TUBERKULOSIS

Dr. Sukartini Sp.A

Lab.Ilmu Kesehatan Anak
FK. UNMUL

BATASAN
Penyakit akibat infeksi
Mycobacterium tuberculosis.
Sifatnya sistemik sehingga dapat
mengenai hampir semua organ tubuh
dengan lokasi terbanyak di paru yang
biasanya merupakan lokasi infeksi
primer

Pathogenesis
droplet nuclei
inhalation

alveoli

ingestion by PAMS

intracellular replication
of bacilli

destruction
of bacilli

destruction of PAMS
Tubercle formation

Lymphogenic spread

Hilar lymph nodes

primary focus

lymphangitis

lymphadenitis

hematogenic spread
acute hematogenic
spread

occult hematogenic
spread

disseminated primary TB

multiple organs
remote foci

primary
complex

Figure. Pathogenesis of primary tuberculosis

CMI

Pathogenesis
M tuberculosis inoculation

M tb destroyed

phagocytocis by PAM
M tb survive, replicate
primary focus formation
lymphogenic spread
hematogenous spread

tuberculin test
(+)

TB disease

primary
complex
CMI (+)

complication of:
(1)primary complex,
(2)lymphogenic and
(3)hematogenous spread

death

cure
d

incubatio
n period
212weeks

TB
infection
optimal

primar
y TB

immunity
reactivatio
n/
reinfection

TB disease

post
primar
y TB

Clinical types of pediatric TB

Infection (2nd class): TST (+), clinical (-),
radiographic (-)
Disease (3rd class):
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

Clinical manifestation
vary, wide spectrum
factors:
TB bacilli: numbers, virulence
host: age, immune state

clinical manifestation
general manifestation
organ specific manifestation

General manifestation
chronic fever, subfebrile
anorexia
weight loss
malnutrition
malaise
chronic recurrent cough, think
asthma!
chronic recurrent diarrhea
others

Organ specific
Respiratory
Neurology

: cough, wheezing, dyspnea

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

Diagnosis
1.
2.
3.
4.
5.
6.
7.
8.

Clinical manifestation
Tuberculin skin test
Chest X ray
Microbiology
Pathology
Hematology
Known infection source
Others : serologic, lung function,
bronchoscopy

Sistim skoring diagnosis tuberkulosis anak

Parameter

Kontak tb

Tidak jelas

Uji tuberkulin

negatif

2
-

BB/TB<90%
Atau
BB/U<80%

Demam tanpa
sebab jelas

2 minggu

Batuk

3 minggu

Pembesaran
kelenjar

1 cm,jml
>1,tidak nyeri

Pembengkakan
tlg/sendi

Ada
pembengkakan
Normal/tidak
jelas

BTA ( + )

Pos 10mm/
5mm
imunokompr

Berat
badab/keadaan
gizi

Foto rontgen
torak

Lap.keluarga
BTA (-),tidak
tahu

infiltrat+kalsifikas
i,pembsr
KGB,konsolidasi
,atelektasis,tuber
koloma

Klins gizi
buruk,BB/TB<70
%,BB/u<60%

Clinical setting management

Suspect
TB
prove TB
infection
Diagnosis
TB
therapy

Mantoux
tuberculin skin
test
positive

negative

complete
d: Ro, lab

not TB
Seek other
etiologies

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

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

Mantoux
tuberculin
skin test

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

Tuberculin negative

1. No TB infection
2. Anergy
3. Incubation period

Anergy
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, ...

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 infection

TB infection + clinical and/or radiological
manifestation

TB classification (ATS/CDC modified)

Class

Contact

Infection

Disease

Treatment

proph II?

therapy

proph I

Imaging diagnostic
routine
: chest X ray
on indication : bone, joint, abdomen
majority of CXR non suggestive TB
pitfall in TB diagnostic

Radiographic picture
primary complex: lymph node enlargement
milliary
atelectasis
cavity
tuberculoma
pneumonia
air trapping - hyperinflation
pleural effusion
honeycombs bronchiectasis
calcification, fibrosis

Microbiology
culture (Lowenstein Jensen)
confirm the diagnosis
negative result do not rule out TB
positive result : 10 - 62 % (old method)
methods:
old method
radiometric (Bactec)
PCR

Polymerase chain reaction

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.

Ped TB therapy principles

Multi drug, NOT single drug (monotherapy)

to prevent drug resistance

risk of fall and rise phenomenon
each TB drug has specific action to certain TB
bacilli population

Long term, continue, uninterrupted

problem of adherence (compliance)
The drug is taken daily and regularly

Number of bacilli per ml of sputum

108

The fall and rise

phenomenon

107
106
105
104
103

Sensitive organisms

Resistant organisms

12

Smear +
Culture +

Smear Culture +

102
101 Smear -

Culture -

100

Start of treatment
(isoniazid alone)

Weeks of treatment

15

18

WHO 78351

Toman K, Tuberculosis, WHO, 1979

Objectives of TB therapy
Rapid reduction of the bacilli number, to
cure the patient
Sterilization to prevent relapses
to achieve two phases:

Initial phase (2 months) intensive, bacilli eradication

Maintenance phase (4 months / more) sterilizing
effect, prevent relaps

Prevention of acquired drug resistance,

to achieve: principles of therapy

Dosage of antituberculosis
drug
Drugs
Adverse reactions
Isoniazid
(INH)

Daily dose
(mg/Kg/day)

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

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

National consensus of tuberculosis in children, 2001

TB therapy regimen
2 mo

6 mo

9 mo

INH
RIF
PZA
ETB
SM
PRED
DOT.S !

12mo

Medikamentosa
Terapi TB terdiri 2 fase :
Fase intensif : 3-5 OAT selama 2 bl
Fase lanjutan :2 OAT ( INH .RIF)
selama 6-12 bl
Pada anak obat tb diberikan secara
harian baik pd fase intensif maupun
lanjutan

Corticosteroid
Anti inflammation
prednison : oral, 1-2mg/kgBW/day, tid
2-4 weeks, tap off
Indications :
Miliary TB
Meningitis TB
Pleuritis TB with effusion

Therapy problems (2)

The other : monotherapy
the doctor factor:
misuse of TB drug: other indications

the patient factor:

too many drugs (tablets, powders, syrups)
limited fund
drug side effects

Lead to mono-therapy drug resistance

therapy failure

Therapy problems (1)

The main : adherence / compliance
The factors :
Long term treatment
Many drugs (tablets, powders, syrups)
Costly
Drug side effects
Initial improvement misinterpreted by parents
Inconvenient health service
Socio-economic-cultural factors

Lead to interrupted therapy or discontinuation

drug resistance therapy failure

Therapy problems (2)

The other : monotherapy
the doctor factor:
misuse of TB drug: other indications

the patient factor:

too many drugs (tablets, powders, syrups)
limited fund
drug side effects

Lead to mono-therapy drug resistance

therapy failure

Therapy problem solutions

DOTS : Directly Observe Treatment
Short-course
FDC : Fixed Dose Combination i.e.
>2 drugs in one tablet / capsule in a
fixed dose formulation

FDC tablet formulation

WHO
H : 30 mg
R : 60 mg
Z : 150 mg

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

FDC with IDAI formulation

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

& H/R:50/75)

BW
(kg)

Intensive, 2 mo
(tablet)

Continuation, 4 mo
(tablet)

5-9

10-14

15-19
20-33

3
4

3
4

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

Fixed Dose Combination

FDC: >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

Therapy 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 !