國際傳染病學雜誌發表《羥氯喹、阿奇黴素和聯合用藥治療新型冠狀病毒肺炎住院患者》

這篇7月1日發表在國際傳染病學雜誌上的文章表明,單獨使用羥氯喹和聯合阿奇黴素治療可以降低一半CCP病毒肺炎的死亡率。這項由亨利福特醫療系統發表的大型多醫院聯合研究和此前其他團隊發表文章的主要區別在於藥物劑量、用藥時機和基礎疾病的篩查不同。此研究使用的藥物計量為:羥氯喹用量第一天每天兩次,每次400毫克; 第二天每天兩次,每次200毫克; 第三天每天兩次,每次200毫克; 第三天每天兩次,每次200毫克; 第三天每天兩次,每次200毫克。阿奇黴素的劑量為500毫克每日一次,第1天隨後250毫克每日一次,連續4天。

翻譯:【Naomi】校對:【Michelle】

戰友之間玫瑰園小隊出品

圖片來源:https://isid.org

原文連結

中英文對照全文:

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

羥氯喹、阿奇黴素和聯合用藥治療新型冠狀病毒肺炎住院患者

Published: July 01, 2020

發表時間: 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 精彩內容

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,在美國有超過1,678,843例確診的新型冠狀病毒肺炎感染病例,奪走了超過10萬人的生命。目前還沒有已知有效的治療方法或疫苗。

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. 

根據一個基於協定的治療演算法,在住院患者中,單獨使用羥氯喹和與阿奇黴素聯合使用,與不使用羥氯喹相比,能顯著降低住院死亡率。

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

本觀察性研究的發現為羥氯喹治療的經驗提供了重要的資料,為新型冠狀病毒肺炎治療實踐提供了必要的臨時指導。

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. 

美國正處於新型冠狀病毒肺炎流感大流行的加速階段。目前還沒有已知的治療 SARS-CoV-2的有效療法或疫苗,這突出表明急需確定有效的治療方法。

Objective 目標

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. 

本研究的目的是評估羥氯喹單獨和聯合阿奇黴素治療住院新型冠狀病毒肺炎陽性患者的作用

Design 設計

Multi-center retrospective observational study 多中心回顧觀察性研究

Setting 環境

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. 

位於密西根州東南部的亨利 · 福特醫療系統: 六家大型醫院的綜合醫療系統; 最大的醫院是位於密西根州底特律市的一家擁有802張病床的第四級學術教學醫院。

Participants 參加者

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. 

從2020年3月10日到2020年5月2日,與COVID相關的按次序入院的病人被納入此研究。對於多次入院的患者,只採用第一次入院資料。所有接受評估的患者年齡在18歲或18歲以上,而且已經接受了至少48小時的住院治療,除非在24小時內已死亡。

Exposure 接受的治療方式

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

單獨使用羥氯喹、羥氯喹聯合阿奇黴素、單獨使用阿奇黴素或兩者都不用

Main Outcome 主要成果

The primary outcome was in-hospital mortality 

住院死亡率

Results 結果

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名患者當中,中位總住院時間為6天(四分位間距 [IQR]:4-10天),中位年齡為64歲(IQR:53-76歲),51%為男性,56%為非裔美國人,中位隨訪時間為28.5天(IQR:3-53)。院內總死亡率為18.1%(95% 置信區間 [CI]:16.6%-19.7%);不同治療方式的死亡率:羥氯喹+阿奇黴素,157/783(20.1% [95% CI:17.3%-23.0%]),單用羥氯喹,162/1202(13.5% [95% CI:11.6%-15.5%]),單用阿奇黴素,33/147(22.4% [95%CI:16.0%-30.1%]),兩種藥物均不使用,108/409(26.4% [95%CI:22.2%-31.0%])。死亡的主要原因是呼吸衰竭(88%);沒有患者有記錄在案的心肌梗死。從Cox回歸模型來看,能預測死亡率的預測因素包括年齡>65歲(風險比:2.6 [95% CI:1.9-3.3])、白人種族(風險比:1.7 [95% CI:1.4-2.1])、慢性腎病CKD(風險比:1. 7 [95% CI:1.4-2.1])、入院時血氧飽和度降低(風險比:1.5 [95% CI:1.1-2.1])、入院時使用呼吸機(風險比:2.2 [95% CI:1.4-3.3])。與兩種治療相比,羥氯喹降低了66%的風險比,羥氯喹+阿奇黴素降低了71%的風險比(p值<0.001)。

Conclusions and Relevance 結論和相關性

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. 

