ROBBINS PATHOLOGIC BASIS OF DISEASE 8TH ED

Tuberculosis

Mycobacterium tuberculosis is responsible for most cases of tuberculosis; the reservoir of infection is
humans with active tuberculosis. Oropharyngeal and intestinal tuberculosis contracted by drinking milk
contaminated with M. bovis is rare in countries where milk is routinely pasteurized, but it is still seen in
countries that have tuberculous dairy cows and unpasteurized milk.

Epidemiology.

Tuberculosis is estimated to affect 1.7 billion individuals worldwide, with 8 to 10 million new cases and
1.6 million deaths each year, a toll second only to HIV disease. Infection with HIV makes people
susceptible to rapidly progressive tuberculosis; over 10 million people are infected with both HIV and M.
tuberculosis. From 1985 to 1992, the number of tuberculosis cases in the United States rose by 20%
because of increase in the disease in people with HIV, immigrants, and those in jail or homeless shelters.
Because of public health efforts, the number of cases of tuberculosis has declined since 1993. Currently,
there are about 14,000 new cases of active tuberculosis in the United States annually, about half of
which occur in foreign-born people.

Tuberculosis flourishes wherever there is poverty, crowding, and chronic debilitating illness. In the
United States tuberculosis is mainly a disease of the elderly, the urban poor, and people with AIDS.
Certain disease states also increase the risk: diabetes mellitus, Hodgkin lymphoma, chronic lung disease
(particularly silicosis), chronic renal failure, malnutrition, alcoholism, and immunosuppression.

It is important that infection with M. tuberculosis be differentiated from disease. Infection is the
presence of organisms, which may or may not cause clinically significant disease. Most infections are
acquired by person-to-person transmission of airborne organisms from an active case to a susceptible
host. In most people primary tuberculosis is asymptomatic, although it may cause fever and pleural
effusion. Generally, the only evidence of infection, if any remains, is a tiny, fibrocalcific nodule at the site
of the infection. Viable organisms may remain dormant in such lesions for decades. If immune defenses
are lowered, the infection may reactivate to produce communicable and potentially life-threatening
disease.

Infection typically leads to the development of delayed hypersensitivity to M. tuberculosis antigens,

which can be detected by the tuberculin (Mantoux) skin test. About 2 to 4 weeks after infection,
intracutaneous injection of purified protein derivative of M. tuberculosis induces a visible and palpable
induration that peaks in 48 to 72 hours. A positive tuberculin test result signifies T cell–mediated
immunity to mycobacterial antigens. It does not differentiate between infection and disease. False-
negative reactions may occur in the setting of certain viral infections, sarcoidosis, malnutrition, Hodgkin
lymphoma, immunosuppression, and (notably) overwhelming active tuberculous disease. False-positive
reactions may result from infection by atypical mycobacteria or prior vaccination with BCG (Bacillus
Calmette-Guerin), an attenuated strain of M. bovis that is used as a vaccine in some countries.
Pathogenesis.

The pathogenesis of tuberculosis in a previously unexposed, immunocompetent person depends on the

development of anti-mycobacterial cell-mediated immunity, which confers resistance to the bacteria
and also results in development of hypersensitivity to mycobacterial antigens. The pathologic
manifestations of tuberculosis, such as caseating granulomas and cavitation, are the result of the
hypersensitivity that develops in concert with the protective host immune response. Because the
effector cells that mediate immune protection also mediate hypersensitivity and tissue destruction, the
appearance of hypersensitivity also signals the acquisition of immunity to the organism. A summary of
the pathogenesis of tuberculosis is shown in Figure 8-27

FIGURE 8-27 The sequence of events in primary pulmonary tuberculosis, commencing with inhalation of
virulent Mycobacterium tuberculosis organisms and culminating with the development of cell-mediated
immunity to the organism. A, Events occurring in the first 3 weeks after exposure. B, Events thereafter.
The development of resistance to the organism is accompanied by the appearance of a positive
tuberculin test. γ-IFN, interferon-γ; iNOS, inducible nitric oxide synthase; MHC, major histocompatibility
complex; MTB, M. tuberculosis; NRAMP1, natural resistance–associated macrophage protein; TNF,
tumor necrosis factor.
Macrophages are the primary cells infected by M. tuberculosis. Early in infection, tuberculosis bacilli
replicate essentially unchecked, while later in infection, the cell response stimulates macrophages to
contain the proliferation of the bacteria.

• M. tuberculosis enters macrophages by endocytosis mediated by several macrophage

receptors: mannose receptors bind lipoarabinomannan, a glycolipid in the bacterial cell wall, and
complement receptors (already discussed) bind opsonized mycobacteria.[23]

• Once inside the macrophage, M. tuberculosis organisms replicate within the phagosome by
blocking fusion of the phagosome and lysosome. M. tuberculosis blocks phagolysosome formation by
inhbiting Ca2+ signals and the recruitment and assembly of the proteins that mediate phagosome-
lysosome fusion.[84] Thus, during the earliest stage of primary tuberculosis (<3 weeks) in the
nonsensitized individual, bacteria proliferate in the pulmonary alveolar macrophages and airspaces,
resulting in bacteremia and seeding of multiple sites. Despite the bacteremia, most people at this stage
are asymptomatic or have a mild flulike illness.

• The genetic makeup of the host may influence the course of the disease. In some people with
polymorphisms in the NRAMP1 gene, the disease may progress due to the absence of an effective
immune response. NRAMP1 is a transmembrane protein found in endosomes and lysosomes that
pumps divalent cations (e.g. Fe2+) out of the lysosome. NRAMP1 may inhibit microbial growth by
limiting availability of ions needed by the bacteria.[85]

• About 3 weeks after infection, a T-helper 1 (TH1) response is mounted that activates
macrophages to become bactericidal.[86] The response is initiated by mycobacterial antigens that enter
draining lymph nodes and are displayed to T cells. Differentiation of TH1 cells depends on IL-12, which is
produced by antigen-presenting cells that have encountered the mycobacteria. M. tuberculosis makes
several molecules that are ligands for TLR2, and stimulation of TLR2 by these ligands promotes
production of IL12 by dendritic cells.

• Mature TH1 cells, both in lymph nodes and in the lung, produce IFN-γ. INF-γ is the critical
mediator that enables macrophages to contain the M. tuberculosis infection. IFNγ stimulates formation
of the phagolysosome in infected macrophages, exposing the bacteria to an inhospitable acidic
environment. IFN-γ also stimulates expression of inducible nitric oxide synthase, which produces nitric
oxide, capable of destroying several mycobacterial constituents, from cell wall to DNA.
 • In addition to stimulating macrophages to kill mycobacteria, the TH1 response orchestrates
the formation of granulomas and caseous necrosis. Macrophages activated by IFN-γ differentiate into
the “epithelioid histiocytes” that characterize the granulomatous response, and may fuse to form giant
cells. In many people this response halts the infection before significant tissue destruction or illness. In
other people the infection progresses due to advanced age or immunosuppression, and the ongoing
immune response results in tissue destruction due to caseation and cavitation. Activated macrophages
also secrete TNF, which promotes recruitment of more monocytes. The importance of TNF is
underscored by the fact that patients with rheumatoid arthritis who are treated with a TNF antagonist
have an increased risk of tuberculosis reactivation.

