PEDIATRIC TUBERCULOSIS

Ridwan M Daulay
Wisman Dalimunthe
Rini Savitri Daulay

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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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 Pathogenesis

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 Droplet nuclei Alveoli Ingestion by PAM’S
inhalation

Intracellular replication
of bacilli
Destruction
Destruction of PAM’S of bacilli

Tubercle formation Lymphogenic spread Hilar lymph nodes

Primary focus Lymphangitis Lymphadenitis

Hematogenic spread
Primary
Acute hematogenic Occult hematogenic
complex
spread spread

Multiple organs
CMI
Disseminated primary TB remote foci
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Figure. Pathogenesis of primary tuberculosis
 Pathogenesis ...
Simon focus Lymphadenitis

Lymphangitis

Primary focus
(Ghon focus)

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 Transmission rate (Shaw ’54)
Adult
TB patient

AFB(-) Culture(-)
AFB(+) Culture(+) CXR (+)

65% 26% 17%

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 Diagnosis

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 Diagnosis
1. Known infection source
2. Clinical manifestation
3. Tuberculin skin test
4. Chest X ray
5. Microbiology
6. Pathology
7. Others : serologic

Critical Analysis
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 Clinical Manifestation

• Vary, wide spectrum

• Factors:
– TB bacilli: numbers, virulence
– Host: age, immune state
• Clinical manifestation
– General/systemic manifestation
– Organ specific manifestation

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 Systemic Manifestation

• Chronic fever, subfebrile

• Anorexia
• Weight loss
• Malnutrition
• Malaise
• Chronic recurrent cough  asthma?
• Chronic recurrent diarrhea

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 Spesific Manifestation

• Respiratory : cough, wheezing, dyspnea

• Neurology : convulsion, neck stiffness,
SOL manifestation
• Orthopedic : gibbus
• Lymph node : enlarge
• Skin : scrofuloderma
• GI tract : chronic diarrhea

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 Tuberculin Skin Test

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 Tuberculin test
TB infection

Cellular immunity

Delayed type hypersensitivity

Tuberculin reaction

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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
test
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 Pengukuran Uji Tuberkulin

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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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 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

• Majority of CXR non suggestive TB
• Pitfall in TB diagnostic

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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

12/26/2018 Vijayan VK. Indian J Clin Biochem 2002;17(2):96-100. 32

 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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 Over diagnosis TB by CXR
100
100
80 Over-
diagnosis
60
40 32

20
0
Diagnosed by X- Actual cases
ray alone
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 Serology
Depends on:
Sensitivity: 19 – 68%
-Type of antigen used
Specificity: 40 – 98% -Type of infection

Disadvantages
Results affected by factors such as
- Age
- History of BCG vaccination
- Exposure to atypical Mycobacteria
- Unable to differentiate between infection and disease
Khan EA and Starke JR. Emerg Infect Dis 1995;1:115-23.

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 Interferon γ
 Detection of interferon- γ (QuantiFERON-TB)
comparable with TST to detect latent TB infection

Advantages
- Less affected by BCG vaccination
- Can discriminates responses due to nontuberculous
mycobacteria
- Avoids variability and subjectivity associated with
placing and reading TST

The utility of QFT in predicting the progression to active

TB has not been evaluated
Mazurek GH et.al. MMWR Dispatch 2002;51.

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 Clinical setting
management
Suspect TB

Prove TB Mantoux tuberculin

infection skin test

Positive Negative

Completed: Not TB
Diagnosis TB
Ro, lab
Seek other
Therapy
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etiologies 37
 Therapy

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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 relapse
• 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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 The ‘fall and rise’ phenomenon
108
Number of bacilli per ml of sputum

107 Sensitive organisms Resistant organisms

106
Smear +
Culture +
105

104
Smear -
Culture +
103

102

101 Smear -
Culture -

100
0 3 6 9 12 15 18 WHO 78351
Start of treatment Weeks of treatment
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Toman K, Tuberculosis, WHO, 1979
 TB therapy regimen
2 mo 6 mo 9 mo 12mo

INH
RIF
PZA

ETB
SM

PRED
DOT.S !

