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

Tuberculosis immunopathogenesis

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

TB, how old?

Why TB is so strong?

3/21/2013

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

Medical problem process

Diagnosis & Treatment
symptomatology pathophysiology pathology pathogenesis adaptive response insults

Tuberculosis
The reaction of the immune system of the human host to the presence and multiplication of Mycobacterium tuberculosis or Mycobacterium bovis

Tuberculosis process
Diagnosis & Treatment
symptomatology pathophysiology granuloma pathogenesis

CMI
M tb

source

Tuberculosis process
Diagnosis & Treatment
symptomatology pathophysiology granuloma pathogenesis

CMI
M tb

source

Etiology
Mycobacterium tuberculosis Mycobacterium bovis Characteristics : 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
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 destruction of PAMS

alveoli

ingestion by PAMS

intracellular replication

destruction of bacilli Hilar lymph nodes

Tubercle formation

Lymphogenic spread

primary focus

lymphangitis
hematogenic spread

lymphadenitis

acute hematogenic spread disseminated primary TB

occult hematogenic spread multiple organs remote foci

primary complex

CMI

TST

Figure. Pathogenesis of primary tuberculosis

M tb bacilli

Multiplication of organisms

Cytokine production:
MIP-1 IL-8 TNF- IL-1, IL-1ra IL-10, IL-12, IL-15 Dendritic cell

Phagocytosis by alveolar macrophage

Lysis/death of alveolar macrophage

Release of bacilli

Migration & chemotaxis of add monocytes

Intracellular killing

Monocytes/ macrophages

Migration to reg lymph nodes Antigen specific response

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

M. tuberculosis inhalation

phagocytosis by PAM

bacilli dead

TB pathogenesis

live bacilli
multiplies

incubation period (2-12 weeks)

primary focus formation lymphogenic spread hematogenic spread1)

TST (+)

Primary complex2)
Cell Mediated Immunity (+)

P r i m a r y T B
3)

TB disease
primary complex complication hematogenic spread complication lymphogenic complication

TB infection
Optimal immunity

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:

o primary complex formation o 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 HS o acute generalized HS o 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

TB infection & TB disease

TB infection: CMI can control infection o primary complex (+) o cell mediated immunity (+), strong o tuberculin sensitivity - DTH (+) o limited amount of TB bacilli, controlled o NO clinical or radiological manifestation

TB disease: CMI cant control TB infection

o TB infection with weak CMI (or strong bacilli) o WITH clinical & radiological manifestation
3/21/2013 22

TB infection

TB

CMI

3/21/2013

TB

CMI

23

TB disease

CMI

TB

3/21/2013

TB

CMI

24

TB classification
TB class Exposure
(contact+)

Infection
(Mantoux+)

Disease
(symptom+)

Explanation Not TB Exposed, Not infected Infected, No disease

+
+

1
2

TB disease

AJRCCM 2000, ATS Diagn standr & classf - modified

Tuberculosis class 1
Diagnosis & Treatment
symptomatology pathophysiology pathology pathogenesis adaptive TST response insults

source +

TB classification
TB class Exposure
(contact+)

Infection
(Mantoux+)

Disease
(symptom+)

Explanation Not TB Exposed, Not infected Infected, No disease

+
+

1
2

TB disease

AJRCCM 2000, ATS Diagn standr & classf - modified

Tuberculosis class 2
symptomatology

pathology

Diagnosis & Treatment

pathophysiology

pathogenesis

adaptive TST response

+
+

source +

insults

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

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 : 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
2.
3.

TB infection!

Anergy?
Incubation period??

TST result
Reading Negative Positive, weak Positive Induration Interpretation NO TB infection 04 Incubation period mm 59 mm 10- 14 mm >15 mm

Anergy Atypical M infection BCG Natural TB infection Technical error Natural TB infection BCG Atypical M infection Natural TB infection, most likely

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, ...

BCG vaccination

BCG vaccination
BCG i.c. injection destruction of PAMS

deltoid

ingestion by macroph

intracellular replication

destruction of bacilli Axilla lymph nodes

Tubercle formation

Lymphogenic spread

primary focus

lymphangitis
hematogenic spread

lymphadenitis

acute hematogenic spread disseminated primary TB

occult hematogenic spread multiple organs remote foci

primary complex

CMI

TST

Figure. Pathogenesis of primary tuberculosis

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

Multiplication of organisms

Cytokine production:
MIP-1 IL-8 TNF- IL-1, IL-1ra IL-10, IL-12, IL-15 Dendritic cell

Phagocytosis by alveolar macrophage

Lysis/death of alveolar macrophage

Release of bacilli

Migration & chemotaxis of add monocytes

Monocytes/ macrophages
Intracellular killing

Migration to reg lymph nodes Antigen specific response

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