Do no harm - re-evaluating the risks of overtreatment in community-wide tuberculosis screening

Background: Community-wide screening is a crucial strategy to end tuberculosis (TB), but a common concern is potential harm from overtreatment following false positive diagnoses. However, current reference standards determining test performance have limitations, with implications for prevalence thresholds and treatment decisions for community-wide screening. Methods: We estimated coverage of community-wide screening at a prevalence threshold of 0.5% (current global standard), 0.25%, and 0.1% for adult pulmonary TB. We considered test performance for Xpert Ultra against different reference standards (sputum culture, plus clinical evaluation, plus disease progression within two years). Potential harm was estimated through disability adjusted life years (DALYs) incurred or averted by treatment. We report net specificity, positive predictive value (PPV), the ratio of false positives to true positives, and DALYs averted for (non-)treatment based on different reference standards. Results: A lower threshold would increase screening coverage from the current 42% to 84% (0.25% threshold) and 89% (0.1% threshold) of the global TB burden. In a population of 100,000 with 0.5% prevalence, specificity was 99.5% for community screening, but increased to 99.7% using disease progression as reference standard, with PPV increasing from 45 to 66%. In addition, estimated harm of withholding appropriate treatment was approximately 1,200 times higher compared to providing inappropriate treatment, with treatment initiation after a positive Xpert Ultra increasing overall DALYs averted (median 5,977 versus 3,750). Discussion: The benefit of TB treatment following a positive molecular test in community-wide screening likely outweighs the harm associated with possible overtreatment, supporting expanding coverage of simplified community-wide screening.