Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 1

Diagnosing Latent TB Infection (LTBI)

Supporting patients with LTBI Infection: What Nurses Need to Know

Thursday, June 20th, 2019

Michelle Haas, M.D.

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

DISCLOSURES

• I have no disclosures or conflicts of interest to report

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 2

Objectives

• By the end of this presentation, participants should be able to:

• Understand how to identify patients who would benefit from testing for LTBI

• Describe how to place and read a tuberculin skin test

• Explain how interferon-gamma release assays (IGRAs) identify true LTBI in individuals who receive BCG vaccination compared to tuberculin skin tests (TSTs)

Tuberculin Skin TestImportant Historical Points

• 1890 - Robert Koch (“old tuberculin”)

• 1907 - Clemens von Pirquet

• 1939 - Florence Seibert

• 1969 - Gryzybowski and Holden

• 1972 - Division of Biologic Standards

• 1976 - FDA appointed a Panel on Skin Test Antigens

• Tubersol (Sanofi Pasteur Limited)

• Aplisol (JHP Pharmaceuticals LLC)

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 3

• Use this tool to identify asymptomatic adults for latent TB infection (LTBI) testing.• Do not repeat testing unless there are new risk factors since the last test.• Do not treat for LTBI until active TB disease has been excluded

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 4

TST—how it works

Tuberculin Skin TestingMantoux Method

48 to 72 hours5 TU of PPD

Interpretation depends

on person’s risk factors

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 5

Tuberculin Skin TestCriteria for a Positive Reaction

Note: Skin test conversion is an increase of ≥10 mm to ≥ 10 mm within a 2-

year period

>=5mm >=10mm >=15 mm

HIV-positive prior BCG vaccination no risk

contactsprior residence in a TB

endemic areaabnormal chest

radiograph injection drug use

immunosuppression children

congregate settings such as correctional

facilities, nursing facilities, hospitals

Stability of Reactions and Inter-reader Variability

• Biologic variation from test to test in the same patient is very small, approximately 1mm.

• Chaparas et al. ARRD 1985;132:175

• Same reader - Standard deviations of 1.3-1.9 mm• Perez-Stable, et al. AJPH 1985;75:1341.

• Erdtmann, et al. JAMA 1974;228:479

• Different readers - Standard deviations of 2.3-2.5 mm• Furcolow et al. ARRD 1967;96:1009.

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 6

Interval From Primary Infection to TST Conversion

Menzies D. AJRCCM 1999;159:15

N = 172

Tuberculin Skin Testing“Boosting”

14 mm11 mm 12 mm

Years

0 5 10 15 20 30 31

Infection TST TST TST TST

20

15

10

5

0

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 7

Tuberculin Skin TestingTwo-step Testing

Positive

Positive

(True positive)Negative

(True negative)

Read at 48-72 hours

Place 2nd TST

Negative

Read at 7 days

Place TST

Positive

Positive(True positive)

Negative(True negative)

Read at 48-72 hours

Place 2nd TST

at one week

Negative

Read at 48-72 hrs

Place TST

4 visits 3 visits

Tuberculin skin test interpretation: False-negative results

• Host factors • Immunosuppression

• Recent TB infection (<3 months)

• Age (newborn, elderly)

• Infections (viral, fungal, bacterial)

• Live virus vaccination

• Overwhelming tuberculosis

• ESRD

• Other illness affecting lymphoid organs

Shankar, et al. Nephrol Dial Transplant 20: 2720–2724, 2005

❑Technical factors ➢Tuberculin product (improper

storage, contamination)

➢Improper method of administration, reading and/or recording of results

Slide courtesy of Dr. Neha Shah

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 8

Tuberculin skin test interpretation: False-positive results • Cross-reactions from atypical mycobacterial infections

• Recent or multiple BCG vaccination

• Misinterpretation of immediate hypersensitivity to tuberculin

• Switching tuberculin products (aplisol > tubersol)

Slide courtesy of Dr. Neha Shah

IGRA vs. TST

• Advantages over TST• Not affected by BCG vaccination

• Not affected by most non-tuberculous mycobacteria

• Interpretation is more objective

• No return visit needed for interpretation of test• Patients and providers may lack confidence in TST results

• Disadvantages over TST• Blood draw

• Cost

CDC, MMWR, 2010 | Pai, Clin Micro Rev, 2014

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 9

Interferon-Gamma Release Assays (IGRAs)

