Pediatric TB Management

Training

Module 2
Epidemiology and
Pathogenesis
Respirology Coordination Working Unit
Epidemiology
Objectives

history of TB
magnitude of the problem of pediatric
TB in Indonesia
special consideration in pediatric TB
prevalence of pediatric TB
risk factors of infection and disease
Definition
Tuberculosis is a disease caused
by Mycobacterium tuberculosis.
The site of primary infection is
usually the lung and it may spread
hematogenously to almost all
organs
 History
ancient Egypt: gibbus
1882, Koch, identification
management: sanatorium, collapse
treatment
chemotherapy:
PAS 1943 Lehmann
Streptomycine 1945 - Waksman & Schats
Isoniazid 1952 Domagk
Rifampicine 1957
PZA
Magnitude of problems
TB, one of the oldest diseases in human
remains one of the deadliest diseases in the world
9 million of new cases yearly, 1 million children
3 million death yearly
20-40% population is infected
re-emergence, global emergency
TB in children : 75 % in countries with high
prevalence TB
Childhood TB reported range 3 - >25%
TB proportion in the world
Indonesia 10 % China
Bangladesh 4% 15 %
Pakistan 4%

Philipines 3% India
Nigeria 3% 30%
South Africa 2%
Russia 1% Others
28%
TB, a Global Emergency
every day 20.000 people getting TB disease
every hour 833 people getting TB disease
every minute 13 people getting TB disease
every 5 second ONE person getting TB disease

every day 5.000 people die due to TB

every hour 208 people die due to TB
every minute 3 people die due to TB
every 20 second ONE person die due to TB

every single second ONE person infected by TB

 Tuberculosis
A Global Emergency
z TB kills 5.000 people a day 2 million each year
z 1/3 of the world population is infected with TB
z >100.000 children may die needlessly from TB
each year
z hundreds of thousands of children will become TB
orphans each year
z HIV and MDR-TB will make the TB epidemic much
more severe unless urgent action is taken
 Problems in children
difficulty in diagnosing active TB
clinical symptoms and radiography is not
specific
specimen for culture as a gold standard
is difficult to obtain
long-term treatment: children adherence
compliance need child-friendly drug
Pediatric TB main problems
1. Diagnosis :
signs & symptoms
tuberculin skin test
chest x-ray
bacteriology
serology
biomolecular
Pediatric TB main problems
2. Adherence to treatment
DOTS
fixed dose combination (FDC)
Pediatric TB main problems
3. Prevention
controversies of BCG
prophylaxis
TB in Indonesia
estimation 583.000 cases per year with
140.000 deaths
19992000 45.248 AFB (+)
WHO-SEARO 2003:
new TB: 271/100.000 population
AFB (+): 122/100.000 population
TB and HIV: 0.3%
pediatric TB prevalence???
 Pediatric TB
under reported
estimation: 5-6% of total TB cases , may
be more
Starke (1988) :
1261 cases TB <15 years old
63% <5 years old

UK and Wales (1983)

452 pediatric TB <15 years old
Alabama (1983 1993)
171 cases TB <15 years old
Prevalence of Tuberculin Positive
TST early detection tool prevalence of infection
ARTI burden of TB disease
1% ARTI estimate 50 cases AFB (+)/100.000
ARTI in Africa Sub-Sahara 1,5-2,5%
ARTI in South East Asia 1-2%
ARTI in North Africa, Middle East and South America
0,5-1,5%
in Indonesia:
Yogyakarta 1963 : 2,50%
Tangerang 1972 : 3,40%
Pati 1972 : 1,90%
Kab Bandung 2000 : 2,35%
Sumbar 2006 : 1-1,3%
RISK FACTORS FOR INFECTION
young age
low socio-economic status
low income
crowded environment
jobless
low education
low funding for community health problems
immigrants
RISK FACTORS FOR DISEASE

