Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal, infectious disease caused by various

strains ofmycobacteria, usually Mycobacterium tuberculosis.[1] Tuberculosis usually attacks the lungs but can also affect other parts of the body. It is spread through the air when people who have an active MTB infection cough, sneeze, or otherwise transmit their saliva through the air.[2] Most infections in humans result in an asymptomatic, latent infection, and about one in ten latent infections eventually progress to active disease, which, if left untreated, kills more than 50% of those infected. The classic symptoms are a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss (the last giving rise to the formerly prevalent colloquial term "consumption"). Infection of other organs causes a wide range of symptoms. Diagnosis relies on radiology (commonly chest X-rays), atuberculin skin test, blood tests, as well as microscopic examination and microbiological culture of bodily fluids. Treatment is difficult and requires long courses of multiple antibiotics. Social contacts are also screened and treated if necessary. Antibiotic resistance is a growing problem in (extensively) multi-drug-resistant tuberculosis. Prevention relies on screening programs and vaccination, usually with Bacillus Calmette-Gurin vaccine. One third of the world's population is thought to be infected with M. tuberculosis,[3][4] and new infections occur at a rate of about one per second.[3] In 2007 there were an estimated 13.7 million chronic active cases,[5] and in 2010 8.8 million new cases, and 1.45 million deaths, mostly in developing countries.[6]The absolute number of tuberculosis cases has been decreasing since 2006 and new cases since 2002.[6] In addition, more people in the developing worldcontract tuberculosis because their immune systems are more likely to be compromised due to higher rates of AIDS.[7] The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 510% of the U.S. population test positive.[1]
Contents
[hide]

1 Signs and symptoms

o o o

1.1 Pulmonary 1.2 Extrapulmonary 1.3 Constitutional

2 Causes

2.1 Mycobacterium

2.2 Risk factors

3 Mechanism

o o

3.1 Transmission 3.2 Pathogenesis

4 Diagnosis

4.1 Screening

5 Prevention

o o

5.1 Vaccines 5.2 Public health

6 Treatment

o o o

6.1 New onset 6.2 Recurrent disease 6.3 Medication resistance

7 Prognosis 8 Epidemiology 9 History 10 In other animals 11 Research 12 References 13 External links

[edit]Signs

and symptoms

Main symptoms of variants and stages of tuberculosis, [8] with many symptoms overlapping with other variants, while others are more (but not entirely) specific for certain variants. Multiple variants may be present simultaneously.

Only about 5-10% of those without HIV, infection with tuberculosis develop active disease.[9] In contrast 30% of those co-infected with HIV develop active disease.[9] Extrapulmonary TB may co-exist with pulmonary TB.[10]
[edit]Pulmonary

If tuberculosis does becomes active, it most commonly involves infection in the lungs (pulmonary TB).[7] Symptoms include chest pain and a productive, prolonged cough. About a quarter of people however may not have any symptoms.[7] Occasionally people may cough up blood in small amounts and in very rare cases the infection may erode into the pulmonary artery resulting in massive bleeding known as Rasmussen's aneurysm.[10] Spitting up stones known as lithoptysis has been described due to bronchial lymph nodes communicated with the airways.[10] Tuberculosis may become chronic with scaring usually in the upper lobes of the lungs.[10] It is believed that the upper lungs are more frequently affected due to their poor lymph supply rather than more air flow.[10]
[edit]Extrapulmonary

In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB, collectively denoted extrapulmonary tuberculosis.[11] This occurs more commonly in immunosuppressed persons and young children. Extrapulmonary infection sites include the pleura in tuberculous pleurisy, thecentral nervous system in meningitis, the lymphatic system in scrofula of the neck, the genitourinary system in urogenital tuberculosis, and the bones and joints in Pott's disease of the spine. When spread to the bones it is also known as "osseous tuberculosis",[12] a form of osteomyelitis (as a complication of tuberculosis[1]). An a potentially more serious form is disseminated TB, more commonly known as miliary tuberculosis.[10]
[edit]Constitutional

