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Risk factors for false-negative results of T-SPOT.TB and tuberculin skin test in extrapulmonary tuberculosis

  • Clinical and Epidemiological Study
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Abstract

Purpose

T-SPOT.TB, a recently developed T cell-based assay, has shown promise in diagnosing extrapulmonary tuberculosis (EPTB). However, a limited number of reports have compared the risk factors for false-negative results of tuberculin skin tests (TSTs) and T-SPOT.TB assays in patients with EPTB. We, thus, conducted a prospective, blinded, observational study to evaluate the risk factors for false-negative T-SPOT.TB and TST results in patients with EPTB.

Methods

Between April 2008 and November 2011, all adult patients with suspected EPTB were prospectively enrolled at Asan Medical Center, Seoul, South Korea (an intermediate TB-burden country). Only patients with confirmed and probable EPTB who underwent TST and T-SPOT.TB were included in the final analysis.

Results

Of the 324 patients who underwent both TST and T-SPOT.TB testing, 128 patients with 96 (75 %) culture- or polymerase chain reaction (PCR)-confirmed and 32 (25 %) probable EPTB were finally analyzed. T-SPOT.TB assays were less likely to yield false-negative results than TSTs [17 % (22/128) vs. 54 % (69/128), p < 0.001]. In a multivariate analysis, miliary TB was associated with false-negative TSTs [odds ratio (OR) = 5.3; 95 % confidence interval (CI) 1.7–16.1], while immunosuppression showed a trend toward false-negative TSTs (OR = 2.5; 95 % CI 0.9–6.8). Conversely, lymph node TB (OR = 0.2; 95 % CI 0.1–0.5) and skeletal TB (OR = 0.2; 95 % CI 0.1–0.5) were associated with true-positive TST results. The only risk factor for false-negative T-SPOT.TB results was TB meningitis (OR = 2.6; 95 % CI 1.0–6.6).

Conclusions

Our findings suggest that T-SPOT.TB has a better sensitivity to diagnose EPTB than TST, especially in patients with immunosuppression or miliary TB.

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References

  1. Cho OH, Park KH, Kim SM, Park SJ, Moon SM, Chong YP, et al. Diagnostic performance of T-SPOT.TB for extrapulmonary tuberculosis according to the site of infection. J Infect. 2011;63:362–9.

    Article  PubMed  Google Scholar 

  2. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection—United States, 2010. MMWR Recomm Rep. 2010;59:1–25.

    PubMed  Google Scholar 

  3. Nash DR, Douglass JE. Anergy in active pulmonary tuberculosis. A comparison between positive and negative reactors and an evaluation of 5 TU and 250 TU skin test doses. Chest. 1980;77:32–7.

    Article  PubMed  CAS  Google Scholar 

  4. Holden M, Dubin MR, Diamond PH. Frequency of negative intermediate-strength tuberculin sensitivity in patients with active tuberculosis. N Engl J Med. 1971;285:1506–9.

    Article  PubMed  CAS  Google Scholar 

  5. Diel R, Loddenkemper R, Nienhaus A. Evidence-based comparison of commercial interferon-gamma release assays for detecting active TB: a metaanalysis. Chest. 2010;137:952–68.

    Article  PubMed  CAS  Google Scholar 

  6. Sester M, Sotgiu G, Lange C, Giehl C, Girardi E, Migliori GB, et al. Interferon-γ release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. Eur Respir J. 2011;37:100–11.

    Article  PubMed  CAS  Google Scholar 

  7. Lee YM, Kim SM, Park SJ, Park KH, Lee SO, Choi SH, et al. Indeterminate T-SPOT.TB test results in patients with suspected extrapulmonary tuberculosis in routine clinical practice. Infect Chemother. 2013;45:44–50.

    Article  CAS  Google Scholar 

  8. Cho CH, Han SH, Chin BS, Choi SH, Lee HS, Kim CO, et al. Diagnosis and species identification of mycobacterial infections by polymerase chain reaction–restriction fragment length polymorphism analysis of sterile body fluids. Korean J Intern Med. 2009;24:135–8.

    Article  PubMed  CAS  Google Scholar 

  9. Kim SH, Choi SJ, Kim HB, Kim NJ, Oh MD, Choe KW. Diagnostic usefulness of a T-cell based assay for extrapulmonary tuberculosis. Arch Intern Med. 2007;167:2255–9.

    Article  PubMed  CAS  Google Scholar 

  10. Kim SH, Song KH, Choi SJ, Kim HB, Kim NJ, Oh MD, et al. Diagnostic usefulness of a T-cell-based assay for extrapulmonary tuberculosis in immunocompromised patients. Am J Med. 2009;122:189–95.

    Article  PubMed  Google Scholar 

  11. Kim SH, Cho OH, Park SJ, Lee EM, Kim MN, Lee SO, et al. Rapid diagnosis of tuberculous meningitis by T cell-based assays on peripheral blood and cerebrospinal fluid mononuclear cells. Clin Infect Dis. 2010;50:1349–58.

    Article  PubMed  CAS  Google Scholar 

  12. Lee YM, Park KH, Kim SM, Park SJ, Lee SO, Choi SH, et al. Diagnostic usefulness of a T-cell-based assay in patients with miliary tuberculosis compared with those with lymph node tuberculosis. Clin Infect Dis. 2013;56:e26–9.

    Article  PubMed  CAS  Google Scholar 

  13. Marais S, Thwaites G, Schoeman JF, Török ME, Misra UK, Prasad K, et al. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis. 2010;10:803–12.

