Skip to main content

Advertisement

Log in

Diagnosis of Latent Tuberculosis Infection with T-SPOT®.TB in a Predominantly Immigrant Population with Rheumatologic Disorders

  • Published:
Lung Aims and scope Submit manuscript

Abstract

Purpose

The objective of this study is to compare how likely positive tuberculin skin test (TST) and T-SPOT®.TB (TSPOT) results predict risk factors for tuberculosis in a predominantly immigrant patient population at risk of latent TB infection (LTBI) and with rheumatologic conditions requiring immunomodulatory therapy (IMT).

Methods

Prospective study conducted at a referral rheumatology clinic. Inclusion criteria included patients on various IMT, including immunosuppressive drugs that could predispose to TB progression. We studied risk factors associated with LTBI, test results, and tests’ agreement.

Results

We studied 101 patients. Eighty (79.2 %) were from countries where TB is prevalent and Bacille Calmette-Guérin vaccination is placed routinely. Seventy-four (73.3 %) had rheumatoid arthritis and 92 (90.7 %) were on IMT. Among patients with both TST and TSPOT results, 25 (30.9 %) were TST+ and 20 (24.7 %) had TSPOT+ results. Fifteen patients (18.5 %) had TST+/TSPOT+ results, and 51 (63.0 %) had TST/TSPOT results (agreement = 81.5 %; kappa = .54 [95 % CI, .34–.74; P < .001]). Each TSPOT+ and TST+ results were independently associated with immigrant status and prior residence in a TB prevalent country after adjustment for immunosuppressive therapy: Adjusted ORTSPOT+=6.6 (95 % CI, 1.2–123.3; P = .027); and adjusted ORTST+=11.2 (95 % CI, 2.0–209.5; P = .003). Seven out of 10 TST+/TSPOT cases had a TST ≥15 mm induration, including three cases with history of TST conversion.

Conclusions

TST+ and TSPOT+ results predict risk factors associated with LTBI independent of immunosuppressive IMT. Some TST+/TSPOT results were unlikely to be false-negatives. The combined use of TST and TSPOT appears to be a reasonable diagnostic strategy to evaluate for LTBI in this population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Burzynski J, Schluger NW (2008) The epidemiology of tuberculosis in the United States. Semin Respir Crit Care Med 29(5):492–498. doi:10.1055/s-0028-1085701

    Article  PubMed  Google Scholar 

  2. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC (1999) Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 282(7):677–686

    Article  CAS  PubMed  Google Scholar 

  3. Liu Y, Painter JA, Posey DL, Cain KP, Weinberg MS, Maloney SA, Ortega LS, Cetron MS (2012) Estimating the impact of newly arrived foreign-born persons on tuberculosis in the United States. PLoS One 7(2):e32158. doi:10.1371/journal.pone.0032158

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Lin PL, Flynn JL (2010) Understanding latent tuberculosis: a moving target. J Immunol 185(1):15–22. doi:10.4049/jimmunol.0903856

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Mack U, Migliori GB, Sester M, Rieder HL, Ehlers S, Goletti D, Bossink A, Magdorf K, Holscher C, Kampmann B, Arend SM, Detjen A, Bothamley G, Zellweger JP, Milburn H, Diel R, Ravn P, Cobelens F, Cardona PJ, Kan B, Solovic I, Duarte R, Cirillo DM (2009) LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement. Eur Respir J 33(5):956–973. doi:10.1183/09031936.00120908

    Article  CAS  PubMed  Google Scholar 

  6. Menzies D, Pai M, Comstock G (2007) Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 146(5):340–354

    Article  PubMed  Google Scholar 

  7. Pai M (2010) Spectrum of latent tuberculosis-existing tests cannot resolve the underlying phenotypes. Nat Rev Microbiol 8(3):242. doi:10.1038/nrmicro2236-c1 author reply 242

    Article  CAS  PubMed  Google Scholar 

  8. Singh N, Paterson DL (1998) Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management. Clin Infect Dis 27(5):1266–1277