在這個多醫院的評估中,當控制新型冠狀病毒肺炎的危險因素時,單獨使用羥氯喹和聯合阿奇黴素治療可以降低新型冠狀病毒肺炎相關的死亡率。需要進行前瞻性試驗來研究這種影響。

Keywords 關鍵字

hydroxychloroquine 羥氯喹

mortality 死亡率

COVID-19 

SARS-COV-2

coronavirus 冠狀病毒

therapy 治療

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,美國有超過1,678,843例COVID-19確診病例,奪去了超過10萬人的生命。(美國病例,2020年)目前還沒有已知的有效療法或疫苗。對治療劑的迫切需求導致了實驗劑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).

羥氯喹是一種抗瘧藥和免疫調節劑,也是氯喹的一種較安全的類似物,已顯示出對SARS-CoV-2的抗病毒活性(Wang等,2020a;Liu等,2020;Yao等,2020,《抗瘧藥的心臟毒性—WHO,2017》)。據推測,它通過增加細胞內pH值導致吞噬體-溶酶體融合減少,損害病毒受體糖基化,直接發揮抗病毒活性。此外,它還具有免疫調節作用,通過抑制toll樣受體信號傳導,減少細胞因數的產生,尤其是 IL-1 和 IL-6(Savarino等,2003)。之前的資料也表明其具有潛在的抗血栓作用(Jung等,2010)。阿奇黴素是一種大環內酯類抗生素,具有體外抗病毒特性,如減少病毒複製,阻斷進入宿主細胞,以及潛在的免疫調節作用(Tran等,2019) 。一項體外研究表明,羥氯喹和阿奇黴素聯合使用對SARS-CoV-2具有協同活性(Andreani等,2020) 。來自法國的一項小型非隨機、開放標籤試驗報導,單用羥氯喹或羥氯喹聯合阿奇黴素治療6天后,SARS-CoV-2清除頻率高於未治療的對照組(70%比12.5%;p值<0.001)(Gautret等,2020a)。羥氯喹的其它早期研究報告了相互矛盾的結果(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)。美國FDA截至2020年6月15日已經撤銷了之前的緊急使用授權(EUA),當無法獲得臨床試驗資料或無法參與臨床試驗時,可以使用羥氯喹和氯喹治療某些住院患者的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,羥氯喹治療和化學預防的隨機試驗正在進行(抗病毒治療,2020,COVID-19相關結果,2020,COVID-19在Hospi-talized成人中的治療試驗,2020,Pagliano等,2020)。這些早期報導,羥氯喹單藥和與阿奇黴素聯合使用被納入我院臨床指南,用於治療住院COVID-19患者。我們在一個大型的住院COVID-19患者佇列中研究了羥氯喹的使用與死亡率之間的關係。

Methods 方法

SETTING 環境設置

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). 

這是一項比較回顧性佇列研究,評估所有在密西根州東南部的亨利福特醫療系統住院接受新型冠狀病毒肺炎治療的患者的臨床結果。本組織是一個大型的六家醫院綜合衛生系統; 最大的醫院是密西根州底特律市一家擁有802張床位的第四級學術教學醫院。亨利·福特醫院的 IRB 批准了這項研究(# 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. 

