HOST AND MICROBIOLOGICAL DETERMINANTS OF INFECTIOUSNESS IN PATIENTS WITH DRUG SEN

药物敏感患者感染的宿主和微生物决定因素

• 批准号: 8990804
• 负责人: Keertan Unkha Dheda
• 金额: $ 13.29万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-12 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990804
• 关键词: Acid Fast Bacillae Staining Method; Adoption; Aerosols; Animals; Bacillus (bacterium); Budgets; Cavia; Cessation of life; Characteristics; Chest; Clinical; Clinical Trials; Collection; Colony-forming units; Communities; Comparative Study; Coughing; Data; Disasters; Disease; Drug resistance in tuberculosis; Environmental Risk Factor; Epidemic; Epidemiologic Studies; Extreme drug resistant tuberculosis; Failure; Functional disorder; Future; HIV; Health; Household; Image; Individual; Infection; Infection Control; Integration Host Factors; Intervention; Laboratories; Life; Methods; Microscopy; Minority; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Newly Diagnosed; Organism; Outcome; Particle Size; Patients; Persons; Pharmaceutical Preparations; Phenotype; Point Mutation; Prospective Studies; Proxy; Public Health; Publications; Research Infrastructure; Resources; Risk; Roentgen Rays; Sampling; Severities; South Africa; Sputum; Staining method; Stains; System; Technology; Translating; Treatment Failure; Tuberculin Test; Tuberculosis; United States; Validation; Viscosity; biosafety level 3 facility; burden of illness; disease transmission; epidemiological model; extensive drug resistance; hospital bed; mycobacterial; new technology; novel; particle; patient registry; prospective; research study; therapy development; tool; transmission process; tuberculosis drugs; tuberculosis treatment

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.

描述（由申请人提供）：在南非，耐多药和广泛耐药结核病（MDR-TB和XDR-TB）在约50-75%的病例中具有不利结果，尽管占结核病总负担不到2%，但却消耗了约60%的年度结核病药物预算。流行病学模型研究（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，提供普遍感染控制设施是不现实的。很好