Tuberculosis is a chronic communicable disease caused by
a variety of tubercle bacilli (Mycobacterium
tuberculosis hominis and Mycobacterium
tuberculosis bovis) and has over centuries been responsible for disease
and death in all social strata.
The lungs are the prime
target, but any organ may be infected.
The characteristic lesion is a
spherical granuloma with central caseous necrosis.
is ordinarily contracted by inhaling contaminating droplets.
tuberculosis bovis is contracted through the gastrointestinal tract, from the raw
milk of diseased cows.
Most people, after exposure, develop a
small, limited pulmonary infection.
This infection is contained by an
inflammatory reaction, and during this course the tuberculin skin test
Thus most tuberculous infections do not progress to
Distributed throughout the world, tuberculosis is
clearly one of the most important bacterial diseases of mankind.
Tubercle bacilli are slender, beaded non-motile, acid-fast, and
gram-positive bacilli, although their gram-positivity may be difficult
The cell wall is waxy and contains components that
confer acid-fastness ; that is, the retention of carbol fuchsin after
rinsing with acid alcohol.
Tubercle bacilli are strict, obligate aerobes that proliferate within
grow slowly in culture and require 3 or more weeks to develop
virulence of tubercle bacilli is associated with a tendency to
aggregate and form filaments or cords in liquid media.
organisms resist heat and disinfectants but are killed quickly by
Delayed cell mediated immunity to tubercle bacillus
is commonly measured by the Mantoux skin test, which use as
test antigen the “purified protein derivative” from media in which
tubercle bacilli have grown.
The skin test is positive if an area of induration at least 10 mm in diameter develops within 48 hours after
the intradermal injection of the antigen.
Patients usually develop
this hypersensitivity 2 to 4 weeks after infection.
positive skin test indicates infection with tubercle bacilli, it is
not necessarily associated with clinical disease.
with positive skin tests have immune systems that have confined and
limited the infection.
A positive skin test also develops after
vaccination with Bacilli Calmette-Guerin (BCG). When BCG is used in an
effort to control natural tuberculosis, the skin test is not reliable
as an indicator of naturally acquired infection. Once positive, the person remains so for life.
Before the patient develops sensitivity, bacilli multiply unchecked
and may move through lymphatics and blood stream to distant sites.
cellular basis of the positive test is granulomatous response,
composed of epithelioid cells and giant cells.
At first, when there is
uncontrolled growth of bacilli, the reaction is histiocytic and
But with time, the appearance of epithelioid cells signals
the destruction of bacilli and the limitation of the infection.
Hypersensitivity (resistance to infection) is associated with
increased phagocytosis of bacilli, conversion of macrophages to
epithelioid cells, the formation of giant cells, and the inhibition of
intracellular replication of tubercle bacilli.
Cutaneous Tuberculosis - Lupus Vulgaris
Primary Tuberculosis is an
infection of persons who have not had prior contact with the tubercle
The bacilli usually enter the body by inhalation but can
also enter through the gastrointestinal tract or by cutaneous or
Inhaled bacilli are commonly deposited in
alveoli immediately beneath the pleura, usually in the lower part of
the upper lobes or the upper part of the lower lobes.
receive the greatest volume of inspired air.
The initial infection
produces only slight abnormalities and may cause only slight malaise
and mild fever.
Since sensitized T cells are lacking, the tubercle
bacilli multiply freely and enter the blood stream and lymphatics.
Cell-mediated immunity develops over a
period of 3 to 6 weeks.
The primary infection characteristically produces a
“Ghon complex”- that is, a single lesion in the pulmonary parenchyma,
usually subpleural, that is accompanied by a lesion of the hilar lymph
nodes draining that part of the lung.
The primary lesion, or Ghon
focus, in the lung is typically a 1cm, grayish, circumscribed nodule.
It becomes granulomatous within a few days and by the second week has
soft caseous, necrotic center.
Tubercle bacilli drain through
lymphatic channels to infect the hilar lymph nodes and form the second
part of the Ghon complex.
In over 90% of normal adults the infection follows
this self-limited course, because the cellular immune response is
sufficient to control the multiplication of bacilli.
both the lung and the lymph nodes the lesions of the Ghon complex
heal, undergoing shrinkage, fibrous scarring, and calcification.
of the organisms die, but a few remain viable for years.
immune mechanisms wane or fail, the resting bacilli may break out and
cause serious tuberculous infection.
Progressive primary tuberculosis is a rarer alternative course, in which the immune response fails to control multiplication
of the tubercle bacilli.
Infection takes this course in less than 10%
of normal adults, but it is common in children under 5 years of age.
In adults, progressive primary tuberculosis most commonly occurs in
patients with suppressed or defective immunity.
The primary Ghon focus
in the lung enlarges rapidly, erodes the bronchial tree, and spreads,
a sequence that results in adjacent “satellite” lesions.
is accompanied by caseous enlargement of the hilar lymph nodes, which
may erode through the wall of the bronchus and discharge bacilli,
thereby producing tuberculous pneumonia.
Clinical manifestations are
abrupt high fever (associated with progression to tuberculous
pneumonia), pleurisy with effusion, and lymphadenitis.