• QuantiFERON®-TB (QFT-Gold plus)• Reported as positive, negative, or indeterminate

• T-SPOT.TB (T-Spot)• Reported as positive, borderline, negative, or indeterminate

17Slide courtesy of Dr. Neha Shah

IFNg-release assays T-SPOT.TB®

Measure [IFNg]

by ELISA

Quantiferon®

Incubate overnight whole blood

with antigens specific for MTB

(ESAT-6, TB7.7, & CFP-10)

Anti-IFNg ab

IFNg

ESAT-6 or CFP-10

Wash

Anti-IFNg ab

Addition of secondary ab

Addition of substrate

Each spot =

the “footprint” of

one IFNg-

producing

cell

IGRAs: how they workFigure courtesy of Ed Chan

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 10

TST and QFT Specificity

Specificity95%

confidence interval

TST without BCG 97 95–99

TST with BCG 59 46–73

QFT 96 94–98

• Menzies, Ann Intern Med, 2007

• Pai, Ann Intern Med, 2008Slide courtesy of Dr. Neha Shah

QuantiFERON-Gold Plus (QFT-plus)

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 11

QFT-plus: interpreting the results

T-SPOT Interpretation

Positive Negative Borderline Indeterminate

T Spot TB ≥ 8 spots* ≤ 4 spots* 5-7 spots*

Controls fail:• High Nil• Poor Mitogen

response

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

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 12

IGRAs –Basic similarities

• Single blood draw

• Incubate blood cells with antigens from the region of difference 1 (RD1)

• not contained in BCG but present in M.bovis

• Antigens present in M. marinum, kansasii, szulgai, and flavescens

• Results available in 1 day

Why do we repeat tests for TB infection?

• You don’t like the first test result so you repeat it to get the one you like

• Positive result in low risk individual (healthcare worker who is required to undergo testing)

• High risk individual who has a negative result• Repeating in person with HIV whose CD4 has risen above 200

• 8 week testing in the context of a contact investigation

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 13

Clinical Scenario #1

• 20-year-old man with prior residence in India:

• Required to undergo TB testing for college

• 11 mm TST, normal CXR

“It’s due to my BCG”• QFT positive (TB-nil = 1.15)

• TB antigen 2.08 IU, nil 0.93 IU, and mitogen > 10 IU. TB antigen- nil = 1.15 IU which was above the cutoff of > 0.35 IU that defines a positive test.

“It’s boosting from the TST. I would like to be tested again.”

What would you do next?

Interpretation and Management

• 1- interpret QFT as positive and offer treatment for LTBI, decline his request for further testing

• 2- Attempt to explain that “boosting” from BCG still means that he was infected with TB at some point in his life, that no additional testing is needed and offer latent treatment

• 3- he lived for a long time in a TB endemic area so agree to will repeat the QFT anyway because of course it will be positive

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 14

Clinical Scenario #1

• 20-year-old man with prior residence in India:

• Required to undergo TB testing for college

• 11 mm TST, normal CXR

“It’s due to my BCG”• QFT positive (TB-nil = 1.15)

• TB antigen 2.08 IU, nil 0.93 IU, and mitogen > 10 IU. TB antigen- nil = 1.15 IU which was above the cutoff of > 0.35 IU that defines a positive test.

“It’s boosting from the TST. I would like to be tested again.”

A second QFT a few weeks later was negative (TB-nil was 0.34 IU). He believed this was the ”true” results and declined further testing

Diagnosing Latent TB Infection

• TSTs and IGRAs cannot distinguish between latent TB infection and active TB disease

• Always evaluate for underlying active TB

• IGRAs and TSTs can be falsely negative in up to 25% of individuals with active TB

Positive TST or IGRA

Latent TB infectionActive TBdisease

? ?

Slide courtesy of Dr. Neha Shah

Michelle Haas, MD

Associate Director

Denver Metro Tuberculosis Program

Denver Public Health

Supporting Patients with Latent TB Infection:

What Nurses Need to Know

Hilo, HI

June 20, 2019 15

Summary: Pros and Cons

IGRA

• in vitro

• Specific Mtb antigens

• 1 patient visit

• phlebotomy

• stimulate within hours

• results possible in 1 day

• complex laboratory test

• Much that is not understood

TST

• in vivo

• PPD

• 2 patient visits

• intracutaneous injection

• injected = done

• results in 2–3 days

• point-of-care test

• data storage—varies

Questions?