• In addition to the TH1 response, NK-T cells that recognize mycobacterial lipid antigens bound
to CD1 on antigen-presenting cells, or T cells that express a γδ T-cell receptor, also make IFN-γ. However,
it is clear that TH1 cells have a central role in this process, since defects in any of the steps in generating
a TH1 response result in absence of resistance and disease progression.

In summary, immunity to M. tuberculosis is primarily mediated by TH1 cells, which stimulate

macrophages to kill the bacteria. This immune response, while largely effective, comes at the cost of
hypersensitivity and accompanying tissue destruction. Reactivation of the infection or re-exposure to
the bacilli in a previously sensitized host results in rapid mobilization of a defensive reaction but also
increased tissue necrosis. Just as hypersensitivity and resistance are correlated, so, too, the loss of
hypersensitivity (indicated by tuberculin negativity in a previously tuberculin-positive individual) may be
an ominous sign that resistance to the organism has faded.

Clinical Features of Tuberculosis.

The many clinicalpathologic patterns of tuberculosis are shown in Figure 8-28 . Primary tuberculosis is
the form of disease that develops in a previously unexposed, and therefore unsensitized, person. About
5% of newly infected people develop clinically significant disease. The elderly and profoundly
immunosuppressed persons may lose their immunity to M. tuberculosis and so may develop primary
tuberculosis more than once. With primary tuberculosis the source of the organism is exogenous.
FIGURE 8-28 The natural history and spectrum of tuberculosis. (Adapted from a sketch provided by
Professor R.K. Kumar, The University of New South Wales, School of Pathology, Sydney, Australia.)

In most people, the primary infection is contained, but in others, primary tuberculosis is progressive.
The diagnosis of progressive primary tuberculosis in adults can be difficult. In contrast to secondary
tuberculosis (apical disease with cavitation; see below), progressive primary tuberculosis more often
resembles an acute bacterial pneumonia, with lower and middle lobe consolidation, hilar adenopathy,
and pleural effusion; cavitation is rare, especially in people with severe immunosuppression.
Lymphohematogenous dissemination may result in the development of tuberculous meningitis and
miliary tuberculosis (discussed below).

Secondary tuberculosis is the pattern of disease that arises in a previously sensitized host . It may follow
shortly after primary tuberculosis, but more commonly it appears many years after the initial infection,
usually when host resistance is weakened. It most commonly stems from reactivation of a latent
infection, but may also result from exogenous reinfection in the face of waning host immunity or when a
large inoculum of virulent bacilli overwhelms the host immune system. Reactivation is more common in
low-prevalence areas, while reinfection plays an important role in regions of high contagion.
Secondary pulmonary tuberculosis classically involves the apex of the upper lobes of one or both lungs.
Because of the pre-existence of hypersensitivity, the bacilli elicit a prompt and marked tissue response
that tends to wall off the focus of infection. As a result, the regional lymph nodes are less prominently
involved early in secondary disease than they are in primary tuberculosis. On the other hand, cavitation
occurs readily in the secondary form. Indeed, cavitation is almost inevitable in neglected secondary
tuberculosis, and erosion of the cavities into an airway is an important source of infection because the
person now coughs sputum that contains bacteria

Localized secondary tuberculosis may be asymptomatic. When manifestations appear, they are usually
insidious in onset. Systemic symptoms, probably related to cytokines released by activated macrophages
(e.g., TNF and IL-1), often appear early in the course and include malaise, anorexia, weight loss, and
fever. Commonly, the fever is low grade and remittent (appearing late each afternoon and then
subsiding), and night sweats occur. With progressive pulmonary involvement, increasing amounts of
sputum, at first mucoid and later purulent, appear. Some degree of hemoptysis is present in about half
of all cases of pulmonary tuberculosis. Pleuritic pain may result from extension of the infection to the
pleural surfaces. Extrapulmonary manifestations of tuberculosis are legion and depend on the organ
system involved.

The diagnosis of pulmonary disease is based in part on the history and on physical and radiographic
findings of consolidation or cavitation in the apices of the lungs. Ultimately, however, tubercle bacilli
must be identified. Acid-fast smears and cultures of the sputum of patients suspected of having
tuberculosis should be performed. Conventional cultures require up to 10 weeks, but culture in liquid
media can provide an answer within 2 weeks. PCR amplification of M. tuberculosis DNA allows for even
more rapid diagnosis. PCR assays can detect as few as 10 organisms in clinical specimens, compared with
more than 10,000 organisms required for smear positivity. However, culture remains the gold standard
because it also allows testing of drug susceptibility. Multidrug resistance is now seen more commonly
than it was in past years; hence, all newly diagnosed cases in the United States are assumed to be
resistant and are treated with multiple drugs. The prognosis is generally good if infections are localized
to the lungs, except when they are caused by drug-resistant strains or occur in aged, debilitated, or
immunosuppressed individuals, who are at high risk for developing miliary tuberculosis (see below).

All stages of HIV infection are associated with an increased risk of tuberculosis. The use of highly active
antiretroviral therapy (HAART) reduces the risk of tuberculosis in people with HIV infection, but even
with HAART, people infected with HIV are more likely to get tuberculosis than the uninfected. A low CD4
count before starting HAART is an important risk factor for development of tuberculosis, which
underscores the role of the immune response in keeping reactivation of M. tuberculosis in check. The
manifestations of tuberculosis differ depending on the degree of immunosuppression. People with less
severe immunosuppression (CD4+ T-cell counts >300 cells/mm3) present with usual secondary
tuberculosis (apical disease with cavitation). People with more advanced immunosuppression (CD4+ T-
cell counts <200 cells/mm3) present with a clinical picture that resembles progressive primary
tuberculosis. The extent of immunodeficiency also determines the frequency of extrapulmonary
involvement, rising from 10% to 15% in mildly immunosuppressed people to greater than 50% in those
with severe immune deficiency. Other atypical features of tuberculosis in HIV-positive people include an
increased frequency of false-negative sputum smears and tuberculin tests (the latter due to “anergy”),
and the absence of characteristic granulomas in tissues, particularly in the late stages of HIV. The
increased frequency of sputum smear-negativity is paradoxical because these immunosuppressed
patients typically have higher bacterial loads. The likely explanation is that cavitation and bronchial
damage are more in immunocompetent individuals, resulting in more bacilli in expelled sputum. In
contrast, the absence of bronchial wall destruction due to reduced T-cell–mediated hypersensitivity
results in the excretion of fewer bacilli in the sputum.

Morphology.

