Tuberculosis or TB (short for Tubercles Bacillus) is a common and often deadly

infectious disease caused by mycobacteria, usually Mycobacterium tuberculosis

in humans.[1] Tuberculosis usually attacks the lungs but can also affect other
parts of the body like central nervous system, lymphatic system, and circulatory
system among others. The disease was called "consumption" in the past
because of the way it would consume from within anyone who became infected.
According to Medilexicon`s medical dictionary, tuberculosis is "A specific disease
caused by infection with Mycobacterium tuberculosis, the tubercle bacillus, which
can affect almost any tissue or organ of the body, the most common site of the
disease being the lungs." It is spread through the air, when people who have the
disease cough, sneeze, or spit[2]. Most infections in humans result in an
asymptomatic, latent infection, and about one in ten latent infections eventually
progresses to active disease, which, if left untreated, kills more than 50% of its
victims.

Mycobacterium tuberculosis has been present in the human population since

antiquity - fragments of the spinal column from Egyptian mummies from 2400
BCE show definite pathological signs of tubercular decay.

The term phthisis, consumption, appears first in Greek literature. Around 460
BCE, Hippocrates identified phthisis as the most widespread disease of the
times, and noted that it was almost always fatal. Due to common phthisis related
fatalities, he wrote something no doctor would dare write today: he warned his
colleagues against visiting cases in late stages of the disease, because their
inevitable deaths might damage the reputations of the attending physicians.

Exact pathological and anatomical descriptions of the disease began to appear in

the seventeenth century. In his Opera Medica of 1679, Sylvius was the first to
identify actual tubercles as a consistent and characteristic change in the lungs
and other areas of consumptive patients. He also described their progression to
abscesses and cavities. Manget described the pathological features of miliary
tuberculosis in 1702. The earliest references to the infectious nature of the
disease appear in seventeenth century Italian medical literature. An edict issued
by the Republic of Lucca in 1699 states that, "henceforth, human health should
no longer be endangered by objects remaining after the death of a consumptive.
The names of the deceased should be reported to the authorities, and measures
undertaken for disinfection."

In 1720, the English physician Benjamin Marten was the first to conjecture, in his
publication, A New Theory of Consumption, that TB could be caused by
"wonderfully minute living creatures", which, once they had gained a foothold in
the body, could generate the lesions and symptoms of the disease. He stated,
moreover, "It may be therefore very likely that by an habitual lying in the same
bed with a consumptive patient, constantly eating and drinking with him, or by
very frequently conversing so nearly as to draw in part of the breath he emits
from the Lungs, a consumption may be caught by a sound person...I imagine that
slightly conversing with consumptive patients is seldom or never sufficient to
catch the disease." For the early eighteenth century, Dr. Marten's writings display
a great degree of epidemiological insight.

In contrast to this significant level of understanding about the etiology of

consumption, which was already enabling prevention and a break in the chain of
infection, those attempting to cure the disease were still groping in the dark

The introduction of the sanatorium cure provided the first really step against TB.
Hermann Brehmer, a Silesian botany student suffering from TB, was instructed
by his doctor to seek out a healthier climate. He travelled to the Himalayan
mountains where he could pursue his botanical studies while trying to rid himself
of the disease. He returned home cured and began to study medicine. In 1854,
he presented his doctoral dissertation bearing the auspicious title, Tuberculosis
is a Curable Disease. In the same year, he built an institution in Gorbersdorf
where, in the midst of fir trees, and with good nutrition, patients were exposed on
their balconies to continuous fresh air. This setup became the blueprint for the
subsequent development of sanatoria, a powerful weapon in the battle against an
insidious opponent.

New advances then followed in rapid succession. In 1865, the French military
doctor Jean-Antoine Villemin single-handedly demonstrated that consumption
could be passed from humans to cattle and from cattle to rabbits. On the basis of
this revolutionary evidence, he postulated a specific microorganism as the cause
of the disease, finally laying to rest the centuries-old belief that consumption
arose spontaneously in each affected organism.

