TB Burden in the World

1/3 of the World Population is Infected

1 Person is Infected per Second
1.9 Million People Die of TB each Year
Philippines is 1 of the worlds 22 high-burden
countries for Tuberculosis

TB Burden in the
Philippines
22 million reported infections
TB kills 75 Filipinos per day
TB is the 6th leading cause of
Mortality and Morbidity
Undiagnosed TB cases remain
high in local communities

What is Tuberculosis?
TUBERCULOSIS is an infectious disease
caused by a micro bacteria called Tubercle

bacilli. It is airborne. It usually affects the

lungs but may also affect other organs in the
body like the meninges, bones, kidneys etc.

Mycobacterium Tuberculosis

Rod-shaped bacilli
Non-spore-forming
Thin aerobic bacterium measuring 0.5 m by 3 m
Acid-fast bacilli

Cell
wall skeleton structure:
Lipoarabinomannan:
involved in
results
the pathogen-host
in very low permeability
interaction
and
facilitates
of M.
of
the
cell wall the
thussurvival
reducing
tuberculosis within
macrophages
effectiveness
of most
antibiotics

1.
2.
3.
4.
5.
6.
7.
8.

Outer lipids
Mycolic acid
Arabinogalactan
Peptidoglycan
Plasma membrane
Lipoarabinomannan
Phosphatidylinositol mannoside
Cell wall skeleton

TB Transmission
M. tuberculosis is carried in airborne particles, called droplet nuclei,
of 1 5 microns in diameter.
Infectious droplet nuclei are generated when persons who have
pulmonary or laryngeal TB disease cough, sneeze, shout, or talk. It
can also occur through the gastrointestinal tract
Depending on the environment, these tiny
particles can remain in the air for several
hours.
M. tuberculosis is transmitted through the
air, not by surface contact.

How can the bacilli

replicate inside the
macrophage?
Lipoarabinomannan: inhibits
Ca2+/calmodulin pathway
(leading to phagosome
lysosome fusion) is impaired,
and the bacilli survive within
the phagosomes

Pattern of Infection
Primary Tuberculosis

Secondary
Tuberculosis

Children

Adult

develops in a
previously unexposed
and therefore
unsensitized, person

arises in a previously
sensitized host

Mid to Lower Zone of

Lungs

Upper Lobes of Lung

granulomatous lesions
are formed at the site of
infection due to delayed
hypersensitivity
reaction
(immunologicalrespons
e)

reactivation of dormant
primary lesions many
decades after initial
infection, particularly
when host resistance is
weakened

Primary Tuberculosis
The progression to clinical disease in a previously unexposed, immunocompetent
person depends on three factors:
(1) The number of M. tuberculosis organisms inhaled
(2) Infecting dose and the virulence of these organisms
(3) The development of anti-mycobacterial cell-mediated immunity
Immunity to M. tuberculosis is primarily mediated by TH1 cells, which stimulate
macrophages to kill the bacteria

 Disease that develops in a previously unexposed

person. Almost always begins in the lungs
Inhaled bacilli implant in the distal airspaces of lower
part of upper lobe or upper part of lower lobe
1-1.5 cm area of grey white inflammation with
consoldation
develops, called as Ghon focus which often caseates
Parenchymal lung lesion + Lnns involvement = Ghons
complex
Ghons complex:
Subpleural granuloma at right along with Granuloma in the
hilar lymph node

FATE OF PRIMARY TUBERCULOSIS

No progression
Healing by fibrosis and calcification
Ghons complex after undergoing progressive fibrosis
produces radiologically detectable calcification called
as Ranke complex
Progressive primary tuberculosis
Primary miliary tuberculosis
Dissemination to organs like liver, spleen, kidney,
..etc.

