9;25.0-29.9 和 ≥30;2)临床特征:入院日期、出院日期、住院时间(LOS)、合并症,包括:心血管疾病(CVD)、慢性肺部疾病、慢性肾脏疾病(CKD)、高血压、哮喘、慢性阻塞性肺部疾病(COPD)、糖尿病、免疫缺陷和癌症(定义为活动或过去/已解决)。此外,还收集了重症监护室(ICU)状态和入院期间任何时候的呼吸机使用情况、急诊科入院当天收集的最低O2饱和度,以及入院时的最大改良序列器官衰竭评估(mSOFA)评分。mSOFA评分利用与完整的SOFA评分相似的准确性来预测ICU死亡率,而不需要大量的实验室检查(ABG、LFTs)来完成(Grissom等,2010)。还收集了COVID-19的所有疗法的持续时间和剂量。

STATISTICAL ANALYSIS 统计分析

Demographic and clinical characteristics were descriptively summarized for all patients and subsets by treatment group, to test the null hypothesis that treatment course between hydroxychloroquine, hydroxychloroquine + azithromycin, azithromycin, and other (no hydroxychloroquine or azithromycin) were similar. Multivariable Cox regression models and Kaplan-Meier survival curves were used to compare survival among treatment groups while controlling for demographics (e.g., age, gender), preexisting medical conditions (e.g. CVD, lung disease) and clinical disease severity (mSOFA, O2 saturation). Bivariate comparisons of the 4 medication groups were made using analysis of variance or Kruskal-Wallis tests for continuous variables, and chi-square tests or Fisher exact tests for categorical variables. Additional analysis was performed using propensity score matching to compare outcomes in mortality across treatment groups. A propensity score was created for each patient based on the set of patient characteristics used in the Cox regression model. Subsequently, 1 to 1 matchups of patients given hydroxychloroquine (either hydroxychloroquine alone or in combination with azithromycin) and patients not given hydroxychloroquine based on the exact propensity score were observed. The resulting matched group status was placed into its own Cox regression model as a mortality predictor with a Kaplan-Meier plot summarizing the survival curves of the two matched groups. P values < 0.05 were considered statistically significant. Additionally, median survival times by treatment strata were calculated to approximate prognosis. No imputations were made for missing data. All data were analyzed using SPSS software version 26 (IBM SPSS Statistics for Windows, version 26, IBM Corp., Armonk, N.Y., USA) and STATA (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC), and SAS version 9.4.

对所有患者的人口统计学和临床特征进行描述性总结,并按治疗组进行子集,以检验羟氯喹、羟氯喹+阿奇霉素、阿奇霉素和其他(不使用羟氯喹或阿奇霉素)之间治疗过程相似的零假设。多变量Cox回归模型和Kaplan-Meier生存曲线用于比较治疗组之间的生存率,同时控制人口统计学变量(如年龄、性别)、已有的医疗条件(如CVD、肺部疾病)和临床疾病严重程度(mSOFA、O2饱和度)。4个药物组的双变量比较采用方差分析或Kruskal-Wallis检验对连续变量进行检验,对分类变量采用chi-square检验或Fisher精确检验。使用倾向性得分匹配进行额外分析,以比较各治疗组的死亡率结果。根据Cox回归模型中使用的一组患者特征,为每个患者创建了一个倾向性得分。随后,根据确切的倾向性得分,观察给予羟氯喹(单独使用羟氯喹或与阿奇霉素联合使用)的患者和未给予羟氯喹的患者的1对1匹配。将得出的匹配组状态放入自身的Cox回归模型中作为死亡率预测因子,用Kaplan-Meier图总结两组匹配组的生存曲线。P值<0.05被认为有统计学意义。此外,计算了各治疗层的中位生存时间以近似预后。对缺失的数据没有进行推算。所有数据均使用SPSS软件26版(IBM SPSS Statistics for Windows,26版,IBM Corp.,Armonk,N.Y.,USA)和STATA(StataCorp.2019. Stata Statistical Software: 第16版。College Station, TX: StataCorp LLC)和SAS 9.4版。

Results 结果

The first COVID-19 case confirmed at HFHS by RT-PCR was on March 10, 2020, any patients admitted before March 10th and subsequently tested positive were also included in the analyses. There was a total of 2,948 COVID-19 admissions, of these, 267 (9%) patients had not been discharged, 15 (0.5%) left against medical advice, and four (0.1%) were transferred to another healthcare facility; these patients were excluded from analysis as we could not ascertain their outcome. In addition, there were 121 (4.1%) readmissions, which were also excluded. 

