Abstract
Background: Tuberculosis incidence in the UK has risen in the past decade. Disease control depends on epidemiological data, which can be difficult to obtain. Whole-genome sequencing can detect microevolution within Mycobacterium tuberculosis strains. We aimed to estimate the genetic diversity of related M tuberculosis strains in the UK Midlands and to investigate how this measurement might be used to investigate community outbreaks. Methods: In a retrospective observational study, we used Illumina technology to sequence M tuberculosis genomes from an archive of frozen cultures. We characterised isolates into four groups: cross-sectional, longitudinal, household, and community. We measured pairwise nucleotide differences within hosts and between hosts in household outbreaks and estimated the rate of change in DNA sequences. We used the findings to interpret network diagrams constructed from 11 community clusters derived from mycobacterial interspersed repetitive-unit-variable-number tandem-repeat data. Findings: We sequenced 390 separate isolates from 254 patients, including representatives from all five major lineages of M tuberculosis. The estimated rate of change in DNA sequences was 0·5 single nucleotide polymorphisms (SNPs) per genome per year (95% CI 0·3-0·7) in longitudinal isolates from 30 individuals and 25 families. Divergence is rarely higher than five SNPs in 3 years. 109 (96%) of 114 paired isolates from individuals and households differed by five or fewer SNPs. More than five SNPs separated isolates from none of 69 epidemiologically linked patients, two (15%) of 13 possibly linked patients, and 13 (17%) of 75 epidemiologically unlinked patients (three-way comparison exact p<0·0001). Genetic trees and clinical and epidemiological data suggest that super-spreaders were present in two community clusters. Interpretation: Whole-genome sequencing can delineate outbreaks of tuberculosis and allows inference about direction of transmission between cases. The technique could identify super-spreaders and predict the existence of undiagnosed cases, potentially leading to early treatment of infectious patients and their contacts. Funding: Medical Research Council, Wellcome Trust, National Institute for Health Research, and the Health Protection Agency.
| Original language | English |
|---|---|
| Pages (from-to) | 137-146 |
| Number of pages | 10 |
| Journal | The Lancet Infectious Diseases |
| Volume | 13 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2013 |
Bibliographical note
Funding Information:JP has received support for conference travel and accommodation from Illumina. PMH has received honoraria for developing and delivering educational presentation for Eumedica, Pfizer, Merck, Novartis, Magus Communications, Wyeth; research funding from Pfizer, Eumedica; consultancy payment from Pfizer, Eumedica, Novartis, Basilea, Novacta, Novolytics, Merck, Wyeth, and Optimer; he is director of Modus Medica, a medical education company. All other authors declare that they have no conflicts of interest.
Funding Information:
This study was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and the UK Clinical Research Collaboration (UKCRC) Modernising Medical Microbiology Consortium, which is funded by the UKCRC Translational Infection Research Initiative supported by Medical Research Council, Biotechnology and Biological Sciences Research Council, and the National Institute for Health Research on behalf of the Department of Health ( grant G0800778 ) and the Wellcome Trust ( 087646/Z/08/Z ). We acknowledge the support of Wellcome Trust core funding ( grant 098051 ) at the Wellcome Trust Sanger Institute, and of the HPA for reference laboratory services. TMW is an MRC Research Training Fellow. DWE is an NIHR Doctoral Research Fellow. DWC and TEAP are NIHR Senior Investigators. We thank the tuberculosis public health teams for their help: the TB Aftercare team at Birmingham Chest Clinic, particularly Cathy Browne (Heart of England NHS Foundation Trust); Deborah Crisp and Jackie Berry (George Eliot Hospital NHS Trust, Coventry and Warwickshire TB Nursing team); Roger Gajraj (West Midlands East HPU); Lindsey Abbott, Helen Thuraisingam, and Gerrit Woltmann (East Midlands South Health Protection Unit, Leicester); Karthik Paranthaman and Cathy Mallaghan (East Midlands South Health Protection Unit, Wellingborough); Maggie Chappell and Liz Townson (Northamptonshire Healthcare NHS Foundation Trust); Nic Coetzee (West Midlands North Health Protection Unit); Rosemary McNaught and Andy Naisby (South Yorkshire Health Protection Unit); Terry Matthews, Kay Crawford, and Debbie Harmer (North Yorkshire and Humber Health Protection Unit); and Andrea Gough (Northern Lincolnshire and Goole Hospitals NHS Foundation Trust).
