Tuberculosis

REVIONO
DEPARTMENT OF PULMONOLOGY AND
RESPIRATORY MEDICINE
MEDICAL FACULTY,
UNIVERSITY OF SEBELAS MARET

LOGO
 Introduction
Tuberculosis is a contagious disease that
progresses from a systemic infection caused by
bacteria of the Mycobacterium tuberculosis
complex.
The generic term ‘‘tubercle bacilli’’ incorporates
at least five species belonging to a group
termed the M. tuberculosis complex: M.
tuberculosis, Mycobacterium bovis,
Mycobacterium africanum, Mycobacterium
canettii, and Mycobacterium microti.
Most commonly, M. tuberculosis is spread from
person to person by airborne transmission of
droplet nuclei.(Palomino, 2007)
 Microbiology
Under favorable laboratory conditions, M.
tuberculosis divides every 12 to 24 hours. This
pace is extremely slow compared to that of most
cultivable bacteria, which duplicate at regular
intervals ranging from about 15 minutes to one
hour.
The low multiplication rate explains the typically
sub-acute to chronic evolution of the disease
and the long time required to attain visible
growth in vitro.
M. tuberculosis complex organisms multiply
within narrow temperature and pH ranges, and
at a high oxygen tension. (Palomino. 2007)
The microorganism also with stands very low
temperatures. Its viability may be increasingly
preserved for a long term between 2-4°C to -
70°C.
The bacilli may survive for many years in low
oxygen tension but need a minimal
concentration of oxygen to induce the switch into
a fermentative metabolism
On the other hand, the bacilli are very sensitive
to heat, sunlight and ultraviolet (UV) irradiation.
(Palomino, 2007)
 Cell Wall
Due to the high content of lipids in their cell wall,
all mycobacteria are acid-fast bacteria (AFB),
which means that special efforts are required to
make the dyes penetrate through the bacterial
cell wall, and it is difficult to decolorize them with
acid–alcohol after they are stained.
Mycobacteria have a high lipid content in the
outer layer of the cell wall, which includes
glycolipids and esters of fatty acids with fatty
alcohols; one of the water-soluble glycolipids
(mycosides), known as ‘‘cord factor,’’ is
considered to be related to the virulence of
tubercle bacilli. Reichman and Hershfield's, 2006
 CLINICAL TUBERCULOSIS
 Tuberculosis is generally insidious at onset; symptoms
may be minimal or absent until the disease advances.
 The cardinal symptoms are cough, fever, sweats or chills,
anorexia, weight loss, and malaise. Persistent cough,
which may be dry or productive, is the most common
symptom. Hemoptysis is usually seen with advanced
illness. Dyspnea is more likely to occur with pleural
involvement (effusion), but with extensive parenchymal or
miliary disease. Chest pain often results from involvement
of the pleura or adjacent parenchyma. Cough, the most
sensitive symptomatic indicator of active disease,
whereas fever and weight loss generally occur in less
than half and hemoptysis is found in less than one-quarter
Reichman and Hershfield's, 2006
 Physical examination findings are both insensitive and
nonspecific for diagnosing pulmonary tuberculosis
 Physical signs in TB are related to the extent of the
lesions, the duration of the disease and the form of
presentation. The longer the duration of the disease,
the more evident are the classic signs of consumption,
such as pallor and weight loss.
 The most common auscultation findings are: coarse
crackles in the area corresponding to the lesion
(generally apical and posterior); wheezing and ronchi in
the area of compromised bronchi; decreased vesicular
murmur and broncophony or tubular blow when pleural
effusion is present; as well as the classic amphoric
breath sounds near cavities. Reichman and Hershfield's, 2006
 Laboratory Examination
The bacteriological diagnosis of TB is most
commonly based on examination of sputum
specimens (smear examination, culture
isolation, molecular methods, etc.). Depending
on the site of infection, other specimens include
various body fluids (pleural, cerebrospinal,
synovial, etc.), blood, lymph nodes, and other
biopsy specimens
Sputum smear examination for AFB detection is
the method most widely used for the provisional
diagnosis of pulmonary TB
Reichman and Hershfield's, 2006
 The principal method of pulmonary TB diagnosis is
microscopic examination of Ziehl-Neelsen stained
sputum samples for AFB
 The sensitivity of this method is limited: the results
can be positive if the specimen contains no less
than 104 AFB/mL of sputum, with variations
depending on the skill of the technologists.
 Cultures are most commonly performed on solid
media (Löwenstein-Jensen or Ogawa Kudoh), giving
results on an average of 30 days. Cultures in liquid
media give faster results and may be more
sensitive, Drug susceptibility testing is indicated
when infection with drug resistant strains is
suspected
Toman, 2004
 Radiological examination
The chest X-ray examination may help to make
the diagnosis in respiratory symptomatic patients
that are repeatedly negative on direct
microscopy sputum examination.
It may also help in those individuals that cannot
produce sputum for the bacteriological
examination.
In patients with positive smear microscopy, the
chest X-ray exam may be indicated to exclude
an associated lung disease, and also allows the
evaluation of the disease evolution, especially in
patients not responding to TB treatment
Reichman and Hershfield's, 2006
The results of the chest X-rays may be described as:
• Normal: absence of pathological images in the
lung fields
• Sequelae: presence of images suggestive of old
scarred lesions
• Suspect: presence of images suggestive of active
TB
- single or multiple condensations in the upper third of
one or of both lungs and in the apical segment of
the lower lobe
- cavities in the upper third or in the apical segment of
the lower lobe unilateral or bilateral pleural effusion
- miliary pattern Reichman and Hershfield's, 2006
 Pathogenesis
 Infection with M. tuberculosis in most instances occurs by
inhalation of droplet nuclei (1–5 µm) contain the infectious
bacteria and are aerosolized from the lung tissue of TB
patients by respiratory maneuvers : coughing or speaking.
 Such infectious droplets, being small enough to reach the
alveolus, allow the bacille to avoid the mucociliary
clearance mechanisms of the airways.
 The alveolar macrophages (AM) are the first line of defense
against Mycobacterium tuberculosis.
 The bacille is engulfed by AMs are continually ingesting
inhaled particulates and as a result are usually in a partially
activated state, depending on the nature of the particulates
and the mechanism by which the material is ingested
Fishman, 2014
 Phagocytosis by an insufficiently activated AM allows the
bacille to avoid being killed and to begin a phase of
exponential replication.
 Droplet nuclei are deposited in the terminal airspaces and
the initial site of exposure is most often in the lower and
middle lobes due to the higher ventilation
 Most latently, M. tuberculosis–infected individuals do not
develop active TB. M. tuberculosis infection in such
persons is typically accompanied only by the development
of a positive tuberculin skin test (TST) or M. tuberculosis
antigen–specific lymphocyte proliferation or interferon
gamma (IFN-γ) production in vitro. The risk of developing
active TB is greatest in the first two years following infection
and is associated with more intense exposure to M.
tuberculosis.
Fishman, 2014
 Cellular immune response

