Pediatric Department Faculty of Medicine

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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(-) culture(-)
AFB(+) 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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 droplet nuclei
alveoli ingestion by PAM’S
inhalation

intracellular replication
of bacilli
destruction
destruction of PAM’S 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
10/18/2019 Figure. Pathogenesis of primary tuberculosis 20
 Incubation period
 first implantation  primary complex
 4-6 weeks (2-12 weeks)  incubation period
3 4
 first weeks: logaritmic growth, : 10 -10  elicit
cellular response
 end of incubation period:
 primary complex formation
 cell mediated immunity
 tuberculin sensitivity
 PrimaryTB infection has established

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 Pathogenesis ...
lymphadenitis

lymphangitis

primary focus

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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
PPD S
Strength PPD RT23
Seibert
first 1 TU 1 TU
intermediate
5-10 TU 2-5 TU
(standard dose)

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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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)
Manage
Class Contact Infection Disease
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

post primary TB no disease

non respir TB respiratory 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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 Pathology
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

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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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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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 Radiographic picture
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

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 Radiographic picture
 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.

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 Radiographic picture
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
röntgenogram

Delacourt C et.al. Arch Dis Child 1993;69:430-2.

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 Over diagnosis TB by CXR
100
100
80 Over-
diagnosis
60
40 32

20
0
Diagnosed by X- Actual cases
ray alone

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 Serology
Depends on:
Sensitivity: 19 – 68%
Type of antigen used
Specificity: 40 – 98% Type of infection

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.

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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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 Interferon γ
 Detection of interferon- γ (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.

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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
Mantoux
Suspect TB test
proveTB
infection positive negative

completed: not TB
Diagnosis TB Ro, lab
Seek other
treatment etiologies
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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 Not TB MDR TB

Continue anti-TB therapy Refer to hospital

ATTENTION
Presence of any dangerous signs: Reevaluation in Referral Hospital:
• Seizure Clinical signs
• Decreased level of consciousness Tuberculin test
• Neck stiffness Radiological findings
Or signs such as: Microbiology and serology examination
• Spinal tumor/lump Histopatology examination
• Limping Diagnostic procedure and therapy according
• Dam board phenomenon to each hospital’s protocol
 Send to hospital
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UKK Pulmonologi –IDAI. Jakarta;2002.
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, severe -
BW malnutrition
Fever - unexplained - -
Cough <3weeks >3weeks - -
Node - >1 node, - -
enlargemnt >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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 The ‘fall and rise’ phenomenon
108
Number of bacilli per ml of sputum

107 Sensitive organisms Resistant organisms

106
Smear +
Culture +
105

104
Smear -
Culture +
103

102

101 Smear -
Culture -

100
0 3 6 9 12 15 18 WHO 78351
Start of treatment Weeks of treatment
10/18/2019 (isoniazid alone) Toman K, Tuberculosis, WHO,751979
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

Pop A = rapidly multiplying (caseum)

A Pop B = slowly multiplying (acidic)
Pop C = sporadically multiplying
B
C

0 1 2 3 4 5 6
Months of therapy

Bacteridal activity & ‘sterilizing’ effect

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 Dosage of antituberculosis drug
2 Time/week
Daily dose
Drugs (mg/Kg/day)
dose Adverse reactions
(mg/Kg/dose))
Isoniazid 5-15 15-40 Hepatitis, peripheral neuritis,
(INH) (300 mg)) (900 mg)) hypersensitivity
Gastrointestinal upset,skin reaction,
Rifampicin 10-15 10-20 hepatitis, thrombocytopenia,
(RIF) (600 mg)) (600 mg) hepatic enzymes, including orange
discolouraution of secretions

Pyrazinamide 15 - 40 50-70 Hepatotoxicity, hyperuricamia,

(PZA) (2 g) (4 g) arthralgia, gastrointestinal upset

Optic neuritis, decreased visual

Ethambutol 15-25 50 acuity, decreased red-green colour
(EMB) (2,5 g) (2,5 g) discrimination, hypersensitivity,
gastrointestinal upset

Streptomycin 15 - 40 25-40
Ototoxicity nephrotoxicity
(SM) (1 g) (1,5 g)

When INH and RIF are used concurrently, the daily doses of the drugs are reduced

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National consensus of tuberculosis in children, 2001
78
 Populasi basil TB pada pasien
Kavitas, Dalam makrofag
Massa kiju
ekstrasel (intrasel)

Jumlah populasi 107 - 109 104 - 105 104 - 105

Metabolisme dan Lambat atau
Aktif Lambat
perkembang biak intermiten
pH Netral/basa Netral Asam
Obat paling efektif INH, RIF,
RIF, INH PZA, RIF, INH
(berturut-turut) STREP

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Drug activities upon TB pop
TB Multiplying Drug
Population rate 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 IDAI
 H : 30 mg  H : 50 mg
 R : 60 mg  R : 75 mg
 Z : 150 mg  Z : 150 mg

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WHO FDC (H/R/Z:30/60/150 & H/R:30/60)

BW Intensive, 2 mo Continuation, 4 mo
(kg) (tablet) (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 Intensive, 2 mo Continuation, 4 mo
(kg) (tablet) (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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 Trace
Adult TB
patient centri-
fugal

centri-
petal

Child TB
patient

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case finding
centripetal centrifugal
 trace the source  trace other ‘victims’
 adult people  children
 close contact  close contact
 by chest X ray  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 (+), Rö (-), klinis (-) :
 Umur < 5 th
 Kortikosteroid lama
 Limfoma, Hodgkin, lekemi
 Morbili, pertusis
 Akil baliq
2. Konversi Mt (-) menjadi (+) dalam 12 bl, Rö (-),
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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