Rapid Diagnosis of Recurrent Paucibacillary Tuberculosis

Main Article Content

Claudia Jafari
Ioana D. Olaru
Franziska Daduna
Christoph Lange
Barbara Kalsdorf


Introduction: The rapid diagnosis of tuberculosis recurrence can be challenging due to persistently positive detection of Mycobacterium tuberculosis-specific DNA from sputum and bronchopulmonary samples in the absence of active disease.

Methods: We compared the diagnostic accuracy of the detection of M. tuberculosis-specific DNA by either Xpert (January 2010-June 2018) or Xpert Ultra (July 2018-June 2020) and M. tuberculosis-specific ELISPOT in bronchoalveolar lavage (BAL) samples with M. tuberculosis culture results from sputum or bronchopulmonary samples in patients with suspected recurrence of pulmonary tuberculosis. 

Results: Among 44 individuals with previous tuberculosis and a presumptive diagnosis of recurrent pulmonary tuberculosis, 4/44 (9.1%) were diagnosed with recurrent tuberculosis by culture. DNA of M. tuberculosis was detected by Xpert in BAL fluid in 1/4 (25%) individuals with recurrent tuberculosis and in 2/40 (5%) cases with past tuberculosis without recurrence, while BAL-ELISPOT with a cut-off of >4,000 early secretory antigenic target-6-specific or culture filtrate protein-10-specific interferon-γ-producing lymphocytes per 1 million BAL-lymphocytes was positive in 4/4 (100%) individuals with recurrent tuberculosis and in 2/40 (5%) cases of past tuberculosis without recurrence. 

Conclusion: M. tuberculosis-specific BAL-ELISPOT is more accurate than BAL-Xpert for the diagnosis of paucibacillary tuberculosis recurrence. 


Download data is not yet available.

Article Details

How to Cite
Jafari C, Olaru ID, Daduna F, Lange C, Kalsdorf B. Rapid Diagnosis of Recurrent Paucibacillary Tuberculosis. PAI [Internet]. 2023 Apr. 19 [cited 2023 Dec. 6];7(2):189–202. Available from: https://www.paijournal.com/index.php/paijournal/article/view/565


1. Ghodbane R, Raoult D, Drancourt M. Dramatic reduction of culture time of Mycobacterium tuberculosis. Scientific Reports. 2014;4(1). doi: 10.1038/srep04236.

2. Badak FZ, Kiska DL, Setterquist S, Hartley C, O’Connell MA, Hopfer RL. Comparison of mycobacteria growth indicator tube with BACTEC 460 for detection and recovery of mycobacteria from clinical specimens. J Clin Microbiol. 1996;34(9):2236-9.

3. Pheiffer C, Carrol NM, Beyers N, Donald P, Duncan K, Uys P, van Helden P. Time to detection of Mycobacterium tuberculosis in BACTEC systems as a viable alternative to colony counting. Int J Tuberc Lung Dis. 2008;12(7):792-8.

4. Global Tuberculosis Report 2020. Geneva: World Health Organization, 2020.

5. Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, Dendukuri N. Xpert(R) MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev. 2014;2014(1):CD009593. Epub 20140121. doi: 10.1002/14651858.CD009593.pub3. PubMed PMID: 24448973; PMCID: PMC4470349.

6. Goletti D, Carrara S, Butera O, Amicosante M, Ernst M, Sauzullo I, Vullo V, Cirillo D, Borroni E, Markova R, Drenska R, Dominguez J, Latorre I, Angeletti C, Navarra A, Petrosillo N, Lauria FN, Ippolito G, Migliori GB, Lange C, Girardi E. . Accuracy of immunodiagnostic tests for active tuberculosis using single and combined results: a multicenter TBNET-Study. PLoS One. 2008;3(10):e3417.

7. Dominguez J, Ruiz-Manzano J, De Souza-Galvao M, Latorre I, Mila C, Blanco S, Jimenez MA, Prat C, Lacoma A, Altet N, Ausina V. Comparison of two commercially available gamma interferon blood tests for immunodiagnosis of tuberculosis. Clin Vaccine Immunol. 2008;15(1):168-71. Epub 20071031. doi: 10.1128/CVI.00364-07. PubMed PMID: 17978008; PMCID: PMC2223867.

8. Carranza C, Pedraza-Sanchez S, de Oyarzabal-Mendez E, Torres M. Diagnosis for Latent Tuberculosis Infection: New Alternatives. Front Immunol. 2020;11(2006. doi: 10.3389/fimmu.2020.02006. eCollection 2020.):2006. Epub 20200910. doi: 10.3389/fimmu.2020.02006. PubMed PMID: 33013856; PMCID: PMC7511583.