第一例通过 RT-PCR 在 HFHS 确诊的新型冠状病毒肺炎病例是在2020年3月10日,任何在3月10日之前入院并随后检测呈阳性的病人也包括在分析中。本新型冠状病毒肺炎共有2948名病人入院,其中267名(9%)病人没有出院,15名(0.5%)病人没有遵从医生的建议离开,4名(0.1%)病人被转往其他医疗机构,由于我们无法确定他们的结果,这些病人被排除在分析之外。此外,还有121人(4.1%)再次入院,这也被排除在外

Overall, 2,541 consecutive patients were included in the analyses with a median age of 64 years (IQR: 53-76 years), 51% male, 56% African American, median inpatient LOS was 6 days (IQR: 4-10 days). The median time to follow-up was 28.5 days (IQR 3-53). Majority of patients (52%, n = 1,250) had BMI ≥ 30. Additional underlying comorbidities are detailed in Table 1. On the day of admission, two variables predicting severity of disease and mortality: highest mSOFA score and lowest O2 saturation were recorded. However, 25% of the population did not have mSOFA scores available, as recording of this metric became institutional standard one month after the index admission. Other indicators of severity were ICU admission and mechanical ventilation status. All baseline characteristics were further stratified by the four treatment groups (hydroxychloroquine alone, hydroxychloroquine + azithromycin, azithromycin alone, and neither treatment). Median time (IQR) from admission to receipt of hydroxychloroquine was 1 day (1-2). Overall crude mortality rates were 18.1% in the entire cohort, 13.5% in the hydroxychloroquine alone group, 20.1% among those receiving hydroxychloroquine + azithromycin, 22.4% among the azithromycin alone group, and 26.4% for neither drug (p < 0.001). Adjunct therapy with corticosteroids (methylprednisolone and/or prednisone) and anti-IL-6 tocilizumab was provided in 68% and 4.5% of patients, respectively.

总体而言,分析中纳入了2541名连续患者,中位年龄64岁(IQR:53-76岁),51%为男性,56%为非裔美国人,中位住院LOS为6天(IQR:4-10天)。中位随访时间为28.5天(IQR 3-53)。大多数患者(52%,n = 1,250)的体重指数≥30。其他潜在的合并症详见表1。入院当天,记录了预测疾病严重程度和死亡率的两个变量:最高mSOFA评分和最低O2饱和度。然而,25%的人群没有mSOFA评分,因为在指标入院一个月后,记录这一指针成为机构标准。其他严重性指标是ICU入院和机械通气状态。所有基线特征按四个治疗组(单独使用羟氯喹、羟氯喹+阿奇霉素、单独使用阿奇霉素和两种治疗)进一步分层。从入院到接受羟氯喹治疗的中位时间(IQR)为1天(1-2)。整个队列的总粗死亡率为18.1%,单用羟氯喹组为13.5%,接受羟氯喹+阿奇霉素治疗者为20.1%,单用阿奇霉素组为22.4%,两种药物均为26.4%(P<0.001)。分别有68%和4.5%的患者接受皮质类固醇(甲基强的松龙和/或强的松)和抗IL-6托西单抗的辅助治疗。

Primary cause of mortality in the 460 patients was: 88% respiratory failure, 4% cardiac arrest (with mean QTc interval from last ECG reading 471 ms), 8% other cardiopulmonary arrest and multi-organ failure. No patient had documented torsades de pointes. 

在460例患者中,死亡的主要原因是: 88% 的呼吸衰竭,4% 的心脏骤停(从上次心电图显示的平均 QTc 间隔为471ms),8% 的其他心脏骤停和多器官衰竭。没有病人有尖端扭转型室性心动过速的记录

In the multivariable Cox regression model of mortality using the group receiving neither hydroxychloroquine or azithromycin as the reference, treatment with hydroxychloroquine alone decreased the mortality hazard ratio by 66% (p < 0.001), and hydroxychloroquine + azithromycin decreased the mortality hazard ratio by 71% (p < 0.001). We did not find statistical significance in the relative effect of adjunct therapy and mortality. Predictors of mortality were age ≥ 65 years (HR, 2.6 [95% CI: 1.9, 3.3]), white race (HR: 1.7 [95% CI: 1.4, 2.1]), CKD (HR, 1.7 [95%CI: 1.4, 2.1]), reduced O2 saturation level on admission (HR, 1.6 [95%CI: 1.1, 2.2]), and ventilator use during admission (HR, 2.2 [95%CI: 1.4, 3.0]), which were all significantly associated with mortality due to COVID-19.

在死亡率的多变量 Cox 回归模型中,以既没有接受羟氯喹也没有接受阿奇霉素作为参考,单独使用羟氯喹治疗可以降低66% 的死亡风险比率(p < 0.001),羟氯喹 + 阿奇霉素可以降低71% 的死亡风险比率(p < 0.001)。我们没有发现辅助治疗的相对效果和死亡率的统计学意义。年龄≥65岁(风险比,2.6 [95% CI: 1.9,3.3]),白种人(风险比: 1.7 [95% CI: 1.4,2.1]),CKD(风险比,1.7 [95% CI: 1.4,2.1]),入院时 O2饱和度降低(风险比,1.6 [95% CI: 1.1,2.2]),入院时使用呼吸机(风险比,2.2 [95% CI: 1.4,3.0]),这些都与新型冠状病毒肺炎死亡有显著关系(表二).

