Epidémiologie et maîtrise de la tuberculose:

situation internationale

Hans L Rieder

Union Internationale Contre la Tuberculose et les Maladies Respiratoires

Paris, 24 mars 2009

GDP (in US$) per head (log scale)

Tube

rcul

osis

cas

espe

r 100

,000

(log

sca

le)

2.55

10

20

50

100 200 500 10,0005,000

100

1,000 2,000

500

200

1,000

20,000 50,000

IndiaChina

France

Janssens JP, Rieder HL. Eur Respir J 2008;32:1415-6

Relationship between estimated tuberculosis incidencerates 2004 and per capita gross domestic product 2005

An individual with tuberculosis who is unable to control replication of M. tuberculosis so that the resulting damage kills the host

Death

An infected individual which is unable to contain replication ofM. tuberculosis to a number that causes clinically manifest tuberculosis

Disease

An exposed individual that has inhaled an infecting dose of M. tuberculosis that has resulted in sub-clinical replication of the latter – the individual has latent (sub-clinical) infection with viable M. tuberculosis

Infection

A non-infected individual is inhaling air that contains a sufficient number of M. tuberculosis as to ensure a reasonably measurable probability of inhaling at least one infecting dose

Exposure

Using a common terminology

In tuberculosis pathogenesis,

the incubation period

(between infection and manifest disease)

is not defined

and there is only

partial protective immunity against reinfection

Incident cases of tuberculosis emerge unpredictably fromthe population prevalently infected with M tuberculosis

Population including persons with and without infection with M tuberculosis

Subclinicalinfection

Infectioustuberculosis

Non-infectioustuberculosis

Prophylactictreatment

Preventivetherapy

Chemotherapy

BCGvaccination

Patient's delay

Doctor's delay

Transmission

DeathExposure

Component of the tuberculosis elimination strategy: identification and preventive chemotherapy for persons already infected

Reduction of the prevalence of tuberculous infection

Essence of the tuberculosis control strategy: identification and curative chemotherapy for cases transmitting M. tuberculosis

Reduction of the incidence of tuberculous infection

An Epidemiologic Approach to Tuberculosis Interventions

Mantoux C. La Presse Médicale 1910;2:10-15

Age-Specific Prevalence of Tuberculous Infectionin Healthy Children, Paris, 1910

Age (years)0 5 10 15

Per

cen

t rea

ctin

g

0

20

40

60

80

100

Mantoux C. Presse Méd 1910;2:10-13

Childhood experience predicts adult experience in every birth cohort!

Andvord K F. Norsk Magasin for Lægevidenskaben 1930;91:642-60

Mortality

Canetti G. Paris: Vigot Frères, 1939, 305 pp

82.182.1Percentage sterile

239291192234Total

--3344Saenz

5058--Anders

--1627Rubinstein

1717--Griffith

70917792Opie

60614040Schroeder

13181721Koenigsfeld

1930--Rabinowitch

1016910Schmitz

SterileLesionsSterileLesionsAuthor

LymphaticPulmonary

Fate of M tuberculosis in calcified lesions

Kristian Andvord’s observation:

A case for prolonged latency with subsequent reactivation,

but….

George Canetti’s findings tell otherwise:

The immune system leads to killing of tubercle bacilli

“Once infected – always infected”:A hypothesis not borne out by facts

Growth of BCG in mice after sub-cutaneous vaccination

Month after BCG vaccination0 1 2 3 4 5

CFU

of B

CG

10

30

50

100

300

500

1000

Lymph nodes

Spleen

Lung

Olsen AW, et al. Scand J Immunol 2004;60:273-77

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

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

Cross-sectional

Birth cohort

Age

Mor

bidi

ty /

mor

talit

y

1930: Andvord

Time / age

Rem

aini

ng li

ve b

acill

i

Primaryinfection

Re-infection

1939: Canetti

Time

Tiss

ue d

estru

ctio

n

Primaryinfection

Re-infection

Progressive

Abortive

1891: Koch

Time

BC

G p

rote

ctio

n

1977: BMRC BCG Trial

A positive tuberculin skin test is neither expression of living bacilli nor of protective immunity, it only reflects the immunologic response following prior infection

o

A primed immune system may protect against subsequent re-infection or alternatively results in a severe tissue damaging response

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

Occam’s razor?

