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Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure

Nature Medicine volume 22, pages 1094–1100 (2016)Cite this article

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A Corrigendum to this article was published on 07 December 2017

A Corrigendum to this article was published on 07 April 2017

This article has been updated

Abstract

The absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (PTB). We detected positron emission tomography and computerized tomography (PET–CT) imaging response patterns consistent with active disease, along with the presence of Mycobacterium tuberculosis (MTB) mRNA in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, HIV-negative patients with PTB after a standard 6-month treatment plus 1 year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of nonresolving and intensifying lesions on PET–CT images might indicate ongoing transcription, suggesting that even apparently curative treatment for PTB may not eradicate all of the MTB bacteria in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies, and better treatment response markers, are probably needed for the successful development of improved and shortened PTB-treatment strategies.

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Figure 1: Flow chart of study design.
Figure 2: Representative Dx, M1 and M6 PET–CT images for cured patients after 6 months of standard treatment.
Figure 3: Clinical outcome and associated PET–CT findings.
Figure 4: Representative Dx, M6 and EOT + 1y PET–CT images for patients after 6 months of standard treatment.
Figure 5: Transformed (arcsinh) principal component one of mRNA transcript PCR data, demonstrating separation by detectable MTB mRNA as captured in PC1.

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Change history

  • 10 November 2017

    In the version of this article initially published, two authors in the Catalysis TB–Biomarker Consortium were incorrectly identified as Lani Theart and Coenie Kogelenberg. The authors’ names are Lani Thiart and Coenie Koegelenberg. Also, in Figure 3c, the three patients who initiated TB retreatment after EOT + 1y had ‘mixed’ response patterns at EOT + 1y, as is written in the text, and not ‘resolved’ response patterns, as is shown in the original version of the figure. The errors have been corrected in the HTML and PDF versions of the article.

  • 19 October 2016

    In the version of this article initially published, one of the authors of the Catalysis TB–Biomarker Consortium was incorrectly identified as Nelita Burger. The author's name is Nelita Du Plessis. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

Funding was provided by grants from the Catalysis Foundation for Health (CFH) (G.W., C.E.B. and D.A.) the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (C.E.B.) and the National Institute of Allergy and Infectious Diseases, International Collaborations in Infectious Disease Research (G.W.), as well as by a bursary from the South African National Research Fund and the Medical Research Council's Clinician Scholarship Program (S.T.M.). We thank our participants for their willingness to take part in this study. We acknowledge R. Thayer and M. Urdea of CFH, the staff at the Stellenbosch University Immunology Research Group, the International TB Research Center (Seoul), the Western Cape Academic PET–CT Centre, Ithemba LABS, Tygerberg Academic Hospital's Nuclear Medicine Department and Pulmonology Unit, as well as the managers and healthcare providers from the City of Cape Town Health Department for assistance with the recruitment of participants and sample collection.

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Authors and Affiliations

  1. Department of Science and Technology–National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Cape Town, South Africa

    Stephanus T Malherbe, Katharina Ronacher, Andre G Loxton, Magdalena Kriel, Gerard Tromp, Clifton E Barry III, Gerhard Walzl, Lance Lucas, Gian van der Spuy, Kim Stanley, Lani Thiart, Bronwyn Smith, Nelita Du Plessis, Caroline G G Beltran & Elizna Maasdorp

  2. Division of Molecular Biology and Human Genetics, South African Medical Research Council Centre for Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    Stephanus T Malherbe, Katharina Ronacher, Andre G Loxton, Magdalena Kriel, Gerard Tromp, Clifton E Barry III, Gerhard Walzl, Lance Lucas, Gian van der Spuy, Kim Stanley, Lani Thiart, Bronwyn Smith, Nelita Du Plessis, Caroline G G Beltran & Elizna Maasdorp

  3. Department of Medicine, Center for Emerging Pathogens, Rutgers New Jersey Medical School, Newark, New Jersey, USA

    Shubhada Shenai & David Alland

  4. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA

    Gregory Dolganov, Tran Van & Gary Schoolnik

  5. Division of Intramural Research, Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Ray Y Chen, Laura E Via & Clifton E Barry III

  6. Western Cape Academic Positron Emission Tomography–Computed Tomography Centre, Tygerberg Academic Hospital, Cape Town, South Africa

    James Warwick & Annare Ellmann

  7. Division of Nuclear Medicine, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    James Warwick & Annare Ellmann

  8. Department of Clinical Laboratory Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa

    Laura E Via & Clifton E Barry III

  9. International Tuberculosis Research Center, Seoul, South Korea

    Taeksun Song, Myungsun Lee & Hongjo Choi

  10. Catalysis Foundation for Health, Emeryville, California, USA

    Jill Winter

  11. National Medical Center, Seoul, South Korea

    Joonsung Joh

  12. Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Lori E Dodd

  13. Division of Pulmonology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    Brian Allwood, Coenie Koegelenberg & Morné Vorster

  14. Division of Radiodiagnosis, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    Stephanie Griffith-Richards

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  1. Stephanus T Malherbe
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  2. Shubhada Shenai
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  17. Jill Winter
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  21. Kim Stanley
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Consortia

the Catalysis TB–Biomarker Consortium

Contributions

S.T.M. managed patient recruitment, follow-up and sample collection, analyzed PET–CT scans and drafted the manuscript; R.Y.C., J. Warwick, L.E.V., D.A., C.E.B., J. Winter and G.W. designed the study, analyzed results and edited the manuscript; G.T. conducted statistical analysis and edited the manuscript; S.S., K.R., A.G.L., G.D., T.V., T.S. and G.S. designed and conducted experiments, analyzed results and edited the manuscript; M.K. and M.L. managed patient recruitment, patient follow-up and sample collection, and edited the manuscript; Catalysis TB–Biomarker Consortium members L.L., L.T., B.S., N.D.P. and C.G.G.B. processed samples and conducted experiments; G.v.d.S. and K.S. managed data collection, and database and sample storage; E.M. and L.E.D. analyzed results; A.E. and S.G.-R. analyzed PET–CT scans; H.C. and J.J. managed patient recruitment and follow-up; and B.A., M.V. and C.K. recruited patients and conducted bronchoscopies.

Corresponding author

Correspondence to Stephanus T Malherbe.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Notes 1–4 (PDF 1711 kb)

Supplementary Dataset 1

Time to diagnosis and supporting evidence for diagnosis of recurrences (XLSX 12 kb)

Supplementary Dataset 2

Demographical data and PET/CT scan responses per patient for South Korean cohort. (XLSX 13 kb)

Supplementary Dataset 3

Sputum MTB mRNA transcript values. (XLSX 26 kb)

Supplementary Dataset 4

Bronchoalveolar lavage MTB mRNA transcript values. (XLSX 21 kb)

Supplementary Dataset 5

Summary of lesion intensities for scan response patterns. (XLSX 16 kb)

Supplementary Dataset 6

Demographical data and PET/CT scan responses per patient in South African cohort. (XLSX 30 kb)

Supplementary Dataset 7

One year after the end of treatment scan responses per patient. (XLSX 16 kb)

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Malherbe, S., Shenai, S., Ronacher, K. et al. Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure. Nat Med 22, 1094–1100 (2016). https://doi.org/10.1038/nm.4177

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