Use of Viremia to Evaluate the Baseline Case Fatality Ratio of Ebola Virus Disease and Inform Treatment Studies: A Retrospective Cohort Study.
Use of Viremia to Evaluate the Baseline Case Fatality Ratio of Ebola Virus Disease and Inform Treatment Studies: A Retrospective Cohort Study.
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使用病毒血症评估埃博拉病毒疾病的基线病例死亡比率和信息治疗研究：一项回顾性队列研究。
DOI：
10.1371/journal.pmed.1001908
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发表时间：
2015-12
期刊：
影响因子：
15.8
通讯作者：
Sall AA
中科院分区：
文献类型：
--
作者：
Faye O;Andronico A;Faye O;Salje H;Boëlle PY;Magassouba N;Bah EI;Koivogui L;Diallo B;Diallo AA;Keita S;Konde MK;Fowler R;Fall G;Cauchemez S;Sall AA
埃博拉病毒病（EVD）的病死率（CFR）可能随着时间和空间的变化而变化，原因尚不完全清楚。这使得在缺乏随机对照的情况下难以确定评估治疗所需的基线CFRs。在这里，我们研究EVD患者的病毒血症是否可以用于评估基线EVD CFRs。我们分析了2014年3月1日至2015年2月28日期间几内亚科纳克里地区经反转录PCR确诊的埃博拉病毒病住院患者的实验室和流行病学记录。我们使用病毒血症和其他变量来模拟CFR。分析了699例EVD患者的数据。在症状出现后的一周内，平均病毒血症保持稳定，CFR随病毒血症V升高，从低病毒血症（V < 104.4拷贝/ml）的21% （95% CI为16%-27%）到中度病毒血症（104.4≤V < 105.2拷贝/ml）的53% （95% CI为44%-61%）和高病毒血症（V≥105.2拷贝/ml）的81% （95% CI为75%-87%）。与成年人（15-44岁）相比。])，幼儿（0-4岁）的CFR更大。（优势比[OR]: 2.44; 95% CI 1.02-5.86）和老年人（≥45岁）。（OR: 2.84; 95% CI 1.81-4.46），但儿童（5-14岁）较低。（or: 0.46; 95% ci 0.24-0.86）。2014年7月之后病例的平均病毒血症与之前相比增加了一个数量级，同时CFR增加了14%。我们的研究结果来自科纳克里的一项大型医院研究，可能无法推广到不同病例的情况，例如从未寻求过治疗的个体。EVD患者的病毒血症是死亡的一个强有力的预测因子，部分解释了研究人群中CFR的变化。本研究提供了病毒血症组的基线CFRs，以便在治疗研究中评估疗效时进行适当调整。在随机对照试验中，对病毒血症组进行分层分析可以减少25%的样本量需求。我们假设，监测住院患者的病毒血症可能会为监测系统检测不同严重程度的EVD患者的能力提供信息。在一项回顾性队列研究中，Simon Cauchemez及其同事发现病毒载量可以预测埃博拉病毒患者的病死率。在2013年12月开始的西非埃博拉病毒病暴发期间，已有2.8万多例埃博拉病毒病确诊、可能和疑似病例，1.1万多例死亡。埃博拉病毒从野生动物传播给人，并通过直接接触感染者的体液（包括血液、唾液和尿液）或器官，或通过接触被体液污染的床上用品和其他材料，在人群中传播。埃博拉病毒病在感染后2-21天开始出现症状，包括发烧、头痛、呕吐、腹泻以及内外出血。受感染的人在出现症状之前是没有传染性的，但只要他们的体液中含有病毒，就会保持传染性。目前尚无针对埃博拉病毒病的经证实的治疗方法或疫苗，尽管在进行有希望的实验室研究后，目前正在对几种治疗方法进行人体评估。支持性护理——在严格隔离的条件下提供，以防止疾病传播给其他患者或医护人员——可提高生存率。理想情况下，对任何疾病的潜在治疗方法的疗效都是在随机对照试验中评估的，这项研究将随机选择接受治疗的人的结果与给予安慰剂（虚拟治疗）的人的结果进行比较。然而，由于埃博拉病毒病往往是致命的，对潜在治疗方法进行随机对照试验被认为是不道德的。相反，评估埃博拉病毒病治疗方法的研究通常比较根据历史数据估计的基线CFR接受治疗的患者的病死率（CFR；由某种疾病引起的死亡人数除以该疾病的病例数；CFR为100%表明所有患该疾病的人都死亡）。但是，埃博拉病毒病的病死率随着时间和空间的变化而显著变化，原因尚不清楚（例如，患者护理的变化或对不同严重程度的疾病患者的检测变化可能会改变病死率）。因此，治疗组的CFR可能与基线CFR不同，原因与治疗无关。为了找到解决这个问题的方法，在这项回顾性队列研究中，研究人员调查了EVD患者的病毒血症（血液中病毒的数量）与CFR之间是否存在关系。研究人员利用实验室和流行病学数据（例如，患者年龄和症状发作和死亡日期；流行病学是对人群疾病模式的研究）调查了2014年3月至2015年2月期间几内亚科纳克里地区699名确诊埃博拉病毒病住院患者的病毒血症与CFR之间的关系。在症状出现后一周内，平均（平均）病毒血症保持稳定，患者的CFR随病毒血症水平升高而升高。因此，低、中、高病毒血症（以每毫升血液中病毒拷贝数定义）患者的cfr分别为21%、53%和81%。与15-44岁的成年人相比，幼儿（小于5岁）和老年人的CFR较高，而5-14岁的儿童的CFR较低。值得注意的是，2014年7月之后，研究人群的CFR比2014年3月至7月增加了14%，这一增加与人群中病毒血症平均水平增加10倍相吻合。这些发现表明，病毒血症是一个强有力的死亡预测因子，可以部分解释EVD病死率的变化。由于这些发现是基于从住院患者收集的数据，因此它们可能无法推广到其他情况。然而，重要的是，这些发现提供了病毒血症组的CFR估计值，现在可用于在进行埃博拉病毒病特异性治疗的临床评估时调整风险。也就是说，通过允许不同水平的病毒血症，将有可能在非随机临床试验中更准确地评估埃博拉病毒病治疗的疗效。此外，研究人员计算出，按病毒血症组对患者进行分层可以将进行的任何随机试验（例如，比较两种潜在治疗方法）所需的样本量减少25%。最后，这组科学家提出，监测因埃博拉病毒病住院患者的病毒血症可能提供有关不同监测系统检测不同疾病严重程度（死亡概率）患者能力的信息。这个资源列表包含可以在设备上查看PDF时访问的链接，也可以通过http://dx.doi.org/10.1371/journal.pmed.1001908上文章的在线版本访问这些链接。世界卫生组织（世卫组织）提供关于埃博拉病毒病的信息，关于埃博拉病毒病潜在治疗方法的信息，并定期更新当前埃博拉病毒病流行情况；世卫组织伦理工作组会议关于与埃博拉病毒病治疗试验有关的伦理问题的讨论摘要已提供；世卫组织网站还提供有关在现场控制埃博拉的努力和埃博拉病毒病幸存者的个人故事的信息，英国国家卫生服务选择网站提供有关埃博拉病毒病的详细信息，美国疾病控制和预防中心也提供有关http://www.cdc.gov/vhf/ebola/EVD的信息
