key: cord-346105-2f6nj4to authors: Yang, T.-H.; Chou, C.-Y.; Yang, Y.-F.; Yang, Y.-P.; Chien, C.-S.; Yarmishyn, A. A.; Yang, T.-Y.; Chiou, S.-H.; Chang, Y.-L. title: Systematic Review and Meta-analysis of the Effectiveness and Safety of Hydroxychloroquine in COVID-19. date: 2020-05-12 journal: nan DOI: 10.1101/2020.05.07.20093831 sha: doc_id: 346105 cord_uid: 2f6nj4to Backgrounds. Since COVID-19 outbreak, various agents have been tested but no proven effective therapies have been identified. This has led to a lot of controversies among associated researches. Hence, in order to address the issue of using hydroxychloroquine in treating COVID-19 patients, we conducted a systematic review and meta-analysis. Methods. A thorough search was carried out to find relevant studies in MEDLINE, medRxiv, PubMed, Cochrane Database, China Academic Journals Full-text Database and Web of Science. Two investigators independently reviewed 274 abstracts and 23 articles. The trials which evaluated hydroxychloroquine for treatment of COVID-19 were included for this systematic review. Two investigators assessed quality of the studies and data extraction was done by one reviewer and cross checked by the other. Results. Five trials involving 677 patients were included while conducting the meta-analysis. Compared with the control group, hydroxychloroquine with or without azithromycin showed benefits in positive-to-negative conversion of SARS-CoV-2 (odds ratio [OR], 1.95 [95% CI,0.19 to 19.73] and a reduction in progression rate (OR, 0.89 [95% CI, 0.58 to 1.37]), but without demonstrating any statistical significance. This systematic review has also suggested a possible synergistic effect of the combination therapy which included hydroxychloroquine and azithromycin. However, the use of hydroxychloroquine alone was associated with increased mortality in COVID-19 patients. Conclusion. The use of hydroxychloroquine with or without azithromycin for treatment of COVID-19 patients, seems to be effective. The combination of hydroxychloroquine and azithromycin has shown synergic effects. However, mortality rate was increased when the treatment was conducted with hydroxychloroquine. In December 2019, the sudden outbreak of newly detected coronavirus (SARS- resulted in spread of coronavirus disease to other countries, leading to a global pandemic. This virus was initially reported in the Hubei province, Wuhan, China [1] . As of April 27, 2020, more than 3 million people have been rapidly affected by COVID-19 worldwide and over two hundred thousand people have died in more than 200 countries due to this deadly disease [2] . As COVID-19 is spreading at a fast pace therefore without wasting time researchers are working tirelessly to find an effective treatment for this disease. However, despite all the efforts there is no proven, effective, pharmacological treatment available currently except following infection control and preventive strategies such as personal protective measures and social distancing,. Various active clinical trials are underway to detect effectiveness of ribavirin, remdesivir, lopinavir/ritonavir and hydroxychloroquine for COVID-19 treatment. The pathogenic mechanisms of SARS-CoV-2 might be related to its impact on immune system since SARS-CoV-2 can infect T cells [3] . Therefore, recently conducted studies have drawn a lot of attention to the possible benefit of hydroxychloroquine, an antimalarial agent with an immunomodulatory activity which has been used at a large-scale for the treatment of rheumatic disease mainly because of its relatively low price and considerable safety. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint 6 Colson et al. has speculated that hydroxychloroquine might be the choice in treating COVID-19 patients [4] . Some in vitro studies have demonstrated that hydroxychloroquine has a potent antiviral activity against SARS-CoV-2 [5, 6] . Based on the outcome seen in some in vitro studies, numerous clinical studies were launched but only few of these which were published, presented relevant results and highlighted the efficacy of different treatment modalities [7] [8] [9] [10] [11] [12] [13] [14] [15] . Additionally, a lot of controversial findings are noticed among the researches. A study conducted by Gautret et al. has supported that hydroxychloroquine is effective in reducing viral load [8] , while there are a few studies which disagree with this [7] . Some research studies have even reported harmful effects of hydroxychloroquine [10, 16] . Moreover, most of the published studies had small sample size [7] [8] [9] 13] or conducted a non-randomized clinical trial (non-RCT), which are major limitations in deriving a sound outcome [8, 10-12, 14, 15] . Many review articles which have discussed the use of hydroxychloroquine in COVID-19 patients showed limitation as they included only few relevant studies, significant Chinese studies were omitted and analysis of treatment effects was not quantified while formulating the results [17] [18] [19] . Recently, two systematic review with meta-analysis were published which had small sample size [20] and there was no clear clarity with regard to the effects of using