Darmawan Budi Setyanto, MD

Born: 11 April 1961

Education: Medical Doctor, Faculty of Medicine, University of Indonesia, 1986 Pediatrician, Faculty of Medicine, University of Indonesia, 1997 Respirology Consultant, 2005

Current position : Head of Respirology Division, Dept of Child Health, Faculty of

Medicine, University of Indonesia

Organization: Chairman of Respirology Coordination Working Unit, Indonesian

Pediatric Society

Darmawan B Setyanto Respirology Division, Department of Child HealthFaculty of Medicine, University of Indonesia

Tuberculosis immunopathoge

nesis

TB, how old?

Why TB is so strong?

04/11/2023 4

TB, strong & robust Nature of the bacilli Very complex & special pathogenesis Very effective & efficient transmission Difficult diagnosis, especially in children Multiple drug Only clinical cure but not bacteriological cure, Drug side effect, no better new drug yet Long term therapy No effective prevention - immunization Sub-standard management MDR, XDR, HIV, … etc Not medical problem only …

symptomatology

pathophysiology

pathology

insults

adaptiveresponse

Medical problem process

Dia

gnosis &

Treatm

ent

pathogenesis

TuberculosisThe reaction of the immune

system of the human host to the presence and multiplication of Mycobacterium tuberculosis or Mycobacterium bovis

symptomatology

pathophysiology

granuloma

M tb

CMI

Tuberculosis process Dia

gnosis &

Treatm

ent

pathogenesis

source

symptomatology

pathophysiology

granuloma

M tb

CMI

Tuberculosis process Dia

gnosis &

Treatm

ent

pathogenesis

source

Etiology Mycobacterium tuberculosis Mycobacterium bovisCharacteristics : live in weeks in dry condition no endotoxins, no exotoxins hematogenic spread grows slowly (24-32 hr) non specific clinical manifestation aerob, organ predilection - lung 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 & lower lobes

Location of primary focus in 2,114 cases, 1909-1928

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

lymphadenitis

lymphangitis

primary focus

TB pathogenesis

TB pathogenesis

Figure. Pathogenesis of primary tuberculosis

droplet nuclei inhalation

alveoli ingestion by PAM’S

intracellular replication destruction

of bacillidestruction

of PAM’S

hematogenic spread

multiple organs remote foci

disseminated primary TB

acute hematogenic spread

occult hematogenic spread

primary focus lymphangitis lymphadenitis

primary complex

TSTCMI

Lymphogenic spreadTubercle formation Hilar lymph nodes

M tb bacilli

Phagocytosisby alveolar

macrophage

Multiplicationof organisms

Cytokineproduction:

MIP-1IL-8

TNF-IL-1, IL-1raIL-10, IL-12,

IL-15

Lysis/deathof alveolar

macrophage

Release ofbacilli

Dendritic cell

Monocytes/macrophages

Antigen specific response

Migration to reg lymph nodesIntracellular killing

Migration &chemotaxis ofadd monocytes

Smith S, Jacobs RF, Wilson CB. J Pediatr; 131: 16-26

M. tuberculosis inhalation

phagocytosis by PAM

live bacilli

multipliesprimary focus formation

lymphogenic spreadhematogenic spread1)

Primary complex2)

Cell Mediated Immunity (+)TST (+)

incubation period(2-12 weeks)

Pri

mary

TB

3)primary complex complication

hematogenic spread complicationlymphogenic complication

TB disease

Dead

TB infection

Cured TB disease4)

immunity reactivation/reinfection

bacilli deadTB pathogenesi

s

Optimal immunity

Incubation period first implantation primary focus 4-6 weeks (2-12 weeks) incubation

period first weeks: logaritmic growth, : 103-

104 elicit cellular response end of incubation period:

o primary complex formationo cell mediated immunity o tuberculin sensitivity PrimaryTB infection has established

