Citywide Transmission of Multidrug-resistant Tuberculosis Under China's Rapid Urbanization: A Retrospective Population-based Genomic Spatial Epidemiological Study

Abstract

Background: Population movement could extend multidrug-resistant tuberculosis (MDR-TB) transmission and complicate its global prevalence. We sought to identify the high-risk populations and geographic sites of MDR-TB transmission in Shenzhen, the most common destination for internal migrants in China.

Methods: We performed a population-based, retrospective study in patients diagnosed with MDR-TB in Shenzhen during 2013-2017. By defining genomic clusters with a threshold of 12-single-nucleotide polymorphism distance based on whole-genome sequencing of their clinical strains, the clustering rate was calculated to evaluate the level of recent transmission. Risk factors were identified by multivariable logistic regression. To further delineate the epidemiological links, we invited the genomic-clustered patients to an in-depth social network investigation.

Results: In total, 105 (25.2%) of the 417 enrolled patients with MDR-TB were grouped into 40 genome clusters, suggesting recent transmission of MDR strains. The adjusted risk for student to have a clustered strain was 4.05 (95% confidence interval, 1.06-17.0) times greater than other patients. The majority (70%, 28/40) of the genomic clusters involved patients who lived in different districts, with residences separated by an average of 8.76 kilometers. Other than household members, confirmed epidemiological links were also identified among classmates and workplace colleagues.

Conclusions: These findings demonstrate that local transmission of MDR-TB is a serious problem in Shenzhen. While most transmission occurred between people who lived distant from each other, there was clear evidence that transmission occurred in schools and workplaces, which should be included as targeted sites for active case finding.The average residential distance between genomic-clustered cases was more than 8 kilometers, while schools and workplaces, identified as sites of transmission in this study, deserve increased vigilance for targeted case finding of multidrug-resistant tuberculosis.

Keywords: internal migrants; multidrug-resistant tuberculosis; spatial analysis; transmission; whole-genome sequencing.

Figure 1.

A, Sample enrollment and study flowchart. B, Provinces of origin of patients with multidrug-resistant tuberculosis before migrating to Shenzhen. The numbers of enrolled patients who were born in the different provinces of China are indicated within circles. Green circles indicate provinces where less than 10 patients were born, blue circles indicated provinces where 10–50 patients were born, and the red circle indicates cases from Guangdong province with the exception of Shenzhen. Abbreviations: MDR-TB, multidrug-resistant tuberculosis; TB, tuberculosis.

Figure 2.

Phylogeny, clustering, and resistance profile of 417 multidrug-resistant tuberculosis (MDR-TB) strains. Purple, red, navy, blue, and cyan branches indicated lineage 1, lineage 4, proto-Beijing, ancient Beijing, and modern Beijing strains, respectively. Solid stars outside the phylogeny indicate genomic-clustered strains differing by ≤12 single-nucleotide polymorphisms. The outer yellow-orange-red circle shows the development of MDR to MDR plus fluoroquinolone resistance, and finally to extensive drug resistance. The outermost colored dots indicate the resistance to 11 anti-TB drugs. Abbreviations: MDR, multidrug resistance; MDR-TB, multidrug-resistant tuberculosis.

Figure 3.

Kernel density maps of unique (A) and clustered (B) multidrug-resistant tuberculosis cases and genomic links and distances between the residences of genomic-linked cases, whose isolates differed by ≤12 single-nucleotide polymorphisms (SNPs) (C), ≤5 SNPs (D), and ≤1 SNP (E), respectively. The maps in panels A and B were colored according to varied kernel density estimation, with the red center representing areas with the most intense concentration of genomic unique (dots) and clustered (stars) patients, respectively. The arrow in panel B indicates the Longgang subdistrict of Longgang district (sub-LG) where patients had the highest risk to be involved in a genomic cluster. Arrows in the histogram indicate the median geographic distance between the paired clustered cases. Abbreviations: MDR-TB, multidrug-resistant tuberculosis; SNP, single-nucleotide polymorphism.

Figure 4.

Social network for 6 large clusters with confirmed or probable epidemiological links. Abbreviations: epi-link, epidemiogical link; FQ, fluoroquinolone; MDR-TB, multidrug-resistant tuberculosis.