Secondary Tuberculosis
arises in a previously sensitized host
may follow shortly after primary tuberculosis, but more commonly it
arises from reactivation of dormant primary lesions many decades after
initial infection, particularly when host resistance is weakened
tendency of walling off the infective site greater than those of
primarily infected patients provided that the immune system of the
patient is not compromised.
Hence, in such patients infection remain localized and regional lymph
nodes are less commonly involved.
In secondary tuberculosis there are greater chances of spread of
infection of the other organs that is, brain, kidneys and bones etc.

SIGNS AND SYMPTOMS OF TUBERCULOSIS

Persistent cough for at least 2 weeks
Chest pains/ Back Pains (breathlessness)
Persistent low grade fever for more than a month
Significant weight loss with or with out loss of appetite
Hemoptysis (Blood-tinged sputum)
Feeling of weakness (tiredness)
Night Sweats

Physical Examination
Dullness to chest percussion, rales
Auscultation revealed vocal fremitus sound
Laboratory Tests
Moderate elevations in the white blood cell (WBC) count with a
lymphocyte predominance

Chest Radiograph:
Patchy or nodular infiltrates in the apical areas of the upper lobes or the superior
segment of the lower lobes
Cavitation that may show air-fluid levels as the
infection progresses

Chest radiographs in pulmonary tuberculosis

B
C

A. Infiltrates in left lung

B. Ghons complex (Primary tuberculosis)
C. Bilateral advanced pulmonary tuberculosis and cavitation in apical area of right lung

LASSIFICATION OF TB DISEAS

General Classification of Tuberculosis

CLASSIFICATION

DEFINITIONS

Presumptive TB

Cough of at least 2 weeks in an adult (age > 15 yo)

Radiologic imaging suggestive of TB
Any person who presents with symptoms or signs
suggestive of TB
Cough of any duration in a high risk individual or a
close contact of an active TB case

Definite case

A patient with MTB Complex identified from a clinical

specimen either by culture or by a newer method such
as molecular line probe assay

New Case

Patient who never had treatment for TB or who has taken

anti-TB medications for < 1 month

DIAGNOSIS

DIAGNOSIS
SKIN TESTING

Infection with M. tuberculosis typically leads to the

development of delayed hypersensitivity to M. tuberculosis
antigens, which can be detected by the tuberculin (Mantoux)
test
About 2 to 4 weeks after infection, intracutaneous injection of
purified protein derivative of M. tuberculosis (PPD) induces a
visible and palpable induration that peaks in 48 to 72 hours
Shall not be used as the sole basis for TB diagnosis. It shall be
used as a screening tool for children. A 10 mm induration is
considered positive

DIAGNOSIS
SKIN TESTING
A positive tuberculin test result signifies cell-mediated

hypersensitivity to tubercular antigens. It does not differentiate

between infection and disease
False-negative reactions may be produced by certain viral
infections, sarcoidosis, malnutrition, immunosuppression
False-positive reactions may also result from infection by atypical
mycobacteria

DIAGNOSIS
DIRECT SPUTUM SMEAR
MICROSCOPY

Sputum smear microscopy is the

primary diagnostic tool in NTP case
finding

Direct smears (unconcentrated

specimen) are most common

Fluorescence microscopy and

chemical processing can increase
sensitivity

Assessment of laboratory quality is

DIAGNOSIS
Direct smears of unconcentrated
sputum:
Fast, simple, inexpensive, widely
applicable
Extremely specific for M. tuberculosis in
high-incidence areas
Ziehl-Neelsen staining (carbol fuchsin
type) most common

DIAGNOSIS
Direct Sputum Smear Examination
2 sputum specimens of good quality shall be collected
either as front-loading or spot-early morning specimens

Are essential to confirm TB Best collected in morning

before any meal

Sputum examination on 3 days, increase chances of

detection
Sputum can be collected from laryngeal swab or bronchial
washing In small children, gastric lavage can be examined.

