Genomic epidemiology of tuberculosis in eastern Malaysia: insights for strengthening public health responses

Abstract

Tuberculosis is a leading public health priority in eastern Malaysia. Knowledge of the genomic epidemiology of tuberculosis can help tailor public health interventions. Our aims were to determine tuberculosis genomic epidemiology and characterize resistance mutations in the ethnically diverse city of Kota Kinabalu, Sabah, located at the nexus of Malaysia, Indonesia, Philippines and Brunei. We used an archive of prospectively collected Mycobacterium tuberculosis samples paired with epidemiological data. We collected sputum and demographic data from consecutive consenting outpatients with pulmonary tuberculosis at the largest tuberculosis clinic from 2012 to 2014, and selected samples from tuberculosis inpatients from the tertiary referral centre during 2012–2014 and 2016–2017. Two hundred and eight M . tuberculosis sequences were available for analysis, representing 8 % of cases notified during the study periods. Whole-genome phylogenetic analysis demonstrated that most strains were lineage 1 (195/208, 93.8 %), with the remainder being lineages 2 (8/208, 3.8 %) or 4 (5/208, 2.4 %). Lineages or sub-lineages were not associated with patient ethnicity. The lineage 1 strains were diverse, with sub-lineage 1.2.1 being dominant (192, 98 %). Lineage 1.2.1.3 isolates were geographically most widely distributed. The greatest diversity occurred in a border town sub-district. The time to the most recent common ancestor for the three major lineage 1.2.1 clades was estimated to be the year 1966 (95 % HPD 1948–1976). An association was found between failure of culture conversion by week 8 of treatment and infection with lineage 2 (4/6, 67 %) compared with lineage 1 strains (4/83, 5 %) (P<0.001), supporting evidence of greater virulence of lineage 2 strains. Eleven potential transmission clusters (SNP difference ≤12) were identified; at least five included people living in different sub-districts. Some linked cases spanned the whole 4-year study period. One cluster involved a multidrug-resistant tuberculosis strain matching a drug-susceptible strain from 3 years earlier. Drug resistance mutations were uncommon, but revealed one phenotype–genotype mismatch in a genotypically multidrug-resistant isolate, and rare nonsense mutations within the katG gene in two isolates. Consistent with the regionally mobile population, M. tuberculosis strains in Kota Kinabalu were diverse, although several lineage 1 strains dominated and were locally well established. Transmission clusters – uncommonly identified, likely attributable to incomplete sampling – showed clustering occurring across the community, not confined to households or sub-districts. The findings indicate that public health priorities should include active case finding and early institution of tuberculosis management in mobile populations, while there is a need to upscale effective contact investigation beyond households to include other contacts within social networks.

Whole-genome single nucleotide variant phylogenetic analysis of Mycobacterium tuberculosis Lineage 1 in endemic regions of Asia and Africa

“…Interestingly, a sublineage in the Napier's scheme 6 not present in our main dataset was L1.2.1, with most isolates being from patients in Europe. Therefore, we inferred a separate phylogeny of L1.2 isolates that included 410 isolates from our dataset and additional 364 isolates from Napier et al 6 and other recent studies 10 , 14 (Fig. 2 ).…”

“…Supplementary Table S3 shows the distribution of samples across countries and sublineages. We also obtained additional 364 L1.2 isolates from three recent studies 6 , 10 , 14 . This set was analyzed together with the 410 L1.2 isolates from the main dataset, referred to as the L1.2 dataset ( n = 364 + 410 = 774) (Supplementary Table S2 ).…”

Improving case detection through TB contact risk stratification by Xpert MTB/RIF Ultra and spatial parameters. Evaluation of an innovative ACF strategy in Mozambique

“…It can be argued that the small window screening period used in this intervention (3months), might be too short to find recent contacts or older primary cases (35). Molecular epidemiology studies should shed more light on the nature of the link between IC and TB cases found among contacts (36)(37) (38).…”

“…It can be argued that the small window screening period used in this intervention (3months), might be too short to find recent contacts or older primary cases(35). Molecular epidemiology studies should shed more light on the nature of the link between IC and TB cases found among contacts (36)(37)(38). Other important questions such as what the best window period for screening is, whether there is a need for time-separated screening visits, the role of HIV status in TB transmission and what role gender plays on the impact of ACF activities need to be answered to refine ACF intervention designs.…”

TransFlow: a Snakemake workflow for transmission analysis ofMycobacterium tuberculosiswhole-genome sequencing data

“…Another population-based, retrospective TB study in Shanghai, China (referred to as CTB), utilized both VNTR and WGS strategies to detect the recent transmission of 324 multidrug-resistant (MDR) tuberculosis strains and demonstrated WGS can measure the heterogeneity of drug-resistant mutations within and between hosts and help to determine the transmission patterns of MDR TB ( Yang et al , 2017 ). Along with the UKTB and CTB studies, multiple studies from around the world have pointed out that the resolution of WGS is superior to that of MIRU-VNTR typing and that epidemiological links can be traced more accurately ( Bainomugisa et al , 2021 ; Bjorn-Mortensen et al , 2016 ; Folkvardsen et al , 2017 ; Ford et al , 2012 ; Jiang et al , 2020 ).…”