diagnosis of childhood TB is a challange, but if we follow a system of screening and then appropriate diagnostic tests following contact tracing, we are likely to identify children with infection or disease and put them on appropriate treatment.

1. Management of Childhood Tuberculosis
2023
Prof. Ashok Rattan,
MD, MAMS,
Common Wealth Fellow, INSA DFG Fellow, ex SEARO Temporary Advisor,
ex WHO Lab Director (CAREC/PAHO)
Chairman Medical Committee & Quality, Redcliffe Labs, India
Online Professor & Mentor, AHRO University, Glasgow, Scotland

2. Since its discovery 140 years ago TB has claimed
more than 1 billion lives
• Which is more than those claimed by (all of the below)
• Malaria
• Small Pox
• HIV/AIDS
• Cholera
• Plague
• Influenza
• Mathematical modelling published in Lancet suggest
that 2,39,000 children died in 2015; 80% were below
5 yrs of age and mostly NOT on ATT
• Huge opportunity to make a difference
[how many children ? Nobody knows !]*

3. Natural History of TB in children
Phase Time frame Features
Phase 1 Occurs 3 to 8 wks
after primary
infection
end of incubation period
Initiation of well defined signs: fever, erythema nodosum,
positive Mantoux, primary complex on chest X Ray
Phase 2 Occurs 1 to 3
months after
Phase 1
Bacillus migrate to other parts of the body via blood, represent
the period of highest risk for development of TBM & military TM
in young children
Phase 3 3 to 7 months Pleural effusion in > 5 yrs old &
bronchial disease in < 5 yrs old child
Phase 4 1 to 3 yrs Osteoarticular tuberculosis in children within 5 yrs or less
Phase 5 > 3 yrs of Phase 1 After calcification in completed,
features of adult TB after this

4. Infection 3 M tb 10 to 100 M tb 131 Gexpt +ve 1000 10,000

5. Disease
state
Main Diagnostic Challenges Current status & limitations of tests
1. Infection Differentiating between TB exposure (without infection)
and TB infection
Current CMI based tests (Mantoux) maynot convert
to positive until 2 to 10 weeks after acquiring M tb
infection
Differentiating between infection and subclinical disease Chest X Ray is the first line imaging modality, but
maynot reveal abnormalities consistent with TB
disease in all cases – especially those in early stages
of the continuum of TB
2. Disease Detection of TB disease and of drug resistance 4th generation IGRA differentiate between LTBI and
active infection
Currently available tests for bacteriological confirmation
have limited sensitivity for detecting M tb in young
children with pauci-bacillary disease – especially in early
states of the continuum of TB
Gene xpert Ultra MTB/RIF can detect 16 cfu/ml
BD Max can detect 1 M tb
BD Max & SD Biosensor POCT can detect Mtb &
INH & Rif susceptibility
Specimen collection for bacteriological confirmation
currently consists of serial sampling of gastric aspirates /
lavage or induced sputum and require trained personnel
and facilities with airborne infection control
Stool testing by Gene xpert Ultra
3. Monitoring
response to
treatment
Mycobacterial culture is only useful in those children who
had positive cultures at time of diagnosis (minority of
cases)
Decrease in INF gamma by CD 8 cells on treatment
[measure at 0, 3 & 6 M]

7. TB disease in children:
clinical epidemiology
• Children acquire infection after close contact with adults with PTB
•Most cases occur in young children ( <5years)
•Most disease occurs within 2 years after exposure/infection
• –The majority within 1 year
•Most cases in children are pulmonary TB, children prone to severe
infection
• –Smear negative or smear not done are the majority
• –Extrapulmonary TB is also common and the type depends on age
• –Smear positive disease is usually in older children

9. End TB Targets
• Children & young adolescents (age below 15 yrs)  11% of all people with
TB (1.1 million cases, atleast 50% below 5 yrs)
• UN Sustainable Development Goal in End TB Strategy
• Reduce TB incidence by 80%
• Reduce TB death by 90% by 2030 compared with 2015 burden
• How (2018) by 2022
• Diagnose & Treat 40 million people with TB (3.5 million children)
• 1.5 million with DR TB (including 115000 children)
• 30 million people (including 4 million children < 5yrs) and
• 20 million other household contacts & 6 million PLWHIV with TPT

10. Guidelines Development Group
Eight new Recommendations for
Management

13. Pathway through Exposure, Infection & Disease

15. Children & Adolescents are a key vulnerable population
• 7.5 million children are newly infected each year
• Cumulatively 67 million children are infected
• Including 2 million with MDR TB
• And 100,000 with XDR TB
• Risk of infection is greater after close & prolonged exposure
• If Index case is a child, contact investigation & screening include
efforts to identify likely source of infection (Reverse Contact
Investigation or Source Case Investigation)
• Systematic screening for TB disease aka Active TB case finding

