3. Evening of March 24th 1882.
Koch made a presentation to Berlin
Physiological society that revolutionalised
medical science.
Its effects are still felt today.
He identified, cultured the TB bacilli that
he described as a rod shaped bacterium.
Cell wall contains 60% lipids thus its
property of resisting up take of stains
and once it has taken them up its difficult
to remove it.
4. Epidemiology.
TB remains one of the deadliest diseases in
the world.
WHO estimates @ yr >8 million new cases of
TB occur and 3M die.(1996).
20-43% of the worlds pop is infected with TB.
Who report 2005 ~ globally 1/3 of the worlds
popn is infected with TB.
95% are in developing countries.
25% of the total TB cases are in Africa (WHO
2000).
5. Background.
15% of these are children resulting into
450,000 deaths annually (Seth et al 1993).
Spread by droplet containing ~3 bacilli for the
tiny ones.
4 factors determine the likelihood of
transmission:
No of organism expelled in air.
[Organism] in air determined by ventilation.
Length of time exposure.
Immune status of exposed individual.
6. Uganda TB Burden.
Is among the 22 high burden TB countries globally.
TB incidence is 411/100,000.
Prevalence is 625/100,000.
TB cases ed. 35,232 in 2000: 44,612 in 2004.
3-4% of all the smear + were < 15yrs.
7. Uganda HIV coinfection.
Co-infection in adults is >50% Uganda inclusive. ( WHO
Report 2005).
HIV + are 100 times more likely to develop TB.
TB occurs any time.
Tb in HIV is cuarable.
8. Tuberculosis infected.
State of harboring viable tubercle bacilli within ones
body without manifesting signs or symptoms of overt
disease.
The great majority of normal hosts who are exposed to
and infected with M. tuberculosis enjoy this status
throughout their entire lives.
9. Tuberculosis diseased.
State of suffering from active, progressive invasion of
an organ or organs by M. tuberculosis.
Typically is manifested by constitutional signs or
symptoms related to a specific organ or system.
In most cases a tuberculin skin test is reactive, but its
not specific nor sensitive for disease status.
10. TB BURDEN.
In Africa: HIV, malnutrition, poor health services have
lead to a TB disease burden.
Children are important in the epidemiology of TB as a
marker of recent disease transmission and a reservoir
for the future.
11. Time table for development of
TB.
Form of TB. Time from infection to onset.
Immune conversion.
Primary complex.
Local lung complications.
Pleural effusion.
Milliary/meningeal.
Bone.
Skin.
Renal.
Secondary breakdown.
4-8 wks.
1-3 months.
3-9 months.
3-12 months.
3 months onwards.
10-36 months.
5 yrs onwards.
10 yrs onwards.
5 yrs onwards.
12. Common presentation in
symptomatic children.
Cough and respiratory symptoms.
Weight loss and anorexia.
Fever.
L-nopathy.
Usually gradual in onset > 3wks, unremitting in nature,
and increasing in severity.
History of contact is extremely essential.
13. Pathophysiology.
Caused by M. tuberculosis through airborne inhalation of
bacilli exhaled by person with active PTB.
Transplacental infection.
Bovine transmission from infected bovine products.
14. Pathology.
Primary complex. At the site of initial
infection the following occurs:
Accumilation of polymorphonuclear
leucocytes.
Epitheliod cells proliferate.
Typical tubercle formation.
Ghon focus: Local inflammation.
Ghon complex: Lung tissue inflammation,
Lymphangitis, local adenopathy (Primary
complex).
15. Pathology.
Primary complex coupled with regional hillar Lnopathy
give the Ranke complex.
Apical fibronodular scarring attributed to transitory
inflammation in the upper lobes following primary
bacillemia may be seen on CXR : Simon foci.
16. Four phase model-TB.
Phase I (transmission).
Diseased generates infected aerosols.
Potential host inhales droplet nuclei.
Droplet nuclei transits bronchial tree and is deposited in
the alveoli.
Bacilli are engulfed by non immune resident alveolar
macrophages.
17. Phase II.
Initiation of infection, proliferation and
dissemination.
Bacilli survive within alveolar macrophages and
proliferate intracellularly.
Proliferating bacilli kill the alveolar macrophages,
and are released, chemokines are released and
attract additional cells.
