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

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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.