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Pediatric Tuberculosis
Pediatric Respirology
Coordination Working Unit
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Definition
Tuberculosis is a disease due to
Mycobacterium tuberculosis
infection with systemic spread thus
can affect almost all organs, and
the most frequent site is in the
lung, which usually as the site of
primary infection
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Tuberculosis
The reaction of the tissues of the
human host to the presence
and multiplication of
Mycobacterium tuberculosis or
Mycobacterium bovis
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History
ancient Egypt : gibbus
1882, Koch, identification
management : sanatorium, collapse
treatment
Chemotherapy :
PAS 1943 Lehmann
Streptomycine 1945 - Waksman & Schats
Isoniazid 1952 Domagk
Rifampicine - 1957
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Magnitude of problem
TB one of the oldest diseases of human
remains one of the deadliest diseases in
the world
8 million of new cases yearly
3 million death yearly
20-40% population is infected
reemergence, global emergency

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The secret
Why TB is so strong and robust?
the secret: specific characters of
the bacilli
special issues:
hematogenic spread
infection vs disease
primary vs post-primary
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The main problems
Diagnosis
Clinical manifestations : not specific
both over/under diagnosis & over/under
treatment
diagnostic specimen : difficult to obtain
TB infection or TB disease ? no
diagnostic tool to distinguish
Adherence / compliance
Drug discontinuation treatment failure
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Etiology
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The bacilli
Mycobacterium tuberculosis
Mycobacterium bovis
features:
slender, often slightly curved, rods
aerobic, non-motile, non-spore forming
acid fail to wash the stain out acid fast bacilli
Mycobacteria : found in environments, some
strictly human pathogen (M tb, bovis), others
animal pathogen and opportunistic pathogens in
human (atypical mycobacteria)
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TB bacilli
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M tuberculosis
Characteristics :
1. live in weeks in dry condition
2. no endotoxins, no exotoxins
3. hematogenic spread
4. grows slowly (24-32 hr)
5. non specific clinical manifestation
6. aerob, organ predilection - lung
7. wide spectrum of replication: dormant
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Transmission
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Transmission ...
airborne human to human transmission by
droplet nuclei
adult pulmonary TB: cough, sneeze, speak, or
sing
droplet nuclei : contain 2-3 bacilli, small size
(1-5) keep in the air for long period
inhalation, reach alveoli
middle and lower lobes
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TB droplet nuclei
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Transmission factors:
doses / numbers
concentration in the air
virulence
exposure duration
host immune state
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Infection source
Known source of infection, has
diagnostic value
Shaw (1954), level of infectiousness :
AFB (+) : 62.5 %
AFB (-), M tb (+) : 26.8 %
AFB (-), M tb (-) : 17.6 %
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Transmission rate (Shaw 54)
adult
TB patient
AFB(+)
AFB(-)
culture(+)
culture(-)
CXR (+)
65%
26% 17%
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Pathogenesis
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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
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Figure. Pathogenesis of primary tuberculosis
droplet nuclei
inhalation
alveoli ingestion by PAMS
intracellular replication
of bacilli
destruction
of bacilli
destruction of PAMS
Tubercle formation Hilar lymph nodes
hematogenic spread
multiple organs
remote foci
Lymphogenic spread
disseminated primary TB
acute hematogenic
spread
occult hematogenic
spread
primary focus lymphangitis lymphadenitis
primary
complex
CMI
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Incubation period
first implantation primary complex
4-6 weeks (2-12 weeks) incubation period
first weeks: logaritmic growth, : 10
3
-10
4

elicit cellular response
end of incubation period:
primary complex formation
cell mediated immunity
tuberculin sensitivity
PrimaryTB infection has established
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lymphadenitis
lymphangitis
primary focus
Pathogenesis ...
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Hematogenous spread
during incubation period, before TB
infection establishment:
lymphogenic spread
hematogenic spread
hematogenic spread (HS):
occult HS
acute generalized HS
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Occult HS
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
CMI (+): silent foci - dormant,
potential for reactivation
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TB hematogenous spread
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Acute HS
less common
large number
immediate clinical manifestation:
disseminated TB
milliary TB, meningitis TB
tubercle in same size, special
appearance in CXR
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Miliary TB
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Primary complex
end of incubation period
TB infection establishment
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
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Tuberculin skin test
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Tuberculin test
TB infection

