Presentation on pediatric tuberculosis

1. Pulmonary
Tuberculosis
Pulmonary
Tuberculosis

2. Background of Tuberculosis (Globally)
 Tuberculosis continues to be
a global public health
problem, particularly in the
developing countries.
 Nearly one-third of the
global population( i.e., two
billion people) is infected
with Mycobacterium
tuberculosis and is at risk of
developing the disease.

3. • WHO recently released an updated Global TB Report on leading
cause of death and disability worldwide between 2000-2019.
According to that report, although TB is now 13th leading cases
of death worldwide with 30% reduction in global TB deaths
between 2000 and 2019.
• Globally, an estimated nearly 8.9-11 million population
developed TB in 2019 and TB caused an estimated 1.2 million
deaths among HIV negative people in the same year. Further, it
estimated that an additional 208,000 HIV positive people died
from TB in 2019.

4. Background of Tuberculosis ( Bangladesh scenario)
 Bangladesh is listed among the 30-high burden countries for
TB.
According to Global TB report 2020: - 2,92,942 TB patients
were notified to the National Tuberculosis Control Program
(NTP) in 2019.
The childhood TB cases reported are nearly 4% of all cases,
which is still a huge challenge in Bangladesh.

5. •In 1993 WHO declared TB as a global emergency and
recommended a standard strategy for control of the
disease known as "DOTS" or Directly Observed
Treatment, Short-course. The NTP adopted the DOTS
strategy in 1993. Since the introduction of DOTS,
remarkable progress has been achieved in TB control in
the country. The program has managed to successfully
treat >85% of TB patients since2003. This has further
improved to above 90% since 2005. Further, the
program achieved the initial target of detecting at least
70% of new smear positive (NSP) cases in 2006 and has
been successful in consistently sustaining this.

6. Points to be noted.
1. Occurrence
2. Epidemiological Determinants
3. Mode Of Transmission
4. Incubation Period
Epidemiology

7. Occurence:
•Pulmonary tuberculosis occurs worldwide.

8. Causative agent :
Mycobacterium
tuberculosis
Fig : Mycobacterium tuberculosis
Epidemiological determinants

9. Mode of transmission
•Inhalation of air droplets nuclei containing
tubercle bacilli.
•Other : Ingestion
Inoculation
Transplacental

10. Incubation period
• 3-6 weeks.
• It may extend to weeks, months or even
years.

11. Factors increasing the risk of tuberculosis
Patient-related
• Age (children > young adults < elderly)
• First-generation immigrants from high-prevalence countries
• Close contacts of patients with smear-positive pulmonary TB
• Overcrowding (prisons, collective dormitories); homelessness (doss houses and
hostels)
• Chest X-ray evidence of self-healed T
• Primary infection<1 year previously
• Smoking: cigarettes, bidis (Indian cigarettes made of tobacco wrapped in
tembhumi leaves and cannabis

12. Associated diseases
• Immunosuppression: HIV, anti-tumour necrosis factor (TNF) and other biologic
therapies, high-dose glucocorticoids, cytotoxic agents
• Malignancy (especially lymphoma and leukaemia)
• Diabetes mellitus
• Chronic kidney disease
• Silicosis
• Gastrointestinal disease associated with malnutrition (gastrectomy, jejuno-ileal
bypass, cancer of the pancreas, malabsorption)
• Deficiency of vitamin D or A
• Recent measles in children

13. What is Pulmonary Tuberculosis?
•Pulmonary tuberculosis
is a chronic infectious
disease caused most
often by
Mycobacterium
tuberculosis and is the
leading infectious
cause of death
worldwide.

14. Morphology of Mycobacterium Tuberculosis
• Acid fast bacilli.
• Obligate aerobes ( They require oxygen
to survive and cannot survive without
oxygen because their ATP generating
system is dependent on oxygen).
• Non spore forming and non motile.
• Non-capsulated.
• Arranged singly or in small group.

