Juzar Ali M.D., FRCP(C), FCCP (Russell C. Klein M.D. LSU ALUMNI Professor of Medicine)

1. The Alphabet Soup in TB and MOTT Juzar Ali M.D., FRCP(C), FCCP (Russell C. Klein M.D.  LSU ALUMNI Professor of Medicine) Vice Chair (Clinical) Department of Medicine Director: LSU Chest & LSU-Wetmore TB Clinics Section of Pulmonary & Critical Care Medicine Louisiana State University Health Sciences Center NEW ORLEANS April 2008

2. Objectives At the end of this presentation, the participants will be able to: • (a) Review issues related to LTBI, BCG and INF-G • (b) Appreciate the importance of DOTS and DOSE • (c) Gain a better understanding of MDRTB and XDRTB • (d) Be informed about MOTT

3. Sm + C – Sm - C+ Sm – C-- MOTT DRTB MDRTB XDRTB DOT DOTS DOST? LTBI ; BCG ; INF-G

4. TUBERCULOSIS • ACTIVE DISEASE • LATENT INFECTION

5. PUBLIC HEALTHCLASSIFICATION • Class 0 No Exposure, No Infection • Class 1 Exposure , No Infection • Class II Infection , No Disease • Class III Current Disease • Class IV No Current Disease • Class V Suspect

6. Part A : LTBI

7. Latent TB InfectionDefinition? • A paucibacillary infection with no detectable bacilli present • Animal models: Bacilli “stunted” due to nutritional depletion, hypoxia or genetic factors Ref: Mol Micro 2002 ; 43: 717 Annu Rev Microbio 2001; 55: 133-163

8. The triple issues of LTBI BCG BCG LTBI *Poor Specificity in BCG vaccinated persons *Low sensitivity in Immune compromised hosts *Logistical drawbacks *Overall no show rate 40%* At Wetmore 21%** completion rate Based on Mycobacterial genomics and antigenic Specific T cell response Deleted segment ROD1 Early secretory antigenic target-6 ESAT-6 Culture filtrate Protein 10 CFP-10 Checking for the “TB footprint” Technical & Cost ? ELISPOT test ELISA Quantiferon Gold INFγ PPD/ TST

9. PPD & BCG • Except in children, the size of the PPD reaction bears no relationship to active TB • BCG induced reactions are smaller and tend to wane more quickly than reactions caused by naturally occurring infections • History of BCG is “generally” ignored

10. Contacts : variable data* Association of prevalence of TB Reactions with closeness of contact among household contacts of new smear positive PTB patients Close intimate close regular not close sporadic 42 % + 34 % + 13 % **+ ** 16 % healthy population sample all household contact 30 % Lutong & Bei Shandong MU China IUTLD 2000 4 ( 3 ) 275 *+ = > 5 mm, 10, 7.5 * CID 2007:44

11. Risk factors for TB infection among household contacts • Cross sectional study; 342 index cases and their 500 household contacts identified. Prevalence of TB infection among household contacts was 47.80 % • Multivariate analysis: close contact; exposure to a female index case; exposure to cavitary disease; a crowded household and those with 3 + smear grade South East Asian journal of Tropical Med 2004 June • addendum: HIV ? Younger patients, males ( Am J Epi 2001; 154: 934-43 )

12. Other recent data • Prevalence of TB Infection among household* contacts was 34 % if smear positive and 10.7 % if only culture positive • If culture negative: it was 7 % * close relatives or friends 4 % Comstock GW : Epidemiology of TB 2000

13. Nosocomial Transmission • Delays in diagnosis and treatment • Median duration between onset of symptoms and initiation of treatment was 44 days ( Australia , Turkey ) • USA: 6-14 days ( One study ) • Only 16 % of patients isolated • N95 vs surgical masks and leakage issues

14. “Ladies and gentlemen, thank you for flying with us……”

15. Air travel • Quality of air better than most similar enclosed places on ground • 20-30 air exchanges per hour ( 6-12 per hour in hospitals isolation room • 50% recycled cabin air through HEPA filters • 99% of particulate matter 0.1-0.3 μm • 2 rows/8 hours limit • Problem when waiting/parked on ground etc

16. Transmission factors • Infectiousness of the index case • Duration of exposure • Proximity and closeness of the contact Essentially the same

17. Quantiferon TB Gold -1 • Unaffected by BCG and NTM • TB-specific antigens are only present in M.TB • INF-Gamma in whole blood with an ELISA measurement • 90% SENSITIVITY IN Culture + TB • 98% SPECIFICITY IN Culture + TB www.cellestis.com Further references : lancet 2004 Dec Volume 4;