cellular immunity

delayed type hypersensitivity

tuberculin reaction
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Tuberculin
Strength
PPD S
Seibert
PPD RT23
first 1 TU 1 TU
intermediate
(standard dose)
5-10 TU 2-5 TU
second 250 TU 100 TU
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Tuberculin delivery
1. Mantoux : intradermal injection
2. Multiple puncture :
Heaf, special apparatus with 6 needles
Tine, disposable, 4 needles
3. Patch test
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Tuberculin
Mantoux 0.1 ml PPD intermediate strength
location : volar lower arm
reading time : 48-72 h post injection
measurement : palpation, marked, measure
report : in millimeter, even 0 mm
Induration diameter :
0 - 5 mm : negative
5 - 9 mm : doubt
> 10 mm : positive
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Mantoux
tuberculin
skin test
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Pengukuran Uji tuberkulin
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Tuberculin positive
1. TB infection :
infection without disease / latent TB infection
infection and disease
disease, post therapy
2. BCG immunization
3. Infection of Mycobacterium atypic
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Anergi
Patient with primary complex do not give reaction
to TST due to supression of CMI :
Severe TB: miliary TB, TB meningitis
Severe malnutrition
Steroid, long term use
Certain viral infection: morbili, varicella
Severe bacterial infection: typhus abdominalis,
diphteria, pertussis
Viral vaccination: morbili, polio
Malignancy: Hodgkin, leukemia, ...
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TB infection & TB disease
TB infection: CMI can control infection
primary complex
tuberculin sensitivity (DTH)
cell mediated immunity
no clinical or radiological manifestation
TB disease: CMI failed to control TB infection
TB infection + clinical and/or radiological
manifestation
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TB classification (ATS/CDC modified)
Class Contact Infection Disease
Manage
ment
0
- - -
-
1
+
- -
proph I
2
+ +
-
proph II?
3
+ + + therapy
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TB Natural history overview
primary TB infection
primary TB disease latent infection
no disease post primary TB
respiratory TB non respir TB
new infection
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Pathology
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Pathology
complicated pathogenesis
varied pathology
clinical manifestation
radiologic appearance
lung represent
tubercle, granuloma, tuberculoma, fibrosis,
fistula, cavity, atelectasis
complication of primary focus: so many
possibilities
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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
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tubercle formation
resolution
primary focus
calcification
2
nd
lung lesions
caseation
liquefaction
granuloma
Pathology
remote foci reg lymph node
tuberculoma
cavity
milliary seed
erodes airway
compresses airway
rupt to pleura rupt to airway
bronchiectasis
fibrosis
br pl fistula
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Clinical
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Clinical types of pediatric TB
Infection: TST (+), clinical (-), radiographic (-)
Disease:
Pulmonary:
primary pulmonary TB
milliary TB
pleuritis TB
progr primary pulm TB: pneumonia, endobr TB
Extrapulmonary:
lymph nodes
brain & meninges
bone & joint
gastrointestinal
other organs
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Clinical manifestation
vary, wide spectrum
factors:
TB bacilli: numbers, virulence
host: age, immune state
clinical manifestation
general manifestation
organ specific manifestation
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General manifestation
chronic fever, subfebrile
anorexia
weight loss
malnutrition
malaise
chronic recurrent cough, think asthma!
chronic recurrent diarrhea
others
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Organ specific
Respiratory : cough, wheezing, dyspnea
Neurology : convulsion, neck stiffness,
SOL manifestation
Orthopedic : gibbus, crippled
Lymph node : enlarge, scrofuloderma
Gastrointestinal: chronic diarrhea
Others
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Miller FJW. Tuberculosis in children, 1982
A minority of children
experience :
1. Febrile illness
2. Erythema Nodosum
3. Phlyctenular Conjunctivitis
Complications of focus
1. Effusion
2. Cavitation
3. Coin shadow
Complications of nodes
1. Extension to bronchus
2. Consolidation
3. Hyperinflation
MENINGITIS OR MILIARY
in 4% of children infected
under 5 years of age
LATE COMPLICATIONS
Renal & Skin
Most after 5 years
1 2
3 4 5 6
BONE LESION
Most within
3 years
24 months
Resistance reduced :
1. Early infection
(esp. in first year)
2. Malnutrition
3. Repeated infections :
measles, whooping cough
streptococcal infections
4. Steroid therapy
infection
BRONCHIAL EROSION
Most children
become tuberculin
sensitive
12 months
DIMINISHING RISK
But still possible
90% in first 2 years
GREATEST RISK OF LOCAL & DISEMINATED LESIONS
Development
Of Complex
4-8 weeks 3-4 weeks fever of onset
PRIMARY COMPLEX
Progressive Healing
Most cases
Uncommon under 5 years of age
25% of cases within 3 months
75% of cases within 6 months
3-9 months
Incidence decreases
As age increased
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Pemeriksaan mikrobiologis
Memastikan D/ TB
Hasil negatif tidak menyingkirkan D/ TB
Hasil positif : 10 - 62 % (cara lama)
Cara :
cara lama,
radiometrik,
PCR
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Radiology, serology , ...
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Imaging diagnostic
routine : chest X ray
on indication : bone, joint, abdomen
majority of CXR non suggestive TB
pitfall in TB diagnostic
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Radiographic picture
primary complex: lymph node enlargement
milliary
atelectasis
cavity
tuberculoma
pneumonia
air trapping - hyperinflation
pleural effusion
honeycombs bronchiectasis
calcification, fibrosis
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do not always help, particularly in small children
at times can be confusing

