Pediatric drug-sensitive TB

Update in management

Darmawan BSetyanto
Dept of Child Health
FMUI – CM Hospital Jakarta
Darmawan B 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 2008-2014
 IPS: Member of C Board, IPSBulletin
 IMA, APSR, ERS, EAACImember
 TB: lung OR systemic disease?

SYSTEMIC
LUNG

Is there TB bacilli in TB patient’s blood?

Why TB is sostrong?

11/19/2019 4
TB, strong & robust
 Nature of thebacilli
 Very complex & special pathogenesis
 Very effective & efficienttransmission
 Difficult diagnosis, especially inchildren
 Multiple drug
 Long term therapy
 Drug side effect, no better new drug yet
 Only clinical cure but not bacteriological cure
 Sub-standard management
 MDR, XDR, HIV, … etc
 Not medical problem only
 No effective prevention –immunization
 …
TB pathogenesis

Franchise pioneer?

Only during
TB! incubation period
 TB transmision

TB pathogenesis lymphadenitis

1 2 lymphangitis

1
primary focus
Incubation period

Hematogenic spr 2 CMI TST+

TB pathogenesis

TB

CMI ‘Kopassus TB’ M tuberculosis

 TB infection

TB CMI

11/19/2019
TB CMI 9
TB disease

CMI

TB

11/19/201 9 TB CMI 10
 TB ‘classification’
TB Exposure Infection Disease
(contact+) (Mantoux+) (symptom+)
Explanation
class
0 - - - Not TB

1 + Exposed,
- - Not infected
2 + + Infected,
- No disease
3 + + + TBdisease

AJRCCM 2000, ATS Diagn standr & classf - modified

Why TB is sostrong?

11/19/2019 12
TB, strong & robust
 Nature of thebacilli
 Very complex & specialpathogenesis
 Very effective & efficienttransmission
 Difficult diagnosis, especially in children
 Multiple drug
 Long term therapy
 Drug side effect, no better new drug yet
 Only clinical cure but not bacteriological cure,
 Sub-standard management
 MDR, XDR, HIV, … etc
 Not medical problem only
 No effective prevention –immunization
 …
Adult patient
Pediatric patient

TB!
 Pediatric TB, a dilemma
Especially in diagnosis aspect
 Non specific clinicalmanifestation
 Extrapolation from adult to pediatric patient
 Difficulty in obtaining repres-tive specimen
 Non specific imaging presentation
 Pitfalls: simplification, over-use & over-rely o
n
unreliable diagnostic tool

Diagnosis TB in children
a special challenge
2014
Recommended approach to diagnose TB inchildren
WHO Guidance for NTP on management of TB in children

 Careful history
o includes history of TBcontact
o symptoms suggestive of TB
 Clinical examination
o includes growth assessment
 Tuberculin skin test
 Bacteriological confirmation whenever possible
 Investigations relevant for suspected Pulmonary TB
or suspected Extra-PTB
 HIV testing

2014
 ‘Ideal’ diagnosis
 Gold standard: identification of the bugs,
o microbiology examination: AFB, culture, PCR-
TB, geneXpert
o Problem: specimen
o Solution: sputum induction, near future:
faeces
 Histopathology examination
o Valid
o Specimen problem
o Wasting the available one
2014
 Practical diagnosis
 Clinical manifestation
 Contact history, source of infection, index
case
 Supporting examination: careful choice&
interpretation
Medical problem pathway

ANY FACTOR AFFECTING THE PHYSIOLOGIC

CONDITION (growth, development, process, or
function of the cell, tissue, organ, system,or
individual) – DBS
insults
Medical problem pathway

The ability to survive

by eliminate, terminate,
defend, avoid, or adjust
to any kind of insults
(fight or flight)

adaptive
responses

insults
Medical problem pathway

Diagnosis & Treatment

symptomatology

pathophysiology

pathology
pathogenesis adaptive
responses

insults
Tuberculosis overview

Diagnosis & Treatment

symptomatology

pathophysiology

pathology
pathogenesis
CMI
Gold
source insults standard
 TB???

Cough
o Non-specific, could be due to many etiologies
o Other DD/ should be excluded
o Sugestive: non-remitting cough
Well defined symptom - cough

Arch Dis Child 2005;90:1162–1165

 TB???
Fever
o Non-specific, could be due to many etiologies
o Other DD/ should be excluded
o Sugestive: low grade fever, intermitten or
continue
 TB???
Decrease appetite, BW:
o Non-specific, could be due to many etiologies
o Other DD/ should be excluded: nurture,
psychologic, inadequate intake, stunting,
hormonal
o Sugestive: no improvement after nutrition
intervention
 TB???
Malaise
o Non-specific, could be due to many etiologies
o Subjective impression
o Suggestive: clear changes from previous
condition
 TB???
Lumps in the neck
o Non-specific, could be due to many etiologies
o Other DD/ should be excluded, most likely non-
specific inflammation
o Sugestive: diameter >2cm, multiple, non-tender,
confluence
 TB diagnosis in children

