IGRAs: Should they replace the TST in the identification of latent tuberculosis?

1. IGRAs: Should they replace the TST in the identification of latent tuberculosis? Allen Kraut, MD, FRCPC Medical Director, Occupational Health WRHA WRHA TB Forum April 12, 2012

2. Objectives • Describe how interferon-gamma release assays (IGRAs) work. • List three advantages and disadvantages of IGRA in comparison to tuberculin skin testing (TST). • Identify populations where IGRA testing may be of benefit in the management of latent tuberculosis infection.

3. Conflict of Interest • Received Quantiferon TB Gold in Tube Tubes from Cellestis as part of a research study.

4. TST has been used for 100 years

5. Standard way to diagnose Latent TB.

6. Many issues with interpretation

7. Some issues with TST • Difficulty reading test. • 6mm inter reader variability • Not specific for Mycobacterium Tuberculosis • False +ve with BCG or Atypical Mycobacterium • Requires two visits days apart for reading • Subject to boosting • Definition of positive test depends on circumstances

8. New Technologies – Blood tests • Interferon Gamma Release Assays (IGRAs) • White blood cells in people infected with TB release Gamma interferon • Detect specific Mycobacterium TB proteins • Less likely to give false positive results • Can not differentiate latent and active disease

9. Interferon Gamma Release Assays (IGRAs) • Quantiferon-TB Gold In-Tube Assay • ESAT-6, CFP – 10, TB7.7 • Measure IFN- Gamma ELISA • T-spot.TB Assay • ESAT-6, CFP – 10 • Count spots which are related to the number of cells releasing Gamma Interferon.

13. T-spot.TB assay Blood needs to be processed within 8 hours. Can be extended to 32 hours by adding a specific reagent

14. T spot TB

15. IGRAs • Advantages • More specific for Mycobacterium TB. • Atypical mycobacteria • M. kansasii, M. szulgai, and M.marinum. • Single patient encounter • Objective criteria for positive response • Disadvantages • Requires blood draw • Requires sophisticated equipment • Elements of processing time sensitive • Results may not be readily available • ? Immunosuppressed - T spot.TB may be better • Higher direct costs, but may have lower costs if include all required follow up and treatment

16. IGRAs in HCP • Significant discordance is found between TST and IGRA positivity rates in healthcare workers (HCWs), • TST+/IGRA- - BCG vaccinations. • IGRAs seem to correlate with markers of exposure in HCWs • Serial testing results limited • CCDR Vol36 June 2010

17. 6,530 healthcare workers (HCWs) screened for latent tuberculosis infection Infection Control and Hospital Epidemiology 2010:31,1279-1285

18. 25 fold increase in conversion rate using QFT vs TST • Direct costs • QFT TB Gold in Tube $436,096 • TST $78,360. • Indirect costs • confirmatory TSTs, additional chest radiographs, extra nurse assessments, and examinations. • Total costs $521,890

19. Are IGRA results constant? • Reversion rates are higher when baseline IFN-γ levels are just above the cut-off point and when baseline results are discordant (i.e. TST-/IGRA+). • Reversion rates low when baseline IFN-γ levels are high and when baseline results are concordantly positive (TST+/IGRA+).

20. IGRA performance in contacts and outbreak investigations • IGRAs correlate well with surrogate markers of exposure in contact and outbreak settings, but not necessarily better than TST in all populations. • Correlation between IGRA results and surrogate markers of exposure is better than TST in low incidence settings where BCG has been commonly used; this is not evident in high incidence countries. • Discordance between TST and IGRAs are almost always found. Concordance levels seem to vary when IGRA and TST cut-off points are changed.

21. CTS recommendations • IGRAs should not be used in the diagnosis of active TB in adults may be a supplemental aide in dx in children. • Contacts – • IGRAs can be used to confirm +ve TSTS • IGRAS or TSTs can be used to identify +ves for TX for LTBI

22. CTS recommendations • Immunocompromised • TST first test • If TST –ve IGRA can be used and if +ve consider treatment • Degree of benefit unknown in TST –ve IGRA +ve. • T Spot .TB may be better in an immunosuppressed population

24. International GuidelinesClinMicrobiol Infect 2011; 17: 806–814 • 33 guidelines and position papers from 25 countries and two supranational organizations. • The results show considerable diversity in the recommendations on IGRAs • (i) two-step approach of tuberculin skin test (TST) first, followed by IGRA either when • the TST is negative (to increase sensitivity, mainly in immunocompromised individuals), • or when the TST is positive (to increase specificity, mainly in BCG vaccinated individuals); • (ii) Either TST or IGRA, but not both; • (iii) IGRA and TST together (to increase sensitivity); • (iv) IGRA only, replacing the TST. • Overall, the use of IGRAs is increasingly recommended,

25. International GuidelinesClinMicrobiol Infect 2011; 17: 806–814 • Most of the current guidelines do not use objective, transparent methods to grade evidence and recommendations, and • Do not disclose conflicts of interests. • Future IGRA guidelines must aim to be transparent, evidence-based, periodically updated, and free of financial conflicts and industry involvement.

26. Conclusions • IGRAs will help identify who needs treatment for LTBI • Exact role need to be determined • Very helpful in low risk TST +ve BCG population • ? immunosuppressed population • Useful for population that is hard to follow • Definition of positive reaction may have to vary depending on situation of testing