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Contribution of Latent TB Diagnosis and Treatment to TB Control with Supporting Evidence

Contribution of Latent TB Diagnosis and Treatment to TB Control with Supporting Evidence Multiple facets and perspectives. TWO DISCLOSURES. PERSONAL INSTITUTIONA L. Juzar Ali  MB.,BS (MD);  FRCP(C); FCCP   

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Contribution of Latent TB Diagnosis and Treatment to TB Control with Supporting Evidence

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  1. Contribution of Latent TB Diagnosis and Treatment to TB Control with Supporting Evidence Multiple facets and perspectives

  2. TWO DISCLOSURES PERSONAL INSTITUTIONAL Juzar Ali  MB.,BS (MD);  FRCP(C); FCCP     Interim LSU Public Hospital  (ILH) & CLINICS System Interim CEO / Medical Director ; UMOB, 2025 Gravier St., 7th Floor NEW ORLEANS , LA 70112                             Off: (504) 903 4900, 4907, 4917,; Fax : 504 903 4952                                          Email: JALI@lsuhsc.eduCell : 504 444 3975 **Russell C. Klein,LSU-Alumni Professor of Clinical Medicine) ; **Faculty: Section of Pulmonary & Critical Care Medicine, LSUHSC      1901 Perdido , Suite 3205, MEB, New Orleans, LA 70112    LSUHSC Academic Office:  504 568 4634   Fax  504 568 4295  ** Adjunct Professor, School of Nursing , LSUHSC **  Medical Director : Region 1 OPH ; Metro- Wetmore TB Clinics **  Adjunct Professor , Dept of Tropical Medicine, Tulane University School of Public Health and TM & Faculty: Tulane University Dept of Preventive Medicine & Community Medicine ** Guest Faculty: Ege University & Hospital , Chest Unit , IZMIR Turkey websites     www.tbeducation.orgwww.tbinfo.lsuhsc.edu ACKNOWLEDGEMENTS WETMORE TB CLINIC TEAM ; TB CONTROL OFFICE LEADERSHIP Ms Maureen Vincent , LSU TB Clinic Coordinator; Drs. Dean Ellithorpe & Louis Trachtman Mr Charles DeGraw et team

  3. TB Elimination or Control ? • Early rapid Dx, Rx …but this is only 50% ( WHO data) ; Implement standard transmission prevention guidelines • Only severe cases under radar • Those untreated infect 20 persons /per year • Transmission before Dx: a huge issue • Transmission by Smear negative cases

  4. CONTROL OF TB INDEX CASE Regular Transmission Factors Infectivity of Index case Primary Prevention Secondary prevention Engineering and administrative Controls Identify TB case ( awareness/sputum ? E NO ??) Rx asap ** Avoid quinolones , non expert consultations/other specialties Rx right and early Target High Risk Contacts Avoid Wasting Resources HCW Immune comp hosts High risk groups Close contacts Identify LTBI and access need for “chemoprophylaxis”

  5. Another approach • Detect LTBI patients • Rx LTBI patients ( reduce subsequent disease by 25-92% ( 6months Rx at least : 69% ) • Reduce reservoir • ………………….But…..

  6. Problems with this approach • Length of Rx • ADRs specially in medically vulnerable pops • Compliance even in non INH , Rif alone Rx, although better with the once weekly 12 weeks DOPT regimen of RP & INH? • Completion of Rx appx 50 % • …..and that leads us to think …….

  7. Thought process • “Philosophy” • Approach • Logistics • Cost of testing • Goals • Priority

  8. LTBI incidence 4.2 % of the civilian , non instutionalized US population aged more than 1 year had LTBI , representing a 60 % decline from 1972 MMWR June 2010

  9. Tests for LTBI Background data of TST and IGRA pros and cons known • Sensitivity of IGRA not compromised in immunocomp hosts , diabetics etc • TST and then IGRA ( proposed by Mahan et al Int J Tuberc Lung dis 20011 ; 15: 628-634 • Newer proteins ( interferon inducible protein IP-10 superior biomarker IN Rh art patients receiving Anti TNF alpha Rx? Chen et al IJTub LD 2011 ;15: 192-199

  10. Curiosity Questions I ask ? • TST and IGRAs : predictors of disease : General • Does quantifying help in either case ? • Specific Quantification in TB spot test : Culture filtrate protein 10 spot count, but not early secretary antigenic target 6 spot count, was significantly associated with subsequent TB development. ( Hongkong study in silicotic pts ) • Issue of discordance & Borderline data • Effect of Smoking Negative effect of smoking on the performance of the QuantiFERON TB gold in • tube test BMC Infectious Diseases 2012, 12:379 doi:10.1186/1471-2334-12-379 • IMPORTANCE OF DEFINITION OF CONVERTORS SPECIALLY IN HCWs Challenges of IGRAs conversion in serial testing of HCW Fong et al Chest 2012 ;142 (1): 55-62