Primary Tuberculosis. In countries where infected milk has been eliminated, primary tuberculosis
almost always begins in the lungs. Typically, the inhaled bacilli implant in the distal airspaces of the
lower part of the upper lobe or the upper part of the lower lobe, usually close to the pleura. As
sensitization develops, a 1- to 1.5-cm area of gray-white inflammation with consolidation emerges,
known as the Ghon focus. In most cases, the center of this focus undergoes caseous necrosis. Tubercle
bacilli, either free or within phagocytes, drain to the regional nodes, which also often caseate. This
combination of parenchymal lung lesion and nodal involvement is referred to as the Ghon complex ( Fig.
8-29 ). During the first few weeks there is also lymphatic and hematogenous dissemination to other
parts of the body. In approximately 95% of cases, development of cell-mediated immunity controls the
infection. Hence, the Ghon complex undergoes progressive fibrosis, often followed by radiologically
detectable calcification (Ranke complex), and despite seeding of other organs, no lesions develop.

Histologically, sites of active involvement are marked by a characteristic granulomatous inflammatory

reaction that forms both caseating and noncaseating tubercles ( Fig. 8-30A to C ). Individual tubercles
are microscopic; it is only when multiple granulomas coalesce that they become macroscopically visible.
The granulomas are usually enclosed within a fibroblastic rim punctuated by lymphocytes. Multinucleate
giant cells are present in the granulomas. Immunocompromised people do not form the characteristic
granulomas ( Fig. 8-30D ).

Secondary Tuberculosis. The initial lesion is usually a small focus of consolidation, less than 2 cm in
diameter, within 1 to 2 cm of the apical pleura. Such foci are sharply circumscribed, firm, gray-white to
yellow areas that have a variable amount of central caseation and peripheral fibrosis ( Fig. 8-31 ). In
immunocomptetent individuals, the initial parenchymal focus undergoes progressive fibrous
encapsulation, leaving only fibrocalcific scars. Histologically, the active lesions show characteristic
coalescent tubercles with central caseation. Tubercle bacilli can often be identified with acid-fast stains
in early exudative and caseous phases of granuloma formation but are usually too few to be found in the
late, fibrocalcific stages. Localized, apical, secondary pulmonary tuberculosis may heal with fibrosis
either spontaneously or after therapy, or the disease may progress and extend along several different
pathways.

Progressive pulmonary tuberculosis may ensue in the elderly and immunosuppressed. The apical lesion
expands into adjacent lung and eventually erodes into bronchi and vessels. This evacuates the caseous
center, creating a ragged, irregular cavity that is poorly walled off by fibrous tissue. Erosion of blood
vessels results in hemoptysis. With adequate treatment the process may be arrested, although healing
by fibrosis often distorts the pulmonary architecture. The cavities, now free of inflammation, may persist
or become fibrotic. If the treatment is inadequate or if host defenses are impaired, the infection may
spread via airways, lymphatic channels, or the vascular system. Miliary pulmonary disease occurs when
organisms draining through lymphatics enter the venous blood and circulate back to the lung. Individual
lesions are either microscopic or small, visible (2-mm) foci of yellow-white consolidation scattered
through the lung parenchyma (the adjective “miliary” is derived from the resemblance of these foci to
millet seeds). Miliary lesions may expand and coalesce, resulting in consolidation of large regions or
even whole lobes of the lung. With progressive pulmonary tuberculosis, the pleural cavity is invariably
involved, and serous pleural effusions, tuberculous empyema, or obliterative fibrous pleuritis may
develop.

Endobronchial, endotracheal, and laryngeal tuberculosis may develop by spread through lymphatic
channels or from expectorated infectious material. The mucosal lining may be studded with minute
granulomatous lesions that may only be apparent microscopically.

Systemic miliary tuberculosis occurs when bacteria disseminate through the systemic arterial system.
Miliary tuberculosis is most prominent in the liver, bone marrow, spleen, adrenals, meninges, kidneys,
fallopian tubes, and epididymis, but could involve any organ

Isolated tuberculosis may appear in any of the organs or tissues seeded hematogenously and may be
the presenting manifestation. Organs that are commonly involved include the meninges (tuberculous
meningitis), kidneys (renal tuberculosis), adrenals (formerly an important cause of Addison disease),
bones (osteomyelitis), and fallopian tubes (salpingitis).

When the vertebrae are affected, the disease is referred to as Pott disease. Paraspinal “cold” abscesses
in these patients may track along tissue planes and present as an abdominal or pelvic mass.

Lymphadenitis is the most frequent presentation of extrapulmonary tuberculosis, usually occurring in

the cervical region (“scrofula”). In HIV-negative individuals, lymphadenitis tends to be unifocal and
localized. HIV-positive people, on the other hand, almost always have multifocal disease, systemic
symptoms, and either pulmonary or other organ involvement by active tuberculosis.

In years past, intestinal tuberculosis contracted by the drinking of contaminated milk was a fairly
common primary focus of disease. In countries where milk is pasteurized, intestinal tuberculosis is more
often caused by the swallowing of coughed-up infective material in patients with advanced pulmonary
disease. Typically the organisms are seed to mucosal lymphoid aggregates of the small and large bowel,
which then undergo granulomatous inflammation that can lead to ulceration of the overlying mucosa,
particularly in the ileum.
GOOGLE

Tuberculosis is an infectious disease that usually affects the lungs. Compared with other
diseases caused by a single infectious agent, tuberculosis is the second biggest killer,
globally.

In 2015, 1.8 million people died from the disease, with 10.4 million falling ill.
In the 18th and 19th centuries, a tuberculosis epidemic rampaged throughout Europe
and North America, before the German microbiologist Robert Koch discovered the
microbial causes of tuberculosis in 1882.

Following Koch's discovery, the development of vaccines and effective drug treatment
led to the belief that the disease was almost defeated. Indeed, at one point, the United
Nations, predicted that tuberculosis (TB) would be eliminated worldwide by 2025.

However, in the mid-80s, TB cases began to rise worldwide, so much so, that in 1993,
the World Health Organization (WHO) declared that TB was a global emergency; the
first time that a disease had been labeled as such.
Fortunately, with proper treatment, the vast majority of cases of tuberculosis are
curable. Cases of TB have decreased in the United States since 1993, but the disease
remains a concern. Without proper treatment, up to two-thirds of people ill with
tuberculosis will die.

Fast facts on tuberculosis

Here are some key points about tuberculosis. More detail and supporting information is
in the main article.
 The World Health Organization estimates that 9 million people a year get sick with
TB, with 3 million of these "missed" by health systems

 TB is among the top 3 causes of death for women aged 15 to 44

 TB symptoms (cough, fever, night sweats, weight loss, etc.) may be mild for many
months, and people ill with TB can infect up to 10-15 other people through close contact
over the course of a year
 TB is an airborne pathogen, meaning that the bacteria that cause TB can spread
through the air from person to person

 What is tuberculosis?
  Doctors make a distinction between two kinds of tuberculosis infection: latent
and active.
 Latent TB - the bacteria remain in the body in an inactive state. They cause no
symptoms and are not contagious, but they can become active.
 Active TB - the bacteria do cause symptoms and can be transmitted to others.
 About one-third of the world's population is believed to have latent TB. There is
a 10 percent chance of latent TB becoming active, but this risk is much higher in
people who have compromised immune systems i.e., people living
with HIV or malnutrition, or people who smoke.
 TB affects all age groups and all parts of the world. However, the disease mostly
affects young adults and people living in developing countries. In 2012, 80
percent of reported TB cases occurred in just 22 countries.