Kaplan-Meier survival curves showed significantly improved survival among patients in the hydroxychloroquine alone and hydroxychloroquine + azithromycin group compared with groups not receiving hydroxychloroquine and those receiving azithromycin alone (Fig. 1). The survival curves suggest that the enhanced survival in the hydroxychloroquine alone group persists all the way out to 28 days from admission.

Kaplan-Meier生存曲线显示,与未接受羟氯喹的组和单独接受阿奇霉素的组相比,单独羟氯喹组和羟氯喹+阿奇霉素组患者的生存率显著提高(图1)。生存曲线表明,单用羟氯喹组的生存率提高一直持续到入院后28天。

Further, a total of 190 hydroxychloroquine patients exactly matched up with 190 corresponding non-hydroxychloroquine treated patients based on the exact underlying propensity score. Table 3 contains a descriptive summarization of these patients within both the unmatched and propensity matched settings, confirming that the propensity matched groups have identical underlying patient characteristics. The Cox regression result for the two propensity matched groups (Table 4) indicates that treatment with hydroxychloroquine resulted in a mortality hazard ratio decrease of 51% (p = 0.009). The resulting Kaplan-Meier survival curves within the propensity matched setting displayed significantly better survival in the hydroxychloroquine treated group, with the enhanced survival persisting all the way out to 28 days from admission (Fig. 2).

此外,共有190名羟氯喹患者与190名相应的非羟氯喹治疗患者根据确切的基础倾向性评分完全匹配。表3包含了这些患者在未匹配和倾向匹配设置内的描述性总结,证实倾向匹配组具有相同的基本患者特征。两个倾向性匹配组的Cox回归结果(表4)表明,使用羟氯喹治疗可使死亡率风险比降低51%(p值= 0.009)。结果在倾向匹配环境内的Kaplan-Meier生存曲线显示羟氯喹治疗组的生存率显著提高,提高的生存率一直持续到入院后28天(图2)。

Discussion 讨论

The results of this study demonstrate that in a strictly monitored protocol-driven in-hospital setting, treatment with hydroxychloroquine alone and hydroxychloroquine + azithromycin was associated with a significant reduction in mortality among patients hospitalized with COVID-19. In this study, among one of the largest COVID-19 hospital patient cohorts (n = 2,541) assembled in a single institution, overall in-hospital COVID-19 associated mortality was 18.1% reflecting a high prevalence of co-morbid conditions in COVID-19 patients admitted to our institution. The independent predictors of mortality in our study included age ≥ 65 years, CKD, and severe illness at initial presentation as measured by the oxygen saturation levels on admission, and ventilator use reflect findings similar to those reported in earlier studies. (Rio and Malani, 2020) These predictors also underscore the high-risk for COVID-19 experienced by residents in our hospital catchment population in Metropolitan Detroit, Michigan. Michigan is among the states with the highest number of cases of COVID-19 and deaths. In Detroit, our residents suffer from substantial preexisting social and racial health disparities that place our patients at increased risk of severe disease and higher mortality. (Cases in the U.S, 2020)

该研究结果表明,在严格监测的协议驱动的院内环境中,单用羟氯喹和羟氯喹+阿奇霉素治疗与COVID-19住院患者的死亡率显著降低相关。在这项研究中,在一个最大的COVID-19医院患者队列(n = 2,541)中,集合在一个机构中,总体院内COVID-19相关死亡率为18.1%,反映了本机构收治的COVID-19患者中共病率高。在我们的研究中,死亡率的独立预测因素包括年龄≥65岁,肺结核病人,以及通过入院时的氧饱和度水平测量的初始表现时的严重疾病,以及呼吸机的使用反映了类似于早期研究中报导的结果 (Rio和Malani,2020年)。这些预测因素也强调了密执安州底特律大都会的居民在我们的医院集聚人群中经历的COVID-19的高风险。密执安州是COVID-19病例和死亡人数最多的州之一。在底特律,我们的居民面临着巨大的社会和种族健康差异,这使得我们的患者面临更多的严重疾病风险和更高的死亡率(美国的病例,2020年)。

