Tuberculosis: Difference between revisions

Tuberculosis
Tuberculosis
Other names	Phthisis, phthisis pulmonalis, consumption
	Chest X-ray of a person with advanced tuberculosis: Infection in both lungs is marked by white arrow-heads, and the formation of a cavity is marked by black arrows.
Specialty	Infectious disease, pulmonology
Symptoms	Chronic cough, fever, blood in the sputum, weight loss
Causes	Mycobacterium tuberculosis
Risk factors	Smoking, HIV/AIDS
Diagnostic method	CXR, culture, tuberculin skin test
Differential diagnosis	Necrotizing pneumonia, histoplasmosis, sarcoidosis, coccidioidomycosis
Treatment	Antibiotics
Frequency	33% of people
Deaths	1.1 million (2015)

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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.^[4] Infection of other organs can cause a wide range of symptoms.^[5]

Tuberculosis is spread through the air when people who have active TB in their lungs cough, spit, speak, or sneeze.^[1]^[6] 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.^[7]

Prevention of TB involves screening those at high risk, early detection and treatment of cases, and vaccination with the bacillus Calmette-Guérin vaccine.^[8]^[9]^[10] Those at high risk include household, workplace, and social contacts of people with active TB.^[10] 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.^[11] 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.^[12] Tuberculosis has been present in humans since ancient times.^[13]

Video explanation

Signs and symptoms

Tuberculosis may infect any part of the body, but most commonly occurs in the lungs (known as pulmonary tuberculosis).^[5] Extrapulmonary TB occurs when tuberculosis develops outside of the lungs, although extrapulmonary TB may coexist with pulmonary TB.^[5]

General signs and symptoms include fever, chills, night sweats, loss of appetite, weight loss, and fatigue.^[5] Significant nail clubbing may also occur.^[15]

Pulmonary

If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases).^[13]^[16] 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").^[13] 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.^[5]^[17] 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.^[5] The reason for this difference is not clear.^[12] It may be due to either better air flow,^[12] or poor lymph drainage within the upper lungs.^[5]

Extrapulmonary

In 15–20% of active cases, the infection spreads outside the lungs, causing other kinds of TB.^[18] These are collectively denoted as "extrapulmonary tuberculosis".^[19] Extrapulmonary TB occurs more commonly in immunosuppressed persons and young children. In those with HIV, this occurs in more than 50% of cases.^[19] 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.^[20] An ulcer originating from nearby infected lymph nodes may occur and is painless, slowly enlarging and has an appearance of "wash leather".^[21]

When it spreads to the bones, it is known as "osseous tuberculosis",^[22] a form of osteomyelitis.^[12] A potentially more serious, widespread form of TB is called "disseminated tuberculosis", also known as miliary tuberculosis.^[5] Miliary TB currently makes up about 10% of extrapulmonary cases.^[23]

Causes

Mycobacteria

The main cause of TB is Mycobacterium tuberculosis (MTB), a small, aerobic, nonmotile bacillus.^[5] The high lipid content of this pathogen accounts for many of its unique clinical characteristics.^[24] 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.^[25] Mycobacteria have an outer membrane lipid bilayer.^[26] 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.^[27] 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.^[28]

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.^[12]^[27] The most common acid-fast staining techniques are the Ziehl–Neelsen stain^[29] and the Kinyoun stain, which dye acid-fast bacilli a bright red that stands out against a blue background.^[30] Auramine-rhodamine staining^[31] and fluorescence microscopy^[32] are also used.

The M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canetti, and M. microti.^[33] M. africanum is not widespread, but it is a significant cause of tuberculosis in parts of Africa.^[34]^[35] 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.^[12]^[36] M. canetti is rare and seems to be limited to the Horn of Africa, although a few cases have been seen in African emigrants.^[37]^[38] M. microti is also rare and is seen almost only in immunodeficient people, although its prevalence may be significantly underestimated.^[39]

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.^[40]

Risk factors

A number of factors make people more susceptible to TB infections. The most important risk factor globally is HIV; 13% of all people with TB are infected by the virus.^[41] This is a particular problem in sub-Saharan Africa, where rates of HIV are high.^[42]^[43] Of people without HIV who are infected with tuberculosis, about 5–10% develop active disease during their lifetimes;^[15] in contrast, 30% of those coinfected with HIV develop the active disease.^[15]

Tuberculosis is closely linked to both overcrowding and malnutrition, making it one of the principal diseases of poverty.^[13] Those at high risk thus include: people who inject illicit drugs, inhabitants and employees of locales where vulnerable people gather (e.g. prisons and homeless shelters), medically underprivileged and resource-poor communities, high-risk ethnic minorities, children in close contact with high-risk category patients, and health-care providers serving these patients.^[44]

Chronic lung disease is another significant risk factor. Silicosis increases the risk about 30-fold.^[45] Those who smoke cigarettes have nearly twice the risk of TB compared to nonsmokers.^[46]

Other disease states can also increase the risk of developing tuberculosis. These include alcoholism^[13] and diabetes mellitus (three-fold increase).^[47]

Certain medications, such as corticosteroids and infliximab (an anti-αTNF monoclonal antibody), are becoming increasingly important risk factors, especially in the developed world.^[13]

Genetic susceptibility also exists,^[48] for which the overall importance remains undefined.^[13]

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.^[49] 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).^[50]

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.^[51] A person with active but untreated tuberculosis may infect 10–15 (or more) other people per year.^[52] Transmission should occur from only people with active TB – those with latent infection are not thought to be contagious.^[12] 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.^[53] 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.^[51] 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.^[54]

Pathogenesis

About 90% of those infected with M. tuberculosis have asymptomatic, latent TB infections (sometimes called LTBI),^[55] with only a 10% lifetime chance that the latent infection will progress to overt, active tuberculous disease.^[56] In those with HIV, the risk of developing active TB increases to nearly 10% a year.^[56] If effective treatment is not given, the death rate for active TB cases is up to 66%.^[52]

TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within endosomes of alveolar macrophages.^[12]^[57] 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.^[12] 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.^[58] This hematogenous transmission can also spread infection to more distant sites, such as peripheral lymph nodes, the kidneys, the brain, and the bones.^[12]^[59] 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.^[60]

Robert Carswell's illustration of tubercle^[61]

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.^[62] 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.^[63] 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.^[62]

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.^[64] This severe form of TB disease, most common in young children and those with HIV, is called miliary tuberculosis.^[65] People with this disseminated TB have a high fatality rate even with treatment (about 30%).^[23]^[66]

In many people, the infection waxes and wanes. Tissue destruction and necrosis are often balanced by healing and fibrosis.^[62] 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.^[62]

Diagnosis

Active tuberculosis

Diagnosing active tuberculosis based only on signs and symptoms is difficult,^[67] as is diagnosing the disease in those who are immunosuppressed.^[68] A diagnosis of TB should, however, be considered in those with signs of lung disease or constitutional symptoms lasting longer than two weeks.^[68] A chest X-ray and multiple sputum cultures for acid-fast bacilli are typically part of the initial evaluation.^[68] Interferon-γ release assays and tuberculin skin tests are of little use in the developing world.^[69]^[70] Interferon gamma release assays (IGRA) have similar limitations in those with HIV.^[70]^[71]

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.^[72] Thus, treatment is often begun before cultures are confirmed.^[73]

Nucleic acid amplification tests and adenosine deaminase testing may allow rapid diagnosis of TB.^[67] These tests, however, are not routinely recommended, as they rarely alter how a person is treated.^[73] Blood tests to detect antibodies are not specific or sensitive, so they are not recommended.^[74]

Latent tuberculosis

The Mantoux tuberculin skin test is often used to screen people at high risk for TB.^[68] Those who have been previously immunized may have a false-positive test result.^[75] The test may be falsely negative in those with sarcoidosis, Hodgkin's lymphoma, malnutrition, and most notably, active tuberculosis.^[12] Interferon gamma release assays, on a blood sample, are recommended in those who are positive to the Mantoux test.^[73] These are not affected by immunization or most environmental mycobacteria, so they generate fewer false-positive results.^[76] However, they are affected by M. szulgai, M. marinum, and M. kansasii.^[77] IGRAs may increase sensitivity when used in addition to the skin test, but may be less sensitive than the skin test when used alone.^[78]

Prevention

Tuberculosis prevention and control efforts rely primarily on the vaccination of infants and the detection and appropriate treatment of active cases.^[13] The World Health Organization has achieved some success with improved treatment regimens, and a small decrease in case numbers.^[13] The US Preventive Services Task Force (USPSTF) recommends screening people who are at high risk for latent tuberculosis with either tuberculin skin tests or interferon-gamma release assays.^[79]

Vaccines

The only available vaccine as of 2011 is Bacillus Calmette-Guérin (BCG).^[80] In children it decreases the risk of getting the infection by 20% and the risk of infection turning into disease by nearly 60%.^[81]

It is the most widely used vaccine worldwide, with more than 90% of all children being vaccinated.^[13] The immunity it induces decreases after about ten years.^[13] As tuberculosis is uncommon in most of Canada, the United Kingdom, and the United States, BCG is administered to only those people at high risk.^[82]^[83]^[84] Part of the reasoning against the use of the vaccine is that it makes the tuberculin skin test falsely positive, reducing the test's use in screening.^[84] A number of new vaccines are currently in development.^[13]

Public health

The World Health Organization declared TB a "global health emergency" in 1993,^[13] and in 2006, the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aimed to save 14 million lives between its launch and 2015.^[85] A number of targets they set were not achieved by 2015, mostly due to the increase in HIV-associated tuberculosis and the emergence of multiple drug-resistant tuberculosis.^[13] A tuberculosis classification system developed by the American Thoracic Society is used primarily in public health programs.^[86]

Management

Treatment of 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 hinders the entry of drugs and makes many antibiotics ineffective.^[87] The two antibiotics most commonly used are isoniazid and rifampicin, and treatments can be prolonged, taking several months.^[53] Latent TB treatment usually employs a single antibiotic,^[88] while active TB disease is best treated with combinations of several antibiotics to reduce the risk of the bacteria developing antibiotic resistance.^[13] People with latent infections are also treated to prevent them from progressing to active TB disease later in life.^[88] Directly observed therapy, i.e., having a health care provider watch the person take their medications, is recommended by the WHO in an effort to reduce the number of people not appropriately taking antibiotics.^[89] The evidence to support this practice over people simply taking their medications independently is of poor quality.^[90] There is no strong evidence indicating that directly observed therapy improves the number of people who were cured or the number of people who complete their medicine.^[90] Moderate quality evidence suggests that there is also no difference if people are observed at home versus at a clinic, or by a family member versus a health care worker.^[90] Methods to remind people of the importance of treatment and appointments may result in a small but important improvement.^[91]

New onset

The recommended treatment of new-onset pulmonary tuberculosis, as of 2010, is six months of a combination of antibiotics containing rifampicin, isoniazid, pyrazinamide, and ethambutol for the first two months, and only rifampicin and isoniazid for the last four months.^[13] Where resistance to isoniazid is high, ethambutol may be added for the last four months as an alternative.^[13]

Recurrent disease

If tuberculosis recurs, testing to determine which antibiotics it is sensitive to is important before determining treatment.^[13] If multiple drug-resistant TB (MDR-TB) is detected, treatment with at least four effective antibiotics for 18 to 24 months is recommended.^[13]

Medication resistance

Primary resistance occurs when a person becomes infected with a resistant strain of TB. A person with fully susceptible MTB may develop secondary (acquired) resistance during therapy because of inadequate treatment, not taking the prescribed regimen appropriately (lack of compliance), or using low-quality medication.^[92] Drug-resistant TB is a serious public health issue in many developing countries, as its treatment is longer and requires more expensive drugs. MDR-TB is defined as resistance to the two most effective first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB is also resistant to three or more of the six classes of second-line drugs.^[93] Totally drug-resistant TB is resistant to all currently used drugs.^[94] It was first observed in 2003 in Italy,^[95] but not widely reported until 2012,^[94]^[96] and has also been found in Iran and India.^[97]^[98] Bedaquiline is tentatively supported for use in multiple drug-resistant TB.^[99]

XDR-TB is a term sometimes used to define extensively resistant TB, and constitutes one in ten cases of MDR-TB. Cases of XDR TB have been identified in more than 90% of countries.^[97]

Prognosis

Progression from TB infection to overt TB disease occurs when the bacilli overcome the immune system defenses and begin to multiply. In primary TB disease (some 1–5% of cases), this occurs soon after the initial infection.^[12] However, in the majority of cases, a latent infection occurs with no obvious symptoms.^[12] These dormant bacilli produce active tuberculosis in 5–10% of these latent cases, often many years after infection.^[15]

