Cited by 166Tuberculosis Research and EpidemiologyInfectious Diseases and TuberculosisDiagnosis and treatment of tuberculosis

The definition of tuberculosis infection based on the spectrum of tuberculosis disease

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Migliori, Giovanni Battista, Ong, Catherine W.M., Petrone, Linda, D'Ambrosio, Lia, Centis, Rosella, Goletti, Delia·2021·Breathe

Abstract

Latent tuberculosis infection was the term traditionally used to indicate tuberculosis (TB) infection. This term was used to define “a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens through tests such as the tuberculin skin test (TST) or an interferon-γ release assay (IGRA) without clinically active TB”. Recent evidence indicates that the spectrum from TB infection to TB disease is much more complex, including a “continuum” of situations didactically reported as uninfected individual, TB infection, incipient TB, subclinical TB without signs/symptoms, subclinical TB with unrecognised signs/symptoms, and TB disease with signs/symptoms. Recent evidence suggests that subclinical TB is responsible for important M. tuberculosis transmission. This review describes the different stages described above and their relationships. It also summarises the new developments in prevention, diagnosis and treatment of TB infection as well as their public health and policy implications. Educational aims: To describe the evolution of the definition of “tuberculosis infection” and didactically describe the continuum of stages existing between TB infection and disease. To discuss the recommended approaches to prevent, diagnose and treat TB infection.