DIAGNOSIS
Sputum TB culture
Primarily recommended for patients at risk for drug
resistance
It is recommended in the following smear positive
patients:
All cases of retreatment
All cases of treatment failure
All other cases of smear positive patients
suspected to have one or multi-drug resistant TB
All household contacts of patients with MDR-TB

DIAGNOSIS
Chest Radiograph
Recommended for patients suspected to have PTB
whose sputum smears are negative
Initiating TB treatment based on chest radiographs
alone is discouraged

DIAGNOSIS
Rapid Diagnostic Test (Xpert MTB/RIF)
is a new test contributing to the rapid diagnosis of TB disease and drug
resistance

The test simultaneously detects Mycobacterium tuberculosis complex

(MTBC) and resistance to rifampin (RIF) in less than 2 hours

used for TB diagnosis among presumptive DR-TB, PLHIV with signs and
symptoms of TM, smear-negative adults with CXR findings suggestive of
TB

TREATMENT

FOUR MAJOR SUBPOPULATIONS OF TB BACILLI

GROUP 1

GROUP 2

GROUP 3

GROUP 4

Organisms living
extracellularly in
pulmonary cavities
(outside
macrophages)

Organisms living
extracellularly in
caseous lesion

Intracellular
organisms that live in
the acidic, hypoxic
environment of
macrophages

Trapped organisms
that are completely
dormant and are
unaffected by both
antimicrobials and
cellular immune
mechanisms

Metabolically very
active, and are rapidly
and continuously
growing in a
hyperoxic, neutral pH
environment

Less or only
intermittently
metabolically active
in a hypoxic and
neutral pH
environment

Have slow or
intermittent growth

Highly susceptible to:

Streptomycin
Isoniazid

Susceptible to:
Rifampicin (RMP)
INH

PZA and RMP are

uniquely effective
against these

Why Tuberculosis is difficult to cure?

CONSIDERATIONS FOR EFFECTIVE

CHEMOTHERAPY
Only actively replicating organisms are killed by
chemotherapy
Those organisms which arent actively replicating or
dormant (Group 4), you cant kill

Differences in mycobacterial metabolic rate are

associated with differences in mycobacteria
susceptibility to anti-TB drugs
The difference in pH, in metabolic rate whether or not they
are intra or extracellulary surviving will determine which
drug will be effective for them

DRUG

DOSE
(DAILY)

MOA

Isoniazid
(H/INH)

5 mg/kg,
max 300
mg

Inhibits fatty acid synthase and mycolic acid synthesis

Excellent bactericidal activity against both intracellular and
extracellular actively dividing MTB
Bacteriostatic against slowly dividing organisms

Rifampicin (R)

10 mg/kg
max 600
mg

Binds to and inhibits mycobacterial DNA-dependent RNA

polymerase thereby blocking RNA synthesis
Has both intracellular and extracellular bactericidal activity,
both in dividing and non-dividing MTB
Also has sterilizing activity
Most active antimycobacterial agent available and therefore the
cornerstone of first-line TB treatment

Pyrazinamide
(Z)

25 mg/kg
max 2 g

Exact mechanism is unclear

More active against slowly replicating organisms than actively
replicating organisms
Active only in acidic environment (pH < 6.0) and are found
within phagocytes or granulomas

DRUG

DOSE
(DAILY)

MOA

Ethambutol
(E)

15 mg/kg

Inhibits arabinosyltransferases involved in cell wall synthesis,

which probably inhibits the formation of arabinogalactan and
lipoarabinomanan
Bacteriostatic antimycobacterial agent which provides synergy
with other drugs
Least potent against MTB

Streptomycin
(S)

15 mg/kg
max 1 g

Inhibits protein synthesis by binding at a site on 30S mycobacterial

ribososme
Bactericidal against dividing MTB but has only low-level early
bactericidal activity

SECOND-LINE AGENTS
Use of second line drugs for tuberculosis:
1. In case of resistance to First-line agents
2. In case of failure of Clinical response to
conventional therapy
3. In case of serious treatment-limiting adverse
drug reaction
4. When expert guidance is available to deal with
the toxic effect

MONITORING RESPONSE TO TREATMENT

TREATMENT OUTCOMES