 Since the tubercle bacilli reside inside acompartment

within the macrophage, their antigens are presented
by MHC class II molecules to CD4+ T lymphocytes.
These cells play an important role in the protective
response against M. tuberculosis and, when they are
absent, growth of the bacilli cannot be controlled
 The main function of CD4+ T cells is the production
of cytokines including IFN-γ, which activates
macrophages and promotes bacilli destruction.
 The participation of CD8+ T cells in the control of the
infection is well recognized
Reichman and Hershfield's, 2006
 Humoral immune response

 The prevailing view has been that humoral immunity has

little or no impact on the course of M. tuberculosis
infection. This may not be accurate.
 Antibodies also may play a pathogenic role during adult
TB by enhancing proinflammatory and by blocking
downregulatory cytokines. PPD-specific immunoglobulin
(Ig) G1 antibodies augment secretion of TNF-a, and IL-6
and IL-10
 Granulomatous tissue reactions are the pathologic
hallmark of TB. The granulomatous tissue reactions
depend on the regulation of apoptosis.
 Initiation of apoptosis requires death-inducing signals
such as lack of survival factors, metabolic supplies,
binding to death signal–transmitting receptors
Reichman and Hershfield's, 2006
 M. tuberculosis
Macrophage APC (LAM)

MHC Klas II CD4 +

Th0
IFN- (activation) IL-2,3,4,5 IL-10 inhibition
1. Proliferasi IL-6,10
2. Fagositosis IFN-
3. Enzim lisosome IgM,IgG
4. ROS IgA
5. Chemokin

Macrophage
activated SEL PLASMA
IL-4,10 (inhibition)
IFN-, IL-1 Th1 Th2
IL-4,5 Sel B
IL-2
IFN-, TNFα 6,10 IL-2
IFN- (inhibition) IFN- rendah
CD4 + CD4 +
Cellular immunity Humoral immunity
Immunopathogenesis TB
 Primary Tuberculosis

