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 Disadvantages 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
CCDR - Canadian communicable disease report

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

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

23. IGRA result
+ve
-ve
TST result
LTBI
Low risk don’t treat.
High risk treat.
High Risk Treat
Low risk ??
No LTBI

24. International Guidelines Clin Microbiol 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 Guidelines Clin Microbiol 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