Mady Slater, M.D.Stanford University Medical CenterDivision of Infectious DiseasesCurry International TB CenterJune 21, 2014Border Health Training

IGRAs for latent TB diagnosis- what are they and how do we interpret them?

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?

7%

7%

48%

37% A. Yes, evaluation onlyB. Yes, evaluation and treatmentC. No, neither evaluation or treatment,

referral to provider

D. Other

If your program provides LTBI evaluation, what test is used?

0%

0%

100%

0%

0% 1. TST only2. QFT only3. T-spot only4. QFT/T-spot and TST5. Other

ObjectivesAt 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, MMWRRicks et al, Plos one, 2011Hill et al, Epidemiol Infect, 2012

Pathogenesis of Tuberculosis

Adapted from CDC TB teaching slides: Module 1 – Transmission and Pathogenesis of Tuberculosis

Adapted from CDC TB teaching slides: Module 1 – Transmission and Pathogenesis of Tuberculosis 9

TB Pathogenesis- 3 outcomes:#1: Immune clearance

#2: Latent TB Infection (LTBI)

specialim m une cells form a barrier shell (in th isexam ple,bacilli arein the lungs)

4

• 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 10

TB Pathogenesis- 3 outcomes:#3: TB Disease

shell breaks down and tuberclebacilli escape

m ultip ly(in th is exam ple,TB d isease develops in the lungs)

and

5

• 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

Module 1 – Transmission and Pathogenesis of Tuberculosis 11

LTBI vs. TB Disease

Latent TB Infection (LTBI) TB Disease (in the lungs)

Inactive, contained tubercle bacilli in the body

Active, multiplying tubercle bacilli 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

Targeted TB testing

Screening should be targeted to those at  higher risk of TB-individuals with:

1. Increased rates of recent TB infectionAnd/or2. Increased risk of progression to active TB

Goals: – Identify active TB cases– Identify LTBI that would benefit from treatment– Surveillance

Targeted TB Testing

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 marginally housed, migrant workers, street drug users, children with parents who have risk factors)

Other medical: silicosis, gastrectomy, low body weight/malnutrition, malabsorption, head/neck cancer, organ transplant, jejunoilieal bypass

Smoking, IVDU, alcoholism

**If no risk, don’t order the test- increased risk of false positives.**

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

- TST

Disadvantages- Subjective- Logistic tracking

difficulties- In vivo

- Adverse effects- Boosting

- Affected by BCG and non-tuberculous mycobacteria

- Requires two visits

Diagnosis of LTBI from 1908 to Dec 2006

‘A 21st Century Solution for Latent TB Detection’

IGRAs entered the scene in 2006-2007 with a lot of promise

(blood test using more specific TB antigens than TST)

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

APC

CD4

IFN-

+

ESAT6CFP-10TB7.7

QFT-ELISA quantifies IFN-gamma

IGRA Interpretation

Memory T cell

Antigen presenting cell

T-SPOT- Elispot detects activated memory T cells

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* Same* (TB Ag - Nil) and assumes appropriate control responses

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 immunocompromising  condition ‐ attribute to BCG

- However, abnormal CXR consistent with old TB + risk factor for  progression to disease, consider treatment

– U.S. born ‐ with no risk factors for exposure or risk factors for  progression 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

AcknowledgementsCurry International TB Center

Kelly MusokeAnn Raftery

Julie Higashi, MD, PhD

Stanford UniversityNiaz Banaei, MDUpi Singh, MDJulie Parsonnet, MD

McGillMadhukar Pai, MD, PhD

Financial SupportStanford SPARK/ Global Health

Does your program provide LTBI evaluation and/or treatment?

0%

0%

0%

0% A. Yes, evaluation onlyB. Yes, evaluation and treatmentC. No, neither evaluation or treatment,

referral to providerD. Other