some cases: extensive disease from radiography
clinical exam revealed little or nothing

more confusing superadded bacterial
pneumonia (+)
Osborne CM et.al. Arch Dis Child 1995;72:369-74
Radiographic picture
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No radiographic picture is typical of TB
Many lung diseases have similar
radiographic appearances mimicking PTB
Cannot distinguish active pulmonary TB
inactive PTB previously treated TB
May not detect early stages of TB disease
under-reading
over-reading
intra-individual inconsistency
Vijayan VK. Indian J Clin Biochem 2002;17(2):96-100.
Radiographic picture
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Commonly found: enlargement of hilar/
paratracheal nodes sometimes difficult
to interpret requires thorax CT with
contrast

Thorax CT reveals enlargement of lymph
node in 60% children with TB infection
and normal Chest rntgenogram


Delacourt C et.al. Arch Dis Child 1993;69:430-2.
Radiographic picture
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100
32
0
20
40
60
80
100
Diagnosed by X-
ray alone
Actual cases
Over diagnosis TB by CXR
Over-
diagnosis
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Sensitivity: 19 68%
Specificity: 40 98%


Disadvantages
results affected by factors such as
- age
- history of BCG vaccination
- exposure to atypical Mycobacteria
- unable to differentiate between infection and disease

Khan EA and Starke JR. Emerg Infect Dis 1995;1:115-23.
Depends on:
Type of antigen used
Type of infection
Serology
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Polymerase chain reaction
PCR
from gastric aspirate diagnosis of TB in children
Sensitivity: 44 90%
Specificity: 94 96,8%
Compared to MTB culture
Lodha R et.al. Indian J Pediatr 2004;71:221-7.

PCR technique using primer containing IS6110
better results
Khan EA and Starke JR. Emerg Infect Dis 1995;1:115-23.

May help in early detection of resistant strain of MTB
Lodha R et.al. Indian J Pediatr 2004;71:221-7.


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Detection of interferon- (QuantiFERON-TB)
comparable with TST to detect latent TB infection

Advantages
- less affected by BCG vaccination
- can discriminates responses due to nontuberculous
mycobacteria
- avoids variability and subjectivity associated with
placing and reading TST

The utility of QFT in predicting the progression to
active TB has not been evaluated

Mazurek GH et.al. MMWR Dispatch 2002;51.
Interferon
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Diagnosis
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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
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The main problems
Diagnosis
Clinical manifestations : not specific
both over/under diagnosis & over/under
treatment
diagnostic specimen : difficult to obtain
No other definitive diagnostic tools
TB infection or TB disease ? no
diagnostic tool to distinguish
Adherence / compliance
Drug discontinuation treatment failure
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Diagnosis
1. Tuberculin skin test
2. Chest X ray
3. Clinical manifestation
4. Microbiologic
5. Pathology
6. Hematological
7. Known infection source
8. Others : serologic, lung function,
bronchoscopy
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Clinical setting management
Suspect TB
proveTB
infection
Mantoux
test
positive negative
not TB
Seek other
etiologies
completed:
Ro, lab
Diagnosis TB
treatment
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Practical clinical approach to Ped TB
Scoring system
Stegen, 1969
Smith, Marquis, 1981
Migliori dkk, 1992
WHO, 1994
Algorithm
IDAI, 1998, 2002
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Algorithm for Early Detection and Referral for Childhood
Tuberculosis in Indonesia
Suspected TB:
Close contact with adult with AFB sputum (+)
Early reaction of BCG (in 3-7 days)
Weight loss with no apparent cause, or underweight with no
improvement in 1 month with adequate nutritional support
(failure to thrive)
Prolonged/recurrent fever with no apparent cause
Cough more than 3 weeks
Specific enlargement of superficial lymph node
Scrofuloderma
Flychten conjunctivitis
Tuberculin test positive (> 10 mm)
Radiological findings suggestive TB