Systemic symptoms include fever, chills, night sweats, appetite loss, weight loss, and fatigue.[10] Finger clubbing may also occur.[9]
[edit]Causes [edit]Mycobacterium

Main article: Mycobacterium tuberculosis

Scanning electron micrograph ofMycobacterium tuberculosis

The main cause of TB is, Mycobacterium tuberculosis, a small aerobic non-motile bacillus or less commonly the closely related Mycobacterium bovis.[10] The high lipid content of this pathogen accounts for many of its unique clinical characteristics.[13] It divides every 16 to 20 hours, an extremely slow rate compared with other bacteria, which usually divide in less than an hour.[14] Since MTB has a cell wall but lacks a phospholipid outer membrane, it is classified as aGram-positive bacterium. However, if a Gram stain is performed, MTB either stains very weakly Gram-positive or does not retain dye as a result of the highlipid and mycolic acid content of its cell wall.[15] 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.[16] Using histological stains on expectorate samples from phlegm (also called sputum), scientists can identify MTB under a regular microscope. Since MTB retains certain stains after being treated with acidic solution, it is classified as an acid-fast bacillus (AFB).[1][15] The most common acid-fast staining technique, the Ziehl-Neelsen stain, dyes AFBs a bright red that stands out clearly against a blue background. Other ways to visualize AFBs include anauramine-rhodamine stain and fluorescent microscopy. The M. tuberculosis complex includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canetti, and M. microti.[17] M. africanum is not widespread, but in parts of Africa it is a significant cause of tuberculosis.[18][19] M. bovis was once a common cause of tuberculosis, but the introduction ofpasteurized milk has largely eliminated this as a public health problem in developed countries.[1][20] M. canetti is rare and seems to be limited to Africa, although a few cases have been seen in African emigrants.[21] M. microti is mostly seen in immunodeficient people, although it is possible that the prevalenceof this pathogen has been underestimated.[22] Other known pathogenic mycobacteria include Mycobacterium

leprae, Mycobacterium avium, and M. kansasii. The latter two are part of the nontuberculous mycobacteria (NTM) group. Nontuberculous mycobacteria cause neither TB nor leprosy, but they do cause pulmonary diseases resembling TB.[23]
[edit]Risk

factors

Main article: Risk factors for tuberculosis There are a number factors that make people more susceptible to TB infections. Worldwide the most important of these is HIV with co-infection present in about 13% of cases.[6] This is a particular problem in Sub-Saharan Africa where rates of HIV are high.[24][25] Tuberculosis is closely linked to both over crowding and malnutrition making it one of the principle diseases of poverty.[7] Chronic lung disease is a riks factor with smoking more than 20 cigarettes a day increases the risk by two to four times[26] and silicosis increases the risk about 30 fold.[27] Other disease states that increase the risk of developing tuberculosis include alcoholism[7] and diabetes mellitus (three fold increase).[28] Certain medications such as corticosteroids and tumor necrosis factor are becoming increasingly important risk factors, especially in the developed world.[7] There is also a genetic susceptibility[29] which's importance overall is still undefined.[7]
[edit]Mechanism

Public health campaigns tried to halt the spread of TB.

[edit]Transmission

When people suffering from active pulmonary TB cough, sneeze, speak, sing, or spit, they expel infectious aerosol droplets 0.5 to 5 m in diameter. A single sneeze can release up to 40,000 droplets.[30] Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very low and inhaling fewer than ten bacteria may cause an infection.[31] People with prolonged, frequent, or intense contact are at particularly high risk of becoming infected, with an estimated 22% infection rate. A person with active but untreated tuberculosis can infect 1015 other people per year.[3] Others at risk include people in areas where TB is common, people who inject illicit drugs, residents and employees of high-risk congregate settings, medically under-served and low-income populations, high-risk racial or ethnic minority populations, children exposed to adults in high-risk categories, those who are immunocompromised by conditions such as HIV/AIDS, people who take immunosuppressant drugs, and health care workers serving these high-risk clients.[32] Transmission can only occur from people with activenot latentTB.[1] The probability of transmission from one person to another depends upon the number of infectious droplets expelled by a carrier, the effectiveness of ventilation, the duration of exposure, and the virulence of the M. tuberculosis strain.[33] The chain of transmission can be broken by isolating people with active disease and starting effective anti-tuberculous therapy. After two weeks of such treatment, people with non-resistant active TB generally cease to be contagious. If someone does become infected, then it will take three to four weeks before the newly infected person can transmit the disease to others.[34]
[edit]Pathogenesis

