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Tuberculosis

pathogenesis & diagnosis


Darmawan B Setyanto

Respirology Division, Department of Child Health


Faculty of Medicine, University of Indonesia

Tuberculosis
The reaction of the tissues of the
human host to the presence and
multiplication of Mycobacterium
tuberculosis or Mycobacterium

bovis

Pediatric TB main problems


Diagnosis
Clinical manifestations & imaging: not specific
both over/under diagnosis & over/under

treatment

diagnostic specimen : difficult to obtain


TB infection or TB disease ? no diagnostic tool
to distinguish

Treatment
Adherence / compliance
Drug discontinuation treatment failure
Multi drug resistance (MDR)
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symptomatology
pathophysiology
pathology
pathogenesis

immunology

etiology

simtomatologi
patofisiologi
patologi
patogenesis

imunologi

etiologi

Penunjang
diagnosis

simtomatologi
patofisiologi

patologi
patogenesis

imunologi

etiologi

Penunjang
diagnosis

simtomatologi
patofisiologi

patologi
patogenesis

imunologi

etiologi

Baku emas
diagnosis

simtomatologi
patofisiologi

patologi
patogenesis

imunologi

etiologi

Etiology
Mycobacterium tuberculosis
Mycobacterium bovis
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

Transmission
adult patient, active lung TB
cough, sneeze, speak, sing
droplet nuclei: 1-5
airborne for long periodes
inhalation, reach alveoli
middle and lower lobes

Location of primary focus


in 2,114 cases, 1909-1928
Location

Lung
Intestine
Skin
Nose
Tonsil
Middle ear (Eustachian tube)
Parotid
Conjunctiva
Undetermined

95.93
1.14
0.14
0.09
0.09
0.09
0.05
0.05
2.41

TB pathogenesis
lymphadenitis

lymphangitis

primary focus

TB pathogenesis
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

disseminated primary TB

occult hematogenic
spread
multiple organs
remote foci

primary
complex

CMI

Figure. Pathogenesis of primary tuberculosis

TST

M. tuberculosis inhalation
phagocytosis by PAM

TB pathogenesis

live bacilli
multiplies

bacilli dead

incubation period
(2-12 weeks)

primary focus formation


lymphogenic spread
hematogenic spread1)
Primary complex2)

TST (+)

Cell mediated immunity (+)

P
r
i
m
a
r
y

TB disease

TB infection

primary complex complication


hematogenic spread complication
lymphogenic complication

T
B

Optimal immunity

3)

Dead
immunity
reactivation/reinfection

Cured

TB disease4)

Incubation period
first implantation primary focus
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

Hematogenous spread
during incubation period, before TB
infection establishment:
lymphogenic spread
hematogenic spread
hematogenic spread (HS):
occult HS
acute generalized HS
protracted HS

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

Acute HS
less common
large number
immediate clinical manifestation:
disseminated TB
milliary TB, meningitis TB
tubercle in same size, special
appearance in CXR

Primary complex
end of incubation period
TB infection establishment
cell mediated immunity (CMI)
tuberculin sensitivity (DTH)
end of hematogenic spread
end of TB bacilli proliferation
small amount, live dormant in granuloma
new exogenous TB bacilli: destroyed / localized

TB infection & TB disease


TB infection: CMI can control infection
primary complex
cell mediated immunity (CMI)
tuberculin hypersensitivity (DTH)
no clinical or radiological manifestation
TB disease: CMI failed to control TB infection
TB infection + clinical and/or radiological
manifestation

TB infection

TB

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CMI

24

TB disease

CMI

TB
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25

Tuberculin skin test

Hypersensitivity type IV
delayed type hypersensitivity (DTH)
cannot transferred by serum, can be by T-cells
cellular mediated
reflects the presence of Ag-specific CD4 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
monocytes 80-90%

endothelial cells
ICAM-1 & VCAM-1

induces, activates

produces

Tuberculin negative

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

Mantoux TST
Mantoux : intracutan injection 0.1 ml PPD
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

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, ...

Diagnosis

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Diagnostic tools
gold standard
capture the trouble maker
microbiologic examination

adult TB

pediatric TB

sputum

scarce specimen

LJ - TB culture
direct - AFB
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NTP: D/ & evaluation

Mantoux
TST
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The main problems


Diagnosis especially in children
Diagnosis Pitfall :
Extrapolation of adult clinical manifestations:
cough as a main TB symptom
Over use of non reliable diagnostic tools
Treatment especially in adult

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Pediatric TB diagnosis PITFALLS


clinical: COUGH !
extrapolation of adult clinical manifestations: cough
as a main TB symptom
cough is NOT a main pediatric TB symptom

supporting examination: RONTGEN !


Need a systematic and critical analysis of all
the clinical and supporting data
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Over diagnosis TB by CXR


100

100

Overdiagnosis

80
60
40

32

20
0
Diagnosed by Xray alone
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Actual cases
40

Diagnostic tools

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

41

Suspect TB clinical manifestation

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Body weight problem


Appetite problem
Recurrent ARI
Multi L

42

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
43

TB classification (ATS/CDC modified)


Class

Exposure Infection Disease

Manage
ment

proph I

proph II?

therapy

Resume diagnosis
Aspek
Simtomatologi
Patologi Anatomik
Patologi pencitraan
Imunologi tuberkulin
Etiologi mikrobiologi

Spesifik

--+++
-++
++++

Sensitif Kemudahan

++
++
+
++
++

+
-+
+
---

Sistem skoring TB anak IDAI


Parameter

Pajanan

Tidak
jelas

dilaporkan,
BTA(-)

BTA(+)

Mantoux

positif

BB(KMS)

BGM
BB

Malnutrisi
berat

Demam

Tidak jelas
sebabnya

Batuk

<3weeks

>3 mgg

P> KGB

>1 KGB,
>1cm,
tdk nyeri

Tulang sendi

Bengkak

Rontgen

Normal

Sugestif

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Skor

Catatan untuk sistem skoring TB


Diagnosis oleh dokter
BB dinilai saat datang
Demam & batuk tidak respons thd terapi baku
Rontgen BUKAN alat diagnostik utama
Semua reaksi cepat BCG harus dievaluasi dengan
sistem skoring
Didiagnosis TB bila skor total >6
Skor 5 pada balita dengan kecurigaan kuat rujuk
ke RS
Profilaksis INH untuk kontak dengan BTA(+) skor
<6
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47

Thank you

Presented
Lecture material
FMUI student
CAH module
26 Aug 2009

BCG vaccination

BCG vaccination
BCG
injection

deltoid

ingestion by Mcrp

intracellular replication
of bacilli

destruction of PAMS
tubercle formation

lymphogenic spread

primary focus

lymphangitis

destruction
of bacilli

axilla lymph nodes


lymphadenitis

hematogenic spread
acute hematogenic
spread

occult hematogenic
spread

disseminated primary TB

multiple organs
remote foci

primary
complex

CMI

Figure. Pathogenesis of primary tuberculosis

TST

Primary & post primary TB


Primary TB :
first infection
usually in children
hematogenic spread
primary complex
tuberculin sensitivity (DTH) & CMI
infection only (class 2) or disease (class 3)
Post primary TB:

Primary & post primary TB


Primary TB :
Post primary TB:
usually in adults
no hematogenic spread
primary complex & CMI already exist
two models:
1. reinfection (new, secondary, exogenous)
2. reactivation of remote foci
(endogenous), as results of occult HS

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