  11. Active Vs latent • IGRA responses are higher in active disease than in LTBI • However, there is a very large overlap in the results so it will not be possible to use IGRAs to differentiate between active disease and latent infection Chee et al Eur J Clin Microbiol Infect Dis (2008) Janssens et al ERJ (2007) T-SPOT.TB spot numbers in subjects with active disease compared to LTBI (TST+ve and TST-ve) T-SPOT.TB spot numbers in subjects with active disease compared to LTBI

  12. No cross-reactivity to BCG and most NTMs

  13. Issue of Borderline results • Both IGRAs are biological assay so results will have some variation around the cut-off • Using a cut-off reduces fluctuations in results that are near the cut-off • Benefit of cut-off is highlighted by CDC in 2010 guidelines: • “Use of a borderline category might address test variation and uncertainty for results near a dichotomous cut point.” • Re-testing borderline results 2 weeks later should give definitive result • Bordeline zones used by IGRAs: • T-SPOT.TB has a borderline of 5, 6 and 6 spots throughout the world • QFT only has borderline zone in Japan (0.1 - 0.35 IU/IFN gamma)

  14. Explaining discordant results; Contact tracing Zellweger et al., Int J Tuberc Lung Dis (2005) “These findings support the extensive literature showing that measurement of TB-specific T-cells using the ex vivo ELISPOT technique (upon which the T-SPOT.TB test is based) is more accurate than the TST, as it has closer correlation to exposure history and is unaffected by prior BCG vaccination.” p. 1246

  15. Explaining discordant results; Contact tracing Zellweger et al., Int J Tuberc Lung Dis (2005) • Setting: contact tracing in an institution for alcoholics in Lausanne, Switzerland • Index case: • 47-year old female, born in Brazil • Smear-positive pulmonary TB, infectious for 1 month • She had stopped TB treatment 3 years before so possibility of MDR-TB • Background • Preventive treatment associated with liver toxicity (most contacts >35 years old, residents all had history of alcoholic liver disease) • Ideally preventive treatment limited to contacts with a proven tuberculosis infection • Study: Duration & intensity of contact with the index case was assessed and subjects divided into high and low exposure groups

  16. Explaining discordant results; Contact tracing Zellweger et al., Int J Tuberc Lung Dis (2005) All BCG vaccinated All close contacts

  17. Explaining discordant results; TNF screening Vassilopoulus et al., J Rheumatology (2008) • 70 subjects attending a rheumatology clinic in Athens • All candidates for anti-TNF therapy • 43/70 on immunosuppressive drugs • 15/70 had co-morbid conditions (e.g. chronic liver disease, diabetes, COPD) • Results of TST and the T-SPOT.TB test compared, multivariate analysis used to analyse discordant results “(BCG) vaccination was associated with TST+/Elispot– discordant results (p = 0.01), whereas steroid use was linked to TST–/Elispot+ discordant results (p = 0.04).” p 1

  18. Indeterminate results • Indeterminate results occur when nil or positive controls fail. • Caused by: • Errors during processing (usually resolved when re-tested) • Maybe patient specific (not usually possible to resolve) • Indeterminate results should be repeated 2 weeks later • ~ two thirds will then give a reportable result

  19. Children and TB • The performance of IGRAs in children is still being studied; little data are available, particularly for preschool-aged children or children with suspected TB • A test with greater specificity for children at intermediate risk (ie, risk factors exist but no identifiable source case) for LTBI would decrease the need for unnecessary intervention1 • Whereas an immunocompetent older child or adult with untreated LTBI has about a 5% to 10% lifetime risk of developing TB, an infant’s risk is as high as 40% to 50%; most disease cases occur within 12 months of infection1 • In general, children < 4 years old are unable to contain the spread of TB from LTBI to active TB2 • In young children, a major limitation of the TST is that false-negative results cannot be detected; while IGRAs show promise of greater accuracy, they may also be impaired by cellular immunity, resulting in indeterminate results2 • Cruz AT, Geltenmeyer AM, Starke JR et al. Pediatrics. 2011;127(1):e31-e38. • Bergamini BM, Losi M, Vaienti F, et al. Pediatrics. 2009;123(3):e419-e424.

  20. Testing High-Risk Populations for TB High Risk for Progression or Reactivation

  21. TB Screening for HIV Patients1Using QFT and T-SPOT.TB • 275 patients had results for all 3 tests • Patients with QFT-Gold positive results had higher CD4 cell counts • T-SPOT.TB results were independent of CD4 cell counts 1. Stephan C, Wolf T, Goetsch U, et al. AIDS. 2008;22:2471-2479.