Hematogenic spread

during incubation period, before TB infection establishment: o lymphogenic spread o hematogenic spread

hematogenic spread (HS):o occult HSo acute generalized HSo 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

Acute HS less common large number immediate clinical

manifestation: disseminated TB

miliary 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

04/11/2023 22

TB infection & TB diseaseTB infection: CMI can control

infectionoprimary complex (+)o cell mediated immunity (+), strongo tuberculin sensitivity - DTH (+)o limited amount of TB bacilli,

controlledoNO clinical or radiological

manifestation TB disease: CMI can’t control TB

infectionoTB infection with weak CMI (or

strong bacilli)oWITH clinical & radiological

manifestation

04/11/2023 23

TB infection

TB CMI

TB CMI

04/11/2023 24

TB disease

TB

CMI

TB CMI

TB classification

TB class

Exposure

(contact+)

Infection

(Mantoux+)

Disease (sympto

m+)Explanatio

n

0 - - - Not TB

1 + - - Exposed, Not

infected

2 + + - Infected, No disease

3 + + + TB disease AJRCCM 2000, ATS Diagn standr & classf - modified

symptomatology

pathophysiology

pathology

insults

adaptiveresponse

Tuberculosis class 1 Dia

gnosis &

Treatm

ent

pathogenesis

source

TST -

+

TB classification

TB class

Exposure

(contact+)

Infection

(Mantoux+)

Disease (sympto

m+)Explanatio

n

0 - - - Not TB

1 + - - Exposed, Not

infected

2 + + - Infected, No disease

3 + + + TB disease AJRCCM 2000, ATS Diagn standr & classf - modified

symptomatology

pathophysiology

pathology

insults

adaptiveresponse

Tuberculosis class 2 Dia

gnosis &

Treatm

ent

pathogenesis

source +

TST +

-

-

+

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 hypersensitivity2. tuberculin type hypersensitivity3. 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. tuberculi

n

Ag-spec Tcells IFN

macrophages

TNF & IL-1

ICAM-1 & VCAM-1

Leucocytes-receptors

recruit cells monocytes

80-90%

Endothelial cells

induces, activates produces

Mantoux TSTMantoux : intracutan injection 0.1

ml PPDlocation : volar lower armreading time : 48-72 h post injectionmeasurement : palpation, marked,

measurereport : in millimeter, even ‘0 mm’Induration diameter :

0 - 5 mm : negative 5 - 9 mm : positive, weak > 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??

TST resultReading Induratio

n Interpretation

Negative

0 – 4mm

• NO TB infection• Incubation period• Anergy

Positive, weak

5 – 9mm

• Atypical M infection• BCG• Natural TB infection• Technical error

Positive 10- 14mm

• Natural TB infection• BCG• Atypical M infection

>15mm

• Natural TB infection, most likely

AnergyPatient 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, ...

BCG vaccination

BCG vaccination

Figure. Pathogenesis of primary tuberculosis

BCG i.c.injection

deltoid ingestion by macroph

intracellular replication destruction

of bacillidestruction

of PAM’S

hematogenic spread

multiple organs remote foci

disseminated primary TB

acute hematogenic spread

occult hematogenic spread

primary focus lymphangitis lymphadenitis

primary complex

TSTCMI

Lymphogenic spreadTubercle formation Axilla lymph nodes

Thank you

Presented as:

Lecture material FMUI, regular & international

class Respiratory module 4th semester, Medical Sciences Wed, 04 Jul 12, 08-09

M tb bacilli

Phagocytosisby alveolar

macrophage

Multiplicationof organisms

Cytokineproduction:

MIP-1IL-8

TNF-IL-1, IL-1raIL-10, IL-12,

IL-15

Lysis/deathof alveolar

macrophage

Release ofbacilli

Dendritic cell

Monocytes/macrophages

Antigen specific response

Migration to reg lymph nodesIntracellular killing

Migration &chemotaxis ofadd monocytes

Smith S, Jacobs RF, Wilson CB. J Pediatr; 131: 16-26