Research Open Access
Like 0



Not all treated tuberculosis (TB) patients achieve long-term recovery and reactivation rates reflect effectiveness of TB treatment.


We aimed to estimate rates and risk factors of TB reactivation and reinfection in patients treated in the Netherlands, after completed or interrupted treatment.


Retrospective cohort study of TB patients with available DNA fingerprint data, registered in the Netherlands Tuberculosis register (NTR) between 1993 and 2016. Reactivation was defined as an identical, and reinfection as a non-identical strain in sequential episodes.


Reactivation rate was 55/100,000 person-years (py) for patients who completed, and 318/100,000 py for patients who interrupted treatment. The risk of reactivation was highest in the first 5 years after treatment in both groups. The incidence rate of reactivation was 228/100,000 py in the first 2 years and 57/100,000 py 2–5 years after completed treatment. The overall rate of reinfection was 16/100,000 py. Among those who completed treatment, patients with male sex, mono or poly rifampicin-resistant TB and a previous TB episode had significantly higher risk of reactivation. Extrapulmonary TB was associated with a lower risk. Among patients who interrupted treatment, directly observed treatment (DOT) and being an undocumented migrant or people experiencing homelessness were associated with a higher risk of reactivation.


Both patients who completed or interrupted TB treatment should be considered as risk groups for reactivation for at least 2–5 years after treatment. They patients should be monitored and guidelines should be in place to enhance early detection of recurrent TB.


Article metrics loading...

Loading full text...

Full text loading...



