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Latent Tuberculosis and Tuberculosis
Postgraduate course: Diagnosis and treatment of tuberculosis, April 23, 2008
Hans L Rieder
Department of Tuberculosis Control and Prevention
International Union Against Tuberculosis and Lung Disease
Very rough estimates indeed…
AnnualPrevalence (%)
incidence (%)
low high low High
Infection with M tuberculosis 0.001 - 3.0 20.0 - 30.0
Tuberculosis 0.0001 - 1.5 0.0005 - 2.0
All too cherished working hypotheses
Once infected with Mycobacterium tuberculosis, infection persists for the remaining life time and may reactivate at any time.
The antigens we have inform us about persisters
Andvord K F. Norsk Magasin for Lægevidenskapen 1930;91:642-60
Kristian Andvord’s break-through observation
Tuberculosis Notification Rates Among Males,Cross-Sectional Observations, Finland 1954 -1994
Age (years)
0 20 40 60 80
Not
ifica
tions
per
100
,000
(log
scal
e)
0.5
1
5
10
50
100
500
Härö AS. Tuberc Respir Dis Yearbook 1998;24:1-151
1954
1964
1974
1984
1994
Tuberculosis Notification Rates Among Males,by Birth Cohort, Finland 1954 -1994
Age (years)
0 20 40 60 80
Not
ifica
tion
s p
er
10
0,0
00
(lo
g s
cale
)
0.5
1
5
10
50
100
500
Härö AS. Tuberc Respir Dis Yearbook 1998;24:1-151
1954
1994
1972
1962
1952
1942
1932 1922 1912
18921902
Andvord’s conclusion
Childhood experience with Mycobacterium tuberculosis predicts adult experience
Fate of M tuberculosis in calcified lesions
Pulmonary Lymphatic
Author Lesions Sterile Lesions Sterile
Schmitz 10 9 16 10
Rabinowitch - - 30 19
Koenigsfeld 21 17 18 13
Schroeder 40 40 61 60
Opie 92 77 91 70
Griffith - - 17 17
Rubinstein 27 16 - -
Anders - - 58 50
Saenz 44 33 - -
Total 234 192 291 239
Percentage sterile 82.1 82.1
Canetti G. Paris: Vigot Frères, 1939, 305 pp
Observation and dilemma
Observation Bacilli are killed in the majority of cases following primary infection
A large proportion of disease in adults is the result of reinfection
Dilemma Reconciling Andvord and Canetti
Drawings: Koch R. Mittheilungen aus dem Kaiserlichen Gesundheitsamte 1884;2:1-88.Phenomenon: Koch R. Dtsch Med Wochenschr 1891;17:101-2.
The “Koch Phenomenon”
A primary infection leads to a delayed response and has often a mild andself-limited course
A reinfection results commonly in a rapid response with tissue necrosis
Reconciliation?
Observation Childhood experience predicts adult mortality (Andvord)
Observation Tubercle bacilli from the primary infection are commonly eliminated (Canetti)
Observation Reinfection results in tissue destruction (Koch)
Reconciliation Primary infection primes the child’s immune system, re-infection in the previously infected adult leads in immunologic response to cavitary tuberculosis
Protection Afforded by BCG Vaccinationin British School Children During Follow-up
Year of follow-up
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
Pro
tect
ion
(%)
0
20
40
60
80
100
D'Arcy Hart P, et al. Br Med J 1977;2:293-5
Cross-sectional
Birth cohort
Age
Mor
bidi
ty /
mor
talit
y
Time / age
Rem
ain
ing
live
baci
lli
Primaryinfection
Re-infection
A
Time
Tis
sue
de
stru
ctio
n
Primaryinfection
Re-infection
Progressive
Abortive
C
B
Time
BC
G p
rote
ctio
n
D
Andvord Canetti
Koch BMRC BCG Trial
Trying to fit observations ….
o A first infection is commonly overcome and frequently ends in the elimination of bacilli but primes the immune system for a decade or more
o A primed immune system may protect against subsequent re-infection or alternatively results in a severe tissue damaging response
o A positive tuberculin skin test is neither expression of living bacilli nor of protective immunity, it only reflects the immune response following prior infection
Repercussions and implications
o Vaccination
o Preventive therapy
o Epidemiology
Risk of Tuberculosis During Follow-up by Sizeof Initial Tuberculin Skin Test Reaction, Malawi
Induration (mm)
Rel
ativ
e ris
k (lo
g sc
ale)
0.2
0.5
1
3
10
Fine PEM, et al. Lancet 1994;344:1245-9
Ref
1 - 5 6 - 10 11 - 15 16 - 20 20 +0
Protection from BCG and from Small Tuberculin SkinTest Reactions During Follow-up, BCG Trial, Great Britain
Year of follow-up
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
Per
cen
t pro
tect
ion
Reacting to100 TU only
BCG vaccinated
D'Arcy Hart P, et al. Br Med J 1977;2:293-5
80
70
50
0
-100
Growth of BCG in mice after sub-cutaneous vaccination
Month after BCG vaccination0 1 2 3 4 5
CF
U o
f BC
G
10
30
50
100
300
500
1000
Lymph nodes
Spleen
Lung
Olsen AW, et al. Scand J Immunol 2004;60:273-77
Effect of Environmental Mycobacteria:Blocking and Masking Hypothesis
Andersen P, et al. Nature Rev 2005;3:656-62
…and another research question:
If an individual is not protected by BCG, istuberculosis more severe in this individual?
Factors Determining Effectiveness of Preventive Chemotherapy
o Probability of tuberculous infection
o Risk of tuberculosis given infection
o Efficacy of regimen
o Adherence to treatment
Distribution of Tuberculin Skin Test Reaction Sizes,Tanzania Schoolchildren, 1988-1992
Induration (mm)
0 5 10 15 20 25 30
Num
ber
of r
eact
ors
0
100
200
300
400
500
Data source: Styblo K, et al. TSRU Progress Report 1995;1:140-91
Cut-off > 4mm
Prevalence:Sensitivity:Specificity:Pred Val Pos:
0.1280.9650.9270.659
Distribution of Tuberculin Skin Test Reaction Sizes,Tanzania Schoolchildren, 1988-1992
Induration (mm)
0 5 10 15 20 25 30
Num
ber
of r
eact
ors
0
100
200
300
400
500
Data source: Styblo K, et al. TSRU Progress Report 1995;1:140-91
Cut-off >9mm
Prevalence:Sensitivity:Specificity:Pred Val Pos:
0.1280.7770.9710.798
Operating Characteristics of IGRAs
Pai M, et al. Expert Rev Mal Diagn 2006;6:413-22
Modeld Prevalence of Infection from Tuberculin Surveysand Measured IGRA Response, by Age, Japan
Age group (years)
40 50 60 70
Pre
vale
nce
(%)
(log
scal
e)
1
3
10
30
50
Mori T, et al. Int J Tuberc Lung Dis 2007;11:1021-5
Tuberculin surveys
IGRA survey
Ratio 3.6
5.05.4
Effectiveness of Preventive Chemotherapy
Probability of infection
Risk of tuberculosis
Efficacy of regimen
Adherence to treatment
Overall effectiveness
Number to treat to prevent
1 case
0.80 0.05 0.60 0.30 0.007 139
0.80 0.10 0.60 0.30 0.014 69
0.80 0.30 0.60 0.30 0.043 23
0.80 0.30 0.90 0.30 0.065 15
0.80 0.30 0.90 0.50 0.108 9
0.90 0.30 0.90 0.80 0.194 5
Thank you for your attention and patience