The case fatality ratio (CFR) of Ebola virus disease (EVD) can vary over time and space for reasons that are not fully understood. This makes it difficult to define the baseline CFRs needed to evaluate treatments in the absence of randomized controls. Here, we investigate whether viremia in EVD patients may be used to evaluate baseline EVD CFRs. We analyzed the laboratory and epidemiological records of patients with EVD confirmed by reverse transcription PCR hospitalized in the Conakry area, Guinea, between 1 March 2014 and 28 February 2015. We used viremia and other variables to model the CFR. Data for 699 EVD patients were analyzed. In the week following symptom onset, mean viremia remained stable, and the CFR increased with viremia, V, from 21% (95% CI 16%–27%) for low viremia (V < 104.4 copies/ml) to 53% (95% CI 44%–61%) for intermediate viremia (104.4 ≤ V < 105.2 copies/ml) and 81% (95% CI 75%–87%) for high viremia (V ≥ 105.2 copies/ml). Compared to adults (15–44 y old [y.o.]), the CFR was larger in young children (0–4 y.o.) (odds ratio [OR]: 2.44; 95% CI 1.02–5.86) and older adults (≥45 y.o.) (OR: 2.84; 95% CI 1.81–4.46) but lower in children (5–14 y.o.) (OR: 0.46; 95% CI 0.24–0.86). An order of magnitude increase in mean viremia in cases after July 2014 compared to those before coincided with a 14% increase in the CFR. Our findings come from a large hospital-based study in Conakry and may not be generalizable to settings with different case profiles, such as with individuals who never sought care. Viremia in EVD patients was a strong predictor of death that partly explained variations in CFR in the study population. This study provides baseline CFRs by viremia group, which allow appropriate adjustment when estimating efficacy in treatment studies. In randomized controlled trials, stratifying analysis on viremia groups could reduce sample size requirements by 25%. We hypothesize that monitoring the viremia of hospitalized patients may inform the ability of surveillance systems to detect EVD patients from the different severity strata. In a retrospective cohort study, Simon Cauchemez and colleagues find viral load can predict case fatality ratios among patients with Ebola Virus. During the current outbreak of Ebola virus disease (EVD) in West Africa, which started in December 2013, there have been more than 28,000 confirmed, probable, and suspected cases of EVD and more than 11,000 deaths from the disease. Ebola virus is transmitted to people from wild animals and spreads in human populations through direct contact with the bodily fluids (including blood, saliva, and urine) or organs of infected people or through contact with bedding and other materials contaminated with bodily fluids. The symptoms of EVD, which start 2–21 days after infection, include fever, headache, vomiting, diarrhea, and internal and external bleeding. Infected individuals are not infectious until they develop symptoms but remain infectious as long as their bodily fluids contain virus. There is no proven treatment or vaccine for EVD, although several treatments are now being assessed in people following promising laboratory studies. Supportive care—given under strict isolation conditions to prevent the spread of the disease to other patients or to healthcare workers—improves survival. Ideally, the efficacy of a potential treatment for any disease is assessed in a randomized controlled trial, a study that compares outcomes among people chosen at random to receive the treatment with outcomes among people given a placebo (dummy treatment). However, because EVD is frequently fatal, randomized controlled trials of potential treatments are considered unethical. Instead, studies evaluating treatments for EVD usually compare the case fatality ratio (CFR; the number of deaths caused by a disease divided by the number of cases of that disease; a CFR