LTBI: Background, Definitions, and Diagnosis

Bijan Ghassemieh, MD Firland Pulmonary/Critical Care Fellow

University of Washington

DISCLOSURES

• I have no disclosures or conflicts of interest to report

OBJECTIVES

• Understand what LTBI is • Understand basic LTBI epidemiology • Understand who to test (briefly) • Understand available resources (TSTin3D, BCG

world atlas) • Understand how to interpret tests for LTBI • Understand the pros/cons of available tests

OBJECTIVES

• Understand what LTBI is

What is LTBI?

• Evidence of cell-mediated immunity to TB antigens (TST or IGRA)

• No evidence of active disease – Clinical – Radiographic – Microbiologic (usually not necessary)

Nunez-Alvarez. Nat Rev Microbiol. 2014

Pathophysiology of LTBI

Coleman. Infect Immun. 2014.

• Macacque monkey model • Inoculated with TB via

bronchoscopy • Followed with PET/CT over 6 mo. • At 6 mo., classified as LTBI vs. TB

disease • Clinical • Radiographic • Microbiologic (BAL) • Inflammatory markers (ESR)

Pathophysiology of LTBI

Jeong. J Korean Med Sci. 2014.

Pathophysiology of LTBI

• Patients with “Old Healed TB” (aka TB class 4)

• No clinical, radiographic, or microbiologic evidence of active TB

• 9/63 pts with “hot” PET/CT imaging

• Followed for at least 6 months. None developed clinical TB

• 50 yo Bangladeshi M with cough X 2 months

• Thoracentesis: Lymphocytic exudative effusion

• Sputum AFB studies pending

LTBI or TB?

• Lost to follow up • Returns 8 weeks later • Feeling well • Sputa AFB culture negative

X 3 • QFT positive

LTBI or TB?

Pai. Clin Microbiol Rev. 2014

LTBI: Clinical Definition

• Evidence of cell-mediated immunity to TB antigens (positive TST or IGRA)

• No evidence of active disease – Clinical – Radiographic – Microbiologic (usually not necessary)

OBJECTIVES

• Understand what LTBI is • Understand basic LTBI epidemiology

Q: LTBI Epidemiology

About what percentage of TB cases in the US are due to reactivation of LTBI rather than recent transmission? A. 10% B. 33% C. 50% D. 80%

LTBI Epidemiology: Why Do We Care?

Small. NEJM. 2001

• LTBI will progress to TB roughly 10% of the time

• >80% of TB cases in US are from reactivation

• Treatment of LTBI (if completed ) up to 90% effective in preventing TB

LTBI Epidemiology

Horsburgh. NEJM. 2004

LTBI Epidemiology: Focus on recent infection and risk of progression

Horsburgh. NEJM. 2011

OBJECTIVES

• Understand what LTBI is • Understand basic LTBI epidemiology • Understand who to test

LTBI: Who To Test

• Targeted Testing: “A decision to test is a decision to treat”

• Goal is to identify patients who are at higher risk for reactivation – Includes those recently infected

• TST interpretation guidelines helpful in remembering who to target

TST Interpretation (and who to test)

WHO 22 High Burden Countries

OBJECTIVES

• Understand what LTBI is • Understand basic LTBI epidemiology • Understand who to test • Understand available resources (TSTin3D, BCG

world atlas) • Understand how to interpret tests for LTBI • Understand the pros/cons of available tests

OBJECTIVES

• Understand how to interpret tests for LTBI

Q: TST Interpretation

Which of the following statements is true? A. The TST will become positive within 30 days

after exposure to TB B. 5 mm of TST induration is considered positive in

foreign-born patients C. BCG vaccination performed in infancy is unlikely

to cause a false positive TST in adulthood D. An increase of 5 mm induration over a 2 year

period is considered a TST “conversion”

Tuberculin Skin Test (TST)

• Intra-dermal injection of tuberculin (PPD) onto inner surface of forearm

• Delayed type hypersensitivity response 48-72 hrs later – Measure induration,

not erythema

Berrian County (MI) Health Dept website: bchdmi.com

Tuberculin Skin Test (TST)

• Contra-indicated if prior severe local reaction, anaphylaxis (both rare)

• Takes 2-8 weeks after exposure for TST to turn positive

• Test Characteristics – Sensitivity: 80% – Specificity: 97% non-BCG vaccinated, 60% BCG

vaccinated

TST Interpretation

TST conversion also considered positive: > 10 mm increase within a 2 year period

TST Issues: False results

• False positives: – BCG vaccination (more to come) – Non-tuberculous mycobacteria (NTM)

• False negatives: – Immunosuppression (HIV, age extremes, meds,

active infection, etc) – Live virus vaccination (co-administer or wait 4-6

wks) – Anergy

TST Issues: Boosting

• TST response may wane over time (especially if > 55 y.o.)