Diagnosis & Treatment

Cough … etc

pathophysiology

pathology
p a t
h o g ene si s
IM AG I N G , in d irectlyCMI
• very subjective
• non-specific
• shousldoubrecevery2careful M tb
 TB diagnosis in children
TUBERCoCuUgLhI…Nsektcintest

Diagnosis & Treatment

• sensitive? YES!
• specific? YES!
• infection VSpadthisoepahseys?i?o?logy
pathology
pathogenesis
CMI

source M tb
Diagnostic tools for TB infection
NEW

OLD
IGRA
TST-- IGRAcomparison

Tuberculin
Skin test

IGRA
test

35
QuantiFERON-TB Gold In-tube (ELISA)
Nil Mitog
Antige
Contr en
ns
ol Contr
ol

Culture overnight.
Obtain blood
TB-infected person
secrete IFN-

COLO
R Standard
TM Curve

OD
B

IFN- IU/m l

Harvest supernatants Wash, add substrate, Measure OD and

and perform ELISA incubate 30 min determine IFN- levels
  T cells of an individualwho
carries an TB infection will
respond to TB antigens &
secrete IFN-.
 The secretion of IFN- is
captured by the anti-IFN-
antibodies coated to the floor
of eachwell.
 The numbers reacting T cells
are visualizing the footprintof
each T-cell in the spot form.

Principles of the
T-SPOTAssay
TB diagnosis in children
Cough … etc

Diagnosis & Treatment

pathophysiology
Strong diagpnaotshtoilcogy
• rarely identified
pathogenesis• must be explored
maximCalMlyI

source M tb
 IDAI Ped TB scoring system
symptom
Feature 0 1 2 3 Scor
e
Contact not clear - reported, AFB+
AFB(-) pat hophy
s
TST - - - positive
BW (KMS) - <red line, BW severe -
malnutritio pa hology
n t
Fever - unexplained - -
Cough <3weeks >3weeks - - ad aptive
Node - >1node, >1cm, - - re sponse
enlargemn painless
t
Bone,joint - swelling - -
 Notes for IDAI scoring system
 Diagnosis by doctor
 BW assessement at present
 Fever & cough no respons to standard tx
 CXRis NOT a main diagnostic tool in children
 All accelerated BCGreaction should be evaluated
with scoring system
 TB diagnosis total score >6
 Score 4 in under5 child or strong suspicion, refer
to hospital
 INH prophylaxis for AFB(+) contact with score <5

11/19/2019 40
Practical practice

2016

IPS scoring system

integrated with
bacteriological
examination using
molecular rapid test
Definition & classification
 Pediatric TB, suspected: symptomatology
 Pediatric TB:
o Bacteriological confirmation
o Clinical

 Classification:
o Location: Pulmonary & Extrapulmonary
o Treatment: New, Treated, Unclear
o Drugs: Sensitive & Resistant
o HIV state
Extrapulmonary TB
 Meningitis TB:
o severe, life threatening.
o convulsion, decrease consciousness
o LCS: very important, cell 10-500/mm3,glucose ,
protein , bacteriological –GeneXpert
o CT-scan or MRI - sign of intracranial pressure
Extrapulmonary TB
 Bone & JointTB
o Spondylitis, Coxitis, Gonitis
o Swollen (gibbus), stiffness, pain, functiolesa
o Plain X-ray, CT-scan,MRI
o Histopathology – surgery specimen
Extrapulmonary TB
 Lymphadenitis TB:
o Superficial lymph node (scrofula)
o Most frequent, colli
o Size: >2cm, seen not only palpable; fixed, multiple
o Definitive: biopsy – PA &/ bacteriological
Extrapulmonary TB
 TB pleural effusion
o Accumulation of liquid in pleural space
o Serous (mostly) & empyema
o Acute fever, non-productivecough, chest pain
o Unilateral (95%)
o Drainage, if massive
Why TB is sostrong?

11/19/2019 50
TB, strong & robust
 Nature of thebacilli
 Very complex & specialpathogenesis
 Very effective & efficienttransmission
 Difficult diagnosis, especially inchildren
 Multiple drug
 Long term therapy
 Drug side effect, no better new drug yet
 Only clinical cure but not bacteriological cure,
 Sub-standard management
 MDR, XDR, HIV, … etc
 Not medical problem only
 No effective prevention –immunization
 …
Ped TB therapy principles
 Multi
drug, should NOT singledrug
(monotherapy)
 each TB drug has specific action to certain
TB bacilli population
 to prevent drug resistance through the
fall and rise phenomenon
 Long term, continue, uninterrupted
problem of adherence (compliance)
 The drugis taken daily and regularly
11/19/2019 52
 Hypothetical model of TB therapy
Pop A = rapidly multiplying (caseum)
A Pop B= slowly multiplying (acidic)
Pop C= sporadically multiplying
B
C
Pop D = dormant, not multiplying