New alveolar macrophages + blood monocytes ingest
bacilli.
ﻻ/δ lymphocytes, natural killer cells, and T
lymphocytes begin to appear in lesions.
Bacilli continue to multiple, kill host cells, spread locally.
Are transmitted to hillar LNs and spread systemically.
18. Phase III.
Evolution of host immune response.
Macrophages present tuberculosis antigens to T
lymphocytes, T cells release cytokines.
Cytokines recruit and activate macrophages,
resulting in protective cellular and tissue
damaging immune responses.
These responses limit proliferation and/ or kill,
bacilli, resulting in involution of the primary lung
lesion and the remote extrapulmonary foci.
Or host fails to mount effective response and
experiences progressive primary disease at initial
lung infection and or extrapulmonary sites.
19. Phase IV.
Liquefaction and accelerated bacillary
proliferation.
Pulmonary focus reactivates and undergoes
liquefaction with cavity formation.
Extra cellular bacilli multiply exponentially
during this accelerated bacillary proliferation.
Retransmission.
Patient expectorates bacilli in secretions,
another person inhales them, cycle is completed.
20. TB case definitions.
Case of TB: Confirmed bacteriologically or clinicians
diagnosis.
Definite case: +culture for M. TB or 2 sputum smear +
for AFBs.
Smear + Pulmonary case: At least 2 smear +, or 1
sputum smear + with CXR that is suggestive, 1 smear +
sputum and culture + for M. TB.
21. Cont’d.
Smear negative: 3 sputum smears are negative, CXR
abnormalities consistent with active PTB, no response
to a course of broad spectrum Abs or + culture but neg
AFBs on sputum smear microscopy.
Extrapulmonary: TB of organs other than the lungs eg
pleura, Lnodes, abd, GUT, skin, bones, meninges etc.
22. Cont’d:
New case: Has never had treatment for TB or who has
taken treatment for < 1month.
Relapse case: previously declared cured, with a new
episode of bacteriologically + sputum smear or culture.
Retreatment: Previously treated, but treatment failed,
or defaulted, or relapsed.
23. DOTS Classification.
Internationally recommended approach to TB control.
Has been adopted in 148 out 210 countries world wide.
55% of the world’s popn lives in countries providing DOTs.
5 elements of DOTs.
Sustained political commitment.
Access to quality-assured TB sputum microscopy.
Standardized short-course chemotherapy to all cases of TB
under proper case-management conditions.
Uninterrupted supply of quality-assured drug.
Recording and reporting system enabling outcome
assessment.
24. MDR and DOTs plus.
Single, multiple, multidrug resistance has been on the
increase.
INH resistance has been found to be 6.8-7.2% isolates in
children <15yrs.( Uk 1995-99).
MDR is resistance to both INH + RF.
Over the same period in the UK was 0.5-0.7%. er in
minority gps. Indians + Sub saharan-Africans.
25. Cont’d.
Rx of MDR should be carried out by specialists with
appropriate experience.
Commonest drug resistance is INH.
Thus important to add Ethambutol. Rx for 9-12 mon
with RZE x 2mon then RE.
RF resistance usually occurs with INH (MDR). Rx involves
at least 5 drugs or more for 2 yrs duration. (DOTS plus).
27. Drug regimens in Pediatrics.
Recommended dosages of 1st line by WHO.
Drug. Daily. Intermittent.
Isoniazide.
Rifampicin.
Pyrazinamide
Ethambutol.
5mg/kg.
10mg/kg.
25mg/kg.
15mg/kg.
10mg/kg x3wkly
10mg/kgx3wkly
35mg/kgx3wkly
30mg/kgx3wkly
28. Recommended TB Rx Schedules
for Children.
WHO Schedule
PTB, severe EPTB
(disseminated acute TB,
Abd, spinal, pericardial).
Smear negative PTB,
less severe EPTB ( TB
adenitis, mediastinal
Lnopathy).
2 mon RHZE, 4mon RH
daily or 3 times wkly.
2 mon RHZ then 4 mons
RH daily or 3 times
weekly.
29. Adverse effects.
May be seen in children when they start treatment.
INH + RF are hepatotoxic causing serum
aminotransferase levels.