In 1882, Robert Koch discovered a staining technique that enabled him to see
Mycobacterium tuberculosis. What excited the world was not so much the
scientific brilliance of Koch's discovery, but the accompanying certainty that now
the fight against humanity's deadliest enemy could really begin.

The measures available to doctors were still modest. Improving social and
sanitary conditions, and ensuring adequate nutrition were all that could be done
to strengthen the body's defenses against the TB bacillus. Sanatoria, now to be
found throughout Europe and the United States, provided a dual function: they
isolated the sick, the source of infection, from the general population, while the
enforced rest, together with a proper diet and the well-regulated hospital life
assisted the healing processes.

These efforts were reinforced by the observation of the Italian Forlanini, that lung
collapse tended to have a favorable impact on the outcome of the disease. With
the introduction of artificial pneumothorax and surgical methods to reduce the
lung volume, the depressing era of helplessness in the face of advanced TB was
over, and active therapy had begun.
A further significant advance came in 1895 when Wilhelm Konrad von Rontgen
discovered the radiation that bears his name. Now the progress and severity of a
patient's disease could be accurately followed and reviewed.

Another important development was provided by the French bacteriologist

Calmette, who, together with Guerin, used specific culture media to lower the
virulence of the bovine TB bacterium, creating the basis for the BCG vaccine still
in widespread use today. Then, in the middle of World War II, came the final
breakthrough, the greatest challenge to the bacterium that had threatened
humanity for thousands of years - chemotherapy.

Tuberculosis - epidemiology

 The most common route of infection is via the respiratory tract. TB

is spread from a person with disease by droplet nuclei that are inhaled
by other people. A child becomes infected with TB after close and
prolonged contact with an adult or adolescent who has active untreated
infectious disease, usually pulmonary TB, in a poorly ventilated space.
But there are people who develop TB without knowledge of an infectious
contact.
 Congenital infection occurs, although rarely, in the setting of an
untreated mother in the last trimester of pregnancy.
 Infection with the tubercle bacillus needs to be differentiated from
disease (i.e., TB).
 The interval between onset of infection and disease is 10–12 weeks
(details later in this chapter).
 The greatest chance of disease occurring (that is, of developing a
positive result in tests using purified protein derivative [PPD], now
renamed tuberculin skin test [TST]) is within the 1st 2 years after
infection. However, for infants and children younger than 5 years,
progression through the spectrum of pediatric TB (exposure–infection–
disease) is age dependent (see “Definition”).
 Postpubertal adolescents and immunosuppressed people, including
people with diabetes, with chronic renal failure, the malnourished, and
those taking steroids for any reason (including pulse doses), have higher
risks of progression of infection to disease.
 Nationwide, the early 1990s had a documented increase in TB in
children <2 years of age in the US states where TB is more common;
this trend had been reversed owing to adherence to the
recommendations for treatment of the American Thoracic Society/US
Centers for Disease Control and Prevention/Infectious Disease Society
of America updated 2003 (see “Bibliography”). However, now an
 increase is being seen related to the increasing proportion of foreign-
born parents of children in the US.

Incidence (annual) of Tuberculosis:

18,361 cases annually in the USA (1998); 8 million people worldwide develop
active TB and 3 million die; 17,531 annual cases notified in USA 1999 (MMWR
1999); 5.50 per 100,000 in Canada 20001 ... see also overview of Tuberculosis.

