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

Abstract 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.