    Article  CAS  PubMed  Google Scholar 

  9. Wallis RS, Schluger NW (2010) Pulmonary infectious complications of tumor necrosis factor blockade. Infect Dis Clin North Am 24(3):681–692. doi:10.1016/j.idc.2010.04.010

    Article  PubMed  Google Scholar 

  10. Gomez-Reino JJ, Carmona L, Angel Descalzo M (2007) Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection. Arthritis Rheum 57(5):756–761. doi:10.1002/art.22768

    Article  CAS  PubMed  Google Scholar 

  11. Baronnet L, Barnetche T, Kahn V, Lacoin C, Richez C, Schaeverbeke T (2011) Incidence of tuberculosis in patients with rheumatoid arthritis. A systematic literature review. Joint Bone Spine 78(3):279–284. doi:10.1016/j.jbspin.2010.12.004

    Article  PubMed  Google Scholar 

  12. Solovic I, Sester M, Gomez-Reino JJ, Rieder HL, Ehlers S, Milburn HJ, Kampmann B, Hellmich B, Groves R, Schreiber S, Wallis RS, Sotgiu G, Scholvinck EH, Goletti D, Zellweger JP, Diel R, Carmona L, Bartalesi F, Ravn P, Bossink A, Duarte R, Erkens C, Clark J, Migliori GB, Lange C (2010) The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement. Eur Respir J 36(5):1185–1206. doi:10.1183/09031936.00028510

    Article  CAS  PubMed  Google Scholar 

  13. Talbot EA, Moore M, McCray E, Binkin NJ (2000) Tuberculosis among foreign-born persons in the United States, 1993–1998. JAMA 284(22):2894–2900

    Article  CAS  PubMed  Google Scholar 

  14. Zwerling A, Pai M (2011) The BCG world atlas: a new, open-access resource for clinicians and researchers. Expert Rev Anti Infect Ther 9(8):559–561. doi:10.1586/eri.11.71

    Article  PubMed  Google Scholar 

  15. van Zyl-Smit RN, Pai M, Peprah K, Meldau R, Kieck J, Juritz J, Badri M, Zumla A, Sechi LA, Bateman ED, Dheda K (2009) Within-subject variability and boosting of T-cell interferon-gamma responses after tuberculin skin testing. Am J Respir Crit Care Med 180(1):49–58. doi:10.1164/rccm.200811-1704OC

    Article  PubMed  Google Scholar 

  16. Winthrop KL, Weinblatt ME, Daley CL (2012) You can’t always get what you want, but if you try sometimes (with two tests-TST and IGRA-for tuberculosis) you get what you need. Ann Rheum Dis 71(11):1757–1760. doi:10.1136/annrheumdis-2012-201979

    Article  PubMed  Google Scholar 

  17. Butera O, Chiacchio T, Carrara S, Casetti R, Vanini V, Meraviglia S, Guggino G, Dieli F, Vecchi M, Lauria FN, Marruchella A, Laurenti P, Singh M, Caccamo N, Girardi E, Goletti D (2009) New tools for detecting latent tuberculosis infection: evaluation of RD1-specific long-term response. BMC Infect Dis 9:182. doi:10.1186/1471-2334-9-182

    Article  PubMed Central  PubMed  Google Scholar 

  18. Pollock NR, Campos-Neto A, Kashino S, Napolitano D, Behar SM, Shin D, Sloutsky A, Joshi S, Guillet J, Wong M, Nardell E (2008) Discordant QuantiFERON-TB Gold test results among US healthcare workers with increased risk of latent tuberculosis infection: a problem or solution? Infect Control Hosp Epidemiol 29(9):878–886. doi:10.1086/590262

    Article  PubMed Central  PubMed  Google Scholar 

  19. Lalvani A, Pareek M (2010) A 100 year update on diagnosis of tuberculosis infection. Br Med Bull 93:69–84. doi:10.1093/bmb/ldp039

    Article  PubMed  Google Scholar 

  20. Behar SM, Shin DS, Maier A, Coblyn J, Helfgott S, Weinblatt ME (2009) Use of the T-SPOT.TB assay to detect latent tuberculosis infection among rheumatic disease patients on immunosuppressive therapy. J Rheumatol 36(3):546–551. doi:10.3899/jrheum.080854