The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In people coinfected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year.^[12] Studies using DNA fingerprinting of M. tuberculosis strains have shown reinfection contributes more substantially to recurrent TB than previously thought,^[101] with estimates that it might account for more than 50% of reactivated cases in areas where TB is common.^[102] The chance of death from a case of tuberculosis is about 4% as of 2008, down from 8% in 1995.^[13]

Epidemiology

World map with sub-Saharan Africa in various shades of yellow, marking prevalences above 300 per 100,000, and with the U.S., Canada, Australia, and northern Europe in shades of deep blue, marking prevalences around 10 per 100,000. Asia is yellow but not quite so bright, marking prevalences around 200 per 100,000 range. South America is a darker yellow. — In 2007, the number of cases of TB per 100,000 people was highest in sub-Saharan Africa, and was also relatively high in Asia.^[103]

Roughly one-third of the world's population has been infected with M. tuberculosis,^[52] with new infections occurring in about 1% of the population each year.^[11] However, most infections with M. tuberculosis do not cause TB disease,^[104] and 90–95% of infections remain asymptomatic.^[55] In 2012, an estimated 8.6 million chronic cases were active.^[105] In 2010, 8.8 million new cases of TB were diagnosed, and 1.20–1.45 million deaths occurred, most of these occurring in developing countries.^[41]^[106] Of these 1.45 million deaths, about 0.35 million occur in those also infected with HIV.^[107]

Tuberculosis is the second-most common cause of death from infectious disease (after those due to HIV/AIDS).^[5] The total number of tuberculosis cases has been decreasing since 2005, while new cases have decreased since 2002.^[41] China has achieved particularly dramatic progress, with about an 80% reduction in its TB mortality rate between 1990 and 2010.^[107] The number of new cases has declined by 17% between 2004 and 2014.^[97] Tuberculosis is more common in developing countries; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5–10% of the US population test positive.^[12] Hopes of totally controlling the disease have been dramatically dampened because of a number of factors, including the difficulty of developing an effective vaccine, the expensive and time-consuming diagnostic process, the necessity of many months of treatment, the increase in HIV-associated tuberculosis, and the emergence of drug-resistant cases in the 1980s.^[13]

In 2007, the country with the highest estimated incidence rate of TB was Swaziland, with 1,200 cases per 100,000 people. India had the largest total incidence, with an estimated 2.0 million new cases.^[108] In developed countries, tuberculosis is less common and is found mainly in urban areas. Rates per 100,000 people in different areas of the world were: globally 178, Africa 332, the Americas 36, Eastern Mediterranean 173, Europe 63, Southeast Asia 278, and Western Pacific 139 in 2010.^[107] In Canada and Australia, tuberculosis is many times more common among the aboriginal peoples, especially in remote areas.^[109]^[110] In the United States Native Americans have a fivefold greater mortality from TB,^[111] and racial and ethnic minorities accounted for 84% of all reported TB cases.^[112]

The rates of TB varies with age. In Africa, it primarily affects adolescents and young adults.^[113] However, in countries where incidence rates have declined dramatically (such as the United States), TB is mainly a disease of older people and the immunocompromised (risk factors are listed above).^[12]^[114] Worldwide, 22 "high-burden" states or countries together experience 80% of cases as well as 83% of deaths.^[97]

History

Tuberculosis has been present in humans since antiquity.^[13] The earliest unambiguous detection of M. tuberculosis involves evidence of the disease in the remains of bison in Wyoming dated to around 17,000 years ago.^[115] However, whether tuberculosis originated in bovines, then was transferred to humans, or whether it diverged from a common ancestor, is currently unclear.^[116] A comparison of the genes of M. tuberculosis complex (MTBC) in humans to MTBC in animals suggests humans did not acquire MTBC from animals during animal domestication, as was previously believed. Both strains of the tuberculosis bacteria share a common ancestor, which could have infected humans even before the Neolithic Revolution.^[117] Skeletal remains show prehistoric humans (4000 BC) had TB, and researchers have found tubercular decay in the spines of Egyptian mummies dating from 3000–2400 BC.^[118] Genetic studies suggest TB was present in the Americas from about 100 AD.^[119]

Before the Industrial Revolution, folklore often associated tuberculosis with vampires. When one member of a family died from it, the other infected members would lose their health slowly. People believed this was caused by the original person with TB draining the life from the other family members.^[120]

Although the pulmonary form associated with tubercles was established as a pathology by Richard Morton in 1689,^[121]^[122] due to the variety of its symptoms, TB was not identified as a single disease until the 1820s. It was not named "tuberculosis" until 1839, by J. L. Schönlein.^[123] During 1838–1845, Dr. John Croghan, the owner of Mammoth Cave, brought a number of people with tuberculosis into the cave in the hope of curing the disease with the constant temperature and purity of the cave air; they died within a year.^[124] Hermann Brehmer opened the first TB sanatorium in 1859 in Görbersdorf (now Sokołowsko), Silesia.^[125]

Robert Koch discovered the tuberculosis bacillus.

The bacillus causing tuberculosis, M. tuberculosis, was identified and described on 24 March 1882 by Robert Koch. He received the Nobel Prize in physiology or medicine in 1905 for this discovery.^[126] Koch did not believe the bovine (cattle) and human tuberculosis diseases were similar, which delayed the recognition of infected milk as a source of infection. Later, the risk of transmission from this source was dramatically reduced by the invention of the pasteurization process. Koch announced a glycerine extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it "tuberculin". While it was not effective, it was later successfully adapted as a screening test for the presence of pre-symptomatic tuberculosis.^[127] The World Tuberculosis Day was established on 24 March for this reason.

Albert Calmette and Camille Guérin achieved the first genuine success in immunization against tuberculosis in 1906, using attenuated bovine-strain tuberculosis. It was called bacille Calmette–Guérin (BCG). The BCG vaccine was first used on humans in 1921 in France,^[128] but received widespread acceptance in the US, Great Britain, and Germany only after World War II.^[129]

Tuberculosis caused widespread public concern in the 19th and early 20th centuries as the disease became common among the urban poor. In 1815, one in four deaths in England was due to "consumption". By 1918, one in six deaths in France was still caused by TB. After TB was determined to be contagious, in the 1880s, it was put on a notifiable disease list in Britain; campaigns were started to stop people from spitting in public places, and the infected poor were "encouraged" to enter sanatoria that resembled prisons (the sanatoria for the middle and upper classes offered excellent care and constant medical attention).^[125] Whatever the benefits of the "fresh air" and labor in the sanatoria, even under the best conditions, 50% of those who entered died within five years (c. 1916).^[125] When the Medical Research Council was formed in Britain in 1913, its initial focus was tuberculosis research.^[130]

In Europe, rates of tuberculosis began to rise in the early 1600s to a peak level in the 1800s, when it caused nearly 25% of all deaths.^[131] By the 1950s, mortality in Europe had decreased about 90%.^[132] Improvements in sanitation, vaccination, and other public health measures began significantly reducing rates of tuberculosis even before the arrival of streptomycin and other antibiotics, although the disease remained a significant threat.^[132] In 1946, the development of the antibiotic streptomycin made effective treatment and cure of TB a reality. Prior to the introduction of this medication, the only treatment was surgical intervention, including the "pneumothorax technique", which involved collapsing an infected lung to "rest" it and allow tuberculous lesions to heal.^[133]

Because of the emergence of MDR-TB, surgery has been re-introduced for certain cases of TB infections. It involves removal of infected chest cavities ("bullae") in the lungs to reduce the number of bacteria and to increase exposure of the remaining bacteria to antibiotics in the bloodstream.^[134] Hopes of completely eliminating TB were ended with the rise of drug-resistant strains in the 1980s. The subsequent resurgence of tuberculosis resulted in the declaration of a global health emergency by the World Health Organization in 1993.^[135]

Society and culture

Names

Phthisis (Φθισις) is a Greek word for consumption, an old term for pulmonary tuberculosis;^[4] around 460 BCE, Hippocrates described phthisis as a disease of dry seasons.^[136] The abbreviation "TB" is short for tubercle bacillus.

"Consumption" was the most common nineteenth century English word for the disease. The Latin root "con" meaning "completely" is linked to "sumere" meaning "to take up from under."^[137] In The Life and Death of Mr. Badman by John Bunyan, the author calls consumption "the captain of all these men of death."^[138]

Public health efforts

The World Health Organization, Bill and Melinda Gates Foundation, and US government are subsidizing a fast-acting diagnostic tuberculosis test for use in low- and middle-income countries.^[139]^[140]^[141] In addition to being fast-acting, the test can determine if there is resistance to the antibiotic rifampicin which may indicate multi-drug resistant tuberculosis and is accurate in those who are also infected with HIV.^[139]^[142] Many resource-poor places as of 2011 have access to only sputum microscopy.^[143]

India had the highest total number of TB cases worldwide in 2010, in part due to poor disease management within the private and public health care sector.^[144] Programs such as the Revised National Tuberculosis Control Program are working to reduce TB levels amongst people receiving public health care.^[145]^[146]

A 2014 the EIU-healthcare report that the need to address apathy and urging for increased funding. The report cites among others Lucica Ditui "[TB] is like an orphan. It has been neglected even in countries with a high burden and often forgotten by donors and those investing in health interventions."^[97]

Slow progress has led to frustration, expressed by the executive director of the Global Fund to Fight AIDS, Tuberculosis and Malaria – Mark Dybul: "we have the tools to end TB as a pandemic and public health threat on the planet, but we are not doing it."^[97] Several international organizations are pushing for more transparency in treatment, and more countries are implementing mandatory reporting of cases to the government, although adherence is often sketchy. Commercial treatment providers may at times overprescribe second-line drugs as well as supplementary treatment, promoting demands for further regulations.^[97] The government of Brazil provides universal TB-care, which reduces this problem.^[97] Conversely, falling rates of TB-infection may not relate to the number of programs directed at reducing infection rates but may be tied to increased level of education, income, and health of the population.^[97] Costs of the disease, as calculated by the World Bank in 2009 may exceed 150 billion USD per year in "high burden" countries.^[97] Lack of progress eradicating the disease may also be due to lack of patient follow-up – as among the 250M rural migrants in China.^[97]

Stigma

Slow progress in preventing the disease may in part be due to stigma associated with TB.^[97] Stigma may be due to the fear of transmission from affected individuals. This stigma may additionally arise due to links between TB and poverty, and in Africa, AIDS.^[97] Such stigmatization may be both real and perceived; for example, in Ghana individuals with TB are banned from attending public gatherings.^[147]

Stigma towards TB may result in delays in seeking treatment,^[97] lower treatment compliance, and family members keeping cause of death secret^[147] – allowing the disease to spread further.^[97] At odds is Russia, where stigma was associated with increased treatment compliance.^[147] TB stigma also affects socially marginalized individuals to a greater degree and varies between regions.^[147]

One way to decrease stigma may be through the promotion of "TB clubs", where those infected may share experiences and offer support, or through counseling.^[147] Some studies have shown TB education programs to be effective in decreasing stigma, and may thus be effective in increasing treatment adherence.^[147] Despite this, studies on the relationship between reduced stigma and mortality are lacking as of 2010, and similar efforts to decrease stigma surrounding AIDS have been minimally effective.^[147] Some have claimed the stigma to be worse than the disease, and healthcare providers may unintentionally reinforce stigma, as those with TB are often perceived as difficult or otherwise undesirable.^[97] A greater understanding of the social and cultural dimensions of tuberculosis may also help with stigma reduction.^[148]

Research

The BCG vaccine has limitations, and research to develop new TB vaccines is ongoing.^[149] A number of potential candidates are currently in phase I and II clinical trials.^[149] Two main approaches are being used to attempt to improve the efficacy of available vaccines. One approach involves adding a subunit vaccine to BCG, while the other strategy is attempting to create new and better live vaccines.^[149] MVA85A, an example of a subunit vaccine, currently in trials in South Africa, is based on a genetically modified vaccinia virus.^[150] Vaccines are hoped to play a significant role in treatment of both latent and active disease.^[151]

To encourage further discovery, researchers and policymakers are promoting new economic models of vaccine development, including prizes, tax incentives, and advance market commitments.^[152]^[153] A number of groups, including the Stop TB Partnership,^[154] the South African Tuberculosis Vaccine Initiative, and the Aeras Global TB Vaccine Foundation, are involved with research.^[155] Among these, the Aeras Global TB Vaccine Foundation received a gift of more than $280 million (US) from the Bill and Melinda Gates Foundation to develop and license an improved vaccine against tuberculosis for use in high burden countries.^[156]^[157]

A number of medications are being studied for multidrug-resistant tuberculosis, including bedaquiline and delamanid.^[158] Bedaquiline received U.S. Food and Drug Administration (FDA) approval in late 2012.^[159] The safety and effectiveness of these new agents are still uncertain, because they are based on the results of a relatively small studies.^[158]^[160] However, existing data suggest that patients taking bedaquiline in addition to standard TB therapy are five times more likely to die than those without the new drug,^[161] which has resulted in medical journal articles raising health policy questions about why the FDA approved the drug and whether financial ties to the company making bedaquiline influenced physicians' support for its use.^[160]^[162]

Other animals

Mycobacteria infect many different animals, including birds,^[163] rodents,^[164] and reptiles.^[165] The subspecies Mycobacterium tuberculosis, though, is rarely present in wild animals.^[166] An effort to eradicate bovine tuberculosis caused by Mycobacterium bovis from the cattle and deer herds of New Zealand has been relatively successful.^[167] Efforts in Great Britain have been less successful.^[168]^[169]

As of 2015^[update], tuberculosis appears to be widespread among captive elephants in the US. It is believed that the animals originally acquired the disease from humans, a process called reverse zoonosis. Because the disease can spread through the air to infect both humans and other animals, it is a public health concern affecting circuses and zoos.^[170]^[171]

References

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External links

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Tuberculosis at Curlie
"Tuberculosis (TB)". Centers for Disease Control.
"Tuberculosis (TB)". UK Health Protection Agency.