D
0 1 2 3 4 5 6
Months of therapy

Bacteridal activity & ‘sterilizing’ effect

11/19/2019 53
TB bacilli population & drug activities
INH
Pop A
Metabolism activities

Active, rapid RIF

replication
Pop B
Less active, slow
replication
PZA
Pop C
Not active, sporadic
replication
Pop D
Dormant, no
replication
 Ped TB therapy regimen

2 mo 6 mo 9 mo 12mo

INH
RMP
PZA

ETB
SM

PREDNISON
DOTS !

11/19/2019 55
2014
Regiment of Anti-TB drugs
Diagnosis Intensive phase Continuing
phase
Clinical TB
Lymphadenopathy TB 2 HRZ 4 HR
TB pleural effusion
Confirmed TB
Pulmonary TB, severe 2 HRZE 4 HR
Extrapulmonary TB
TB of bone & joint
Miliary TB 2 HRZE 10HR
Meningitis TB
Kemkes RI 2016, Juknis manajemen TB anak
Treatment problems
 The main : adherence / compliance
 Lead to interrupted therapy or treatment
discontinuation drug resistance failure

 The other : monotherapy

 Lead to monotherapy fall & rise phenomenon
drug resistance treatment failure

11/19/2019 58
Drug resistance TB
 Drug resistance TB, especially Multi-drug
resistance (MDR) will be very difficult to
manage:
 For the patient, the family, health care provider,
and government
 Need numerous second line drugs (8 drugs or
more)
 Very high cost (ten– hundreds fold)
 More adverse reaction, lessadherence
 Less successfully result
 >2 drugs in one tablet / capsule
in a fixed doseformulation

fixed dose combination

11/19/2019 60
 FDC advantage
medical
FDCsingle perspective
program drug posology
perspective

simple
prevent
simple drug treatment
monotherapy
logistic
patient doctor
friendly friendly
easier drug easier drug
supply monitoring
adherence prevent
misprescr

MDR
NTP
success complete
11/19/2019 treatment 61
IDAI FDC (H50R75Z150 & H50R75) OLD
Body Intensiv Continuati
weigh e 2 on 4 month
t month (tablet)
(kg) (tablet)
5-9 1 1
10-14 2 2
15-19 3 3
20-30 4 4
Note: BW < 5kg should be referred and need tailored dosing
11/19/2019 62
 Ped FDC based on BW NEW
Ped BW Bodyweight
FDC (kg) (kg)
1tab 05 - 07 05, 06, 07 (3 BW)

2 tab 08 - 11 08, 09, 10, 11 (4 BW)

3 tab 12 - 16 12, 13, 14, 15, 16 (5 BW)

4 tab 17 - 22 17, 18, 19, 20, 21, 22 (6 BW)

5 tab 23 - 30 23, 24, 25, 26, 27, 28, 29, 30

BW <5kg should be referred & need tailored dosing
11/19/2019 BW >30kg 6 ped FDC tablet, or use adult FDC tablet 63
 Ped FDC based on BW NEW
Ped BW Body weight
FDC (kg) (kg)
1tab 05 - 07 05, 06, 07 (3 BW)

2 tab 08 - 11 08, 09, 10, 11 (4 BW)

3 tab 12 - 16 12, 13, 14, 15, 16 (5 BW)

4 tab 17 - 22 17, 18, 19, 20, 21, 22 (6 BW)

5 tab 23 - 30 23, 24, 25, 26, 27, 28, 29, 30

BW <5kg should be referred & need tailored dosing
11/19/2019 BW >30kg 6 ped FDC tablet, or use adult FDC tablet 64
FDC with IDAI formulation

11/19/2019 65
 Summary

• Very special, franchise pioneer

• TB bacilli in TB patient’s blood?
Pathogenesis

• Primary focus – primary

complex: incubation period
• Hematogenic spread
• End of period: CMI  Kopassus
TB; TST (+)
• CMI > TB: TB infection
• CMI < TB: TB disease
 Summary
• Diagnosis of pediatric TB is very3
difficult under & over3-diagnosis
• Should be very careful in assessing
Diagnosis

clinical & supporting data

• IDAI pediatric TB scoring system is
meant to reduce the problem
• TST or IGRA has a pivotal role in
diagnosis of pediatric TB
• Bacteriological confirmation
should be tried to bedone
 Summary

• Treatment of pediatric TB is less

complicated compared to adult TB
• Principles: multidrugs – long term –
Treatme

regular
• Problems: monotherapy & adherence
drug resistance
• Solution: fixed drug combinationTB
drug
nt

• IDAI FDC formulation: doctor & patient

friendly
Thank you