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Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model

Jan Heyckendorf, Sebastian Marwitz, Maja Reimann, Korkut Avsar, Andrew DiNardo, Gunar Günther, Michael Hoelscher, Elmira Ibraim, Barbara Kalsdorf, Stefan H.E. Kaufmann, Irina Kontsevaya, Frank van Leth, Anna Maria Mandalakas, Florian P. Maurer, Marius Müller, Dörte Nitschkowski, Ioana D. Olaru, Cristina Popa, Andrea Rachow, Thierry Rolling, Jan Rybniker, Helmut J.F. Salzer, Patricia Sanchez-Carballo, Maren Schuhmann, Dagmar Schaub, Victor Spinu, Isabelle Suárez, Elena Terhalle, Markus Unnewehr, January Weiner 3rd, Torsten Goldmann, Christoph Lange
European Respiratory Journal 2021; DOI: 10.1183/13993003.03492-2020
Jan Heyckendorf
1Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany
2German Center for Infection Research (DZIF), Borstel, Germany
3International Health/Infectious Diseases, University of Lübeck, Lübeck, Germany
34Authors contributed equally
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Sebastian Marwitz
4Pathology of the Universal Medical Center Schleswig-Holstein (UKSH) and the Research Center Borstel, Campus Borstel, Airway Research Center North (ARCN), Borstel, Germany
5German Center for Lung Research (DZL), Borstel, Germany
34Authors contributed equally
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Maja Reimann
1Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany
2German Center for Infection Research (DZIF), Borstel, Germany
3International Health/Infectious Diseases, University of Lübeck, Lübeck, Germany
34Authors contributed equally
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Korkut Avsar
6Asklepios Fachkliniken München-Gauting, Munich, Germany
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Andrew DiNardo
7The Global Tuberculosis Program, Texas Children's Hospital, Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, USA
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Gunar Günther
8Department of Medicine, University of Namibia School of Medicine, Windhoek, Namibia
9Inselspital Bern, Department of Pulmonology, Bern, Switzerland
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Michael Hoelscher
10Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU Munich, Munich, Germany
11German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
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Elmira Ibraim
12Institutul de Pneumoftiziologie “Marius Nasta”, MDR-TB Research Department, Bucharest, Romania
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Barbara Kalsdorf
1Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany
2German Center for Infection Research (DZIF), Borstel, Germany
3International Health/Infectious Diseases, University of Lübeck, Lübeck, Germany
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Stefan H.E. Kaufmann
13Max Planck Institute for Infection Biology, Berlin, Germany
14Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
15Hagler Institute for Advanced Study, Texas A&M University, College Station, USA
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Irina Kontsevaya
1Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany
2German Center for Infection Research (DZIF), Borstel, Germany
3International Health/Infectious Diseases, University of Lübeck, Lübeck, Germany
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Frank van Leth
16Department of Global Health, Amsterdam University Medical Centres, Location AMC, Amsterdam, The Netherlands
17Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands
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Anna Maria Mandalakas
7The Global Tuberculosis Program, Texas Children's Hospital, Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, USA
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Florian P. Maurer
18National and WHO Supranational Reference Laboratory for Mycobacteria, Research Center Borstel, Borstel, Germany
19Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Marius Müller
20Sankt Katharinen-Krankenhaus, Frankfurt, Germany
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Dörte Nitschkowski
4Pathology of the Universal Medical Center Schleswig-Holstein (UKSH) and the Research Center Borstel, Campus Borstel, Airway Research Center North (ARCN), Borstel, Germany
5German Center for Lung Research (DZL), Borstel, Germany
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Ioana D. Olaru
21London School of Hygiene and Tropical Medicine, London, United Kingdom
22Biomedical Research and Training Institute, Harare, Zimbabwe
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Cristina Popa
12Institutul de Pneumoftiziologie “Marius Nasta”, MDR-TB Research Department, Bucharest, Romania
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Andrea Rachow
10Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU Munich, Munich, Germany
11German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
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Thierry Rolling
2German Center for Infection Research (DZIF), Borstel, Germany
23Division of Infectious Diseases, I. Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
24Department of Clinical Immunology of Infectious Diseases, Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany
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Jan Rybniker
25Department I of Internal Medicine, Division of Infectious Diseases, University of Cologne, Cologne, Germany
26German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany
27Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
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Helmut J.F. Salzer
28Department of Pulmonology, Kepler University Hospital, Linz, Austria
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Patricia Sanchez-Carballo
1Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany
2German Center for Infection Research (DZIF), Borstel, Germany
3International Health/Infectious Diseases, University of Lübeck, Lübeck, Germany
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Maren Schuhmann
29Universitäts Thoraxklinik-Heidelberg, Heidelberg, Germany
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Dagmar Schaub
1Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany
2German Center for Infection Research (DZIF), Borstel, Germany
3International Health/Infectious Diseases, University of Lübeck, Lübeck, Germany
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Victor Spinu
12Institutul de Pneumoftiziologie “Marius Nasta”, MDR-TB Research Department, Bucharest, Romania
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Isabelle Suárez
25Department I of Internal Medicine, Division of Infectious Diseases, University of Cologne, Cologne, Germany
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Elena Terhalle
1Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany
2German Center for Infection Research (DZIF), Borstel, Germany
3International Health/Infectious Diseases, University of Lübeck, Lübeck, Germany
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Markus Unnewehr
30Department of Respiratory Medicine and Infectious Diseases, St. Barbara-Klinik, Hamm, Germany
31University of Witten-Herdecke, Witten, Germany
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January Weiner 3rd
32Berlin Institute of HealthCUBI (Core Unit Bioinformatics), Berlin, Germany
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Torsten Goldmann
4Pathology of the Universal Medical Center Schleswig-Holstein (UKSH) and the Research Center Borstel, Campus Borstel, Airway Research Center North (ARCN), Borstel, Germany
5German Center for Lung Research (DZL), Borstel, Germany
34Authors contributed equally
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Christoph Lange
1Division of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany
2German Center for Infection Research (DZIF), Borstel, Germany
3International Health/Infectious Diseases, University of Lübeck, Lübeck, Germany
33Department of Medicine, Karolinska Institute, Stockholm, Sweden
34Authors contributed equally
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Abstract