15. Growth characteristics
• Mycobacterium tuberculosis
grows slowly (i.e., it has
doubling time of 18 hours, in
contrast to most bacteria, which
can double in number in 1 hour
or less). Because growth is so
slow, cultures of clinical
specimen must be held for 6-8
weeks on solid media before
being recorded as negative.
• Media used for growth: Solid
media ; Lowenstein Jensen
media, Liquid media ;
mycobacterial growth indicator
tube (MGIT).
.
Fig : Lowenstein- Jensen Medium.
.
.

16. What is acid fast bacilli ?
The term acid-fast refers to an organism’s ability
to retain the Carbol fuschin stain despite subsequent
treatment with ethanol- hydrochloric acid.
•The Mycobacterium do not stain readily but
once stained they resist decolorization by
acid/ alchohol and are therefore called“ Acid Fast Bacilli”.
Reason for acid fastness :
1.) The high lipid content.
2.) Long chain fatty acid ( C78 - C90 ) called
mycolic acids in the cell wall.
3.) Integrity of cell wall

17. Virulence factors of Mycobacterium tuberculosis.
1. Cord factor : Cord factor is chemically a
glycolipid(trehalose dimycolate). It plays an
important role in virulence of mycobacterium
tuberculosis. Virulent strains grow in a
characteristic “serpentine” cord like pattern,
where as avirulent strains do not.
Function :
•It inhibits migration of leukocytes.
•It causes chronic granuloma formation.
So, if serpentine cord like growth is found in
culture media under microscope – it is indicative
of tuberculosis.
Fig : Serpentine pattern of
m.tuberculosis under microscope.

18. 2. Pthiocerol dimycocerosate : A lipid located in bacterial
cell wall is required for pathogenesis in lung.
3. Lipoarabinomannan(LAM) etc

19. Pathogenesis of Pulmonary tuberculosis:
It can be classified into-
1. Primary pulmonary tuberculosis
2. Post primary pulmonary tuberculosis

20. Pathogenesis of primary pulmonary tuberculosis:
It develops in a previously unexposed and therefore
unsensitised person. Depends on virulence of the organism,
cell mediated immunity and delayed type of hypersensitivity.
M.tuberculosis is transmitted by inhalation of respiratory
droplets
Organisms reach the alveoli of the upper part of lower
lobes/lower part of upper lobes

21. Enters macrophages by phagocytosis mediated by receptors
such as mannose binding lectin and type 3 complement
receptor
M.tuberculosis inhibits maturation and blocks formation of
phagolysosome by recruiting host protein called coronin
Bacteria proliferate in pulmonary alveolar macrophages
resulting in bacteremia and seeding of multiple sites

22. After 3 weeks of infection, antigen presenting cells
secrete IL-12 and IL-18 which causes differentiation of
Th1 cells
Th1 cells both in lymph nodes and in lung produce IFN-ꙋ
which-
1)Stimulates maturation of phagolysosome
2)Stimulates expression of inducible NO(nitric oxide)
synthase producing NO.

23. 3)Mobilizes antimicrobial peptides(defensins).
4)Stimulates autophagy, which sequesters then destroys
M.tuberculosis.
Macrophage activated by IFN-Y differentiate into
‘epithelioid histiocytes’ that aggregate to form
granulomas, some may fuse to form multinucleated
giant cells

24. In lungs, the central focus of granuloma undergoes caseous
necrosis and causes parenchymal lung lesion known as Ghon
focus
If the infection is not controlled, it drains to hilar lymph
nodes and causes lymphadenopathy. This combination of
parenchymal lung lesion and hilar lymphadenopathy is called
Ghon Complex. This granuloma formation halts the spread of
infection before significant tissue destruction

26. Fate/Outcomes of Primary pulmonary TB:

27. Pathogenesis of post primary pulmonary
Tuberculosis:
Occurs in previously sensitized host. More prevalent in
impaired immune status i.e. malnutrition, advanced age,
immunosuppressive drugs or disease like AIDS or DM.
Reactivation of latent infection or reinfection with exogenous
bacilli
Due to pre-existence of hypersensitivity, bacilli elicit a prompt
and marked tissue response that tends to wall off the focus of
infection. So regional lymph nodes less involved.

