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

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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

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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.

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Conflict of Interest

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

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TST has been used for 100 years
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Standard way to diagnose Latent TB.
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Many issues with interpretation
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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

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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

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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.

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

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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

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6,530 healthcare workers (HCWs) screened for
latent tuberculosis infection
Infection Control and Hospital Epidemiology
201031,1279-1285
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• 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

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Are IGRA results constant?

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

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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.

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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

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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

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IGRA result IGRA result
ve -ve
TST result ve LTBI Low risk dont treat. High risk treat.
-ve High Risk Treat Low risk ?? No LTBI
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International GuidelinesClin Microbiol Infect
2011 17 806814

• 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,

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International GuidelinesClin Microbiol Infect
2011 17 806814

• 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.

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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