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Tuberculosis
Original research
Association between bacterial homoplastic variants and radiological pathology in tuberculosis
  1. Louis Grandjean1,2,3,
  2. Joha Monteserin4,
  3. Robert Gilman2,5,
  4. Julia Pauschardt2,
  5. Sakib Rokadiya6,
  6. Cesar Bonilla7,
  7. Viviana Ritacco4,
  8. Julia Rios Vidal7,
  9. Julian Parkhill8,
  10. Sharon Peacock9,
  11. David AJ Moore10,
  12. Francois Balloux11
  1. 1 Department of Medicine, Imperial College London, London, UK
  2. 2 Laboratorio de Investigacion y Enfermedades Infecciosas, Cayetano Heredia Pervuvian University, Lima, Peru
  3. 3 Institute of Child Health, UCL Division of Infection and Immunity, London, UK
  4. 4 Instituto Nacional de Enfermedades Infecciosas INEI-ANLIS, Administración Nacional de Laboratorios e Institutos de Salud Dr Carlos G Malbrán, Buenos Aires, Argentina
  5. 5 Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
  6. 6 Faculty of Medicine, Imperial College London, London, UK
  7. 7 Unidad Tecnica de Tuberculosis MDR, Ministerio de Salud, Lima, Peru
  8. 8 Pathogen Genomics Group, Wellcome Trust Sanger Institute, Cambridge, UK
  9. 9 Faculty of Medicine, University of Cambridge, Cambridge, UK
  10. 10 TB Centre, London School of Hygiene and Tropical Medicine, London, UK
  11. 11 UCL Genetics Institute, University College London, London, UK
  1. Correspondence to Dr Louis Grandjean, Imperial College London, London W2 1NY, UK; l.grandjean{at}imperial.ac.uk

Abstract

Background Understanding how pathogen genetic factors contribute to pathology in TB could enable tailored treatments to the most pathogenic and infectious strains. New strategies are needed to control drug-resistant TB, which requires longer and costlier treatment. We hypothesised that the severity of radiological pathology on the chest radiograph in TB disease was associated with variants arising independently, multiple times (homoplasies) in the Mycobacterium tuberculosis genome.

Methods We performed whole genome sequencing (Illumina HiSeq2000 platform) on M. tuberculosis isolates from 103 patients with drug-resistant TB in Lima between 2010 and 2013. Variables including age, sex, HIV status, previous TB disease and the percentage of lung involvement on the pretreatment chest radiograph were collected from health posts of the national TB programme. Genomic variants were identified using standard pipelines.

Results Two mutations were significantly associated with more widespread radiological pathology in a multivariable regression model controlling for confounding variables (Rv2828c.141, RR 1.3, 95% CI 1.21 to 1.39, p<0.01; rpoC.1040 95% CI 1.77 to 2.16, RR 1.9, p<0.01). The rpoB.450 mutation was associated with less extensive radiological pathology (RR 0.81, 95% CI 0.69 to 0.94, p=0.03), suggestive of a bacterial fitness cost for this mutation in vivo. Patients with a previous episode of TB disease and those between 10 and 30 years of age also had significantly increased radiological pathology.

Conclusions This study is the first to compare the M. tuberculosis genome to radiological pathology on the chest radiograph. We identified two variants significantly positively associated with more widespread radiological pathology and one with reduced pathology. Prospective studies are warranted to determine whether mutations associated with increased pathology also predict the spread of drug-resistant TB.

  • tuberculosis
  • imaging/CT MRI etc
  • clinical epidemiology
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/thoraxjnl-2019-213281

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    Footnotes

    • Contributors Contributed to conception and design, acquisition, analysis and interpretation of data: LG, JM, RG, JP, SR, CB, VR, JRV, JP, SP, DAJM and FB. Contributed to drafting the work and critical revisions: LG, JM, RG, JP, SR, CB, VR, JRV, JP, SP, DAJM and FB. Contributed to final approval of the version submitted: LG, JM, RG, JP, SR, CB, VR, JRV, JP, SP, DAJM and FB. Contributed to the accountability, accuracy and integrity of the work: LG, JM, RG, JP, SR, CB, VR, JRV, JP, SP, DAJM and FB.

    • Funding This work was supported by the Wellcome Trust (Grant Number 201470/Z/16/Z). JM acknowledges the EU FP7-PEOPLE-2013-IRSES-Marie Curie Action DEANN “International Research Staff Exchange Scheme” (19061), which covered the costs for a 3-month visit to London to work with LG. FB acknowledges support from the BBSRC GCRF scheme and the National Institute for Health Research University College London Hospitals Biomedical Research Centre. SP acknowledges funding by the Health Innovation Challenge Fund (WT098600, HICF-T5-342), a parallel funding partnership between the Department of Health and Wellcome Trust.

    • Disclaimer The funding bodies had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

    • Competing interests JP and SP are consultants to Next Gen Diagnostics Llc.

    • Patient consent for publication Not required.

    • Ethics approval Ethical approval was obtained from the Institutional Review Board of Universidad Peruana Cayetano Heredia before the study began and institutional approval was obtained from the Peruvian Ministry of Health.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. The genomes associated with the publication have already been made freely available to other researchers by upload to the European Nucleotide Archive with the study accession number ERP004677.

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