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Latent TB infection Dr CC Leung TB & Chest Service Public Health Services Branch Centre for Health Protection Department of Health 香港特別行政區衞生署 衞生防護中心胸肺科.

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Presentation on theme: "Latent TB infection Dr CC Leung TB & Chest Service Public Health Services Branch Centre for Health Protection Department of Health 香港特別行政區衞生署 衞生防護中心胸肺科."— Presentation transcript:

1 Latent TB infection Dr CC Leung TB & Chest Service Public Health Services Branch Centre for Health Protection Department of Health 香港特別行政區衞生署 衞生防護中心胸肺科

2 香港地理及人口 中國大陸之南部 人口數目 = ~6,800,000 土地面積 = 1098 平方公里 人口密度 = 每平方公里 ~6500 人

3 香港的醫療系統 公營私營 基層醫療服務 30%70% 醫院服務 90%10%

4 香港診治結核病之服務 結核病患者 私家醫生 衞生署 胸肺診所 19 間診所 每年約 6,000 症 衞生署 胸肺診所 19 間診所 每年約 6,000 症 衞生署 普通科 門診部 衞生署 普通科 門診部 醫管局 急症部 醫管局 急症部 私家醫院 醫管局胸肺醫院 主要有 5 間醫院 約 800 病床 7,000 住院人次 醫管局胸肺醫院 主要有 5 間醫院 約 800 病床 7,000 住院人次 醫管局 一般醫院 醫管局 一般醫院 醫管局 專科門診 醫管局 專科門診 基層 第二層


6 LTBI: Screen and Treat ? Disease Natural History / Impact Diagnostic / Treatment Tools Effectiveness / Limitations Goal of Intervention Personal protection / Public health control Cost-effectiveness Individual level / Community perspective

7 Latent TB Infection Infection by the tubercle bacillus is pre- requisite for development of disease Latent Period Long and Variable Asymptomatic and Non-infectious Provide an opportunity for intervention

8 From Infection to Disease Risk of developing disease Multiple factors related to interaction between pathogen and human host Lifetime Risk: About one in ten (average) The risk is greater initially 5% within initial 2-5 years 5% during the rest of lifetime

9 Predisposing Conditions HIV infection Steriod / Immunosuppresant / anti-TNF Silicosis Chronic Renal Failure / hemodialysis Diabetes Mellitus Underweight Gastrectomy / Jejunoileal Bypass Malignancy / Debilitated State Alcoholism / Smoking / Injection Drug Use

10 Active TB Disease - 2003 WHO Fact sheet N°104 (Revised April 2005) West Pacific Global Morbidity Cases 1,933,000 8,810,000 Rate per100,000 112 140 Mortality Cases 327,000 1,747,000 Rate per100,000 19 28

11 Can we wait until disease ? Airborne spread major challenge in control Nonspecific symptoms delay in diagnosis Serious forms grave consequences High bacilli load mutation and resistance

12 Diagnostic tools Traditional standard Tuberculin test Newer interferon-γrelease test T Spot-TB ® (Oxford Immunotec) QuantiFERON ® -TB Gold (Cellestis)

13 Tuberculin test Intradermal injection preferred for better standardization 2 units of PPD-RT23 (equivalent to 5 units of PPD-S)


15 Largest transverse diameter of induration read between 48-72 h

16 Specificity (TST) PPD contains a mixture of proteins not entirely specific to the tubercle bacillus potential cross-reactivity with other mycobacterial species Positive reaction can occur with: Active disease / Latent Infection BCG vaccination / Booster Other mycobacterial species

17 BCG Vaccination (HK) BCG vaccination First introduced in April 1952 Neonatal vaccination 99% coverage since 1970 ’ s Revaccination Stopped only in 2000

18 Sensitivity (TST) Exact sensitivity for latent TB infection uncertain in absence of gold standard Around 80%-90% sensitivity in active TB cases, Varies with strength of tuberculin / cut-off point Trade-off between sensitivity and specificity False negative can also occur with a number of other conditions

19 False-negative (TST)

20 Predictive values (TST)

21 Interferon-γRelease Test Earlier version: Measures the production of interferon-  (IFN-  ) in T-lymphocytes upon stimulation with PPD. Newer assays: PPD is replaced by ESAT-6 and CFP10 (specific for MTB and not present in BCG and most MOTT)

22 QuantiFERON ® -TB Gold Whole blood assay Stimulate lymphocytes in fresh whole blood with ESAT-6 and CFP10 Measure IFN-  level by Enzyme-linked immunosorbent assay Cell isolation not required Variable background response: Cut-off value may not be too sharp Approved by FDA, USA in May 2005