of 100% indicates that everyone who develops the disease dies) among treated patients with a baseline CFR estimated from historical data. But the CFR of EVD varies markedly over time and space for poorly understood reasons (for example, changes in patient care or variations in the detection of people with disease of different severity might change the CFR). Thus, the CFR in the treatment group could differ from the baseline CFR for reasons that are independent of the treatment. To find a way around this problem, in this retrospective cohort study, the researchers investigate whether there is a relationship between viremia (the amount of virus in the blood) and the CFR among patients with EVD. The researchers used laboratory and epidemiological data (for example, patient age and date of symptom onset and death; epidemiology is the study of disease patterns in populations) to investigate the relationship between viremia and CFR among 699 patients with confirmed EVD hospitalized in the Conakry area of Guinea between March 2014 and February 2015. In the week following symptom onset, mean (average) viremia remained stable, and the CFR among the patients increased with the level of viremia. Thus, the CFRs for patients with low, intermediate, and high viremia (defined by the number of virus copies per milliliter of blood) were 21%, 53%, and 81%, respectively. Compared to adults aged 15–44 years, young children (aged less than five years) and older adults had a higher CFR, but children aged 5–14 years had a lower CFR. Notably, the CFR in the study population was 14% higher after July 2014 than in the months of March–July 2014, an increase that coincided with a ten-fold increase in the average level of viremia in the population. These findings suggest that viremia is a strong predictor of death that can partly explain variations in the CFR of EVD. Because these findings are based on data collected from hospitalized patients, they may not be generalizable to other settings. Importantly, however, these findings provide estimates of CFR by viremia group that can now be used to adjust risk when undertaking clinical evaluations of EVD-specific treatments. That is, by allowing for differing levels of viremia, it will be possible to assess the efficacy of treatments for EVD more accurately in nonrandomized clinical trials. Moreover, the researchers calculate that stratification of patients by viremia group could reduce the sample size needed in any randomized trials that are undertaken (for example, comparisons of two potential treatments) by 25%. Finally, the researchers suggest that monitoring viremia among patients hospitalized for EVD might provide information about the ability of different surveillance systems to detect patients with different levels of disease severity (probability of death). This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001908. The World Health Organization (WHO) provides information about EVD, information about potential EVD therapies, and regular updates on the current EVD epidemic; a summary of the discussion of a WHO Ethics Working Group Meeting on the ethical issues related trials of EVD treatments is available; the WHO website also provides information about efforts to control Ebola in the field and personal stories from people who have survived EVD The UK National Health Service Choices website provides detailed information on EVD The US Centers for Disease Control and Prevention also provides information about http://www.cdc.gov/vhf/ebola/EVD