  22. If TST had its problems with administration variability , inter- observer variation etc IGRAs are problematic too in some ways as they are dynamic assays with we see frequent conversions and reversions

  23. So ? Do we need to do TST or IGRA testing at all prior to therapy ? • HIV population data mainly • Definite benefit if given to TST positive cases even in high incidence and other countries Multiple references available

  24. TRUE IMPACT OF LARGE SCALE SCREENING PROGRAMS Multiple references : Base reference IJMR 2011 ; 133(3) 257-266 Table III True impact of large scale screening programmes

  25. 1. TST vs T-SPOT ? What we did ? Beginning in April 2010, the Wetmore TB Clinic IN NEW ORLEANS began using the T-SPOT blood assay in place of the Tuberculin Skin Test. All patients referred to Wetmore with a positive TST/hx.of positive TST are now administered the T-SPOT in order to “confirm” TB Infection. If the results of the test are positive, the patient is SCREENED FOR ACTIVE TB AND AFTER THAT EXCLUSION , diagnosed as infected and Latent TB treatment is offered. DISCORDANT AND BORDERLINE RESULTS ARE REVIEWED ON A CASE BY CASE BASIS In patient we created a protocol of use for selected group of patients

  26. 2, Assessing Risk Risk factors algorithm • www.tstin3d.com IJMR 2011 March ;133(3)257-266 Menzies et al The Online TST/IGRA InterpreterVersion 3.0

  27. TST /QST Interpreterwww.TSTin3d.com TST/IGRA status, Country of birth, Ethnicity CXR , BCG history, contact history 30 yr old , Turkish man , smoker BCG vaccinated, granulomas on CXR Close contact ; casual contact ; no contact PPV 94.43% Risk of developing active TB disease in 2 years 21.35% Annual Risk after 2 years 0.42% Cumulative risk up to age 80 is 41.64% Probability of DILI 0.3% PPV 98 Annual Risk after 2 years 0.69% Cumulative risk up to age 80 is 34 % Probability of DILI 0.3% PPV 94% Annual risk 0.42% Cumulative risk 21.15 % DILI 0.3 %

  28. Risk factors for MTB infection • Close contacts • Foreign born in USA • Frequent visitors to high prevalence areas • Residents and employees of congregate settings such as nursing homes and shelters • HCWs • In areas which are medically underserved ; low income populations, substance abuse • Infants and children

  29. Risk of infection to disease progression • HIV • Infants • On immunosuppressive therapy • Recent infection • Old fibrotic lesions on CXR with undocumented or incomplete Rx hx • Specific medical conditions : DM /malignancy etc Hazard ratios increase 3 to 17 ( refs available ) • Low weight, low income population, Vit D def. ( increased risk and higher level of resistance

  30. Population attributable factor 7.5% to 26% in all groups J Infec Dis 2011 May 203: 1240 Study in mice Smoking suppresses TNF alpha and I-12 WHO REVIEW LANCET 2010 ; 375:1814-29

  31. High Risk for Progression/Reactivation: HIV • 19 newly diagnosed HIV patients with active TB • T-SPOT.TB test positive results were independent of CD4 T-cell counts “In conclusion, in HIV-infection, immune responses in the TST and QFT-G-IT are both strongly related to the degree of immunodeficiency, while the T-SPOT.TB seems to function independently of the level of CD4+ T-cell depletion.”1 1. Leidl L, Mayanja-Kizza H, Sotgiu G, et al. ERJ Express. 2009;.

  32. High Risk for Progression/Reactivation: HIV • Performance of T-SPOT.TB test for diagnosis of active/probable TB in HIV-1 patients1 1. Clark SA, Martin SL, Pozniak A, et al. Clin Exp Immunol. 2007;150:238-244.

  33. A “positive” TST / IGRA : suggested plan JALI A : DATA B: EVALUATE C: SCAN D : RECAP E: TREAT steps *ATS 2006 DILI consensus statement

  34. Individuals with LTBI had a 79% lower risk of progressive TB after re infection than uninfected individuals • Andrews et al CID Jan 19th 2012 So then : Why Rx LTBI?

  35. Issues with Low to Middle Income Resource Challenged Countries and communities • Who to give • Quality of data and evaluation • How : logistics • Cost • Total program buy- in WHO Policy statement 2011

  36. Perspectives on Rx for LTBI • Different priorities • General Reluctance; What is the goal? • Imprudent applications of Rx • Up and down enthusiasm of regimens • ADRs and press thereof • Poor performance of programs • Contradictory risk benefit studies • If we should treat Asymptomatic Hypertension why should we not treat asymptomatic LTBI ?

  37. Why should we treat LTBI? 1 Table I Summary of LTBI regimens in common use

  38. Why should we treat LTBI ? 2 Table II Risk benefit studies of INH for tuberculin reactors

  39. Factors related to public health impact by LTBI Screening & Rx • Non participation in initial screening • Failure of follow up at various levels • Non compliance of Rx doctors • Pt refusal and non completion • Bottom line ; it is not the test , treatment but the program that needs to be evaluated and reviewed

  40. How to achieve control vis a vis LTBI ? Targeted testing and prioritization Almost Universally accepted approach ( National programs/ Societies Guidelines*) *Multiple references

  41. The “ Onion whorl” approach ; better to have The “Mango core” approach

  42. We all have got to do what we got to do and get it done Further • Use of TST / IGRAs as applicable • Augment Measures to stress completion of Rx a. Shorter course b. DOPT ? Resources c. Registry and tracking d. Public/ Private/ Community liaison e. Academic and “non academic” par f. Communication and HIEs g. Incentives and User friendly approach

  43. Some issues are sometimes as “simple” or “complex” as these….

  44. J Thank you

  45. TEŞEKKÜRLER teşekkür ederim/ sağ olun for your kind attention JA Honored to be a “self declared” honorary citizen of Turke and Ege University

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