The long-term risk of tuberculosis among individuals with Xpert Ultra "trace" screening results: a longitudinal follow-up study.

BACKGROUND: Systematic screening for tuberculosis using Xpert Ultra generates "trace" results of uncertain significance. Additional microbiological testing in this context is often negative, but untreated individuals might still progress to culture-positive disease. We aimed to estimate the two-year risk of tuberculosis among screening participants with trace-positive sputum.

METHODS: We screened 31,505 people for tuberculosis in Uganda using sputum Xpert Ultra as an initial test, through event-based and door-to-door screening. We enrolled 128 participants with trace-positive sputum (PWTS), 139 Ultra-negative controls into a prospective cohort, and 110 Ultra-positive (>trace) controls for cross-sectional comparison. All participants underwent extensive initial evaluation, and untreated PWTS and negative controls were followed with re-testing for up to 24 months. We estimated cumulative hazards of tuberculosis among PWTS versus negative controls, using two definitions of tuberculosis: one incorporating clinician judgment (primary) and one based strictly on microbiological results (secondary). We then compared hazards between subgroups of PWTS.

FINDINGS: Of 128 PWTS, 79 (62%) were male and 19 (15%) HIV-positive. Forty-five (35%) PWTS were recommended for treatment upon enrollment, eight lost to follow-up within three months, and 75 followed for median 706 (interquartile range 344-714) days, of whom 19 were recommended for treatment during follow-up. The cumulative hazard of tuberculosis among PWTS not treated at baseline was 0.24 (95% confidence interval: 0.15-0.40) at one year and 0.33 (0.21-0.54) at two years, versus 0.03 (0.01-0.10) at two years for negative controls. Hazards were similar for microbiologically defined tuberculosis (0.36 [0.22-0.58] at 2 years). Tuberculosis diagnosis during follow-up was strongly associated with abnormal baseline chest X-ray (hazard ratio 14.6 [3.3-63.8]) but not with baseline symptoms.

INTERPRETATION: Individuals with trace-positive sputum during screening have a substantial two-year risk of tuberculosis, even when extensive initial evaluations do not confirm disease. Treatment should be considered for most screening participants with trace-positive sputum and abnormal chest imaging.

FUNDING: National Institutes of Health and Gates Foundation.