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  1. [2]Loddenkemper R, Murray JF. History of tuberculosis. In: Migliori GB, Raviglione MC, eds. Essential Tuberculosis. Cham, Springer Nature Switzerland AG, 2021; pp. 6– 9.
  2. [3]Tagliani E, Nikolayevskyy V, Tortoli E, et al. Laboratory diagnosis of tuberculosis. In: Migliori GB, Bothamley G, Duarte R, Rendon A, eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 99– 115.
  3. [4]Migliori GB, Nardell E, Yedilbayev A, et al. Reducing tuberculosis transmission: a consensus document from the World Health Organization Regional Office for Europe. Eur Respir J 2019; 53: 1900391. doi: 10.1183/13993003.00391-2019 31023852 · DOI
  4. [5]Goletti D, Martineau AR. Pathogenesis and immunology of tuberculosis. In: Migliori GB, Raviglione MC, eds. Essential Tuberculosis. Cham, Springer Nature Switzerland AG, 2021; pp. 20– 28.
  5. [6]Barreira-Silva P, Torrado E, Nebenzahl-Guimaraes H, et al. Aetiopathogenesis, immunology and microbiology of tuberculosis. In: Migliori GB, Bothamley G, Duarte R, Rendon A, eds. Tuberculosis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 62– 82.
  6. [7]World Health Organization. WHO consolidated guidelines on tuberculosis. Module 1: prevention — tuberculosis preventive treatment. Geneva, World Health Organization, 2020. https://apps.who.int/iris/bitstream/handle/10665/331170/9789240001503-eng.pdf 32186832
  7. [9]Goletti D, Petrone L, Ippolito G, et al. Preventive therapy for tuberculosis in rheumatological patients undergoing therapy with biological drugs. Expert Rev Anti Infect Ther 2018; 16: 501– 512. doi: 10.1080/14787210.2018.1483238 29848120 · DOI
  8. [10]Petrone L, Cannas A, Aloi F, et al. Blood or urine IP-10 cannot discriminate between active tuberculosis and respiratory diseases different from tuberculosis in children. Biomed Res Int 2015; 2015: 589471. doi: 10.1155/2015/589471 26346028 PMC4540955 · DOI
  9. [11]Ong CWM, Migliori GB, Raviglione M, et al. Epidemic and pandemic viral infections: impact on tuberculosis and the lung. Eur Respir J 2020; 56: 2001727. doi: 10.1183/13993003.01727-2020 32586885 PMC7527651 · DOI
  10. [12]Boulle A, Davies MA, Hussey H, et al. Risk factors for coronavirus disease 2019 (COVID-19) death in a population cohort study from the Western Cape Province, South Africa. Clin Infect Dis 2020; in press [ 10.1093/cid/ciaa1198]. PMC7499501 32860699 · DOI
  11. [13]Faqihi F, Alharthy A, Noor A, et al. COVID-19 in a patient with active tuberculosis: a rare case-report. Respir Med Case Rep 2020; 31: 101146. 32665887 PMC7334644
  12. [14]Motta I, Centis R, D'Ambrosio L, et al. Tuberculosis, COVID-19 and migrants: preliminary analysis of deaths occurring in 69 patients from two cohorts. Pulmonology 2020; 26: 233– 240. doi: 10.1016/j.pulmoe.2020.05.002 32411943 PMC7221402 · DOI
  13. [15]Musso M, Di Gennaro F, Gualano G, et al. Concurrent cavitary pulmonary tuberculosis and COVID-19 pneumonia with in vitro immune cell anergy. Infection 2021; in press [ 10.1007/s15010-021-01576-y]. PMC7811686 33454928 · DOI
  14. [16]Davies MA. HIV and risk of COVID-19 death: a population cohort study from the Western Cape Province, South Africa. medRxiv 2020; preprint [ 10.1101/2020.07.02.20145185]. · DOI
  15. [17]Riou C, Du Bruyn E, Stek C, et al. Relationship of SARS-CoV-2-specific CD4 response to COVID-19 severity and impact of HIV-1 and tuberculosis co-infection. J Clin Invest 2021; 131: e149125. doi: 10.1172/JCI149125 PMC8203446 33945513 · DOI
  16. [18]Getahun H, Matteelli A, Abubakar I, et al. Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. Eur Respir J 2015; 46: 1563– 1576. doi: 10.1183/13993003.01245-2015 26405286 PMC4664608 · DOI
