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M. tuberculosis Microvariation Is Common and Is Associated with Transmission: Analysis of Three Years Prospective Universal Sequencing in England

40 Pages Posted: 28 Jun 2019

See all articles by David Wyllie

David Wyllie

Imperial College London - NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance; NHS Foundation Trust - Addenbrooke's Hospital

Trien Do

Imperial College London - NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance

Richard Myers

Government of the United Kingdom - Public Health England

Vlad Nikolayevskyy

Government of the United Kingdom - Public Health England

Derrick W. Crook

University of Oxford - Nuffield Department of Medicine; University of Oxford - John Radcliffe Hospital

Eliza Alexander

Government of the United Kingdom - Public Health England

Esther Robinson

Government of the United Kingdom - Public Health England

A. Sarah Walker

University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital

Colin Campbell

Government of the United Kingdom - Public Health England

E. Grace Smith

Government of the United Kingdom - Public Health England

More...

Abstract

Background: The prevalence, association with disease status, and public health impact of infection with mixtures of M. tuberculosis strains is unclear, in part due to limitations of existing methods for detecting mixed infections.

Methods: We developed an algorithm to identify mixtures of M. tuberculosis strains using next generation sequencing data, assessing performance using simulated sequences. We identified mixed M. tuberculosis strains when there was at least one mixed nucleotide position, and where both the mixture's components were present in similar isolates from other individuals. We determined risk factors for mixed infection among isolations of M. tuberculosis in England using logistic regression. We used survival analyses to assess the association between mixed infection and putative transmission.

Findings 6,560 isolations of TB were successfully sequenced in England 2016-2018. Of 3,691 (56%) specimens for which similar sequences had been isolated from at least two other individuals, 341 (9.2%) were mixed. Infection with lineages other than Lineage 4 were associated with mixed infection. Among the 1,823 individuals with pulmonary infection with Lineage 4 M. tuberculosis, mixed infection was associated with significantly increased risk of subsequent isolation of closely related organisms from a different individual (HR 1.43, 95% CI 1.05,1.94), indicative of transmission.

Interpretation Mixtures of transmissible strains occur in at least 5% of tuberculosis infections in England; where present in pulmonary disease, such mixtures are associated with an increased risk of tuberculosis transmission.

Funding Statement: This study was supported by the National Institute for Health Research (NIHR) Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at University of Oxford in partnership with Public Health England [HPRU-2012-10041], and by the NIHR Biomedical Research Centre, Oxford. VN received funding from the European Centre for Disease Control under Grants 2014/001 and 2018/001. TEAP, DCW and ASW are NIHR Senior Investigators.

Declaration of Interests: The authors state: "No conflicts of interest are declared."

Ethics Approval Statement: The authors declared: "The Health and Social Care Act 2012 and related statutory instruments provide a legal basis for the activity. This work is part of service development carried out under this framework, and as such explicit ethical approval is unnecessary."

Keywords: M. tuberculosis, Transmission, Mixed infection

Suggested Citation

Wyllie, David and Do, Trien and Myers, Richard and Nikolayevskyy, Vlad and Crook, Derrick W. and Alexander, Eliza and Robinson, Esther and Walker, A. Sarah and Campbell, Colin and Smith, E. Grace, M. tuberculosis Microvariation Is Common and Is Associated with Transmission: Analysis of Three Years Prospective Universal Sequencing in England (June 27, 2019). Available at SSRN: https://ssrn.com/abstract=3410906 or http://dx.doi.org/10.2139/ssrn.3410906

David Wyllie (Contact Author)

Imperial College London - NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance ( email )

London
United Kingdom

NHS Foundation Trust - Addenbrooke's Hospital ( email )

Cambridge Biomedical Campus
Hills Road
Cambridge, CB2 0QQ
United Kingdom

Trien Do

Imperial College London - NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance

London
United Kingdom

Richard Myers

Government of the United Kingdom - Public Health England

Wellington House
133-155 Waterloo Road
London, SE1 8UG
United Kingdom

Vlad Nikolayevskyy

Government of the United Kingdom - Public Health England

Wellington House
133-155 Waterloo Road
London, SE1 8UG
United Kingdom

Derrick W. Crook

University of Oxford - Nuffield Department of Medicine

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

University of Oxford - John Radcliffe Hospital ( email )

Oxford, Oxfordshire, England
United Kingdom

Eliza Alexander

Government of the United Kingdom - Public Health England

Wellington House
133-155 Waterloo Road
London, SE1 8UG
United Kingdom

Esther Robinson

Government of the United Kingdom - Public Health England

Wellington House
133-155 Waterloo Road
London, SE1 8UG
United Kingdom

A. Sarah Walker

University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital ( email )

Oxford, Oxfordshire, England
United Kingdom

Colin Campbell

Government of the United Kingdom - Public Health England

Wellington House
133-155 Waterloo Road
London, SE1 8UG
United Kingdom

E. Grace Smith

Government of the United Kingdom - Public Health England

Wellington House
133-155 Waterloo Road
London, SE1 8UG
United Kingdom

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