1. A typical day in the TB clinic You see the following patients in the TB clinic. All have normal CXRs: 1. A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam. He wants to work in your hospital. 2. A 64 year old woman from Jamaica with a 12 mm PPD who is referred for immigration purposes. She has no risk factors and her exam is negative 3. An 18 year old young woman from Lima, Peru with a 14 mm PPD for immigration purposes. Her history and exam are negative 4. A 54 year old man born and raised in Hartford, who has a 20 mm PPD. He cannot recall having had a previous TST. He used to be an IV drug abuser. He says his HIV was negative 3 months earlier. What is the risk of developing TB disease and what is the role, if any, for IGRA testing in these patients, and how would you treat them?

2. LTBI vs. TB Disease LTBI TB Disease Tubercle bacilli in the body Skin test or blood test usually positive Chest x-ray normal Chest x-ray abnormal Bacteriology negative Bacteriology positive No symptoms Cough, weight loss, night sweats Not infectious, not a case Often infectious before treatment

3. nyc.gov/health Interpretation of TST Results

4. False-positive and false-negative PPDs The PPD is only about 70% sensitive False positive –BCG vaccination –Nontuberculous mycobacterial infection –Improper administration or interpretation False negative –Very young (<6 months old) –Inability to mount an immune response (e.g., HIV or TB itself) –Recent infection (<10 weeks since exposure) –Very remote infection –Recent live virus vaccination –Improper administration or interpretation

5. Interferon Gamma Release Assays (IGRAs) Quantiferon Gold/Gold In-Tube (QFT-GIT)Quantiferon Gold/Gold In-Tube (QFT-GIT) –2 nd /3 rd generation tests –Available from commercial labs –ELISA that measures amount of IFN-gamma released by patients cells T-Spot.TBT-Spot.TB –Approved July 2008 –Elispot

6. Indeterminate IGRA Less frequent with QFT-GITLess frequent with QFT-GIT Several possible reasonsSeveral possible reasons –High background IFN- : patient illness, mitogen in wrong well, defective tubes –Low mitogen: immune suppression, defective tubes, overfilling, inadequate shaking Options?Options? –Repeat QFT –Place TST instead

7. Comparison of IGRAs and TST IGRA About 70% sensitiveAbout 70% sensitive Not affected by BCGNot affected by BCG Not cheapNot cheap New: less experienceNew: less experience In vitro testl; requires phlebotomyIn vitro testl; requires phlebotomy No boostingNo boosting Only need 1 patient visitOnly need 1 patient visit Gives numbers, lessens variabilityGives numbers, lessens variability Results possible in 1 dayResults possible in 1 day May decline in response to test after treatmentMay decline in response to test after treatmentTST About 70% sensitiveAbout 70% sensitive Fairly specificFairly specific CheapCheap Been around a long timeBeen around a long time In vivo testIn vivo test Potential boostingPotential boosting Requires 2 patient visitsRequires 2 patient visits Inter-reader variabilityInter-reader variability Results in 2-3 daysResults in 2-3 days May be more sensitive in detecting remote infectionsMay be more sensitive in detecting remote infections

8. Potential to cause big problems versus the hassle required to reduce this risk

9. Latent Tuberculosis Infection (LTBI) and progression to real disease About 5–10% of persons with LTBI will develop TB disease if untreatedAbout 5–10% of persons with LTBI will develop TB disease if untreated –50% in the first two years –50% later in life The most effective treatment would be to identify and treat LTBI in all these individualsThe most effective treatment would be to identify and treat LTBI in all these individuals However, treatment of LTBI is:However, treatment of LTBI is: –Is lengthy: 4 to 9 months, generally –Is costly: not from medications but because patients have to come in regularly for monitoring, thereby missing work, school, etc. –Carries a very small but real risk for side effects

10. High Risk for Conversion of LTBI to TB Disease Recent infection, documented conversion (within the last 2 years) HIV infection Substance abuse (alcohol or drugs) Old healed TB lesions on CXR Children under 5 years of age Certain medical conditions

11. Medical Conditions HIV infectionHIV infection <90% of ideal body weight, recent weight loss<90% of ideal body weight, recent weight loss Diabetes mellitus (poorly controlled)Diabetes mellitus (poorly controlled) Chronic renal failureChronic renal failure Solid organ transplant recipientsSolid organ transplant recipients Certain cancers and / or treatmentCertain cancers and / or treatment Higher-dose steroid treatment (15mg, >4 weeks)Higher-dose steroid treatment (15mg, >4 weeks) Tumor necrotizing factor antagonist therapy (TNF-α antagonists)Tumor necrotizing factor antagonist therapy (TNF-α antagonists) History of gastrectomy or jejunoileal bypass surgeryHistory of gastrectomy or jejunoileal bypass surgery

12. Dealing with the uncertain

13. The Online TST/IGRA Interpreter: https://www.tstin3d.com

14. Statistics and risks derived from website (1) A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital.A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital. What do you think? Should he be offered LTBI rx?What do you think? Should he be offered LTBI rx? Stats from history as given above:Stats from history as given above: –Likelihood of a true positive PPD: 100% –Annual risk of TB disease: 0.1% –Lifetime risk of TB disease: 4.5% –Risk of hepatotoxicity from treatment: 0.2%

15. Statistics and risks derived from website (2) A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital.A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital. New data: the patient had diabetes:New data: the patient had diabetes: What do you think? Should he be offered LTBI rx?What do you think? Should he be offered LTBI rx? Likelihood of a true positive PPD: 100%Likelihood of a true positive PPD: 100% –Annual risk of TB disease: 0.28% (originally 0.1%) –Lifetime risk of TB disease: 12.6% (originally 4.5%) –Risk of hepatotoxicity from treatment: 1.2%