    Article  PubMed  Google Scholar 

  14. Kang YA, Lee HW, Yoon HI, Cho B, Han SK, Shim YS, et al. Discrepancy between the tuberculin skin test and the whole-blood interferon gamma assay for the diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country. JAMA. 2005;293:2756–61.

    Article  PubMed  CAS  Google Scholar 

  15. Simsek H, Alpar S, Ucar N, Aksu F, Ceyhan I, Gözalan A, et al. Comparison of tuberculin skin testing and T-SPOT.TB for diagnosis of latent and active tuberculosis. Jpn J Infect Dis. 2010;63:99–102.

    PubMed  Google Scholar 

  16. Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis. 2004;4:761–76.

    Article  PubMed  CAS  Google Scholar 

  17. Liao CH, Lai CC, Tan CK, Chou CH, Hsu HL, Tasi TH, et al. False-negative results by enzyme-linked immunospot assay for interferon-gamma among patients with culture-confirmed tuberculosis. J Infect. 2009;59:421–3.

    Article  PubMed  CAS  Google Scholar 

  18. Ak O, Dabak G, Ozer S, Saygi A, Dabak R. The evaluation of the Quantiferon-TB Gold test in pulmonary and extrapulmonary tuberculosis. Jpn J Infect Dis. 2009;62:149–51.

    PubMed  Google Scholar 

  19. Boussiotis VA, Tsai EY, Yunis EJ, Thim S, Delgado JC, Dascher CC, et al. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest. 2000;105:1317–25.

    Article  PubMed  CAS  Google Scholar 

  20. Girard JP, Paychère M, Cuevas M, Fernandes B. Cell-mediated immunity in an ageing population. Clin Exp Immunol. 1977;27:85–91.

    PubMed  CAS  Google Scholar 

  21. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis. 2005;5:415–30.

    Article  PubMed  CAS  Google Scholar 

  22. Hillinger SM, Herzig GP. Impaired cell-mediated immunity in Hodgkin’s disease mediated by suppressor lymphocytes and monocytes. J Clin Invest. 1978;61:1620–7.

    Article  PubMed  CAS  Google Scholar 

  23. Pesanti EL. The negative tuberculin test. Tuberculin, HIV, and anergy panels. Am J Respir Crit Care Med. 1994;149:1699–709.

    Article  PubMed  CAS  Google Scholar 

  24. Aydoğan O, Gürgün A, Başoğlu OK, Aşçi G, Ertilav M, Bacakoğlu F, et al. Tuberculin skin test reactivity in patients with chronic renal failure. Tuberk Toraks. 2009;57:268–76.

    PubMed  Google Scholar 

  25. Starr S, Berkovich S. Effects of measles, gamma-globulin-modified measles and vaccine measles on the tuberculin test. N Engl J Med. 1964;270:386–91.

    Article  PubMed  CAS  Google Scholar 

  26. Borgström E, Andersen P, Atterfelt F, Julander I, Källenius G, Maeurer M, et al. Immune responses to ESAT-6 and CFP-10 by FASCIA and multiplex technology for diagnosis of M. tuberculosis infection; IP-10 is a promising marker. PLoS One. 2012;7:e43438.

    Article  PubMed  Google Scholar 

  27. Kobashi Y, Shimizu H, Ohue Y, Mouri K, Obase Y, Miyashita N, et al. False negative results of QuantiFERON TB-2G test in patients with active tuberculosis. Jpn J Infect Dis. 2009;62:300–2.

    PubMed  Google Scholar 

  28. Mazurek GH, Weis SE, Moonan PK, Daley CL, Bernardo J, Lardizabal AA, et al. Prospective comparison of the tuberculin skin test and 2 whole-blood interferon-gamma release assays in persons with suspected tuberculosis. Clin Infect Dis. 2007;45:837–45.

    Article  PubMed  CAS  Google Scholar 

  29. Chee CB, Gan SH, Khinmar KW, Barkham TM, Koh CK, Liang S, et al. Comparison of sensitivities of two commercial gamma interferon release assays for pulmonary tuberculosis. J Clin Microbiol. 2008;46:1935–40.

    Article  PubMed  Google Scholar 

  30. Lee JY, Choi HJ, Park IN, Hong SB, Oh YM, Lim CM, et al. Comparison of two commercial interferon-gamma assays for diagnosing Mycobacterium tuberculosis infection. Eur Respir J. 2006;28:24–30.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Professor Jung Bok Lee for reviewing the statistical methods used in our study. This study was supported by the Basic Science Research Program of the National Research Foundation funded by the Ministry of Education, Science and Technology (grant 2010-0005898).

Conflict of interest

There are no potential conflicts of interest.

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Author notes

  1. Y.-M. Lee

    Present address: Department of Infectious Diseases, Busan Paik Hospital, Inje University College of Medicine, Busan, South Korea

Authors and Affiliations

  1. Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul, 138-736, Republic of Korea

    Y.-M. Lee, K.-H. Park, S.-M. Kim, S. J. Park, S.-O. Lee, S.-H. Choi, Y. S. Kim, J. H. Woo & S.-H. Kim

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  1. Y.-M. Lee
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Correspondence to S.-H. Kim.

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Lee, YM., Park, KH., Kim, SM. et al. Risk factors for false-negative results of T-SPOT.TB and tuberculin skin test in extrapulmonary tuberculosis. Infection 41, 1089–1095 (2013). https://doi.org/10.1007/s15010-013-0478-z

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  • DOI: https://doi.org/10.1007/s15010-013-0478-z

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