In the present study, multivariate analysis performed using Cox regression modeling and propensity score matching to control for potential confounders affirmed that treatment with hydroxychloroquine alone and hydroxychloroquine in combination with azithromycin was associated with higher survival among patients with COVID-19. Patients that received neither medication or azithromycin alone had the highest cumulative hazard. The benefits of hydroxychloroquine in our cohort as compared to previous studies maybe related to its use early in the disease course with standardized, and safe dosing, inclusion criteria, comorbidities, or larger cohort. The postulated pathophysiology of COVID-19 of the initial viral infection phase followed by the hyperimmune response suggest potential benefit of early administration of hydroxychloroquine for its antiviral and antithrombotic properties. Later therapy in patients that have already experienced hyperimmune response or critical illness is less likely to be of benefit. Others have shown that COVID-19 hospitalized patients are not diagnosed in the community and often rapidly deteriorate when hospitalized with fulminant illness. (Mc McCullough and Arunthamakun, 2020) 

在本研究中,使用Cox回归模型和倾向性评分匹配控制潜在混杂因素进行的多变量分析肯定了单用羟氯喹和羟氯喹联合阿奇霉素治疗与COVID-19患者的较高生存率相关。既不接受药物治疗也不单独接受阿奇霉素治疗的患者累积危险度最高。与以前的研究相比,羟氯喹在我们的队列中的益处也许与它在病程早期使用标准化、和安全剂量、纳入标准、合并症或更大的队列有关。COVID-19的初始病毒感染阶段后的超免疫反应的推测病理生理学表明,早期使用羟氯喹的抗病毒和抗血栓形成特性的潜在益处。对于已经出现高免疫反应或危重病的患者,后期治疗的获益可能性较小。另有研究表明,COVID-19住院患者在社区中没有被诊断出来,当住院时往往迅速恶化,出现溃烂性疾病(Mc McCullough和Arunthamakun,2020)。

Limitations to our analysis include the retrospective, non-randomized, non-blinded study design. Also, information on duration of symptoms prior to hospitalization was not available for analysis. However, our study is notable for use of a cohort of consecutive patients from a multi-hospital institution, regularly updated and standardized institutional clinical treatment guidelines and a QTc interval-based algorithm specifically designed to ensure the safe use of hydroxychloroquine. To mitigate potential limitations associated with missing or inaccurate documentation in electronic medical records, we manually reviewed all deaths to confirm the primary mortality outcome and ascertain the cause of death. A review of our COVID-19 mortality data demonstrated no major cardiac arrhythmias; specifically, no torsades de pointes that has been observed with hydroxychloroquine treatment. This finding may be explained in two ways. First, our patient population received aggressive early medical intervention, and were less prone to development of myocarditis, and cardiac inflammation commonly seen in later stages of COVID-19 disease. Second, and importantly, inpatient telemetry with established electrolyte protocols were stringently applied to our population and monitoring for cardiac dysrhythmias was effective in controlling for adverse events. Additional strengths were the inclusion of a multi-racial patient composition, confirmation of all patients for infection with PCR, and control for various confounding factors including patient characteristics such as severity of illness by propensity matching. 

我们分析的局限性包括回顾性、非随机、非盲的研究设计。此外,住院前的症状持续时间信息也无法用于分析。然而,我们的研究值得注意的是,使用了来自多医院机构的连续患者队列,定期更新和标准化的机构临床治疗指南和基于QTc区间的算法,专门设计以确保羟氯喹的安全使用。为了减轻与电子医疗记录中缺失或不准确的记录相关的潜在限制,我们人工审查了所有死亡病例,以确认主要死亡结果并确定死因。对我们的COVID-19死亡率资料的审查表明,没有主要的心律失常;特别是,没有观察到羟氯喹治疗的心肌梗死。这一发现可能有两种解释。首先,我们的患者群体接受了积极的早期医疗干预,不太容易出现心肌炎,以及COVID-19疾病后期常见的心脏炎症。其次,重要的是,住院病人的遥测与建立的电解质协议被严格应用于我们的人群,心律失常的监测有效地控制了不良事件。其它的优势是纳入了多种族的患者组成,用PCR确认所有患者的感染,并通过倾向性匹配控制各种混杂因素,包括患者特征,如疾病的严重程度。

Recent observational retrospective studies and randomized trials of hydroxychloroquine have reported variable results. (Gautret et al., 2020a, Gao et al., 2020, Gautret et al., 2020b, Jun et al., 2020, Tang et al., 2020, Chen et al., 2020, Yu et al., 2020, Geleris et al., 2020, Rosenberg et al., 2020, Magagnoli et al., 2020, Million et al., 2020) In a randomized controlled study of 62 patients from China with COVID-19, hydroxychloroquine was associated with a shortened duration of fever and time to cough and pneumonia resolution (Chen et al., 2020). In contrast, a study of 1376 consecutive hospitalized COVID-19 patients in New York that used respiratory failure as the primary endpoint found no significant reduction in the likelihood of death or intubation among those receiving hydroxychloroquine compared to those who did not. (Geleris et al., 2020) In a separate multicenter cohort study of 1438 patients from 25 hospitals in New York, no reduction in hospitalized patient mortality was observed with hydroxychloroquine treatment (Rosenberg et al., 2020). Among a number of limitations, this study included patients who were initiated on hydroxychloroquine therapy at any time during their hospitalization. In contrast, in our patient population, 82% received hydroxychloroquine within the first 24 hours of admission, and 91% within 48 hours of admission. Because treatment regimens likely varied substantially (including delayed initiation) across the 25 hospitals that contributed patients to the study, it is not surprising that the case-fatality rate among the New York patients was significantly higher than in our study.

