TUBERCULOSIS

Approach in Children

Dr Zulfiqar Ali
PG FCPS Paediatrics
EMW
TUBERCULOSIS

 Tuberculosis is an infectious, systemic, chronic granulomatous

disease caused by a bacterium called Mycobacterium
Tuberculosis (tubercle bacilli).
 Acid-fast,
 gram-positive,
 aerobic, non-motile,
 rod-shaped organism
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 Incubation period : 1st 6 months to years.

 Delayed type hypersensitivity reaction ( skin test conversion) is

02-12 weeks duration
IDENTIFYING PRESUMPTIVE TB
IN CHILDREN
 Every child less than 14 years should be assessed for
presumptive TB if he/she presents with:

 “Prolonged or Unexplained illness of more than 2 weeks”

WITH ONE OR MORE OF THE FOLLOWING

 Cough more than 2 weeks (or uncertain duration)

 Fever (usually low grade at evening), or

 Enlarged cervical lymph nodes, or

 Failure to thrive

 Known contact of pulmonary TB patient (Bacteriologically positive)

 HIV infected child

Meningitis
DIAGNOSIS

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 DIAGNOSTIC TOOLS FOR TUBERCULOSIS

 Careful history

 Clinical examination

 Investigations

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 Index Case (Index Patient): The initially identified case of new or recurrent
TB in a person of any age in a specific household or other comparable
setting in which others may have been exposed.

 Contact: Any person who has been exposed to an index case.

 Close Contact: A person who is not in the household but who shared an
enclosed space, such as a social gathering place, workplace, or facility, with
the index case for extended daytime periods during the 3 months before the
start of the current treatment episode.

 Household Contact: A person who shared the same enclosed living space as
the index case for one or more nights or for frequent or extended daytime
periods during the 3 months before the start of the current treatment
episode.

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HISTORY AND EXAMINATION

 Chest
 Cough > 2 weeks (unremitting and not improving)
 Sputum
 Shortness of breath
 Unilateral wheeze, dullness

 Constitutional symptoms:
 Loss of appetite
 Weight loss
 Fever
 Night sweats
 Fatigue
SYSTEMIC

 Fever > 2 weeks, low grade (99 ° F)

 Sweating at night

 Malnutrition or failure to gain weight (PCM Grade 3), has not responded to 02 month
dietary plan

 Low immune status: H/O pertussis or measles (in last 6 months)

 Lymph nodes: Cervical lymph nodes (enlarged, painless, matted, or there is an abscess
with or without discharge)

 BCG scar absent

Meningitis
 Headache, vomiting, irritability, lethargic
 Neck stiffness, bulging anterior fontanella, coma

 Abdomen
 Chronic diarrhea, distended abdomen, any mass, or ascitieS
 Bones and joints
 Backache, stiffness, lump, deformity, limp
 Unilateral swelling of joint, any tenderness(slow onset)
 Weakness in lower limbs when there is gibbous
INVESTIGATIONS
AFB SMEAR MICROSCOPY

 Mycobacteria are distinguished from other micro-organisms

 is simple ,inexpensive and quickly detecting infectious cases .

 BUT

 Acid-fast bacilli (AFB) cannot distinguish Mycobacterium tuberculosis from NTM .

 drug-susceptible from drug-resistant strains
 at least 5,000 bacilli per millilitre of sputum are required for direct microscopy to be
positive.

 Diagnostic yield: induced sputum has high yield as compared to gastric aspirates .
 Smear sensitivity is further reduced in patients with extra-pulmonary TB
TUBERCULIN / MANTOUX TEST

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TUBERCULIN / MANTOUX TEST

 The test is done by putting a small amount of TB protein (antigens)

under the top layer of skin on your inner forearm. If you have ever been
exposed to the TB bacteria (Mycobacterium tuberculosis), your skin
will react to the antigens by developing a firm red bump at the site
within 2 days.
 TST requires two patient visits
 Results are available in 48-72hrs,
 TST is not expensive
 It is a test that measures immune response not the presence/absence
of bacteria.
 A "positive" tuberculin test is infrequently followed by disease and a
"negative" tuberculin test does not exclude active tuberculosis .

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FALSE NEG AND POSITIVE

 False negative
 Recent TB infection (less than 8–10 weeks)
Corticosteroid therapy/steroid use
 Malnutrition Immunological compromise

 False positive = BCG , Latent TB, Atypical MTB

INTERFERON-GAMMA RELEASE
ASSAYS (IGRAS)
 QuantiFERON®-TB Gold
 T-SPOT®.TB

 Are not affected by BCG vaccines and most nontuberculous

mycobacteria.