  17. [19]Migliori GB, Visca D, van den Boom M, et al. Tuberculosis, COVID-19 and hospital admission: consensus on pros and cons based on a review of the evidence. Pulmonology 2021; 27: 248– 256. doi: 10.1016/j.pulmoe.2020.12.016 33547028 PMC7843149 · DOI
  18. [20]Tadolini M, Codecasa LR, García-García JM, et al. Active tuberculosis, sequelae and COVID-19 co-infection: first cohort of 49 cases. Eur Respir J 2020; 56: 2001398. doi: 10.1183/13993003.01398-2020 32457198 PMC7251245 · DOI
  19. [21]Barry CE 3rd, Boshoff HI, Dartois V, et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 2009; 7: 845– 855. doi: 10.1038/nrmicro2236 19855401 PMC4144869 · DOI
  20. [22]Lewinsohn DM, Lewinsohn DA. New concepts in tuberculosis host defense. Clin Chest Med 2019; 40: 703– 719. doi: 10.1016/j.ccm.2019.07.002 31731979 · DOI
  21. [23]Delogu G, Goletti D. The spectrum of tuberculosis infection: new perspectives in the era of biologics. J Rheumatol Suppl 2014; 91: 11– 16. doi: 10.3899/jrheum.140097 24788995 · DOI
  22. [24]Drain PK, Bajema KL, Dowdy D, et al. Incipient and subclinical tuberculosis: a clinical review of early stages and progression of infection. Clin Microbiol Rev 2018; 31: e00021-18. doi: 10.1128/CMR.00021-18 PMC6148193 30021818 · DOI
  23. [25]Esmail H, Barry CE 3rd, Young DB, et al. The ongoing challenge of latent tuberculosis. Philos Trans R Soc Lond B Biol Sci 2014; 369: 20130437. doi: 10.1098/rstb.2013.0437 24821923 PMC4024230 · DOI
  24. [26]Esmail H, Cobelens F, Goletti D. Transcriptional biomarkers for predicting development of tuberculosis: progress and clinical considerations. Eur Respir J 2020; 55: 1901957. doi: 10.1183/13993003.01957-2019 31949119 PMC7057180 · DOI
  25. [27]Mendelsohn SC, Fiore-Gartland A, Penn-Nicholson A, et al. Validation of a host blood transcriptomic biomarker for pulmonary tuberculosis in people living with HIV: a prospective diagnostic and prognostic accuracy study. Lancet Glob Health 2021; 9: e841– e853. doi: 10.1016/S2214-109X(21)00045-0 33862012 PMC8131200 · DOI
  26. [28]Scriba TJ, Fiore-Gartland A, Penn-Nicholson A, et al. Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial. Lancet Infect Dis 2021; 21: 354– 365. doi: 10.1016/S1473-3099(20)30914-2 33508224 PMC7907670 · DOI
  27. [29]Kendall EA, Shrestha S, Dowdy DW. Reply to: subclinical tuberculosis: some flies in the ointment. Am J Respir Crit Care Med 2021; 203: 1328– 1329. doi: 10.1164/rccm.202102-0367LE 33689676 PMC8456463 · DOI
  28. [30]Onozaki I, Law I, Sismanidis C, et al. National tuberculosis prevalence surveys in Asia, 1990–2012: an overview of results and lessons learned. Trop Med Int Health 2015; 20: 1128– 1145. doi: 10.1111/tmi.12534 25943163 · DOI
  29. [31]van't Hoog AH, Meme HK, Laserson KF, et al. Screening strategies for tuberculosis prevalence surveys: the value of chest radiography and symptoms. PLoS One 2012; 7: e38691. doi: 10.1371/journal.pone.0038691 22792158 PMC3391193 · DOI
  30. [33]Patterson B, Wood R. Is cough really necessary for TB transmission? Tuberculosis (Edinb) 2019; 117: 31– 35. doi: 10.1016/j.tube.2019.05.003 31378265 PMC6688829 · DOI
  31. [34]Esmail H, Dodd PJ, Houben RMGJ. Tuberculosis transmission during the subclinical period: could unrelated cough play a part? Lancet Respir Med 2018; 6: 244– 246. doi: 10.1016/S2213-2600(18)30105-X 29595504 · DOI
  32. [35]Styblo K. The relationship between the risk of tuberculous infection and the risk of developing infectious tuberculosis. Bull Int Union Tuberc Lung Dis 1985; 60: 117– 119.
  33. [36]Goletti D, Lee MR, Wang JY, et al. Update on tuberculosis biomarkers: from correlates of risk, to correlates of active disease and of cure from disease. Respirology 2018; 23: 455– 466. doi: 10.1111/resp.13272 29457312 · DOI
  34. [37]Barcellini L, Borroni E, Brown J, et al. First evaluation of QuantiFERON-TB Gold Plus performance in contact screening. Eur Respir J 2016; 48: 1411– 1419. doi: 10.1183/13993003.00510-2016 27390280 · DOI