28. Extensive immune response produces area of extensive
caseation with resultant formation of tuberculoma.
Release of protease from activated macrophage causes
softening and liquefaction of caseous material. Thus
cavitation occurs readily in secondary form.
Erosion of the cavities into airway causes shedding of
bacilli in sputum.

29. Characteristics of Primary and Post-Primary
Characteristics Primary Post-primary
Size of lesion Small Large
Lymphatic involvement Yes Minimal
Cavity formation Rare Frequent
Tuberculin sensitivity Negative initially Positive
Infectivity Uncommon Usual
Site Any part of the lung Lung apices
Local spread Uncommon Common

30. Natural History of untreated primary tuberculosis
Time from infection Manifestation
3-8 weeks Primary complex, positive tuberculin skin test
3-6 months Meningeal, miliary and pleural disease
Up to 3 years Gastrointestinal, bone and joint, and lymph node disease
Around 8 years Renal tract disease
From 3 years onwards Post-primary disease due to reactivation or re-infection
Adapted from Davies PDO, ed. Clinical tuberculosis. London: Hodder Arnold; 1998.

31. Features of primary tuberculosis
Infection (4–8 weeks)
• Influenza-like illness
• Skin test conversion
• Primary complex
Disease
• Lymphadenopathy: hilar (often unilateral), paratracheal or mediastinal
• Collapse (especially right middle lobe)
• Consolidation (especially right middle lobe)
• Obstructive emphysema
• Cavitation (rare)
• Pleural effusion
• Miliary disease
• Meningitis
• Pericarditis
Hypersensitivity
• Erythema nodosum • Phlyctenular conjunctivitis • Dactylitis

32. • Chronic cough, often with haemoptysis
• Pyrexia of unknown origin
• Unresolved pneumonia
• Exudative pleural effusion
• Asymptomatic (diagnosis on chest x-ray)
• Weight loss, general debility
• Spontaneous pneumothorax

33. What is miliary tuberculosis?
• Blood-borne dissemination gives rise
to miliary TB, which may present
acutely but more frequently is
characterised by 2–3 weeks of fever,
night sweats, anorexia, weight loss
and a dry cough.
• The classical appearances on chest X-
ray are of fine 1–2 mm lesions (‘millet
seed’) distributed throughout the lung
fields, although occasionally the
appearances are coarser.
• Two types: i) Classical
ii) Cryptic

34. Comparison between classical and Cryptic forms of Miliary Tuberculosis
Feature Cryptic Classical acute
Age Majority above 60 years Majority under 40 years
TB history or contact Up to 25% Up to 33%
Malaise/weight loss 75% 75%
Fever 90% 75%
Choroidal tubercles Absent Up to 20%
Meningitis Rare unless terminal Up to 20%
Lymphadenopathy Absent Up to 20%
Miliary shadowing on x-ray Rare Usual except in early stages
Tuberculin test Usually negative Usually positive
Pancytopenia/leukaemoid reaction Common Rare
Bacteriological confirmation Urine; sputum; bone marrow Sputum, CSF
Biopsy evidence Liver up to 75%; bone marrow,
lymph node
Seldom required

35. 1. Specimen collection:
a. Two sputum samples (including at least one
obtained in the early morning, induced with nebulized
hypertonic saline if patient is not expectorating.
b. Bronchoscopy with washings and bronchoalveolar lavage
c. Gastric washing (mainly used for children)
2. Diagnostic tests
a. Tuberculin skin test:
Low sensitivity/specificity; useful only in primary or deep-seated
infection

36. b. Microscopic examination
 Ziehl-Neelsen stain:
Finding- Acid Fast Bacilli appears as red, rod, beaded,
slightly curved bacilli in blue background
 Light-emitting diodes Fluorescence microscopy:
With auramine staining (For rapid screening purpose)
Finding- Orange red bacilli against dark background
5,000 to 10,000 bacilli/ml
c. Isolation and identification from culture:
i. Lowenstein- Jensen medium: Brown, granular colony sometimes called “Rough,
buff and Tough”
ii. Liquid media : e.g.- MGIT( BACTEC)
Only 10-100 viable organisms are required for sputum to be culture positive.