 They do not help differentiate latent tuberculosis infection

(LTBI) from tuberculosis disease.
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X-PERT MTB/RIF ASSAY

 Rapid Molecular Test for diagnosis of TB.

 Detect both TB and resistance to rifampicin in less than two hours.

 Real-time DNA based test and more sensitive then microscopy.

 Detect MTB even when present in very small numbers detection limit is 136 (MTB/Ml of
sputum).

 Sensitivity of a single X-pert MTB/RIF test is reported to be 72.5% and increased to 90.2%
when three samples are tested.

 X-pert MTB/RIF specificity is 99 %.
CONT…

 Pleural TB : Pleural fluid is a suboptimal sample for the bacterial

confirmation
 A pleural biopsy is the preferred sample. The sensitivity of
 Xpert MTB/RIF in pleural fluid is very low.

 These recommendations do not apply to stool, urine or blood,

given the lack of data on the utility of Xpert MTB/RIF on theses
specimens
CULTURE AND SPECIES
INDENTIFICATION
 Is the gold stan dard for diagnosis.

 It can detect far lower numbers of AFB, the detection limit being
around 100 organisms/ ml.

 identify the mycobacterial species and drug resistance (HRZE).

 requires a much longer wait of 2-6 weeks for results and it

demands more resources .
 TYPES OF SPECIMENS
Specimen Brief description Reco Reco Optimal Comments
of sample mmen mmen Collection
collection ded ded Time
procedure Age min.
Group vol.
for
studie
s

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Specimen Brief description Reco Reco Optimal Comments
of sample mmen mmen Collection
collection ded ded Time
procedure Age min.
Group vol.
for
studie
s
HISTOLOGY (CERVICAL LYMPH NODE OR
GRANULOMA)

 If biopsy is found positive for AFB, no further investigation for

TB, Start treatment.

 A Caseating granulomatous lesion found on histopathology, no

further investigations
ROLE OFX-RAYS IN DIAGNOSIS
OF TUBERCULOSIS

 Recommended for diagnoses of TB in but not always specific

and reliable
.
 . Suggestive of TB
 Miliary mottling
 Lymphadenopathy: para-tracheal, tracheal or mediastinal
 Consolidation: No response to antibiotics
Uncomplicated hilar lymph gland
Mediastinal lymph gland enlargement with
enlargement on the right-hand side
lung infiltration is seen on the left
 Blood examination e.g. Hb, CBC and ESR are not useful tests.
 PAKISTAN PEDIATRIC ASSOCIATION SCORING CHART FOR
DIAGNOSIS OF TB IN CHILDREN
HISTORY
Features 1 2 3 4 5 Score

Age <2 years - - -

Close contact in last 2 With TB patient With sputum

years in last 2 years +ve TB patient
BCG Scar Absent -

History of Measles and Between 3-6 <3 months

Whooping Cough months
Immunocompromise/ Yes -
Immunosuppressant*
PCM3 Yes - Not improving
EXAMINATION AND INVESTIGATION
Physical Examination§ - Suggestive of Strong
TB suggestive
Radiological Findings¶ Non specific Suggestive of
TB
Tuberculin Skin Test 5-10 mm >10mm

Granuloma Non-specific Specific TB

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 PAKISTAN PEDIATRIC ASSOCIATION SCORING
CHART FOR DIAGNOSIS OF TB IN CHILDREN

INTERPRETATION
 0-2 points TB unlikely
 3-4 points Keep under observation for possible TB
for three months
 5-6 points TB probable, investigations may justify
therapy
 7 or more points TB “confirmed”

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 TB CASE DEFINITIONS

Presumptive TB refers to a patient who presents with symptoms

or signs suggestive of TB (previously known as a TB suspect).
 CASE DEFINITIONS:

a) Bacteriologically confirmed TB case:

 One from whom a biological specimen is positive by smear
microscopy, culture or X-pert MTB/RIF.
 All such cases should be notified, regardless of whether TB
treatment has started.

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 TB CASE DEFINITIONS

b) Clinically diagnosed TB case:

 One who does not fulfill the criteria for bacteriological

confirmation but has been diagnosed with active TB by a
medical practitioner who has decided to give the patient a full
course of TB treatment.

 This definition includes cases diagnosed on the basis of X-ray

abnormalities or suggestive history,suggestive histology and
extra-pulmonary cases without laboratory confirmation.