Incidence Rate:

approx 1 in 14,814 or 0.01% or 18,360 people in USA [Source statistic for

calcuation: "18,361 cases annually in the USA (1998); 8 million people
worldwide develop active TB and 3 million die; 17,531 annual cases notified in
USA 1999 (MMWR 1999); 5.50 per 100,000 in Canada 20001" -- see also
general information about data sources]

Incidence extrapolations for USA for Tuberculosis:

18,360 per year, 1,530 per month, 353 per week, 50 per day, 2 per hour, 0 per
minute, 0 per second. [Source statistic for calculation: "18,361 cases
annually in the USA (1998); 8 million people worldwide develop active TB and 3
million die; 17,531 annual cases notified in USA 1999 (MMWR 1999); 5.50 per
100,000 in Canada 20001" -- see also general information about data sources]

Prevalance of Tuberculosis:

between 10 and 15 million people in the United States. (Source: excerpt from
Microbes in Sickness and in Health - Publications, National Institute of Allergy
and Infectious Diseases: NIAID) ... In 1998, a total of 18,371 active TB cases, in
all 50 states and the District of Columbia, were reported to the Centers for
Disease Control and Prevention (CDC). (Source: excerpt from Tuberculosis,
NIAID Fact Sheet: NIAID)

Worldwide prevalence of Tuberculosis:

According to the World Health Organization (WHO), nearly 2 billion people,
one-third of the world's population, have TB. (Source: excerpt from Microbes in
Sickness and in Health - Publications, National Institute of Allergy and
Infectious Diseases: NIAID)

Prevelance statistics for Tuberculosis:

The following statistics relate to the prevalence of Tuberculosis:

 42 was the mean age of patients hospitalised for tuberculosis in

England 2002-03 (Hospital Episode Statistics, Department of Health,
England, 2002-03)
 69% of hospitalisations for tuberculosis was for 15-59 year olds in
England 2002-03 (Hospital Episode Statistics, Department of Health,
England, 2002-03)
 10% of hospitalisations for tuberculosis was for over 75 year olds in
England 2002-03 (Hospital Episode Statistics, Department of Health,
England, 2002-03)
 more statistics...»

Incidence statistics for Tuberculosis:

The following statistics relate to the incidence of Tuberculosis:

 16,337 new cases of tuberculosis occurred annually in the US 2000

(Health, United States: 2002, NCHS, CDC)
 21,327 cases in the USA 1996 (New Jersey Department of Health,
2004)
 22,860 cases in the USA 1995 (New Jersey Department of Health,
2004)
 25,287 cases in the USA 1994 (New Jersey Department of Health,
2004)
 25,313 cases in the USA 1993 (New Jersey Department of Health,
2004)
 more statistics...»

Death statistics for Tuberculosis:

The following statistics relate to deaths and Tuberculosis:

 749 deaths in the USA 2001 (National Center for Health Statistics,
CDC)
 776 deaths in the USA 2000 (National Center for Health Statistics,
CDC)
 930 deaths in the USA 1999 (National Center for Health Statistics,
CDC)
 1,112 deaths in the USA 1998 (National Center for Health
Statistics, CDC)
 Tuberculosis death statistics for various countries:
o About 348,000 deaths from tuberculosis in Africa 2002 (The
World Health Report, WHO, 2004)

Mycobacterium tuberculosis

Mycobacterium tuberculosis (MTB) is a pathogenic bacterial species in the

genus Mycobacterium and the causative agent of most cases of tuberculosis.[1]
First discovered in 1882 by Robert Koch, M. tuberculosis has an unusual, waxy
coating on the cell surface (primarily mycolic acid), which makes the cells
impervious to Gram staining; acid-fast techniques are used instead. The
physiology of M. tuberculosis is highly aerobic and
Colonies of Mycobacterium tuberculosis on Lowenstein-Jensen medium.
CDC.

