Who are the Ultra-positive, culture-negative? Understanding the trajectories of individuals in Uganda with trace M. tuberculosis nucleic acid in sputum

谁是极端阳性、文化阴性的人？

• 批准号: 10683370
• 负责人: Emily A Kendall
• 金额: $ 62.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683370
• 关键词: Adolescent; Adult; Age; Bacillus; Biological; Biological Assay; Blood; C-reactive protein; Cessation of life; Characteristics; Clinical; Communicable Diseases; Communities; Coughing; Data; Diagnostic; Diagnostic tests; Disease; Early Diagnosis; Epidemiology; Ethics; Evaluation; Exposure to; Failure; Future; HIV; Health Status; Human immunodeficiency virus test; Image; Immunologics; Incidence; Individual; Infection; Inflammatory; Investigation; Laboratories; Learning; Measurement; Methods; Modeling; Molecular; Monitor; Mycobacterium tuberculosis; Notification; Nucleic Acid Amplification Tests; Nucleic Acids; Outcome; Patients; Persons; Play; Population; Prevalence; Process; Public Health; Recording of previous events; Risk; Role; Sample Size; Sputum; Surveys; Symptoms; Testing; Time; Tuberculosis; Tuberculosis diagnosis; Uganda; Whole Blood; care seeking; case finding; clinical decision-making; clinically significant; cohort; community setting; comparative; cytokine; design; detection limit; follow-up; high risk; high risk population; improved; inflammatory marker; insight; lung imaging; meetings; molecular dynamics; preference; programs; prospective; public health ethics; radiological imaging; rapid diagnosis; reduce symptoms; screening; sex; transcriptomics; transmission process; unnecessary treatment

PROJECT SUMMARY/ABSTRACT Xpert® MTB/RIF Ultra (“Ultra”) is a highly sensitive and widely used rapid molecular test for diagnosing tuberculosis (TB), with potential to play a much-needed role in finding people with undiagnosed TB. Results at Ultra’s lowest semi-quantitative result level, “trace,” account for much of the assay’s enhanced ability to detect TB. However, the usefulness of Ultra is jeopardized by the large number of people (including asymptomatic, treatment-naïve people) whose sputum is positive at the trace level by Ultra, but negative for M. tuberculosis by culture. The cause of these Ultra-trace-positive but culture-negative results is uncertain: They might include people who are in the early stages of developing TB disease, people with recent TB that is resolving, people recently exposed to M. tuberculosis and possibly infected, or laboratory error. Because the associated risk of developing TB for people with trace-positive Ultra results is unknown, it is unclear how these individuals should be managed. Furthermore, in the context of efforts to achieve earlier diagnosis of TB by screening asymptomatic individuals in the community, it is unclear whether trace-positive Ultra results with negative corresponding cultures represent false-positive tests (and thus should prompt more cautious use of the Ultra assay) or represent very early TB that is likely to progress to advanced TB disease (making people with trace- positive Ultra results the ideal target for efforts at early detection of TB). This study seeks to clarify the current burden and future risk of TB in people with Ultra-trace-positive sputum, while gaining insight into the dynamics that underlie trace-positive Ultra results. By offering sputum-based testing for TB on a community-wide basis to asymptomatic adolescents and adults in Uganda, we will test tens of thousands of people for TB with Ultra. In the process, we will identify 250 people with trace-positive sputum Ultra results in community settings in Uganda, along with positive and negative controls who clearly have or clearly do not have TB. In Specific Aim 1, we will collect extensive clinical and laboratory data in order to determine how many of these individuals have evidence of TB disease at the time that they test Ultra-trace- positive, and to understand what other mechanisms might explain the Ultra results of those in whom we find no further evidence of TB. In Specific Aim 2, we will closely follow those who were not found to have TB initially. Among these individuals, we will evaluate the incidence of TB and the dynamics of any molecular, imaging, and immunological abnormalities over time. Finally, in Specific Aim 3, we will use several approaches (decision analytic modeling of individual outcomes, dynamic transmission modeling of population impact, and a public health ethics analysis) to place what we learn from Ultra-trace-positive individuals into context, in order to help public health decision-makers use our results to improve how they go about finding people with TB.

项目摘要/摘要 Xpert®MTB/RIF Ultra(“Ultra”)是一种高灵敏度和广泛使用的诊断快速分子检测方法 结核病(TB)，有可能在发现未确诊结核病患者方面发挥亟需的作用。结果显示： ULTRA最低的半定量结果水平“TRACE”在很大程度上解释了该分析增强的检测能力 结核病。然而，大量的人(包括无症状的， 治疗-幼稚的人)其痰在痕量水平上Ula呈阳性，但对结核分枝杆菌呈阴性 按文化划分。这些超痕量阳性但培养阴性的结果的原因尚不确定：它们可能包括 处于结核病早期阶段的人，最近正在好转的结核病患者， 最近接触过结核分枝杆菌，并可能感染，或实验室错误。因为与之相关的风险 目前尚不清楚超微结果为阳性的人是否会患上结核病，也不清楚这些人应该如何 被管理。此外，在努力通过筛查实现结核病早期诊断的背景下 社区中无症状的个体，尚不清楚痕量阳性的超阳性结果是否与阴性 相应的区域性代表假阳性测试(因此应促使更谨慎地使用Ultra 化验)或代表很可能进展为晚期结核病的非常早期的结核病(使有痕迹的人- 阳性的超级结果是努力早期发现结核病的理想目标)。 这项研究旨在阐明超痕量痰阳性患者目前的结核病负担和未来的风险， 同时洞察跟踪阳性超级结果背后的动态。通过提供基于痰的 在乌干达，我们将在全社区范围内对没有症状的青少年和成年人进行结核病检测，我们将检测数十 数以千计的人患上了超级结核病。在这一过程中，我们将确认250名痰微量呈阳性的人 在乌干达的社区环境中取得了极端的结果，以及明显患有或 显然没有患上结核病。在具体目标1中，我们将收集广泛的临床和实验室数据，以便 确定这些人中有多少人在测试超痕量时有结核病的证据- 积极的，并理解什么其他机制可以解释那些我们发现没有 结核病的进一步证据。在具体目标2中，我们将密切跟踪那些最初未被发现患有结核病的人。 在这些个体中，我们将评估结核病的发病率以及任何分子、成像、 以及随着时间推移的免疫异常。最后，在具体目标3中，我们将使用几种方法(决定 个人结果的分析模型，人口影响的动态传递模型，以及公众 健康伦理分析)将我们从超痕量阳性患者那里学到的放在背景中，以便帮助 公共卫生决策者利用我们的结果来改进他们寻找结核病患者的方式。

项目成果

Infectious and clinical tuberculosis trajectories: Bayesian modeling with case finding implications.

• DOI: 10.1073/pnas.2211045119
• 发表时间: 2022-12-27
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1