Age : <5 year, adolescent

New infection
Immunocompromise
HIV
Malignancy
Long term immunosupressive treatment
Malnutrition
 RISK OF DISEASE IN CHILDREN
INFECTED WITH M.TB
Age at primary No disease Pulmonary Miliary TB, TB of
infection (yr) (%) disease (%) CNS, severe TB (%)
<1 50 30 - 40 10 - 20
1-2 75 - 80 10 - 20 2-5
2-5 95 5 0.5
5 - 10 98 2 < 0.5
> 10 80 - 90 10 - 20 < 0.5

Am J Respir Crit Care Med 2006; 173:1078-1090

TB and AIDS
Lifetime Risk
of TB
70% 60%
60%
50%
40%
30%
20% 10%
10%
0%
PPD+/HIV-negative PPD+/HIV+
Transmission rate (Shaw 54)
adult
TB patient

AFB(-) culture(-)
AFB(+) culture(+) CXR (+)

65% 26% 17%

Pathogenesis
Objectives

transmission of TB
pathogenesis of primary TB and post
primary TB
lymphogenous and hematogenous
spread
TB infection vs TB disease
Why does TB so difficult to erradicate ?
specific characteristics of the
bacilli
special issues:
hematogenous spread
infection vs disease
primary vs post-primary
 The bacilli
Mycobacterium tuberculosis
Mycobacterium bovis
features:
slender, often slightly curved, rods
aerobic, non-motile, non-spore forming
acid failed to washed the stain out acid fast bacilli
Mycobacteria: is found in environment, some strictly
human pathogen (M. tb, M. bovis), other animals
pathogens and opportunistic pathogens in human
(atypical mycobacteria)
TB bacilli
 M. tuberculosis
Unique characteristics :
1. live for weeks in dry condition

2. no endotoxins, no exotoxins

3. hematogenous spread

4. grows slowly (24-32 hr)

5. nonspecific clinical manifestation

6. aerob, organ predilection : lung

7. wide spectrum of replication: dormant,

persister
 Transmission
airborne human to human transmission by
droplet nuclei
adult pulmonary TB: cough, sneeze, speak, or
sing
droplet nuclei: contains 2-3 bacilli, small size
(1-5), remain in the air for a long period
inhalation, reach alveoli
middle and lower lobes
TB droplet nuclei
Factors influencing transmission
dose / number
concentration in the air
virulence
duration of exposure
immune state of the host
 Source of infection

known source of infection has

diagnostic value
Shaw (1954), transmission rate:
AFB (+) : 62.5 %
AFB (-), M tb (+) : 26.8 %
AFB (-), M tb (-) : 17.6 %
Location of primary focus
in 2,114 cases, 1909-1928
Location %
Lung 95.93
Intestine 1.14
Skin 0.14
Nose 0.09
Tonsil 0.09
Middle ear (Eustachian tube) 0.09
Parotid 0.05
Conjunctiva 0.05
Undetermined 2.41
Pathogenesis alveoli ingestion by PAMS

droplet nuclei intracellular replication

inhalation of bacilli
destruction
destruction of PAMS of bacilli

Tubercle formation Lymphogenic spread Hilar lymph nodes

primary focus lymphangitis lymphadenitis

hematogenic spread
primary
acute hematogenic occult hematogenic
complex
spread spread

multiple organs
CMI
disseminated primary TB remote foci

Figure. Pathogenesis of primary tuberculosis

 Pathogenesis
Simon focus lymphadenitis

lymphangitis

primary focus
Ghon focus
 M. tuberculosis inhalation

phagocytosis by PAM bacilli dead

TB pathogenesis live bacilli

incubation period
multiplies (2-12 weeks)

primary focus formation

lymphogenic spread
hematogenic spread1)