The highly active lesions may seed the
blood stream with tubercle bacilli and result in life-threatening
dissemination of the bacilli.
Secondary (cavitary) tuberculosis usually results from
reactivation of dormant, endogenous tubercle bacilli in a sensitized
patient who has had previous contact with the tubercle bacillus.
cases, the disease is caused by reinfection with exogenous bacilli.
Secondary tuberculosis may develop any
time after primary infection, even decades later.
Reactivation typically begins in the
apical or posterior segments of one or both upper lobes (Simon’s
foci), where the organisms were seeded during the primary infection.
Radiographically, the lesions are spherical and cavitary- the
so-called coin lesions. A fibrous capsule surrounds the caseous, acellular center, which contains numerous tubercle bacilli.
From these cavitary nodules the organisms can spread through the lung
and be discharged into the air during bouts of coughing.
The symptoms of secondary tuberculosis begin with
cough, which may be erroneously attributed to smoking or to a “cold”.
Low-grade fever develops, with general malaise, fatigue,
weight loss, and often night sweats.
As the disease progresses, the
cough worsens and the sputum may be streaked with blood. The rupture
of a branch of the pulmonary artery in the wall of a cavity leads to
massive hemoptysis and asphyxiation or exanguination.
These pulmonary lesions of secondary tuberculosis are
often complicated by a variety of secondary effects, including
Scarring and calcification;
(2) Spread to other areas;
fibrosis and adhesions, with associated pleurisy, sharp pleuritic
pain, and shortness of breath;
(4) Rupture of a caseous lesion, which
spills bacilli into the pleural cavity;
(5) Erosion into a bronchus,
which seeds the mucosal lining of bronchioles, bronchi, and trachea;
(6) Implantation of bacilli in the larynx, which causes
laryngitis, hoarseness, and pain on swallowing.
Lesions of secondary
tuberculosis acquired through the gastrointestinal tract (usually with
M. t. bovis) can lead to entrapment of bacilli in lymphoid patches of
small and large bowel.
Miliary tuberculosis is the disseminated form of
tuberculosis and is caused by seeding of the bacilli through
lymphatics or blood vessels to produce minute, yellow-white lesions
resembling millet seeds (hence military).
The lung, lymph nodes,
kidneys, adrenals, bone marrow, spleen, liver, meninges, brain, eye
grounds, and genitalia are common sites of miliary lesions.
tubercles rarely develop in the pancreas, thyroid, striated muscle, or
Regardless of the organs involved, all granulomas have similar
features and follow the same progression, namely focal collections of
histiocytes, followed by epithelioid cells, Langhan’s giant cells,
central caseation necrosis and eventually fibrosis and mineralization.
Diagnosis of Tuberculosis:
Clinical suspicions of tuberculosis are confirmed by
the microscopic demonstration of acid-fast bacilli within smears of
The diagnosis is usually confirmed by the demonstration, within
tissue sections from effected organs, of bacilli that have a symmetric
or consistent relationship to the lesions.
The slender, rod shaped
and slightly curved orgnanisms are acid-fast stain intensely red with carbol-fuchsin and are found in the granuloma.
Bacilli are usually found
in the caseous centers or in histiocytes or giant cells at the
The detection of acid fast bacilli in granulomas may be problematic
and is largely dependent on the underlying response that is initiated
by the patient's immune system.
In those patients in whom there is a
vigorous granulomatous reaction, few if any bacilli are found and
microbiological confirmation of the disease depends on culture or
molecular identification of mycobacterial genomic material. Both
T. hominis and
Mycobacterium T. bovis can be cultured from
sputum or tissue specimens.
bacilli are best identified in tissue sections using the Ziehl-Neelsen
or Triff stains.
The latter stain is particularly good at
demonstrating the organisms and the backround tissue allowing the
histopathologist to better visualise and correlate the pathological
process, specially important if scanty bacilli are present.
methods such as the Dieterle or Warthin Starry are more sensitive and
may be used to assist with the identification of mycobacteria in those
cases where carbol-fuchsin methods have failed ; they show beaded
bacilli, nocardia-like filamentous organisms and granular debris
probably representing degenerate mycobacteria. Their specificity is
limited as morphological similarities are shared with
cat scratch disease
microscopy using the Auramine-Rhodamine and Papanicolaou stains may
also be used to identify bacilli in cytological specimens. An
immunohistochemical method has also been developed.
Treatment of Tuberculosis:
is effectively treated with at least two bactericidal or
drugs are included to provide activity against bacilli that are
resistant to the primary drug.
To succeed, the chemo- therapeutic regimen must
eliminate extracellular bacilli in both solid and cavitary lesions,
and intracellular bacilli in histiocytes or in giant cells.
drugs in use isoniazid, rifampin, streptomycin, capreomycin and
kanamycin, pyrazinamide, ethambutol, para-aminosalicylic acid (PAS),
ethionamide, and thiacetazone.
Isoniazid is the most valuable
antituberculous drug, since it can be taken orally as well as
parenterally and kills both extracellular and intracellular bacilli
and is especially important for eradicating “persisters” during the