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[WHO2015Fact-1] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ "Tuberculosis Fact sheet N°104". WHO. October 2015. Archived from the original on 23 August 2012. Retrieved 11 February 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[2] Ferri, Fred F. (2010). Ferri's differential diagnosis : a practical guide to the differential diagnosis of symptoms, signs, and clinical disorders (2nd ed.). Philadelphia, PA: Elsevier/Mosby. p. Chapter T. ISBN 0323076998.

[GBD2015De-3] GBD 2015 Mortality and Causes of Death, Collaborators. (8 October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/s0140-6736(16)31012-1. PMC 5388903. PMID 27733281. {{cite journal}}: |first1= has generic name (help)CS1 maint: numeric names: authors list (link)

[Cha1998-4] The Chambers Dictionary. New Delhi: Allied Chambers India Ltd. 1998. p. 352. ISBN 978-81-86062-25-8. Archived from the original on 6 September 2015. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[ID10-5] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Dolin, [edited by] Gerald L. Mandell, John E. Bennett, Raphael (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases (7th ed.). Philadelphia, PA: Churchill Livingstone/Elsevier. pp. Chapter 250. ISBN 978-0-443-06839-3. {{cite book}}: |first= has generic name (help)CS1 maint: multiple names: authors list (link)

[CDC2012B-6] "Basic TB Facts". CDC. 13 March 2012. Archived from the original on 6 February 2016. Retrieved 11 February 2016. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[AP-7] Konstantinos A (2010). "Testing for tuberculosis". Australian Prescriber. 33 (1): 12–18. Archived from the original on 4 August 2010. {{cite journal}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[8] Hawn, TR; Day, TA; Scriba, TJ; Hatherill, M; Hanekom, WA; Evans, TG; Churchyard, GJ; Kublin, JG; Bekker, LG; Self, SG (December 2014). "Tuberculosis vaccines and prevention of infection". Microbiology and molecular biology reviews: MMBR. 78 (4): 650–71. doi:10.1128/MMBR.00021-14. PMC 4248657. PMID 25428938.

[9] Harris, Randall E. (2013). Epidemiology of chronic disease: global perspectives. Burlington, MA: Jones & Bartlett Learning. p. 682. ISBN 9780763780470. {{cite book}}: External link in |ref= (help)

[TBCon2008-10] Organization, World Health (2008). Implementing the WHO Stop TB Strategy: a handbook for national TB control programmes. Geneva: World Health Organization. p. 179. ISBN 9789241546676. Archived from the original on 16 February 2016. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[WHO2002-11] "Tuberculosis". World Health Organization. 2002. Archived from the original on 17 June 2013. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)

[Robbins-12] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. 516–522. ISBN 978-1-4160-2973-1.

