Transcript IGRAs for latent TB diagnosiswhat are they and how do we interpret them? Mady Slater, M.D. Stanford University Medical Center Division of Infectious Diseases Curry.

IGRAs for latent TB diagnosiswhat are they and how do we
interpret them?
Mady Slater, M.D.
Stanford University Medical Center
Division of Infectious Diseases
Curry International TB Center
June 21, 2014
Border Health Training
I DO NOT HAVE ANY FINANCIAL
ARRANGEMENTS OR AFFILIATIONS
WITH COMMERCIAL SPONSORS
WHICH HAVE DIRECT INTEREST IN
THE SUBJECT MATTER: IGRA OR TST.
Does your program provide LTBI
evaluation and/or treatment?
37%
A. Yes, evaluation only
48%
B. Yes, evaluation and treatment
C. No, neither evaluation or treatment, referral to
7%
provider
7%
D. Other
If your program provides LTBI
evaluation, what test is used?
0%
1. TST only
0%
2. QFT only
100%
3. T-spot only
0%
4. QFT/T-spot and TST
0%
5. Other
Objectives
At the end of this session, participants will be able to:
·
Identify the two primary IGRAs used in the US and
describe how they are utilized and interpreted to
accurately diagnose TB infection
·
Describe performance characteristics of IGRAs and
compare to those of the TST to choose the best testing
modality for their patient population
·
Summarize guidelines on the usage of IGRAs and
discuss scenarios in which these test results may inform
clinical decisions
US Tuberculosis epidemiology in
foreign born-2013 (MMWR)
 FB cases – 64.6% of TB cases in the US (6172/9588); 20%
of these from Mexico
 The proportion of TB among the FB is increasing
 FB rate 13-times rate of U.S.-born persons (1.2 vs. 15.6)
Why is latent TB infection important?
Goal of TB elimination= <1 case per million
 Current US status:
 Overall 30 cases per million
 US born 14 cases per million
 Hispanic 50 cases per million
 Estimated that ~85% of active TB cases in foreign born
are secondary to progression from LTBI
 Modeling studies clearly show latent TB (LTBI)
identification and treatment is an essential component
of reaching the elimination goal.
Trends in Tuberculosis-US 2013, MMWR
Ricks et al, Plos one, 2011
Hill et al, Epidemiol Infect, 2012
Pathogenesis of Tuberculosis
Adapted from CDC TB teaching slides: Module 1 – Transmission and Pathogenesis of Tuberculosis
TB Pathogenesis- 3 outcomes:
#1: Immune clearance
#2: Latent TB Infection (LTBI)
4
special
immune cells
form a barrier
shell (in this
example,
bacilli are
in the lungs)
• Within 2 to 8 weeks macrophages surround the pathogen
and form a granuloma
• These cells form a barrier that keeps the bacilli contained
and under control (LTBI)
• Not infectious
Adapted from CDC TB teaching slides: Module 1 – Transmission and Pathogenesis of Tuberculosis
9
TB Pathogenesis- 3 outcomes:
#3: TB Disease
5
shell breaks
down and
tubercle
bacilli escape
and multiply
(in this example,
TB disease
develops in
the lungs)
• If the immune system CANNOT keep tubercle bacilli under
control, bacilli multiply and cause disease
• Can occur at any time, with LTBI 5-10% lifetime risk
• Infectious
Adapted from CDC TB teaching slides: Module 1 – Transmission and Pathogenesis of Tuberculosis
10
LTBI vs. TB Disease
Latent TB Infection (LTBI)
TB Disease (in the lungs)
Inactive, contained tubercle bacilli Active, multiplying tubercle bacilli
in the body
in the body
Chest x-ray usually normal
Chest x-ray usually abnormal
Sputum smears and cultures
negative
Sputum smears and cultures may
be positive
No symptoms
Symptoms such as cough, fever,
weight loss
Not infectious
Often infectious before treatment
Not a case of TB
A case of TB
Module 1 – Transmission and Pathogenesis of Tuberculosis
11
Targeted TB testing
 Screening should be targeted to those at higher risk
of TB-individuals with:
1. Increased rates of recent TB infection
And/or
