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Latent Tuberculosis Infection: An Update on Diagnosis

Latent Tuberculosis Infection: An Update on Diagnosis. Christopher J. Crnich, MD MS June 13, 2007. TB: Immunopathogenesis. Bacillus Destroyed. Bacillus Multiplies. Distant Spread (Regional Lymph Nodes, Bloodstream). Stage 1. Stage 2 (Logarithmic Growth). Stages of TB Infection.

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Latent Tuberculosis Infection: An Update on Diagnosis

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  1. Latent Tuberculosis Infection: An Update on Diagnosis Christopher J. Crnich, MD MS June 13, 2007

  2. TB: Immunopathogenesis Bacillus Destroyed Bacillus Multiplies

  3. Distant Spread (Regional Lymph Nodes, Bloodstream) Stage 1 Stage 2 (Logarithmic Growth) Stages of TB Infection

  4. Multinucleated Giant Cell Un-activated Macrophage Activated Macrophage Caseous Necrosis Cytotoxic T-cell Good CMI Response Infected & Dying Macrophage Non-replicating bacillus Stages of TB Infection Stage 3: (Early DTH) Stage 4a: (Late DTH)

  5. Stage 5 (Caseous Liquefaction) TB: Reactivation

  6. TB: Natural History

  7. Rationale behind diagnosis and treatment of LTBI • There are individuals who in whom there is: • An increased risk of developing active TB over their lifetime (> 10%) • Or, in which the consequences of developing TB, even if the risk of active disease would is low, would be catastrophic • Treatment of LTBI reduces risk of developing active infection by 65% to 75% • Risk of therapy of LTBI is low in studies published since 1991 • Hospitalization: 1 in 1,500 • Death: 1 in 3,300

  8. Rates of active TB among selected populations ATS, MMWR 2000; 44(RR-6): 1-51

  9. ATS Guidelines for TST ATS, MMWR 2000; 44(RR-6): 1-51

  10. Effectiveness of Isoniazid for Treatment of LTBI Comstock GW. Int J Tuberc Lung Dis 1999; 3(10): 347 - 50

  11. Risk of hepatitis with LTBI treatment regimens

  12. TST: Using DTH to Indirectly Detect Latent TB Infection • Intradermal PPD causes influx of lymphocytes, macrophages & monocytes • Local production of cytokines: TNF-alpha, IFN-gamma, IL-10, IL-12 • Release of serotonin & histamine leads to erythema and induration*

  13. TST and Risk of TB Palmer & Edwards, JAMA 1969; 205(3): 167-9

  14. TST and Risk of TB Comstock et al. AM J Epidemiol 1974; 99(2): 131-8

  15. Limitations of TST • Absolute operating characteristics unknown • Significant problems with implementation • Requires patient follow-up • Significant inter-rater variability • Prone to rounding up errors • Prone to false-negatives (reduced sensitivity) • Anergy • Booster phenomenon • Active tuberculosis (IL-10 effect) • Prone to false-positive (reduced specificity) • Due to rounding-up error • Due to endemic NTM • Due to prior BCG vaccination

  16. Edwards et al. Am Rev Respir Dis 1969; 99(4): Suppl 1- 132

  17. Edwards et al. Am Rev Respir Dis 1969; 99(4): Suppl 1- 132

  18. False-Positives Due to NTM • Cross-reactivity with PPD-B explained 50% of the reactions to PPD-S in the 5-9mm range • Cross-reactivity with PPD-B only explained 4% of the reactions to PPD-S in the 10+ range. • PPD-B reactions in excess of 15mm seen in only 1.9% of subjects (and many of these may have been due to cross-reactivity with PPD-S) • Reactivity to PPD-B decreased the longer the individual had resided in Montreal Am Rev Respir Dis 1992; 146(3): 752-6

  19. False Positive Due to NTM Von Reyn et al. Int J Tuberc Lung Dis 2001; 5(12): 1122-8

  20. False Positives Due to BCG Wang et al. Thorax 2002; 57(9): 804-9

  21. False Positives Due to BCG Wang et al. Thorax 2002; 57(9): 804-9

  22. False Positives Due to BCG Tissot et al. Clin Infect Dis 2005; 40: 211-7

  23. False Positives Due to BCG Wang et al. Thorax 2002; 57(9): 804-9

  24. Diagnosis of LTBI, 2007? Diagnosis of LTBI, 1907 Testing for LTBI: Historical Perspective

  25. Mazurek et al. MMWR Recomm Reports 2005; 54(RR15): 49-55

  26. Interferon- Release Assays (IGRA) APC + T-Cell Interferon- + TB Antigen

  27. IGRA’s Antigen Are Specific

  28. Commercial IGRA’s • ELISA-based tests • Quantiferon-TB • Quantiferon-TB Gold • Quantiferon Gold In-Tube Assay • ELISPOT-based tests • T-SPOT.TB

