Dr. Michelle Haas Denver Metro Tuberculosis Program Denver Public Health Focus on TB Prevention Modesto, CA June 5, 2019 1 LTBI Basics Focus on TB Prevention June 5th, 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
39
Embed
LTBI Basics - Curry International Tuberculosis Center...•LP: WBC 149, t prot 152, glucose 14 •M. tuberculosis PCR positive Patient with Preventable TB •Bronchoalveolar lavage,
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 1
LTBI Basics
Focus on TB PreventionJune 5th, 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
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 2
Objectives
• List causes of indeterminate results for IGRAs
• Describe limitations of using IGRAs to diagnose LTBI in low risk populations
• Understand evidence supporting treatment of latent TB infection (LTBI)
• Understand advantages/disadvantages of current treatment options for LTBI
Patient with Preventable TB
• 28 year old woman, originally from Mexico, presented to her primary care provider 5 years ago essentially for well visit
• Went back to PCP 5 years later:• Cough for 2 months, wheezing noted on exam• Inhaler offered, PFTs scheduled
• Urgent care visit 3 days after that visit• Continued cough, CXR obtained…
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 3
“atypical
pneumonia”:
azithromycin for 5
days
Patient with Preventable TB
• 5 months later: repeat PCP visit:
• continued cough, no relief with albuterol
• 8 lb. weight loss: BMI 18.6.
• QVAR and Claritin were added to her albuterol.
• Chest radiograph findings were noted→ referred to pulmonary, CT chest ordered.
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 4
Patient with Preventable TB
• One month later: seen in the ED• continued chronic cough, tachycardic to 115. Was discharged
• Two days after ED visit in pulmonary clinic:• Working diagnosis of possible bronchiolitis, bronchoscopy planned but she
didn’t have the funds to cover to copay
Patient with Preventable TB
• 3 weeks after pulm visit, 7 months into her illness• Went to the ED with headache for 7 days, fever, nausea/vomiting
and body aches and sore throat
• DX→ strep throat • RX→ azithromycin
• Chest x-ray was noted to have “no acute findings.”
• Went back twice in one week: persistent headaches, nausea vomiting and now photophobia, visual disturbances
• DX→ tension headache
• RX → follow up with her primary care provider
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 5
Patient with Preventable TB
• Two days later, 8 months into her illness: family took her to another hospital
• Somnolence, confusion• Continued nausea/vomiting
• Her hospital course was further notable for the development of seizures.
• Started on TB treatment with isoniazid, rifampin, pyrazinamide and ethambutol and steroids due to meningitis.
• Profoundly debilitated/confused and unable to care for herself at discharge
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 6
A review of how to identify individuals at risk for TB infection
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 7
Who should get tested?
• 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
• No gold standard for diagnosing LTBI
• All tests assess T-cells for prior exposure to TB antigens
Slide courtesy of Dr. David Horne
Tests for identifying TB infection
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 8
TST—how it works
Tuberculin Skin TestingMantoux Method
48 to 72 hours5 TU of PPD
Interpretation depends
on person’s risk factors
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 9
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.
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 10
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
Tuberculin skin test interpretation: False-positive results • Cross-reactions from atypical mycobacterial infections
• Recent or multiple BCG vaccination
• Misinterpretation of immediate hypersensitivity to tuberculin
* (TB Ag - Nil) and assumes appropriate control responses
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
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 17
Indeterminate/borderline results
• Cannot determine whether someone has TB infection
• Low lymphocyte count
• Low lymphocyte activation potential
• Specimen collection errors
• Repeat test with valid result (pos/neg) in 68% (Banach IJTLD 2011)• Repeating the test is often the next step
Sources of variability and indeterminate results
Pai, Clin Micro Rev, 2014
• IFN-γ may vary by +0.24 IU/ml
when result between 0.25-0.80
(Metcalfe AJRCCM 2013)
• S. Africa study of serial QFTs –
“converters” who had levels <
0.7 IU/ml had same TB risk as
those with levels <0.2
IU/ml(Nemes AJRCCM 2017)
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 18
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
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?
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 19
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
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
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 20
Clinical Scenario #2
• 35-year-old woman who returned from a 1-month trip to Ethiopia, no reported TB contacts. Had lived previously in Ethiopia, two prior QFTs in 2016 and 2017 were negative.