研究物件包括2020年3月10日至2020年5月2日在衛生系統接受 COVID相關治療的患者。對於多次入院的患者,只採用第一次入院資料。所有的病人都通過我們的急診室住院了。COVID相關入院被定義為住院期間有一次陽性 SARS-CoV-2檢驗的患者。經逆轉錄聚合酶鏈反應(RT-PCR)檢測,確診為 SARS-CoV-2。所有接受評估的患者年齡均在18歲或18歲以上,而且已經接受了至少48小時的住院治療,除非在24小時內已死亡。主要目的是評估羥氯喹與羥氯喹 + 阿奇黴素、阿奇黴素單獨使用以及其他治療新型冠狀病毒肺炎的療效。治療是由協議驅動的,在所有醫院都是用統一的協議,並且由一個全系統跨學科的新型冠狀病毒肺炎工作組建立。羥氯喹用量第一天每天兩次,每次400毫克; 第二天每天兩次,每次200毫克; 第三天每天兩次,每次200毫克; 第三天每天兩次,每次200毫克; 第三天每天兩次,每次200毫克。阿奇黴素的劑量為500毫克每日一次,第1天隨後250毫克每日一次,連續4天。聯合使用羥氯喹 + 阿奇黴素治療某些有嚴重新型冠狀病毒肺炎並且心臟危險因素很小的患者。一個基於心電圖(ECK)的演算法被用於羥氯喹。大於500ms 被認為是心臟風險增加的,因此,對於有遙測監測和連續 QTc 檢查的嚴重疾病患者保留羥氯喹。臨床指南包括皮質類固醇和西利珠單抗輔助免疫調節治療

DATA SOURCES 資料來源

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.

分析患者資訊的資料來源來自於電子資訊系統中的電子病歷。對每位元患者收集的研究變數包括以下內容;1)患者人口學資料:年齡、性別、種族、入院時體重指數(BMI),分層為四類:<18.5;18.5-24.9;25.0-29.9 和 ≥30;2)臨床特徵:入院日期、出院日期、住院時間(LOS)、合併症,包括:心血管疾病(CVD)、慢性肺部疾病、慢性腎臟疾病(CKD)、高血壓、哮喘、慢性阻塞性肺部疾病(COPD)、糖尿病、免疫缺陷和癌症(定義為活動或過去/已解決)。此外,還收集了重症監護室(ICU)狀態和入院期間任何時候的呼吸機使用情況、急診科入院當天收集的最低O2飽和度,以及入院時的最大改良序列器官衰竭評估(mSOFA)評分。mSOFA評分利用與完整的SOFA評分相似的準確性來預測ICU死亡率,而不需要大量的實驗室檢查(ABG、LFTs)來完成(Grissom等,2010)。還收集了COVID-19的所有療法的持續時間和劑量。

STATISTICAL ANALYSIS 統計分析

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.

對所有患者的人口統計學和臨床特徵進行描述性總結,並按治療組進行子集,以檢驗羥氯喹、羥氯喹+阿奇黴素、阿奇黴素和其他(不使用羥氯喹或阿奇黴素)之間治療過程相似的零假設。多變數Cox回歸模型和Kaplan-Meier生存曲線用於比較治療組之間的生存率,同時控制人口統計學變數(如年齡、性別)、已有的醫療條件(如CVD、肺部疾病)和臨床疾病嚴重程度(mSOFA、O2飽和度)。4個藥物組的雙變數比較採用方差分析或Kruskal-Wallis檢驗對連續變數進行檢驗,對分類變數採用chi-square檢驗或Fisher精確檢驗。使用傾向性得分匹配進行額外分析,以比較各治療組的死亡率結果。根據Cox回歸模型中使用的一組患者特徵,為每個患者創建了一個傾向性得分。隨後,根據確切的傾向性得分,觀察給予羥氯喹(單獨使用羥氯喹或與阿奇黴素聯合使用)的患者和未給予羥氯喹的患者的1對1匹配。將得出的匹配組狀態放入自身的Cox回歸模型中作為死亡率預測因數,用Kaplan-Meier圖總結兩組匹配組的生存曲線。P值<0.05被認為有統計學意義。此外,計算了各治療層的中位生存時間以近似預後。對缺失的資料沒有進行推算。所有資料均使用SPSS軟體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 結果

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. 

第一例通過 RT-PCR 在 HFHS 確診的新型冠狀病毒肺炎病例是在2020年3月10日,任何在3月10日之前入院並隨後檢測呈陽性的病人也包括在分析中。本新型冠狀病毒肺炎共有2948名病人入院,其中267名(9%)病人沒有出院,15名(0.5%)病人沒有遵從醫生的建議離開,4名(0.1%)病人被轉往其他醫療機構,由於我們無法確定他們的結果,這些病人被排除在分析之外。此外,還有121人(4.1%)再次入院,這也被排除在外

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.