About 90% of those infected with Mycobacterium tuberculosis have asymptomatic, latent TB infection (sometimes called LTBI), with only a 10% lifetime chance that a latent infection will progress to TB disease.[1] However, if untreated, the death rate for these active TB cases is more than 50%.[3] TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within the endosomes of alveolar macrophages.[1][35]The primary site of infection in the lungs is called the Ghon focus, and is generally located in either the upper part of the lower lobe, or the lower part of theupper lobe.[1] Simon foci may also be present. Bacteria are picked up by dendritic cells, which do not allow replication, although these cells can transport the bacilli to local (mediastinal) lymph nodes. Further spread is through the bloodstream to other tissues and organs where secondary TB lesions can develop in other parts of the lung (particularly the apex of the upper lobes), peripheral lymph nodes, kidneys, brain, and bone.[1][36] All parts of the body

can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid.[37] Tuberculosis is classified as one of the granulomatous inflammatory conditions. Macrophages, T lymphocytes, B lymphocytes, and fibroblasts are among the cells that aggregate to form granulomas, with lymphocytes surrounding the infected macrophages. The granuloma prevents dissemination of the mycobacteria and provides a local environment for interaction of cells of the immune system. Bacteria inside the granuloma can become dormant, resulting in a latent infection. Another feature of the granulomas of human tuberculosis 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.[38] If TB bacteria gain entry to the bloodstream from an area of damaged tissue they spread through the body and set up many foci of infection, all appearing as tiny white tubercles in the tissues. This severe form of TB disease is most common in infants and the elderly and is called miliary tuberculosis. People with this disseminated TB have a fatality rate near 100% if untreated. However, if treated early, the fatality rate is reduced to about 10%.[39] In many people the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis.[38] Affected tissue is replaced by scarring and cavities filled with cheese-like white 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 and can therefore 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.[38]
[edit]Diagnosis

Main articles: Tuberculosis diagnosis and Tuberculosis classification

Mycobacterium tuberculosis (stained red) in sputum

Tuberculosis is diagnosed definitively by identifying the causative organism (Mycobacterium tuberculosis) in a clinical sample (for example, sputum or pus). When this is not possible, a probablealthough sometimes inconclusive[2]diagnosis may be made using imaging (X-rays or scans), a tuberculin skin test (Mantoux test),[2] or a, Interferon Gamma Release Assay (IGRA). The main problem with tuberculosis diagnosis is the difficulty in culturing this slow-growing organism in the laboratory (it may take 4 to 12 weeks for blood or sputum culture). A complete medical evaluation for TB must include a medical history, a physical examination, a chest X-ray, microbiological smears, and cultures. It may also include a tuberculin skin test, a serological test. The interpretation of the tuberculin skin test depends upon the person's risk factors for infection and progression to TB disease, such as exposure to other cases of TB or immunosuppression.[33] New TB tests have been developed that are fast and accurate. These include polymerase chain reaction assays for the detection of bacterial DNA.[40] One such molecular diagnostics test gives results in 100 minutes and is currently being offered to 116 low- and middle-income countries at a discount with support from WHO and the Bill and Melinda Gates foundation.[41] Another such test, which was approved by the FDA in 1996, is the amplified mycobacterium tuberculosis direct test (MTD, Gen-Probe). This test yields results in 2.5 to 3.5 hours, and it is highly sensitive and specific when used to test smears positive for acid-fast bacilli (AFB).[42]
[edit]Screening