37. d. Nucleic Acid Amplification Tests (NAATs) :
Polymerase chain reaction is a common form of NAATs
used in laboratory diagnosis. For example, the Cepheid
GeneXpert MTB/RIF has the capacity to detect MTB
(and certain molecular markers of rifampicin resistance)
in less than 2 hours. Other tests LPA and True Nat.
e. Diagnosis of latent infection:
a. PPD skin test
b. Interferon-gamma release assay (IGRA) called Quantiferon –TB
f. Chest X-ray
Finding: Apical opacity with or without cavitation and consolidation in
other lobe, hilar adenopathy and pleural effusion.

39. Fig : Chest x-ray showing a) consolidation and b) cavitation in pulmonary tuberculosis

40. It is the classic example of delayed- type
hypersensitivity, which is produced by the
intracutaneous injection of purified protein
derivative (PPD also called tuberculin), a protein
containing antigen of tubercle bacillus. In a
previously sensitized individual, reddening and
induration of the site appear in 8 to 12 hours, reach
a peak in 24 to 72 hours, and thereafter slowly
subside.
Reagent: Tuberculin reagent is a purified protein
derivative (PPD) of mycobacterial cell wall.

41. Procedure of tuberculin test
• 5 TU of PPD contained in 0.1 ml
normal saline is injected intra-
dermally on the flexor aspect of the
forearm. The object is observed for
about half an hour for any
hypersensitivity reaction and
advised to report after 72 hours for
final reading.

42. Interpretation of tuberculin test:
Induration Reaction Interpretation
10 mm or more Positive reaction • Past infection or disease
• Present infection or disease
• BCG vaccination
Less than 6 mm Negative reaction • No infection by M. tuberculosis
6-9 mm Doubtful reaction • Infection by atypical mycobacteria
False positive: It means skin test is positive but the
patient has no TB
• Infection by atypical mycobacteria
• Past TB
• Previous Vaccination
False negative: It means skin test is negative but the
patient has TB
• Overwhelming TB
• Miliary TB
• Measles
• Malnutrition
• HIV (if CD4 count <200 cells/ml)
Immunosuppressive drugs
• Malignancy
• Hodgkin’s lymphoma
• Leprosy

43. Management
Anti-tubercular Drugs Classification
First-line anti-TB drugs
Description Drug
Oral drugs
Isoniazid(H)
Rifampicin(R)
Ethambutol (E)
Pyrazinamide(Z)

44. Second-line anti-TB drugs
Groups Drugs
Group A:
Include all three medicines
Levofloxacin(Lfx) OR Moxifloxacin(Mfx)
Bedaquiline(Bdq)
Linezolid(Lzd)
Group B:
Add one or both medicines
Clofazimine(Cfz)
Cycloserine(Cs) OR Terizidone(Trd)
Group C:
Add to complete the regimen and when medicines from
Group A and B cannot be used
Ethambutol(E)
Delamanid(Dlm)
Pyrazinamide(Z)
Imipenam-cilastatin(Ipm-Cln) OR Meropenam(Mpm)
Amikacin(Am) OR Streptomycin(S)
Ethionamide(Eto) OR Prothionamide(Pto)
p-aminosalicylic acid(PAS)

45. Standardized treatment regimen for each
diagnostic category(adults)
TB diagnostic category Types of Patient Treatment regimen
Intensive phase(Daily) Continuation phase (Daily)
New cases (never been
treated for TB or have
taken ATT for <1month)
Bacteriologically positive PTB patients
2(HRZE) 4(HR)
Bacteriologically negative PTB patients
TB/HIV co-infected
Previously Treated Cases
(received 1 month or
more than 1 month of
ATT in the past)
If no resistance to
TB drugs(both H
and R sensitive)
SS+ PTB 6HRZE-Lfx
SS- PTB 6HRZE
Clinically diagnosed PTB 6HRZE
If Rif susceptible and INH resistant or
unknown in bacteriologically
confirmed PTB
6(H)RZE-Lfx

46. Fixed-dose combinations (FDCs)
In the management of TB patients with first line drugs, fixed-dose
combinations (FDCs) of anti-TB drugs are recommended over individual drugs.
Fixed Dose Combinations refer to products containing two or more active
ingredients in fixed doses, used for a particular indication(s).
Advantages
 Prescription error are likely to be less frequent because dosage
recommendations are more straightforward and adjustment of dosage
according to patient weight is easier.
 With less number of tablets to ingest, FDCs are more patient friendly and
helps improve treatment adherence.
 It prevents concealed irregularity as, in the absence of DOT, the patient
cannot be selective in the choice if drugs to ingest.