What causes tuberculosis?

 The Mycobacterium tuberculosis bacterium causes TB. It is spread through the
air when a person with TB (whose lungs are affected) coughs, sneezes, spits,
laughs, or talks.
 TB is contagious, but it is not easy to catch. The chances of catching TB from
someone you live or work with are much higher than from a stranger. Most
people with active TB who have received appropriate treatment for at least 2
weeks are no longer contagious.
 Since antibiotics began to be used to fight TB, some strains have become
resistant to drugs. Multidrug-resistant TB (MDR-TB) arises when an antibiotic
fails to kill all of the bacteria, with the surviving bacteria developing resistance to
that antibiotic and often others at the same time.
 MDR-TB is treatable and curable only with the use of very specific anti-TB drugs,
which are often limited or not readily available. In 2012, around 450,000 people
developed MDR-TB.
Symptoms of tuberculosis
While latent TB is symptomless, the symptoms of active TB include the following:

 Coughing, sometimes with mucus or blood

 Chills

 Fatigue
 Fever

 Loss of weight

 Loss of appetite

 Night sweats

Tuberculosis usually affects the lungs, but can also affect other parts of the body. When
TB occurs outside of the lungs, the symptoms vary accordingly. Without treatment, TB
can spread to other parts of the body through the bloodstream:

 TB infecting the bones can lead to spinal pain and joint destruction

 TB infecting the brain can cause meningitis

 TB infecting the liver and kidneys can impair their waste filtration functions and lead
to blood in the urine

 TB infecting the heart can impair the heart's ability to pump blood, resulting in a
condition called cardiac tamponade that can be fatal

Diagnosis of tuberculosis
To check for TB, a doctor will use a stethoscope to listen to the lungs and check for
swelling in the lymph nodes. They will also ask about symptoms and medical history as
well as assessing the individual's risk of exposure to TB.

The most common diagnostic test for TB is a skin test where a small injection of PPD

tuberculin, an extract of the TB bacterium, is made just below the inside forearm.

The injection site should be checked after 2-3 days, and, if a hard, red bump has
swollen up to a specific size, then it is likely that TB is present.
Unfortunately, the skin test is not 100 percent accurate and has been known to give
incorrect positive and negative readings.

However, there are other tests that are available to diagnose TB. Blood tests, chest X-
rays, and sputum tests can all be used to test for the presence of TB bacteria and may
be used alongside a skin test.

MDR-TB is more difficult to diagnose than regular TB. It is also difficult to diagnose
regular TB in children.

Treatments for tuberculosis

The majority of TB cases can be cured when the right medication is available and
administered correctly. The precise type and length of antibiotic treatment depends on a
person's age, overall health, potential resistance to drugs, whether the TB is latent or
active, and the location of infection (i.e. the lungs, brain, kidneys).

People with latent TB may need just one kind of TB antibiotics, whereas people with
active TB (particularly MDR-TB) will often require a prescription of multiple drugs.

Antibiotics are usually required to be taken for a relatively long time. The standard
length of time for a course of TB antibiotics is about 6 months.

TB medication can be toxic to the liver, and although side effects are uncommon, when
they do occur, they can be quite serious. Potential side effects should be reported to a
doctor and include:

 Dark urine

 Fever

 Jaundice
 Loss of appetite

 Nausea and vomiting

Learn About Tuberculosis
Tuberculosis (TB) is an airborne bacterial infection caused by the
organism Mycobacterium tuberculosis that primarily affects the
lungs, although other organs and tissues may be involved.
Key Points
 It is not easy to become infected with tuberculosis.

 Most infected people have latent TB, meaning they have the
tuberculosis germs in their bodies, but their immune system
protects them from becoming sick and they are not
contagious.

 TB can almost always be treated and cured if you take

medicine as directed.

 There are forms of TB that are drug resistant.

What Is TB?
Tuberculosis (TB) is an infectious disease that usually attacks the
lungs, but can attack almost any part of the body. Tuberculosis is
spread from person to person through the air. When a person with
TB in their lungs or throat coughs, laughs, sneezes, sings, or even
talks, the germs that cause TB may spread through the air. If
another person breathes in these germs there is a chance that they
will become infected with tuberculosis.

It is important to understand that there is a difference between

being infected with TB (latent TB) and having clinically active TB
disease. Someone who is infected with TB has the TB germs, or
bacteria, in their body. The body's immune system is protecting
them from the germs and they are not sick. This is referred to as
latent TB.

Someone with TB disease is sick and can spread the disease to

other people. A person with TB disease needs to see a doctor as
soon as possible. This is referred to as active TB.

There are also forms of TB that are drug resistant, or even worse—
multi-drug resistant. This means that some of the drugs used to
treat the infection are not effective against the resistant TB germs in
the body. Learn more about the types of drug resistant TB.
How Does Someone Become Infected
with TB?
It is not easy to become infected with tuberculosis. Usually a person
has to be close to someone with TB disease for a long period of
time. TB is usually spread between family members, close friends,
and people who work or live together. TB is spread most easily in
closed spaces over a long period of time.

How TB Affects Your Body

People with weakened immune systems (those with HIV/AIDS, those
receiving chemotherapy, or children under 5 years old, for example)
are at a greater risk for developing TB disease. When they breathe
in TB bacteria, the bacteria settle in their lungs and start growing
because their immune systems cannot fight the bacteria. In these
people, TB disease may develop within days or weeks after the
infection.

In other people who are healthy at the time of the initial limited
infection, TB disease may develop months or years after the initial
infection, at a time when the immune system becomes weak for
other reasons and they are no longer able to fight the germs
(Mycobacteria).

When a person gets active TB disease, it means TB bacteria are

multiplying and attacking the lung(s) or other parts of the body,
such as the lymph nodes, bones, kidney, brain, spine, and even the
skin. From the lungs, TB bacteria move through the blood  or
lymphatic system to different parts of the body. Symptoms of active
disease include cough, loss of weight and appetite, fever, chills and
night sweats as well as symptoms related to the function of a
specific organ or system that is affected; for example, coughing up
blood or sputum in TB of the lungs, or bone pain if the bacteria have
invaded the bones.

Diagnosing and Treating

Tuberculosis
If it is not treated, TB can be fatal. But TB can almost always be treated and
cured if you take medicine as directed by your healthcare provider. Once you
begin treatment, within weeks you will no longer be contagious. That means
you can't spread the disease to others. If you take your medicine just as your
healthcare provider tells you, you should be cured (although there are
occasional relapses, indicating some of the germs may survive.)
How Is TB Diagnosed?
TB can be detected through a skin test or a TB blood test.