• Response to remote infection can be “boosted” by repeating TST 1-4 weeks after initial test

• “2 step” initial testing – Those expected to undergo serial testing, also

consider in those age >55 – Differentiates remote versus recent infection

OBJECTIVES

• Understand what LTBI is • Understand basic LTBI epidemiology • Understand who to test • Understand available resources (TSTin3D, BCG

world atlas) • Understand how to interpret tests for LTBI • Understand the pros/cons of available tests

Zwerling. PLoS Med. 2011

BCG World Atlas

• BCG unlikely to give false positive if given once in infancy and not repeated

• CDC recommendations: • Ignore BCG when

interpreting TST • BUT…IGRA is preferred

test if history of BCG • BCG atlas: online database of

BCG practices (when, how often)

Q: IGRA Interpretation

Which of the following statements is true? A. A person with an indeterminate IGRA has an

intermediate risk of TB disease B. IGRAs are preferred over the TST for serial

testing (ie of health care workers) C. IGRAs are not affected by BCG and have less

cross reactivity with NTMs compared to the TST D. The QFT measures the number of cells

producing Interferon-gamma

Interferon Gamma Release Assays

• In vivo blood tests of cell mediated immune response – Measure T cell release of IFN-γ after stimulation

by TB specific antigens • 2 commercially available

– QuantiFERON Gold In-Tube (QFT) • Measures in tube production of IFN-γ

– T-SPOT.TB • Measures number of mononuclear cells in wells that

produce IFN-γ (spot-forming cells)

QFT: How it’s done

• 3 tubes: – Nil (negative control) – Mitogen (positive control) – Antigen

Quigen.com

What is a positive QFT?

Harada. J Infect. 2008.

QFT: How it’s interpreted

T-SPOT.TB: How it’s done

Tspot.com

T-SPOT.TB: How it’s done

Nil Control

Positive Control

Infection

Infection

Tspot.com

T-SPOT.TB: How it’s interpreted

tspot.com

IGRAs: Issues

• Questions regarding reproducibility and serial testing, especially when value near the cut-point (next slide)

• Increased material costs compared to TST • What to do with indeterminate (or borderline

T-SPOT.TB) results? • IGRAs may cross-react with some of the NTMs

– M. marinum, M. kansasii, M. szulgai, and M. flavescens

IGRAs: Issues with serial testing

Dorman. AJRCCM. 2014

Pai. Clin Microbiol Rev. 2014

Sources of QFT Variability

VS.

OBJECTIVES

• Understand the pros/cons of available tests

LTBI Test Characteristics

SENSITIVITY SPECIFICITY

TST 80% 97% in non-BCG vaccinated 60% BCG vaccinated

QFT 80% >95%

T-SPOT.TB 90% >95%

Pai. Clin Microbiol Rev. 2014. Miramontes. PLoS One. 2015.

• Remember that sensitivity/specificity are not the same as positive/negative predictive value

• PPV= probability of infection if test positive • NPV= probability that not infected if test negative • PPV and NPV are dependent on prevalence • Assuming LTBI prevalence of 1.5% in U.S.-Born (Miramontes), with a

sensitivity of 80% and a specificity of 97%, the PPV of a positive TST is only 29%!!!

Pinto. Med Princ Pract. Oct 2012

Are the TST and IGRAs really even comparable?

• NHANES 2011-2012 data • US Born (TST cut-off of 10mm)

• Foreign Born (TST cut-off of 10mm)

• Saw similar results after varying TST cut-points (5mm and

15 mm) and QFT cut-points (0.7 and 1 IU/mL)

TST + TST-

QFT+ 0.6% 2.2%

QFT- 0.8% 96.4%

Ghassemieh. AJRCCM. 2016

TST+ TST-

QFT+ 9.1% 7.2%

QFT- 11.2% 72.5%

CDC: TST vs IGRA? • Either are acceptable for all situations, but “preferred” to

use…… – TST for: children < 5 – IGRA for: prior BCG, patient unlikely to return

• Consider performing both (not at same time) if:

– Negative initial test and risk for infection/progression/poor outcome are all high

– Positive initial test and low risk of infection/progression/poor outcome

• Indeterminate IGRA result? – Repeat, or perform TST

QUESTIONS?

LTBI: Background, Definitions, and Diagnosis DISCLOSURESOBJECTIVES OBJECTIVES What is LTBI? Pathophysiology of LTBIPathophysiology of LTBIPathophysiology of LTBILTBI or TB? Slide Number 10Slide Number 11LTBI: Clinical Definition OBJECTIVES Q: LTBI EpidemiologyLTBI Epidemiology: Why Do We Care?LTBI EpidemiologyLTBI Epidemiology: Focus on recent infection and risk of progression OBJECTIVES LTBI: Who To TestTST Interpretation (and who to test) Slide Number 21OBJECTIVES OBJECTIVES Q: TST InterpretationTuberculin Skin Test (TST)Tuberculin Skin Test (TST)TST Interpretation TST Issues: False resultsTST Issues: BoostingOBJECTIVES BCG World Atlas Q: IGRA Interpretation Interferon Gamma Release AssaysQFT: How it’s done What is a positive QFT? QFT: How it’s interpreted T-SPOT.TB: How it’s doneT-SPOT.TB: How it’s doneT-SPOT.TB: How it’s interpretedIGRAs: IssuesIGRAs: Issues with serial testingSources of QFT VariabilityOBJECTIVES LTBI Test Characteristics Slide Number 45Are the TST and IGRAs really even comparable? CDC: TST vs IGRA?QUESTIONS?