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Kultur Dokumente
9/20/2010
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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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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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
15
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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AFB(+)
AFB(-)
culture(+)
culture(-)
CXR (+)
65%
26%
17%
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Pathogenesis
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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
19
droplet nuclei
inhalation
alveoli
ingestion by PAMS
intracellular replication
of bacilli
destruction of PAMS
destruction
of bacilli
Tubercle formation
Lymphogenic spread
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
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
21
Pathogenesis ...
lymphadenitis
lymphangitis
primary focus
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Hematogenous spread
during incubation period, before TB
infection establishment:
lymphogenic spread
hematogenic spread
23
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
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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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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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primary complex
tuberculin sensitivity (DTH)
cell mediated immunity
no clinical or radiological manifestation
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Class
Contact
Infection
Disease
proph II?
therapy
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proph I
43
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
46
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
rupt to pleura
rupt to airway
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Clinical
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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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Organ specific
Respiratory
Neurology
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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
infection
4-8 weeks
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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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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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 (+)
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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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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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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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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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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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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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Algorithm
IDAI, 1998, 2002
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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
80
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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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
82
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,
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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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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
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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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B
C
Months of therapy
90
Daily dose
(mg/Kg/day)
2 Time/week
dose
(mg/Kg/dose))
Adverse reactions
Isoniazid
(INH)
5-15
(300 mg))
15-40
(900 mg))
Rifampicin
(RIF)
10-15
(600 mg))
10-20
(600 mg)
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)
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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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
pH
Obat paling efektif
(berturut-turut)
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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
99
:
:
:
:
:
Supervised
Medication
In
a Loving
Environment
(Grange
JM, Int J Tuberc Lung Dis 1999; 3:360-100
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IDAI
H : 50 mg
R : 75 mg
Z : 150 mg
102
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
& H/R:50/75)
BW
(kg)
Intensive, 2 mo
(tablet)
Continuation, 4 mo
(tablet)
5-9
10-19
20-33
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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
110
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
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