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@@ Line 23: / Line 23: @@
 }}
 <!-- Definition and symptoms -->
-'''Tuberculosis''' ('''TB''') is an [[infectious disease]] caused by the bacterium ''[[Mycobacterium tuberculosis]]'' (MTB).<ref name=WHO2015Fact/> Tuberculosis generally affects the [[lung]]s, but can also affect other parts of the body.<!-- <ref name=WHO2015Fact/> --> Most infections do not have symptoms, in which case it is known as [[latent tuberculosis]].<!-- <ref name=WHO2015Fact/> --> About 10% of latent infections progress to active disease which, if left untreated, kills about half of those infected.<!-- <ref name=WHO2015Fact/> --> The classic symptoms of active TB are a chronic [[cough]] with [[hemoptysis|blood-containing]] [[sputum]], [[fever]], [[night sweats]], and [[weight loss]].<ref name=WHO2015Fact/> The historical term "'''consumption'''" came about due to the weight loss.<ref name=Cha1998>{{cite book|title=The Chambers Dictionary.|year=1998|publisher=Allied Chambers India Ltd.|location=New Delhi|isbn=978-81-86062-25-8|pages=352|url=https://books.google.com/books?id=pz2ORay2HWoC&pg=RA1-PA352}}</ref> Infection of other organs can cause a wide range of symptoms.<ref name=ID10>{{cite book|last=Dolin|first=[edited by] Gerald L. Mandell, John E. Bennett, Raphael|title=Mandell, Douglas, and Bennett's principles and practice of infectious diseases|year=2010|publisher=Churchill Livingstone/Elsevier|location=Philadelphia, PA|isbn=978-0-443-06839-3|pages=Chapter 250|edition=7th}}</ref>
+'''Tuberculosis''' ('''TB''') is an [[infectious disease]] caused by the bacterium ''[[Mycobacterium tuberculosis]]'' (MTB).<ref name=WHO2015Fact/> Tuberculosis generally affects the [[lung]]s, but can also affect other parts of the body.<!-- <ref name=WHO2015Fact/> --> Most infections do not have symptoms, in which case it is known as [[latent tuberculosis]].<!-- <ref name=WHO2015Fact/> --> About 10% of latent infections progress to active disease which, if left untreated, kills about half of those infected.<!-- <ref name=WHO2015Fact/> --> The classic symptoms of active TB are a chronic [[cough]] with [[hemoptysis|blood-containing]] [[sputum]], [[fever]], [[night sweats]], and [[weight loss]].<ref name=WHO2015Fact/> The historical term "'''consumption'''" came about due to the weight loss.<ref name=Cha1998>{{cite book|title=The Chambers Dictionary.|year=1998|publisher=Allied Chambers India Ltd.|location=New Delhi|isbn=978-81-86062-25-8|pages=352|url=https://books.google.com/books?id=pz2ORay2HWoC&pg=RA1-PA352|deadurl=no|archiveurl=https://web.archive.org/web/20150906201311/https://books.google.com/books?id=pz2ORay2HWoC&pg=RA1-PA352|archivedate=6 September 2015|df=dmy-all}}</ref> Infection of other organs can cause a wide range of symptoms.<ref name=ID10>{{cite book|last=Dolin|first=[edited by] Gerald L. Mandell, John E. Bennett, Raphael|title=Mandell, Douglas, and Bennett's principles and practice of infectious diseases|year=2010|publisher=Churchill Livingstone/Elsevier|location=Philadelphia, PA|isbn=978-0-443-06839-3|pages=Chapter 250|edition=7th}}</ref>
 <!-- Cause and diagnosis -->
-Tuberculosis is [[Airborne disease|spread through the air]] when people who have active TB in their lungs cough, spit, speak, or sneeze.<ref name=WHO2015Fact/><ref name=CDC2012B>{{cite web|title=Basic TB Facts|url=http://www.cdc.gov/tb/topic/basics/default.htm|website=CDC|accessdate=11 February 2016|date=March 13, 2012}}</ref> People with latent TB do not spread the disease.<!-- <ref name=WHO2015Fact/> --> Active infection occurs more often in people with [[HIV/AIDS]] and in those who [[Tobacco smoking|smoke]].<ref name=WHO2015Fact/> Diagnosis of active TB is based on [[chest X-ray]]s, as well as [[microscopic]] examination and [[microbiological culture|culture]] of body fluids.<!-- <ref name=AP/> --> Diagnosis of latent TB relies on the [[Mantoux test|tuberculin skin test]] (TST) or blood tests.<ref name=AP>{{cite journal |author=Konstantinos A |year=2010 |title=Testing for tuberculosis |journal=Australian Prescriber |volume=33 |issue=1 |pages=12–18 |url=http://www.australianprescriber.com/magazine/33/1/12/18/ |deadurl=yes |archiveurl=https://web.archive.org/web/20100804052035/http://www.australianprescriber.com/magazine/33/1/12/18 |archivedate=4 August 2010 |df=dmy-all }}</ref>
+Tuberculosis is [[Airborne disease|spread through the air]] when people who have active TB in their lungs cough, spit, speak, or sneeze.<ref name=WHO2015Fact/><ref name=CDC2012B>{{cite web|title=Basic TB Facts|url=http://www.cdc.gov/tb/topic/basics/default.htm|website=CDC|accessdate=11 February 2016|date=March 13, 2012|deadurl=no|archiveurl=https://web.archive.org/web/20160206032136/http://www.cdc.gov/tb/topic/basics/default.htm|archivedate=6 February 2016|df=dmy-all}}</ref> People with latent TB do not spread the disease.<!-- <ref name=WHO2015Fact/> --> Active infection occurs more often in people with [[HIV/AIDS]] and in those who [[Tobacco smoking|smoke]].<ref name=WHO2015Fact/> Diagnosis of active TB is based on [[chest X-ray]]s, as well as [[microscopic]] examination and [[microbiological culture|culture]] of body fluids.<!-- <ref name=AP/> --> Diagnosis of latent TB relies on the [[Mantoux test|tuberculin skin test]] (TST) or blood tests.<ref name=AP>{{cite journal |author=Konstantinos A |year=2010 |title=Testing for tuberculosis |journal=Australian Prescriber |volume=33 |issue=1 |pages=12–18 |url=http://www.australianprescriber.com/magazine/33/1/12/18/ |deadurl=yes |archiveurl=https://web.archive.org/web/20100804052035/http://www.australianprescriber.com/magazine/33/1/12/18 |archivedate=4 August 2010 |df=dmy-all }}</ref>
 <!-- Prevention and treatment -->
-Prevention of TB involves screening those at high risk, early detection and treatment of cases, and [[vaccination]] with the [[bacillus Calmette-Guérin]] vaccine.<ref>{{cite journal|last1=Hawn|first1=TR|last2=Day|first2=TA|last3=Scriba|first3=TJ|last4=Hatherill|first4=M|last5=Hanekom|first5=WA|last6=Evans|first6=TG|last7=Churchyard|first7=GJ|last8=Kublin|first8=JG|last9=Bekker|first9=LG|last10=Self|first10=SG|title=Tuberculosis vaccines and prevention of infection.|journal=Microbiology and molecular biology reviews: MMBR|date=December 2014|volume=78|issue=4|pages=650–71|pmid=25428938|doi=10.1128/MMBR.00021-14|pmc=4248657}}</ref><ref>{{cite book|last1=Harris|first1=Randall E.|title=Epidemiology of chronic disease: global perspectives|date=2013|publisher=Jones & Bartlett Learning|location=Burlington, MA|isbn=9780763780470|page=682|ref=https://books.google.ca/books?id=KJLEIvX4wzoC&pg=PA682}}</ref><ref name=TBCon2008>{{cite book|last1=Organization|first1=World Health|title=Implementing the WHO Stop TB Strategy: a handbook for national TB control programmes|date=2008|publisher=World Health Organization|location=Geneva|isbn=9789241546676|page=179|url=https://books.google.ca/books?id=EUZXFCrlUaEC&pg=PA179}}</ref> Those at high risk include household, workplace, and social contacts of people with active TB.<ref name=TBCon2008/> Treatment requires the use of multiple [[antibiotic]]s over a long period of time.<ref name=WHO2015Fact/> [[Antibiotic resistance]] is a growing problem with increasing rates of [[multi-drug-resistant tuberculosis|multiple drug-resistant tuberculosis]] (MDR-TB).<ref name=WHO2015Fact/>
+Prevention of TB involves screening those at high risk, early detection and treatment of cases, and [[vaccination]] with the [[bacillus Calmette-Guérin]] vaccine.<ref>{{cite journal|last1=Hawn|first1=TR|last2=Day|first2=TA|last3=Scriba|first3=TJ|last4=Hatherill|first4=M|last5=Hanekom|first5=WA|last6=Evans|first6=TG|last7=Churchyard|first7=GJ|last8=Kublin|first8=JG|last9=Bekker|first9=LG|last10=Self|first10=SG|title=Tuberculosis vaccines and prevention of infection.|journal=Microbiology and molecular biology reviews: MMBR|date=December 2014|volume=78|issue=4|pages=650–71|pmid=25428938|doi=10.1128/MMBR.00021-14|pmc=4248657}}</ref><ref>{{cite book|last1=Harris|first1=Randall E.|title=Epidemiology of chronic disease: global perspectives|date=2013|publisher=Jones & Bartlett Learning|location=Burlington, MA|isbn=9780763780470|page=682|ref=https://books.google.ca/books?id=KJLEIvX4wzoC&pg=PA682}}</ref><ref name=TBCon2008>{{cite book|last1=Organization|first1=World Health|title=Implementing the WHO Stop TB Strategy: a handbook for national TB control programmes|date=2008|publisher=World Health Organization|location=Geneva|isbn=9789241546676|page=179|url=https://books.google.ca/books?id=EUZXFCrlUaEC&pg=PA179|deadurl=no|archiveurl=https://web.archive.org/web/20160216180345/https://books.google.ca/books?id=EUZXFCrlUaEC&pg=PA179|archivedate=16 February 2016|df=dmy-all}}</ref> Those at high risk include household, workplace, and social contacts of people with active TB.<ref name=TBCon2008/> Treatment requires the use of multiple [[antibiotic]]s over a long period of time.<ref name=WHO2015Fact/> [[Antibiotic resistance]] is a growing problem with increasing rates of [[multi-drug-resistant tuberculosis|multiple drug-resistant tuberculosis]] (MDR-TB).<ref name=WHO2015Fact/>
 <!-- History and epidemiology -->
-One-third of the world's population is thought to be infected with TB.<ref name=WHO2015Fact/><!-- Quote = About one-third of the world's population has latent TB --> New infections occur in about 1% of the population each year.<ref name=WHO2002>{{cite web|title=Tuberculosis|url=http://www.who.int/mediacentre/factsheets/who104/en/print.html|work=World Health Organization|year=2002}}</ref> In 2014, there were 9.6 million cases of active TB which resulted in 1.5&nbsp;million deaths.<!-- <ref name=WHO2015Fact/> --> More than 95% of deaths occurred in [[developing countries]].<!-- <ref name=WHO2015Fact/> --> The number of new cases each year has decreased since 2000.<ref name=WHO2015Fact>{{cite web|title=Tuberculosis Fact sheet N°104|url=http://www.who.int/mediacentre/factsheets/fs104/en/|website=WHO|accessdate=11 February 2016|date=October 2015}}</ref> 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.<ref name=Robbins>{{cite book |vauthors=Kumar V, Abbas AK, Fausto N, Mitchell RN |year=2007 |title=Robbins Basic Pathology |edition=8th |publisher=Saunders Elsevier |pages=516–522 |isbn=978-1-4160-2973-1}}</ref> Tuberculosis has been present in humans since [[Ancient history|ancient times]].<ref name=Lancet11>{{cite journal|last=Lawn|first=SD|author2=Zumla, AI |title=Tuberculosis|journal=Lancet|date=2 July 2011|volume=378|issue=9785|pages=57–72|pmid=21420161|doi=10.1016/S0140-6736(10)62173-3}}</ref>
+One-third of the world's population is thought to be infected with TB.<ref name=WHO2015Fact/><!-- Quote = About one-third of the world's population has latent TB --> New infections occur in about 1% of the population each year.<ref name=WHO2002>{{cite web|title=Tuberculosis|url=http://www.who.int/mediacentre/factsheets/who104/en/print.html|work=World Health Organization|year=2002|deadurl=yes|archiveurl=https://web.archive.org/web/20130617193438/http://www.who.int/mediacentre/factsheets/who104/en/print.html|archivedate=17 June 2013|df=dmy-all}}</ref> In 2014, there were 9.6 million cases of active TB which resulted in 1.5&nbsp;million deaths.<!-- <ref name=WHO2015Fact/> --> More than 95% of deaths occurred in [[developing countries]].<!-- <ref name=WHO2015Fact/> --> The number of new cases each year has decreased since 2000.<ref name=WHO2015Fact>{{cite web|title=Tuberculosis Fact sheet N°104|url=http://www.who.int/mediacentre/factsheets/fs104/en/|website=WHO|accessdate=11 February 2016|date=October 2015|deadurl=no|archiveurl=https://web.archive.org/web/20120823143802/http://www.who.int/mediacentre/factsheets/fs104/en/|archivedate=23 August 2012|df=dmy-all}}</ref> 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.<ref name=Robbins>{{cite book |vauthors=Kumar V, Abbas AK, Fausto N, Mitchell RN |year=2007 |title=Robbins Basic Pathology |edition=8th |publisher=Saunders Elsevier |pages=516–522 |isbn=978-1-4160-2973-1}}</ref> Tuberculosis has been present in humans since [[Ancient history|ancient times]].<ref name=Lancet11>{{cite journal|last=Lawn|first=SD|author2=Zumla, AI |title=Tuberculosis|journal=Lancet|date=2 July 2011|volume=378|issue=9785|pages=57–72|pmid=21420161|doi=10.1016/S0140-6736(10)62173-3}}</ref>
 [[File:Tuberculosis video.webm|thumb|upright=1.4|Video explanation]]
 {{TOC limit|3}}
 ==Signs and symptoms==
-[[File:Tuberculosis symptoms.svg|thumb|upright=1.5|The main symptoms of variants and stages of tuberculosis are given,<ref>{{cite web|url=http://www.emedicinehealth.com/tuberculosis/page3_em.htm|title=Tuberculosis Symptoms|publisher=[[eMedicine]]Health|author=Schiffman G|date=15 January 2009}}</ref> with many symptoms overlapping with other variants, while others are more (but not entirely) specific for certain variants. Multiple variants may be present simultaneously.]]