If > 3 positive
Next page
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Considered TB
Give anti-TB therapy
Observation in 2 months
Clinical response (+)
No clinical response/worsening
TB
Continue anti-TB therapy
Not TB MDR TB
Refer to hospital
Reevaluation in Referral Hospital:
Clinical signs
Tuberculin test
Radiological findings
Microbiology and serology examination
Histopatology examination
Diagnostic procedure and therapy
according to each hospitals protocol
ATTENTION
Presence of any dangerous signs:
Seizure
Decreased level of consciousness
Neck stiffness
Or signs such as:
Spinal tumor/lump
Limping
Dam board phenomenon
Send to hospital
UKK Pulmonologi IDAI. Jakarta;2002.
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Encountered problem
Increasing demands of TB drugs
for Pediatric TB
Increasing diagnosis of Pediatric
TB using the IDAI algorhitm
Over diagnosis ?
Need improvement IDAI scoring
system
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Proposed IDAI scoring system
Feature 0 1 2 3 Score
Contact
not clear reported,
AFB(-)
- AFB(+)
TST
- - - positive
BW (KMS)
- <red line,
BW
severe
malnutrition
-
Fever
- unexplained - -
Cough
<3weeks >3weeks - -
Node
enlargemnt
- >1 node,
>1cm,painless
- -
Bone,joint
- swelling - -
CXR
normal sugestive - -
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Notes for IDAI scoring system
Diagnosis by doctor
BW assessement at present
Fever & cough no respons to standard tx
CXR is NOT a main diagnostic tool in children
All accelerated BCG reaction should be evaluated
with scoring system
TB diagnosis total score >5
Score 4 in under5 child or strong suspicion, refer
to hospital
INH prophylaxis for AFB(+) contact with score <5
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Diagnosis of TB in children
If you find the diagnosis of TB in children easy,
you probably overdiagnosing TB
If you find the diagnosis of TB in children
difficult, you are not alone
It is easy to over-diagnose TB in children
It is also easy to miss TB in children
Carefully assess all the evidence, before
making the diagnosis
Anthony Harries & Dermot Maher, 1997
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Treatment
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Objectives of treatment
Rapid reduction of the number
of bacilli
Preventing acquired drug
resistance
Sterilization to prevent relapses
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Treatment principles
Drug combination, not single drug
Two phases :
Initial phase (2 months) intensive,
bactericidal effect
Maintenance phase (4 months / more)
sterilizing effect, prevent relaps
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Smear +
Culture +
Smear -
Culture +
Smear -
Culture -
10
8

10
7

10
6

10
5

10
4

10
3

10
2

10
1

10
0

Start of treatment
(isoniazid alone)
Weeks of treatment
0 3 6 9 12 15 18
WHO 78351
Sensitive organisms Resistant organisms
N
u
m
b
e
r

o
f

b
a
c
i
l
l
i

p
e
r

m
l

o
f

s
p
u
t
u
m

Toman K, Tuberculosis, WHO, 1979
The fall and rise phenomenon
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Treatment principles
Long duration problem of
adherence (compliance)
Other aspects :
Nutrition improvement
prevent / search & treat other
disease

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Hypothetical model of TB therapy
A
B
C
Bacteridal activity & sterilizing effect
0 1 2 3 4 5 6
Pop A = rapidly multiplying (caseum)
Pop B = slowly multiplying (acidic)
Pop C = sporadically multiplying
Months of therapy
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Drugs
Daily dose
(mg/Kg/day)
Adverse reactions
2 Time/week
dose
(mg/Kg/dose))
Isoniazid
(INH)
5-15
(300 mg))
Hepatitis, peripheral neuritis,
hypersensitivity
15-40
(900 mg))
Rifampicin
(RIF)
10-15
(600 mg))
Gastrointestinal upset,skin reaction,
hepatitis, thrombocytopenia,
hepatic enzymes, including orange
discolouraution of secretions
10-20
(600 mg)
Pyrazinamide
(PZA)
15 - 40
(2 g)
Hepatotoxicity, hyperuricamia,
arthralgia, gastrointestinal upset
50-70
(4 g)
Ethambutol
(EMB)
15-25
(2,5 g)
Optic neuritis, decreased visual
acuity, decreased red-green colour
discrimination, hypersensitivity,
gastrointestinal upset
50
(2,5 g)
Streptomycin
(SM)
15 - 40
(1 g)
Ototoxicity nephrotoxicity
25-40
(1,5 g)
When INH and RIF are used concurrently, the daily doses of the drugs are reduced
National consensus of tuberculosis in children, 2001
Dosage of antituberculosis drug
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RIF, INH
Netral
Populasi basil TB pada pasien
Kavitas,
ekstrasel
Massa kiju
Dalam makrofag
(intrasel)
Jumlah populasi 10
7
- 10
9
10
4
- 10
5
10
4
- 10
5

