TB ANAK

Yeni Haryani
 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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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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History
• Ancient Egypt : gibbus,
• 1882, Koch, identification
• management : sanatorium, collapse treatment
• Chemotherapy :
• PAS – 1943 – Lehmann
• Streptomycine – 1945 - Waksman & Schats
• Isoniazid – 1952 – Domagk
• Rifampicine - 1957

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 Magnitude of problem
• TB one of the oldest diseases of human
• remains one of the deadliest diseases in the world
• 9 million of new cases yearly (2013)
• 1.5 million death yearly
• 360.000 of whom were HIV postive
• 20-40% population is infected
• Re-emergence, global emergency

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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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M tuberculosis
Unique 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 (1-5μ)
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:
• doses / numbers
• concentration in the air
• virulence
• exposure duration
• host immune state

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Infection source
• Known source of infection, has
diagnostic value
• Shaw (1954), transmission rate:
• AFB (+) : 62.5 %
• AFB (-), M tb (+) : 26.8 %
• AFB (-), M tb (-) : 17.6 %

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Transmission rate (Shaw ’54)
adult
TB
patient

AFB(-) culture(
AFB(+ -)
culture(
) +) CXR
(+)
65 26 17
% % %
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Pathogenesis
 Location of primary focus
in 2,114 cases, 1909-1928
Location %
Lung 95.93
Intestine 1.14
Skin 0.14
Nose 0.09
Tonsil 0.09
Middle ear (Eustachian tube) 0.09
Parotid0.05
Conjunctiva 0.05
Undetermined 2.41
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Pathogenesis alveoli ingestion by PAM’S

droplet
nuclei intracellular replication
inhalation of bacilli
destruction
destruction of PAM’S of bacilli

Tubercle Hilar lymph

Lymphogenic spread
formation nodes
primary lymphangi lymphade
focus tis nitis

hematogenic spread
primar
y
acute hematogenic occult hematogenic compl
ex
spread spread
C
disseminated primary
TB
multiple organs
remote foci
MI
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Figure. Pathogenesis of primary tuberculosis
 Pathogenesis
M tuberculosis inoculation
M tb destroyed phagocytocis by PAM

M tb survive, replicate incubation

period
primary focus formation
2-12weeks
lymphogenic spread
hematogenous spread

primary complex
tuberculin test (+)
CMI (+)
TB disease TB infection
primary
complication of: TB
(1)primary complex, (2)lymphogenic optimal immunity
and (3)hematogenous spread

post
death cured reactivation
TB disease primary
/ reinfection
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 Incubation period
• first implantation 🡆 primary complex
• 4-6 weeks (2-12 weeks) 🡆 incubation period
• first weeks: logaritmic growth, : 103-104 🡆 elicit
cellular response
• end of incubation period:
• primary complex formation
• cell mediated immunity
• tuberculin sensitivity
⮞⮞ Primary TB infection has established

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 Hematogenous spread

• during incubation period, before TB

infection establishment:
• lymphogenic spread
• hematogenic spread
• hematogenic spread (HS):
• occult HS -> terhadap beberapa organ
tertentu
• acute generalized HS

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 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 (Simon focus)
• CMI (+): silent foci - dormant, potential for
reactivation

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 Pathogenesis ... 24

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Simon focus lymphadenitis

lymphangitis

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

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TB natural history overview 28

primary TB infection

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primary TB disease latent TB infection

post primary TB no disease

non respir TB respiratory TB

new infection
Prognostic factors
A. TB bacilli :
• virulence
• infection dose
B. Patient :
• general condition
• age
• nutritional state
• coinfection: morbili, pertussis
• genetic
• stress; physically (trauma, surgery) or mentally

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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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 Clinical

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Tuberculosis infection Vs Disease
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
• chronic fever, subfebrile
• anorexia
• weight loss
• malnutrition
• malaise
• chronic recurrent cough, think asthma!
• chronic recurrent diarrhea
• others

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Organ specific
• Respiratory: cough, wheezing, dyspnea
• Neurology : convulsion, neck stiffness,
SOL manifestation
• Orthopedic : gibbus, crippled
• Lymph node : enlarge, scrofuloderma
• Gastrointestinal: chronic diarrhea
• Others

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 Tuberculin skin test

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Tuberculin
PPD S
Strength PPD RT23
Seibert
first 1 TU 1 TU
intermediate
5-10 TU 2-5 TU
(standard dose)

second 250 TU 100 TU

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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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Tuberculin negative

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

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 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, ...

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 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

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 Microbiology

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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

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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.

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 Radiology

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

Osborne CM et.al. Arch Dis Child 1995;72:369-74

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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

3/30/2020 Vijayan VK. Indian J Clin Biochem 2002;17(2):96-100. 52

 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
röntgenogram

Delacourt C et.al. Arch Dis Child 1993;69:430-2.

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 Over diagnosis TB by CXR

Over-
diagnosi
s

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 Diagnosis

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Diagnosis TB in Children
 Diagnosis of TB in children
• If you find the diagnosis of TB in children easy, you
probably overdiagnosing TB
• If you find the diagnosis of TB in children difficult,
you are not alone
• It is easy to over-diagnose TB in children
• It is also easy to miss TB in children
• Carefully assess all the evidence, before making the
diagnosis

Anthony Harries & Dermot Maher, 1997

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 Treatment

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 TB treatment outline
• TB therapy
• TB tracking
• TB prophylaxis
• TB prevention – BCG
• Other aspects

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 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

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 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

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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

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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

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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

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Prophylaxis

• exposure (+), infection (-) 🠆 tuberculin negative

• drug: INH 5 - 10 mg/kgBW/day
• as long as contact take place, the source should be
treated
• at least for 3 months
• repeat TST:
• negative: success, stop INH
• positive: fail, become TB treatment

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Prevention

• socio-economic improvement
• BCG immunization
• ‘therapy’

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BCG immunization
• mimicking the TB pathogenesis with attenuated TB
bacilli
• without hematogenic spread and/or without
establishment of remote foci
• CMI (+) 🠆 DTH (+) 🠆 TST (+)
• older neonate (>2 month not vaccinated) 🠆 TST
first
• mass immunization : BCG without TST first
• accelerated BCG reaction: help the screening

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Other aspects

∙ nutrition improvement
∙ prevent / search & treat other
disease(s)

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Terima kasih