+[[File:Tuberculosis symptoms.svg|thumb|upright=1.5|The main symptoms of variants and stages of tuberculosis are given,<ref>{{cite web|url=http://www.emedicinehealth.com/tuberculosis/page3_em.htm|title=Tuberculosis Symptoms|publisher=[[eMedicine]]Health|author=Schiffman G|date=15 January 2009|deadurl=no|archiveurl=https://web.archive.org/web/20090516075020/http://www.emedicinehealth.com/tuberculosis/page3_em.htm|archivedate=16 May 2009|df=dmy-all}}</ref> with many symptoms overlapping with other variants, while others are more (but not entirely) specific for certain variants. Multiple variants may be present simultaneously.]]
 Tuberculosis may infect any part of the body, but most commonly occurs in the lungs (known as pulmonary tuberculosis).<ref name=ID10/> Extrapulmonary TB occurs when tuberculosis develops outside of the lungs, although extrapulmonary TB may coexist with pulmonary TB.<ref name=ID10/>
@@ Line 43: / Line 43: @@
 ===Pulmonary===
-If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases).<ref name=Lancet11/><ref>{{cite book|last=Behera|first=D.|title=Textbook of Pulmonary Medicine|year=2010|publisher=Jaypee Brothers Medical Publishers|location=New Delhi|isbn=978-81-8448-749-7|pages=457|url=https://books.google.com/books?id=0TbJjd9eTp0C&pg=PA457|edition=2nd}}</ref> Symptoms may include [[chest pain]] and a prolonged cough producing sputum.<!-- <ref name=Lancet11/> --> About 25% of people may not have any symptoms (i.e. they remain "asymptomatic").<ref name=Lancet11/> Occasionally, people may [[hemoptysis|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.<ref name=ID10/><ref>{{cite journal|last1=Halezeroğlu|first1=S|last2=Okur|first2=E|title=Thoracic surgery for haemoptysis in the context of tuberculosis: what is the best management approach?|journal=Journal of Thoracic Disease|date=March 2014|volume=6|issue=3|pages=182–5|pmid=24624281|doi=10.3978/j.issn.2072-1439.2013.12.25|pmc=3949181}}</ref> Tuberculosis may become a chronic illness and cause extensive scarring in the upper lobes of the lungs.<!-- <ref name=ID10/> --> The upper lung lobes are more frequently affected by tuberculosis than the lower ones.<ref name=ID10/> The reason for this difference is not clear.<ref name="Robbins" /> It may be due to either better air flow,<ref name="Robbins" /> or poor [[lymph]] drainage within the upper lungs.<ref name=ID10/>
+If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases).<ref name=Lancet11/><ref>{{cite book|last=Behera|first=D.|title=Textbook of Pulmonary Medicine|year=2010|publisher=Jaypee Brothers Medical Publishers|location=New Delhi|isbn=978-81-8448-749-7|pages=457|url=https://books.google.com/books?id=0TbJjd9eTp0C&pg=PA457|edition=2nd|deadurl=no|archiveurl=https://web.archive.org/web/20150906185549/https://books.google.com/books?id=0TbJjd9eTp0C&pg=PA457|archivedate=6 September 2015|df=dmy-all}}</ref> Symptoms may include [[chest pain]] and a prolonged cough producing sputum.<!-- <ref name=Lancet11/> --> About 25% of people may not have any symptoms (i.e. they remain "asymptomatic").<ref name=Lancet11/> Occasionally, people may [[hemoptysis|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.<ref name=ID10/><ref>{{cite journal|last1=Halezeroğlu|first1=S|last2=Okur|first2=E|title=Thoracic surgery for haemoptysis in the context of tuberculosis: what is the best management approach?|journal=Journal of Thoracic Disease|date=March 2014|volume=6|issue=3|pages=182–5|pmid=24624281|doi=10.3978/j.issn.2072-1439.2013.12.25|pmc=3949181}}</ref> Tuberculosis may become a chronic illness and cause extensive scarring in the upper lobes of the lungs.<!-- <ref name=ID10/> --> The upper lung lobes are more frequently affected by tuberculosis than the lower ones.<ref name=ID10/> The reason for this difference is not clear.<ref name="Robbins" /> It may be due to either better air flow,<ref name="Robbins" /> or poor [[lymph]] drainage within the upper lungs.<ref name=ID10/>
 ===Extrapulmonary===
-In 15–20% of active cases, the infection spreads outside the lungs, causing other kinds of TB.<ref>{{cite book|last=Jindal|first=editor-in-chief SK|title=Textbook of Pulmonary and Critical Care Medicine|publisher=Jaypee Brothers Medical Publishers|location=New Delhi|isbn=978-93-5025-073-0|pages=549|url=https://books.google.com/books?id=EvGTw3wn-zEC&pg=PA549|year=2011}}</ref> These are collectively denoted as "extrapulmonary tuberculosis".<ref name=Extra2005>{{cite journal|pmid=16300038|year=2005|vauthors=Golden MP, Vikram HR |title=Extrapulmonary tuberculosis: an overview|volume=72|issue=9|pages=1761–8|journal=American Family Physician }}</ref> Extrapulmonary TB occurs more commonly in [[Immunosuppression|immunosuppressed]] persons and young children. In those with HIV, this occurs in more than 50% of cases.<ref name=Extra2005/> Notable extrapulmonary infection sites include the [[Pleural cavity|pleura]] (in tuberculous pleurisy), the [[central nervous system]] (in tuberculous [[meningitis]]), the [[lymphatic system]] (in [[Tuberculous cervical lymphadenitis|scrofula]] of the neck), the [[genitourinary system]] (in [[urogenital tuberculosis]]), and the bones and joints (in [[Pott disease]] of the spine), among others.
+In 15–20% of active cases, the infection spreads outside the lungs, causing other kinds of TB.<ref>{{cite book|last=Jindal|first=editor-in-chief SK|title=Textbook of Pulmonary and Critical Care Medicine|publisher=Jaypee Brothers Medical Publishers|location=New Delhi|isbn=978-93-5025-073-0|pages=549|url=https://books.google.com/books?id=EvGTw3wn-zEC&pg=PA549|year=2011|deadurl=no|archiveurl=https://web.archive.org/web/20150907185434/https://books.google.com/books?id=EvGTw3wn-zEC&pg=PA549|archivedate=7 September 2015|df=dmy-all}}</ref> These are collectively denoted as "extrapulmonary tuberculosis".<ref name=Extra2005>{{cite journal|pmid=16300038|year=2005|vauthors=Golden MP, Vikram HR |title=Extrapulmonary tuberculosis: an overview|volume=72|issue=9|pages=1761–8|journal=American Family Physician }}</ref> Extrapulmonary TB occurs more commonly in [[Immunosuppression|immunosuppressed]] persons and young children. In those with HIV, this occurs in more than 50% of cases.<ref name=Extra2005/> Notable extrapulmonary infection sites include the [[Pleural cavity|pleura]] (in tuberculous pleurisy), the [[central nervous system]] (in tuberculous [[meningitis]]), the [[lymphatic system]] (in [[Tuberculous cervical lymphadenitis|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.<ref>{{cite journal|last1=Rockwood|first1=RR|title=Extrapulmonary TB: what you need to know.|journal=The Nurse practitioner|date=August 2007|volume=32|issue=8|pages=44–9|pmid=17667766|doi=10.1097/01.npr.0000282802.12314.dc}}</ref> An ulcer originating from nearby infected lymph nodes may occur and is painless, slowly enlarging and has an appearance of "wash leather".<ref>{{cite book|last=Burkitt|first=H. George|title=Essential Surgery: Problems, Diagnosis & Management 4th ed|year=2007|isbn=9780443103452|pages=34}}</ref>
-When it spreads to the bones, it is known as "osseous tuberculosis",<ref>{{cite book|last=Kabra|first=[edited by] Vimlesh Seth, S.K.|title=Essentials of tuberculosis in children|year=2006|publisher=Jaypee Bros. Medical Publishers|location=New Delhi|isbn=978-81-8061-709-6|pages=249|url=https://books.google.com/books?id=HkH0YbyBHDQC&pg=PA249|edition=3rd}}</ref> a form of [[osteomyelitis]].<ref name="Robbins" />  A potentially more serious, widespread form of TB is called "disseminated tuberculosis", also known as [[miliary tuberculosis]].<ref name=ID10/> Miliary TB currently makes up about 10% of extrapulmonary cases.<ref name=Gho2008/>
+When it spreads to the bones, it is known as "osseous tuberculosis",<ref>{{cite book|last=Kabra|first=[edited by] Vimlesh Seth, S.K.|title=Essentials of tuberculosis in children|year=2006|publisher=Jaypee Bros. Medical Publishers|location=New Delhi|isbn=978-81-8061-709-6|pages=249|url=https://books.google.com/books?id=HkH0YbyBHDQC&pg=PA249|edition=3rd|deadurl=no|archiveurl=https://web.archive.org/web/20150906204238/https://books.google.com/books?id=HkH0YbyBHDQC&pg=PA249|archivedate=6 September 2015|df=dmy-all}}</ref> a form of [[osteomyelitis]].<ref name="Robbins" />  A potentially more serious, widespread form of TB is called "disseminated tuberculosis", also known as [[miliary tuberculosis]].<ref name=ID10/> Miliary TB currently makes up about 10% of extrapulmonary cases.<ref name=Gho2008/>
 ==Causes==
@@ Line 57: / Line 57: @@
 {{Main article| Mycobacterium tuberculosis}}
 [[File:Mycobacterium tuberculosis.jpg|thumb|[[Scanning electron micrograph]] of ''M. tuberculosis'']]
-The main cause of TB is ''[[Mycobacterium tuberculosis]]'' (MTB), a small, [[aerobic organism|aerobic]], nonmotile [[bacillus]].<ref name=ID10/> The high [[lipid]] content of this pathogen accounts for many of its unique clinical characteristics.<ref>{{cite book |author=Southwick F |title=Infectious Diseases: A Clinical Short Course, 2nd ed. |publisher=McGraw-Hill Medical Publishing Division |date=10 December 2007 |pages=104, 313–4 |chapter=Chapter 4: Pulmonary Infections |isbn=0-07-147722-5}}</ref> It [[cell division|divides]] every 16 to 20 hours, which is an extremely slow rate compared with other bacteria, which usually divide in less than an hour.<ref>{{cite book|last=Jindal|first=editor-in-chief SK|title=Textbook of Pulmonary and Critical Care Medicine|publisher=Jaypee Brothers Medical Publishers|location=New Delhi|isbn=978-93-5025-073-0|pages=525|url=https://books.google.com/books?id=rAT1bdnDakAC&pg=PA525|year=2011}}</ref> Mycobacteria have an [[Bacterial cell structure|outer membrane]] lipid bilayer.<ref name=Niederweis2010>{{cite journal |vauthors=Niederweis M, Danilchanka O, Huff J, Hoffmann C, Engelhardt H |title=Mycobacterial outer membranes: in search of proteins |journal=Trends in Microbiology |volume=18 |issue=3 |pages=109–16 |date=March 2010 |pmid=20060722 |pmc=2931330 |doi=10.1016/j.tim.2009.12.005 }}</ref> 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.<ref name=Madison_2001>{{cite journal |author=Madison B |title=Application of stains in clinical microbiology |journal=Biotechnic & Histochemistry |volume=76 |issue=3 |pages=119–25 |year=2001 |pmid=11475314 |doi=10.1080/714028138}}</ref> MTB can withstand weak [[disinfectant]]s and survive in a [[Endospore|dry state]] for weeks. In nature, the bacterium can grow only within the cells of a [[host (biology)|host]] organism, but ''M. tuberculosis'' can be cultured [[in vitro|in the laboratory]].<ref name=Parish_1999>{{cite journal |author1=Parish T. |author2=Stoker N. |title=Mycobacteria: bugs and bugbears (two steps forward and one step back) |journal=Molecular Biotechnology |volume=13 |issue=3 |pages=191–200 |year=1999| pmid=10934532 |doi = 10.1385/MB:13:3:191}}</ref>
+The main cause of TB is ''[[Mycobacterium tuberculosis]]'' (MTB), a small, [[aerobic organism|aerobic]], nonmotile [[bacillus]].<ref name=ID10/> The high [[lipid]] content of this pathogen accounts for many of its unique clinical characteristics.<ref>{{cite book |author=Southwick F |title=Infectious Diseases: A Clinical Short Course, 2nd ed. |publisher=McGraw-Hill Medical Publishing Division |date=10 December 2007 |pages=104, 313–4 |chapter=Chapter 4: Pulmonary Infections |isbn=0-07-147722-5}}</ref> It [[cell division|divides]] every 16 to 20 hours, which is an extremely slow rate compared with other bacteria, which usually divide in less than an hour.<ref>{{cite book|last=Jindal|first=editor-in-chief SK|title=Textbook of Pulmonary and Critical Care Medicine|publisher=Jaypee Brothers Medical Publishers|location=New Delhi|isbn=978-93-5025-073-0|pages=525|url=https://books.google.com/books?id=rAT1bdnDakAC&pg=PA525|year=2011|deadurl=no|archiveurl=https://web.archive.org/web/20150906211342/https://books.google.com/books?id=rAT1bdnDakAC&pg=PA525|archivedate=6 September 2015|df=dmy-all}}</ref> Mycobacteria have an [[Bacterial cell structure|outer membrane]] lipid bilayer.<ref name=Niederweis2010>{{cite journal |vauthors=Niederweis M, Danilchanka O, Huff J, Hoffmann C, Engelhardt H |title=Mycobacterial outer membranes: in search of proteins |journal=Trends in Microbiology |volume=18 |issue=3 |pages=109–16 |date=March 2010 |pmid=20060722 |pmc=2931330 |doi=10.1016/j.tim.2009.12.005 }}</ref> 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.<ref name=Madison_2001>{{cite journal |author=Madison B |title=Application of stains in clinical microbiology |journal=Biotechnic & Histochemistry |volume=76 |issue=3 |pages=119–25 |year=2001 |pmid=11475314 |doi=10.1080/714028138}}</ref> MTB can withstand weak [[disinfectant]]s and survive in a [[Endospore|dry state]] for weeks. In nature, the bacterium can grow only within the cells of a [[host (biology)|host]] organism, but ''M. tuberculosis'' can be cultured [[in vitro|in the laboratory]].<ref name=Parish_1999>{{cite journal |author1=Parish T. |author2=Stoker N. |title=Mycobacteria: bugs and bugbears (two steps forward and one step back) |journal=Molecular Biotechnology |volume=13 |issue=3 |pages=191–200 |year=1999| pmid=10934532 |doi = 10.1385/MB:13:3:191}}</ref>