2. Increased risk of progression to active TB
 Goals:
– Identify active TB cases
– Identify LTBI that would benefit from treatment
– Surveillance
Targeted TB Testing
**If no risk, don’t order the test- increased risk of false positives.**
Risk of TB Infection
Risk of TB Progression
Contacts/converters
HIV
Recent immigrants
Abnl CXR suggestive of prior TB
Residents/employees of high-risk
congregate settings (corrections,
nursing home, dialysis unit)
< 5 years of age
Foreign-born from high risk countries
Diabetes
Health care workers (HCWs)
Immunosuppression (prednisone,
chemo, TNF‐alpha inhibitor)
Medically underserved (homeless or
Other medical: silicosis, gastrectomy,
marginally housed, migrant workers,
low body weight/malnutrition,
street drug users, children with parents malabsorption, head/neck cancer,
organ transplant, jejunoilieal bypass
who have risk factors)
Smoking, IVDU, alcoholism
TB risk screen includes:
 Prior TB infection/disease, treatment
 Prior TB testing
 TB symptom review
 Medical conditions / risk factors
 Sociodemographic factors
 HIV status
LTBI Testing
-No “gold standard” since there is no way to
microbiologically diagnose LTBI
-Must use proxy of the host immunologic
response to TB antigens to infer the
diagnosis
Diagnosis of LTBI from 1908 to Dec 2006
- TST
 Disadvantages
-
Subjective
Logistic tracking
difficulties
- In vivo
- Adverse effects
- Boosting
- Affected by BCG
and non-tuberculous
mycobacteria
- Requires two visits
IGRAs entered the scene in 2006-2007 with a
lot of promise
(blood test using more specific TB antigens than TST)
‘A 21st Century Solution for Latent TB Detection’
Many medical centers have switched to
IGRAs for LTBI screening

QFT-GIT Advantages
-1 step testing
-Automated (ease of surveillance)
-Improved specificity in BCG vaccinated
and individuals with non-tuberculous
mycobacterial infection
-Likely more cost-effective
-No boosting
QFT-GIT Disadvantages
-Blood draw
-Performance data in long term studies
lacking
-Caution in young children,
immunocompromised/HIV
-Serial testing showing high variability
TST Interpretation
>5mm
>10mm
>15mm
HIV
Recent immigrant
All others
Immunosuppresion
prednisone >15mg daily x 1mo
TNF alpha inhibitor
Residents or
employees of jails,
nursing homes,
hospitals
Recent contact to active TB
IVDU
Abnl CXR
High risk medical
conditions
Organ transplant
Children
ATS/CDC guidelines 2000
IGRA Interpretation
Memory T cell
CD4
IFN-
+
Antigen presenting cell
QFT-ELISA
quantifies IFNgamma
T-SPOT- Elispot
detects activated
memory T cells
APC
ESAT6
CFP-10
TB7.7
Test
Positive
Negative
Grey zone
Ind.
QFT
≥0.35 IU/ml*
<0.35 IU/ml*
None
Controls fail:
-High nil
-Low mitogen
T-spot TB
≥ 8 spots*
< 8 spots*
5‐7 spots*
* (TB Ag - Nil) and assumes appropriate control responses
Same
What is the QFT assay?
 The QFT assay is comprised of 3 tubes:
-Antigen: inside of tube is coated with TB-specific antigens
-Nil: contains heparin and serves as a negative control.
-Mitogen: contains phytohaeamagluttinin (PHA) and serves as
positive control providing information about correct blood
sample handling and the immune status of pt
 ELISA is performed in all 3 tubes to measure the Interferon-
gamma level (IU/ml)
***QFT result (IU/ml)= Antigen-Nil***
How do IGRAs perform?
 Key performance characteristics of any
diagnostic:
-Sensitivity (true positive proportion identified)
-Specificity (true negative proportion identified)
 HOWEVER, ability to assess performance limited
by lack of gold standard for LTBI diagnosis
-Most accepted method is testing populations
with known characteristics (ie active TB patients
for sensitivity estimates and low risk individuals
for specificity estimates)
Accuracy of the current LTBI
diagnostics
Sensitivity (%)
Specificity (%)
TST
89
85
T.SPOT.TB
90
88
QFT
81
99
Mazurek MMWR 2010.
