Friday, November 22, 2024
11/22/2024
ABSTRACT At least 15-30% of symptomatic tuberculosis (TB) is estimated to be culture-negative, of whom approximately half progress to culture-positive TB. Improved diagnostics for sputum culture- negative TB thus represents a major opportunity for early intervention to prevent morbidity and development of transmissible disease. However, there are currently no validated diagnostic strategies to confirm or screen for culture-negative TB. Only recently, progress in non-sputum based near-patient diagnostics – including cartridge-based tests of TB host response signatures and lateral flow assays to detect TB antigen from urine – have provided progressively more sensitive readouts of TB infection independent of sputum culture. Together, these methods have unexplored potential as complementary diagnostic biomarkers with an ability to detect TB patients otherwise missed by slow, inaccessible sputum culture-based methods. With the long-term goal of developing rapid and feasible diagnostic approach for culture-negative TB, we will evaluate the latest, most promising urine LAM platforms and TB host response signatures among an existing cohort of symptomatic but culture-negative individuals who have been clinically and microbiologically characterized over 12 months. Our central hypothesis is that host-response signatures and urine LAM detection - alone or combined - will have an AUC ROC of over 70% for discriminating individuals with “probable” versus “unlikely” culture-negative TB – referenced by their longitudinal clinical and extended microbiologic signals of TB. We will test our hypothesis through the following complementary aims: Aim 1 will compare a panel of previously validated TB host response gene expression signatures between culture-confirmed TB, TB-negative controls, and the well-characterized cohort of culture- negative individuals, with the hypothesis that readouts of symptomatic, culture-negative individuals will fall between that of culture-confirmed TB and TB-negative controls. We will then evaluate the ability of these signatures to discriminate probable versus unlikely culture negative TB. In Aim 2, we will follow the same approach to evaluate for presence of TB LAM using existing and novel high-affinity urine LAM assays between these three cohorts, and evaluate the individual and combined value of urine LAM and host response signatures for discriminating probable versus unlikely culture-negative TB. The expected outcome of this study is the foundation of a diagnostic strategy for culture-negative TB to facilitate early appropriate treatment, thereby halting development of a significant population of culture-positive disease with far-reaching impact in preventing TB morbidity and transmission.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