The skin test is done by injecting a small amount of fluid called tuberculin into
the skin in the arm. You will be told to return within 48 to 72 hours to have a
healthcare worker check the arm to see if a bump or an induration
(thickening)  of the skin has developed. These may be difficult to feel and an
experienced healthcare worker should examine the reaction. The healthcare
worker will measure the bump or induration and tell you if your reaction to the
test is positive or negative. If it's positive, it usually means you have been
infected with the TB germ.

www.lung.org > Lung Health and Diseases > Lung Disease Lookup > Tuberculosis (TB)

Diagnosing and Treating

Tuberculosis
Top 5 Questions for Your Doctor
See 5 important questions to ask your healthcare provider about TB.
Learn more
If it is not treated, TB can be fatal. But TB can almost always be
treated and cured if you take medicine as directed by your
healthcare provider. Once you begin treatment, within weeks you
will no longer be contagious. That means you can't spread the
disease to others. If you take your medicine just as your healthcare
provider tells you, you should be cured (although there are
occasional relapses, indicating some of the germs may survive.)
How Is TB Diagnosed?
TB can be detected through a skin test or a TB blood test.

The skin test is done by injecting a small amount of fluid called

tuberculin into the skin in the arm. You will be told to return within
48 to 72 hours to have a healthcare worker check the arm to see if a
bump or an induration (thickening)  of the skin has developed.
These may be difficult to feel and an experienced healthcare worker
should examine the reaction. The healthcare worker will measure
the bump or induration and tell you if your reaction to the test is
positive or negative. If it's positive, it usually means you have been
infected with the TB germ.

The TB blood test measures how your immune system reacts to the
germs that cause TB. If you have a positive test for TB infection, it
only means that you have been infected with TB germs. It does not
tell whether you have developed clinically active TB disease. You
will be given other tests, such as a chest X-ray and a check of your
sputum (coughed up mucus), to see whether you have clinically
activeTB disease.

How Is TB Treated?
Treatment for TB depends on whether a person has clinically active
TB disease or only TB infection.

If you have become infected with TB, but do not have clinically
active TB disease (this is called latent TB), you should
get preventive therapy. This treatment kills germs that are not
doing any damage right now, but could so do in the future. The most
common preventive therapy is a daily dose of isoniazid (INH) taken
as a single daily pill for 6 to 9 months.
If you have active TB disease you will probably be treated with a
combination of several drugs for 6 to 12 months. You may only have
to stay a short time in the hospital, if at all, and can then continue
taking medication at home. After a few weeks you can probably
even return to normal activities and not have to worry about
infecting others.

The most common treatment for active TB is INH plus three other
drugs—rifampin, pyrazinamide and ethambutol. You will probably
begin to feel better only a few weeks after starting to take the
drugs.

It is very important that you continue to take the medicine correctly

(regularly and under medical supervision) for the full length of
treatment. If you are being treated in a public clinic you may be
asked to take your medicines in the presence of a healthcare worker
who will ensure that you have done so. This is called Directly
Observed Therapy (DOT).

Drug-Resistant TB

If you take the medicine(s) incorrectly or stop taking the medicine(s)

altogether, you may become sick again and will be able to infect others with
TB. The TB may be harder to treat a second time if it has become drug
resistant. This means that some drugs initially used to treat TB will no longer
be able to fight the TB germs in your body. TB that is resistant to more than
one drug, called multidrug-resistant TB (MDR TB) is very dangerous to you
and to others to whom you can spread the infection.

WHO

Tuberculosis (TB) is caused by bacteria (Mycobacterium tuberculosis) that most often

affect the lungs. Tuberculosis is curable and preventable.
TB is spread from person to person through the air. When people with lung TB cough,
sneeze or spit, they propel the TB germs into the air. A person needs to inhale only a few
of these germs to become infected.
About one-third of the world's population has latent TB, which means people have been
infected by TB bacteria but are not (yet) ill with the disease and cannot transmit the
disease.
People infected with TB bacteria have a 10% lifetime risk of falling ill with TB. However,
persons with compromised immune systems, such as people living with HIV, malnutrition
or diabetes, or people who use tobacco, have a much higher risk of falling ill.
When a person develops active TB disease, the symptoms (such as cough, fever, night
sweats, or weight loss) may be mild for many months. This can lead to delays in seeking
care, and results in transmission of the bacteria to others. People with active TB can
infect 10–15 other people through close contact over the course of a year. Without proper
treatment, 45% of HIV-negative people with TB on average and nearly all HIV-positive
people with TB will die.
Symptoms and diagnosis
Common symptoms of active lung TB are cough with sputum and blood at times, chest
pains, weakness, weight loss, fever and night sweats. Many countries still rely on a long-
used method called sputum smear microscopy to diagnose TB. Trained laboratory
technicians look at sputum samples under a microscope to see if TB bacteria are present.
Microscopy detects only half the number of TB cases and cannot detect drug-resistance.
The use of the rapid test Xpert MTB/RIF® has expanded substantially since 2010, when
WHO first recommended its use. The test simultaneously detects TB and resistance to
rifampicin, the most important TB medicine. Diagnosis can be made within 2 hours and
the test is now recommended by WHO as the initial diagnostic test in all persons with
signs and symptoms of TB. More than 100 countries are already using the test and 6.2
million cartridges were procured globally in 2015.
Diagnosing multi-drug resistant and extensively drug-resistant TB (see Multidrug-
resistant TB section below) as well as HIV-associated TB can be complex and expensive.
In 2016, 4 new diagnostic tests were recommended by WHO – a rapid molecular test to
detect TB at peripheral health centres where Xpert MTB/RIF cannot be used, and 3 tests
to detect resistance to first- and second-line TB medicines.
Tuberculosis is particularly difficult to diagnose in children and as yet only the Xpert
MTB/RIF assay is generally available to assist with the diagnosis of paediatric TB.
TB tests – Skin test, sputum & other
types of TB test
There are several TB tests available to diagnosis TB. There are also TB
tests to find out whether someone has TB bacteria that are susceptible to
TB drug treatment or are drug resistant. TB tests to find out if someone
has drug resistant TB, are known as drug susceptibility tests.

Even if a person has symptoms of TB, it is often difficult to diagnose TB,

and is particularly difficult to diagnose rapidly. Rapid diagnosis is what is
needed to provide effective TB treatment for drug resistant TB.

Evidence of TB bacteria

TB tests look for evidence of these TB bacteria, Mycobacterium tuberculosis, © NIAID

The development of TB disease is a two stage process. In the first stage,

known as latent TB, a person is infected with TB bacteria. In the second
stage, known as active TB or TB disease, the bacteria have reproduced
sufficiently to usually cause the person to have become sick. Some tests
are for latent TB, others are for active TB, and some are for both.