最近对羟氯喹的观察性回顾性研究和随机试验报导了不同的结果(Gautret等,2020a;Gao等,2020;Gautret等,2020b;Jun等,2020;Tang等,2020;Chen等,2020;Yu等,2020;Geleris等,2020;Rosenberg等,2020;Magagnoli等,2020;Million等,2020)。在一项对62名来自中国的COVID-19患者的随机对照研究中,羟氯喹与发热持续时间和咳嗽及肺炎缓解时间缩短有关(Chen等,2020)。相比之下,一项对纽约1376名连续住院的COVID-19患者进行的以呼吸衰竭为主要终点的研究发现,与没有接受羟氯喹的患者相比,接受羟氯喹的患者死亡或插管的可能性没有显著降低(Geleris等,2020)。在一项单独的多中心队列研究中,对来自纽约25家医院的1438名患者进行了研究,观察到羟氯喹治疗没有降低住院患者的死亡率(Rosenberg等,2020)。在一些限制因素中,这项研究包括了在住院期间任何时候开始接受羟氯喹治疗的患者。相反,在我们的患者群体中,82%的患者在入院后的前24小时内接受了羟氯喹治疗,91%的患者在入院后48小时内接受了羟氯喹治疗。由于为研究提供患者的25家医院的治疗方案可能有很大差异(包括起始延迟),因此纽约患者的病例死亡率明显高于我们的研究也就不足为奇了。

Globally, the overall crude mortality from SARS-COV-2 is estimated to be approximately 6-7%. (Cases in the U.S, 2020, WHO, 2020)Multiple descriptive studies report higher mortality in hospitalized COVID-19 patients from 10-30% (Huang et al., 2020, Zhou et al., 2020, Wu et al., 2020, Wang et al., 2020b, W-jie et al., 2020, Richardson et al., 2020, Arentz et al., 2020, A Trial of Lopinavir–Ritonavir in Covid-19, 2020, Grein et al., 2020). Not surprisingly, mortality as high as 58% was observed among patients requiring ICU care and mechanical ventilation (W-jie et al., 2020, Richardson et al., 2020).This high mortality associated with COVID-19 in many populations has led to a search for effective drug therapies. The randomized controlled trial of lopinavir–ritonavir in COVID-19 hospitalized patients showed a mortality of 19.2% on lopinavir–ritonavir and 25% for standard of care; therapy had to be terminated in 13.8% patients due to adverse events (Arentz et al., 2020). In the compassionate use remdesivir trial, 13% mortality was observed in the cohort of 61 patients (A Trial of Lopinavir–Ritonavir in Covid-19, 2020). The interim analysis randomized trial of remdesivir showed a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p = 0.059). Grein et al., 2020) In our study, overall mortality was 18.1% and in ICU patients 45%. Our cohort included patients with severe disease, with 24% and 18% requiring ICU care and mechanical ventilation at presentation, respectively.

全球范围内,SARS-COV-2的总体死亡率粗估计约为6-7%(美国的病例,2020,WHO,2020)。多项描述性研究报导,住院的COVID-19患者死亡率较高,从10-30%(Huang等,2020;Zhou等,2020;Wu等,2020;Wang等,2020b;W-jie等,2020;Richardson等,2020;Arentz等,2020;A Trial of Lopinavir-Ritonavir in Covid-19,2020;Grein等,2020) 不足为奇的是,在需要ICU护理和机械通气的患者中观察到了高达 58% 的死亡率(W-jie等,2020;Richardson等,2020)。在许多人群中,COVID-19相关的这种高死亡率导致了对有效药物疗法的寻找。在COVID-19住院患者中进行的洛匹那韦-利托那韦的随机对照试验显示,洛匹那韦-利托那韦的死亡率为19.2%,标准护理的死亡率为25%;13.8%的患者因不良事件不得不终止治疗(Arentz等,2020)。在同情性使用雷米西韦试验中,61名患者的队列中观察到13%的死亡率(一个洛匹那韦-利托那韦在Covid-19中的应用试验,2020)。雷米替西韦的中期分析随机试验显示,接受雷米替西韦组的死亡率为8.0%,而安慰剂组为11.6%(p值=0.059) Grein等,2020)在我们的研究中,总体死亡率为18.1%,ICU患者的死亡率为45%。我们的队列包括严重疾病的患者,分别有24%和18%的患者在出现时需要ICU护理和机械通气。

Funding 资金

None, Internal Support Henry Ford Health System 

无,内部支持 亨利·福特卫生系统

Conflict of Interest 利益冲突

S.H. received speakers’ bureau honoraria from Bayer. I.B. received speakers’ bureau honoraria from Gilead, ViiV, and Jansssen, M.Z received consultation honoraria from contrafact. All others have no conflicts of interests. 

