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