總體而言,分析中納入了2541名連續患者,中位年齡64歲(IQR:53-76歲),51%為男性,56%為非裔美國人,中位住院LOS為6天(IQR:4-10天)。中位隨訪時間為28.5天(IQR 3-53)。大多數患者(52%,n = 1,250)的體重指數≥30。其他潛在的合併症詳見表1。入院當天,記錄了預測疾病嚴重程度和死亡率的兩個變數:最高mSOFA評分和最低O2飽和度。然而,25%的人群沒有mSOFA評分,因為在指標入院一個月後,記錄這一指標成為機構標準。其他嚴重性指標是ICU入院和機械通氣狀態。所有基線特徵按四個治療組(單獨使用羥氯喹、羥氯喹+阿奇黴素、單獨使用阿奇黴素和兩種治療)進一步分層。從入院到接受羥氯喹治療的中位時間(IQR)為1天(1-2)。整個佇列的總粗死亡率為18.1%,單用羥氯喹組為13.5%,接受羥氯喹+阿奇黴素治療者為20.1%,單用阿奇黴素組為22.4%,兩種藥物均為26.4%(P<0.001)。分別有68%和4.5%的患者接受皮質類固醇(甲基強的松龍和/或強的松)和抗IL-6托西單抗的輔助治療。

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% 的心臟驟停(從上次心電圖顯示的平均 QTc 間隔為471ms),8% 的其他心臟驟停和多器官衰竭。沒有病人有尖端扭轉型室性心動過速的記錄

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.

在死亡率的多變數 Cox 回歸模型中,以既沒有接受羥氯喹也沒有接受阿奇黴素作為參考,單獨使用羥氯喹治療可以降低66% 的死亡風險比率(p < 0.001),羥氯喹 + 阿奇黴素可以降低71% 的死亡風險比率(p < 0.001)。我們沒有發現輔助治療的相對效果和死亡率的統計學意義。年齡≥65歲(風險比,2.6 [95% CI: 1.9,3.3]),白種人(風險比: 1.7 [95% CI: 1.4,2.1]),CKD(風險比,1.7 [95% CI: 1.4,2.1]),入院時 O2飽和度降低(風險比,1.6 [95% CI: 1.1,2.2]),入院時使用呼吸機(風險比,2.2 [95% CI: 1.4,3.0]),這些都與新型冠狀病毒肺炎死亡有顯著關係(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生存曲線顯示,與未接受羥氯喹的組和單獨接受阿奇黴素的組相比,單獨羥氯喹組和羥氯喹+阿奇黴素組患者的生存率顯著提高(圖1)。生存曲線表明,單用羥氯喹組的生存率提高一直持續到入院後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名羥氯喹患者與190名相應的非羥氯喹治療患者根據確切的基礎傾向性評分完全匹配。表3包含了這些患者在未匹配和傾向匹配設置內的描述性總結,證實傾向匹配組具有相同的基本患者特徵。兩個傾向性匹配組的Cox回歸結果(表4)表明,使用羥氯喹治療可使死亡率風險比降低51%(p值= 0.009)。結果在傾向匹配環境內的Kaplan-Meier生存曲線顯示羥氯喹治療組的生存率顯著提高,提高的生存率一直持續到入院後28天(圖2)。

Discussion 討論

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)