Mantoux tuberculin skin test

Mantoux tuberculin skin tests are often used for routine screening of high risk individuals.[43] Currently, latent infection is diagnosed in a non-immunized person by a tuberculin skin test, which yields a delayed hypersensitivity type response to an extract made from M. tuberculosis.[1] Those immunized for TB or with past-cleared infection will respond with delayed hypersensitivity parallel to those currently in a state of infection, so the test must be used with caution, particularly with regard to persons from countries where TB immunization is common.[44]Tuberculin tests have the disadvantage of producing false negatives, especially when the person is co-morbid with sarcoidosis, Hodgkins lymphoma, malnutrition, or most notably

active tuberculosis disease.[1] The newer interferon release assays (IGRAs) such as TSPOT.TB and QuantiFERON-TB Gold In Tube overcome many of these problems. IGRAs are in vitro blood tests that are more specific than the skin test. IGRAs detect the release of interferon gamma in response to mycobacterial proteins such as ESAT-6.[45]These are not affected by immunization or environmental mycobacteria, so generate fewer false positive results.[46] There is also evidence that IGRAs are more sensitive than the skin test.[47]
[edit]Prevention

Tuberculosis prevention and control efforts primarily rely on the vaccination of infants and the detection and appropriate treatment of active cases.[7] The World Health Organization has achieved some success with improved treatment success and a small decreases in case numbers.[7]
[edit]Vaccines

The only currently available vaccine as of 2011 is Bacillus Calmette-Gurin (BCG) which while effective against disseminated disease in childhood confers inconsistent protection against pulmonary disease.[48] World wide it is the most widely used vaccine with more than 90% of children vaccinated.[7] However the immunity that it induces decreases after about ten years.[7] As tuberculosis is uncommon in most of the Canada, the United Kingdom, and the United States it is not administered except to people at high risk.[49][50][51] Part of the reason against the use of vaccine is that it makes the tuberculin skin test falsely positive and thus of no use in screening.[51] A number of new vaccines are in development.[7]
[edit]Public

health

The World Health Organization (WHO) declared TB a global health emergency in 1993.[7] and in 2006 the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aims to save 14 million lives between its launch and 2015.[52] A number of targets that they have set are not likely to be acheived by 2015 due to the increase in HIV associated tuberculosis and multi-drug resistant tuberculosis.[7]
[edit]Treatment

Main article: Tuberculosis treatment Treatment for TB uses antibiotics to kill the bacteria. Effective TB treatment is difficult, due to the unusual structure and chemical composition of the mycobacterial cell wall, which makes many antibiotics ineffective and hinders the entry of drugs.[53] The two antibiotics most commonly used are isoniazid and rifampicin and treatments can be prolonged.[33] Latent TB treatment usually uses a single antibiotic, while active TB disease is best treated with

combinations of several antibiotics, to reduce the risk of the bacteria developing antibiotic resistance.[54] People with latent infections are treated to prevent them from progressing to active TB disease later in life.
[edit]New

onset

The recommended treatment of new onset pulmonary tuberculosis as of 2010 is six months of a combination of antibiotic containing rifampin along isoniazid, pyrazinamide and ethambutol for the first two months and with just isoniazid for the last four months.[7] Where resistance to insoniazid is high ethambutol may be added for the last four month.[7]
[edit]Recurrent

disease

If tuberculosis recurs testing to determine what antibiotics it is sensitive to is important before determining treatment.[7] If multi-drug-resistant tuberculosis is detected treatment with at least four effective antibiotics for 18-24 month is recommended.[7]
[edit]Medication

resistance

Primary resistance occurs in persons infected with a resistant strain of TB. A person with fully susceptible TB develops secondary resistance (acquired resistance) during TB therapy because of inadequate treatment, not taking the prescribed regimen appropriately, or using low-quality medication.[54] Drug-resistant TB is a public health issue in many developing countries, as treatment is longer and requires more expensive drugs. Multi-drug-resistant tuberculosis (MDRTB) is defined as resistance to the two most effective first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB (XDR-TB) is also resistant to three or more of the six classes of second-line drugs.[55]
[edit]Prognosis