    Article  PubMed  Google Scholar 

  21. American Thoracic Society (2000) Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep 49(RR-6):1–51

    Google Scholar 

  22. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K (2010) IGRA Expert Committee, Centers for Disease Control and Prevention (CDC) (2010) Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection-United States. MMWR Recomm Rep 59(RR-5):1–25

    PubMed  Google Scholar 

  23. Ferrara G, Losi M, D’Amico R, Roversi P, Piro R, Meacci M, Meccugni B, Dori IM, Andreani A, Bergamini BM, Mussini C, Rumpianesi F, Fabbri LM, Richeldi L (2006) Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study. Lancet 367(9519):1328–1334. doi:10.1016/s0140-6736(06)68579-6

    Article  CAS  PubMed  Google Scholar 

  24. Ewer K, Deeks J, Alvarez L, Bryant G, Waller S, Andersen P, Monk P, Lalvani A (2003) Comparison of T-cell-based assay with tuberculin skin test for diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 361(9364):1168–1173. doi:10.1016/s0140-6736(03)12950-9

    Article  PubMed  Google Scholar 

  25. Kleinbaum D, Kupper L, Muller K, Nizam A (1998) Applied regression analysis and other multivariable methods, 3rd edn. Duxbury Press, Boston

    Google Scholar 

  26. World Health Organization (WHO) (2012) Global tuberculosis report 2012. WHO, Geneva

    Google Scholar 

  27. British Thoracic Society Standards of Care Committee (2005) BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax 60(10):800–805. doi:10.1136/thx.2005.046797

    Article  Google Scholar 

  28. Beglinger C, Dudler J, Mottet C, Nicod L, Seibold F, Villiger PM, Zellweger JP (2007) Screening for tuberculosis infection before the initiation of an anti-TNF-alpha therapy. Swiss Med Wkly 137(43–44):620–622

    PubMed  Google Scholar 

  29. Carmona L, Gomez-Reino JJ, Rodriguez-Valverde V, Montero D, Pascual-Gomez E, Mola EM, Carreno L, Figueroa M (2005) Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum 52(6):1766–1772. doi:10.1002/art.21043

    Article  CAS  PubMed  Google Scholar 

  30. National Tuberculosis Advisory Committee (2012) Position statement on interferon-gamma release assays in the detection of latent tuberculosis infection. Commun Dis Intell Q Rep 36(1):125–131

    Google Scholar 

  31. Duarte R, Campainha S, Cotter J, Rosa B, Varela P, Correia A, Canhao H, Fonseca JE (2012) Position paper on tuberculosis screening in patients with immune mediated inflammatory diseases candidates for biological therapy. Acta Reumatologica Port 37(3):253–259

    CAS  Google Scholar 

  32. Kavanagh PM, Gilmartin JJ, O’Donnell J, O’Flanagan D (2008) Tumour necrosis factor-alpha and tuberculosis: guidance from the National TB Advisory Committee. Ir Med J 101(1):6–7

    CAS  PubMed  Google Scholar 

  33. Mariette X, Salmon D (2003) French guidelines for diagnosis and treating latent and active tuberculosis in patients with RA treated with TNF blockers. Ann Rheum Dis 62(8):791

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Casas S, Andreu A, Juanola X, Bordas X, Alcaide F, Moure R, Anibarro L, Cuchi E, Esteve M, Ortiz V, Guerra MR, Rodriguez J, Reina D, Salvador G, Guardiola J, Suris X, Pascual MA, Marti C, Martinez-Lacasa X, Cuquet J, Gonzalez L, Santin M (2011) Diagnosis of tuberculosis infection by tuberculin skin test and a whole-blood interferon-gamma release assay in patients considered for anti-tumor necrosis factor-alpha therapy. Diagn Microbiol Infect Dis 71(1):57–65. doi:10.1016/j.diagmicrobio.2010.12.020