-Using [[histology|histological]] stains on [[expectorate]]d 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]].<ref name=Robbins/><ref name="Madison_2001"/> The most common acid-fast staining techniques are the [[Ziehl–Neelsen stain]]<ref name=Stain2000>{{cite book |title=Medical Laboratory Science: Theory and Practice |publisher=Tata McGraw-Hill |location=New Delhi |year=2000 |pages=473 |isbn=0-07-463223-X |url=https://books.google.com/books?id=lciNs3VQPLoC&pg=PA473}}</ref> and the [[Kinyoun stain]], which dye acid-fast bacilli a bright red that stands out against a blue background.<ref>{{cite web |title=Acid-Fast Stain Protocols |url=http://www.microbelibrary.org/component/resource/laboratory-test/2870-acid-fast-stain-protocols |accessdate=26 March 2016 |date=21 August 2013 |deadurl=yes |archiveurl=https://web.archive.org/web/20111001132818/http://www.microbelibrary.org/component/resource/laboratory-test/2870-acid-fast-stain-protocols |archivedate=1 October 2011 |df= }}</ref> [[Auramine-rhodamine stain]]ing<ref name=Kommareddi_1984>{{cite journal|author1=Kommareddi S. |author2=Abramowsky C. |author3=Swinehart G. |author4=Hrabak L. |title=Nontuberculous mycobacterial infections: comparison of the fluorescent auramine-O and Ziehl-Neelsen techniques in tissue diagnosis|journal=Human Pathology|volume=15|issue=11|pages=1085–1089|year=1984|pmid=6208117|doi=10.1016/S0046-8177(84)80253-1}}</ref> and [[Fluorescence microscope|fluorescence microscopy]]<ref>{{cite book|last1=van Lettow|first1=Monique|last2=Whalen|first2=Christopher|title=Nutrition and health in developing countries|year=2008|publisher=Humana Press|location=Totowa, N.J. (Richard D. Semba and Martin W. Bloem, eds.)|isbn=978-1-934115-24-4|pages=291|url=https://books.google.com/books?id=RhH6uSQy7a4C&pg=PA291|edition=2nd}}</ref> are also used.
+Using [[histology|histological]] stains on [[expectorate]]d 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]].<ref name=Robbins/><ref name="Madison_2001"/> The most common acid-fast staining techniques are the [[Ziehl–Neelsen stain]]<ref name=Stain2000>{{cite book |title=Medical Laboratory Science: Theory and Practice |publisher=Tata McGraw-Hill |location=New Delhi |year=2000 |pages=473 |isbn=0-07-463223-X |url=https://books.google.com/books?id=lciNs3VQPLoC&pg=PA473 |deadurl=no |archiveurl=https://web.archive.org/web/20150906213737/https://books.google.com/books?id=lciNs3VQPLoC&pg=PA473 |archivedate=6 September 2015 |df=dmy-all }}</ref> and the [[Kinyoun stain]], which dye acid-fast bacilli a bright red that stands out against a blue background.<ref>{{cite web |title=Acid-Fast Stain Protocols |url=http://www.microbelibrary.org/component/resource/laboratory-test/2870-acid-fast-stain-protocols |accessdate=26 March 2016 |date=21 August 2013 |deadurl=yes |archiveurl=https://web.archive.org/web/20111001132818/http://www.microbelibrary.org/component/resource/laboratory-test/2870-acid-fast-stain-protocols |archivedate=1 October 2011 |df= }}</ref> [[Auramine-rhodamine stain]]ing<ref name=Kommareddi_1984>{{cite journal|author1=Kommareddi S. |author2=Abramowsky C. |author3=Swinehart G. |author4=Hrabak L. |title=Nontuberculous mycobacterial infections: comparison of the fluorescent auramine-O and Ziehl-Neelsen techniques in tissue diagnosis|journal=Human Pathology|volume=15|issue=11|pages=1085–1089|year=1984|pmid=6208117|doi=10.1016/S0046-8177(84)80253-1}}</ref> and [[Fluorescence microscope|fluorescence microscopy]]<ref>{{cite book|last1=van Lettow|first1=Monique|last2=Whalen|first2=Christopher|title=Nutrition and health in developing countries|year=2008|publisher=Humana Press|location=Totowa, N.J. (Richard D. Semba and Martin W. Bloem, eds.)|isbn=978-1-934115-24-4|pages=291|url=https://books.google.com/books?id=RhH6uSQy7a4C&pg=PA291|edition=2nd|deadurl=no|archiveurl=https://web.archive.org/web/20150906215906/https://books.google.com/books?id=RhH6uSQy7a4C&pg=PA291|archivedate=6 September 2015|df=dmy-all}}</ref> are also used.
-The ''M. tuberculosis'' complex (MTBC) includes four other TB-causing [[mycobacterium|mycobacteria]]: ''[[Mycobacterium bovis|M. bovis]]'', ''[[Mycobacterium africanum|M. africanum]]'', ''[[Mycobacterium canetti|M. canetti]]'', and ''[[Mycobacterium microti|M. microti]]''.<ref>{{cite journal |author=van Soolingen D. |title=A novel pathogenic taxon of the Mycobacterium tuberculosis complex, Canetti: characterization of an exceptional isolate from Africa |journal=International Journal of Systematic Bacteriology |volume=47 |issue=4 |pages=1236–45 |year=1997 |pmid=9336935 |doi=10.1099/00207713-47-4-1236 |name-list-format=vanc |display-authors=1 |last2=Hoogenboezem |first2=T. |last3=De Haas |first3=P.E.W.|last4=Hermans |first4=P.W.M. |last5=Koedam |first5=M.A. |last6=Teppema |first6=K.S. |last7=Brennan |first7=P.J.|last8=Besra |first8=G.S.|last9=Portaels |first9=F.}}</ref> ''M. africanum'' is not widespread, but it is a significant cause of tuberculosis in parts of Africa.<ref>{{cite journal |author=Niemann S. |title=Mycobacterium africanum Subtype II Is Associated with Two Distinct Genotypes and Is a Major Cause of Human Tuberculosis in Kampala, Uganda |journal=Journal of Clinical Microbiology |volume=40 |issue=9 |pages=3398–405 |year=2002 |pmid=12202584 |pmc=130701 |doi=10.1128/JCM.40.9.3398-3405.2002 |name-list-format=vanc |display-authors=1 |last2=Rusch-Gerdes |first2=S.|last3=Joloba |first3=M.L.|last4=Whalen |first4=C.C.|last5=Guwatudde |first5=D.|last6=Ellner |first6=J.J.|last7=Eisenach |first7=K.|last8=Fumokong |first8=N. |last9=Johnson |first9=J.L.}}</ref><ref>{{cite journal |author=Niobe-Eyangoh S.N.|title=Genetic Biodiversity of Mycobacterium tuberculosis Complex Strains from Patients with Pulmonary Tuberculosis in Cameroon |journal=Journal of Clinical Microbiology |volume=41 |issue=6 |pages=2547–53 |year=2003 |pmid=12791879 |pmc=156567 |doi=10.1128/JCM.41.6.2547-2553.2003 |name-list-format=vanc |display-authors=1 |last2=Kuaban |first2=C. |last3=Sorlin |first3=P. |last4=Cunin |first4=P. |last5=Thonnon |first5=J. |last6=Sola |first6=C. |last7=Rastogi |first7=N. |last8=Vincent |first8=V. |last9=Gutierrez |first9=M.C.}}</ref> ''M. bovis'' was once a common cause of tuberculosis, but the introduction of [[pasteurisation|pasteurized milk]] has almost completely eliminated this as a public health problem in developed countries.<ref name=Robbins/><ref>{{cite journal |vauthors=Thoen C, Lobue P, de Kantor I |title=The importance of ''Mycobacterium bovis'' as a zoonosis |journal=Veterinary Microbiology |volume=112 |issue=2–4 |pages=339–45 |year=2006 |pmid=16387455 |doi=10.1016/j.vetmic.2005.11.047}}</ref> ''M. canetti'' is rare and seems to be limited to the [[Horn of Africa]], although a few cases have been seen in African emigrants.<ref>{{cite book|last=Acton|first=Q. Ashton|title=Mycobacterium Infections: New Insights for the Healthcare Professional|year=2011|publisher=ScholarlyEditions|isbn=978-1-4649-0122-5|pages=1968|url=https://books.google.com/books?id=g2iFfV6uEuAC&pg=PA1968}}</ref><ref>{{cite journal|last=Pfyffer|first=GE|author2=Auckenthaler, R |author3=van Embden, JD|author4=van Soolingen, D|title=Mycobacterium canettii, the smooth variant of M. tuberculosis, isolated from a Swiss patient exposed in Africa|journal=Emerging Infectious Diseases|date=Oct–Dec 1998|volume=4|issue=4|pages=631–4|pmid=9866740|pmc=2640258|doi=10.3201/eid0404.980414}}</ref> ''M. microti'' is also rare and is seen almost only in immunodeficient people, although its [[prevalence]] may be significantly underestimated.<ref>{{cite journal|last=Panteix|first=G|author2=Gutierrez, MC |author3=Boschiroli, ML |author4=Rouviere, M |author5=Plaidy, A |author6=Pressac, D |author7=Porcheret, H |author8=Chyderiotis, G |author9=Ponsada, M |author10=Van Oortegem, K |author11=Salloum, S |author12=Cabuzel, S |author13=Bañuls, AL |author14=Van de Perre, P |author15=Godreuil, S |title=Pulmonary tuberculosis due to Mycobacterium microti: a study of six recent cases in France|journal=Journal of Medical Microbiology|date=August 2010|volume=59|issue=Pt 8|pages=984–9|pmid=20488936|doi=10.1099/jmm.0.019372-0}}</ref>
+The ''M. tuberculosis'' complex (MTBC) includes four other TB-causing [[mycobacterium|mycobacteria]]: ''[[Mycobacterium bovis|M. bovis]]'', ''[[Mycobacterium africanum|M. africanum]]'', ''[[Mycobacterium canetti|M. canetti]]'', and ''[[Mycobacterium microti|M. microti]]''.<ref>{{cite journal |author=van Soolingen D. |title=A novel pathogenic taxon of the Mycobacterium tuberculosis complex, Canetti: characterization of an exceptional isolate from Africa |journal=International Journal of Systematic Bacteriology |volume=47 |issue=4 |pages=1236–45 |year=1997 |pmid=9336935 |doi=10.1099/00207713-47-4-1236 |name-list-format=vanc |display-authors=1 |last2=Hoogenboezem |first2=T. |last3=De Haas |first3=P.E.W.|last4=Hermans |first4=P.W.M. |last5=Koedam |first5=M.A. |last6=Teppema |first6=K.S. |last7=Brennan |first7=P.J.|last8=Besra |first8=G.S.|last9=Portaels |first9=F.}}</ref> ''M. africanum'' is not widespread, but it is a significant cause of tuberculosis in parts of Africa.<ref>{{cite journal |author=Niemann S. |title=Mycobacterium africanum Subtype II Is Associated with Two Distinct Genotypes and Is a Major Cause of Human Tuberculosis in Kampala, Uganda |journal=Journal of Clinical Microbiology |volume=40 |issue=9 |pages=3398–405 |year=2002 |pmid=12202584 |pmc=130701 |doi=10.1128/JCM.40.9.3398-3405.2002 |name-list-format=vanc |display-authors=1 |last2=Rusch-Gerdes |first2=S.|last3=Joloba |first3=M.L.|last4=Whalen |first4=C.C.|last5=Guwatudde |first5=D.|last6=Ellner |first6=J.J.|last7=Eisenach |first7=K.|last8=Fumokong |first8=N. |last9=Johnson |first9=J.L.}}</ref><ref>{{cite journal |author=Niobe-Eyangoh S.N.|title=Genetic Biodiversity of Mycobacterium tuberculosis Complex Strains from Patients with Pulmonary Tuberculosis in Cameroon |journal=Journal of Clinical Microbiology |volume=41 |issue=6 |pages=2547–53 |year=2003 |pmid=12791879 |pmc=156567 |doi=10.1128/JCM.41.6.2547-2553.2003 |name-list-format=vanc |display-authors=1 |last2=Kuaban |first2=C. |last3=Sorlin |first3=P. |last4=Cunin |first4=P. |last5=Thonnon |first5=J. |last6=Sola |first6=C. |last7=Rastogi |first7=N. |last8=Vincent |first8=V. |last9=Gutierrez |first9=M.C.}}</ref> ''M. bovis'' was once a common cause of tuberculosis, but the introduction of [[pasteurisation|pasteurized milk]] has almost completely eliminated this as a public health problem in developed countries.<ref name=Robbins/><ref>{{cite journal |vauthors=Thoen C, Lobue P, de Kantor I |title=The importance of ''Mycobacterium bovis'' as a zoonosis |journal=Veterinary Microbiology |volume=112 |issue=2–4 |pages=339–45 |year=2006 |pmid=16387455 |doi=10.1016/j.vetmic.2005.11.047}}</ref> ''M. canetti'' is rare and seems to be limited to the [[Horn of Africa]], although a few cases have been seen in African emigrants.<ref>{{cite book|last=Acton|first=Q. Ashton|title=Mycobacterium Infections: New Insights for the Healthcare Professional|year=2011|publisher=ScholarlyEditions|isbn=978-1-4649-0122-5|pages=1968|url=https://books.google.com/books?id=g2iFfV6uEuAC&pg=PA1968|deadurl=no|archiveurl=https://web.archive.org/web/20150906201531/https://books.google.com/books?id=g2iFfV6uEuAC&pg=PA1968|archivedate=6 September 2015|df=dmy-all}}</ref><ref>{{cite journal|last=Pfyffer|first=GE|author2=Auckenthaler, R |author3=van Embden, JD|author4=van Soolingen, D|title=Mycobacterium canettii, the smooth variant of M. tuberculosis, isolated from a Swiss patient exposed in Africa|journal=Emerging Infectious Diseases|date=Oct–Dec 1998|volume=4|issue=4|pages=631–4|pmid=9866740|pmc=2640258|doi=10.3201/eid0404.980414}}</ref> ''M. microti'' is also rare and is seen almost only in immunodeficient people, although its [[prevalence]] may be significantly underestimated.<ref>{{cite journal|last=Panteix|first=G|author2=Gutierrez, MC |author3=Boschiroli, ML |author4=Rouviere, M |author5=Plaidy, A |author6=Pressac, D |author7=Porcheret, H |author8=Chyderiotis, G |author9=Ponsada, M |author10=Van Oortegem, K |author11=Salloum, S |author12=Cabuzel, S |author13=Bañuls, AL |author14=Van de Perre, P |author15=Godreuil, S |title=Pulmonary tuberculosis due to Mycobacterium microti: a study of six recent cases in France|journal=Journal of Medical Microbiology|date=August 2010|volume=59|issue=Pt 8|pages=984–9|pmid=20488936|doi=10.1099/jmm.0.019372-0}}</ref>