Progression from TB infection to TB disease occurs when the TB bacilli overcome the immune system defenses and begin to multiply. In primary TB disease15% of casesthis occurs soon after infection.[1] However, in the majority of cases, a latent infection occurs that has no obvious symptoms.[1] These dormant bacilli can produce tuberculosis in 223% of these latent cases, often many years after infection.[56] The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In people co-infected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year.[1] Studies utilizing DNA fingerprinting of M. tuberculosis strains have shown that reinfection contributes more substantially to recurrent TB than previously thought,[57] with estimates that it might account for more than 50% in areas where TB is common.[58] The chance of death from a case of tuberculosis is about 4%.[7]

[edit]

Pathology of Tuberculosis

Return to the tutorial menu.

General Features
Mycobacterium tuberculosis is the organism that is the causative agent for tuberculosis (TB). There are other "atypical" mycobacteria such as M. kansasii that may produced a similar clincal and pathologic appearance of disease. M. avium-intracellulare (MAI) seen in immunocompromised hosts (particularly in persons with AIDS) is not primarily a pulmonary infection in terms of its organ distribution (mostly in organs of the mononuclear phagocyte system). Tuberculosis is becoming a world-wide problem. War, famine, homelessness, and a lack of medical care all contribute to the increasing incidence of tuberculosis among disadvantaged persons. Since TB is easily transmissible between persons, then the increase in TB in any segment of the population represents a threat to all segments of the population. This means that it is important to institute and maintain appropriate public health measures, including screening, vaccination (where deemed of value), and treatment. A laxity of public health measures will contribute to an increase in cases. Failure of adequate treatment promotes the development of resistant strains of tuberculosis.

Patterns of Infection
There are two major patterns of disease with TB:

Primary tuberculosis: seen as an initial infection, usually in children. The initial focus of infection is a small subpleural granuloma accompanied by granulomatous hilar lymph node infection. Together, these make up the Ghon complex. In nearly all cases, these granulomas resolve and there is no further spread of the infection. Secondary tuberculosis: seen mostly in adults as a reactivation of previous infection (or reinfection), particularly when health status declines. The granulomatous inflammation is much more florid and widespread. Typically, the upper lung lobes are most affected, and cavitation can occur.

When resistance to infection is particularly poor, a "miliary" pattern of spread can occur in which there are a myriad of small millet seed (1-3 mm) sized granulomas, either in lung or in other organs. Dissemination of tuberculosis outside of lungs can lead to the appearance of a number of uncommon findings with characteristic patterns: Skeletal Tuberculosis: Tuberculous osteomyelitis involves mainly the thoracic and lumbar vertebrae (known as Pott's disease) followed by knee and hip. There is extensive necrosis and