    Article  CAS  PubMed  Google Scholar 

  35. Centers for Disease Control and Prevention (CDC) (2004) Tuberculosis associated with blocking agents against tumor necrosis factor-alpha-California, 2002–2003. MMWR Morb Mortal Wkly Rep 53(30):683–686

    Google Scholar 

  36. Keystone EC, Papp KA, Wobeser W (2011) Challenges in diagnosing latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. J Rheumatol 38(7):1234–1243. doi:10.3899/jrheum.100623

    Article  CAS  PubMed  Google Scholar 

  37. Mariette X, Baron G, Tubach F, Liote F, Combe B, Miceli-Richard C, Flipo RM, Goupille P, Allez M, Salmon D, Emilie D, Carcelain G, Ravaud P (2012) Influence of replacing tuberculin skin test with ex vivo interferon gamma release assays on decision to administer prophylactic antituberculosis antibiotics before anti-TNF therapy. Ann Rheum Dis 71(11):1783–1790. doi:10.1136/annrheumdis-2011-200408

    Article  CAS  PubMed  Google Scholar 

  38. Vassilopoulos D, Tsikrika S, Hatzara C, Podia V, Kandili A, Stamoulis N, Hadziyannis E (2011) Comparison of two gamma interferon release assays and tuberculin skin testing for tuberculosis screening in a cohort of patients with rheumatic diseases starting anti-tumor necrosis factor therapy. Clin Vaccine Immunol 18(12):2102–2108. doi:10.1128/CVI.05299-11

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Bartalesi F, Vicidomini S, Goletti D, Fiorelli C, Fiori G, Melchiorre D, Tortoli E, Mantella A, Benucci M, Girardi E, Cerinic MM, Bartoloni A (2009) QuantiFERON-TB Gold and the TST are both useful for latent tuberculosis infection screening in autoimmune diseases. Eur Respir J 33(3):586–593. doi:10.1183/09031936.00107608

    Article  CAS  PubMed  Google Scholar 

  40. Kleinert S, Kurzai O, Elias J, Marten K, Engelke C, Feuchtenberger M, Sandstede J, Frosch M, Tony HP, Kneitz C (2010) Comparison of two interferon-gamma release assays and tuberculin skin test for detecting latent tuberculosis in patients with immune-mediated inflammatory diseases. Ann Rheum Dis 69(4):782–784. doi:10.1136/ard.2009.113829

    Article  CAS  PubMed  Google Scholar 

  41. Smith R, Cattamanchi A, Steingart KR, Denkinger C, Dheda K, Winthrop KL, Pai M (2011) Interferon-gamma release assays for diagnosis of latent tuberculosis infection: evidence in immune-mediated inflammatory disorders. Curr Opin Rheumatol 23(4):377–384. doi:10.1097/BOR.0b013e3283474d62

    Article  CAS  PubMed  Google Scholar 

  42. Singanayagam A, Manalan K, Sridhar S, Molyneaux PL, Connell DW, George PM, Kindelerer A, Seneviratne S, Lalvani A, Wickremasinghe M, Kon OM (2013) Evaluation of screening methods for identification of patients with chronic rheumatological disease requiring tuberculosis chemoprophylaxis prior to commencement of TNF-alpha antagonist therapy. Thorax 68(10):955–961. doi:10.1136/thoraxjnl-2013-203436

    Article  PubMed  Google Scholar 

  43. Hatemi G, Yazici H (2013) Tuberculosis screening before and during treatment with tumor necrosis factor antagonists: something old, something new. J Rheumatol 40(12):1938–1940. doi:10.3899/jrheum.131218

    Article  PubMed  Google Scholar 

  44. Costantino F, de Carvalho Bittencourt M, Rat AC, Loeuille D, Dintinger H, Bene MC, Faure G, Chary-Valckenaere I (2013) Screening for latent tuberculosis infection in patients with chronic inflammatory arthritis: discrepancies between tuberculin skin test and interferon-gamma release assay results. J Rheumatol 40(12):1986–1993. doi:10.3899/jrheum.130303

