Transmission of drug-resistant tuberculosis (TB) is a major threat to TB control, especially in high HIV prevalence settings. We have previously shown that nearly 70% of extensively drug-resistant (XDR) TB cases in KwaZulu-Natal province, South Africa are due to transmission, rather than unsuccessful TB treatment. We identified epidemiologic links through close contacts or hospital admission for 30% of cases, but found no epidemiologic link for the remaining 70%. We hypothesize that genomically-linked cases live or seek healthcare near one another and may have unrecognized epidemiologic links. We compared geospatial distances between homes and health facilities for participants with ≤ 5 single nucleotide polymorphism (SNP) differences to determine geographic proximity.
We enrolled culture-confirmed XDR TB cases in KwaZulu-Natal from 2011-2014. We collected clinical and demographic characteristics, GPS coordinates of homes and XDR TB diagnosis facility, and performed whole genome sequencing (WGS) of TB isolates. We defined a SNP difference of ≤ 5 as genomic evidence of transmission between two cases (‘case-pair’). We calculated spatial distances using Haversine’s formula and defined geographic proximity as < 20 km. We stratified the analysis by participants’ HIV status to determine the association with spatial clustering.
We enrolled 296 participants with WGS results, from all 11 districts in KwaZulu-Natal. Among these, 179 (66%) participants formed 671 case-pairs with ≤ 5 SNPs. The median distance between home residences of case-pairs was 115 km (IQR 63-154) (Figure 1); the median distance between diagnosing facilities was 93 km (IQR 44-131). Only 116 (17%) case-pairs lived or were diagnosed within 20 km of each other. Median distance did not vary significantly when the SNP threshold was reduced to 3 and 1 SNP (p=0.27 for homes, p=0.56 for diagnosing facilities). There was no significant difference in geographic distances for case-pairs based on whether both were HIV-positive, HIV-negative or had discordant HIV status (p=0.87 for homes, p=0.20 for diagnosing facilities).
Although two-thirds of XDR TB participants from KwaZulu-Natal, South Africa were genomically-linked, only 17% lived or were diagnosed at a health facility within 20 km of their case-pair. Further research examining migratory patterns, particularly between rural and urban areas, is needed to determine their role in TB transmission and the spread of drug resistance.