Background The World Health Organization recommends standardised treatment durations for patients with tuberculosis. We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-tuberculosis.

Methods Adult patients with pulmonary tuberculosis were prospectively enrolled into 5 independent cohorts in Germany and Romania. Clinical and microbiological data, and whole-blood for RNA transcriptomic analysis were collected at pre-defined timepoints throughout therapy. Treatment outcomes were ascertained Treatment outcomes were ascertained by TBNET criteria (6-month culture status/one-year follow-up). A whole-blood RNA therapy end model was developed in a multi-step process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment timepoints.

Results Fifty patients with drug-susceptible (DS)-tuberculosis and 30 patients with MDR-tuberculosis were recruited in the German identification cohorts (DS- and MDR-GIC), 28 patients with DS-tuberculosis and 32 patients with MDR-tuberculosis in the German validation cohorts (DS- and MDR-GVC), and 52 patients with MDR-tuberculosis in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model that defined cure-associated end-of-therapy timepoints was derived from the DS- and MDR-GIC data. The model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (AUC=0.94 [95%CI:0.9–0.98]) and suggests that cure may be achieved with shorter treatment durations for tuberculosis patients in the MDR-GIC (mean reduction 218.0 days, 34.2%, p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%, p<0.001), and the MDR-RVC (mean reduction of 161.0 days, 23.4%, p=0.001).

Conclusion Biomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-tuberculosis.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Kohli has nothing to disclose.

Conflict of interest: Dr. Heyckendorf reports no conflicts of interest. The Research Center Borstel has a patent EP20158652.6.

Conflict of interest: Dr. Marwitz has nothing to disclose.

Conflict of interest: Dr. Reimann has nothing to disclose.

Conflict of interest: Dr. Avsar has nothing to disclose.

Conflict of interest: Dr. DiNardo has nothing to disclose.

Conflict of interest: Dr. Günther has nothing to disclose.

Conflict of interest: Dr. Hoelscher has nothing to disclose.

Conflict of interest: Dr. Ibraim reports grants, personal fees and non-financial support from Deutsches Zentrum fur Infektionsforschung - DZIF, during the conduct of the study;.