bony destruction with compressed fractures (with kyphosis) and extension to soft tissues, including psoas "cold" abscess. Genital Tract Tuberculosis: Tuberculous salpingitis and endometritis result from dissemination of tuberculosis to the fallopian tube that leads to granulomatous salpingitis, which can drain into the endometrial cavity and cause a granulomatous endometritis with irregular menstrual bleeding and infertility. In the male, tuberculosis involves prostate and epididymis most often with non-tender induration and infertility. Urinary Tract Tuberculosis: A "sterile pyuria" with WBC's present in urine but a negative routine bacterial culture may suggest the diagnosis of renal tuberculosis. Progressive destruction of renal parenchyma occurs if not treated. Drainage to the ureters can lead to inflammation with ureteral stricture. CNS Tuberculosis: A meningeal pattern of spread can occur, and the cerebrospinal fluid typically shows a high protein, low glucose, and lymphocytosis. The base of the brain is often involved, so that various cranial nerve signs may be present. Rarely, a solitary granuloma, or "tuberculoma", may form and manifest with seizures. Gastrointestinal Tuberculosis: This is uncommon today because routine pasteurization of milk has eliminated Mycobacterium bovis infections. However, M. tuberculosis organisms coughed up in sputum may be swallowed into the GI tract. The classic lesions are circumferential ulcerations with stricture of the small intestine. There is a predilection for ileocecal involvement because of the abundant lymphoid tissue and slower rate of passage of lumenal contents. Adrenal Tuberculosis: Spread of tuberculosis to adrenals is usually bilateral, so that both adrenals are markedly enlarged. Destruction of cortex leads to Addison's disease. Scrofula: Tuberculous lymphadenitis of the cervical nodes may produce a mass of firm, matted nodes just under the mandible. There can be chronic draining fistulous tracts to overlying skin. This complication may appear in children, and Mycobacterium scrofulaceum may be cultured. Cardiac Tuberculosis: The pericardium is the usual site for tuberculous infection of heart. The result is a granulomatous pericarditis that can be hemorrhagic. If extensive and chronic, there can be fibrosis with calcification, leading to a constrictive pericarditis. The following images illustrate gross pathologic findings with tuberculosis:
1. 2. 3. 4. 5. 6. Ghon complex in lung, gross. Ghon complex in lung, closer view, gross. Cavitary tuberculosis in lung, gross. Cavitary tuberculosis in lung, closer view, gross. Cavitary tuberculosis in lung, florid, gross. Miliary tuberculosis in lung, gross.

7. Miliary tuberculosis in lung, closer view, gross.

Microscopic Findings
Microscopically, the inflammation produced with TB infection is granulomatous, with epithelioid macrophages and Langhans giant cells along with lymphocytes, plasma cells, maybe a few PMN's, fibroblasts with collagen, and characteristic caseous necrosis in the center. The inflammatory response is mediated by a type IV hypersensitivity reaction. This can be utilized as a basis for diagnosis by a TB skin test. An acid fast stain (Ziehl-Neelsen or Kinyoun's acid fast stains) will show the organisms as slender red rods. An auramine stain of the organisms as viewed under fluorescence microscopy will be easier to screen and more organisms will be apparent. The most common specimen screened is sputum, but the histologic stains can also be performed on tissues or other body fluids. Culture of sputum or tissues or other body fluids can be done to determine drug sensitivities.
1. 2. 3. 4. 5. 6. Granulomas in lung, low power microscopic. Granuloma with caseous necrosis, high power microscopic. Granuloma with epithelioid macrophages and a Langhans giant cell, high power microscopic. Granulomatous endometritis, high power microscopic. Ziehl-Neelsen acid fast stain, microscopic, AFB stain. Auramine stain, M. tuberculosis, fluorescence microscopy.

Tuberculin Skin Testing

Skin testing for tuberculosis is useful in countries where the incidence of tuberculosis is low, and the health care system works well to detect and treat new cases. In countries where BCG vaccination has been widely used, the TB skin test is not useful, because persons vaccinated with BCG will have a positive skin test. The TB skin test is based upon the type 4 hypersensitivity reaction. If a previous TB infection has occurred, then there are sensitized lymphocytes that can react to another encounter with antigens from TB organisms. For the TB skin test, a measured amount (the intermediate strength of 5 tuberculin units, used in North America) of tuberculin purified protein derivative (PPD) is injected intracutaneously to form a small wheal, typically on the forearm. In 48 to 72 hours, a positive reaction is marked by an area of red induration that can be measured by gentle palpation (redness from itching and scratching doesn't count). Reactions over 10 mm in size are considered positive in non-immunocompromised persons. Repeated testing may increase the size of the reaction (induration), but repeated TB skin testing will not lead to a positive test in a person not infected by TB. Anergy, or absence of PPD reactivity in persons infected with TB, can occur in immunocompromised persons, or it may even occur in persons newly infected with TB, or in persons with miliary TB.
1. Injecting PPD intracutaneously, gross. 2. A properly placed TB skin test, gross.

3. A positive TB skin test, gross.