  1. World Health Organization (WHO). Global tuberculosis report 2020. Geneva: WHO. [Accessed: 6 Feb 2020]. Available from: https://www.who.int/publications/i/item/9789240013131
  2. World Health Organization (WHO). Definitions and reporting framework for tuberculosis. Geneva: WHO. [Accessed: 14 Feb 2018]. Available from: http://apps.who.int/iris/bitstream/10665/79199/1/9789241505345_eng.pdf
  3. McIvor A, Koornhof H, Kana BD. Relapse, re-infection and mixed infections in tuberculosis disease. Pathog Dis. 2017;75(3):1-16.  https://doi.org/10.1093/femspd/ftx020  PMID: 28334088 
  4. Dobler CC, Crawford AB, Jelfs PJ, Gilbert GL, Marks GB. Recurrence of tuberculosis in a low-incidence setting. Eur Respir J. 2009;33(1):160-7.  https://doi.org/10.1183/09031936.00104108  PMID: 18829676 
  5. Mathema B, Kurepina NE, Bifani PJ, Kreiswirth BN. Molecular epidemiology of tuberculosis: current insights. Clin Microbiol Rev. 2006;19(4):658-85.  https://doi.org/10.1128/CMR.00061-05  PMID: 17041139 
  6. Caminero JA, Pena MJ, Campos-Herrero MI, Rodríguez JC, Afonso O, Martin C, et al. Exogenous reinfection with tuberculosis on a European island with a moderate incidence of disease. Am J Respir Crit Care Med. 2001;163(3):717-20.  https://doi.org/10.1164/ajrccm.163.3.2003070  PMID: 11254530 
  7. Dale KD, Globan M, Tay EL, Trauer JM, Trevan PG, Denholm JT. Recurrence of tuberculosis in a low-incidence setting without directly observed treatment: Victoria, Australia, 2002-2014. Int J Tuberc Lung Dis. 2017;21(5):550-5.  https://doi.org/10.5588/ijtld.16.0651  PMID: 28399970 
  8. Luzze H, Johnson DF, Dickman K, Mayanja-Kizza H, Okwera A, Eisenach K, et al. Relapse more common than reinfection in recurrent tuberculosis 1-2 years post treatment in urban Uganda. Int J Tuberc Lung Dis. 2013;17(3):361-7.  https://doi.org/10.5588/ijtld.11.0692  PMID: 23407224 
  9. Marx FM, Dunbar R, Enarson DA, Williams BG, Warren RM, van der Spuy GD, et al. The temporal dynamics of relapse and reinfection tuberculosis after successful treatment: a retrospective cohort study. Clin Infect Dis. 2014;58(12):1676-83.  https://doi.org/10.1093/cid/ciu186  PMID: 24647020 
  10. Millet JP, Shaw E, Orcau A, Casals M, Miró JM, Caylà JA, et al. Tuberculosis recurrence after completion treatment in a European city: reinfection or relapse? PLoS One. 2013;8(6):e64898.  https://doi.org/10.1371/journal.pone.0064898  PMID: 23776440 
  11. Gadoev J, Asadov D, Harries AD, Parpieva N, Tayler-Smith K, Isaakidis P, et al. Recurrent tuberculosis and associated factors: A five - year countrywide study in Uzbekistan. PLoS One. 2017;12(5):e0176473.  https://doi.org/10.1371/journal.pone.0176473  PMID: 28472053 
  12. Kim L, Moonan PK, Heilig CM, Woodruff RSY, Kammerer JS, Haddad MB. Factors associated with recurrent tuberculosis more than 12 months after treatment completion. Int J Tuberc Lung Dis. 2016;20(1):49-56.  https://doi.org/10.5588/ijtld.15.0442  PMID: 26688528 
  13. Korhonen V, Soini H, Vasankari T, Ollgren J, Smit PW, Ruutu P. Recurrent tuberculosis in Finland 1995-2013: a clinical and epidemiological cohort study. BMC Infect Dis. 2017;17(1):721.  https://doi.org/10.1186/s12879-017-2818-6  PMID: 29145819 
  14. Guerra-Assunção JA, Houben RM, Crampin AC, Mzembe T, Mallard K, Coll F, et al. Recurrence due to relapse or reinfection with Mycobacterium tuberculosis: a whole-genome sequencing approach in a large, population-based cohort with a high HIV infection prevalence and active follow-up. J Infect Dis. 2015;211(7):1154-63.  https://doi.org/10.1093/infdis/jiu574  PMID: 25336729 
  15. Sonnenberg P, Murray J, Glynn JR, Shearer S, Kambashi B, Godfrey-Faussett P. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet. 2001;358(9294):1687-93.  https://doi.org/10.1016/S0140-6736(01)06712-5  PMID: 11728545 
  16. Bang D, Andersen AB, Thomsen VO, Lillebaek T. Recurrent tuberculosis in Denmark: relapse vs. re-infection. Int J Tuberc Lung Dis. 2010;14(4):447-53. PMID: 20202303 
  17. Schiroli C, Carugati M, Zanini F, Bandera A, Di Nardo Stuppino S, Monge E, et al. Exogenous reinfection of tuberculosis in a low-burden area. Infection. 2015;43(6):647-53.  https://doi.org/10.1007/s15010-015-0759-9  PMID: 25754899 