A diagnosis of active TB disease can only be confirmed when there is

definite evidence of TB bacteria in the person’s body. Some of the TB
tests, such as the skin test, look directly for TB bacteria. Others such as
the chest X-ray look for the effect of the bacteria on the person
suspected of having TB.

The accuracy of TB tests

Some of the current TB tests take a long time to obtain a result, and
some TB tests are not very accurate. The TB tests either have low
sensitivity (the ability to correctly detect people with TB) and/or low
specificity (the ability to correctly detect people who haven’t got TB).

If a TB test has low sensitivity, it means that there will be a significant

number of “false negatives”, meaning that the test result is suggesting
that a person has not got TB when they actually have. Similarly, a low
specificity means that there will be a significant number of “false
positives” suggesting that a person has TB when they actually haven’t.

The most accurate tests such as culture take a long time to do. Some
tests are also very expensive and require complex laboratory facilities.

- See more at: http://www.tbfacts.org/tb-tests/#sthash.ms47IHwc.dpuf

The TB skin test

The TB skin test is a widely used test for diagnosing TB. In countries with
low rates of TB it is often used to test for latent TB infection. The problem
with using it in countries with high rates of TB infection is that the
majority of people may have latent TB.

The TB skin test involves injecting a small amount of fluid (called

tuberculin) into the skin in the lower part of the arm. Then the person
must return after 48 to 72 hours to have a trained health care worker look
at their arm. The health care worker will look for a raised hard area or
swelling, and if there is one then they will measure its size. They will not
include any general area of redness.1

The TB skin test result depends on the size of the raised hard area or
swelling. The larger the size of the affected area the greater the
likelihood that the person has been infected with TB bacteria at some
time in the past. But interpreting the TB skin test result, that is whether it
is a positive result, may also involve considering the lifestyle factors of
the person being tested for TB.2 The TB skin test also cannot tell if the
person has latent TB or active TB disease.

The Mantoux TB test is the type of TB test most often used, although the
Heaf and Tine tests are still used in some countries. None of these TB
tests though will guarantee a correct result. False positive results
happen with the TB skin test because the person has been infected with
a different type of bacteria, rather than the one that causes TB. It can
also happen because the person has been vaccinated with the BCG
vaccine. This vaccine is widely used in countries with high rates of TB
infection. False negative results particularly happen with children, older
people and people with HIV.

TB Interferon gamma release assays (IGRAs)

The Interferon Gamma Release Assays (IGRAs), are a new type of more
accurate TB test. In this context referring to an assay is simply a way of
referring to a test or procedure.

IGRAs are blood tests that measure a person’s immune response to the
bacteria that cause TB. The immune system produces some special
molecules called cytokines. These TB tests work by detecting a cytokine
called the interferon gamma cytokine.  In practice you carry out one of
these TB tests by taking a blood sample and mixing it with special
substances to identify if the cytokine is present.
Two IGRAs that have been approved by the U.S. Food and Drug
Administration (FDA), and are commercially available in the U.S., are the
QuantiFERON® TB Gold test, and the T-SPOT® TB test.

The advantages of an IGRA TB test includes the fact that it only requires
a single patient visit to carry out the TB test. Results can be available
within 24 hours, and prior BCG vaccination does not cause a false
positive result. Disadvantages include the fact that the blood sample
must be processed fairly quickly, laboratory facilities are required, and
the test is only for latent TB. It is also thought that the IGRAs may not be
as accurate in people who have HIV.3 In low prevalence resource rich
settings, IGRAs are beginning to be used in place of the TB skin test. 4

Sputum smear microscopy as a test for TB

Smear microscopy of sputum is often the first TB test to be used in

countries with a high rate of TB infection. Sputum is a thick fluid that is
produced in the lungs and the airways leading to the lungs. A sample of
sputum is usually collected by the person coughing.

To test for TB several samples of sputum will normally be collected. 5 In

2012 it was suggested that two specimens can be collected on the same
day without any loss of accuracy.6 7

To do the TB test a very thin layer of the sample is placed on a glass

slide, and this is called a smear. A series of special stains are then
applied to the sample, and the stained slide is examined under a
microscope for signs of the TB bacteria.8

Sputum smear microscopy is inexpensive and simple, and people can be

trained to do it relatively quickly and easily. In addition the results are
available within hours. The sensitivity though is only about 50-60%. 9 In
countries with a high prevalence of both pulmonary TB and HIV infection,
the detection rate can be even lower, as many people with HIV and
TB co-infection have very low levels of TB bacteria in their sputum, and
are therefore recorded as sputum negative.

Fluorescent microscopy
The use of fluorescent microscopy is a way of making sputum TB tests
more accurate. With a fluorescent microscope the smear is illuminated
with a quartz halogen or high pressure mercury vapour lamp, allowing a
much larger area of the smear to be seen and resulting in more rapid
examination of the specimen.

One disadvantage though is that a mercury vapour lamp is expensive and

lasts a very short time. Such lamps also take a while to warm up, they
burn significant amounts of electricity, and electricity supply problems
can significantly shorten their life span. One way of overcoming these
problems is the use of light emitting diodes (LEDs). These switch on
extremely quickly, have an extremely long life, and they don’t explode.10

In 2011 the World Health Organisation issued a policy statement

recommending that conventional fluorescence microscopy should be
replaced by LED microscopy. It also recommended that in a phased way,
that LED microscopy should replace conventional Ziehl-Neelsen light
microscopy.11

Chest X-ray as a TB test

If a person has had TB bacteria which have caused inflammation in the

lungs, an abnormal shadow may be visible on a chest x-ray.12 Also, acute
pulmonary TB can be easily seen on an X-ray. However, what it shows is
not specific. A normal chest X-ray cannot exclude extra pulmonary TB.

Also, in countries where resources are more limited, there is often a lack
of X-ray facilities.

Serological tests for TB

Serological tests for TB are tests carried out on samples of blood, and
they claim to be able to diagnose TB by detecting antibodies in the blood.
However, testing for TB by looking for antibodies in the blood is very
difficult.

As a result serological TB tests, sometimes called serodiagnostic tests,

for TB are inaccurate and unreliable.  The World Health Organisation has
warned that these tests should not be used to try and diagnose active TB.
Some countries have banned the use of serological or serodiagnostic
tests for TB.

Serological tests for TB are very different from the IGRA tests described
above.

TB tests summary
There is no single test that can be used to test for TB in all
circumstances. Some tests are cheap but not very accurate. Some, such
as most of the tests on this page can only be used to test for TB. Others
such as the  TB culture test and the new Genexpert TB test can be
used to diagnose TB and they can also test for some types of TB drug
resistance.

