XDR-TB transmission in London: Case management and contact tracing investigation assisted by early whole genome sequencing

Arnold, Amber; Witney, Adam A.; Vergnano, Stephania; Roche, A.; Cosgrove, Catherine; Houston, Angela; Gould, Katherine A.; Hinds, Jason; Riley, Peter; Macallan, Derek C.; Butcher, Philip D.; Harrison, Thomas S.

doi:10.1016/j.jinf.2016.04.037

Cited by 32 publications

(20 citation statements)

References 27 publications

(22 reference statements)

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“…Deciphering tuberculosis transmission dynamics is crucial for the optimisation of local and global control measures and the early detection of MDR and XDR outbreaks. [142][143][144] Whole-genome sequencing also provides a robust system for differentiating clinical isolates into major lineages and sublineages using an accurate nomenclature framework, 75 paving the way for investigations of lineagespecific pathobiological characteristics.…”

Section: The Lancet Respiratory Medicine Commissionmentioning

confidence: 99%

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Dheda

Gumbo

Maartens

et al. 2017

The Lancet Respiratory Medicine

521

474

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Section: The Lancet Respiratory Medicine Commissionmentioning

confidence: 99%

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Dheda

Gumbo

Maartens

et al. 2017

The Lancet Respiratory Medicine

521

474

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“…Second, the difference in drug resistance profiles and related parameters, such as treatment efficacy between the original and validation cohorts of strains for the PhyC, could have introduced bias in measurement of the transmissibility phenotype (Table E2). The facts that transmission of drug-resistant strains has been widely documented (38,39) and that mathematical models have estimated the transmission cost of drug resistance to be as low as 10% (40) suggest that the overall fitness for transmission of drug-resistant strains is comparable to that of sensitive strains. The possibility for epistasis indeed exists; in 2016, for example, multidrugresistant strains in China with rpoC compensatory mutations were found to be more likely than their drug-sensitive counterparts to be clustered (41).…”

Section: Discussionmentioning

confidence: 99%

Transmissible Mycobacterium tuberculosis Strains Share Genetic Markers and Immune Phenotypes

Nebenzahl-Guimaraes

Laarhoven²,

Mustafa

et al. 2017

Am J Respir Crit Care Med

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Rationale: Successful transmission of tuberculosis depends on the interplay of human behavior, host immune responses, and Mycobacterium tuberculosis virulence factors. Previous studies have been focused on identifying host risk factors associated with increased transmission, but the contribution of specific genetic variations in mycobacterial strains themselves are still unknown.Objectives: To identify mycobacterial genetic markers associated with increased transmissibility and to examine whether these markers lead to altered in vitro immune responses.Methods: Using a comprehensive tuberculosis registry (n = 10,389) and strain collection in the Netherlands, we identified a set of 100 M. tuberculosis strains either least or most likely to be transmitted after controlling for host factors. We subjected these strains to wholegenome sequencing and evolutionary convergence analysis, and we repeated this analysis in an independent validation cohort. We then performed immunological experiments to measure in vitro cytokine production and neutrophil responses to a subset of the original strains with or without the identified mutations associated with increased transmissibility. Measurements and Main Results:We identified the loci espE, PE-PGRS56, Rv0197, Rv2813-2814c, and Rv2815-2816c as targets of convergent evolution among transmissible strains. We validated four of these regions in an independent set of strains, and we demonstrated that mutations in these targets affected in vitro monocyte and T-cell cytokine production, neutrophil reactive oxygen species release, and apoptosis.Conclusions: In this study, we identified genetic markers in convergent evolution of M. tuberculosis toward enhanced transmissibility in vivo that are associated with altered immune responses in vitro.

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“…Mutations and gene presence/absence alone do not solely determine phenotypic resistance and the associated success or failure of antibiotic therapy—resistance may depend on gene expression levels, and treatment failure can be influenced by host genetic polymorphisms . Nevertheless, for slow‐growing organisms like Mtb, genomics offers a rapid alternative to traditional DSTs that is already affecting patient care …”

Section: Step 4: Rapid Resistance Predictionmentioning

confidence: 99%

A brief primer on genomic epidemiology: lessons learned fromMycobacterium tuberculosis

Guthrie

Gardy

2016

Annals of the New York Academy of Sciences

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Genomics is now firmly established as a technique for the investigation and reconstruction of communicable disease outbreaks, with many genomic epidemiology studies focusing on revealing transmission routes of Mycobacterium tuberculosis. In this primer, we introduce the basic techniques underlying transmission inference from genomic data, using illustrative examples from M. tuberculosis and other pathogens routinely sequenced by public health agencies. We describe the laboratory and epidemiological scenarios under which genomics may or may not be used, provide an introduction to sequencing technologies and bioinformatics approaches to identifying transmission-informative variation and resistance-associated mutations, and discuss how variation must be considered in the light of available clinical and epidemiological information to infer transmission.

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XDR-TB transmission in London: Case management and contact tracing investigation assisted by early whole genome sequencing

Abstract: WGS of Mtb enabled rapid effective individualized treatment and facilitated public health interventions by early identification of transmission events.

Cited by 32 publications

References 27 publications

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Transmissible Mycobacterium tuberculosis Strains Share Genetic Markers and Immune Phenotypes

A brief primer on genomic epidemiology: lessons learned fromMycobacterium tuberculosis

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