23 T Spot-TB ® ELISPOT test Isolation of lymphocytes from fresh blood Incubation with ESAT-6 and CFP10 Enzyme-Linked ImmunoSPOT assay For INF-  -producing T-lymphocytes More tedious, but may be more sensitive Approved for use in Europe

24 Sensitivity and Specificity Estimation is difficult No gold standard for latent TB infection Estimate of Sensitivity positive rate in bacteriologically confirmed TB 45/47 (Elispot, Lavani 2001) Estimate of specificity negative rate in BCG vaccinated subjects without risk factor for exposure 26/26 (Elispot, Lavani 2001) Lavani et al, Lancet 2001;23:2017-21

25 ELISPOT vs TST (School Outbreak, UK) Good Agreement 89% concordance, kappa=0 · 72, p<0 · 0001 ELISPOT correlated better with proximity (p=0 · 03) duration of exposure (p=0 · 007) TST more likely to be positive in BCG-vaccinated vs unvaccinated (p=0 · 002) ELISPOT results Not associated with BCG vaccination (p=0 · 44). Ewer K, et al. Lancet 2003; 361: 1168–73

26 Potential advantages Higher sensitivity ?Help rule out infection / disease More specific (specific antigens) ?Help to rule in infection / disease No booster effect on repeated testing Good for serial surveillance One clinic visit instead of two: May facilitate uptake

27 Limitations Require prompt delivery of fresh blood Technically much more demanding Currently much more expensive Test for infection rather than disease Clinical experience is limited at this stage Changes with time after exposure and treatment Not fully evaluated in terms of the risk of disease development

28 Treatment of LTBI Single drugs or simple combinations of two drugs Isoniazid for 6 to 12 months 5mg/kg daily (maximum 300mg) 15mg twice weekly (maximum 900mg) (US) Alternative regimens Rifampicin for 4 months (US) Isonoazid and Rifampicin for 3 months (Europe)

29 Hepatotoxicity Notwithstanding the use of only one or two drugs, hepatotoxicity remains an important side effect While untreated active TB often kills, only one out of ten latently infected subjects will actually develop disease. Caution is therefore required in subjecting these asymptomatic individuals to treatment.

30 Possible Approaches Population Approach: All infected individuals within the community Targeted Approach: High risk of Disease / Grave Consequence

31 Factors for Consideration Goal of intervention Personal Protection / Public Health Control Cost-effectiveness Prevalence of infection / Risk of Disease Limitations of Diagnostic / Treatment Tools

32 TB Notification Rate (Hong Kong)

33 Progressive primary * Exogenous reinfection * Endogenous reactivation # Year1950 TB cases 2000 Ageing of the TB epidemic Reactivation vs Recent Transmission

34 Aging of the TB Epidemic Population-based IS6110-based RFLP study 24.5% (of 691 isolates) belonged to clusters Recent transmission: 15 to 20% Endogenous reactivation Treat active disease by DOTS Control recent transmission But Little impact on endogenous reactivation Chan-Yeung M, et al. J Clin Microb 2003;41:2706-8

35 Population Approach Treatment of latent TB reduces endogenous reactivation Can we treat every infected one to eliminate TB from our population?

36 Estimated Infection Rate (HK) *Estimation based on: Incidence (smear-positive cases) = ARI * Styblo ratio

37 TST Profile (HK Primary Students 1999)

38 Number to Treat ( HK Primary Students) Leung CC et al. Risk of TB among school children in Hong Kong. Arch Ped Adol Med, in press

39 Targetted Approach (HK) High-risk groups: Recent Contacts HIV Silicosis Immunosuppressive Treatment / Anti-TNF

40 Household Contacts ( HK 2002-2003)

41 Recent vs Remote Infection Remote infection Much lower risk of disease Increases with age Interferon-γrelease test More specific BUT May not differentiate between recent and remote Infection

42 Predictive Value of Positive Test for Recent Infection / Reinfection Assume: 100% sensitivity & specificity; 20% recent transmission

43 Targetted Approach: Impact Personal protection More cost-effective than population approach Limited Impact on TB control Prevent few cases, e.g. Close contacts Initial screening: Only 2% of all notifications locally Not directly preventable as already disease Later 5 years: only another 4% at best

44 Looking into Future Researches and Development: Better characterization of disease risk Newer diagnostic tools Simpler, and more affordable Better ability to predict actual disease risk Better treatment regimen Shorter, safer and more effective Affordable and Acceptable for wide application

45 Thank You

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