CDC 2010 MMWR IGRA
Recommendations
IGRA preferred
• Persons with likely poor return rate for TST
reading
• Persons who have received BCG vaccine
CDC 2010 MMWR IGRA
Recommendations
IGRA or TST recommended
(without preference)
• Recent contacts to person infected with TB
• Periodic screening of HCWs
CDC 2010 MMWR IGRA
Recommendations
TST preferred
(IGRA acceptable)
• Children <5 years
Should I test with both a TST and IGRA?
Not recommended!
However, cases where it can be helpful:
If the initial test is negative AND
• high risk of infection, progression, or poor outcomes
(HIV positive, < 5 years of age, immunocompromised)
– If the initial test is positive AND
• There is need for additional evidence to encourage compliance
•It is a healthy person with low risk of both infection and progression
TST vs. IGRA: What to do with
discordant results
 Avoid using two tests for TB screening
• TST(+) / IGRA(‐)
–
Foreign born with BCG and no severe immunocompromisin
g condition ‐ attribute to BCG
- However, abnormal CXR consistent
with old TB + risk factor for progression to disease, conside
r treatment
– U.S. born ‐
with no risk factors for exposure or risk factors for progress
ion may be NTM colonization
TST vs. IGRA: What to do with
discordant results
 TST(‐) / IGRA(+)
- If FB but no risk for TB progression: consider
repeat IGRA if near cutoff point ie <0.7UL/ml
*controversial
-US born with no risk factors for exposure or
progression- repeat IGRA
** If severe immunocompromising condition: and
discordant TST/ IGRA OR TST/IGRA negative and
abnl CXR c/w old TB, offer LTBI treatment
Discordant results summary
1. Immunocompromised with infection risk:
use any positive result (high risk with
missing true LTBI)
2. BCG vaccinated and healthy: use IGRA
3. Low risk: shouldn’t be tested but negative
result is more likely true.
4. Moderate risk: evaluate exposure and
medical risk, assess risk-benefit of LTBI
treatment
What about indeterminates?
(indeterminate = either a low positive control
or a high negative control value)
Per QFT Package insert:
The 2 main causes of indeterminate results are due to technical errors (ie
improper incubation, insufficient mixing of blood collection tubes)
Other less common causes are:
-Transient (viral illness, recent vaccination)
-Chronic (immunosuppression)
If the QFT result is indeterminate…
 Repeat the test in ~3-4 weeks (can help if the
indeterminate is secondary to technical
problems or transient patient abnormality)
 If the repeat is indeterminate, then IGRA can’t be
used for clinical decision making, except to
assume that the patient is probably anergic.
 Other tests (ie TST), clinical information, TB risk
factors and risk of progression must be used
instead.
IGRA and TST limitations
 The CDC and WHO advises against the use
of both IGRAs and TST for diagnosis of
active TB.
-~20% of individuals with active TB will
have a negative IGRA or TST
-So a negative IGRA/TST does NOT rule
out active TB
IGRA and TST limitations (cont.)
• IGRAs/TST should NOT be used to monitor
response to TB therapy; studies in this area are
inconsistent.
• IGRAs/TST can NOT accurately predict the risk
of infected individuals developing active TB
disease
• IGRAs/TST can NOT distinguish old from new
infection
IGRAs: timing of conversions
• Most IGRA conversions occur within four
to eight weeks after exposure (similar to
TST)
• However, conversion after three months
has been reported
Conclusions
 LTBI diagnosis is a combination of evaluation of risk factors





for TB infection and risk of TB progression AND TST/IGRA
results
IGRAs are logistically easier but interpretation is as equally
challenging as the TST
IGRAs do have advantage in reducing false positives in BCG
vaccinated individuals
Discordant TST/IGRA results do occur- if a person is
immunocompromised, be conservative and err on the side
of treatment
If an indeterminate IGRA result is obtained, repeat the test
in 3-4 weeks
Do not use TST/IGRA results to monitor response to
treatment for LTBI
Acknowledgements
Curry International TB Center
Kelly Musoke
Ann Raftery
Julie Higashi, MD, PhD
Stanford University
Niaz Banaei, MD
Upi Singh, MD
Julie Parsonnet, MD
McGill
Madhukar Pai, MD, PhD
Financial Support
Stanford SPARK/ Global Health
Does your program provide LTBI
evaluation and/or treatment?
0%
A. Yes, evaluation only
0%
B. Yes, evaluation and treatment
0%
0%
C. No, neither evaluation or treatment, referr
to provider
D. Other