• CXR was normal.
• HIV negative#1-2016 #2-2017 #3- 4 weeks post
trip
QFT - Nil 0.091 0.126 0.13
QFT- MITOGEN >10 >10 >10
QFT - RESULT Negative Negative Positive (A)
Quantiferon - TB1
Ag
0.239 0.323 0.29
Quantiferon - TB2
Ag
0.48
Interpretation and Management options
• #1-treat as a conversion and offer LTBI treatment
• #2—consider this a false positive as it is in one tube (TB Ag2) and repeat in 4-6 weeks. If negative, then consider this the “true result” and discharge from public health follow-up
• #3—consider this early conversion as it is in the TB Ag2 but repeat in 4-6 weeks to see if TB Ag1 turns positive and then offer treatment
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 21
Clinical Scenario #2
#1-2016 #2-2017 #3- 4 weeks post
trip
#4-one month after #3
QFT - Nil 0.091 0.126 0.13 0.14
QFT- MITOGEN >10 >10 >10 >10
QFT - RESULT Negative Negative Positive (A) Negative
Quantiferon - TB1
Ag
0.239 0.323 0.29 0.21
Quantiferon - TB2
Ag
0.48 0.28
Clinical Scenario #2
• Prior positive considered a false-positive
• She was discharged from further public health follow up.
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 22
• IGRA responses may change over time
• 2400 U.S. HCW, serial TST, QFT, T-SPOT (Dorman AJRCCM 2014)
• 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
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 23
Can IGRAs be use to monitor a response to treatment?
Clifford Tuberculosis 2015
• 15 studies that evaluated LTBI responses
• No consistent pattern using reversions or quantitative IFN-gamma levels
Slide courtesy of Dr. David Horne
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
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 24
TB infection screening risk: examples of different work flows• Medical assistant asks about TB risk during rooming of the patient
• Orders IGRA or TST if at risk
• Health maintenance sections in electronic health record• Maintained by clinic nurses
• Taking a travel history only• Registration? (similar to Ebola?)• Medical assistant• Clinic nurse• Provider driven
• Assessing birth country at the time of registration
Perform TST/IGRAReason for test: ICD-10 Z91.89 “At high risk for tuberculosis infection”
Yes
No
Perform symptom screen if you determine they are at risk for TB infection: new/progressive cough for 2-3 weeks, night sweats, unexplained weight loss, subjective feverAre symptoms present?
Example Work-flow for TB infection diagnosis and treatment
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 25
Diagnostic testing for active M. tuberculosis
Chest radiography
(AFB) sputum smear
30-50% may be AFB smear negative
AFB sputum culture—gold standard, limit of detection 10 organisms/mL sputum
Nucleic acid amplification test (NAAT) to detect M. tuberculosis in sputum samples Molecular beacon assays (”Xpert”)
Line probe assays “Hain)
MTB probe: amplified mycobacterium direct test
Your patient has no symptoms of active TB—what next?
Dr. Michelle Haas
Denver Metro Tuberculosis Program
Denver Public Health
Focus on TB Prevention
Modesto, CA
June 5, 2019 26
Perform chest radiograph and consider repeat symptom screen and/or review of systems. Are either abnormal?
IGRA/TST positive?
Evaluation for active TB and/or refer to public health
Yes
NoNo further intervention
Yes
Offer LTBI therapy if risk of developing active TB is >3%-5* by the age of 80 or greater than 0.1% annually: (http://www.tstin3d.com/)
No
Perform TST/IGRAReason for test: ICD-10 Z91.89 “At high risk for tuberculosis infection”
Perform chest radiograph and consider repeating symptom screen. Are either abnormal?
If risk factors present, perform symptom screen. Symptom screen positive?
Evaluate for active TB/refer to public health
Yes
No
No further intervention
Yes
Offer LTBI therapy if risk of developing active TB is >3% by the age of 80 or >0.1% annually: (http://www.tstin3d.com/)Options:1) Rifampin 10mg/kg max dose 600mg daily x 4 months. Review drug
interactions.2) Isoniazid/rifapentine once weekly for 12 doses. Review drug interactions.3) INH 5mg/kg max dose 300mg daily with 25mg B6 x 9 months.
No
Example Work-flow for TB infection diagnosis and treatment