Incidence Case Rate Among Household Contacts of Smear-Positive Tuberculosis, by Intitial Tuberculin and IGRA Test, Gambia

Inci

denc

e pe

r 100

,000

p-y

r

100

500

1000

1500

2000

Mx-ES- Mx- ES- Mx+ Mx+

ES- ES+ Mx-ES+

Mx+ES+

Mx+or

ES+

Hill PC, et al. PLoS One 2008;3(1): e1379. doi:10.1371/journal.pone.0001379

Mx:ES:

MantouxElispot

0.8-1.3% !

A simplified view of a problem:Tuberculin skin test versus IGRAs

Both tests measure the wrong thing,but IGRAs do it more specifically

An immunologic response to mycobacterialantigens acquired in the past does notequate currently live bacilli ready to causedisease (BCG!)

Preventive Therapy for HIV Infected PoliceOfficers in Dar es Salaam, Tanzania

Num

ber o

f per

sons

0

100

200

300

400HIV+

Gotresult

AcceptPT

EvaluatedStarted

INH Adherent

Bakari M, et al. East Afr Med J 2000;77:494-7

Tuberculosis Incidence in an HIV-Infected Cohort ofPatients on Anti-Retroviral Therapy, Switzerland, 1996-2005

Num

ber o

f Pat

ient

s

0

1000

2000

3000

4000

5000

6000

Missed 30 10 16 0Averted 9.4

Subjects 6,018 4,168 390 144

Cohort HIV pos <5mm >=5mm Prev ther

Elzi L, et al. Clin Infect Dis 2007;44:94-102

0.20.10

Total569.7

Subclinicalinfection

Infectioustuberculosis

Non-infectioustuberculosis

BCGvaccination

Exposure

Effectiveness of BCG Against Meningeal Tuberculosis,Meta-Analysis of Case-Control Studies, 1947-1993

Per cent protection (log scale)0-40 50 80 9020

Buenos Aires, 1988

São Paulo, 1990/93

Delhi, 1989Bela Horizonte, 1988

Chennai, 1996Summary measure

São Paulo, 1990/93Bahia, 1991

Nagpur, 1996

Papua New Guinea, 1958

Lucknow, 1947Yangon, 1952

Bela Horizonte, 1965Delhi, 1964

Delhi, 1956

Bourdin Trunz B, et al. Lancet 2006;367:1173-80

…but tuberculous meningitisis no more the biggestconcern in Europe

Subclinicalinfection

Infectioustuberculosis

Non-infectioustuberculosis

Prophylactictreatment

Preventivetherapy

Chemotherapy

BCGvaccination

Patient's delay

Doctor's delay

Transmission

DeathExposure

Fate of Untreated Pulmonary Tuberculosis in SanatoriumPatients, Long-Term Follow-Up, Barmelweid, Switzerland

Years after first admission0 2 4 6 8 10 12 14 16 18

Per

cen

t dea

d

0

20

40

60

80

100

"Open" tuberculosis

"Closed" tuberculosis

Krebs W. Beitr Klin Tbk 1930;74:345-79

Sensitivity of Direct Sputum Smear Examinationin Identifying Pulmonary Tuberculosis and Transmitters

Frac

tion

of c

ases

/ in

fect

ed

0.0

0.2

0.4

0.6

0.8

1.0

Smear-negCulture-pos

Smear-posCulture-pos

Fraction due tosmear-neg cases

Fraction due tosmear-pos cases

Calculated from data from:Grzybowski S, et al. Bull Int Union Tuberc Lung Dis 1975;50:90-106

Cases ofpulmonary

tuberculosis

Infectedcontacts< 15 yr

0 1 10 100 1000 10.000 100.000 1.000.000AFB per ml of sputum

Freq

uenc

y

X-Ray and clinical (15%)

Poor microscopy (35%)

Excellent microscopy (65%)

PCR (80%)Culture (85%)

Slide courtesy: Van Deun A, November 22, 2007

Schematic Presentation of Relative Frequency of Patients,Number of bacilli, and Available Diagnostic Methods

Improve identification of transmitters:=

Improve microscopy

Improve identification of patients:=

Improve clinical skills

After 2 months chemotherapy After 6 months chemotherapy

Miliary Tuberculosis