S.H.接受拜耳公司提供的演讲者酬金。I.B.接受了Gilead、ViiV和Jansssen的演讲者酬金,M.Z.接受了contrafact的咨询酬金。所有其他人没有利益冲突。

Ethical Approval 道德认可

Approval for this study was granted by the Henry Ford Hospital Institutional Review Board (#13897). 

这项研究得到了亨利·福特医院机构审查委员会的批准(# 13897)。

Declaration of interests 利益申报

S.H. received speakers’ bureau honoraria from Bayer. I.B. received speakers’ bureau honoraria from Gilead, ViiV, and Jansssen, M.Z received consultation honoraria from contrafact. All others have no conflicts of interests. 

S.H.接受拜耳公司提供的演讲者酬金。I.B.接受了Gilead、ViiV和Jansssen的演讲者酬金,M.Z.接受了contrafact的咨询酬金。所有其他人没有利益冲突。

Uncited References 引用

(NIH clinical, 2020 国家卫生研究院临床,2020年).

Acknowledgements 鸣谢

David Allard, MD; Robert C Brooks; Erika Hadley; Gil Armon for assistance with data from the electronic medical record 

戴维 · 阿拉德,医学博士; 罗伯特 · C · 布鲁克斯; 艾丽卡 · 哈德利; 吉尔 · 艾蒙协助处理电子医疗记录中的数据

Appendix A.

附录 A

Henry Ford COVID-19 Task Force: 

亨利-福特COVID-19工作组

Varidhi Nauriyal1,2, Asif Abdul Hamed2, Owais Nadeem2, Jennifer Swiderek2, Amanda Godfrey2, Jeffrey Jennings2, Jayna Gardner-Gray3, Adam M Ackerman4, Jonathan Lezotte4, Joseph Ruhala4, Raef Fadel5, Amit Vahia11, Smitha Gudipati1, Tommy Parraga1, Anita Shallal1, Gina Maki1, Zain Tariq1, Geehan Suleyman1, Nicholas Yared1, Erica Herc1, Johnathan Williams1, Odaliz Abreu Lanfranco1, Pallavi Bhargava1, Katherine Reyes1, Anne Chen1

1Infectious Diseases, Henry Ford Hospital, Detroit, MI.

2Pulmonary Medicine, Henry Ford Hospital, Detroit, MI.

3Emergency Medicine, Henry Ford Hospital, Detroit, MI.

4Surgical Critical Care, Henry Ford Hospital, Detroit, MI.

5Internal Medicine, Henry Ford Hospital, Detroit, MI.

References 参考文献(见原文)

Article Info 文章信息

Publication History 出版历史

Accepted: June 29, 2020  接受: 2020年6月29日

Received in revised form: June 22, 2020  收到修订版: 2020年6月22日

Received: May 28, 2020  收到: 2020年5月28日

Publication stage 出版阶段

In Press Journal Pre-Proof 新闻期刊中的预校对

Identification 识别

DOI: https://doi.org/10.1016/j.ijid.2020.06.099

Copyright 版权所有

© 2020 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. 