18. QUANTIFERON GOLD - 2INF-Gamma based assay • Advantages: More Specific ,( BCG/MOTT), One visit; good correlation with TST • Disadvantages: Technical, Analysis software, Blood, Cost,Usage, Refrigerated • Components: ESAT-6 antigen, CFP-antigens • Limitations: Not tested in IM states/children

19. ELISPOT & ELISA • Both tests have higher specificity than TST • Higher diagnostic sensitivity than TST 70-97% • Further increase in sensitivity with T cell INF γ release assay (TIGRA) • ?? Decreased levels as a marker for treatment response??? Ref: Lalvani Chest 2007;131:1898-1906

20. Relative Increased Risk for developing Active TB by selected conditions • Silicosis………………… 30% • DM……………………… 2-4 % • CRF…………………….. 10-25% • Gastrectomy…………… .2-5% • J-I Bypass………………. 27-63% • Solid Organ Transplant….37% / 70% • Carcinoma of head or neck 16%

21. A “positive” PPD: suggested plan JALI A : DATA B: EVALUATE C: SCAN D : RECAP E: TREAT steps

22. Part B: Active Disease Specific Diagnosis & “DOST” Treatment Issues & DOTS

23. Latest National Statistics* MMWR 2007 • 13767 TB cases in 2007 @ 4.6 per 100K • 3.2 % decline from 2005 • Less decline than previously ( 7.3 % ) • Highest rates in FB individuals • Blacks 8.4 times higher • Asians 2 times higher • Hispanics 7.6 times higher than whites

24. Contd… • Mainly from Mexico, Philippines, Vietnam , China and India • 124 MDRTB in 2005 • FB 81 % of MDRTB • XRDTB: 17 cases reported between 2000 -2006

25. “In the future it will not be difficult to decide what is tuberculosis and what is not. The demonstration of tubercle bacilli ….will settle the question” Robert Koch

26. Verily thou dost DOTS* But pray, dost thou DOST** and this is not Shakespeare DOTS*: Direct Observed Therapy Strategy DOST**: Direct Observed Induced Sputum Test J Validated by Swiss study See reference quoted. & CID 2007;44:1415-20

27. Sputum • Timing & Technique : “DOST” * • Character • Quantity • Labeling as Induced sputum looks like saliva and may be discarded by lab • To be AFB positive we need 10000 organisms /cc of sputum Yaeger et al Am Rev 1966;95 998-1004 * my term

28. Volume • Sputum > 5 cc • 1849 patients 39 month period sensitivity was 92 % when volume was > 5 cc • 3486 patients 24 month period when all sputum processed regardless of volume Sensitivity was 72 .5 % Warren et al Am J Respir CC 2000 May; 161(5): 1559-52

29. Direct vs. conc. smears • 2693 specimens evaluated; 353 were culture positive . • Of them : • Sensitivity of direct smear 34- 42 % • Sensitivity of conc. smear 58- 71 % Peterson et al J Clin Micro 1999 37 ( 11)

30. The issues • Little supervision; the “give the cup” approach • Bacterial contamination • Only 30 % positivity in the first sputum although incremental yield beyond 3 is doubtful • ( S:47%/C:74% to S:58%/ C: 90%) • Depends upon cavitary disease or non cavitary disease • Single vs.24-72 hour pooled specimen: No difference except increased bacterial contamination (2%) increased to 15 % Krasnow et al Appl Micro 1969;18:915-917 Kestle DG et al Am J Clin Path 1967;48:347-349

31. 2 vs. 3 • Screening TB suspects using 2 sputum smears • 2 smear :186 / 1152 16 % suspects were smear positive • 3 smear: 173/1106 ( 16 % ) were smear positive Harries et al NTB control Prog Liver pool In J Tb 2000 4 (1) 36-40

32. The second and the third smear • Incremental yield from a third serial smear ranged from 0.7 % to 7.2 5 Between 122- 796 smears are required to identify one additional case with a third serial sputum smear. • Incremental yield from second serial follow up smear ranged from 4.5 % to 26.9 % and 164-2133 slides were reqd. to identify one additional failure with a second serial smear. IUATLD 2005 Vol 9 # 4 Reider and Chang

33. Sputum Induction (SI ) • SI produced a positive smear in 29 % of patients with suspected TB who were previously been smear negative or unable to expectorate Harrtoung et al S AFR Med J 2002 Jun 92 (6)