Tubercle bacilli can disseminate by the

lymphatic route to regional lymph nodes,
constituting the tuberculous primary complex of
Ranke, composed by the original granuloma at
the inoculation site (Gohn’s nodule), the
lymphangitis and the hilar lymph node
enlargement
From the hilar lymph nodes, tubercle bacilli
disseminate to tracheal and vertebral lymph
nodes. Through the thoracic duct, they reach the
blood stream, spreading to the upper areas of
the lungs or to different organs, such as kidney,
brain, and bones.
 The post-primary disease

 The existence of post-primary TB, also known as secondary

TB, means that the infection can progress after the
development of an adequate specific immune response. This
TB episode can develop in two ways: by inhalation of new
bacilli or by reactivation of the primary focus.
 Pulmonary TB is the most common form of post-primary
disease. Lymphatic dissemination can occur, but in this case
the hilar lymph nodes are usually not affected. The response to
bacillary multiplication provokes caseous necrosis that
eventually blends and progresses to liquefaction. Tubercle
bacilli, whose multiplication had been until then inhibited by
granuloma formation, find favorable conditions for population
growth after liquefaction of the caseum and subsequent
cavitation, and may produce more than 108 bacilli per cavity
with a diameter of less than 2 cm.
TB 1
TB 2
Bekas TB
 Extrapulmonary tuberculosis
 Extrapulmonary tuberculosis is seen in only about
15% of cases of immunocompetent individuals, but
is found in up to 70% of patients with advanced HIV
 The most common sites of extrapulmonary
tuberculosis are peripheral lymph nodes, the pleura,
the bones and joints, the genitourinary system,
peritoneum, gastrointestinal tract, and the central
nervous system (CNS)
 When disease is isolated to an extrapulmonary site,
collection of excretions (urine or stool), aspiration of
fluid (e.g., pleural fluid, ascites, cerebral spinal fluid),
or tissue biopsy for AFB smear, culture, and
histology may be necessary for diagnosis
 Case definitions

 Tuberculosis suspect. Any person who presents with

symptoms or signs suggestive of TB. The most
common symptom of pulmonary TB is a productive
cough for more than 2 weeks, which may be
accompanied by other respiratory symptoms
(shortness of breath, chest pains, haemoptysis)
and/or constitutional symptoms (loss of appetite,
weight loss, fever, night sweats, and fatigue)
 Case of tuberculosis. A definite case of TB (defined
below) or one in which a health worker (clinician or
other medical practitioner) has diagnosed TB and
has decided to treat the patient with a full course of
TB treatment
Definite case of tuberculosis. A patient with
Mycobacterium tuberculosis complex
identified from a clinical specimen, either by
culture or by a newer method such as molecular
line probe assay. In countries that lack the
laboratory capacity to routinely identify M.
tuberculosis, a pulmonary case with one or more
initial sputum smear examinations positive for
acid-fast bacilli (AFB) is also considered to be a
“definite” case, provided that there is a functional
external quality assurance (EQA) system with
blind rechecking. WHO, 2013
Pulmonary tuberculosis (PTB) refers to a case of
TB (defined above) involving the lung
parenchyma. Miliary tuberculosis is classified as
pulmonary TB because there are lesions in the
lungs. Tuberculous intrathoracic
lymphadenopathy (mediastinal and/or hilar) or
tuberculous pleural effusion, without
radiographic abnormalities in the lungs,
constitutes a case of extrapulmonary TB. A
patient with both pulmonary and extrapulmonary
TB should be classified as a case of pulmonary
TB.
 Extrapulmonary tuberculosis (EPTB) refers to a
case of TB (defined above) involving organs other
than the lungs, e.g. pleura, lymph nodes, abdomen,
genitourinary tract, skin, joints and bones,
meninges. Diagnosis should be based on at least
one specimen with confirmed M. tuberculosis or
histological or strong clinical evidence consistent
with active EPTB, followed by a decision by a
clinician to treat with a full course of tuberculosis
chemotherapy. The case definition of an EPTB case
with several sites affected depends on the site
representing the most severe form of disease.
The case of pulmonary TB is considered to be
smear-positive if one or more sputum smear
specimens at the start of treatment are positive
for AFB (provided that there is a functional EQA
system with blind rechecking).
The definition of a new sputum smear-positive
pulmonary TB case is based on the presence of
at least one acid fast bacillus (AFB+) in at least
one sputum sample in countries with a well
functioning EQA system.
 Smear-negative PTB
A. have sputum that is smear-negative but culture-
positive for M. tuberculosis:
• a case of pulmonary TB is considered to be
smear-negative if at least two sputum specimens
at the start of treatment are negative for AFB1 in
countries with a functional EQA system, where
the workload is very high and human resources
are limited
• in all settings with an HIV prevalence of >1% in
pregnant women or ≥5% in TB patients, sputum
culture for M. tuberculosis should be performed
in patients who are sputum smear-negative to
confirm the diagnosis of TB WHO, 2013
OR
B. meet the following diagnostic criteria:
• decision by a clinician to treat with a full course of
anti-TB therapy; and
• radiographic abnormalities consistent with active
pulmonary TB and
either:
— laboratory or strong clinical evidence of HIV infection
or:
— if HIV-negative (or unknown HIV status living in an
area of low HIV prevalence), no improvement in
response to a course of broad-spectrum antibiotics
(excluding anti-TB drugs and fluoroquinolones and
aminoglycosides).
WHO, 2013
 History of previous treatment: patient
registration group
 New patients have never had treatment for TB, or
have taken anti-TB drugs for less than 1 month.
New patients may have positive or negative
bacteriology and may have disease at any
anatomical site.
Previously treated patients have received 1
month or more of anti-TB drugs in the past, may
have positive or negative bacteriology and may
have disease at any anatomical site. They are
further classified by the outcome of their most
recent course of treatment as shown in Table
2.1 below WHO, 2013
WHO, 2013
 Aims of treatment
— to cure the patient and restore quality of life and
productivity;
— to prevent death from active TB or its late
effects;
— to prevent relapse of TB;
— to reduce transmission of TB to others;
— to prevent the development and transmission of
drug resistance
 New patients with pulmonary TB should receive a
regimen containing 6 months of rifampicin: 2HRZE/4HR
 The 2HRZE/6HE treatment regimen should be phased
out
 New patients with pulmonary TB may receive a daily
intensive phase followed by three times weekly
continuation phase [2HRZE/4(HR)3] provided that each
dose is directly observed
 In populations with known or suspected high levels of
isoniazid resistance, new TB patients may receive HRE
as therapy in the continuation phase as an acceptable
alternative to HR
Intensive phase treatment Continuation phase