hydroxychloroquine alone, or when combined with azithromycin, for the treatment of COVID-19 [21] . These systematic review did not include any national trials All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint and also excluded population of non-Hispanic black while conducting their research [20, 21] . On April 24, FDA issued a warning against use of hydroxychloroquine and chloroquine for treating patients with COVID-19 due to its serious adverse effect, such as heart arrhythmias being reported in some patients. Therefore, efficacy and safety of hydroxychloroquine for patient with COVID-19 is still uncertain. In view of severe outbreak of COVID-19 and rapid increase of studies being conducted, it is crucial to systematically evaluate the relevant studies in a rigorous manner. Hence, we conducted a systematic review and meta-analysis to demonstrate the significance of present evidence regarding benefits and safety of hydroxychloroquine use, for the treatment of COVID-19 patients. We systematically searched the MEDLINE, medRxiv, PubMed, China Academic Journals Full-text Database, Cochrane database and Web of Science database up till April 27, 2020, with no language restrictions taken into consideration. In addition, relevant articles were also obtained from the reference list of reports which were identified using All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint this search strategy. The main key words included the following terms, "COVID-19", "SARS-CoV-2" and "hydroxychloroquine". Two reviewers reviewed 251 abstracts and 23 full-text articles independently. Our study included only comparative studies that examined the efficacy or safety of hydroxychloroquine with or without azithromycin in comparison with standard treatment based on factors such as virological cure, degree of progression to severe illness and allcause mortality as identified in COVID-19 patients. Out of all the selected search material, 257 articles were excluded due to their inappropriate study design (review, editorial News and letter). Among these, we also excluded a RCT as the results showed that 8 % (n=6) of the patients assigned to hydroxychloroquine group did not receive any dose of hydroxychloroquine and this might have caused misclassification bias in the study [22] . One reviewer extracted study-level data into standardized working tables, and the other checked data accuracy. Two independent reviewers critically appraised the eligible articles by using the Modified Downs and Black risk assessment scale [23] . This scale consists of 27 items which assesses different study characteristics such as internal validity, All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint statistical power and external validity. Publication bias was also assessed by using a funnel plot. The efficacy outcome of interest in this article was virological clearance and progression of disease. The safety outcome which we planned to investigate through this review, was mortality. We analyzed the main beneficial outcome based on the consistency and availability of results which were reported across various recruited trials such as the level of virological clearance noticed after the treatment, which was defined as a negative result of SARS-COV-2 after detecting it by real-time reverse transcription-PCR. We performed the meta-analysis by using Mantel Hazel method for dichotomous data. In our present study, either fixed-effect model or random effect model was used according to the level of heterogeneity. The odds ratio (OR) was used as the common measure of association across studies. We assessed statistical heterogeneity through the I 2 index. Meta-analysis was undertaken by using Cochrane Collaboration Review Manager (RevMan) software version 5.3. Subgroup analysis was carried out by including the clinical status (symptomatic or All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint asymptomatic) and age so as to assess the impact of these variables on outcome. After selecting the relevant articles we found five eligible comparative trials that focused on the benefits of hydroxychloroquine alone or in combination with azithromycin, for the treatment of COVID-19. There were a total of 677 participants, and each trial included in this research had sample size ranging from 30 to 368 [7] [8] [9] [10] [11] . Supplementary table 1 shows the main characteristics of the eligible studies included in the research. Follow-up duration of included trials ranged from 6 to 7 days. Among the included trials, two trials which were conducted in China studied hydroxychloroquine effect at a dose of 400 mg when given daily for 5 days [7, 9] and other French trial studied hydroxychloroquine outcome at a doses of 600 mg given daily with or without azithromycin (500 mg at day 1 and 250 mg at days 2 to 5) [8] . In addition, another French trial tested hydroxychloroquine effect when given at a dose of 600 mg daily [11] and another trial investigated benefits of hydroxychloroquine, with or without azithromycin but dosage was not mentioned in the research [10] . Among the five trials which were included, four trials mentioned their exclusion criteria as -the patients who had known allergy to hydroxychloroquine or any other known contraindication in terms of usage of the study drugs, such as retinopathy or All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint pregnancy [7] [8] [9] 11 ]. However, one trial was conducted without considering any exclusion criteria [10] and where the average age of participants was reported to be 62.6 years. The risk of bias assessment is reported in supplementary figure 1. The average Downs and Black score was 19, with a range between 18 and 22 (A higher score indicates less bias).Various studies have shown different degree of bias wherein the RCT conducted by Chen et al. has displayed the lowest risk of bias [9] and the open-label non-RCT had shown the highest risk of bias [8] . One Chinese trial was described as randomized, although the method of randomization, allocation concealment and blinding of assessors during outcome evaluation was not mentioned [7] whereas another randomized control trial properly described the method of randomization and double-blinding [9] . With regard to the study design, one French trial was designed as open-label non-randomized trial [8] and two other studies were planned as controlled retrospective studies [10, 11] . A trial reported a loss of follow-up by participants while undergoing treatment hence they were excluded during analysis planning due to their withdrawal from the study [8] . Antiviral clearance was calculated using results obtained from PCR which were All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint documented as SARS-CoV-2 carriage during the follow-up period after treatment was over. For conducting the meta-analysis, we used one-time observation of negative results seen in PCR which were carried forward during analysis. Two studies have reported treatment effects based on antiviral clearance [7, 8] . Only two trials were included for meta-analysis, assessing a total of 66 participants. We found no significant evidence to verify whether hydroxychloroquine with or without azithromycin used for the treatment was effective in reducing viral carriage (OR 1.95 [95% CI 0.19 to 19.73]). There was substantial and statistically significant heterogeneity present while conducting this analysis (I 2 = 62%) (figure 2A). As for the treatment undertaken by using hydroxychloroquine alone, the meta-analysis showed an increment by 1.74 times as compared with control group (95% CI 0.51 to 5.91; I 2 = 35%) while evaluating the viral clearance (figure 2B). One trial compared the effectiveness of combination therapy of hydroxychloroquine and azithromycin with control group and the results indicated that there was a significant reduction in viral load when combination therapy was used (OR 27.18 [95% CI 1.29 to 574.32]) (figure 2C) [8] . Based on intention-to-treat method, we also included 6 patients in the research who did not follow up after the treatment was over during the French trial All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint [8] . The pooled analysis implied a trend that treatment by hydroxychloroquine with or without azithromycin was effective in reducing viral load in Covid-19 patients (OR 1.72 [95% CI 0.26 to 11.50]; I 2 =49%) (figure 2D). A statistically significant reduction of the viral carriage was noticed at D6-post inclusion while performing a French trial [8] . However, another trial conducted in Chinese patients indicated a shift towards favoring the control group in reducing viral load at D7-post inclusion [7] . A Chinese study reported that the use of hydroxychloroquine as compared to the control group where only standard treatment was followed, could shorten clinical recovery time (TTCR) and promote development of pneumonia (CT) [9] . Subgroup analysis was undertaken to explore the impact of different factors relating to the context of the study that may influence the effectiveness of the intervention including, clinical status and age. or lower respiratory tract infection (LRTI) [8] . Another trial conducted in China included All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. figure 2A) . Among the selected studies there were two studies that included symptomatic patients who used hydroxychloroquine monotherapy [7, 8] . When meta-analysis was conducted by including these two trials, no significant difference between intervention and control groups was seen, in addition substantial statistical heterogeneity was identified (I 2 = 69%) (supplementary figure 2B) . A meta-analysis has reported that in patients with symptomatic clinical status, usage of hydroxychloroquine along with azithromycin for treatment of COVID-19 has showed beneficial outcome with regard to seroconversion (OR 99.67 [95% CI 3.52 to 2818.12]) (supplementary figure 2C ). Out of all the included trials in our present research, one trial [8] has included only adults All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. We conducted another meta-analysis to compare the antiviral effects of using hydroxychloroquine alone, or when combined with azithromycin and the results showed that there is an inclination of more benefits being detected with regard to reduction in viral load in the combination group (OR 9.94 [95% CI 0.47 to 210.41]) (figure 3). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint During the research period, progression to severe illness as seen in COVID-19 patients in association with the study drug was noticed in all the five included trials [7] [8] [9] [10] [11] . Although, quantitatively lower rate of progression to severe illness was reported in the hydroxychloroquine usage groups, whether with or without azithromycin combination, but there was no significant difference documented when compared with control groups (OR 0.89 [95% CI 0.58 to 1.37]; I 2 =30%) (figure 4A). We analyzed the efficacy of treatment in association with worsening of disease and the research findings showed a more favorable outcome in the study drug groups. ( figure 4B and 4C ). For analyzing all-cause mortality, we included three trials which had relevant results associated with regard to mortality [7, 8, 10] . The research findings concluded that hydroxychloroquine use, whether in combination with azithromycin or not, was associated with increased mortality in COVID-19 patients (figure 5A-C) The overall pooled OR was 1.00 for death or progression to severe illness in patients All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint treated with hydroxychloroquine, with or without azithromycin versus control groups for four studies that had complete data regarding the same [7-9, 11] (95% CI 0.27-3.75, I 2 =33%) ( figure 6A) . However, the pooled OR was 1.37 when a comparison of hydroxychloroquine alone versus the control group was conducted (95% CI 0.09-21.97, In total, five trials were included in the present study and were appropriately evaluated for publication bias by conducting funnel plot analysis. As shown in supplementary figure 4 , there was no obvious publication bias reported. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. To solve the COVID-19 pandemic, it is urgently required to find effective pharmacological agents. Hydroxychloroquine is a repositioning candidate, still with reports of unclear efficacy and safety issue when used for the treatment of COVID-19. Therefore, we conducted a systematic review and meta-analysis to address not only the efficacy and safety issue of hydroxychloroquine, but also to explore its efficacy when used in combination with azithromycin for treating COVID-19 patients. The present study yielded several important findings. Firstly, hydroxychloroquine might show benefits in virological clearance of SARS-CoV-2 and a reduction in the risk of disease progression, although no statistical significant findings were reported. Secondly, the combination therapy of hydroxychloroquine and azithromycin seems to show a synergistic effect. Thirdly, use of hydroxychloroquine was associated with an increased mortality. To the best of our knowledge, this study is the first systematic review and meta-analysis which has addressed the issue of combining hydroxychloroquine and azithromycin in COVID-19 patients, by summarizing available results extracted from clinical trials. Our results have suggested that hydroxychloroquine use, whether in the form of monotherapy or combined with azithromycin, has shown a beneficial response in conversion of nucleic acid in COVID-19 patients as compared to the control groups. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. [15] . A study which was conducted in Iraq reported that 79 patients were treated with a protocol which included hydroxychloroquine and other antiviral drugs for dealing with diverse COVID-19 categories, showed a promising rate of complete All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint clinical recovery [14] . In the present study, we found that hydroxychloroquine monotherapy might decrease COVID-19 patients' progression to worse illness but without any reports of statistical significance. Although our results showed higher rate of viral elimination and lower rate of disease worsening in patients treated with combination of hydroxychloroquine and azithromycin, there was no significant difference in the outcome when compared with control groups. The anti-inflammatory effect of hydroxychloroquine on the immune system has been well recognized. The antiviral mechanisms of hydroxychloroquine in treating COVID-19 patients has also been discovered, including increasing pH values of endosomes or lysosomes, stopping the glycosylation of angiotensin converting enzyme (ACE) 2 receptor, inhibiting antigen processing and following major histocompatibility complex (MHC)-II presentation to T cells and interrupting the interaction between cytosolic viral DNA/RNA and toll-like receptors (TLRs) [24, 25] . Azithromycin, a member of the macrolide family, has antibacterial, anti-inflammatory, and antiviral properties [26, 27] . Although azithromycin has been found to block influenza virus internalization into host cells, its mechanism of action against SARS-CoV-2 is still uncertain [28] . Regarding the antiviral effects of using combination of hydroxychloroquine and azithromycin, Andreani et al. demonstrated that such combination showed a synergistic effect against SARS-CoV-All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint 