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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. 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%

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Latent tb infection

Latent TB infection

Dr CC Leung

TB & 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

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

基層

私家醫生

醫管局胸肺醫院

主要有5 間醫院

約800 病床

7,000 住院人次

私家醫院

醫管局

專科門診

醫管局

一般醫院

第二層


Ltbi screen and treat
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


Latent tb infection1
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


From infection to disease
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


Predisposing conditions
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


Active tb disease 2003
Active TB Disease - 2003

WHO Fact sheet N°104 (Revised April 2005)


Can we wait until disease
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


Diagnostic tools
Diagnostic tools

  • Traditional standard

    • Tuberculin test

  • Newer interferon-γrelease test

    • T Spot-TB®(Oxford Immunotec)

    • QuantiFERON®-TB Gold (Cellestis)


Tuberculin test
Tuberculin test

  • Intradermal injection preferred for better standardization

  • 2 units of PPD-RT23 (equivalent to 5 units of PPD-S)



Specificity tst
Specificity (TST) h

  • 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


Bcg vaccination hk
BCG Vaccination h(HK)

  • BCG vaccination

    • First introduced in April 1952

  • Neonatal vaccination

    • 99% coverage since 1970’s

  • Revaccination

    • Stopped only in 2000


Sensitivity tst
Sensitivity (TST) h

  • 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




Interferon release test
Interferon- hγRelease 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)


Quantiferon tb gold
QuantiFERON h® -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


T spot tb
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


Sensitivity and specificity
Sensitivity and Specificity h

  • 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


Elispot vs tst school outbreak uk
ELISPOT vs TST h(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


Potential advantages
Potential advantages h

  • 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


Limitations
Limitations h

  • 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
Treatment of LTBI h

  • 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
Hepatotoxicity h

  • 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
Possible Approaches h

  • Population Approach:

    • All infected individuals within the community

  • Targeted Approach:

    • High risk of Disease / Grave Consequence


Factors for consideration
Factors for Consideration h

  • Goal of intervention

    • Personal Protection / Public Health Control

  • Cost-effectiveness

    • Prevalence of infection / Risk of Disease

    • Limitations of Diagnostic / Treatment Tools



Reactivation vs Recent Transmission h

TB

cases

Progressive primary *

Exogenous reinfection *

Endogenous reactivation #

1950

2000

Year

Ageing of the TB epidemic


Aging of the tb epidemic
Aging of the TB Epidemic h

  • 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
Population Approach h

  • Treatment of latent TB reduces endogenous reactivation

  • Can we treat every infected one to eliminate TB from our population?


Estimated infection rate hk
Estimated Infection Rate (HK) h

*Estimation based on: Incidence (smear-positive cases) = ARI * Styblo ratio


Tst profile hk primary students 1999
TST Profile h (HK Primary Students 1999)


Number to treat hk primary students
Number to Treat h( HK Primary Students)

Leung CC et al. Risk of TB among school children in Hong Kong. Arch Ped Adol Med, in press


Targetted approach hk
Targetted Approach (HK) h

  • High-risk groups:

    • Recent Contacts

    • HIV

    • Silicosis

    • Immunosuppressive Treatment / Anti-TNF



Recent vs remote infection
Recent vs Remote Infection h

  • Remote infection

    • Much lower risk of disease

    • Increases with age

  • Interferon-γrelease test

    • More specific BUT

    • May not differentiate between recent and remote Infection


Predictive value of positive test for recent infection reinfection
Predictive Value of Positive Test hfor Recent Infection / Reinfection

Assume: 100% sensitivity & specificity; 20% recent transmission


Targetted approach impact
Targetted Approach: Impact h

  • 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


Looking into future
Looking into Future h

  • 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



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