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TREATMENT OF
TUBERCULOSIS

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 CATEGORIES OF TB PATIENTS

Category -1:
This includes: New cases
a) Of smear + ve / -ve pulmonary TB
b) New extra-pulmonary TB and HIV positive

 Category-2:
(Re-treatment) this includes
Relapses,
Treatment after failure,
Treatment after loss to follow
,others previously treated and patients with unknown TB treatment
history

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PRINCIPLE OF CHEMOTHERAPY

 Anti-TB drugs must always be given in combinations

 Drugs should be prescribed in correct dosages

 Anti-TB drugs should be taken for defined duration (based on

categories)

 Anti-TB drugs should preferably be taken on an empty stomach on

a regular basis
 Patient councelling …. Colour/LFTs/ drug side effects

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DOSAGES OF ANTI-TB MEDICINES

:
 Isoniazid (H) : 10 mg/kg (range 7–15 mg/kg)

 Rifampicin (R): 15 mg/kg (range 10–20 mg/kg)

 Pyrazinamide (Z): 35 mg/kg (range 30–40 mg/kg)

 Ethambutol (E) : 20 mg/kg (range 15–25 mg/k

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 TREATMENT OF CHILDHOOD TB
TREATMENT REGIMENS

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•

TREATMENT
06 MONTHS 08 MONTHS 12 MONTHS
 Relapses  Tuberculous Meningitis
 Smear negative pulmonary TB  Treatment after failure  Osteoarticular
 Intrathoracic lymph node TB  Treatment after loss to follow  T.B Spine
 Tuberculosis peripheral lymphadenitis  Previously treated patients  TB + HIV +VE
HRZ— 02 months (intensive phase) HRZE --- 03 months (intensive phase) HRZE – 02 months (intensive phase)
HRE --- 05 months (continuation) HR --- 10 months (continuation )
HR --- 04 months (continuation phase )

 Extensive pulmonary disease

 Smear-positive pulmonary TB
 Severe forms of extra-pulmonary TB (other than
tuberculous meningitis/ osteoarticular TB)

HRZE – 02 months (intensive phase)

HR --- 04 months (continuation phase )

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 SPUTUM SMEAR EXAMINATION SCHEDULE ACCORDING TO CATEGORY OF TB
PATIENT

Category of AFB smear Management

Patient examination

Month Result

New 0M Positive START treatment intensive phase (2HRZE)

Bacteriologically
Positive End of Negative START continuation phase treatment (4RH)
2M
Positive Do X-pert test. If RR not detected. START continuation phase
treatment .If RR detected then refer to PMDT site for
Management of DR TB.

End of Negative Continue treatment

5M
Positive Declare treatment outcome as CAT-I TREATMENT FAILURE
For further management refer protocol for CAT-II
End of Negative Stop treatment and declare treatment outcome- CURED
6M If last sputum not done, declare treatment completed

Positive Declare treatment outcome as CAT-I TREATMENT FAILURE

For further management refer protocol for CAT-II

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 CLASSIFICATION BASED ON HISTORY OF PREVIOUS
TB TREATMENT

CAT-II

Previously Treated Patients: Have received 1 month or more of anti-TB drugs in the past
Relapse A patient previously treated for TB and declared cured or treatment completed by the
program, and now diagnosed with a recurrent episode of TB
Treatment after A patient who is started on a retreatment regimen after having failed previous (CAT-I)
failure treatment
Treatment after Patients who have previously been treated for TB and were declared lost to follow-up
loss to follow-up at the end of their most recent course of treatment.
Others The patients who have previously been treated for TB but whose outcome after their
most recent course of treatment is unknown or undocumented.

Unknown Patients with unknown previous TB treatment history do not fit into any of the
previous TB categories listed above.
treatment history

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 TREATMENT REGIMEN FOR CAT-II

 INTENSIVE PHASE…………..04 drugs (HRZE) 03 months.

 CONTINUATION PHASE, 03 drugs Isoniazid, Rifampicin
 Ethambutol (HRE) 05 months.

.

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 SPUTUM SMEAR EXAMINATION SCHEDULE ACCORDING TO CATEGORY OF TB
PATIENT

Category of AFB smear Management

Patient examination

Month Result

All retreatment End of Negative Start continuation phase treatment (5RHE)

cases after 3M
failure, default or Positive Repeat X-pert test- if DST available send specimen for DST
relapse also. If X-pert report as RR refer patient to PMDT site for
management
If RR not detected start continuation phase of re-treatment.

End of Negative Continue continuation phase

5M
Positive Declare Treatment outcome CAT-II TREATMENT FAILURE
Declare MDR presumptive case. Refer Patient to DRTBMU

End of Negative Declare treatment outcome “ CURED”

8M
Positive Declare Treatment outcome CAT-II TREATMENT FAILURE
Declare MDR presumptive case. Refer Patient to DR-TBMU

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 DEFAULTERS
 Rx given for more then 01 month and stopped.