SCIENTIFIC CLASSIFICATION

Kingdom: Bacteria
Phylum: Actinobacteria
Order: Actinomycetales
Suborder: Corynebacterineae
Family: Mycobacteriaceae
Genus: Mycobacterium
Species: M. tuberculosis

requires high levels of oxygen. Primarily a pathogen of the mammalian

respiratory system, MTB infects the lungs, causing tuberculosis.[1]

The M. tuberculosis genome was sequenced in 1998

Physiology

M. tuberculosis requires oxygen to grow. It does not retain any bacteriological

stain due to high lipid content in its wall, and thus is neither Gram positive nor
Gram negative; hence Ziehl-Neelsen staining, or acid-fast staining, is used.
While Mycobacteria do not seem to fit the Gram-positive category from an
empirical standpoint (i.e., they do not retain the crystal violet stain), they are
classified as acid-fast Gram-positive bacteria due to their lack of an outer cell
membrane.[1]

M. tuberculosis divides every 15–20 hours, which is extremely slow compared to

other bacteria, which tend to have division times measured in minutes
(Escherichia coli (E. coli) can divide roughly every 20 minutes). It is a small
bacillus that can withstand weak disinfectants and can survive in a dry state for
weeks. Its unusual cell wall, rich in lipids (e.g., mycolic acid), is likely responsible
for this resistance and is a key virulence factor.[4]

When in the lungs, M. tuberculosis is taken up by alveolar macrophages, but they

are unable to digest the bacterium. Its cell wall prevents the fusion of the
phagosome with a lysosome. Specifically, M. tuberculosis blocks the bridging
molecule, early endosomal autoantigen 1 (EEA1); however, this blockade does
not prevent fusion of vesicles filled with nutrients. Consequently, the bacteria
multiply unchecked within the macrophage. The bacteria also carried the UreC
gene, which prevents acidification of the phagosome.[5] The bacteria also evade
macrophage killing by neutralizing reactive nitrogen intermediates.

The ability to construct M. tuberculosis mutants and test individual gene products
for specific functions has significantly advanced our understanding of the
pathogenesis and virulence factors of M. tuberculosis. Many secreted and
exported proteins are known to be important in pathogenesis.[6]

[edit] Strain variation

M. tuberculosis appears to be genetically diverse. This genetic diversity results in

significant phenotypic differences between clinical isolates. M. tuberculosis
exhibits a biogeographic population structure and different strain lineages are
associated with different geographic regions. Phenotypic studies suggest that
this strain variation never has implications for the development of new
diagnostics and vaccines. Micro-evolutionary variation affects the relative fitness
and transmission dynamics of antibiotic-resistant strains.[7]

[edit] Hypervirulent strains

Mycobacterium outbreaks are often caused by hypervirulent strains of M.

tuberculosis. In laboratory experiments, these clinical isolates elicit unusual
immunopathology and may be either hyperinflammatory or hypoinflammatory.
 Studies have shown that the majority of hypervirulent mutants
have deletions in cell wall modifying enzymes or regulators that
respond to environmental stimuli. Studies of these mutants have
indicated the mechanisms that enable M. tuberculosis to mask its
full pathogenic potential, inducing a granuloma that provides a
protective niche and enables the bacilli to sustain a long-term
persistent infection.[8]

Mycobacterium tuberculosis (stained red) in tissue (blue).

[edit] Microscopic

M. tuberculosis is characterized by caseating granulomas containing Langhans

giant cells, which have a "horseshoe" pattern of nuclei. Organisms are identified
by their red color on acid-fast staining.

Mycobacteria are Gram-resistant (waxy cell walls), non-motile, pleomorphic

rods, related to the Actinomyces. Most Mycobacteria are found in habitats such
as water or soil. However, a few are intracellular pathogens of animals and
humans. Mycobacterium tuberculosis, along with M. bovis, M. africanum, and M.
microti all cause the disease known as tuberculosis (TB) and are members of the
tuberculosis species complex. Each member of the TB complex is pathogenic,
but M. tuberculosis is pathogenic for humans while M. bovis is usually pathogenic
for animals.

