Automated bioinformatic pipeline for unbiased detection of tuberculosis transmission clusters: Real-time impact and retrospective insights

Background[RP1.1] In low-burden countries such as France, whole-genome sequencing (WGS) is increasingly integrated into routine tuberculosis (TB) surveillance to improve case management and transmission monitoring. However, applying WGS to all TB cases generates large volumes of data, requiring automated tools for timely interpretation and outbreak response. Methods Since November 2016, all clinical M. tuberculosis isolates diagnosed in eight hospitals from three cities of Auvergne-Rhone-Alpes in France have undergone WGS. In July 2023, an automated pipeline for anti-TB drug resistance prediction and unbiased detection of transmission clusters based on SNP distances was implemented. Epidemiological, microbiological and clinical data were collected, with contact duration classified as household, frequent, or occasional. Index cases were stratified by their level of extra-household transmission (EHT), and statistical analyses were performed to identify associated factors. Findings Among 1,152 TB patients diagnosed between 2016 and 2025, 75 clusters involving 247 patients (21.4%) were identified. WGS reliably detected resistance to first-line anti-TB drugs, leveraging the WHO mutation catalogue. Routine WGS enabled real-time alerts for TB control centres, leading to expanded field investigations, including community spillover, nosocomial transmissions, and school outbreak. Classical indicators of contagiousness (smear results, cavitary disease) were not associated with EHT level. Instead, lower TB severity indices and longer duration of symptoms were linked to higher EHT level. Interpretation Systematic WGS supports timely identification of drug resistance and transmission events and provides new insights into contagiousness factors. The automated pipeline enables direct interpretation by clinical microbiologists, facilitating real-time public health action. In this study, we demonstrate how, with the appropriate pipeline, WGS offered a time- and cost-effective solution for routine TB management. Funding This work was supported by SHAPE-Med@Lyon, a French government grant managed by the French National Research Agency under the France 2030 program (reference ANR-22-EXES-0012).