1. IGRAs: Should they replace the TST in the identification of latent tuberculosis? 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. AllenKraut, MD, frcpc Medical Director, Occupational Health WRHA WRHA T8 Forum April 12.2012 Conflict of Interest Received Quantiferon TB Gold in Tube Tubes from Cellestis as part of a research study.

2. 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 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 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. ■ i [:i,i | v,.o' <«0»0 35 lll'mi ami lK1 o( NilAny NO0J!*»"MO<0 35iU'.tiIo-<2SSoINiiOi ndulemi nale"58 0<0 35 IU rvi o- <25S d Ni<05 >B0AnyArty SJVSSJff*"*

3. T-spot.TB assay TspotTB K A *-!.-*...*..« ------_. Y Q-- n«-*i«*.«. Blood needs to be C processed within 8 hours. Can be O KKCSSt extended to 32 hours by adding a specific reagent - PY*.- Rl i ■ IGRAs 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 CCDRVol36 June 2010 Advantages More specific for Mycobacterium TB. " Atypical mycobacteria M. koniosii. M siulgoi. and M matmum 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 -Tspot.TB may be better Higher direct costs, but may have lower costs if include all required follow up and treatment 6,530 healthcare workers (HCWs) screened for latent tuberculosis infection AS 10 I It U >.crcou-d »iiMJI'l <;i f 25 fold increase in conversion rate using QFT vs TST Direct costs QFTTB Gold in Tube $436,096 TST $78,360. Indirect costs confirmatory TSTs, additional chest radiographs, extra nurse assessments, and examinations. Total costs $521,890 :»^r-~u>cb>Qn <-ii IIM h(«of> F"«>n»cl I 13 (idiimcti liw folk ixctoimoithfji i-tunI lciicd«ilh ISI I (Kc»cfliJi iKriiuinolpio'tivcJ (Ncjjlivcl ll'.i.mvcl IDfdncK Inlrctun Control and Hoipi|alCp«l«niiiloa 2010:11.HIS !>8S

4. Are IGRA results constant? Reversion rates are higher when baseline IFN-y levels are just above the cut-off point and when baseline results are discordant (i.e. TST-/IGRA+). Reversion rates low when baseline IFN-y levels are high and when baseline results are concordantly positive (TST+/IGRA+). 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 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 +vesforTXforLTBI CTS recommendations Immunocompromised TSTfirst 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 IGRA result ♦ve -ve TST result «veLTBI low risk don't treat. High risk treat. -ve High Risk Treat Low risk ?? No LTBI 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,

5. 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-basea. periodically updated, and free of financial conflicts and industry involvement. 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