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 Dosage of antituberculosis drug
2 Time/week
Daily dose
Drugs (mg/Kg/day)
dose Adverse reactions
(mg/Kg/dose))
Isoniazid 5-15 15-40 Hepatitis, peripheral neuritis,
(INH) (300 mg)) (900 mg)) hypersensitivity
Gastrointestinal upset,skin reaction,
Rifampicin 10-15 10-20 hepatitis, thrombocytopenia,
(RIF) (600 mg)) (600 mg) hepatic enzymes, including orange
discolouraution of secretions

Pyrazinamide 15 - 40 50-70 Hepatotoxicity, hyperuricamia,

(PZA) (2 g) (4 g) arthralgia, gastrointestinal upset

Optic neuritis, decreased visual

Ethambutol 15-25 50 acuity, decreased red-green colour
(EMB) (1,5 g) (1,5 g) discrimination, hypersensitivity,
gastrointestinal upset

Streptomycin 15 - 40 25-40
Ototoxicity nephrotoxicity
(SM) (1 g) (1,5 g)

When INH and RIF are used concurrently, the daily doses of the drugs are reduced
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National consensus of tuberculosis in children, 2001
 Corticosteroid
• Anti inflammation
• prednisone : oral, 1-2mg/kgBW/day, tid
2-4 weeks, tap off
• Indications :
– Miliary TB
– Meningitis TB
– Pleuritis TB with effusion

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 Treatment problems
• The main : compliance / adherence
• The factors :
– Long duration
– Drug side effect
– Initial improvement – misinterpreted by
patients / parents
– Inconvenient health service
– Socio-economic-cultural factors
• The following : drug resistance

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 Treament problem solution:
FDC

Fixed dose combination: >2 drugs in one

tablet in a fixed dose formulation
• Simple dosing
• Patient friendly, doctor friendly
• Increase adherence
• Reduce MDR
• Easier drug supplying
• Easier drug monitoring
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 DOTS with a SMILE
S : Supervised
M : Medication
I : In
L : a Loving
E : Environment
(Grange JM, Int J Tuberc Lung Dis 1999; 3:360-362)
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 TB drugs & pharmaceutical
formulation

Isoniazid (H) monosubstance

Rifampicin (R)
combi-packs
Pyrazinamide (Z)

Ethambutol (E) fixed dose comb

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 Combipack drugs
two or more separate drugs put in one pack

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 FDC with IDAI formulation

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 WHO FDC (H/R/Z:30/60/150 & H/R:30/60)

BW Intensive, 2 mo Continuation, 4 mo
(kg) (tablet) (tablet)
<7 1 1
8-9 1,5 1,5
10-14 2 2
15-19 3 3
20-24 4 4
25-29 5 5
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 IDAI FDC (H/R/Z:50/75/150 & H/R:50/75)

BW Intensive, 2 mo Continuation, 4 mo
(kg) (tablet) (tablet)
5-9 1 1
10-14 2 2
15-19 3 3
20-33 4 4
Note: BW < 5kg should be referred and need tailored dosing
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 fixed dose combination
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 Therapy evaluation

• Clear improvement in clinical

and supporting examination,
especially in the first 2 month
• Main : clinical
• Supporting exam as adjuvant

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 Therapy evaluation
• Clinical improvement :
– Increased body weight
– Increased appetite
– Diminished / reduced symptoms (fever, cough,
etc)
• Supporting examination :
– Chest X rays : 2 / 6 months (on indication)
– Blood : ESR
– Tuberculin test : once positive, should not be
repeated
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 TB classification (ATS/CDC modified)

Class Contact Infection Disease Treatment

0 - - - -
1 + - - proph I

2 + + - proph II?

3 + + + therapy
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 Primary prophylaxis
• To prevent TB infection in TB Class 1 person
• 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 Class 2 continue as 2nd proph

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 Secondary prophylaxis
• To prevent TB disease in TB Class 2 person
(exposure (+), infection (+), disease (-)
• High risk population
– Under five, puberty
– Long term use of steroid
– Malignancy
– Viral infection: morbili, pertussis
– Conversion of tuberculin test
• Drug: INH 5 - 10 mg/kgBW/day  6-12 month

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 Prevention

• Socio-economic improvement
• BCG immunization
• Chemoprophylaxis (1st & 2nd)
• ‘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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 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

Anthony Harries & Dermot Maher, 1997

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Thank You

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