© 2020 作者。由Elsevier Ltd代表国际传染病协会出版。

User License 用户许可证

Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) | 

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ScienceDirect

Access this article on ScienceDirect 

访问这篇文章在 ScienceDirect

Tables

表1. 各治疗组的患者特征

特征总和(n=2541)无药物 (n=409)只用羟氯喹(n=1202)只用阿奇霉素(n=147)羟氯喹+阿奇霉素 (n=783)P
死亡率, n (%)460 (18.1)108 (26.4)162 (13.5)33 (22.4)157 (20.1)<0.001 ***
Hospital LOS in Days,8.3 ± 6.5,5.6 ± 4.8,8.0 ± 5.8,5.3 ± 4.5,10.7 ± 7.5,<0.001 ***
平均值 ± SD, 中位数 (IQR)6 (4 – 10)(4 (3 – 7)6 (4 – 10)4 (2 – 6)8 (5 – 14)
年龄(岁)63.7 ± 16.5,68.1 ± 18.9,63.2 ± 15.6,63.3 ± 17.3,62.3 ± 15.9,<0.001 ***
平均值 ± SD, 中位数 (IQR)64 (53 – 76)71 (56 – 83)53 (64 – 74)64 (52 – 76)62 (51 – 74)
Age,< 65 岁1278 (50.3)158 (38.6)614 (51.1)79 (53.7)427 (54.5%)<0.001 ***
n (%)> 65 岁1263 (49.7)251 (64.1)588 (48.9)68 (46.3)356 (45.5%)
性别,1298 (51.1)199 (48.7)634 (52.8)62 (42.2)403 (51.5%)0.072
n (%)1243 (48.9)210 (51.3)568 (47.2)85 (57.8)380 (48.5%)
种族,1411 (55.5)187 (45.7)724 (60.2)76 (51.7)424 (54.2%)<0.001 ***
n (%)852 (33.5)186 (45.5)332 (27.6)63 (42.9)271 (34.6%)
 亚洲/太平洋岛民47 (1.8)6 (1.5)24 (2.0)0 (0.0)17 (2.2%)
 Other231 (9.1)30 (7.3)122 (10.1)8 (5.4)71 (9.1%)
体重指数,31.7 ± 8.5,28.8 ± 7.6,31.9 ± 8.6,31.4 ± 8.7,32.9 ± 8.4,<0.001 ***
平均值 ± SD, 中位数 (IQR)30 (26 – 36)28 (23 – 33)30 (26 – 36)29 (25 – 36)32 (27 – 37)
体重指数,<18.548 (2.0)22 (5.7)15 (1.4)3 (2.1)8 (1.1%)<0.001 ***
n (%)18.5-24.9430 (18.0)108 (28.2)198 (17.9)25 (17.5)99 (13.1%)
 25.0-29.9662 (27.7)104 (27.2)314 (28.4)49 (34.3)195 (25.8%)
 >30.01250 (52.3)149 (38.9)580 (52.466 (46.2)455 (60.1%)
慢性肺病, n (%)1619 (63.7)195 (47.7)806 (67.1)93 (63.3)525 (67.0)<0.001 ***
免疫缺陷, n (%)30 (1.2)2 (0.5)15 (1.2)2 (1.4)11 (1.4)0.502
心血管疾病, n (%)222 (8.7)45 (11.0)100 (8.3)10 (6.8)67 (8.6)0.306
慢性肾炎, n (%)1099 (43.3)196 (47.9)528 (43.9)62 (42.2)313 (40.0)0.062
慢性阻塞性肺炎, n (%)325 (12.8)58 (14.2)144 (12.0)24 (16.3)99 (12.6)0.38
高血压, n (%)1663 (65.4)256 (62.6)807 (67.1)93 (63.3)507 (64.8)0.324
哮喘, n (%)251 (9.9)28 (6.8)130 (10.8)19 (12.9)74 (9.5)0.069
癌症, n (%)380 (15.0)78 (19.1)165 (13.7)17 (11.6)120 (15.3)0.041 *
糖尿病, n (%)955 (37.6)130 (31.8)484 (40.3)45 (30.6)296 (37.8)0.006 **
记录最大的mSOFA数3.7 ± 3.0,4.0 ± 3.6,3.2 ± 2.7,5.0 ± 3.9,4.2 ± 3.1,<0.001 ***
平均值±SD,中位数(IQR)3 (1 – 5)3 (1 – 6)3 (1 – 5)4 (2 – 6)4 (2 – 6)
mSOFA评分<1497 (26.4)92 (31.5)295 (28.5)12 (19.7)98 (20.0%)<0.001 ***
分数,2 – 4799 (42.5)95 (32.5)481 (46.4)19 (31.1)204 (41.5%)
n (%)>5584 (31.1)105 (36.0)260 (25.1)30 (49.2)189 (38.5%)
记录最大氧饱合数,90.0 ± 8.1,89.8 ± 10.9,90.5 ± 6.7,90.7 ± 8.7,89.2 ± 8.1,<0.001 ***
平均值 ± SD, 中位数 (IQR)(92 (89 – 94)93 (89 – 95)92 (89 – 94)92 (90 – 94)91 (88 – 93)
O2 饱和度,正常( >95%)504 (19.8)126 (30.8)233 (19.4)34 (23.1)111 (14.2%)<0.001 ***
n (%)轻度低氧血症(90-94%)1275 (50.2)180 (44.0)619 (51.5)84 (57.1)392 (50.1%)
 中度低氧血症(86-89%)408 (16.1)38 (9.3)202 (16.8)13 (8.8)155 (19.8%)
 严重低氧血症( <85%)354 (13.9)65 (15.9)148 (12.3)16 (10.9)125 (16.0%)
曾在ICU, n (%)614 (24.2%)62 (15.2)243 (20.2)19 (12.9)290 (37.0)<0.001 ***
共在 ICU 天数,2.3 ± 5.3,0.8 ± 2.9,1.9 ± 4.7,0.7 ± 2.3,4.0 ± 6.9,<0.001 ***
平均值 ± SD, 中位数 (IQR)0 (0 – 0)0 (0 – 0)0 (0 – 0)0 (0 – 0)0 (0 – 0)
曾使用机械呼吸, n (%)448 (17.6%)34 (8.3)166 (13.8)14 (9.5)234 (29.9)<0.001 ***
Total Vent Days,1.6 ± 4.5,0.5 ± 2.2,1.2 ± 3.7,0.5 ± 2.0,3.1 ± 6.1,<0.001 ***
平均值 ± SD, 中位数 (IQR)0 (0 – 0)0 (0 – 0)0 (0 – 0)0 (0 – 0)0 (0 – 0)
给定类固醇, n (%)1733 (68.2)146 (35.7)948 (78.9)57 (38.8)582 (74.3)<0.001 ***
给予托西力-珠单抗 n (%)114 (4.5)5 (1.2)32 (2.7)5 (3.4)72 (9.2)<0.001 ***