 Duration of treatmnt Interuption Rx to be given

 01-02 month < 02 weeks ??
 02-08 weeks ??
 > 08 weeks ??

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 Steroids…… 06-08 weeks
 1. TBM
 2. Pericarditis
 3. Miliary TB
 4. Endobronchial TB

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MONITORING

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ADVERSE EFFECTS

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 Type of Adverse Likely Culprit Identification Management
Event Drugs
Hepatotoxity INH, PZA, RIF
ADVERSE
jaundice EFFECTS
Tender liver, visible Stop all drugs;
Wait for liver function to return to normal;
Re-introduce drugs one-by-one sequentially, every
2 days with monitoring of liver function before
introducing the next drug

Visual Problems EMB Regular testing with Stop EMB or substitute for alternative drug
Ishihara Chart
Severe Rash (SJS) Any Drug Severe rash, peeling Stop all drugs;
mucus membranes, Wait until clinical condition has improved;
child unwell Re-introduce drugs one-by-one sequentially every 2
days, monitoring clinically

Peripheral INH Clinically Give or increase pyridoxine;

Neuropathy If persistent or severe, stop INH

Neuropsychiatric INH Seizures, headaches, Verify correct dosage;

Problems behavior changes, sleep Stop likely culprit drug;
disturbances If symptoms persist, re-introduce and stop next
most likely drug;
If symptoms severe or persistent, stop all likely
drugs or reduce dose

Joint Problems PZA Clinically Verify correct dosage;

Consider reducing dose/ stopping possible culprit
drug;
Consider trial of allopurinol 54
 MANAGEMENT OF
HEPATOTOXITY BY ATT

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 HEPATOTOXICITY: IN ACTIVE TB
DISEASE
The incidences of hepatotoxicity are ranged as the following (from high to
low): INH>PZA>RIF.
Ethambutol (EMB) can be used safely in patients with hepatic disease.

Symptoms:
unexplained anorexia, nausea, vomiting, dark urine,
yellow skin or eyes, fever, persistent fatigue,
abdominal tenderness especially right upper quadrant discomfort.

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HEPATOTOXICITY: IN ACTIVE TB
DISEASE

A.Routine baseline liver function test (LFT) is recommended prior

to starting the standard four-drug therapy for suspect or active TB
disease..
.
B. If results less than 2X upper limits and no side effects repeat in
one month..
C. If any of LFT > 3X upper limit of normal (ULN) at any time,
consider stopping therapy and following protocol.
.

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HEPATOTOXITY: MANAGEMENT

Drug induced hepatotoxicity is defined…..

If LFT (AST/ALT) =3x upper limit of normal PLUS symptoms; or
LFT >=5x ULN with or without symptoms:
a. STOP immediately all anti-tuberculosis drugs.
.
Perform serologic testing for Hepatitis A, B, and C on patients
who are high risk for hepatitis.

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HEPATOTOXITY: MANAGEMENT

How to re-challenge anti-tuberculosis drugs?

 Continue checking LFT. If LFT <2x ULN, re-challenge first with
Rifampin because of its efficacy and is least likely to cause
hepatotoxicity. Also, EMB should be added to the regimen.
 If LFT does not increase after 1 week, then INH should be added to the
regimen.
 Pyrazinamide (PZA) can be added next (1 week after INH) if LFT does
not increase.
 Important point: if at any time of re-challenged period, symptoms
recur or AST increases, the last drug added should be stopped.

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TREATMENT
OUTCOME

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 TREATMENT OUTCOMES

Cured A patient registered as smear-positive, has completed the duration of

treatment, and becomes sputum smear negative at the end of treatment and
on at least one previous occasion
Treatment Completed A smear positive patient who has completed the duration of treatment and has
at least one follow up smear negative results but none at the end of treatment
due to any reason
Smear negative and extra pulmonary cases complete six months of treatment
successfully
Treatment Failure A sputum smear positive patient who remains or becomes sputum smear
positive at 5M or later
Also a patient who was smear negative initially before starting treatment and
became smear positive after completing the initial phase of treatment
Died A patient who dies for any reason during the course of treatment

Lost to follow up A patient whose treatment was interrupted for 2 consecutive months after
registration
Not evaluated A TB patient for whom,no treatment outcome is assigned (includes “Transfer
out” to another treatment unit and whose treatment outcome is unknown).
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MANAGE THE HOUSEHOLD CONTACTS

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CANDIDATES FOR IPT (INH
PROPHYLAXIS) TREATMENT)
 The children below 5 year of age and are close contact of
Bacteriologically Positive (B+ive) TB patient, give
dosage of 10 mg/kg and is given for a period of 6 months.

