Heyckendorf, Jan, Marwitz, Sebastian, Reimann, Maja, Avsar, Korkut, DiNardo, Andrew R., Guenther, Gunar, Hoelscher, Michael ORCID: 0000-0002-7642-1835, Ibraim, Elmira, Kalsdorf, Barbara, Kaufmann, Stefan H. E., Kontsevaya, Irina, van Leth, Frank ORCID: 0000-0002-5490-8968, Mandalakas, Anna M., Maurer, Florian P., Mueller, Marius, Nitschkowski, Dorte, Olaru, Ioana D., Popa, Cristina, Rachow, Andrea, Rolling, Thierry, Rybniker, Jan, Salzer, Helmut J. F., Sanchez-Carballo, Patricia, Sanchez-Carballo, Patricia, Schuhmann, Maren, Schaub, Dagmar, Spinu, Victor, Suarez, Isabelle, Terhalle, Elena, Unnewehr, Markus, Weiner, January ORCID: 0000-0003-1438-7819, Goldmann, Torsten and Lange, Christoph (2021). Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model. Eur. Resp. J., 58 (3). SHEFFIELD: EUROPEAN RESPIRATORY SOC JOURNALS LTD. ISSN 1399-3003

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Abstract

Background The World Health Organization recommends standardised treatment durations for patients with tuberculosis (TB). 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)-TB. Methods Adult patients with pulmonary TB were prospectively enrolled into five independent cohorts in Germany and Romania. Clinical and microbiological data and whole blood for RNA transcriptomic analysis were collected at pre-defined time points throughout therapy. Treatment outcomes were ascertained by TBnet criteria (6-month culture status/1-year follow-up). A whole-blood RNA therapy-end model was developed in a multistep process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment time points. Results 50 patients with DS-TB and 30 patients with MDR-TB were recruited in the German identification cohorts (DS-GIC and MDR-GIC, respectively); 28 patients with DS-TB and 32 patients with MDR-TB in the German validation cohorts (DS-GVC and MDR-GVC, respectively); and 52 patients with MDR-TB in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model (TB22) that defined cure-associated end-of-therapy time points was derived from the DS-and MDR-GIC data. The TB22 model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (area under the curve 0.94, 95% CI 0.9-0.98) and suggests that cure may be achieved with shorter treatment durations for TB 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-TB.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Heyckendorf, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marwitz, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reimann, MajaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Avsar, KorkutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
DiNardo, Andrew R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenther, GunarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelscher, MichaelUNSPECIFIEDorcid.org/0000-0002-7642-1835UNSPECIFIED
Ibraim, ElmiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kalsdorf, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaufmann, Stefan H. E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kontsevaya, IrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Leth, FrankUNSPECIFIEDorcid.org/0000-0002-5490-8968UNSPECIFIED
Mandalakas, Anna M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maurer, Florian P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, MariusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nitschkowski, DorteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olaru, Ioana D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Popa, CristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rachow, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rolling, ThierryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rybniker, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salzer, Helmut J. F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchez-Carballo, PatriciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchez-Carballo, PatriciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuhmann, MarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaub, DagmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spinu, VictorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suarez, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Terhalle, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Unnewehr, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weiner, JanuaryUNSPECIFIEDorcid.org/0000-0003-1438-7819UNSPECIFIED
Goldmann, TorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lange, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-606749
DOI: 10.1183/13993003.03492-2020
Journal or Publication Title: Eur. Resp. J.
Volume: 58
Number: 3
Date: 2021
Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD
Place of Publication: SHEFFIELD
ISSN: 1399-3003
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MULTIDRUG-RESISTANT TUBERCULOSIS; PULMONARY TUBERCULOSIS; GENE-EXPRESSION; SIGNATURE; BIOMARKERS; DIAGNOSIS; OUTCOMESMultiple languages
Respiratory SystemMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60674

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