  18. de Boer AS, Borgdorff MW, Vynnycky E, Sebek MM, van Soolingen D. Exogenous re-infection as a cause of recurrent tuberculosis in a low-incidence area. Int J Tuberc Lung Dis. 2003;7(2):145-52. PMID: 12588015 
  19. Interrante JD, Haddad MB, Kim L, Gandhi NR. Exogenous Reinfection as a Cause of Late Recurrent Tuberculosis in the United States. Ann Am Thorac Soc. 2015;12(11):1619-26. PMID: 26325356 
  20. Cacho J, Pérez Meixeira A, Cano I, Soria T, Ramos Martos A, Sánchez Concheiro M, et al. Recurrent tuberculosis from 1992 to 2004 in a metropolitan area. Eur Respir J. 2007;30(2):333-7.  https://doi.org/10.1183/09031936.00005107  PMID: 17504801 
  21. National Institute for Public Health and the Environment (RIVM). Code book Netherlands Tuberculosis Register. Bilthoven: RIVM; 2013. [Accessed: 19 Mar 2022]. Available from: https://www.rivm.nl/documenten/codeboek-nederlands-tuberculose-register
  22. World Health Organization (WHO) Regional Office for Europe/European Centre for Disease Prevention and Control. Tuberculosis surveillance and monitoring in Europe, 2019. Copenhagen: WHO Regional Office for Europe; 2019. Available from: https://www.ecdc.europa.eu/en/publications-data/tuberculosis-surveillance-and-monitoring-europe-2019
  23. KNCV Tuberculosis Foundation. Handboek Tuberculose. The Hague: KNCV Tuberculosis Foundation; 2021. [Accessed: 8 Feb 2022]. Available from: https://www.rivm.nl/sites/default/files/2022-01/6.1%20Handboek%20Tuberculose%20Nederland%202021.pdf.
  24. Dooley KE, Lahlou O, Ghali I, Knudsen J, Elmessaoudi MD, Cherkaoui I, et al. Risk factors for tuberculosis treatment failure, default, or relapse and outcomes of retreatment in Morocco. BMC Public Health. 2011;11(1):140-57.  https://doi.org/10.1186/1471-2458-11-140  PMID: 21356062 
  25. Dale K, Tay E, Trauer JM, Trevan P, Denholm J. Gender differences in tuberculosis diagnosis, treatment and outcomes in Victoria, Australia, 2002-2015. Int J Tuberc Lung Dis. 2017;21(12):1264-71.  https://doi.org/10.5588/ijtld.17.0338  PMID: 29297447 
  26. World Health Organization (WHO). Global tuberculosis report, 2021.Geneva: WHO; 2021. [Accessed: 19 Mar 2022].Available from: https://www.who.int/publications/digital/global-tuberculosis-report-2021
  27. World Health Organization (WHO). WHO treatment guidelines for drug-resistant tuberculosis. Geneva: WHO; 2016. Available from: https://apps.who.int/iris/bitstream/handle/10665/250125/9789241549639-eng.pdf
  28. Jajou R, Neeling A, Hunen R, Vries G, Schimmel H, Mulder A, et al. Epidemiological links between tuberculosis cases identified twice as efficiently by whole genome sequencing than conventional molecular typing: A population-based study. PLoS One. 2018;13(4):e0195413.  https://doi.org/10.1371/journal.pone.0195413  PMID: 29617456 
  29. Crofts JP, Andrews NJ, Barker RD, Delpech V, Abubakar I. Risk factors for recurrent tuberculosis in England and Wales, 1998-2005. Thorax. 2010;65(4):310-4.  https://doi.org/10.1136/thx.2009.124677  PMID: 20388755 
  30. Kim L, Moonan PK, Heilig CM, Woodruff RSY, Kammerer JS, Haddad MB. Factors associated with recurrent tuberculosis more than 12 months after treatment completion. Int J Tuberc Lung Dis. 2016;20(1):49-56.  https://doi.org/10.5588/ijtld.15.0442  PMID: 26688528 
  31. Vos AM, Meima A, Verver S, Looman CWN, Bos V, Borgdorff MW, et al. High incidence of pulmonary tuberculosis persists a decade after immigration, The Netherlands. Emerg Infect Dis. 2004;10(4):736-9.  https://doi.org/10.3201/eid1004.030530  PMID: 15200873 
  32. Purohit M, Mustafa T. Laboratory diagnosis of extra-pulmonary TB (EPTB) in resource-constrained setting: state of the art, challenges and the need. J Clin Diagn Res. 2015;9(4):EE01-06. PMID: 26023563 
  33. Turkova A, Wills GH, Wobudeya E, Chabala C, Palmer M, Kinikar A, et al. Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children. N Engl J Med. 2022;386(10):911-22.  https://doi.org/10.1056/NEJMoa2104535  PMID: 35263517 

Data & Media loading...

Supplementary data

Submit comment
Comment moderation successfully completed
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error