Respirology Division

Pediatric Department Faculty of Medicine

USU/Adam Malik Hospital
06/05/17 1
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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 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 ...
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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 adult
TB patient

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

65% 26% 17%

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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 PAMS
inhalation

intracellular replication
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
06/05/17 Figure. Pathogenesis of primary tuberculosis 20
 Incubation period
first implantation primary complex
4-6 weeks (2-12 weeks) incubation period
first weeks: logaritmic growth, : 103-104
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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DivisiRespirologi
DIKA FK USU
What is tuberculin?

a complex mixture of culture filtrate

components obtained from sterilized
cultures of tubercle bacilli.
two types of tuberculin:
Old Tuberculin (OT)
Purified Protein Derivative (PPD)
Route
Patch test
multiple puncture devices (Tine, Heaf)
intradermal injection (Mantoux test)
 The Immune Mechanisms
Responsible for Skin Reactions
to Tuberculin
infected with mycobacteria T-cells primarily
in the regional lymph nodes proliferate.
Several weeks lymphocytes circulate in the
bloodstream the injection of tuberculin into
the skin stimulates the sensitized
lymphocytes local reaction.
 The Immune Mechanisms
Responsible for Skin Reactions to
Tuberculin
delayed-type hypersensitivity (DTH)
reaction usually begins at six to eight
hours after administration of the antigen
maximal at 48-72 hours usually wanes
after several days.
sensitized lymphocytes release
cytokines and chemokines initiation of
the immune response of tuberculin.
The Immune Mechanisms
Responsible for Skin Reactions to
Tuberculin
Dermal reactivity involves :
Vasodilation
Edema
cellular infiltration of lymphocytes, basophils,
monocytes and neutrophils.
A small proportion of the cells at the site of
dermal reactivity sensitized to
mycobacterial antigens
most of the cellular recruitment occurs in
response to the lymphokine release by the
sensitized T-cells.
Tuberculin test
TB infection

cellular immunity

delayed type
hhypersensitivity

tuberculin reaction
 Hypersensitivity type
IV type hypersensitivity (DTH)
delayed
cannot be transferred by serum, but by
T-cells cell mediated
reflects the presence of Ag-specific CD 4
T-cells
associated with protective immunity,
but not a complete correlation
three variants of DTH:
1. contact hypersensitivity
2. tuberculin type hypersensitivity
3. granulomas
 Tuberculin
hypersensitivity
originally described by Koch Koch
phenomenon
TB patients tuberculin filtrate fever &
generalized sickness
at the injection site, developed area of
swelling & hardening
TST is an example of the recall response
to soluble antigen previously
encountered during infection
 Tuberculin skin test
(TST)
i.c. tuberculin Ag-spec Tcells IFN

macrophages

Leucocytes-receptors
TNF & IL-1

recruit cells endothelial cells

monocytes 80-90%

ICAM-1 & VCAM-1

induces, activates produces

Uji tuberkulin

Cellular and molecular immunology, updated edition. Edisi ke-5. Philadelphia: Elsevier-Saunders; 2005. h. 298-311.
Immunology. Edisi ke-6. London: Mosby-Wolfe; 2001. h. 371-83.
 Tuberculin route of
delivery
1. Mantoux: intradermal injection
2. Multiple puncture:
heaf, special apparatus with 6
needles
tine, disposable, 4 needles

3. Patch test
Mantoux injection
Needle too deep
Tuberculin injection
Needle too shallow
Tuberculin injection
Inserted properly
Tuberculin injection
 TST
Measurement
Positive reaction
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

Tine test
 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: doubtful positive
> 10 mm: positive
Tuberculin positive
1. TB infection:
infection without disease/latent TB infection
infection AND disease
disease, post therapy/clinical cure

2. BCG immunization
3. Infection of Mycobacterium other than
tuberculosis (MOTT)
Tuberculin negative
1. No TB infection
2. Anergy
3. Incubation period
Anergy
Patient with primary complex do not give
reaction to TST due to the supression of CMI:
severe TB: miliary TB, TB meningitis
severe malnutrition
steroid, long term use
certain viralinfection: morbili, varicella
severe bacterial infection: typhus abdominalis,
diphteria, pertussis
viral vaccination: morbili, polio
malignancy: Hodgkin, leukemia, ...
 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
infectionTB infection + clinical
and/orradiological manifestation
 Contac Infectio Diseas Treatmen
Class
t n e t

0 - - - -
1 + - - proph I
proph
2 + + - II?
3 + + + therapy
 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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 Manage
Class Contact Infection Disease
ment

0 - - - -
1 + - - proph I

2 + + - proph II?

3 + + + therapy

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 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
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 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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Microbiologic
Culture (Lowenstein Jensen)
Confirmed the diagnostic
Negative result do not rule out TB
Positif result: 10 - 62 % (old method)
Method :
Old method
Radiometric (bactec)
PCR

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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 rntgenogram

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

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 Over diagnosis TB by CXR

Over-
diagnosis

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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
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.

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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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 Mantoux
Suspect test
TB
proveTB
infection positive negative

complete not TB
Diagnosis d: Ro, lab
TB
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 consciousnessTuberculin test
Neck stiffness Radiological findings
Or signs such as: Microbiology and serology
Spinal tumor/lump examination
Limping Histopatology examination
Dam board phenomenon Diagnostic procedure and therapy
Send to hospital according to each hospitals protocol
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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

06/05/17 95
 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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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
108 phenomenon
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
06/05/17 (isoniazid alone) 1021979
Toman K, Tuberculosis, WHO,
Treatment principles
Long duration problem of
adherence (compliance)
Other aspects :
Nutrition improvement
prevent / search & treat
other disease

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 Pop A = rapidly multiplying
A (caseum)
Pop B = slowly multiplying
B (acidic)

C Pop C = sporadically multiplying

0 1 2 3 4 5 6
Months of therapy

Bacteridal activity & sterilizing effec

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 Dosage of
antituberculosis
Drugs
drug
Daily dose
2 Time/week
Adverse reactions dose
(mg/Kg/day)
(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
 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
Populatio rate activities
n
rapidly INH>>SM>
A RIF>EMB
slowly PZA>>RIF>>
B INH
sporadicall RIF>>INH
C y
06/05/17 107
 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 Continuation, 4 mo
(kg) mo (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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 Adult TB
patient centri-
fugal

centri-
petal

Child TB
patient

06/05/17 120
case finding
centripetal centrifugal
trace the source trace other
adult people victims
close contact children
by chest X ray close contact
by tuberculin

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Pencegahan
Perbaikan sosio ekonomi
Kemoprofilaksis
Imunisasi BCG

06/05/17 122
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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