 Child breast- fed by B+ive mother would continue to breast

feed.
INH in same dosage for six months and is given BCG at end of six
months, if not already given.

HIV-positive with no active TB household or close contacts

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 CONCLUSION

 The main objectives of anti-TB treatment are to:

- cure the patient of TB;
- prevent death from TB disease or its late effects;
prevent relapse of TB;
prevent the development and transmission of drug-resistant TB;
reduce transmission of TB to others;
achieve all this with minimal toxicity.
 All children treated for TB should be registered with the NTP.

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MULTI DRUG RESISTANT
TUBERCULOSIS

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DEFINITIONS

 Mono-resistance: Resistance to one anti-TB drug.

 Poly-resistance: Resistance to more than one first

line anti-TB drug (excluding both Isoniazid (H) and
Rifampicin (R) at a time)

 Multi-drug-resistance (MDR): Resistance to both

Isoniazid (H) and Rifampicin (R) with or without
resistance to any other drug
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DEFINITIONS

 Extensive drug-resistance (XDR): Resistance to

any Fluoroquinolone and at least one of the three
injectable second-line drugs (Kanamycin,
Amikacin or Capreomycin) in addition to
multidrug resistance

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68
TREATMENT…
REGIMEN DESIGN
Children with MDR-TB should be managed according
to the same principles that guide adult therapy.
These include:
• Use of any first-line medication to which susceptibility is
documented or likely.

• Use of minimum of 4 second-line drugs to which the strain is

likely to be sensitive; One of these agents should be an
injectable, one a fluoroquinolone (preferably a later
generation quinolone if available), and PZA should be
continued.

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REGIMEN DESIGN

• Treatment duration should be for 18-24 months, at least 12

months after the last negative culture/smear with minimal
disease or 18 months with extensive (lung cavities or
widespread parenchymal involvement)

• Balance must be achieved between an effective MDR

regimen and the development of adverse events.

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REGIMEN DESIGN
1) Use any Group 1 first-line oral drugs that have certain, or
almost certain, efficacy, for example, drugs showing
susceptibility in DST. These drugs should be administered
for the duration of therapy.
2) Add one Group 2 injectable agent based on DST results
and treatment history. This agent is normally given for a
minimum of 6 months and for 4 months after culture
conversion. Preferably, it should be an aminoglycoside such
as amikacin. Do not use streptomycin (unless other Group 2
drugs are unavailable) because of high rates of resistance
with DR-TB strains and higher incidence of ototoxicity.
3) Add one Group 3 fluoroquinolone based on DST results
and treatment history, for the duration of therapy.
Levofloxacin and moxifloxacin are preferred to ofloxacin.
Note that ciprofloxacin is not recommended. 71
REGIMEN DESIGN

4) Group 4 second-line oral drugs should be added for the

duration of therapy,. The Group 4 drugs should be chosen on
the basis of treatment history, adverse effect profile and cost.
DST is not standardized for Group 4 drugs.

5) If a regimen of minimum of four effective drugs cannot be

built from Groups 1-4, consider adding, in consultation with
an MDR-TB expert, at least two Group 5 third-line drugs.
DST is not standardized for Group 5 drugs.

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KEY POINTS

 PAS (including PAS Na) is administered in acidic medium (e.g.

yoghurt or orange juice) for improved absorption.
 Consider use of group5 drugs if there are insufficient drugs in other
groups to build an acceptable regimen. Each drug is considered as
only half a drug - therefore two drugs in this group count as one
additional drug.
 In adults, high-dose isoniazid is defined as 16-20 mg/kg per day.
 Linezolid dosage for TB is uncertain, but lower doses (300 mg twice
daily or even 300 mg daily in adults) cause fewer adverse effects and
still seem effective.
 Thioacetazone should not be used in people living with HIV because
of the serious risk of life-threatening adverse reaction.

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KEY POINTS
 In children, doses of all drugs, including the fluoroquinolones,
should be at the higher end of the recommended ranges
wherever possible, except ethambutol. Ethambutol should be
dosed at 15 mg/kg, and not at 25 mg/kg as sometimes used in
adults with DR-TB, as monitoring for optic neuritis is more
difficult in children.
.
 Choose one drug in each of 2nd groups; amikacin is preferred to
kanamycin in children. Intramuscular injection of amikacin is
very painful -intravenous infusion should be preferred

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TREATMENT PHASES

75
THANKYOU

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