M. tuberculosis microvariation is common and is associated with transmission: Analysis of three years prospective universal sequencing in England

David Wyllie; Trien Do; Richard Myers; Vlad Nikolayevskyy; Derrick Crook; Tim Peto; Eliza Alexander; Esther Robinson; A. Sarah Walker; Colin Campbell; E. Grace Smith

doi:10.1016/j.jinf.2022.05.011

M. tuberculosis microvariation is common and is associated with transmission: Analysis of three years prospective universal sequencing in England

David Wyllie^*, Trien Do, Richard Myers, Vlad Nikolayevskyy, Derrick Crook, Tim Peto, Eliza Alexander, Esther Robinson, A. Sarah Walker, Colin Campbell, E. Grace Smith

^*Corresponding author for this work

UK Health Security Agency

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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, compatible with transmission of the component strains. 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. Mixed infection was more common in lineages other than Lineage 4. 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; when present in pulmonary disease, such mixtures are associated with an increased risk of tuberculosis transmission. Funding: Public Health England; NIHR Health Protection Research Units; European Union.

Original language	English
Pages (from-to)	31-39
Number of pages	9
Journal	Journal of Infection
Volume	85
Issue number	1
DOIs	https://doi.org/10.1016/j.jinf.2022.05.011
Publication status	Published - Jul 2022

Bibliographical note

Funding Information:
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-2012–10,041], by the NIHR Biomedical Research center, Oxford, and the NIHR HPRU in Genomics and Enabling Data at the University of Warwick [NIHR200892]. VN received funding from the European center for Disease Control under Grants 2014/001 and 2018/001. TEAP, DCW and ASW are NIHR Senior Investigators. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or the UK Health Security Agency. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Publisher Copyright:
© 2022

Keywords

M. tuberculosis
Mixed infection
Transmission

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jinf.2022.05.011

Cite this

Wyllie, D., Do, T., Myers, R., Nikolayevskyy, V., Crook, D., Peto, T., Alexander, E., Robinson, E., Walker, A. S., Campbell, C., & Smith, E. G. (2022). M. tuberculosis microvariation is common and is associated with transmission: Analysis of three years prospective universal sequencing in England. Journal of Infection, 85(1), 31-39. https://doi.org/10.1016/j.jinf.2022.05.011

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title = "M. tuberculosis microvariation is common and is associated with transmission: Analysis of three years prospective universal sequencing in England",

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, compatible with transmission of the component strains. 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. Mixed infection was more common in lineages other than Lineage 4. 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; when present in pulmonary disease, such mixtures are associated with an increased risk of tuberculosis transmission. Funding: Public Health England; NIHR Health Protection Research Units; European Union.",

keywords = "M. tuberculosis, Mixed infection, Transmission",

author = "David Wyllie and Trien Do and Richard Myers and Vlad Nikolayevskyy and Derrick Crook and Tim Peto and Eliza Alexander and Esther Robinson and Walker, {A. Sarah} and Colin Campbell and Smith, {E. Grace}",

note = "Funding Information: 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-2012–10,041], by the NIHR Biomedical Research center, Oxford, and the NIHR HPRU in Genomics and Enabling Data at the University of Warwick [NIHR200892]. VN received funding from the European center for Disease Control under Grants 2014/001 and 2018/001. TEAP, DCW and ASW are NIHR Senior Investigators. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or the UK Health Security Agency. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Publisher Copyright: {\textcopyright} 2022",

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Wyllie, D, Do, T, Myers, R, Nikolayevskyy, V, Crook, D, Peto, T, Alexander, E, Robinson, E, Walker, AS, Campbell, C & Smith, EG 2022, 'M. tuberculosis microvariation is common and is associated with transmission: Analysis of three years prospective universal sequencing in England', Journal of Infection, vol. 85, no. 1, pp. 31-39. https://doi.org/10.1016/j.jinf.2022.05.011

TY - JOUR

T1 - M. tuberculosis microvariation is common and is associated with transmission

T2 - Analysis of three years prospective universal sequencing in England

AU - Wyllie, David

AU - Do, Trien

AU - Myers, Richard

AU - Nikolayevskyy, Vlad

AU - Crook, Derrick

AU - Peto, Tim

AU - Alexander, Eliza

AU - Robinson, Esther

AU - Walker, A. Sarah

AU - Campbell, Colin

AU - Smith, E. Grace

N1 - Funding Information: 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-2012–10,041], by the NIHR Biomedical Research center, Oxford, and the NIHR HPRU in Genomics and Enabling Data at the University of Warwick [NIHR200892]. VN received funding from the European center for Disease Control under Grants 2014/001 and 2018/001. TEAP, DCW and ASW are NIHR Senior Investigators. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or the UK Health Security Agency. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Publisher Copyright: © 2022

PY - 2022/7

Y1 - 2022/7

N2 - 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, compatible with transmission of the component strains. 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. Mixed infection was more common in lineages other than Lineage 4. 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; when present in pulmonary disease, such mixtures are associated with an increased risk of tuberculosis transmission. Funding: Public Health England; NIHR Health Protection Research Units; European Union.

AB - 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, compatible with transmission of the component strains. 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. Mixed infection was more common in lineages other than Lineage 4. 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; when present in pulmonary disease, such mixtures are associated with an increased risk of tuberculosis transmission. Funding: Public Health England; NIHR Health Protection Research Units; European Union.

KW - M. tuberculosis

KW - Mixed infection

KW - Transmission

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ER -

M. tuberculosis microvariation is common and is associated with transmission: Analysis of three years prospective universal sequencing in England

Abstract

Bibliographical note

Keywords

UN SDGs

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