 Other known pathogenic mycobacteria include ''[[Mycobacterium leprae|M. leprae]]'', ''[[Mycobacterium avium complex|M. avium]]'', and ''[[Mycobacterium kansasii|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.<ref name=ALA_1997>{{cite journal |title=Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Medical Section of the American Lung Association |journal=American Journal of Respiratory and Critical Care Medicine |volume=156 |issue=2 Pt 2 |pages=S1–25 |year=1997 |pmid = 9279284 |author=American Thoracic Society |doi=10.1164/ajrccm.156.2.atsstatement }}</ref>
@@ Line 67: / Line 67: @@
 ===Risk factors===
 {{Main article|Risk factors for tuberculosis}}
-A number of factors make people more susceptible to TB infections. The most important risk factor globally is HIV; 13% of all people with TB are infected by the virus.<ref name=WHO2011>{{cite web|title=The sixteenth global report on tuberculosis |author=World Health Organization |url=http://www.who.int/tb/publications/global_report/2011/gtbr11_executive_summary.pdf |year=2011 |deadurl=yes |archiveurl=https://web.archive.org/web/20120906223650/http://www.who.int/tb/publications/global_report/2011/gtbr11_executive_summary.pdf |archivedate=6 September 2012 |df= }}</ref> This is a particular problem in [[sub-Saharan Africa]], where rates of HIV are high.<ref>{{cite web|author=World Health Organization|url=http://www.who.int/tb/publications/global_report/en/index.html|title=Global tuberculosis control–surveillance, planning, financing WHO Report 2006|accessdate=13 October 2006}}</ref><ref>{{cite journal|last=Chaisson|first=RE|author2=Martinson, NA |title=Tuberculosis in Africa—combating an HIV-driven crisis|journal=The New England Journal of Medicine|date=13 March 2008|volume=358|issue=11|pages=1089–92|pmid=18337598|doi=10.1056/NEJMp0800809}}</ref> Of people without HIV who are infected with tuberculosis, about 5–10% develop active disease during their lifetimes;<ref name=Pet2005>{{cite book|last1=Gibson|first1=Peter G. (ed.)|last2=Abramson|first2=Michael (ed.)|last3=Wood-Baker|first3=Richard (ed.)|last4=Volmink|first4=Jimmy (ed.)|last5=Hensley|first5=Michael (ed.)|last6=Costabel|first6=Ulrich (ed.)|title=Evidence-Based Respiratory Medicine|date=2005|publisher=BMJ Books|isbn=978-0-7279-1605-1|page=321|edition=1st|url=http://www.wiley.com/WileyCDA/WileyTitle/productCd-072791605X.html}}</ref> in contrast, 30% of those coinfected with HIV develop the active disease.<ref name=Pet2005/>
+A number of factors make people more susceptible to TB infections. The most important risk factor globally is HIV; 13% of all people with TB are infected by the virus.<ref name=WHO2011>{{cite web|title=The sixteenth global report on tuberculosis |author=World Health Organization |url=http://www.who.int/tb/publications/global_report/2011/gtbr11_executive_summary.pdf |year=2011 |deadurl=yes |archiveurl=https://web.archive.org/web/20120906223650/http://www.who.int/tb/publications/global_report/2011/gtbr11_executive_summary.pdf |archivedate=6 September 2012 |df= }}</ref> This is a particular problem in [[sub-Saharan Africa]], where rates of HIV are high.<ref>{{cite web|author=World Health Organization|url=http://www.who.int/tb/publications/global_report/en/index.html|title=Global tuberculosis control–surveillance, planning, financing WHO Report 2006|accessdate=13 October 2006|deadurl=no|archiveurl=https://web.archive.org/web/20061212123736/http://www.who.int/tb/publications/global_report/en/index.html|archivedate=12 December 2006|df=dmy-all}}</ref><ref>{{cite journal|last=Chaisson|first=RE|author2=Martinson, NA |title=Tuberculosis in Africa—combating an HIV-driven crisis|journal=The New England Journal of Medicine|date=13 March 2008|volume=358|issue=11|pages=1089–92|pmid=18337598|doi=10.1056/NEJMp0800809}}</ref> Of people without HIV who are infected with tuberculosis, about 5–10% develop active disease during their lifetimes;<ref name=Pet2005>{{cite book|last1=Gibson|first1=Peter G. (ed.)|last2=Abramson|first2=Michael (ed.)|last3=Wood-Baker|first3=Richard (ed.)|last4=Volmink|first4=Jimmy (ed.)|last5=Hensley|first5=Michael (ed.)|last6=Costabel|first6=Ulrich (ed.)|title=Evidence-Based Respiratory Medicine|date=2005|publisher=BMJ Books|isbn=978-0-7279-1605-1|page=321|edition=1st|url=http://www.wiley.com/WileyCDA/WileyTitle/productCd-072791605X.html|deadurl=no|archiveurl=https://web.archive.org/web/20151208072842/http://www.wiley.com/WileyCDA/WileyTitle/productCd-072791605X.html|archivedate=8 December 2015|df=dmy-all}}</ref> in contrast, 30% of those coinfected with HIV develop the active disease.<ref name=Pet2005/>
 Tuberculosis is closely linked to both overcrowding and [[malnutrition]], making it one of the principal [[diseases of poverty]].<ref name=Lancet11/> Those at high risk thus include: people who inject illicit drugs, inhabitants and employees of locales where vulnerable people gather (e.g. prisons and homeless shelters), medically underprivileged and resource-poor communities, high-risk ethnic minorities, children in close contact with high-risk category patients, and health-care providers serving these patients.<ref name=Griffith_1996>{{cite journal |vauthors=Griffith D, Kerr C | title=Tuberculosis: disease of the past, disease of the present | journal=Journal of Perianesthesia Nursing | volume=11 | issue=4 | pages=240–5 | year=1996 | pmid=8964016 | doi=10.1016/S1089-9472(96)80023-2 }}</ref>
-Chronic lung disease is another significant risk factor. [[Silicosis]] increases the risk about 30-fold.<ref name=table3>{{cite journal |title=Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society |journal=MMWR. Recommendations and Reports |volume=49 |issue=RR–6 |pages=1–51|date=June 2000|pmid=10881762|url=http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4906a1.htm#tab3 |author1=ATS/CDC Statement Committee on Latent Tuberculosis Infection}}</ref> Those who smoke [[cigarette]]s have nearly twice the risk of TB compared to nonsmokers.<ref>{{cite journal|last=van Zyl Smit|first=RN|author2=Pai, M |author3=Yew, WW |author4=Leung, CC |author5=Zumla, A |author6=Bateman, ED |author7=Dheda, K |title=Global lung health: the colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD| journal=European Respiratory Journal |date=January 2010|volume=35|issue=1|pages=27–33|pmid=20044459|quote=These analyses indicate that smokers are almost twice as likely to be infected with TB and to progress to active disease (RR of about 1.5 for latent TB infection (LTBI) and RR of ∼2.0 for TB disease). Smokers are also twice as likely to die from TB (RR of about 2.0 for TB mortality), but data are difficult to interpret because of heterogeneity in the results across studies.|doi=10.1183/09031936.00072909}}</ref>
+Chronic lung disease is another significant risk factor. [[Silicosis]] increases the risk about 30-fold.<ref name=table3>{{cite journal |title=Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society |journal=MMWR. Recommendations and Reports |volume=49 |issue=RR–6 |pages=1–51 |date=June 2000 |pmid=10881762 |url=http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4906a1.htm#tab3 |author1=ATS/CDC Statement Committee on Latent Tuberculosis Infection |deadurl=no |archiveurl=https://web.archive.org/web/20041217172736/http://www.cdc.gov/MMWR/preview/mmwrhtml/rr4906a1.htm#tab3 |archivedate=17 December 2004 |df=dmy-all }}</ref> Those who smoke [[cigarette]]s have nearly twice the risk of TB compared to nonsmokers.<ref>{{cite journal|last=van Zyl Smit|first=RN|author2=Pai, M |author3=Yew, WW |author4=Leung, CC |author5=Zumla, A |author6=Bateman, ED |author7=Dheda, K |title=Global lung health: the colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD| journal=European Respiratory Journal |date=January 2010|volume=35|issue=1|pages=27–33|pmid=20044459|quote=These analyses indicate that smokers are almost twice as likely to be infected with TB and to progress to active disease (RR of about 1.5 for latent TB infection (LTBI) and RR of ∼2.0 for TB disease). Smokers are also twice as likely to die from TB (RR of about 2.0 for TB mortality), but data are difficult to interpret because of heterogeneity in the results across studies.|doi=10.1183/09031936.00072909}}</ref>
 Other disease states can also increase the risk of developing tuberculosis. These include [[alcoholism]]<ref name=Lancet11/> and [[diabetes mellitus]] (three-fold increase).<ref>{{cite journal|last=Restrepo|first=BI|title=Convergence of the tuberculosis and diabetes epidemics: renewal of old acquaintances|journal=Clinical Infectious Diseases |date=15 August 2007|volume=45|issue=4|pages=436–8|pmid=17638190|doi=10.1086/519939|pmc=2900315}}</ref>
@@ Line 85: / Line 85: @@
 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.<ref name=Cole_1998>{{cite journal |vauthors=Cole E, Cook C |title=Characterization of infectious aerosols in health care facilities: an aid to effective engineering controls and preventive strategies |journal=Am J Infect Control |volume=26 |issue=4 |pages=453–64 |year=1998 |pmid=9721404|doi = 10.1016/S0196-6553(98)70046-X}}</ref> 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).<ref>{{cite journal |vauthors=Nicas M, Nazaroff WW, Hubbard A |title=Toward understanding the risk of secondary airborne infection: emission of respirable pathogens |journal=J Occup Environ Hyg |volume=2 |issue=3 |pages=143–54 |year=2005 |pmid=15764538|doi = 10.1080/15459620590918466}}</ref>
-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.<ref name=Ahmed_2011>{{cite journal |vauthors=Ahmed N, Hasnain S |title=Molecular epidemiology of tuberculosis in India: Moving forward with a systems biology approach |journal=Tuberculosis |volume=91 |issue=5 |pages=407–3 |year=2011|pmid = 21514230|doi = 10.1016/j.tube.2011.03.006}}</ref> A person with active but untreated tuberculosis may infect 10–15 (or more) other people per year.<ref name="WHO2012data"/> Transmission should occur from only people with active TB – those with latent infection are not thought to be contagious.<ref name=Robbins/> 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 (biology)|strain]], the level of immunity in the uninfected person, and others.<ref name=CDCcourse>{{cite web|publisher=[[Centers for Disease Control and Prevention]] (CDC), Division of Tuberculosis Elimination|url=http://www.cdc.gov/tb/education/corecurr/pdf/corecurr_all.pdf|title=Core Curriculum on Tuberculosis: What the Clinician Should Know|page=24|edition=5th|year=2011}}</ref> 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 [[Antibiotic resistance|nonresistant]] active infections generally do not remain contagious to others.<ref name="Ahmed_2011"/> 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.<ref>{{cite web | url=http://www.mayoclinic.com/health/tuberculosis/DS00372/DSECTION=3|title=Causes of Tuberculosis|accessdate=19 October 2007|date=21 December 2006|publisher=[[Mayo Clinic]]}}</ref>
+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.<ref name=Ahmed_2011>{{cite journal |vauthors=Ahmed N, Hasnain S |title=Molecular epidemiology of tuberculosis in India: Moving forward with a systems biology approach |journal=Tuberculosis |volume=91 |issue=5 |pages=407–3 |year=2011|pmid = 21514230|doi = 10.1016/j.tube.2011.03.006}}</ref> A person with active but untreated tuberculosis may infect 10–15 (or more) other people per year.<ref name="WHO2012data"/> Transmission should occur from only people with active TB – those with latent infection are not thought to be contagious.<ref name=Robbins/> 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 (biology)|strain]], the level of immunity in the uninfected person, and others.<ref name=CDCcourse>{{cite web|publisher=[[Centers for Disease Control and Prevention]] (CDC), Division of Tuberculosis Elimination|url=http://www.cdc.gov/tb/education/corecurr/pdf/corecurr_all.pdf|title=Core Curriculum on Tuberculosis: What the Clinician Should Know|page=24|edition=5th|year=2011|deadurl=no|archiveurl=https://web.archive.org/web/20120519141115/http://www.cdc.gov/tb/education/corecurr/pdf/corecurr_all.pdf|archivedate=19 May 2012|df=dmy-all}}</ref> 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 [[Antibiotic resistance|nonresistant]] active infections generally do not remain contagious to others.<ref name="Ahmed_2011"/> 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.<ref>{{cite web|url=http://www.mayoclinic.com/health/tuberculosis/DS00372/DSECTION=3|title=Causes of Tuberculosis|accessdate=19 October 2007|date=21 December 2006|publisher=[[Mayo Clinic]]|deadurl=no|archiveurl=https://web.archive.org/web/20071018051807/http://www.mayoclinic.com/health/tuberculosis/DS00372/DSECTION%3D3|archivedate=18 October 2007|df=dmy-all}}</ref>
