Latent TB infection
Dr CC LeungTB & Chest ServicePublic Health Services BranchCentre for Health ProtectionDepartment of Health香港特別行政區衞生署衞生防護中心胸肺科香港地理及人口
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%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 衞生署普通科門診部 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 醫管局一般醫院 醫管局專科門診 基層 第二層
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 perspectiveLatent 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 interventionFrom 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 lifetimePredisposing 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
28
19Rate per100,000
1,747,000
327,000
Cases
Mortality
140
112
Rate per100,000
8,810,000
1,933,000
Cases
Morbidity
Global
West Pacific
Active TB Disease - 2003
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 resistanceDiagnostic tools
Traditional standardTuberculin test Newer interferon-γrelease test T Spot-TB® (Oxford Immunotec)QuantiFERON®-TB Gold (Cellestis)Tuberculin test
Intradermal injection preferred for better standardization 2 units of PPD-RT23 (equivalent to 5 units of PPD-S)Largest transverse diameter of induration read between 48-72 h
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 speciesBCG Vaccination (HK)
BCG vaccinationFirst introduced in April 1952Neonatal vaccination99% coverage since 1970’sRevaccinationStopped only in 2000Sensitivity (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 conditionsFalse-negative (TST)
Predictive values (TST)
Interferon-γRelease TestEarlier 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)
Whole blood assayStimulate lymphocytes in fresh whole bloodwith ESAT-6 and CFP10 Measure IFN- level byEnzyme-linked immunosorbent assayCell isolation not requiredVariable background response:Cut-off value may not be too sharpApproved by FDA, USA in May 2005
ELISPOT test Isolation of lymphocytes from fresh bloodIncubation with ESAT-6 and CFP10 Enzyme-Linked ImmunoSPOT assay For INF--producing T-lymphocytesMore tedious, but may be more sensitiveApproved for use in Europe
Lavani et al, Lancet 2001;23:2017-21
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)
Ewer K, et al. Lancet 2003; 361: 1168–73
ELISPOT vs TST (School Outbreak, UK)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 uptakeLimitations
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
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)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.Possible Approaches
Population Approach: All infected individuals within the community Targeted Approach: High risk of Disease / Grave ConsequenceFactors for Consideration
Goal of intervention Personal Protection / Public Health Control Cost-effectiveness Prevalence of infection / Risk of Disease Limitations of Diagnostic / Treatment Tools
TB Notification Rate (Hong Kong)
Progressive primary *Exogenous reinfection *
Endogenous reactivation #
Year
1950
TB cases
2000
Ageing of the TB epidemic
Reactivation vs Recent Transmission
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
Population Approach
Treatment of latent TB reduces endogenous reactivation Can we treat every infected one to eliminate TB from our population?*Estimation based on: Incidence (smear-positive cases) = ARI * Styblo ratio
Estimated Infection Rate (HK)TST Profile (HK Primary Students 1999)
Leung CC et al. Risk of TB among school children in Hong Kong. Arch Ped Adol Med, in pressNumber to Treat ( HK Primary Students)
Targetted Approach (HK)
High-risk groups: Recent Contacts HIV Silicosis Immunosuppressive Treatment / Anti-TNFHousehold Contacts ( HK 2002-2003)
Recent vs Remote InfectionRemote infectionMuch lower risk of diseaseIncreases with ageInterferon-γrelease testMore specific BUTMay not differentiate between recent and remote Infection
Assume: 100% sensitivity & specificity; 20% recent transmission
Predictive Value of Positive Test for Recent Infection / ReinfectionTargetted 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