16. Pathway through Exposure, Infection & Disease

17. TB screening and contact investigation
Screening for TB in targeted populations
• Household contacts and other close contacts of individuals with TB
disease should be systematically screened for TB disease.
• People living with HIV should be systematically screened for TB
disease at each visit to a health facility.
• Systematic screening for TB disease may be conducted among
subpopulations with structural risk factors for TB. These include urban
poor communities, homeless communities, communities in remote or
isolated areas, indigenous populations, migrants, refugees, internally
displaced persons and other vulnerable or marginalized groups with
limited access to health care.

18. Tools for screening
• Among individuals aged 15 years and older in populations in which TB
screening is recommended, systematic screening for TB disease may be
conducted using a symptom screen, chest X-ray or molecular WHO-
recommended rapid diagnostic tests, alone or in combination.
• screening is recommended, computer-aided detection software
programmes may be used in place of human readers for interpreting digital
chest X-rays for screening and triage for TB disease.
• Among adults and adolescents living with HIV, systematic screening for TB
disease should be conducted using the WHO-recommended four symptom
screen and those who report any one of the symptoms of current cough,
fever, weight loss or night sweats may have TB and should be evaluated for
TB and other diseases.

19. Tools for screening
• Among adults and adolescents living with HIV, C-reactive protein
using a cut-off of >5 mg/L may be used to screen for TB disease.
• Among adults and adolescents living with HIV, chest X-ray may be
used to screen for TB disease.
• Among adults and adolescents living with HIV, molecular WHO-
recommended rapid diagnostic tests may be used to screen for TB
disease
• Adult and adolescent inpatients with HIV in medical wards where the
TB prevalence is >10% should be tested systematically for TB disease
with a molecular WHO-recommended rapid diagnostic test.

20. Tools for screening
• Among individuals younger than 15 years who are close contacts of
someone with TB, systematic screening for TB disease should be
conducted using a symptom screen including any one of cough, fever
or poor weight gain; or chest radiography; or both.
• Among children younger than 10 years who are living with HIV,
systematic screening for TB disease should be conducted using a
symptom screen including any one of current cough, fever, poor
weight gain or close contact with a TB patient.

21. Known symptoms & signs highly associated with PTB
• Cough
• Haemoptysis
• Fever
• Night sweats
• Fatigue
• Loss of appetite & weight loss
• In child: failure to thrive , decreased playfulness

26. TB specific Antigens for skin test
• Cy-Tb was manufactured by the
Statens Serum Institut (SSI),
Denmark, as a solution of two
recombinant proteins of ESAT-6
and CFP-10 (in a 1:1 ratio),
produced by genetically modified
Lactobacillus lactis. One single test
dose of 0.1 mL contains 0.05 μg of
rd ESAT-6 and 0.05 μg of rCFP-10.
In 2019, SSI entered into a
partnership with the Serum
Institute of India, which is licensed
to produce and distribute the test.

27. Other TB specific Antigens for Skin Test
Diaskintest C -TST

32. CD8 T-cells
• Suppress Mycobacteria tuberculosis growth
• Kill infected cells
• Directly lyse intracellular Mycobacteria
• TB specific CD8 T cells that produce IFN-Ύ have been
• More frequently detected in those with active TB disease vs latent infection
• Associated with recent exposure
• Detectable in active TB subjects with HIV co-infection & young children

33. We are calling this test TB Sure to avoid any confusion
TB SURE

36. Other IGRA Tests
WANTAI TB-IGRA kits and components T SPOT

42. Pathway through Exposure, Infection & Disease

43. To administer the BCG vaccine:
• a short narrow needle (15 mm, 26 gauge) is used;
• the needle should be introduced just under the skin over the left deltoid area;
• the syringe should be held at a 5- to 15-degree angle from the site;
• the needle should be placed almost flat against the patient’s skin, bevel side up;
• the needle should be partially inserted into the skin until the entire bevel is
covered by skin;
• when injecting the solution, there should be some resistance and a small weal
or bleb should appear, indicating the fluid is in the dermis
Despite its safety, BCG is an attenuated live vaccine (M. bovis BCG).
Contraindications include:
• pregnancy;
• people living with HIV but not on ART, or on ART but not immunologically stable;
• people with other forms of immunosuppression (e.g. candidates for organ
transplants, people on immunosuppressive therapy).

