1. بسم الله الرحمن الرحيم

2. A 25 year old Saudi male applied to work as paramedic. He has no symptoms or history of contact with sick patients. His physical examination is unremarkable. His CBC, U&E, LFTs, urinalysis and CXR were all normal. Tuberculin skin test led to an induration of 12 mm after 48 hours. What is your diagnosis? What is your plan of management?

3. Latent Tuberculosis Outline: During this talk the following will be discussed: Pathogenesis of latency in tuberculosis Diagnosis of latent TB infection (LTBI) Role of interferon gamma assays in the diagnosis

5. Latent Tuberculosis Very common (2 billion people) Asymptomatic ( dormant ) A major source of active TB In healthy; risk of reactivation is 0.1% /yr In recent converters; risk is 5 – 10% in 2-5 yrs Risk is increased by immunosuppression and chronic diseases Diagnosis is difficult to confirm

6. Latent Tuberculosis: Pathogenesis After infection: 10% develop active TB Primary infections leads to hematogenous dissemination and metastatic foci Is post primary TB always due to reactivation?

7. Evidence of latency Autopsy studies PPD and CXR surveys Lower rate of drug resistance in elderly Relapses after effective chemotherapy INH prohylaxis decreases reactivation

8. Evidence of latency MacCune et al experiment on Cornell model: - Infected mice treated for 12 weeks with INH & PZA - At end of therapy: no m. TB could be cultured - after 3 months: m. TB cultured from 65% of mice ( 100% if given cortisone for 3 wks )

9. Latent Tuberculosis: Pathogenesis But: most primary foci become sterile in few years Within granuloma: environment is microaerophilic, acidic & & & contain toxic oxygen and nitrogen radicals How does M. TB survive such stressful environment?

10. Latent Tuberculosis: Pathogenesis Studies showed that m. TB cannot survive anerobic conditions for prolonged periods Possibly: m. TB can go into a state of dormancy with low metabolic activity for a long time How to explain INH effect?

11. Latent TB : Diagnosis TST is the standard test for diagnosis PPD contains > 200 antigens BCG vaccinated: more likely to have +ve TST Low specificity in BCG vaccinated Low sensitivity with impaired immunity Interpret in view of pretest risk

12. Table 1. Interpretation of Tuberculin Testing Diameter of Induration Groups Considered Positive (CDC) 5 mm HIV positive Recent contact with infectious TB case Abnormal chest x-ray suggestive of TB Immunosuppressed receiving the equivalent of 15 mg/day of prednisone for 1 month* 10mm Recent immigrant (within last 5 years) from high-prevalence country Injection drug users Residents and employees† in high-risk settings (nursing homes and other long-term facilities for the elderly, prisons etc) Medical risk factors (silicosis, diabetes mellitus, chronic renal failure, leukemias and lymphomas, carcinoma ….. Mycobacteriology laboratory personnel Children younger than 4 years old, or infants,children, and adolescents exposed to adult at high risk 15 mm All persons with no known risk factors

13. Alternative tests No gold standard to diagnose LTBI Test performance in high risk individuals IGRA tests: - T-spot TB assay - Quantiferon TB test Specific IGRA tests: - Quantiferon TB Gold

15. IGRA Tests Quantiferon TB evaluated in 216 healthy Japanese nursing students, no TB exposure. All had BCG. - TST +ve (>10 mm) in 64.6% - Quantiferon TB +ve in 1.9% Quantiferon TB Gold studied in 99 healthy Korean adults, no TB exposure. BCG in 90%. - TST +ve in 51% - Quantiferon TB +ve in 4%

16. IGRA tests in contact tracing T-spot TB test evaluated in 535 secondary school students exposed to infectious TB case. Most had BCG. - T-spot TB test was as sensitive as TST. - It correlated better with degree of exposure.

17. Can IGRA tests predict development of TB Diel et al evaluated 601 contacts of TB patient: 278(46%) had BCG. TST +ve in 243(40%). Quantiferon +ve in 66(11%). INH offered to contacts with +ve Quantiferon. 41 contacts declined to take INH. FU for 2 years : 6 contacts developed TB, all were Quantiferon +ve

18. Can IGRA tests predict development of TB Higushi et al: 88 TST +ve contacts were followed up for 3.5 years. Only 4 were quantiferon +ve. None of 84 Quantiferon -ve contacts developed TB.

19. Role of IGRA tests in diagnosis of LTBI Do IGRA test replace or complement TST? IGRA tests are more expensive ($40/test) More specific CDC suggested replacing TST by Quantiferon In UK (and Europe) IGRA tests are used as confirmatory in TST +ve s. Most cost effective approach in contact evaluation. Other areas remain controversial.

20. Thank you

22. Latent Tuberculosis: Pathogenesis

23. Latent Tuberculosis