INH has been associated with symptomatic pyridoxine
def esp in severely malnourished. Thus need to
supplement in PEM + breastfeeding infants.
30. Adverse effects!!!!!!!
Ethabutol causes retrobulbar neuritis. Which presents
with blurred vision, central scrotomas, colour blindness.
31. Definitions of treatment
outcomes.
Cured: Initially smear + , patient is smear neg
in the last one month of treatment.
Completed treatment: Has completed
treatment but does not meet the criteria for
cure or failure.
Died: Pt who dies for any reason during
treatment.
Failed: Smear positive patient who remained
smear + or became smear positive again at
least 5 months after the start of treatment.
32. Cont’d:
Defaulted: Treatment was interrupted for 2 consecutive
months or more.
Transferred out. Pt has been transferred to another
reporting unit and for whom the treatment outcome is
not known.
Successfully treated: The sum of cases that were cured
and that completed treatment ( expressed as a % of the
number registered in the cohort).
34. CXR findings in TB.
A number of features may suggest but none is
diagnostic with the exception of milliary TB.
Typical post primary cavitation is rare,
occasionally seen in teenagers.
Most typical feature is hillar
Lnopathy/paratracheal →
collapse/consolidation.
Localized hyperinflation from partial bronchial
obstruction esp in infants with B/pneumonia.
In adolescents esp pleural effusion.
35. Microscopy and Culture.
Early and timely dx of TB relies heavily on microscopy of
clinical samples for AFBs using ZN stain.
Microscopy can detect 60-70% of culture + samples with
lower limit of detection of 5x10³ organisms/ml.
< than 20% of children with proven TB will have a
sputum/gastric aspirate + for ZN compared to adults
75%.
36. Cont’d.
Mycobacterial culture of GA has provided a more useful
dx method in PTB children.
3 consecutive morning GA yield M.tb in 30-50% of cases
and may be as high as 70% in infants.
Culture yield in EPTB from other body fields is usually
<50% due to paucibacillary nature.
37. Sputum.
Minimum of 3 samples not more than 6.
Collected in series, early morning.
Induced sputum for those who can’t
expectorate.
Done by inhalation of an aeresol of sterile
hypertonic saline (3-15%) by nebulization
to stimulate sputum production.
Done in high efficacy particulate air
(HEPA) filter to prevent transmission.
38. Bronchial washings, bronchoalveolar
lavage, transbronchial biopsy.
Use a fiberoptic broncoscopy under ideal environment.
In the presence of significant PTB bronchoalveolar fluid
may be neg.
Topical anesthetic drug used also kills the bacilli
reducing on the yield.
39. Gastric aspirates.
50mls of GA early morning after pt has fasted for 8-
10hrs.
Should be neutralized immediately on collection
Yield ~40% of those with radiologic evidence of PTB.
40. Pleural Aspirate and Bx.
PA can be analysed for protein and
glucose and compared to serum protein
and glucose
Cell differential counts.
protein > 50% of serum [protein],
lymphocytosis, low glucose are usually fd
in TB.
ADA ( Adenosine deaminase) a purine
degrading enzyme for maturation and
differentiation of lymphoid cells.
41. Cont’d.
Has been reported in a no of studies to be
elevated in these fluids when TB involves
these sites.
Culture yield is low fd in < 20% of cases.
Pleural bx shows granulomatous inflammation
in ~ 60%of pts.
Culture of 3 bx specimens + microscopy yield
is 90%.
Pleuroscopy guided bxs increase the yield in
pleural sampling.
42. Tuberculin skin testing.
A + TST reaction is a hallmark of primary infection with
M.Tb.
Not ideal and has to be interpreted in context.
In children TST becomes apparent in 3-6 wks, but can
take up to 3 months.
Tuberculin reactivity due to M.tb infection usually
remains + for life even after treatment.
43. TST cont’d.
Its based on the fact that M.tb produces a delayed
hypersensitivity reaction.
Directed to certain antigenic components of the
organisms that are contained in extracts of culture
filtrates: “tuberculins.”
There are 2 major techniques: Mantoux and multi-
puncture tecnique.
44. Mantoux Test:
Uses 5-10 tuberculin units of purified
protein derivative.
Involves intradermal inj of PPD into the
most superficial layer skin of the forearm
raises an immediate wheal.
