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
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.
Conflict of Interest
• Received Quantiferon TB Gold in Tube
Tubes from Cellestis as part of a
research study.
TST has been used for 100 years
Standard way to diagnose Latent TB.
Many issues with interpretation
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.
T-spot.TB assay
Blood needs to be
processed within 8
hours. Can be
extended to 32 hours
by adding a specific
reagent
T spot TB
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
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
6,530 healthcare workers (HCWs) screened
for latent tuberculosis infection
Infection Control and Hospital Epidemiology 2010:31,1279-1285
• 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
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+).
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
+ves for TX for LTBI
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
IGRA result
+ve
TST
result
+ve
-ve
LTBI
High Risk Treat
Low risk ??
-ve
Low risk don’t treat.
High risk treat.
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,
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, evidencebased, 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