Primary complex2)
TST (+) Cell mediated immunity (+) P
r
i
m
TB disease Low immunity TB infection a
primary complex complication r
Optimal immunity
hematogenic spread complication y
lymphogenic complication
T
B
Dead
3)

immunity 
reactivation

Cured TB disease4)
Catatan :
Penyebaran hematogen umumnya terjadi
secara sporadik (occult hematogenic
spread). Kuman TB kemudian membuat
fokus koloni di berbagai organ dengan
vaskularisasi yang baik. Fokus ini berpotensi
mengalami reaktivasi di kemudian hari.
Kompleks primer terdiri dari fokus primer
(1), limfangitis (2), dan limfadenitis regional
(3).
Catatan (lanjutan..):
Tuberkulosis primer adalah kompleks primer
dan komplikasinya.
Sakit TB pada keadaan ini disebut TB
pascaprimer karena mekanismenya dapat
melalui proses reaktivasi fokus lama TB
(endogen). TB pascaprimer terjadi pada anak
besar dan orang dewasa. TB dewasa dapat
juga terjadi dari infeksi baru (eksogen)
 Incubation period
first implantation primary focus
4-6 weeks (2-12 weeks) incubation period
first weeks: logaritmic growth, 103-104 elicit
the cellular response
end of incubation period:
primary complex formation
cell mediated immunity
tuberculin sensitivity
hh Primary TB infection established
 Hematogenous spread

during
incubation period, before TB
immune response established:
lymphogenous spread
hematogenous spread
hematogenous spread (HS):
occult HS
acute generalized HS
Protracted / repeated
 Occult Hematogenous spread
most common
sporadic, small number
no immediate clinical manifestation
remote foci in almost every organ
rich vascularization: brain, liver, bones &
joints, kidney
including: lung apex region (Simon focus)
CMI (+): silent foci - dormant, potential for
reactivation
TB hematogenous spread
Acute generalized Hematogenous TB
less common
large number
immediate clinical manifestation:
disseminated TB
milliary TB, meningitis TB
tubercle of the same size, specific
appearance in CXR
may affect the retina/choroid, liver,
lymph node
Miliary TB
Primary complex
end of incubation period
TB infection established
tuberculin sensitivity (DTH)
cell mediated immunity
end of hematogenic spread
end of TB bacilli proliferation
small amount, live dormant in granuloma
new exogenous TB bacilli: destroyed/localized
 TB infection & TB disease

TB infection: CMI can control infection

primary complex (+)
cell mediated immunity (+)
tuberculin sensitivity (DTH) (+)
limited amount of TB bacilli
no clinical or radiological manifestation
TB disease: CMI failed to control TB infection
TB infection + clinical and/or radiological
manifestation
TB infection

TB CMI
TB disease

CMI

TB
TB classification (ATS/CDC modified)
Class Contact Infection Disease Treatment

0 - - - -
1 + - - proph I

2 + + - proph II?

3 + + + therapy
TB natural history overview
primary TB infection

primary TB disease latent TB infection

post primary TB no disease

non respir TB respiratory TB

new infection
 Pathology
complicated pathogenesis
varied pathology
clinical manifestation
radiologic appearance
lung presentation
tubercle, granuloma, tuberculoma, fibrosis,
fistula, cavity, atelectasis
complication of primary complex: many
possibilities
 Lesions of pulmonary TB
Parenchym: primary focus, pneumonia,
atelectasis, tuberculoma, cavitary
Lymph node: hilar, paratracheal, mediastinal
Airway: air trapping, endobronchial TB,
bronchial stenosis, fistula, bronchiectasis
Pleura: effusion, fistula, empyema,
pneumothorax, hemothorax
Blood vessels: milliary, hemorrhage
The palest ink is stronger
than the strongest memory

Uibol zpv
Prognostic factors
A. TB bacilli :
virulence
infection dose
B. Patient :
general condition
age
nutritional state
coinfection: morbili, pertussis
genetic
stress; physically (trauma, surgery) or
mentally
 Pathology jungle
reg lymph node primary focus remote foci

resolution milliary seed

tubercle formation

calcification caseation granuloma

compresses airway fibrosis tuberculoma

liquefaction
cavity
erodes airway

bronchiectasis 2nd lung lesions rupt to pleura rupt to airway

br pl fistula