2 months of HRZE 4 months of HRE

Previously treated patients and multidrug
resistance
 Previous TB treatment is a strong determinant of
drug resistance
 Specimens for culture and drug susceptibility testing
(DST) should be obtained from all previously treated
TB patients at or before the start of treatment. DST
should be performed for at least isoniazid and
rifampicin
 TB patients returning after defaulting or relapsing
from their first treatment course may receive the
retreatment regimen containing first-line drugs
2HRZES/1HRZE/5HRE if country-specific data show
low or medium levels of MDR in these patients or if
such data are not available
 Ideally, DST is done for all patients at the start of
treatment, so that the most appropriate therapy for
each individual can be determined
 All previously treated patients (17, 21, 22). The
highest levels of MDR are found in patients whose
prior course of therapy has failed (6).
• All persons living with HIV who are diagnosed with
active TB, especially if they live in areas of moderate
or high MDR prevalence. It is essential to detect
MDR as soon as possible in persons living with HIV,
given their high risk of mortalityshould they have
MDR-TB. Some programmes recommend DST for
HIV-infected TB patients with CD4 counts below 200
cells/mm3
 Rapid DST
In contrast to conventional methods, molecular-
amplification assays such as line probe assays
allow detection of rifampicin resistance (alone or
in combination with isoniazid) within days of
sputum specimens being obtained from the
patient (and can also be used on cultures
obtained from rapid liquid culture systems).
Patients with MDR-TB can avoid delays in
starting an MDR regimen, and TB patients
without MDR will avoid unnecessary second-line
drug treatment. WHO strongly encourages the
use of rapid molecular (and culture-based) DST
in smear-positive persons living with HIV
 Monitoring the patient
For smear-positive pulmonary TB patients
treated with first-line drugs, sputum smear
microscopy may be performed at completion of
the intensive phase of treatment
In new patients, if the specimen obtained at the
end of the intensive phase (month 2) is smear-
positive, sputum smear microscopy should be
obtained at the end of the third month
In new patients, if the specimen obtained at the
end of month 3 is smear-positive, sputum culture
and drug susceptibility testing (DST) should be
performed
 Sputum smear examination is performed at the end
of the intensive phase of treatment (the 3rd month),
at the end of the fifth month and at the end of
treatment (the eighth month)
 In previously treated patients, if the specimen
obtained at the end of the intensive phase (month 3)
is smear-positive, sputum culture and drug
susceptibility testing (DST) should be performed
For patients with extrapulmonary TB, clinical
monitoring is the usual way of assessing the
response to treatment (Standard 10 of the
ISTC). As in pulmonary smear-negative disease,
the weight of the patient is a useful indicator.
 Monitoring and recording adverse
effects
Most TB patients complete their treatment
without any significant adverse drug effects.
However, a few patients do experience adverse
effects
If a patient develops itching without a rash and
there is no other obvious cause, the
recommended approach is to try symptomatic
treatment with antihistamines and skin
moisturizing, and continue TB treatment while
observing the patient closely.
 Management of drug-induced hepatitis

