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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?