50. Pathway through Exposure, Infection & Disease

51. Diagnosis of TB disease in children
• Young children have a higher risk of developing TB compared with other
age groups. Risk of TB disease is more pronounced among children and
adolescents who
• are a household or other close contact with a person with PTB, especially if
bacteriologically confirmed;
• are aged under 5 years;
• are living with HIV, especially if poorly controlled;
• have severe acute malnutrition (SAM), especially if not responding to nutritional
rehabilitation;
• are hospitalized with pneumonia, especially if not responding to antibiotic
treatment.

52. Diagnosing TB in children and adolescents
relies on a combination of
• careful history, including any TB contact (especially in the past 12 months),
previous TB treatment, and signs and symptoms consistent with TB;
• clinical examination, including growth assessment;
• HIV testing if status unknown;
• bacteriological testing (if available);
• CXR (preferably anteroposterior and lateral in children aged under 5 years and
posteroanterior in older children and adolescents);
• TB infection testing (TST or IGRA);
• investigations relevant for presumed EPTB.

53. Typical symptoms of pulmonary TB
• The most common symptoms of TB
in children are :
• cough, especially if persistent and
not resolving;
• prolonged fever with or without
night sweats;
• not eating well or anorexia;
• weight loss or failure to thrive
(abnormal growth curves
suggestive of TB);
• unusual fatigue, reduced
playfulness or decreased activity.
Different pattern of cough

57. CBNAAT
Gene Xpert ULTRA
LOD 131 cfu/ml 16 cfu/ml
Better version

61. 2nd generation molecular tests
Moderate Complex Automated NAAT
• 1. Abbott Molecular test
• A. Detection of MTB
• B. Detection of MTB and INH & Rif Resistance
• 2. BD Max for MTB and INH & Rif Resistance
• 3. Bruker Hain Diagnostics
• A. Fluorotype MTB
• B. Fluorotype MTBDR for INH & Rif Resistance
• 4. Roche Diagnostics
• A. MTB
• B. MTB DR for INH & Rif Resistance

65. Comparison of Moderately complex NAAT
Attribute BD Max Abbott Bruker Hains Roche
detect MTB + INH, Rif a) MTB a) MTB a) MTB
b) MTB + INH, Rif b) MTB + INH, Rif b) MTB + INH, Rif
Target/s IS 6110 + IS 1081 (both
multicopy) + a single copy
devR + RRDR of rpoB + INH
promotor + kat G 315
IS 6110, pab gene for
detection
RRDR of rpoB
INH promotor, kat G
IS 6110,
rpoB, inhA,KatG
16s rRNA + esx gene for
detection
RRDR of rpoB
INH promotor, kat G
LOD 0.5 cfu/ml for detection,
6 cfu for DST
17 cfu/ml for detection
60 cfu/ml for DST
15 cfu/ml detection
20 cfu/ml for DST
7.6 cfu/ml detection
8.8 cfu/ml DST
Sample
preparation
Manual, 1.5 min / sample Automated 4.5 hours automated automated
PCR Automated multiplex real
time
Automated real time Asymetric excess PCR &
light on / off probe
PCR in 3 hours
IQC In every cartridge + and -- controls + and -- controls + and -- controls
Tests per run 24 96 96 96, 384

66. All these four WHO approved tests are high throughput
A POCT being reviewed by WHO & ICMR
SD Biosensor
Advantage
•All-in-one cartridge (NA extraction +
amplification)
•Simultaneous detection of M. tuberculosis
complex and INH & Rif Resistance
•Fast result in 77 minutes
•Simple sputum pretreatment process
•Room temperature storage

68. All patients with PTB should be treated with an appropriate
regimen as recommended by the WHO and/or national
guidelines (Standard 3)
• Each patient with diagnosis of drug-susceptible PTB should be treated with a regimen
recommended by WHO and national guidelines
• Adults:
6-month regimen (2HRZE/4HR)
4-month regimen (2HPZMfx/2PMfx) for children aged 12 years and adults
• Children:
6-month regimen (2HRZ(E)*/4HR), with higher R and H dosing
(see WHO-recommended dosages)
•
SHINE regimen (2HRZ(E)*/2HR) for age , 16 years with non-severe TB
(SHINE : Shorter treatment for Minimal Tuberculosis in children)

70. Role of chest X-ray
• Abnormalities on CXR suggestive of PTB include:
• enlarged perihilar or paratracheal lymph nodes;
• dense alveolar opacification in a child who is not acutely ill;
• miliary pattern of opacification;
• cavitation (more frequent in adolescents);
• pleural or pericardial effusion in a child or adolescent who is not acutely ill.