Diagnosing TB, and in particular diagnosing drug resistant TB, promptly

and accurately, remains a significant challenge. This is particularly the
case in resource poor settings. New TB tests such as the Genexpert
molecular test are now becoming available, but are quite expensive for
use in developing countries. Along with Line Probe Assay technology
they require significant laboratory facilities, including the availability of
highly trained staff. This results in delays in providing patients with the
appropriate drug treatment. It also contributes to the on going global TB
epidemic. It has been said regarding TB in India, and this applies to many
other countries as well:
- See more at: http://www.tbfacts.org/tb-tests/#sthash.ms47IHwc.dpuf

WIKIPEDIA

Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium

tuberculosis (MTB).[1] Tuberculosis generally affects the lungs, but can also affect other parts of the
body. Most infections do not have symptoms; in which case it is known as latent tuberculosis. About
10% of latent infections progress to active disease which, if left untreated, kills about half of those
infected. The classic symptoms of active TB are a chronic cough with blood-
containing sputum, fever, night sweats, and weight loss.[1] The historical term "consumption" came
about due to the weight loss.[2] Infection of other organs can cause a wide range of symptoms. [3]
Tuberculosis is spread through the air when people who have active TB in their lungs cough, spit,
speak, or sneeze.[1][4]People with latent TB do not spread the disease. Active infection occurs more
often in people with HIV/AIDS and in those who smoke.[1] Diagnosis of active TB is based on chest
X-rays, as well as microscopic examination and culture of body fluids. Diagnosis of latent TB relies
on the tuberculin skin test (TST) or blood tests.[5]
Prevention of TB involves screening those at high risk, early detection and treatment of cases,
and vaccination with the bacillus Calmette-Guérin vaccine.[6][7][8] Those at high risk include household,
workplace, and social contacts of people with active TB.[8] Treatment requires the use of
multiple antibiotics over a long period of time.[1] Antibiotic resistance is a growing problem with
increasing rates of multiple drug-resistant tuberculosis (MDR-TB).[1]
One-third of the world's population is thought to be infected with TB.[1] New infections occur in about
1% of the population each year.[9] In 2014, there were 9.6 million cases of active TB which resulted in
1.5 million deaths. More than 95% of deaths occurred in developing countries. The number of new
cases each year has decreased since 2000. [1] About 80% of people in many Asian and African
countries test positive while 5–10% of people in the United States population tests positive by the
tuberculin test.[10] Tuberculosis has been present in humans since ancient times.[11]

Signs and symptoms

Tuberculosis may infect any part of the body, but most commonly occurs in the lungs (known as
pulmonary tuberculosis).[3] Extrapulmonary TB occurs when tuberculosis develops outside of the
lungs, although extrapulmonary TB may coexist with pulmonary TB. [3]
General signs and symptoms include fever, chills, night sweats, loss of appetite, weight loss,
and fatigue.[3] Significant nail clubbing may also occur.[13]
Pulmonary
If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of
cases).[11][14]Symptoms may include chest pain and a prolonged cough producing sputum. About 25%
of people may not have any symptoms (i.e. they remain "asymptomatic"). [11] Occasionally, people
may cough up blood in small amounts, and in very rare cases, the infection may erode into
the pulmonary artery or a Rasmussen's aneurysm, resulting in massive bleeding. [3][15] Tuberculosis
may become a chronic illness and cause extensive scarring in the upper lobes of the lungs. The
upper lung lobes are more frequently affected by tuberculosis than the lower ones. [3] The reason for
this difference is not clear.[10] It may be due to either better air flow,[10] or poor lymph drainage within
the upper lungs.[3]

Extrapulmonary
In 15–20% of active cases, the infection spreads outside the lungs, causing other kinds of TB.
[16]
 These are collectively denoted as "extrapulmonary tuberculosis". [17] Extrapulmonary TB occurs
more commonly in immunosuppressed persons and young children. In those with HIV, this occurs in
more than 50% of cases.[17] Notable extrapulmonary infection sites include the pleura (in tuberculous
pleurisy), the central nervous system (in tuberculous meningitis), the lymphatic system (in scrofula of
the neck), the genitourinary system (in urogenital tuberculosis), and the bones and joints (in Pott
disease of the spine), among others.
Spread to lymph nodes is the most common.[18] An ulcer originating from nearby infected lymph
nodes may occur and is painless, slowly enlarging and has an appearance of "wash leather". [19]
When it spreads to the bones, it is known as "osseous tuberculosis", [20] a form of osteomyelitis.[10] A
potentially more serious, widespread form of TB is called "disseminated tuberculosis", also known
as miliary tuberculosis.[3] Miliary TB currently makes up about 10% of extrapulmonary cases.[21]

Causes
Mycobacteria
Main article: Mycobacterium tuberculosis

The main cause of TB is Mycobacterium tuberculosis (MTB), a small, aerobic, nonmotile bacillus.

[3]
 The high lipid content of this pathogen accounts for many of its unique clinical characteristics.
[22]
 It divides every 16 to 20 hours, which is an extremely slow rate compared with other bacteria,
which usually divide in less than an hour.[23] Mycobacteria have an outer membrane lipid bilayer.[24] If
a Gram stain is performed, MTB either stains very weakly "Gram-positive" or does not retain dye as
a result of the high lipid and mycolic acid content of its cell wall.[25] MTB can withstand
weak disinfectants and survive in a dry state for weeks. In nature, the bacterium can grow only within
the cells of a host organism, but M. tuberculosis can be cultured in the laboratory.[26]
Using histological stains on expectorated samples from phlegm (also called "sputum"), scientists can
identify MTB under a microscope. Since MTB retains certain stains even after being treated with
acidic solution, it is classified as an acid-fast bacillus.[10][25] The most common acid-fast staining
techniques are the Ziehl–Neelsen stain[27] and the Kinyoun stain, which dye acid-fast bacilli a bright
red that stands out against a blue background. [28] Auramine-rhodamine staining[29] and fluorescence
microscopy[30] are also used.
The M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria: M. bovis, M.
africanum, M. canetti, and M. microti.[31]M. africanum is not widespread, but it is a significant cause of
tuberculosis in parts of Africa.[32][33] M. bovis was once a common cause of tuberculosis, but the
introduction of pasteurized milk has almost completely eliminated this as a public health problem in
developed countries.[10][34] M. canetti is rare and seems to be limited to the Horn of Africa, although a
few cases have been seen in African emigrants.[35][36] M. microti is also rare and is seen almost only in
immunodeficient people, although its prevalence may be significantly underestimated.[37]
Other known pathogenic mycobacteria include M. leprae, M. avium, and M. kansasii. The latter two
species are classified as "nontuberculous mycobacteria" (NTM). NTM cause neither TB nor leprosy,
but they do cause pulmonary diseases that resemble TB. [38]