表2. 死亡率预测的多变量Cox回归模型

参数P风险比95%风险比可信限值
单独使用羟氯喹(与两种药物治疗相比)<0.001 ***0.340.2540.455
单独使用阿奇霉素(与两种药物都不使用)0.8251.050.6821.616
羟氯喹 + 阿奇霉素(vs. 两种药物都不使用)<0.001 ***0.2940.2180.396
年龄 > 65 Years<0.001 ***2.5791.9893.345
M 性别0.1551.1570.9461.414
白种人<0.001 ***1.7381.4132.137
体重指数> 300.021 *0.7750.6240.962
肺部合并症0.3930.9080.7271.134
免疫缺陷并发症0.4291.3980.6093.206
心血管并发症0.6781.0620.81.41
慢性肾脏病合并症<0.001 ***1.6991.372.108
慢性阻塞性肺病并发症0.171.2020.9241.563
高血压合并症0.0640.7980.6281.014
哮喘并发症0.6430.9160.6321.327
癌症合并症0.5770.9330.7311.19
糖尿病合并症0.8220.9750.7861.211
氧气饱和度百分比<950.021 *1.4881.0632.084
送入重症监护室0.8820.9690.6351.478
呼吸机<0.001 ***2.1591.4273.268
给予类固醇0.0850.8020.6251.031
给予托西鲁单抗0.490.8940.6511.228
* P-值在 0.01 0.05之间



** P-值在0.001 0.01之间



*** P-值小于 0.001




表3. 倾向性得分匹配前后给予与未给予羟氯喹患者的特征

特征
未匹配的患者
给予 羟氯喹 (N= 1985)未 给予 羟氯喹 (N = 556)给予 羟氯喹 (N = 190)未 给予 羟氯喹 (N = 190)
年龄> 65 岁944 (47.6%)319 (57.4%)96 (50.5%)96 (50.5%)
男性1037 (52.2%)261 (46.9%)88 (46.3%)88 (46.3%)
白种人603 (30.4%)249 (44.8%)67 (35.3%)67 (35.3%)
体重指数> 301035 (55.5%)215 (40.9%)87 (45.8%)87 (45.8%)
肺部合并症1331 (67.1%)288 (51.8%)103 (54.2%)103 (54.2%)
免疫缺陷并发症26 (1.3%)4 (0.7%)1 (0.5%)1 (0.5%)
心血管并发症167 (8.4%)55 (9.9%)7 (3.7%)7 (3.7%)
慢性肾脏病合并症841 (42.4%)258 (46.4%)69 (36.3%)69 (36.3%)
慢性阻塞性肺病并发症243 (12.2%)82 (14.7%)10 (5.3%)10 (5.3%)
高血压合并症1314 (66.2%)349 (62.8%)118 (62.1%)118 (62.1%)
哮喘并发症204 (10.3%)47 (8.5%)6 (3.2%)6 (3.2%)
癌症合并症285 (14.4%)95 (17.1%)8 (4.2%)8 (4.2%)
糖尿病合并症780 (39.3%)175 (31.5%)51 (26.8%)51 (26.8%)
氧气饱和度百分比<951641 (82.7%)396 (71.2%)141 (74.2%)141 (74.2%)
送入重症监护室533 (26.9%)81 (14.6%)12 (6.3%)12 (6.3%)
呼吸机400 (20.2%)48 (8.6%)10 (5.3%)10 (5.3%)
给予 类固醇1530 (77.1%)203 (36.5%)84 (44.2%)84 (44.2%)
给予 托西珠单抗104 (5.2%)10 (1.8%)2 (1.1%)2 (1.1%) 

表4. 死亡率预测的倾向性匹配Cox回归结果

参数P危险率95%风险比置信度
给予羟氯喹0.009 **0.4870.2850.832
** P0.001 0.01之间



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