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Latent Infection of Tuberculosis
in China
HUASHAN HOSPITAL,
FUDAN UNIVERSITY, Shanghai, China
Wenhong Zhang, M.D & PhD.
TB: A leading infectious killer
- top 3 infectious killer
• TB kills about 2 million people each year
• 8 million people become sick with TB each year
• TB is the leading killer of HIV/AIDS patients
• 50 million people infected with drug-resistant TB
The New Tuberculosis
HIV and Drug-resistant TB – A lethal
combination and a major threat to TB
control
WHO declared TB a global emergency
in 1993
TB Chemotherapy:
THE Effective TB Control
• Pre-antibiotic era: before 1940s (e.g., cod liver oils,
bed rest, fresh air)
• Drugs used to treat TB: Streptomycin first TB drug
(1944), followed by PAS (1946), isoniazid (1952),
pyrazinamide (1952), rifampin (1963)
•
(a) Front-line Drugs: isoniazid (INH) rifampicin
(RMP), pyrazinamide (PZA), streptomycin, ethambutol.
•
(b) Second-line Drugs: PAS, kanamycin,
cycloserine, ethionamide, thiacetazone,
ciprofloxacin/ofloxacin, rifapentine, amikacin, viomycin,
capreomycin.
DOTS-The Best TB Therapy
since 1991
• DOTS: 6 month therapy - The best
therapy against TB (78%-96% cure
rate).
• Initial phase (daily, 2 months) with 4
drugs: INH, RMP, PZA, Ethambutol.
• Continuation phase (3 times a week, 4
months) with 2 drugs: INH and RMP.
DOTS-Plus
• DOTS + second-line TB drugs (PAS, ethionamide,
cycloserine, kanamycin, amikacin etc.)
• Too expensive (TB case: $11 to $100, cost of treating
an MDR-TB case: $150,000)
• MDR-TB requires extensive chemotherapy (also
more toxic to patients- side effects) for up to two
years
• DOTS-Plus works as a supplement to the DOTS, to
address both drug-susceptible and MDR-TB in areas
with significant MDR-TB.
Disease Burden of Tuberculosis in China,
2000 data
• Prevalence of active pulmonary diseases is 367
／100,000
• Prevalence of Sear positive pulmonary diseases
is 122／100,000
• 130,000 patients die from tuberculosis every
year
• No data of latent tuberculosis in China up to
now
China CDC 2006
prevalence (1/100,000)
Prevalence of Smear Positive
Tuberculosis in China
200
180
160
140
120
100
80
60
40
20
0
1979
1990
2000
But incidence do not decrease!
Incidence of tuberculosis according to the report
from China CDC
1600000
1400000
1200000
1000000
800000
600000
400000
200000
0
2003
2004
2005
2006
China CDC 2006
Factors contribute to tuberculosis
reemerging in China
• MDR TB?
• HIV increasing?
• Latent infection?
• Diagnosis tools are more accurate to
find more new cases?
HIV infected Tuberculosis Cases < 1/100,000 population in China
Latency
• TB bacilli can persist for long periods of
time (decades) in the host before
reactivating and causing active disease
• Host factors: immunocompromised
conditions, viral infections (e.g. HIV and
measles), steroids, anti-TNF antibody
(REMICADE® infliximab) as part of the
treatment of rheumatoid arthritis
• Bacterial factors: e.g. isocitrate lyase, alphacrystallin, 48-gene dormancy regulon, etc.
Dormant or Persistent Bacilli
Cornell model: Mice infected with TB
bacilli are treated for 3 months with INH
and PZA --> No bacilli found in infected
organs (spleens/lungs) by plating --> stop
treatment --> 3 months later, 1/3 mice
relapse with TB (drug susceptible) and all
mice relapse with TB if treated with
immonosuppressing steroids --> suggest
existence of dormant bacilli or persisters
(phenotypic resistance).
Latent tuberculosis is the reservoir of active tuberculosis
•
•
•
•
•
New TB cases are driven by the
reservoir of latently infected people.
If we want to stop active TB cases,
we need to eliminate this reservoir of
infection.
This “hidden epidemic” of people
infected with latent TB is enormous.
The growth in latent TB is becoming
a clinical time bomb.
We need to defuse this bomb by
increasing our efforts to identify and
treat latently infected people.
Active TB
– 8 million new cases a year
- Unfortunately just the tip of the iceberg
Latent TB
- the “hidden epidemic”
-2 billion people infected
Epidemiology of latent infection
in the world
Frothingham R, et al.International Journal of Infectious
Diseases (2005) 9, 297—311
TST positive in China, 2000
Infected
No infection
45%
55%
Shortage of TST
• Poor specificity: antigenic
cross-reactivity of PPD with BCG
and environmental mycobacteria
• Poor sensitivity: 75-90% in
active disease (lower in disseminated
TB and HIV infection; unknown for
latent infection)
Factors leading to False-Positive
TST Reactions
• Nontuberculous mycobacteria
– Reactions caused by nontuberculous mycobacteria
are usually  10 mm of induration
• BCG vaccination
– Reactivity in BCG vaccine recipients generally
wanes over time; positive TST result is likely due to
TB infection if risk factors are present
TM
T SPOT detect INF-r released by specific T cells
Collect white cells using BD CPT tube or Ficoll extraction.
Add white cells and TB antigens to wells. T cells release
interferon gamma.
Interferon gamma captured by antibodies.
Incubate, wash and add conjugated second antibody to
interferon gamma.
Add substrate and count spots by eye or use reader.
Each spot is an individual T cell that has
released interferon gamma.
How does T-spot Technology Work
Patient Whole blood Sample
PBMC
ESAT-6 CFP10
T cell secreting INF
Ab capture INF
Blue spot
2 commercial Kit available for detecting
latent or active tuberculosis
• T cell-based assay for interferon gamma, the
enzyme-linked immunosorbent spot test (ELISPOT),
has promise in the diagnosis of Mycobacterium
tuberculosis infection after exposure to a
known tuberculosis (TB) patient.
• Commercialisation of two T cellbased tests for
the diagnosis of M. tuberculosis infection (T
Spot TB by Oxford Immunotec and Quantiferon-TB
Gold by Cellestis)
T-cell based assay is recommended for detecting
infection of M. Tb
• measures individual reacting T cells:
– Even individual cells can be detected in a sample.
– Therefore even those who are severely immunocompromised, if a
single cell reacts then it can be detected.
• measures all types of T cells:
– Both CD4 and CD8 type T cells are detected.
– Therefore if one type of T cells is depleted in a patient (e.g. CD4 T
cells in HIV infected patients) a response can still be detected from the
CD8 T cells.
This sensitivity is key to the test’s excellent
performance in immunosuppressed populations
The strategic for treating latent
infection of tuberculosis in China?
Lifetime Risk of Reactivation Tuberculosis
C. Robert Horsburgh. n engl j med 2004;350;20:2060-7
Latent infection of tuberculosis in
China: Treat or not Treat?
• BCG strategic or “find and treat” strategic?
• Conditionally treatment focusing high-risk
groups: close house contacts and
immunocompromised cases
• Chemotherapy or Immunotherapy?