34. Comparison of SI with FOB • 101 patients • High prevalence area ( Brazil ) • **In both HIV and non HIV patients; • Sen & NPV For FOB 73% & 91 % resp. • Sen. & NPV for SI 87 % and 91 % resp. • with kappa value 0.92 Anderson et al Am J Resp CC 1995 , Nov 152 Conde et al Am Rev 2000 Dec**

35. In Endobronchial Disease • 50 smear negative TB ( India ) • Br. Aspirate and Post bronch sputum positive in 12 and 14 cases respectively • Bronch was positive in 28, being the only positive sample • 45/ 50 were culture positive with brushings Chawla et al Eur Respi J 1988 Oct (9)

36. Bullets • 2 sputum smears as good as 3 even for infection control purposes but…. • Volume of sputum 5cc or more improves sensitivity • If ES negative; SI adds up to 19-30 % in sensitivity in suspected cases • FOB with Bronchial washing if less than 50 cc, there is no difference in sensitivity • FOB with BAL better if return more than 50 cc and sensitivity increased if PCR also done Ref: Thorax 2002 : 57 1010 Nelson et al J Clin Micro 1999 36 (2)

37. The success of DOTS

38. Completion range of Rx strategies JAMA 1998; 279: 943-948

39. The Real Life Algorithm* .. 2/4 or 2/7 or 3/3 Dx of TB (Class 3 or 5 Start RIPE DOT DAILY/Bi weekly* RIPE ******* Culture back ********** Pan sensitive ***RIP(drop E) 2 month Sputum culture negative ***Drop PZA *** RI ****** 0…… 2-4 weeks……..6 weeks 8-12 wks …….6mths ………….9mths * Check dosage

40. Smear negative………….Looks like……..

41. Looks like TB but is smear negative! Low Index of suspicion High Index of suspicion RIPE Rx No ATT; pursue other Dx If cultures +…..continue protocol Rx If cultures negative Culture Negative No CXR change If Improved, Complete Rx If no change Complete Rx? Reevaluate ? Rx for LTBI

42. Part C: DRUG RESISTANT TB

43. Primary drug-resistance is said to occur in a patient who has never received antituberculosis therapy. Secondary resistance refers to the development of resistance during or following chemotherapy, for what had previously been drug-susceptible tuberculosis

44. DRTB: The term "drug-resistant tuberculosis" refers to cases of tuberculosis caused by an isolate of Mycobacterium tuberculosis, which is resistant to one of the first-line antituberculosis drugs: isoniazid, rifampin, pyrazinamide, or ethambutol. • Multidrug-resistant tuberculosis (MDR-TB) is caused by an isolate of M. tuberculosis, which is resistant to at least isoniazid and rifampin, and possibly additional chemotherapeutic agents. • Extensively drug-resistant tuberculosis (XDR-TB) is caused by an isolate of M. tuberculosis, which is resistant to at least isoniazid, rifampin, fluoroquinolones, and either aminoglycosides (amikacin, kanamycin) or capreomycin, or both

45. The Story of MDRTB • Exists and ongoing throughout the world over the years.. Russia, Far East, South Asia; Globally 400K cases reported • 1990s Several outbreaks in hospitals and correctional facilities in NY and Florida; Mostly HIV, 80% mortality; Dx-Death time 4-16 weeks • Nosocomial transmission; not more contagious but more difficult to treat • Lower cure rate and Cost differential

46. XDRTB in the limelight Lancet 2006: Gandhi et al Dx-Death period: 16 days HIV population

47. This report summarizes the results of that survey, which determined that, during 2000--2004, of 17,690 TB isolates, 20% were MDR and 2% were XDR. Population-based data on drug susceptibility of TB isolates were obtained from the United States (for 1993--2004),Latvia (for 2000--2002),and South Korea (for 2004), where 4%,19%, and 15% of MDR TB cases, respectively, were XDR. MMWR 3/2006 55(11);301-305

49. Public Health & Research agenda for TB Control • Streamline rapid diagnostic methods: more studies on INF-γ tests • Shorten and simplify Rx for DS TB • Improve Rx for DR TB • Efficient and effective Dx & RX and registry for LTBI • Once a week regimens • Combination of Moxifloxacin and Rifapentine? • Improved drug delivery system • ?Nutritional supplements; • Identification of predictors of relapse • Identification of predictors of non- compliance!!!! • Cytokine inhibitors / Role of arginase / iNO • ?INF-γ /Interleukin 2 administration

50. At a Public Health level Societal / Public Health Patient care State/Public Health Experts Clinics Politics Lab Support Field Workers Community MDs Academia $$ Priorities Pivotal roles or the “Bermuda Triangle”