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? • 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. ■ i • [:i,i | v, .o' <«0 »0 35 lll'mi ami lK1 o( Nil Any NO0J!*»" MO <0 35iU'.tiIo-<2SSoINi iOi ndulemi nale" 58 0 <0 35 IU rvi o- <25S d Ni <05 >B0 Any Arty SJVSSJff*"* • 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 • 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 • 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.

3. 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 - T-spot.TB assay TspotTB • 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-tun I 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. IGRA result ♦ve -ve TST result «ve LTBI low risk don't treat. High risk treat. -ve High Risk Treat Low risk ?? No LTBI • 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 • 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+). • 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 • 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 • 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