9. Global Tuberculosis Report 2021. Geneva: World Health Organization, 2021.

10. Jafari C, Ernst M, Kalsdorf B, Greinert U, Diel R, Kirsten D, Marienfeld K, Lalvani A, Lange C. Rapid diagnosis of smear-negative tuberculosis by bronchoalveolar lavage enzyme-linked immunospot. Am J Respir Crit Care Med. 2006;174(9):1048-54. Epub 20060720. doi: 10.1164/rccm.200604-465OC. PubMed PMID: 16858013.

11. Jafari C, Thijsen S, Sotgiu G, Goletti D, Dominguez Benitez JA, Losi M, Eberhardt R, Kirsten D, Kalsdorf B, Bossink A, Latorre I, Migliori GB, Strassburg A, Winteroll S, Greinert U, Richeldi L, Ernst M, Lange C, Tuberculosis Network European T. Bronchoalveolar lavage enzyme-linked immunospot for a rapid diagnosis of tuberculosis: a Tuberculosis Network European Trialsgroup study. Am J Respir Crit Care Med. 2009;180(7):666-73. Epub 20090709. doi: 10.1164/rccm.200904-0557OC. PubMed PMID: 19590020; PMCID: PMC2753791.

12. Wilkinson KA, Wilkinson RJ, Pathan A, Ewer K, Prakash M, Klenerman P, Maskell N, Davies R, Pasvol G, Lalvani A. Ex vivo characterization of early secretory antigenic target 6-specific T cells at sites of active disease in pleural tuberculosis. Clin Infect Dis 2005;40(1):184-7.

13. Dheda K, van Zyl-Smit RN, Meldau R, Meldau S, Symons G, Khalfey H, Govender N, Rosu V, Sechi LA, Maredza A, Semple P, Whitelaw A, Wainwright H, Badri M, Dawson R, Bateman ED, Zumla A. Quantitative lung T cell responses aid the rapid diagnosis of pulmonary tuberculosis. Thorax. 2009;64(10):847-53. Epub 20090709. doi: 10.1136/thx.2009.116376. PubMed PMID: 19592392.

14. Losi M, Bossink A, Codecasa L, Jafari C, Ernst M, Thijsen S, Cirillo D, Ferrarese M, Greinert U, Fabbri LM, Richeldi L, Lange C, European Tuberculosis Network T. Use of a T-cell interferon-gamma release assay for the diagnosis of tuberculous pleurisy. Eur Respir J. 2007;30(6):1173-9. Epub 20070822. doi: 10.1183/09031936.00067307. PubMed PMID: 17715165.

15. Jafari C, Olaru ID, Daduna F, Ernst M, Heyckendorf J, Lange C, Kalsdorf B. Rapid diagnosis of pulmonary tuberculosis by combined molecular and immunological methods. Eur Respir J. 2018;51(5):1702189. Epub 20180503. doi: 10.1183/13993003.02189-2017. PubMed PMID: 29599184.

16. Global Tuberculosis Report 2015, 20th ed. Geneva: World Health Organization, 2015.

17. Report on the Epidemiology of Tuberculosis in Germany – 2019. Germany: The Robert Koch Institute, September 24, 2020.

18. Steininger WJ, Howard WL. A study of re-treatment cases vs original treatment cases of pulmonary tuberculosis. Dis Chest. 1959;35(5):480-93. doi: 10.1378/chest.35.5.480. PubMed PMID: 13652757.

19. El Sahly HM, Wright JA, Soini H, Bui TT, Williams-Bouyer N, Escalante P, Musser JM, Graviss EA. Recurrent tuberculosis in Houston, Texas: a population-based study. Int J Tuberc Lung Dis. 2004;8(3):333-40. PubMed PMID: 15139472.

20. Caminero JA. Multidrug-resistant tuberculosis: epidemiology, risk factors and case finding. Int J Tuberc Lung Dis. 2010;14(4):382-90.

21. Boyles TH, Hughes J, Cox V, Burton R, Meintjes G, Mendelson M. False-positive Xpert(R) MTB/RIF assays in previously treated patients: need for caution in interpreting results. Int J Tuberc Lung Dis. 2014;18(7):876-8. doi: 10.5588/ijtld.13.0853. PubMed PMID: 24902569.

22. Theron G, Venter R, Smith L, Esmail A, Randall P, Sood V, Oelfese S, Calligaro G, Warren R, Dheda K. False positive Xpert MTB/RIF results in re-tested patients with previous tuberculosis: frequency, profile, and prospective clinical outcomes. J Clin Microbiol 2018;56(3):e01696-17. J Clin Microbiol 2018;56(3):e01696-17.