該研究結果表明,在嚴格監測的協議驅動的院內環境中,單用羥氯喹和羥氯喹+阿奇黴素治療與COVID-19住院患者的死亡率顯著降低相關。在這項研究中,在一個最大的COVID-19醫院患者佇列(n = 2,541)中,集合在一個機構中,總體院內COVID-19相關死亡率為18.1%,反映了本機構收治的COVID-19患者中共病率高。在我們的研究中,死亡率的獨立預測因素包括年齡≥65歲,肺結核病人,以及通過入院時的氧飽和度水準測量的初始表現時的嚴重疾病,以及呼吸機的使用反映了類似於早期研究中報導的結果 (Rio和Malani,2020年)。這些預測因素也強調了密西根州底特律大都會的居民在我們的醫院集聚人群中經歷的COVID-19的高風險。密西根州是COVID-19病例和死亡人數最多的州之一。在底特律,我們的居民面臨著巨大的社會和種族健康差異,這使得我們的患者面臨更多的嚴重疾病風險和更高的死亡率(美國的病例,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回歸模型和傾向性評分匹配控制潛在混雜因素進行的多變數分析肯定了單用羥氯喹和羥氯喹聯合阿奇黴素治療與COVID-19患者的較高生存率相關。既不接受藥物治療也不單獨接受阿奇黴素治療的患者累積危險度最高。與以前的研究相比,羥氯喹在我們的佇列中的益處也許與它在病程早期使用標準化、和安全劑量、納入標準、合併症或更大的佇列有關。COVID-19的初始病毒感染階段後的超免疫反應的推測病理生理學表明,早期使用羥氯喹的抗病毒和抗血栓形成特性的潛在益處。對於已經出現高免疫反應或危重病的患者,後期治療的獲益可能性較小。另有研究表明,COVID-19住院患者在社區中沒有被診斷出來,當住院時往往迅速惡化,出現潰爛性疾病(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. 

我們分析的局限性包括回顧性、非隨機、非盲的研究設計。此外,住院前的症狀持續時間資訊也無法用於分析。然而,我們的研究值得注意的是,使用了來自多醫院機構的連續患者佇列,定期更新和標準化的機構臨床治療指南和基於QTc區間的演算法,專門設計以確保羥氯喹的安全使用。為了減輕與電子醫療記錄中缺失或不準確的記錄相關的潛在限制,我們人工審查了所有死亡病例,以確認主要死亡結果並確定死因。對我們的COVID-19死亡率資料的審查表明,沒有主要的心律失常;特別是,沒有觀察到羥氯喹治療的心肌梗死。這一發現可能有兩種解釋。首先,我們的患者群體接受了積極的早期醫療干預,不太容易出現心肌炎,以及COVID-19疾病後期常見的心臟炎症。其次,重要的是,住院病人的遙測與建立的電解質協議被嚴格應用于我們的人群,心律失常的監測有效地控制了不良事件。其它的優勢是納入了多種族的患者組成,用PCR確認所有患者的感染,並通過傾向性匹配控制各種混雜因素,包括患者特徵,如疾病的嚴重程度。

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.

最近對羥氯喹的觀察性回顧性研究和隨機試驗報導了不同的結果(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)。在一項對62名來自中國的COVID-19患者的隨機對照研究中,羥氯喹與發熱持續時間和咳嗽及肺炎緩解時間縮短有關(Chen等,2020)。相比之下,一項對紐約1376名連續住院的COVID-19患者進行的以呼吸衰竭為主要終點的研究發現,與沒有接受羥氯喹的患者相比,接受羥氯喹的患者死亡或插管的可能性沒有顯著降低(Geleris等,2020)。在一項單獨的多中心佇列研究中,對來自紐約25家醫院的1438名患者進行了研究,觀察到羥氯喹治療沒有降低住院患者的死亡率(Rosenberg等,2020)。在一些限制因素中,這項研究包括了在住院期間任何時候開始接受羥氯喹治療的患者。相反,在我們的患者群體中,82%的患者在入院後的前24小時內接受了羥氯喹治療,91%的患者在入院後48小時內接受了羥氯喹治療。由於為研究提供患者的25家醫院的治療方案可能有很大差異(包括起始延遲),因此紐約患者的病例死亡率明顯高於我們的研究也就不足為奇了。

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.

全球範圍內,SARS-COV-2的總體死亡率粗估計約為6-7%(美國的病例,2020,WHO,2020)。多項描述性研究報導,住院的COVID-19患者死亡率較高,從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) 不足為奇的是,在需要ICU護理和機械通氣的患者中觀察到了高達 58% 的死亡率(W-jie等,2020;Richardson等,2020)。在許多人群中,COVID-19相關的這種高死亡率導致了對有效藥物療法的尋找。在COVID-19住院患者中進行的洛匹那韋-利托那韋的隨機對照試驗顯示,洛匹那韋-利托那韋的死亡率為19.2%,標準護理的死亡率為25%;13.8%的患者因不良事件不得不終止治療(Arentz等,2020)。在同情性使用雷米西韋試驗中,61名患者的佇列中觀察到13%的死亡率(一個洛匹那韋-利托那韋在Covid-19中的應用試驗,2020)。雷米替西韋的中期分析隨機試驗顯示,接受雷米替西韋組的死亡率為8.0%,而安慰劑組為11.6%(p值=0.059) Grein等,2020)在我們的研究中,總體死亡率為18.1%,ICU患者的死亡率為45%。我們的佇列包括嚴重疾病的患者,分別有24%和18%的患者在出現時需要ICU護理和機械通氣。

