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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

slide2
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
slide3
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%

slide4

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)
  • 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(HK)
  • BCG vaccination
    • First introduced in April 1952
  • Neonatal vaccination
    • 99% coverage since 1970’s
  • Revaccination
    • Stopped only in 2000
sensitivity tst
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
interferon release test
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)
quantiferon tb gold
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
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
  • 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(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
  • 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
  • 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
  • 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
  • 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
  • Population Approach:
    • All infected individuals within the community
  • Targeted Approach:
    • High risk of Disease / Grave Consequence
factors for consideration
Factors for Consideration
  • Goal of intervention
    • Personal Protection / Public Health Control
  • Cost-effectiveness
    • Prevalence of infection / Risk of Disease
    • Limitations of Diagnostic / Treatment Tools
slide32

Reactivation vs Recent Transmission

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
  • 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
  • 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)

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

number to treat hk primary students
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

targetted approach hk
Targetted Approach (HK)
  • High-risk groups:
    • Recent Contacts
    • HIV
    • Silicosis
    • Immunosuppressive Treatment / Anti-TNF
recent vs remote infection
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
predictive value of positive test for recent infection reinfection
Predictive Value of Positive Testfor Recent Infection / Reinfection

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

targetted approach impact
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
looking into future
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
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