47.  Drug resistance is less likely to occur because mono therapy is avoided.
 It helps simplify drug management.
Disadvantages
 Risk of over dosage or under dosage (sub therapeutic blood levels) of all drugs
occurring if number of tablets prescribed or taken is more or less than
treatment guidelines.
 Poor rifampicin bioavailability is a problem with low quality FDCs. Quality
assurance is therefore essential.
 Using FDCs do not obviate the need for individual drugs for a minority of
patients who develop drug toxicity.

48. FDC tablets are composed as follows-
*4FDC: isoniazid 75mg+ rifampicin 150mg+
pyrazinamide 400mg + ethambutol 275mg
*2FDC: isoniazid 75mg + rifampicin 150mg

49. Drug Resistance TB
•MDR-TB(Multidrug resistant tuberculosis)
It is defined by resistance to at least rifampicin and isoniazid,
with or without other drug resistance.
•XDR-TB (Extensive drug resistant tuberculosis)
It is defined as MDR TB with resistant to levofloxacin or
moxifloxacin and bedaquiline and/or linezolid.

50. DOTS Strategy
• The World Health Organization(WHO) and the International Union
against TB and Lung Disease(IUATLD) promote universal adoption of
Directly Observed Treatment, Short-Course(DOTS) as a means to
improve TB treatment outcomes.
• DOTS means that an observer watches the patient swallow their
drugs.

51. Aims of DOTS Strategy:
To ensure a TB patient takes:
-right drug
-in the right time
-in the right dose

52. The NTP now applies the WHO recommended
DOTS strategy for detection and cure of
tuberculosis which combines 5 elements-

53. PREVENTION
According to EPI schedule, BCG vaccination is recommended just after
birth, because the baby does not get any immunity against
tuberculosis from mother and as a result he/she is susceptible to have
tuberculosis at any time.
Vaccine Disease Number
of dose
Amount
of dose
Starting
time of
dose
Route of
administration
Site of
vaccination
BCG Tuberculosis 1 0.05ml After
birth
Intradermal Upper part of
left arm

54. Prognosis
TB is a severe and often deadly disease without treatment. After 5years
without treatment, the outcome of smear-positive pulmonary TB (PTB)
in HIV-negative patients is as follows:
• 50-60% die (case fatality ratio for untreated TB)
• 20-25% are cured (spontaneous cure)
• 20-25% develop chronic smear-positive TB.

57. Diagnostic algorithm
Microscopy-sites
Presumptive TB case
GeneXpert sites
Smear
Negative test
Smear Positive Test Result
To be tested by GeneXpert if available
or would be enrolled for treatment
Further clinical
evaluations by
physician eg. CXR,
GeneXpert highly
suggestive) etc
First line
Drugs (FLD)
GeneXpert Test
MTB not
detected
Further clinical
evaluations by physician
eg. CXR, culture,
Histopathology and
cytopathology etc
MTB detected,
RR not detected
First line drugs
(FLD)
MTB detected,
RR detected
Second line
drugs (FLD)
Error/ Invalid/No
result/MTB detected; RIF
resistance Inderminate
Repeat Xpert test

58. Chemoprophylaxis
Preventive therapy with isoniazid(INH) is given to children of less than 5years
of age or immune compromised children(e.g. severely malnourished or HIV-
infected, or on steroids/immunosuppressive drugs), irrespective of their age
who do not have TB disease but are at high risk to develop TB disease. These
children had close contact with a TB index case and highly likely to be
infected with the TB organism.
Preventive therapy comprises of INH mono-therapy at a dose 10mg/kg/day
for 6 months irrespective BCG status.
Always exclude TB disease before providing preventive therapy. If a child
during preventive therapy develops symptoms suggestive of TB s/he should
be evaluated for TB disease. An infant born to mother suffering from
pulmonary TB can be safely breastfed if INH is prophylactically given. If the
child has not been given BCG vaccine; BCG should be given after completion
of treatment.

