Cumulative TB disease burden following sputum Xpert Ultra ‘Trace’ results in clinical settings: Results from a multi-site observational clinical study

Background: Highly sensitive molecular tests, like Xpert Ultra, are reshaping TB diagnosis-detecting paucibacillary TB but sometimes creating uncertainty when they detect DNA in extremely low quantities that may not signal disease. This ambiguity also complicates the evaluation of novel diagnostic strategies. We sought to monitor adults with a 'Trace' result on an Xpert Ultra test to estimate the risk of tuberculosis disease up to 24 months later. Methods: We conducted a multi-site clinical observational study in South Africa and Uganda, where we enrolled ambulatory participants aged >=15 years with a sputum Xpert Ultra Trace result who had not yet initiated TB treatment. All participants underwent comprehensive clinical evaluation and repeated, standard sputum TB testing. Clinicians deferred treatment recommendations if TB status remained uncertain after evaluation. Untreated participants were followed regularly until TB diagnosis and/or treatment initiation. We estimated cumulative incidence of TB disease, defined by three reference standards. Results: Of 311 participants with Trace results (50% male, 57% PLHIV, 37% treated for TB within the last 5 years), 24% were positive for TB within 12 months by culture, 37% by sputum Xpert or culture, and 54% by culture or clinical diagnosis. After excluding those diagnosed with TB at baseline, patients identified at baseline as having recent TB history, abnormal chest x-ray, or positive tongue swab, had higher risk of TB diagnosis (hazard ratios: 2.6, 2.4, 4.5, respectively) during follow-up. This hazard was highest in the first three months after the negative baseline evaluation (0.22 [95% CI: 0.19-0.26] per person-month) and decreased to 0.01 [95% CI: 0-0.02] per person-month in both the 3-6 and 6-12-month intervals. Conclusion: Approximately half of adults and adolescents with a sputum Trace result were diagnosed with TB disease within twelve months. Although most TB diagnoses were made within 3 months, risk remained higher than estimated population incidence rates through the follow-up period. Individuals with sputum Trace results should receive close clinical monitoring, despite initial clinical treatment decision.