HOST AND MICROBIOLOGICAL DETERMINANTS OF INFECTIOUSNESS IN PATIENTS WITH DRUG SEN

描述（由申请人提供）：在南非，多重耐药结核病和广泛耐药结核病（MDR-TB和XDR-TB）在约50-75%的病例中结局不利，尽管占结核病总负担的不到2%，但消耗了约60%的年度结核病药物预算。流行病学模拟研究（1，2）表明，阻断人与人之间的传播将大大限制耐药结核病的流行。然而，鉴于疾病的巨大负担，提供普遍的感染控制设施是不现实的。公 已经确定，痰中有显微镜可检测到的抗酸杆菌的结核病患者比那些没有抗酸杆菌的患者更具传染性（3），然而，流行病学和实验研究表明，存在一系列传染性，并且只有少数此类患者（10-20%）负责大部分传播。这些个体，通常被称为“超级传播者”（4），是有针对性的感染控制干预措施的理想候选人，包括使用有限的隔离设施或新的粘液调节方法，使他们迅速无传染性。然而，我们不知道是什么宿主和细菌特性驱动了“超级传播者”状态和疾病传播。因此，我们缺乏必要的信息来快速识别传染性个体或设计新的解决方案。咳嗽气溶胶采样是美国开发的一种新技术，以前曾用于量化结核病患者个体咳嗽气溶胶颗粒的数量和尺寸分布。与依赖动物（如豚鼠）的方法不同，该方法相对简单实用，并且可以从单个气溶胶颗粒中分离杆菌。我们的数据表明，咳嗽飞沫中的杆菌数量是活动性结核病例家庭接触者近期感染的强有力预测因素（已提交供出版; NEJM），因此可以作为传染性的替代标志。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耐药结核病患者传播的病理学。我们力求：（i）对痰涂片呈阳性的耐多药结核病和广泛耐药结核病患者进行咳嗽气雾剂取样，并确认少数人的咳嗽气雾剂中含有可培养的结核杆菌，这与耐多药结核病类似;（二）研究细菌的差异（转录和“惰性持续”表型、菌株类型和点突变）和宿主因子（肺结核病的病程和严重程度、咳嗽强度和咳嗽量、痰液粘稠度、HIV状态、胸部影像学特征）。我们将利用这些信息来更好地了解传播的起源，并在适当的情况下，生成一个初步的临床预测规则，可用于快速识别疾病的“超级传播者”。这一工具需要在今后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的人际传播。

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.