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Pediatric Tuberculosis

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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 :

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PAS 1943 Lehmann


Streptomycine 1945 - Waksman & Schats
Isoniazid 1952 Domagk
Rifampicine - 1957
4

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:

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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

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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
Intestine
Skin
Nose
Tonsil
Middle ear (Eustachian tube)
Parotid
Conjunctiva
Undetermined
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%
95.93
1.14
0.14
0.09
0.09
0.09
0.05
0.05
2.41
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droplet nuclei
inhalation

alveoli

ingestion by PAMS

intracellular replication
of bacilli

destruction of PAMS

destruction
of bacilli

Tubercle formation

Lymphogenic spread

Hilar lymph nodes

primary focus

lymphangitis

lymphadenitis

hematogenic spread

acute hematogenic
spread

occult hematogenic
spread

primary
complex

CMI
disseminated primary TB
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multiple organs
remote foci

Figure. Pathogenesis of primary tuberculosis

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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
Strength

PPD S
Seibert

PPD RT23

first

1 TU

1 TU

5-10 TU

2-5 TU

250 TU

100 TU

intermediate
(standard dose)

second
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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)


Manage
ment

Class

Contact

Infection

Disease

proph II?

therapy

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proph I

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TB Natural history overview


primary TB infection

primary TB disease

latent infection

post primary TB
non respir TB

no disease

respiratory TB
new infection

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Pathology

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Pathology

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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

resolution

tubercle formation

caseation

calcification

compresses airway

fibrosis

remote foci

milliary seed

granuloma

tuberculoma
liquefaction

cavity

erodes airway

br pl fistula
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bronchiectasis

2nd lung lesions

rupt to pleura

rupt to airway
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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:

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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

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chronic fever, subfebrile


anorexia
weight loss
malnutrition
malaise
chronic recurrent cough, think asthma!
chronic recurrent diarrhea
others
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Organ specific
Respiratory
Neurology

: cough, wheezing, dyspnea


: convulsion, neck stiffness,
SOL manifestation
Orthopedic
: gibbus, crippled
Lymph node : enlarge, scrofuloderma
Gastrointestinal: chronic diarrhea
Others

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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

Most children
become tuberculin
sensitive

BRONCHIAL EROSION
3-9 months

A minority of children
experience :
1. Febrile illness
2. Erythema Nodosum
3. Phlyctenular Conjunctivitis

PRIMARY COMPLEX
Progressive Healing
Most cases

Uncommon under 5 years of age


25% of cases within 3 months
75% of cases within 6 months

infection

4-8 weeks

3-4 weeks fever of onset

Incidence decreases
As age increased

12 months

Development
Of Complex

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GREATEST RISK OF LOCAL & DISEMINATED LESIONS

Resistance reduced :
1. Early infection
(esp. in first year)
2. Malnutrition
3. Repeated infections :
measles, whooping cough
streptococcal infections
4. Steroid therapy

BONE LESION
Most within
3 years

24 months

DIMINISHING RISK
But still possible
90% in first 2 years

61
Miller FJW. Tuberculosis in children, 1982

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

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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
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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


100

100

Overdiagnosis

80
60

32

40
20
0
Diagnosed by Xray alone
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Actual cases

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Serology
Sensitivity: 19 68%
Specificity: 40 98%

Depends on:
Type of antigen used
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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Diagnosis

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Prognostic factors
A. TB bacilli :
virulence
infection dose

B. Patient :

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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.
2.
3.
4.
5.
6.
7.
8.
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Tuberculin skin test


Chest X ray
Clinical manifestation
Microbiologic
Pathology
Hematological
Known infection source
Others : serologic, lung function,
bronchoscopy
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Clinical setting management


Suspect TB

Mantoux
test

proveTB
infection

positive

negative

Diagnosis TB

completed:
Ro, lab

not TB

treatment
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Seek other
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
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Next page
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Considered TB
Give anti-TB therapy
Observation in 2 months
Clinical response (+)
TB
Continue anti-TB therapy
ATTENTION
Presence of any dangerous signs:
Seizure
Decreased level of consciousness
Neck stiffness
Or signs such as:
Spinal tumor/lump
Limping
Dam board phenomenon
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 Send
to hospital

No clinical response/worsening
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
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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

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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Score

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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

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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


Number of bacilli per ml of sputum

108
107

Sensitive organisms

Resistant organisms

12

106
Smear +
Culture +

105
104
103

Smear Culture +

102
101 Smear -

Culture -

100
0

Start of treatment
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Weeks of treatment

15

18

WHO 78351

88

Toman K, Tuberculosis, WHO, 1979

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)

Pop B = slowly multiplying (acidic)


Pop C = sporadically multiplying

B
C

Months of therapy

Bacteridal activity & sterilizing effect


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Dosage of antituberculosis drug


Drugs

Daily dose
(mg/Kg/day)

2 Time/week
dose
(mg/Kg/dose))

Adverse reactions

Isoniazid
(INH)

5-15
(300 mg))

15-40
(900 mg))

Hepatitis, peripheral neuritis,


hypersensitivity

Rifampicin
(RIF)

10-15
(600 mg))

10-20
(600 mg)

Gastrointestinal upset,skin reaction,


hepatitis, thrombocytopenia,
hepatic enzymes, including orange
discolouraution of secretions

Pyrazinamide
(PZA)

15 - 40
(2 g)

50-70
(4 g)

Hepatotoxicity, hyperuricamia,
arthralgia, gastrointestinal upset

Ethambutol
(EMB)

15-25
(2,5 g)

50
(2,5 g)

Optic neuritis, decreased visual


acuity, decreased red-green colour
discrimination, hypersensitivity,
gastrointestinal upset

Streptomycin
(SM)

15 - 40
(1 g)

25-40
(1,5 g)

Ototoxicity nephrotoxicity

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,
ekstrasel

Massa kiju

Dalam makrofag
(intrasel)

Jumlah populasi

107 - 109

104 - 105

104 - 105

Metabolisme dan
perkembang biak

Aktif

Lambat atau
intermiten

Lambat

Netral/basa

Netral

Asam

INH, RIF,
STREP

RIF, INH

PZA, RIF, INH

pH
Obat paling efektif
(berturut-turut)

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Drug activities upon TB pop


TB
Population

Multiplying
rate

Drug
activities

rapidly

slowly

sporadically

INH>>SM>
RIF>EMB
PZA>>RIF>>
INH
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
M
I
L
E

:
:
:
:
:

Supervised
Medication
In
a Loving
Environment

(Grange
JM, Int J Tuberc Lung Dis 1999; 3:360-100
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362)

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

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IDAI
H : 50 mg
R : 75 mg
Z : 150 mg

102

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


BW
(kg)
<7
8-9
10-14
15-19
20-24
25-29
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Intensive, 2 mo
(tablet)
1
1,5
2
3
4
5

& H/R:30/60)

Continuation, 4 mo
(tablet)
1
1,5
2
3
4
5
103

IDAI FDC (H/R/Z:50/75/150

& H/R:50/75)

BW
(kg)

Intensive, 2 mo
(tablet)

Continuation, 4 mo
(tablet)

5-9

10-19

20-33

Note: BW < 5kg should be referred and need tailored dosing

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104

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

centrifugal

centripetal

Child TB
patient
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case finding

centripetal
trace the source
adult people
close contact
by chest X ray

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centrifugal
trace other
victims
children
close contact
by tuberculin

107

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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111

Thank you
9/20/2010

112