  35. [38]Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 2003; 361: 1168– 1173. doi: 10.1016/S0140-6736(03)12950-9 12686038 · DOI
  36. [39]Hamada Y, den Boon S, Cirillo DM, et al. Framework for the evaluation of new tests for tuberculosis infection. Eur Respir J 2021; 58: 2004078. doi: 10.1183/13993003.04078-2020 33479110 PMC8374690 · DOI
  37. [40]Azzurri A, Sow OY, Amedei A, et al. IFN-gamma-inducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in Mycobacterium tuberculosis infection. Microbes Infect 2005; 7: 1– 8. doi: 10.1016/j.micinf.2004.09.004 15716076 · DOI
  38. [41]Petrone L, Cannas A, Vanini V, et al. Blood and urine inducible protein 10 as potential markers of disease activity. Int J Tuberc Lung Dis 2016; 20: 1554– 1561. doi: 10.5588/ijtld.16.0342 27776600 · DOI
  39. [42]Petrone L, Vanini V, Chiacchio T, et al. Evaluation of IP-10 in Quantiferon-Plus as biomarker for the diagnosis of latent tuberculosis infection. Tuberculosis (Edinb) 2018; 111: 147– 153. doi: 10.1016/j.tube.2018.06.005 30029901 · DOI
  40. [43]Abubakar I, Drobniewski F, Southern J, et al. Prognostic value of interferon-γ release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study. Lancet Infect Dis 2018; 18: 1077– 1087. doi: 10.1016/S1473-3099(18)30355-4 30174209 PMC6192014 · DOI
  41. [44]Zak DE, Penn-Nicholson A, Scriba TJ, et al. A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet 2016; 387: 2312– 2322. doi: 10.1016/S0140-6736(15)01316-1 27017310 PMC5392204 · DOI
  42. [45]Esmail H, Lai RP, Lesosky M, et al. Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission and computed tomography. Nat Med 2016; 22: 1090– 1093. doi: 10.1038/nm.4161 27595321 PMC5055809 · DOI
  43. [46]Goletti D, Sanduzzi A, Delogu G. Performance of the tuberculin skin test and interferon-γ release assays: an update on the accuracy, cutoff stratification, and new potential immune-based approaches. J Rheumatol Suppl 2014; 91: 24– 31. doi: 10.3899/jrheum.140099 24788997 · DOI
  44. [47]Nikitina IY, Karpina NL, Kasimceva OV, et al. Comparative performance of QuantiFERON-TB Gold versus skin test with tuberculosis recombinant allergen (Diaskintest) among patients with suspected pulmonary tuberculosis in Russia. Int J Infect Dis 2019; 86: 18– 24. doi: 10.1016/j.ijid.2019.06.014 31269455 · DOI
  45. [48]Ruhwald M, Aggerbeck H, Gallardo RV, et al. Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon γ release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial. Lancet Respir Med 2017; 5: 259– 268. doi: 10.1016/S2213-2600(16)30436-2 28159608 · DOI
  46. [50]Belay M, Tulu B, Younis S, et al. Detection of Mycobacterium tuberculosis complex DNA in CD34-positive peripheral blood mononuclear cells of asymptomatic tuberculosis contacts: an observational study. Lancet Microbe 2021; 2: e267– e275. doi: 10.1016/S2666-5247(21)00043-4 34100007 PMC8172384 · DOI
  47. [51]Bender JG, Unverzagt KL, Walker DE, et al. Identification and comparison of CD34-positive cells and their subpopulations from normal peripheral blood and bone marrow using multicolor flow cytometry. Blood 1991; 77: 2591– 2596. doi: 10.1182/blood.V77.12.2591.2591 1710512 · DOI
  48. [52]Reece ST, Vogelzang A, Tornack J, et al. Mycobacterium tuberculosis-infected hematopoietic stem and progenitor cells unable to express inducible nitric oxide synthase propagate tuberculosis in mice. J Infect Dis 2018; 217: 1667– 1671. doi: 10.1093/infdis/jiy041 29471332 PMC5913604 · DOI
  49. [53]Tornack J, Reece ST, Bauer WM, et al. Human and mouse hematopoietic stem cells are a depot for dormant Mycobacterium tuberculosis. PLoS One 2017; 12: e0169119. doi: 10.1371/journal.pone.0169119 28046053 PMC5207496 · DOI