16. Statistics and risks derived from website (3) A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital.A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital. New data: the patient had documented close contact:New data: the patient had documented close contact: What do you think? Should he be offered LTBI rx?What do you think? Should he be offered LTBI rx? –Likelihood of a true positive PPD: 100% –Annual risk of TB disease: 0.10% –Lifetime risk of TB disease: 9.3% (originally 4.5%) –Risk of hepatotoxicity from treatment: 1.2% –Risk of developing TB in next two years: 5% (originally 1.2%)

17. Statistics and risks derived from website (4) A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital.A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital. New data: patient had documented new infection (< 2 years):New data: patient had documented new infection (< 2 years): What do you think? Should he be offered LTBI rx?What do you think? Should he be offered LTBI rx? Likelihood of a true positive PPD: 100%Likelihood of a true positive PPD: 100% –Annual risk of TB disease: 0.10% –Lifetime risk of TB disease: 5.8% (originally 4.5%) –Risk of hepatotoxicity from treatment: 1.2% –Risk of developing TB in next two years: 1.5% (originally 1.2%)

18. Statistics and risks derived from website (5) A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital.A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital. New data: the patient had a granuloma on chest x-rayNew data: the patient had a granuloma on chest x-ray What do you think? Should he be offered LTBI rx?What do you think? Should he be offered LTBI rx? Likelihood of a true positive PPD: 100%Likelihood of a true positive PPD: 100% –Annual risk of TB disease: 0.2% (originally 0.10%) –Lifetime risk of TB disease: 9% (originally 4.5%) –Risk of hepatotoxicity from treatment: 1.2% –Risk of developing TB in next two years: 1.5% (originally 1.2%)

19. Statistics and risks derived from website (6) A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital.A 35 year old man from Hartford with a 16 mm positive PPD. He has no known exposure to MTB, no risk factors, normal exam, normal chest x-ray. He wants to work in your hospital. New data: Abnormality (more than a granuloma) on chest x-ray:New data: Abnormality (more than a granuloma) on chest x-ray: What do you think? Should he be offered LTBI rx?What do you think? Should he be offered LTBI rx? Likelihood of a true positive PPD: 100%Likelihood of a true positive PPD: 100% –Annual risk of TB disease: 1.25% (originally 0.10%) –Lifetime risk of TB disease: 56% (originally 4.5%) –Risk of hepatotoxicity from treatment: 1.2%

20. Statistics and risks derived from website (7) 1. A 64 year old woman from Jamaica with a 12 mm PPD who is referred for immigration purposes. She has no risk factors and her exam is negative. She came to USA 10 years ago. What do you think? Should she be offered LTBI rx?What do you think? Should she be offered LTBI rx? Stats: Stats: – Likelihood of a true positive PPD: 62% – Annual risk of TB disease: 0.06% – Lifetime risk of TB disease: 0.99% – Risk of hepatotoxicity from treatment: 2.3%

21. Statistics and risks derived from website (8) 1. A 64 year old woman from Jamaica with a 12 mm PPD who is referred for immigration purposes. She has no risk factors and her exam is negative. She came to USA 10 years ago. New data: she is taking a TNF alpha drug:New data: she is taking a TNF alpha drug: What do you think? Should she be offered LTBI rx?What do you think? Should she be offered LTBI rx? Likelihood of a true positive PPD: 62%Likelihood of a true positive PPD: 62% – Annual risk of TB disease: 0.33% (originally 0.06%) – Lifetime risk of TB disease: 5.3% (originally 0.99%) – Risk of hepatotoxicity from treatment: 2.3%

22. Statistics and risks derived from website (9) A 18 year old from Lima, Peru with a 14 mm PPD for immigration purposes. She has been in USA for 2 years. Her history and exam are negativeA 18 year old from Lima, Peru with a 14 mm PPD for immigration purposes. She has been in USA for 2 years. Her history and exam are negative What do you think? Should she be offered LTBI rx?What do you think? Should she be offered LTBI rx? Stats:Stats: – Likelihood of a true positive PPD: 91% – Annual risk of TB disease: 0.07% – Lifetime risk of TB disease: 5.6% – Risk of hepatotoxicity from treatment: 0%

23. Statistics and risks derived from website (10) A 54 year old man born and raised in Hartford, who has a 20 mm PPD. He cannot recall having had a previous TST. He used to be an IV drug abuser. He says his HIV was negative 3 months earlier. A 54 year old man born and raised in Hartford, who has a 20 mm PPD. He cannot recall having had a previous TST. He used to be an IV drug abuser. He says his HIV was negative 3 months earlier. What do you think? Should he be offered LTBI rx?What do you think? Should he be offered LTBI rx? Stats: Stats: – Likelihood of a true positive PPD: 100% – Annual risk of TB disease: 0.25% – Lifetime risk of TB disease: 6.5% – Risk of hepatotoxicity from treatment: 2.3%

24. Statistics and risks derived from website (11) A 54 year old man born and raised in Hartford, who has a 20 mm PPD. He cannot recall having had a previous TST. He used to be an IV drug abuser. He says his HIV was negative 3 months earlier.A 54 year old man born and raised in Hartford, who has a 20 mm PPD. He cannot recall having had a previous TST. He used to be an IV drug abuser. He says his HIV was negative 3 months earlier. New data: the patient is HIV positiveNew data: the patient is HIV positive What do you think? Should he be offered LTBI rx?What do you think? Should he be offered LTBI rx? – Likelihood of a true positive PPD: 100% – Annual risk of TB disease: 8% (originally 0.25%) – Lifetime risk of TB disease: 100% (originally 6.5%) – Risk of hepatotoxicity from treatment: 2.3%

25. Questions?