M. bovis was causing TB in the animal kingdom long before invading humans.
However, after the domestication of cattle between 8000-4000 BC, there is
archaeological evidence of human infection by M. bovis probably through milk
consumption. M. tuberculosis is probably a human-specialized form of M. bovis
developed among milk-drinking Indo-Europeans who then spread the disease
during their migration into western Europe and Eurasia. By 1000 BC, M.
tuberculosis and pulmonary TB had spread throughout the known world.

What are Mycobacteria?

Tuberculosis complex organisms are:

 • Obligate aerobes growing most successfully in tissues
with a high oxygen content, such as the lungs.
• Facultative intracellular pathogens usually infecting
mononuclear phagocytes (e.g. macrophages).
• Slow-growing with a generation time of 12 to 18 hours
(c.f. 20-30 minutes for Escherichia coli).
• Hydrophobic with a high lipid content in the cell wall.
Because the cells are hydrophobic and tend to clump together, they are
impermeable to the usual stains, e.g. Gram's stain.
• Known as "acid-fast bacilli" because of their lipid-rich cell walls, which
are relatively impermeable to various basic dyes unless the dyes are
combined with phenol. Once stained, the cells resist decolorization with
acidified organic solvents and are therefore called "acid-fast". (Other
bacteria which also contain mycolic acids, such as Nocardia, can also
exhibit this feature.)

Mycobacteria are Gram-resistant (waxy cell walls), non-motile, pleomorphic

rods, related to the Actinomyces. Most Mycobacteria are found in habitats such
as water or soil. However, a few are intracellular pathogens of animals and
humans. Mycobacterium tuberculosis, along with M. bovis, M. africanum, and M.
microti all cause the disease known as tuberculosis (TB) and are members of the
tuberculosis species complex. Each member of the TB complex is pathogenic,
but M. tuberculosis is pathogenic for humans while M. bovis is usually pathogenic
for animals.

M. bovis was causing TB in the animal kingdom long before invading humans.
However, after the domestication of cattle between 8000-4000 BC, there is
archaeological evidence of human infection by M. bovis probably through milk
consumption. M. tuberculosis is probably a human-specialized form of M. bovis
developed among milk-drinking Indo-Europeans who then spread the disease
during their migration into western Europe and Eurasia. By 1000 BC, M.
tuberculosis and pulmonary TB had spread throughout the known world.

What are Mycobacteria?

Tuberculosis complex organisms are:

• Obligate aerobes growing most successfully in tissues with a high oxygen

content, such as the lungs.
• Facultative intracellular pathogens usually infecting mononuclear
phagocytes (e.g. macrophages).
• Slow-growing with a generation time of 12 to 18 hours (c.f. 20-30 minutes
for Escherichia coli).
 • Hydrophobic with a high lipid content in the cell wall. Because the cells
are hydrophobic and tend to clump together, they are impermeable to the
usual stains, e.g. Gram's stain.
• Known as "acid-fast bacilli" because of their lipid-rich cell walls, which
are relatively impermeable to various basic dyes unless the dyes are
combined with phenol. Once stained, the cells resist decolorization with
acidified organic solvents and are therefore called "acid-fast". (Other
bacteria which also contain mycolic acids, such as Nocardia, can also
exhibit this feature.)
• Mycobacterium tuberculosis complex (MTBC) members are causative
agents of human and animal tuberculosis. Species in this complex include:

M. tuberculosis, the major cause of human tuberculosis

M. bovis
M. bovis BCG
M. africanum
M. canetti
M. caprae
M. microti
M. pinnipedii

Mycobacteria are a family of small, rod-shaped bacilli that can be classified into 3
main groups for the purpose of diagnosis and treatment:

• Mycobacterium tuberculosis complex which can cause tuberculosis: M.

tuberculosis, M. bovis, M. africanum, , M. microti and M. canetti.
• M. leprae which causes Hansen's disease or leprosy.
• Nontuberculous mycobacteria (NTM) are all the other mycobacteria which
can cause pulmonary disease resembling tuberculosis, lymphadenitis,
skin disease, or disseminated disease.