Metabolisme dan
perkembang biak
Aktif
Lambat atau
intermiten
Lambat
pH Netral/basa Asam
Obat paling efektif
(berturut-turut)
INH, RIF,
STREP
PZA, RIF, INH
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Drug activities upon TB pop
TB
Population
Multiplying
rate
Drug
activities
A
rapidly INH>>SM>
RIF>EMB
B
slowly PZA>>RIF>>
INH
C
sporadically RIF>>INH
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TB therapy regimen
2 mo 6 mo 9 mo 12mo


INH
RIF
PZA

EMB
SM

PRED
DOT.S !

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Corticosteroid
Anti inflammation
prednison : 1 - 3 mg/kg BB/hari,
3x/hari oral 2 - 4 minggu,
tapering off
Indications :
TB milier
Meningitis TB
Pleuritis TB with effusion
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Treatment evaluation
Clear improvement in clinical
and supporting examination,
especially in the first 2 month
Main : clinical
supporting exam as adjuvant
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Treatment evaluation
Clinical improvement :
Increased body weight
Increased appetite
Diminished / reduced symptoms (fever,
cough, etc)
Supporting examination :
Chest X rays : 2 / 6 month (on indication)
Blood : BSR
Tuberculin test : once positive, do not
needed to repeat !
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Treatment failure
Inadequate response, despite adequate
therapy :
Review the diagnosis, not a TB case ?
Review other aspects : nutrition, other
disease
MDR rarely in children
Treatment discontinuation
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Treatment problems
The main : compliance / adherence
The factors :
Long duration
Drug side effect
Initial improvement misinterpreted by patients /
parents
Inconvenient health service
Socio-economic-cultural factors
The following : drug resistance


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DOTS with a SMILE
S : Supervised
M : Medication
I : In
L : a Loving
E : Environment

(Grange JM, Int J Tuberc Lung Dis 1999; 3:360-
362)
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Treament problem solution: FDC
Fixed dose combination: >2 drugs in one
tablet in a fixed dose formulation
simple dosing
patient friendly, doctor friendly
increase adherence
reduce MDR
easier drug supplying
easier drug monitoring
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FDC tablet formulation
WHO
H : 30 mg
R : 60 mg
Z : 150 mg
IDAI
H : 50 mg
R : 75 mg
Z : 150 mg
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WHO FDC (H/R/Z:30/60/150 & H/R:30/60)
BW
(kg)
Intensive, 2 mo
(tablet)
Continuation, 4 mo
(tablet)
<7 1 1
8-9 1,5 1,5
10-14 2 2
15-19 3 3
20-24 4 4
25-29 5 5
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IDAI FDC (H/R/Z:50/75/150 & H/R:50/75)
BW
(kg)
Intensive, 2 mo
(tablet)
Continuation, 4 mo
(tablet)
5-9 1 1
10-19 2 2
20-33 4 4
Note: BW < 5kg should be referred and need tailored dosing
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WHO vs IDAI fdc formulation
WHO:
INH: 4-6 mg/kgBW
BW grouping: too many
not practical
hard to remember
a gap for BW 30-33 kg
IDAI
INH: 5-10 mg/kgBW
simple BW grouping
more friendly both for doctor and patient
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Child TB
patient
Adult TB
patient
centri-
petal
centri-
fugal
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case finding
centripetal
trace the source
adult people
close contact
by chest X ray
centrifugal
trace other
victims
children
close contact
by tuberculin

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Pencegahan
Perbaikan sosio ekonomi
Kemoprofilaksis
Imunisasi BCG
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Kemoprofilaksis primer
Mencegah infeksi
Anak kontak dengan pasien TB aktif, tetapi
belum terinfeksi (uji tuberkulin negatif)
Obat : INH 5 - 10 mg/kg BB/hari
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Kemoprofilaksis sekunder
Mencegah penyakit TB pada anak yang
terinfeksi :
1. Mantoux (+), R (-), klinis (-) :
Umur < 5 th
Kortikosteroid lama
Limfoma, Hodgkin, lekemi
Morbili, pertusis
Akil baliq
2. Konversi Mt (-) menjadi (+) dalam 12 bl, R (-),
klinis (-)
Obat INH 5 - 10 mg/kg BB/hari
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Imunisasi BCG
Imunitas spesifik
Uji tuberkulin menjadi (+)
Mt (-) baru BCG
Masal : langsung BCG tanpa Mt
Reaksi lokal : membantu screening
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Thank you