 Of the first-line anti-TB drugs, isoniazid,

pyrazinamide and rifampicin can all cause liver
damage (drug-induced hepatitis). Rifampicin can
cause asymptomatic jaundice without evidence of
hepatitis. It is important to try to rule out other
possible causes before deciding that the hepatitis is
induced by the TB regime
 If it is thought that the liver disease is caused by the
anti-TB drugs, all drugs should be stopped. If the
patient is severely ill with TB and it is considered
unsafe to stop TB treatment, a non-hepatotoxic
regimen consisting of streptomycin, ethambutol and
a fluoroquinolone should be started
 If TB treatment has been stopped, it is necessary to
wait for liver function tests to revert to normal and
clinical symptoms (nausea, abdominal pain) to
resolve before reintroducing the anti-TB drugs. If it is
not possible to perform liver function tests, it is
advisable to wait an extra 2 weeks after resolution of
jaundice and upper abdominal tenderness before
restarting TB treatment. If the signs and symptoms
do not resolve and the liver disease is severe, the
non-hepatotoxic regimen consisting of streptomycin,
ethambutol and a fluoroquinolone should be started
(or continued) for a total of 18–24 months
Once drug-induced hepatitis has resolved, the
drugs are reintroduced one at a time. If
symptoms recur or liver function tests become
abnormal as the drugs are reintroduced, the last
drug added should be stopped. Some advise
starting with rifampicin because it is less likely
than isoniazid or pyrazinamide to cause
hepatotoxicity and is the most effective agent.
After 3–7 days, isoniazid may be reintroduced.
In patients who have experienced jaundice but
tolerate the reintroduction of rifampicin and
isoniazid, it is advisable to avoid pyrazinamide.
 TBtreatment in people living with HIV

 New TB patients1 living with HIV should be treated

with the regimens given in Tables 3.2 and 3.3.
However, the three times weekly intensive phase is
no longer an option
 TB patients with known positive HIV status and all
TB patients living in HIV-prevalent settings1 should
receive daily TB treatment at least during the
intensive phase
 For the continuation phase, the optimal dosing
frequency is also daily for these patients
 If a daily continuation phase is not possible for these
patients, three times weekly dosing during the
continuation phase is an acceptable alternative
 Co-trimoxazole preventive therapy

In all HIV-positive TB patients, co-trimoxazole

preventive therapy should be initiated as soon
as possible and given throughout TB treatment.
(See also Standard 15 of the ISTC (8).) Co-
trimoxazole preventive therapy substantially
reduces mortality in HIV-positive TB patients
(16, 20). The exact mode of activity is not clear
but co-trimoxazole is known to prevent
Pneumocystis jirovecii and malaria and is likely
to have an impact on a range of bacterial
infections in HIV-positive TB patients.
 Tuberculosis control
 The objective of tuberculosis (TB) control is to
reduce morbidity, mortality, and transmission of TB
 In May 1991, the 44th World Health Assembly
(WHA) set out global targets for TB control for the
year 2000 and urged member states to control TB
through the introduction of an effective TB control
strategy
 Based on a predictive model to evaluate the impact
of interventions, the global targets for TB control,
which are detecting at least 70% of the infectious
cases estimated and curing at least 85% of them,
might be expected to lead to a 40% decrease in
contacts infected (17), and a decrease in the
mortality, prevalence, and incidence of TB
 DOTS
 This strategy, called DOTS (Directly Observed
Treatment, Short-course), encompassed five elements
necessary for basic TB control
• government commitment;
• case detection by predominantly passive case
finding;
• standardized short-course chemotherapy for, at least,
all confirmed sputum AFB smear-positive cases,
provided under proper case management
conditions;
• a system of regular drug supply; and
• a monitoring system for program supervision and
evaluation.
 The Stop TB Strategy
 The DOTS framework has subsequently been
expanded, further clarified, and implemented in 182
countries. DOTS implementation has helped
countries to improve National TB Programs (NTPs)
and make major progress in TB control
 Current rates of progress are insufficient to allow the
targets of halving TB mortality and prevalence by
2015 to be achieved
 This chapter defines such a strategy, called the Stop
TB Strategy