M. Claassens, University of Namibia - Hotspots, hospitals and households: enhanced drug-resistant tuberculosis case finding in Namibia (H3TB)

背景每年有超过50万人患上多药耐药(MDR)结核病(TB)，这是一种由对两种最有效的抗结核病药物利福平和异烟肼耐药的微生物引起的结核病。虽然这只占结核病总负担的5%，但在许多结核病负担高的国家，它消耗了结核病预算的50%以上，对消除结核病的计划构成了重大威胁。为了防止耐多药结核病的持续传播，必须及早发现、诊断和治疗感染病例。通常，患者在寻求治疗之前等待很长时间，直到他们感染了许多其他人。通过在可能发现耐多药结核病的地方积极搜索耐多药结核病病例，可以更有效地找到个人。寻找病人的最佳方法目前尚不清楚。全基因组测序(WGS)是一项相对较新的技术，可以告诉我们生物体的基因指纹。通过观察不同患者的微生物之间的微小变化，你可以知道这些微生物之间的关联程度，从而可以看出传播可能发生的顺序和时间。如果这与绘制患者的社会网络地图以了解他们在哪里生活、社交、工作和开展日常生活的方法相结合，就可以确定地理传播热点，并将其作为可能有效发现耐多药结核病患者的活跃病例的地方。发现新结核病患者的其他方法是a)筛查结核病患者的密切接触者和家庭接触者，以及b)筛查结核病医院的来访者。这两组人自身患结核病的风险都增加了。是否可以结合使用WGS和社会网络地图来确定传播热点？2.识别耐多药结核病病例的三种积极病例查找策略的有效性如何，即针对传播热点、密切接触者和医院访客？3.如果在全国范围内扩大活跃病例查找工作，将对耐多药结核病流行产生什么影响，是否具有成本效益？建议的研究我们计划在纳米比亚的两个地区开展工作，并在两年内确定所有确诊的耐多药结核病病例(约300例)。我们将对来自个体的分离株进行WGS，以评估相关性和传播动力学。我们将联系和采访患者，收集临床、流行病学和社会网络数据。我们将结合WGS和社交网络数据来确定可能发生传播的地理地点。我们将开展可行性研究，评估三种主动发现病例的方法。这将通过针对传播热点、通过筛查耐多药结核病患者的密切接触者和家庭接触者以及通过对耐多药结核病医院的来访者进行评估来实现。这些可行性研究将包括定性研究，我们采访患者和工作人员，以了解干预措施的可接受程度，以及定量研究，我们测量确定的病例比例和活动成本。最后一部分是使用数学模型来确定，如果采用这些不同的病例发现战略，在减少传播和减少新的耐多药结核病病例的总体负担方面，将对国家耐多药结核病负担产生什么影响。我们还将评估这些方法的成本和成本效益。世卫组织参与了这项研究。这项研究将由Claassens博士和纳米比亚大学的一个研究小组在纳米比亚进行。该团队将得到该项目的PI James Seddon博士和由Stefan Niemann教授领导的Borstel团队的支持。伦敦帝国理工学院将支持纳米比亚的研究小组。如果有可能确定传播热点，如果将病例发现定向到这些地点是有效和具有成本效益的，这可能被证明是一项重要的战略，可能被用来抗击耐多药结核病疫情。

BACKGROUNDEach year over half a million individuals develop multidrug-resistant (MDR) tuberculosis (TB), a type of TB caused by organisms that are resistant to the two most effective anti-TB drugs, rifampicin and isoniazid. Although this is only 5% of the total TB burden, it consumes over 50% of the TB budget in many high TB burden countries and is a major threat to plans to eliminate TB. To prevent ongoing transmission of MDR-TB, infectious cases must be identified early, diagnosed and put on treatment. Frequently, patients wait a long time before they seek care, by when they have infected many others. By actively searching for MDR-TB cases, in places where they are likely to be found, individuals can be found more effectively. The best methods of finding patients are currently unclear. Whole genome sequencing (WGS) is a relatively new technology that can tell us the genetic 'fingerprint' of organisms. By looking at small changes between the organisms in different patients, you can tell how related the organisms are and consequently in which order, and when, transmission likely took place. If this is combined with methods to map the social networks of patients to see where they live, socialise, work and carry out their daily lives, geographical transmission hotspots can be identified and targeted as places in which active case finding of MDR-TB patients may be effective. Other ways of finding new TB patients are a) screening close and household contacts of TB patients and b) screening visitors to TB hospitals. Both groups are at increased risk of having TB themselves.RESEARCH QUESTIONS1. Can transmission hotspots be identified using a combination of WGS and social network mapping?2. How effective are three active case finding strategies for identifying MDR-TB cases, namely targeting transmission hotspots, close contacts, and hospital visitors?3. If active case finding were scaled nationally, what would be the impact on the MDR-TB epidemic and would it be cost effective?PROPOSED RESEARCHWe plan to work in two regions of Namibia and over a two-year period identify all MDR-TB cases that are diagnosed (about 300 cases). We will carry out WGS on the isolates from individuals to evaluate relatedness and transmission dynamics. We will contact and interview the patients, collecting clinical, epidemiological and social network data. We will combine WGS and social network data to identify geographical sites where transmission could take place. We will carry out feasibility studies to evaluate three methods of active case-finding. These will be through the targeting of the transmission hotspots, through screening of close and household contacts of MDR-TB patients and through evaluation of visitors to MDR-TB hospitals. These feasibility studies will involve qualitative research in which we interview patients and staff, to find out how acceptable the interventions are, as well as quantitative research, where we measure the proportion of cases that are identified and how much the activities cost. The final part is to use mathematical models to determine what would be the impact on the national burden of MDR-TB if these different strategies for case finding were employed, in terms of transmission reduction and reducing the overall burden of new MDR-TB cases. We would also evaluate the cost and cost effectiveness of these approaches.WHO IS INVOLVED IN THE RESEARCHThe research will be carried out in Namibia by Dr. Claassens and a team of researchers at the University of Namibia. This team will be supported by the PI of the project, Dr. James Seddon, and the team in Borstel, led by Prof. Stefan Niemann. Imperial College London will support the Namibian research team.POTENTIAL BENEFITSIf it is possible to identify transmission hotspots and if targeting case finding to these locations is effective and cost effective, this could prove to be an important strategy that might be employed to fight the MDR-TB epidemic.