Role of Casual Contact in Drug-Resistant Tuberculosis Transmission: A Molecular Epidemiology Study

RATIONALE: Transmission is the primary driver of tuberculosis (TB) and drug-resistant (DR) TB in high-burden countries; however, where and between whom spread occurs is poorly understood. OBJECTIVE: We conducted universal whole genome sequencing (WGS) to evaluate the role of casual contact in Mtb transmission. METHODS: We recruited persons diagnosed with second-line DR-TB (eg, XDR, pre-XDR TB) from June 2018-December 2022 in metropolitan Durban, South Africa. We collected named contacts and GPS coordinates of homes, clinics, and community locations visited regularly before diagnosis. Among participants genotypically clustered by WGS (≤12 SNPs), we quantified the proportion attributable to close vs. casual contact. Close contact was defined as person-to-person links or overlapping hospitalizations. Casual contact links were based on geographic proximity of homes and community locations, or shared outpatient clinics. MEASUREMENTS AND MAIN RESULTS: We enrolled 305 (80%) of 383 persons diagnosed with second-line DR-TB. TB isolates were sequenced for 251 (83%) participants; 141 (56%) were genotypically linked, forming 25 clusters (range: 2-49 persons/cluster). Among clustered participants, 69 (49%) were epidemiologically linked by casual contact and 13 (9%) through close contact. Multivariable analysis identified living within 1 km (OR 17.9), visiting proximate community locations (OR 1.88), shared outpatient clinic (OR 1.72), and person-to-person links (OR 5.38) as significant risk factors associated with genotypic clustering. CONCLUSIONS: Casual contact in community locations accounted for half of transmission among genotypic clusters in a high-burden setting. Efforts to curb TB will require a greater emphasis on community-based measures to identify cases from casual contact or undetected intermediate cases, in addition to the current mainstay of contact tracing.