  29. QuantiFERON TB - Gold TB Neg. TB Pos. TB Pos. Indeterm. Indeterm. Nil Mitogen ESAT-6 CFP-10

  30. QuantiFERON TB - Gold Mazurek et al. MMWR 2005; 54(RR-15): 49-55

  31. Mazurek et al. MMWR Recomm Reports 2005; 54(RR15): 49-55

  32. Performance of IGRA’s • Animal studies • Cattle (M. bovis) • Studies of patients with active TB • Level of exposure studies • Performance in low-prevalence populations

  33. Developed in Cattle – An Excellent Model for Human TB • Bovine TB is an excellent model for human TB • Immune response to infection is very similar • Most infected cattle have LTBI • Active TB disease normally found only in old or undernourished animals M.bovis PPD injected intradermally and read 72 hrs later M.avium PPD is used as well for Comparative Testing

  34. SID and IGRA in Cattle Sens = 68.2 / Spec = 95.7 / PPV = 20.5 / NPV = 99.5 Sens = 81.8 / Spec = 97.8 / PPV = 37.5 / NPV = 99.7 Wood et al. Vet Microbiol 1992; 31(1): 71-9

  35. IGRA’s in Active TB Menzies et al. Ann Intern Med 2007; 146(5): 340-54

  36. IGRAs: Exposure Level Kang et al. JAMA 2005; 293(22): 2756-61

  37. IGRA’s: Exposure Level Ewer et al. Lancet 2003; 361(9364): 1168-73

  38. IGRA’s: Exposure Level Menzies et al. Ann Intern Med 2007; 146(5): 340-54

  39. IGRA’s: Exposure Level Arend et al. Am J Respir Crit Care Med 2007; 175(6): 618-27

  40. IGRA’s Reduce BCG Effect Johnson et al. Clin Diagn Lab Immunol 1999; 6(6): 934-7

  41. Specificity of IGRA’s Menzies et al. Ann Intern Med 2007; 146(5): 340-54

  42. IGRA’s: The Good • IGRA’s are more sensitive than TST in patient’s with active TB • T-SPOT.TB is more “sensitive” than QFT-G but associated with lower “specificity” • QFT-G In-Tube may be less sensitive than QFT-G

  43. QFT-G vs. T-SPOT.TB Active TB Low-Risk Lee et al. Eur Respir J 2006; 28(1): 24-30

  44. QFT-G vs. T-SPOT.TB Active TB Low-Risk Lee et al. Eur Respir J 2006; 28(1): 24-30

  45. IGRA’s: The Good • IGRA’s are more sensitive than TST in patient’s with active TB • T-SPOT.TB is more “sensitive” than QFT-G but associated with lower “specificity” • QFT-G In-Tube may be less sensitive than QFT-G

  46. IGRA’s: The Good • IGRA’s are more sensitive than TST in patient’s with active TB • T-SPOT.TB is more “sensitive” than QFT-G but associated with lower “specificity” • QFT-G In-Tube may be less sensitive than QFT-G • IGRA’s correlate better with level of exposure than TST in contact tracing studies

  47. IGRA’s: The Good • IGRA’s are more sensitive than TST in patient’s with active TB • T-SPOT.TB is more “sensitive” than QFT-G but associated with lower “specificity” • QFT-G In-Tube may be less sensitive than QFT-G • IGRA’s correlate better with level of exposure than TST in contact tracing studies • IGRA’s do not appear to be influenced by prior BCG status, TST clearly is

  48. IGRA’s: The Bad • No data on predictive ability for the development of TB • Few published effectiveness studies • Limited data on performance in immunosuppressed patients • Limited data on performance in children • Problem with indeterminate results

  49. IGRA’s and HIV Rangaka et al. Am J Respir Crit Care Med 2007 (in press)

  50. IGRA’s and HIV Brock et al. Respir Res 2006; 7: 56-64

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