2 when research was conducted in vitro [29] . In terms of safety issue, two RCT trials and one case series reported mild adverse effects such as rash and diarrhea among patients [7, 9, 11 ]. . One comparative study which has used hydroxychloroquine alone, found that 9.5% of patients experienced ECG change, leading to its discontinuation [11] . Another case series which was conducted in France, involving 11 patients reported that one patient developed QT prolongation [13] . Chorin et al. also found that 11% of patient receiving combination therapy (hydroxychloroquine and azithromycin) suffered from severe QT prolongation (>300 milliseconds) [16] . Notably, reports have suggested that both azithromycin and hydroxychloroquine are associated with QT prolongation, and their combined use may potentiate this adverse effect [30, 31] . In addition, we found that the incidence of mortality favored control group rather than the use of hydroxychloroquine with or without azithromycin as demonstrated with an OR of 2.54 in the pooled analysis. Most of the included trials had small sample size which might have impacted the significance of our results [8, 9] . Among the included studies, one of them investigated by Magagnoli et al. had few findings which were different from the rest. Here, subjects with contraindication to usage of hydroxychloroquine or had All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint significant comorbidities were not excluded from the patients population, comprised only men whose median age was over 65 years, and majorly who were non-Hispanic black [10] . Reports have indicated that the average age of COVID-19 patients was about 50 years, and the percentage distribution among male and female was nearly equal [30] [31] [32] Since the mortality risk for COVID-19 varies by age, the current evidence suggests that older people are at a higher risk of getting affected from COVID-19 than younger ones [33, 34] and it might be related to multiple comorbidities commonly seen in older people [35] . Higher rates of COVID-19 -related hospitalization among the elder population and non-Hispanic black have also been found in the United States [36] . The mortality rate in different countries might be also associated with socio-economic and political factors [37] . Therefore, our present results of pooled analysis might be biased as we also included the demographic composition of patients, mentioned in the study conducted by Magagnoli et al. Despite the pertinent information demonstrated above, our systematic review has its own limitations. As far as the lack of compiling sufficient data with regard to virological cure as efficacy outcome is concerned, we tried to solve this problem by conducting a search for unpublished literature and non-English journals to increase the quantity of relevant integrated literature.. Most studies which are published are mainly observational studies All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . and case series with substantial methodology concerns such as no framework of exclusion criteria, and therefore susceptible to bias and confounding. Therefore, as there are limited related RCTs in the literature at present, only those were included in our study. In the lack of experimental random allocation to the intervention, the effects of the hydroxychloroquine might be overestimated. Furthermore, the two single-center RCTs which were conducted in China had some limitations as it included small sample size, did not conduct an international trial, and only limited data was available regarding the viral load. In our present study, bias might be present since little information was provided on demographic data, comorbidity, severity of disease, and the adverse effects of hydroxychloroquine or azithromycin such as QT prolongation. In addition, we have not performed a dose-response meta-analysis, due to the lack of original data. Finally, the limited number of available studies which were included, made it unworkable to evaluate the true effect of hydroxychloroquine. Therefore, the present results should be interpreted cautiously, and further large, prospective RCTs needs to be conducted in a methodologically rigorous manner. The present study has suggested that hydroxychloroquine alone, or in combination with azithromycin for COVID-19 treatment showed beneficial outcome but also higher All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint mortality. The combination of hydroxychloroquine and azithromycin has demonstrated synergistic effects. In future, large, randomized, placebo-controlled trials with longer follow-up are needed to further confirm these findings. None. None. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported partly by Taipei Veterans General Hospital (V109EA-014, VGH-2017/2020 C and E project). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint Figure 5 . All-cause mortality. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093831 doi: medRxiv preprint Figure 6 . Death or clinical worsening of disease. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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