Funding 資金

None, Internal Support Henry Ford Health System 

無,內部支援 亨利·福特衛生系統

Conflict of Interest 利益衝突

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講者酬金。I.B.接受了Gilead、ViiV和Jansssen的演講者酬金,M.Z.接受了contrafact的諮詢酬金。所有其他人沒有利益衝突。

Ethical Approval 道德認可

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

這項研究得到了亨利·福特醫院機構審查委員會的批准(# 13897)。

Declaration of interests 利益申報

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講者酬金。I.B.接受了Gilead、ViiV和Jansssen的演講者酬金,M.Z.接受了contrafact的諮詢酬金。所有其他人沒有利益衝突。

Uncited References 引用

(NIH clinical, 2020 國家衛生研究院臨床,2020年).

Acknowledgements 鳴謝

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

大衛 · 阿拉德,醫學博士; 羅伯特 · C · 布魯克斯; 艾麗卡 · 哈德利; 吉爾 · 艾蒙協助處理電子醫療記錄中的資料

Appendix A.

附錄 A

Henry Ford COVID-19 Task Force: 

亨利-福特COVID-19工作組

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 參考文獻(見原文)

Article Info 文章資訊

Publication History 出版歷史

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

Received in revised form: June 22, 2020  收到修訂版: 2020年6月22日

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

Publication stage 出版階段

In Press Journal Pre-Proof 新聞期刊中的預校對

Identification 識別

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

Copyright 版權所有

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

© 2020 作者。由Elsevier Ltd代表國際傳染病協會出版。

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ScienceDirect

Access this article on ScienceDirect 

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Tables

表1. 各治療組的患者特徵

特徵總和(n=2541)無藥物 (n=409)只用羥氯喹(n=1202)只用阿奇黴素(n=147)羥氯喹+阿奇黴素 (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, 中位數 (IQR)6 (4 – 10)(4 (3 – 7)6 (4 – 10)4 (2 – 6)8 (5 – 14)
年齡(歲)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, 中位數 (IQR)64 (53 – 76)71 (56 – 83)53 (64 – 74)64 (52 – 76)62 (51 – 74)
Age,< 65 歲1278 (50.3)158 (38.6)614 (51.1)79 (53.7)427 (54.5%)<0.001 ***
n (%)> 65 歲1263 (49.7)251 (64.1)588 (48.9)68 (46.3)356 (45.5%)
性別,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%)
種族,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%)
 亞洲/太平洋島民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%)
體重指數,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, 中位數 (IQR)30 (26 – 36)28 (23 – 33)30 (26 – 36)29 (25 – 36)32 (27 – 37)
體重指數,<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
慢性腎炎, 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
高血壓, 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 **
記錄最大的mSOFA數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,中位數(IQR)3 (1 – 5)3 (1 – 6)3 (1 – 5)4 (2 – 6)4 (2 – 6)
mSOFA評分<1497 (26.4)92 (31.5)295 (28.5)12 (19.7)98 (20.0%)<0.001 ***
分數,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%)
記錄最大氧飽合數,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, 中位數 (IQR)(92 (89 – 94)93 (89 – 95)92 (89 – 94)92 (90 – 94)91 (88 – 93)
O2 飽和度,正常( >95%)504 (19.8)126 (30.8)233 (19.4)34 (23.1)111 (14.2%)<0.001 ***
n (%)輕度低氧血症(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%)
 嚴重低氧血症( <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 天數,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, 中位數 (IQR)0 (0 – 0)0 (0 – 0)0 (0 – 0)0 (0 – 0)0 (0 – 0)
曾使用機械呼吸, 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, 中位數 (IQR)0 (0 – 0)0 (0 – 0)0 (0 – 0)0 (0 – 0)0 (0 – 0)
給定類固醇, n (%)1733 (68.2)146 (35.7)948 (78.9)57 (38.8)582 (74.3)<0.001 ***
給予托西力-珠單抗 n (%)114 (4.5)5 (1.2)32 (2.7)5 (3.4)72 (9.2)<0.001 ***