23. Theron G, Venter R, Calligaro G, Smith L, Limberis J, Meldau R, Chanda D, Esmail A, Peter J, Dheda K. Xpert MTB/RIF results in patients with previous tuberculosis: can we distinguish true from false positive results? Clin Infect Dis 2016;62(8):995-1001.

24. Costantini L, Marando M, Gianella P Long-term GeneXpert positivity after treatment for pulmonary tubercolosis. EJCRIM. 2020;7. doi: 10.12890/2020_001737.

25. Stevenson DR, Biswas JR, Lievesley A, Quinn G, Buckley J, John L, Davidson RN. False-positive Xpert® MTB/RIF more than seven years after cure. Int J Tuberc Lung Dis. 2015;19(10):1264-65.

26. Wu-Hsieh BA, Chen CK, Chang JH, Lai SY, Wu CH, Cheng WC, Andersen P, Doherty TM. . Long-lived immune response to early secretory antigenic target 6 in individuals who had recovered from tuberculosis. Clin Infect Dis 2001;33(8):1336-40.

27. Ferrand RA, Bothamley GH, Whelan A, Dockrell HM. I. Ferrand RA, Bothamley GH, Whelan A, Dockrell HM. Interferon-gamma responses to ESAT-6 in tuberculosis patients early into and after anti-tuberculosis treatment. Int J Tuberc Lung Dis 2005;9(9):1034-9.

28. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig L, Lijmer JG, Moher D, Rennie D, de Vet HC, Kressel HY, Rifai N, Golub RM, Altman DG, Hooft L, Korevaar DA, Cohen JF; STARD Group. . STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies. BMJ. 2015(351:h5527. ).

29. Oxford Immunotec. T-Spot.TB test [cited 2023]. Available from: www.tspot.com.

30. Hofland RW, Thijsen SF, van Lindert AS, de Lange WC, van Gorkom T, van der Tweel I, Lammers JJ, Bossink AW. Positive predictive value of ELISpot in BAL and pleural fluid from patients with suspected pulmonary tuberculosis. Infect Dis (Lond). 2017;49(5):347-55.

31. Xpert MTB/RIF Implementation Manual. Technical and Operational ‘How-To’: Practical Considerations Geneva: World Health Organization, 2014.

32. Nunn AJ, Phillips PP, Mitchison DA. Timing of relapse in short-course chemotherapy trials for tuberculosis. Int J Tuberc Lung Dis. 2010;14(2):241-2. PubMed PMID: 20074418.

33. Rosser A, Richardson M, Wiselka MJ, Free RC, Woltmann G, Mukamolova GV, Pareek M. A nested case-control study of predictors for tuberculosis recurrence in a large UK Centre. BMC Infect Dis. 2018;18(1):94. Epub 20180227. doi: 10.1186/s12879-017-2933-4. PubMed PMID: 29486715; PMCID: PMC5830048.

34. Erkens C, Tekeli B, van Soolingen D, Schimmel H, Verver S. Recurrent tuberculosis in the Netherlands – a 24-year follow-up study, 1993 to 2016. Euro Surveill. 2022;27(12). doi: 10.2807/1560-7917.Es.2022.27.12.2100183. PubMed PMID: 35332864; PMCID: PMC8950855.

35. Li Z, Qin W, Li L, Wu Q, Chen X. Accuracy of bronchoalveolar lavage enzyme-linked immunospot assay to diagnose smear-negative tuberculosis: a meta-analysis. Int J Clin Exp Med. 2015;8(8):12637-43. Epub 20150815. PubMed PMID: 26550176; PMCID: PMC4612861.

36. Pang C, Wu Y, Wan C, Shen K, Hu Y, Yang T, Shen Y, Wen F. Accuracy of the Bronchoalveolar Lavage Enzyme-Linked Immunospot Assay for the Diagnosis of Pulmonary Tuberculosis: A Meta-analysis. Medicine (Baltimore). 2016;95(12):e3183. doi: 10.1097/MD.0000000000003183. PubMed PMID: 27015211; PMCID: PMC4998406.

37. Kalsdorf B, Scriba TJ, Wood K, Day CL, Dheda K, Dawson R, Hanekom WA, Lange C, Wilkinson RJ. HIV-1 infection impairs the bronchoalveolar T-cell response to mycobacteria. Am J Respir Crit Care Med. 2009;180(12):1262-70. Epub 20090924. doi: 10.1164/rccm.200907-1011OC. PubMed PMID: 19797156; PMCID: PMC2796736.

Most read articles by the same author(s)