  50. [54]Verma R, Swift BMC, Handley-Hartill W, et al. A novel, high-sensitivity, bacteriophage-based assay identifies low-level Mycobacterium tuberculosis bacteremia in immunocompetent patients with active and incipient tuberculosis. Clin Infect Dis 2020; 70: 933– 936. 31233122
  51. [55]Matteelli A, Rendon A, Tiberi S, et al. Tuberculosis elimination: where are we now? Eur Respir Rev 2018; 27: 180035. doi: 10.1183/16000617.0035-2018 29898905 PMC9488456 · DOI
  52. [56]WHO Regional Office for Europe. Tuberculosis elimination in the WHO European Region: review of key actions, with a special focus on tuberculosis infection management. Copenhagen, WHO Regional Office for Europe, 2020.
  53. [58]Lange C, Aarnoutse R, Chesov D, et al. Perspective for precision medicine for tuberculosis. Front Immunol 2020; 11: 566608. doi: 10.3389/fimmu.2020.566608 33117351 PMC7578248 · DOI
  54. [59]Kontsevaya I, Lange C, Comella-Del-Barrio P, et al. Perspectives for systems biology in the management of tuberculosis. Eur Respir Rev 2021; 30: 200377. doi: 10.1183/16000617.0377-2020 34039674 PMC9488731 · DOI
  55. [60]Bustamante J, Boisson-Dupuis S, Abel L, et al. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity. Semin Immunol 2014; 26: 454– 470. doi: 10.1016/j.smim.2014.09.008 25453225 PMC4357480 · DOI
  56. [61]Tobin DM, Roca FJ, Oh SF, et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 2012; 148: 434– 446. doi: 10.1016/j.cell.2011.12.023 22304914 PMC3433720 · DOI
  57. [62]Lalvani A, Behr MA, Sridhar S. Innate immunity to TB: a druggable balancing act. Cell 2012; 148: 389– 391. doi: 10.1016/j.cell.2012.01.026 22304907 · DOI
  58. [63]DiNardo AR, Rajapakshe K, Nishiguchi T, et al. DNA hypermethylation during tuberculosis dampens host immune responsiveness. J Clin Invest 2020; 130: 3113– 3123. doi: 10.1172/JCI134622 32125282 PMC7260034 · DOI
  59. [64]Lönnroth K, Migliori GB, Abubakar I, et al. Towards tuberculosis elimination: an action framework for low-incidence countries. Eur Respir J 2015; 45: 928– 952. doi: 10.1183/09031936.00214014 25792630 PMC4391660 · DOI
  60. [65]Alsdurf H, Hill PC, Matteelli A, et al. The cascade of care in diagnosis and treatment of latent tuberculosis infection: a systematic review and meta-analysis. Lancet Infect Dis 2016; 16: 1269– 1278. doi: 10.1016/S1473-3099(16)30216-X 27522233 · DOI
  61. [66]Migliori GB. Global tuberculosis network (GTN). Evolution of programmatic definitions used in tuberculosis prevention and care. Clin Infect Dis 2019; 68: 1787– 1789. doi: 10.1093/cid/ciy990 30462170 · DOI

Cited by

Sorted by citations

Authors
Migliori, G. B., Ong, C. W. M., Petrone, L., D'Ambrosio, L., Centis, R., & Goletti, D.
Affiliations
  • Istituti Clinici Scientifici Maugeri (IT)
  • National University of Singapore (SG)
  • Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani (IT)
Corresponding author
Migliori, Giovanni Battista
Venue
Breathe
Published
2021-09
Volume
17
Issue
3
Pages
210079
ISSN
  • 1810-6838 (ISSN-L)
  • 2073-4735
OpenAlex
W3196428738
Cited by
166
References
63
Citations by year
2026: 24 · 2025: 43 · 2024: 33 · 2023: 38 · 2022: 25 · 2021: 3
FWCI
2.90
Type
journal article
Language
en
Open access
Locations
  • Breathe (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Ministero della Salute (Linea 4)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
  • Health Sciences › Medicine › Surgery › Diagnosis and treatment of tuberculosis
Keywords
tuberculosis infection, latent tuberculosis infection, subclinical tuberculosis, Mycobacterium tuberculosis, tuberculin skin test, interferon-gamma release assay, tuberculosis transmission, tuberculosis prevention, tuberculosis diagnosis, tuberculosis treatment, public health policy

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