表2. 死亡率預測的多變數Cox回歸模型

參數P風險比95%風險比可信限值
單獨使用羥氯喹(與兩種藥物治療相比)<0.001 ***0.340.2540.455
單獨使用阿奇黴素(與兩種藥物都不使用)0.8251.050.6821.616
羥氯喹 + 阿奇黴素(vs. 兩種藥物都不使用)<0.001 ***0.2940.2180.396
年齡 > 65 Years<0.001 ***2.5791.9893.345
M 性別0.1551.1570.9461.414
白種人<0.001 ***1.7381.4132.137
體重指數> 300.021 *0.7750.6240.962
肺部合併症0.3930.9080.7271.134
免疫缺陷併發症0.4291.3980.6093.206
心血管併發症0.6781.0620.81.41
慢性腎臟病合併症<0.001 ***1.6991.372.108
慢性阻塞性肺病併發症0.171.2020.9241.563
高血壓合併症0.0640.7980.6281.014
哮喘併發症0.6430.9160.6321.327
癌症合併症0.5770.9330.7311.19
糖尿病合併症0.8220.9750.7861.211
氧氣飽和度百分比<950.021 *1.4881.0632.084
送入重症監護室0.8820.9690.6351.478
呼吸機<0.001 ***2.1591.4273.268
給予類固醇0.0850.8020.6251.031
給予托西魯單抗0.490.8940.6511.228
* P-值在 0.01 0.05之間



** P-值在0.001 0.01之間



*** P-值小於 0.001



表3. 傾向性得分匹配前後給予與未給予羥氯喹患者的特徵

特徵未匹配的患者
給予 羥氯喹 (N= 1985)未 給予 羥氯喹 (N = 556)給予 羥氯喹 (N = 190)未 給予 羥氯喹 (N = 190)
年齡> 65 歲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%)
白種人603 (30.4%)249 (44.8%)67 (35.3%)67 (35.3%)
體重指數> 301035 (55.5%)215 (40.9%)87 (45.8%)87 (45.8%)
肺部合併症1331 (67.1%)288 (51.8%)103 (54.2%)103 (54.2%)
免疫缺陷併發症26 (1.3%)4 (0.7%)1 (0.5%)1 (0.5%)
心血管併發症167 (8.4%)55 (9.9%)7 (3.7%)7 (3.7%)
慢性腎臟病合併症841 (42.4%)258 (46.4%)69 (36.3%)69 (36.3%)
慢性阻塞性肺病併發症243 (12.2%)82 (14.7%)10 (5.3%)10 (5.3%)
高血壓合併症1314 (66.2%)349 (62.8%)118 (62.1%)118 (62.1%)
哮喘併發症204 (10.3%)47 (8.5%)6 (3.2%)6 (3.2%)
癌症合併症285 (14.4%)95 (17.1%)8 (4.2%)8 (4.2%)
糖尿病合併症780 (39.3%)175 (31.5%)51 (26.8%)51 (26.8%)
氧氣飽和度百分比<951641 (82.7%)396 (71.2%)141 (74.2%)141 (74.2%)
送入重症監護室533 (26.9%)81 (14.6%)12 (6.3%)12 (6.3%)
呼吸機400 (20.2%)48 (8.6%)10 (5.3%)10 (5.3%)
給予 類固醇1530 (77.1%)203 (36.5%)84 (44.2%)84 (44.2%)
給予 托西珠單抗104 (5.2%)10 (1.8%)2 (1.1%)2 (1.1%) 

表4. 死亡率預測的傾向性匹配Cox回歸結果

參數P危險率95%風險比置信度
給予羥氯喹0.009 **0.4870.2850.832
** P0.001 0.01之間



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