Conflict of interest: Dr. Kalsdorf has nothing to disclose.

Conflict of interest: Dr. Kaufmann has nothing to disclose.

Conflict of interest: Dr. Kontsevaya reports grants from German Center for Infectious Research (DZIF), German Center for Lung Research (DZL), during the conduct of the study; grants from EU Horizon 2020 AnTBiotic (733079) and CARE (825673), outside the submitted work.

Conflict of interest: Dr. van Leth has nothing to disclose.

Conflict of interest: Dr. Mandalakas has nothing to disclose.

Conflict of interest: Dr. Maurer has nothing to disclose.

Conflict of interest: Dr. Müller has nothing to disclose.

Conflict of interest: Dörte Nitschkowski has nothing to disclose.

Conflict of interest: Dr. Olaru has nothing to disclose.

Conflict of interest: Dr. Popa has nothing to disclose.

Conflict of interest: Dr. Rachow has nothing to disclose.

Conflict of interest: Dr. Rolling has nothing to disclose.

Conflict of interest: Dr. Rybniker has nothing to disclose.

Conflict of interest: Dr. Salzer has nothing to disclose.

Conflict of interest: Dr. Sanchez Carballo has nothing to disclose.

Conflict of interest: Dr. Schuhmann has nothing to disclose.

Conflict of interest: Dr. Schaub has nothing to disclose.

Conflict of interest: Dr. Spinu reports grants, personal fees and non-financial support from Deutsches Zentrum fur Infektionsforschung - DZIF, during the conduct of the study.

Conflict of interest: Dr. Suarez has nothing to disclose.

Conflict of interest: Dr. Terhalle has nothing to disclose.

Conflict of interest: Dr. Unnewehr has nothing to disclose.

Conflict of interest: Dr. Weiner has nothing to disclose.

Conflict of interest: Dr. Goldmann reports In addition, Dr. Goldmann has a patent null pending.Dr. Goldmann reports In addition, Dr. Goldmann has a patent null pending.

Conflict of interest: Dr. Lange reports personal fees from Chiesi, personal fees from Gilead, personal fees from Janssen, personal fees from Lucane, personal fees from Novartis, personal fees from Oxoid, personal fees from Berlin Chemie, personal fees from Thermofisher, personal fees from Oxfordimmunotec, outside the submitted work.

  • Received September 14, 2020.
  • Accepted January 20, 2021.
  • ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
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Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model
Jan Heyckendorf, Sebastian Marwitz, Maja Reimann, Korkut Avsar, Andrew DiNardo, Gunar Günther, Michael Hoelscher, Elmira Ibraim, Barbara Kalsdorf, Stefan H.E. Kaufmann, Irina Kontsevaya, Frank van Leth, Anna Maria Mandalakas, Florian P. Maurer, Marius Müller, Dörte Nitschkowski, Ioana D. Olaru, Cristina Popa, Andrea Rachow, Thierry Rolling, Jan Rybniker, Helmut J.F. Salzer, Patricia Sanchez-Carballo, Maren Schuhmann, Dagmar Schaub, Victor Spinu, Isabelle Suárez, Elena Terhalle, Markus Unnewehr, January Weiner, Torsten Goldmann, Christoph Lange
European Respiratory Journal Jan 2021, 2003492; DOI: 10.1183/13993003.03492-2020

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Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model
Jan Heyckendorf, Sebastian Marwitz, Maja Reimann, Korkut Avsar, Andrew DiNardo, Gunar Günther, Michael Hoelscher, Elmira Ibraim, Barbara Kalsdorf, Stefan H.E. Kaufmann, Irina Kontsevaya, Frank van Leth, Anna Maria Mandalakas, Florian P. Maurer, Marius Müller, Dörte Nitschkowski, Ioana D. Olaru, Cristina Popa, Andrea Rachow, Thierry Rolling, Jan Rybniker, Helmut J.F. Salzer, Patricia Sanchez-Carballo, Maren Schuhmann, Dagmar Schaub, Victor Spinu, Isabelle Suárez, Elena Terhalle, Markus Unnewehr, January Weiner, Torsten Goldmann, Christoph Lange
European Respiratory Journal Jan 2021, 2003492; DOI: 10.1183/13993003.03492-2020
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