HOST AND MICROBIOLOGICAL DETERMINANTS OF INFECTIOUSNESS IN PATIENTS WITH DRUG SEN

说明(申请人提供)：在南非，耐多药和广泛耐药结核病(耐多药结核病和广泛耐药结核病)在约50%-75%的病例中产生不利结果，尽管占结核病总负担的不到2%，但消耗了每年结核病药物预算的约60%。流行病学模拟研究(1、2)表明，阻断人与人之间的传播将极大地限制耐药结核病的流行。然而，考虑到疾病的沉重负担，提供普遍的感染控制设施是不现实的。这很好 (3)然而，流行病学和实验研究表明，在痰中含有显微镜可检测到的抗酸杆菌的结核病患者比没有抗酸杆菌的患者更具传染性(3)，但流行病学和实验研究表明，存在一系列传染性，而且只有少数此类患者(10%-20%)是大多数传播的罪魁祸首。这些人通常被称为“超级传播者”(4)，他们是有针对性的感染控制干预措施的理想对象，包括使用有限的隔离设施或新的相互调节方法，使他们迅速不具传染性。然而，我们不知道是什么宿主和细菌特征驱动了超级传播者的状态和疾病的传播。因此，我们缺乏必要的信息来快速识别有传染性的个人或设计新的解决方案。咳嗽气溶胶采样是美国开发的一项新技术，以前曾用于量化结核病患者单个咳嗽气溶胶颗粒的数量和大小分布。与依赖动物(如豚鼠)的方法不同，这种方法相对简单和实用，可以从单个气溶胶颗粒中分离出细菌。我们的数据表明，咳嗽飞沫中的杆菌数量是最近在活动性结核病病例的家庭接触者中感染的强有力的预测因子(提交供发表；《新英格兰医学杂志》)，因此可以作为传染性的代理标志。这项技术尚未在南非或广泛耐药结核病患者中应用。我们的首要目标是了解DR-TB患者传播的病理生物学。我们寻求：(I)对耐多药结核病和广泛耐药结核病涂片阳性患者进行咳嗽气雾剂采样，并确认与DS-TB相似，少数患者的咳嗽气雾剂中含有可培养的结核杆菌；(Ii)研究咳嗽气雾剂培养阳性与阴性患者在细菌(转录和“懒惰的持久性”表型、菌株类型和点突变)和宿主因素(结核病病程和严重程度、咳嗽强度和咳嗽量、痰黏度、艾滋病毒状况、胸部影像特征)方面的差异。我们将利用这些信息更好地了解传播的起源，并在适当的情况下产生一个初步的临床预测规则，该规则可用于快速识别疾病的“超级传播者”。这一工具需要在未来的前瞻性研究中进一步完善和验证。采用这一规则可能产生的长期影响是显著减少结核病在人与人之间的传播。

DESCRIPTION (provided by applicant): In South Africa, multi- and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB) have unfavourable outcomes in ~50-75% of cases, and despite comprising less than 2% of the total TB burden, consumes ~60% of the annual TB drug budget. Epidemiological modeling studies (1, 2) have shown that the disruption of person-to-person transmission would drastically limit the DR-TB epidemic. However, the provision of universal infection control facilities is unrealistic given the sheer burden of disease. It is well established that TB patients who have microscopically-detectable acid-fast bacilli in their sputum are more infectious that those who do not (3), however, epidemiological and experimental studies have shown that there is a spectrum of infectiousness, and that only a minority of such patients (10-20%) are responsible for the majority of transmission. Such individuals, frequently termed 'super-spreaders' (4), are ideal candidates for targeted infection control interventions, including use of limited isolation facilities or novel mucomodulatory approaches to render them rapidly non-infectious. However, we do not know what host and bacillary characteristics drive 'super-spreader' status and disease transmission. We therefore lack the information necessary to rapidly identify infectious individuals or to devise novel solutions. Cough aerosol sampling is a novel technology developed in the United States that has previously been used to quantify the numerical and size distribution of individual cough aerosol particles from TB patients. Unlike methods that rely on animals, such as guinea pigs, it is relatively simple and practical to perform and allows for isolation of bacilli from individual aerosol particles. Our data indicate that the quantity of bacilli in cough droplets is the stronges predictor of recent infection in household contacts of active TB cases (submitted for publication; NEJM), and can therefore serve as a proxy marker of infectiousness. This technology has not been applied in South Africa or to patients with XDR-TB. Our overarching objective is to understand the pathobiology of transmission in patients with DR-TB. We seek to: (i) apply cough aerosol sampling to smear-positive patients with MDR-TB and XDR-TB and confirm that, similar to DS-TB, a minority have culturable TB bacilli in their cough aerosol; (ii) study differences in bacterial (transcriptional and 'lazy persister' phenotype, strain type and point mutations) and host factors (duration and severity of TB disease, cough strength and volume, sputum viscosity, HIV status, chest imaging characteristics) in those patients that are cough aerosol culture-positive versus culture-negative. We will use this information to better understand the genesis of transmission and, if appropriate, generate a preliminary clinical prediction rule which can be used to rapidly identify disease 'super-spreaders'. This tool would require further refinement and validation in future prospective studies. The possible long-term impact of the adoption of such a rule would be a marked reduction in the person-to-person transmission of TB.