Mechanism
Transmission
When people with active pulmonary TB cough, sneeze, speak, sing, or spit, they expel
infectious aerosol droplets 0.5 to 5.0 µm in diameter. A single sneeze can release up to 40,000
droplets.[47] Each one of these droplets may transmit the disease, since the infectious dose of
tuberculosis is very small (the inhalation of fewer than 10 bacteria may cause an infection). [48]
People with prolonged, frequent, or close contact with people with TB are at particularly high risk of
becoming infected, with an estimated 22% infection rate. [49] A person with active but untreated
tuberculosis may infect 10–15 (or more) other people per year. [50] Transmission should occur from
only people with active TB – those with latent infection are not thought to be contagious. [10] The
probability of transmission from one person to another depends upon several factors, including the
number of infectious droplets expelled by the carrier, the effectiveness of ventilation, the duration of
exposure, the virulence of the M. tuberculosis strain, the level of immunity in the uninfected person,
and others.[51] The cascade of person-to-person spread can be circumvented by segregating those
with active ("overt") TB and putting them on anti-TB drug regimens. After about two weeks of
effective treatment, subjects with nonresistant active infections generally do not remain contagious
to others.[49] If someone does become infected, it typically takes three to four weeks before the newly
infected person becomes infectious enough to transmit the disease to others. [52]

Pathogenesis
About 90% of those infected with M. tuberculosis have asymptomatic, latent TB infections
(sometimes called LTBI),[53] with only a 10% lifetime chance that the latent infection will progress to
overt, active tuberculous disease.[54] In those with HIV, the risk of developing active TB increases to
nearly 10% a year.[54] If effective treatment is not given, the death rate for active TB cases is up to
66%.[50]
TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and
replicate within endosomes of alveolar macrophages.[10][55] Macrophages identify the bacterium as
foreign and attempt to eliminate it by phagocytosis. During this process, the bacterium is enveloped
by the macrophage and stored temporarily in a membrane-bound vesicle called a phagosome. The
phagosome then combines with a lysosome to create a phagolysosome. In the phagolysosome, the
cell attempts to use reactive oxygen species and acid to kill the bacterium. However, M.
tuberculosis has a thick, waxy mycolic acid capsule that protects it from these toxic substances. M.
tuberculosis is able to reproduce inside the macrophage and will eventually kill the immune cell.
The primary site of infection in the lungs, known as the "Ghon focus", is generally located in either
the upper part of the lower lobe, or the lower part of the upper lobe.[10] Tuberculosis of the lungs may
also occur via infection from the blood stream. This is known as a Simon focus and is typically found
in the top of the lung.[56] This hematogenous transmission can also spread infection to more distant
sites, such as peripheral lymph nodes, the kidneys, the brain, and the bones. [10][57] All parts of the
body can be affected by the disease, though for unknown reasons it rarely affects the heart, skeletal
muscles, pancreas, or thyroid.[58]
Tuberculosis is classified as one of the granulomatous inflammatory diseases. Macrophages, T
lymphocytes, B lymphocytes, and fibroblasts aggregate to form granulomas,
with lymphocytes surrounding the infected macrophages. When other macrophages attack the
infected macrophage, they fuse together to form a giant multinucleated cell in the alveolar lumen.
The granuloma may prevent dissemination of the mycobacteria and provide a local environment for
interaction of cells of the immune system.[60] However, more recent evidence suggests that the
bacteria use the granulomas to avoid destruction by the host's immune system. Macrophages
and dendritic cells in the granulomas are unable to present antigen to lymphocytes; thus the immune
response is suppressed.[61] Bacteria inside the granuloma can become dormant, resulting in latent
infection. Another feature of the granulomas is the development of abnormal cell death (necrosis) in
the center of tubercles. To the naked eye, this has the texture of soft, white cheese and is
termed caseous necrosis.[60]
If TB bacteria gain entry to the blood stream from an area of damaged tissue, they can spread
throughout the body and set up many foci of infection, all appearing as tiny, white tubercles in the
tissues.[62] This severe form of TB disease, most common in young children and those with HIV, is
called miliary tuberculosis.[63] People with this disseminated TB have a high fatality rate even with
treatment (about 30%).[21][64]
In many people, the infection waxes and wanes. Tissue destruction and necrosis are often balanced
by healing and fibrosis.[60] Affected tissue is replaced by scarring and cavities filled with caseous
necrotic material. During active disease, some of these cavities are joined to the air
passages bronchi and this material can be coughed up. It contains living bacteria, so can spread the
infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon
cure, affected areas are eventually replaced by scar tissue. [60]

Diagnosis
Active tuberculosis
Diagnosing active tuberculosis based only on signs and symptoms is difficult, [65] as is diagnosing the
disease in those who are immunosuppressed.[66] A diagnosis of TB should, however, be considered
in those with signs of lung disease or constitutional symptoms lasting longer than two weeks.
[66]
 A chest X-ray and multiple sputum cultures for acid-fast bacilli are typically part of the initial
evaluation.[66] Interferon-γ release assays and tuberculin skin tests are of little use in the developing
world.[67][68] IGRA have similar limitations in those with HIV.[68][69]
A definitive diagnosis of TB is made by identifying M. tuberculosis in a clinical sample (e.g.,
sputum, pus, or a tissue biopsy). However, the difficult culture process for this slow-growing
organism can take two to six weeks for blood or sputum culture. [70] Thus, treatment is often begun
before cultures are confirmed. [71]
Nucleic acid amplification tests and adenosine deaminase testing may allow rapid diagnosis of TB.
[65]
 These tests, however, are not routinely recommended, as they rarely alter how a person is
treated.[71] Blood tests to detect antibodies are not specific or sensitive, so they are not
recommended.[72]
Active tuberculosis
Diagnosing active tuberculosis based only on signs and symptoms is difficult, [65] as is diagnosing the
disease in those who are immunosuppressed.[66] A diagnosis of TB should, however, be considered
in those with signs of lung disease or constitutional symptoms lasting longer than two weeks.
[66]
 A chest X-ray and multiple sputum cultures for acid-fast bacilli are typically part of the initial
evaluation.[66] Interferon-γ release assays and tuberculin skin tests are of little use in the developing
world.[67][68] IGRA have similar limitations in those with HIV.[68][69]
A definitive diagnosis of TB is made by identifying M. tuberculosis in a clinical sample (e.g.,
sputum, pus, or a tissue biopsy). However, the difficult culture process for this slow-growing
organism can take two to six weeks for blood or sputum culture. [70] Thus, treatment is often begun
before cultures are confirmed. [71]
Nucleic acid amplification tests and adenosine deaminase testing may allow rapid diagnosis of TB.
[65]
 These tests, however, are not routinely recommended, as they rarely alter how a person is
treated.[71] Blood tests to detect antibodies are not specific or sensitive, so they are not
recommended.[72]

Latent tuberculosis
The Mantoux tuberculin skin test is often used to screen people at high risk for TB.[66] Those who
have been previously immunized may have a false-positive test result. [73] The test may be falsely
negative in those with sarcoidosis, Hodgkin's lymphoma, malnutrition, and most notably, active
tuberculosis.[10] Interferon gamma release assays (IGRAs), on a blood sample, are recommended in
those who are positive to the Mantoux test.[71] These are not affected by immunization or
most environmental mycobacteria, so they generate fewer false-positive results.[74] However, they are
affected by M. szulgai, M. marinum, and M. kansasii.[75] IGRAs may increase sensitivity when used in
addition to the skin test, but may be less sensitive than the skin test when used alone. [76]