Measured in mm of induration not
erythema after 48-72hrs.
There has been so much uncertainty of
effect of BCG vaccination on TST results.
45. BCG effect on TST.
BCG vaccination may cause a transiently reactive TST.
Most children who received BCG as infants have a non
reactive TST at 5yrs of age. (Lifschitiz et al 1965).
Meta analysis suggested that effects of BCG on TST was
less after 15yrs and an induration> 15mm was most
likely to be TB infection. ( Wang et al 2002).
46. Uganda-study on effect of
BCG vaccination on TST.
BCG vaccination coverage in Uganda is 82-84% at
birth.
360 children were evaluated from an on going
prevalence study of household contacts of
new TB cases.
Classified as contacts(179) and non contacts
(186) depending on smear +/- adult.
Found that BCG had no important effect on the
interpretation of TST reactivity still valuable.
(P.Musoke et al 1999 Int J. Tuber Lung Dis).
47. Cut offs of TST results.
British thorasic Society. WHO.
Mantoux:
Positive:
5-14mm (no BCG).
>15mm(BCG).
>10mm(no BCG)
>15mm(BCG).
HIV: >5mm is positive.
48. WHO guidelines for Dx of PTB
in Children. (1994).
Suspected TB.
Any ill child with a h/o contact with a confirmed case of
PTB.
Any child:
Non regaining normal health after measles or whooping cough.
With wt loss, cough, and wheeze not responding to Abs.
With painless swelling in a group of superficial nodes.
49. Cont’d.
Probable TB. A suspect case and any of the
following:
+PPD >10mm induration.
Suggestive appearance on Xray.
Suggestive appearance on Bx material.
Favorable response to anti TB therapy.
Confirmed TB.
Detection by microscopy or culture of tubercle
bacilli from secretions or tissue.
Identification of bacilli by culture.
50. Newer diagnostic methods.
PCR: Uses amplification of small amts of nucleic acid
material.
Specificity can be but sensitivity low and less than that
of cultures.
Sensitivity of good quality PCR is expected to be 90-
100% and 60-70% on smear + and – culture + respiratory
samples respectively. (Hessling et al 2002)
51. Cont’d.
Several studies in children have found
sensitivity of 40-60%compared with
clinical dx.
This compares favorable with standard
cultures which have a sensitivity of 30-
40%.
Specificity of PCR 80-96%.
Further more 39% of children with no
radiological /clinical evidence also had a
+ PCR.
52. BACTEC.
Is a radiometric method.
Uses radioactive carbon. Organisms use the carbon for
energy.
Thus give off radioactivity which is picked up by a
counter thus signifying growth.
53. Serological testing.
ELISA has been used to detect antibodies to M.TB
antigens. Eg PPD derivatives, killed M.TB, and antigen
A60.
Has no adequate sensitivity, specificity or
reproducibility in dx of TB in children..
54. Immunodiagnosis.
TST suffers poor specificity due to variable host
responses and antigenic cross reactivity of M.TB.
This makes M.Tb infection difficult to differentiate
from the effects of BCG and environmental MB.
The early secretory antigenic target or ESAT-6 antigen is
present in M.Tb complex and absent in all the other
strains.
55. Cont’d.
Lalvani et al developed an ELISPOT assay of ESAT-6
specific interferon-ﻻ secreting lymphocytes that can
reliably differentiate M.tb from BCG immunization.
South African study
56. RFLP!
Restrictive fragment length Polymorphism. Also known
as DNA finger printing. Uses a specific enzyme that
fragments the DNA at specific bonds.
57. Treatment of TB infection.
Other than the disease involves use of one or
more drugs to prevent the future
development of TB.
Many studies have shown INH to be highly
efffective as a single drug.
For 12 months.
Shorter courses 6-9months.
Double drug regumens.
RH/INH for 3mon.
RF/Z for 2 mon.
58. Mx of children who are close
contacts of smear + adults.
They are at very high risk of developing dse.
Categories include:
Young children<2yrs for BTS.
<5yrs for WHO.
<4yrs for ATS/CDC.
Should begin on INH chemoprophylaxis
irrespective of TST at baseline.
If TST is + at baseline or becomes +on
retesting(6-12wks) duration of therapy should
be that of TB infection.