59. Treatment of Tuberculosis in Special Situation
Pregnancy
The basic principles of treatment of TB in pregnancy are the same. Most anti-
TB drugs are safe to use during pregnancy.
• All pregnant women should also receive preventive treatment for isoniazid-
related peripheral neuropathy. For this, they should be given oral Vit
B6(Pyridoxine) at a dosage of 10mg/day along with their anti-TB drugs for
the entire duration of treatment.
• Rifampicin can increase the metabolism of vitamin K, resulting in clotting
disorders. Prophylactic administration of vitamin K to the mother and the
neonate is recommended to prevent the risk of post-natal haemorrhage
when the mother has received rifampicin during pregnancy
• Streptomycin causes ototoxicity to the fetus, so it cannot be given.

60. Breast-feeding women
• Breast feeding should be continued in the normal manner while the
mother is taking anti-TB treatments. Breastfeeding should be avoided only
in cases where the mother has TB/HIV co-infection.
• Breast-feeding women on ATT should routinely receive preventive
treatment for isoniazid-related peripheral neuropathy. For this, they should
be given oral Vit B6 (Pyridoxine) at a dosage of 10 mg/day along with their
anti-TB drugs for the entire duration of treatment. In addition, the breast-
fed infant should receive INH preventive therapy after ruling out active TB.
• The mother should be advised about cough hygiene measures such as
covering the nose and mouth while coughing, sneezing or any act which
can produce sputum droplets. Constant use of a face mask by the mother
should be encouraged.

61. Use of contraceptives in TB patients
• Rifamycins (Rifampicin, Rifabutin etc.) are potent inducer of hepatic
enzymes, and hence, the protective efficacy of oral contraceptive pills
may be decreased. Hence, female TB patients of reproductive age
group on ATT may choose alternate methods of contraception like use
of IM medroxyprogesterone, barrier methods like diaphragm,
condom, IUD etc. or, as a last option, an OCP containing a higher dose
of oestrogen (50 μg /tab), throughout the course of treatment.

62. Drug-induced hepatitis
• Anti-TB drugs can cause liver damage. Pyrazinamide is the most
hepatotoxic, followed by isoniazid and rifampicin .
• If the diagnosis of drug-induced hepatitis is made, the anti-TB drugs should
be stopped and withheld until the jaundice or hepatic symptoms have
resolved and liver function tests have returned to normal.
• However, if the hepatitis produced severe jaundice, it is advisable to avoid
rifampicin and pyrazinamide altogether.
Acute viral hepatitis
TB treatment should be deferred until the acute hepatitis has resolved. Once
the hepatitis resolves, patients can receive the usual anti-TB regimens
provided there is no clinical and bio-chemical evidence of liver function
impairment. In patients with unstable and persistent hepatitis, treat with 8
months of isoniazid, rifampicin plus ethambutol and avoid pyrazinamide.

63. Chronic liver disease
Patients with chronic liver disease should not receive pyrazinamide. Isoniazid
plus rifampicin plus ethambutol can be used for a total treatment duration of
9 months (2HRE/7HR).
Tuberculosis and renal insufficiency
• Isoniazid and rifampicin are eliminated by biliary excretion, so no change in
dosing is necessary.
• Ethambutol and metabolites of pyrazinamide have significant renal
excretion and thus, dosing adjustments are required. Three times per week
administration of these two drugs at the following doses is recommended:
pyrazinamide (25mg/kg), and ethambutol (15 mg/kg) specifically in late
stages of renal disease (Stage 4 and Stage 5).
• While receiving isoniazid, patients with severe renal insufficiency or failure
should receive pyridoxine 10 mg daily in order to prevent peripheral
neuropathy.

64. Adverse Effect Management

67. Treatment outcome of TB patients

68. Bacteriological Status

69. Classification based on history of previous TB treatment