    Article  PubMed  Google Scholar 

  45. Wang L, Turner MO, Elwood RK, Schulzer M, FitzGerald JM (2002) A meta-analysis of the effect of Bacille Calmette Guérin vaccination on tuberculin skin test measurements. Thorax 57(9):804–809

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Hsia EC, Schluger N, Cush JJ, Chaisson RE, Matteson EL, Xu S, Beutler A, Doyle MK, Hsu B, Rahman MU (2012) Interferon-gamma release assay versus tuberculin skin test prior to treatment with golimumab, a human anti-tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. Arthritis Rheum 64(7):2068–2077. doi:10.1002/art.34382

    Article  CAS  PubMed  Google Scholar 

  47. Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Breban M, Pallot-Prades B, Pouplin S, Sacchi A, Chichemanian RM, Bretagne S, Emilie D, Lemann M, Lortholary O, Mariette X (2009) Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 60(7):1884–1894. doi:10.1002/art.24632

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Song GG, Bae SC, Lee YH (2013) Interferon-gamma release assays versus tuberculin skin testing in patients with rheumatoid arthritis. Int J Rheum Dis 16(3):279–283. doi:10.1111/1756-185x.12098

    Article  CAS  PubMed  Google Scholar 

  49. Fine PE, Ponnighaus JM, Maine N (1989) The distribution and implications of BCG scars in northern Malawi. Bull World Health Organ 67(1):35–42

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Stauffer WM, Maroushek S, Kamat D (2003) Medical screening of immigrant children. Clin Pediatr 42(9):763–773

    Article  Google Scholar 

  51. Janossy G, Barry SM, Breen RA, Hardy GA, Lipman M, Kern F (2008) The role of flow cytometry in the interferon-gamma-based diagnosis of active tuberculosis and its coinfection with HIV-1: A technically oriented review. Cytometry B Clin Cytom 74(Suppl 1):S141–S151. doi:10.1002/cyto.b.20381

    Article  PubMed  Google Scholar 

  52. Sester U, Junker H, Hodapp T, Schutz A, Thiele B, Meyerhans A, Kohler H, Sester M (2006) Improved efficiency in detecting cellular immunity towards M. tuberculosis in patients receiving immunosuppressive drug therapy. Nephrol Dial Transplant 21(11):3258–3268. doi:10.1093/ndt/gfl416

    Article  CAS  PubMed  Google Scholar 

  53. Hsu DC, Zaunders JJ, Plit M, Leeman C, Ip S, Iampornsin T, Pett SL, Bailey M, Amin J, Ubolyam S, Avihingsanon A, Ananworanich J, Ruxrungtham K, Cooper DA, Kelleher AD (2012) A novel assay detecting recall response to Mycobacterium tuberculosis: comparison with existing assays. Tuberculosis 92(4):321–327. doi:10.1016/j.tube.2012.03.008

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the support of Oxford Immunotec, manufacturer of the T-SPOT®.TB assay. This support was limited to providing laboratory reagents and laboratory technical support. Part of this project was supported by Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Health. No other financial or material support was provided to the authors and participants. Dr. Escalante and his institution have filed two patent applications related to immunodiagnostic laboratory methodologies for LTBI. There is no income or royalties associated with those filed patent applications. We appreciate Ms. Gladys Hebl, Debra Hanson, and Patricia Simonson from the Research and Academic Support Services at Mayo Clinic for their excellent manuscript editing support.

Conflict of interest

None of the authors have any other conflicts of interest to declare.

Ethical Standards

This study was conducted in accordance with the amended Declaration of Helsinki (ICH-GCP). The University of Southern California (USC) Medical Center Institutional Review Board approved the protocol (#HS-07-002125), and written informed consent was obtained from all patients.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Patricio Escalante.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 21 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Escalante, P., Kooda, K.J., Khan, R. et al. Diagnosis of Latent Tuberculosis Infection with T-SPOT®.TB in a Predominantly Immigrant Population with Rheumatologic Disorders. Lung 193, 3–11 (2015). https://doi.org/10.1007/s00408-014-9655-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-014-9655-9

Keywords

Navigation