 ===Pathogenesis===
 [[File:Tuberculous epididymitis Low Power.jpg|thumb|Microscopy of tuberculous epididymitis.  [[H&E]] stain]]
-About 90% of those infected with ''M. tuberculosis'' have [[asymptomatic]], latent TB infections (sometimes called LTBI),<ref name=Book90>{{cite book|last=Skolnik|first=Richard|title=Global health 101|year=2011|publisher=Jones & Bartlett Learning|location=Burlington, MA|isbn=978-0-7637-9751-5|pages=253|url=https://books.google.com/books?id=sBQRpj4uWmYC&pg=PA253|edition=2nd}}</ref> with only a 10% lifetime chance that the latent infection will progress to overt, active tuberculous disease.<ref name=Arch2009>{{cite book|last=editors|first=Arch G. Mainous III, Claire Pomeroy,|title=Management of antimicrobials in infectious diseases: impact of antibiotic resistance.|year=2009|publisher=Humana Press|location=Totowa, N.J.|isbn=978-1-60327-238-4|pages=74|url=https://books.google.com/books?id=hwVFAPLYznsC&pg=PA74|edition=2nd rev.}}</ref> In those with HIV, the risk of developing active TB increases to nearly 10% a year.<ref name=Arch2009/> If effective treatment is not given, the death rate for active TB cases is up to 66%.<ref name=WHO2012data>{{cite web|url=http://www.who.int/mediacentre/factsheets/fs104/en/index.html|title=Tuberculosis Fact sheet N°104|publisher=[[World Health Organization]]|date=November 2010|accessdate=26 July 2011}}</ref>
+About 90% of those infected with ''M. tuberculosis'' have [[asymptomatic]], latent TB infections (sometimes called LTBI),<ref name=Book90>{{cite book|last=Skolnik|first=Richard|title=Global health 101|year=2011|publisher=Jones & Bartlett Learning|location=Burlington, MA|isbn=978-0-7637-9751-5|pages=253|url=https://books.google.com/books?id=sBQRpj4uWmYC&pg=PA253|edition=2nd|deadurl=no|archiveurl=https://web.archive.org/web/20150906174239/https://books.google.com/books?id=sBQRpj4uWmYC&pg=PA253|archivedate=6 September 2015|df=dmy-all}}</ref> with only a 10% lifetime chance that the latent infection will progress to overt, active tuberculous disease.<ref name=Arch2009>{{cite book|last=editors|first=Arch G. Mainous III, Claire Pomeroy,|title=Management of antimicrobials in infectious diseases: impact of antibiotic resistance.|year=2009|publisher=Humana Press|location=Totowa, N.J.|isbn=978-1-60327-238-4|pages=74|url=https://books.google.com/books?id=hwVFAPLYznsC&pg=PA74|edition=2nd rev.|deadurl=no|archiveurl=https://web.archive.org/web/20150906224212/https://books.google.com/books?id=hwVFAPLYznsC&pg=PA74|archivedate=6 September 2015|df=dmy-all}}</ref> In those with HIV, the risk of developing active TB increases to nearly 10% a year.<ref name=Arch2009/> If effective treatment is not given, the death rate for active TB cases is up to 66%.<ref name=WHO2012data>{{cite web|url=http://www.who.int/mediacentre/factsheets/fs104/en/index.html|title=Tuberculosis Fact sheet N°104|publisher=[[World Health Organization]]|date=November 2010|accessdate=26 July 2011|deadurl=no|archiveurl=https://web.archive.org/web/20061004013508/http://www.who.int/mediacentre/factsheets/fs104/en/index.html|archivedate=4 October 2006|df=dmy-all}}</ref>
 TB infection begins when the mycobacteria reach the [[Pulmonary alveolus|pulmonary alveoli]], where they invade and replicate within [[endosomes]] of alveolar [[macrophages]].<ref name=Robbins/><ref name=Houben>{{cite journal |vauthors=Houben E, Nguyen L, Pieters J | title=Interaction of pathogenic mycobacteria with the host immune system | journal=Curr Opin Microbiol | volume=9 | issue=1 | pages=76–85 | year=2006 | pmid=16406837 | doi=10.1016/j.mib.2005.12.014 }}</ref> 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 [[lung|upper lobe]].<ref name=Robbins/> 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.<ref>{{cite book|last=Khan|title=Essence Of Paediatrics|year=2011|publisher=Elsevier India|isbn=978-81-312-2804-3|pages=401|url=https://books.google.com/books?id=gERCc6KTxwoC&pg=PA401}}</ref> This hematogenous transmission can also spread infection to more distant sites, such as peripheral lymph nodes, the kidneys, the brain, and the bones.<ref name=Robbins/><ref name=Herrmann_2005>{{cite journal |vauthors=Herrmann J, Lagrange P |title=Dendritic cells and ''Mycobacterium tuberculosis'': which is the Trojan horse? |journal=Pathol Biol (Paris) |volume=53 |issue=1 |pages=35–40 |year=2005|pmid = 15620608 |doi=10.1016/j.patbio.2004.01.004}}</ref> All parts of the body can be affected by the disease, though for unknown reasons it rarely affects the [[heart]], [[skeletal muscle]]s, [[pancreas]], or [[thyroid]].<ref>{{cite journal |vauthors=Agarwal R, Malhotra P, Awasthi A, Kakkar N, Gupta D |pmc=1090580 |title=Tuberculous dilated cardiomyopathy: an under-recognized entity? |journal=BMC Infect Dis |volume=5 |issue=1 |page=29 |year=2005 |pmid=15857515 |doi=10.1186/1471-2334-5-29}}</ref>
+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 [[lung|upper lobe]].<ref name=Robbins/> 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.<ref>{{cite book|last=Khan|title=Essence Of Paediatrics|year=2011|publisher=Elsevier India|isbn=978-81-312-2804-3|pages=401|url=https://books.google.com/books?id=gERCc6KTxwoC&pg=PA401|deadurl=no|archiveurl=https://web.archive.org/web/20150906193259/https://books.google.com/books?id=gERCc6KTxwoC&pg=PA401|archivedate=6 September 2015|df=dmy-all}}</ref> This hematogenous transmission can also spread infection to more distant sites, such as peripheral lymph nodes, the kidneys, the brain, and the bones.<ref name=Robbins/><ref name=Herrmann_2005>{{cite journal |vauthors=Herrmann J, Lagrange P |title=Dendritic cells and ''Mycobacterium tuberculosis'': which is the Trojan horse? |journal=Pathol Biol (Paris) |volume=53 |issue=1 |pages=35–40 |year=2005|pmid = 15620608 |doi=10.1016/j.patbio.2004.01.004}}</ref> All parts of the body can be affected by the disease, though for unknown reasons it rarely affects the [[heart]], [[skeletal muscle]]s, [[pancreas]], or [[thyroid]].<ref>{{cite journal |vauthors=Agarwal R, Malhotra P, Awasthi A, Kakkar N, Gupta D |pmc=1090580 |title=Tuberculous dilated cardiomyopathy: an under-recognized entity? |journal=BMC Infect Dis |volume=5 |issue=1 |page=29 |year=2005 |pmid=15857515 |doi=10.1186/1471-2334-5-29}}</ref>
-[[File:Carswell-Tubercle.jpg|thumb|left|upright=90%|[[Robert Carswell (pathologist)|Robert Carswell]]'s illustration of tubercle<ref name="GoodCooper1835">{{cite book|author1=John Mason Good|author2=Samuel Cooper|author3=Augustus Sidney Doane|title=The Study of Medicine|url=https://books.google.com/books?id=K906AQAAMAAJ&pg=PA32|year=1835|publisher=Harper|page=32}}</ref>]]
+[[File:Carswell-Tubercle.jpg|thumb|left|upright=90%|[[Robert Carswell (pathologist)|Robert Carswell]]'s illustration of tubercle<ref name="GoodCooper1835">{{cite book|author1=John Mason Good|author2=Samuel Cooper|author3=Augustus Sidney Doane|title=The Study of Medicine|url=https://books.google.com/books?id=K906AQAAMAAJ&pg=PA32|year=1835|publisher=Harper|page=32|deadurl=no|archiveurl=https://web.archive.org/web/20160810194616/https://books.google.com/books?id=K906AQAAMAAJ&pg=PA32|archivedate=10 August 2016|df=dmy-all}}</ref>]]
 Tuberculosis is classified as one of the [[granuloma]]tous inflammatory diseases. [[Macrophage]]s, [[T cell|T lymphocytes]], [[B cell|B lymphocytes]], and [[fibroblast]]s <!-- are among the cells that --> aggregate to form [[granuloma]]s, 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.<ref name=Grosset />  However, more recent evidence suggests that the bacteria use the granulomas to avoid destruction by the host's immune system.  Macrophages and [[dendritic cell]]s in the granulomas are unable to present antigen to lymphocytes; thus the immune response is suppressed.<ref>{{cite journal | author=Bozzano F | title=Immunology of tuberculosis | journal=Mediterr J Hematol Infect Dis | volume=6 | issue=1 | page=e2014027 | year=2014 | pmid=24804000 | doi=10.4084/MJHID.2014.027 | pmc=4010607 }}</ref> 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 [[Tubercle (anatomy)|tubercles]].  To the naked eye, this has the texture of soft, white cheese and is termed [[caseous necrosis]].<ref name=Grosset>{{cite journal |author=Grosset J |title=Mycobacterium tuberculosis in the Extracellular Compartment: an Underestimated Adversary |journal=Antimicrob Agents Chemother |volume=47 |issue=3 |pages=833–6 |year=2003|pmid = 12604509|doi = 10.1128/AAC.47.3.833-836.2003 |pmc=149338}}</ref>
-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.<ref>{{cite book|last=Crowley|first=Leonard V.|title=An introduction to human disease: pathology and pathophysiology correlations|year=2010|publisher=Jones and Bartlett|location=Sudbury, Mass.|isbn=978-0-7637-6591-0|pages=374|url=https://books.google.com/books?id=TEiuWP4z_QIC&pg=PA374|edition=8th}}</ref>  This severe form of TB disease, most common in young children and those with HIV, is called miliary tuberculosis.<ref>{{cite book|last=Anthony|first=Harries|title=TB/HIV a Clinical Manual.|year=2005|publisher=World Health Organization|location=Geneva|isbn=978-92-4-154634-8|pages=75|url=https://books.google.com/books?id=8dfhwKaCSxkC&pg=PA75|edition=2nd }}</ref>  People with this disseminated TB have a high fatality rate even with treatment (about 30%).<ref name=Gho2008>{{cite book|last=Ghosh|first=editors-in-chief, Thomas M. Habermann, Amit K.|title=Mayo Clinic internal medicine: concise textbook|year=2008|publisher=Mayo Clinic Scientific Press|location=Rochester, MN|isbn=978-1-4200-6749-1|pages=789|url=https://books.google.com/books?id=YJtodBwNxokC&pg=PA789}}</ref><ref>{{cite journal|last=Jacob|first=JT |author2=Mehta, AK |author3=Leonard, MK|title=Acute forms of tuberculosis in adults|journal=The American Journal of Medicine|date=January 2009|volume=122|issue=1|pages=12–7|pmid=19114163|doi=10.1016/j.amjmed.2008.09.018}}</ref>
+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.<ref>{{cite book|last=Crowley|first=Leonard V.|title=An introduction to human disease: pathology and pathophysiology correlations|year=2010|publisher=Jones and Bartlett|location=Sudbury, Mass.|isbn=978-0-7637-6591-0|pages=374|url=https://books.google.com/books?id=TEiuWP4z_QIC&pg=PA374|edition=8th|deadurl=no|archiveurl=https://web.archive.org/web/20150906193726/https://books.google.com/books?id=TEiuWP4z_QIC&pg=PA374|archivedate=6 September 2015|df=dmy-all}}</ref>  This severe form of TB disease, most common in young children and those with HIV, is called miliary tuberculosis.<ref>{{cite book|last=Anthony|first=Harries|title=TB/HIV a Clinical Manual.|year=2005|publisher=World Health Organization|location=Geneva|isbn=978-92-4-154634-8|pages=75|url=https://books.google.com/books?id=8dfhwKaCSxkC&pg=PA75|edition=2nd|deadurl=no|archiveurl=https://web.archive.org/web/20150906195514/https://books.google.com/books?id=8dfhwKaCSxkC&pg=PA75|archivedate=6 September 2015|df=dmy-all}}</ref>  People with this disseminated TB have a high fatality rate even with treatment (about 30%).<ref name=Gho2008>{{cite book|last=Ghosh|first=editors-in-chief, Thomas M. Habermann, Amit K.|title=Mayo Clinic internal medicine: concise textbook|year=2008|publisher=Mayo Clinic Scientific Press|location=Rochester, MN|isbn=978-1-4200-6749-1|pages=789|url=https://books.google.com/books?id=YJtodBwNxokC&pg=PA789|deadurl=no|archiveurl=https://web.archive.org/web/20150906190055/https://books.google.com/books?id=YJtodBwNxokC&pg=PA789|archivedate=6 September 2015|df=dmy-all}}</ref><ref>{{cite journal|last=Jacob|first=JT |author2=Mehta, AK |author3=Leonard, MK|title=Acute forms of tuberculosis in adults|journal=The American Journal of Medicine|date=January 2009|volume=122|issue=1|pages=12–7|pmid=19114163|doi=10.1016/j.amjmed.2008.09.018}}</ref>
 In many people, the infection waxes and wanes. Tissue destruction and necrosis are often balanced by healing and [[fibrosis]].<ref name=Grosset/> 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 [[antibiotic]]s kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.<ref name=Grosset/>
@@ Line 111: / Line 111: @@
 Diagnosing active tuberculosis based only on signs and symptoms is difficult,<ref name=DiagP2011>{{cite journal|last=Bento|first=J |author2=Silva, AS |author3=Rodrigues, F |author4=Duarte, R|title=[Diagnostic tools in tuberculosis]|journal=[[Acta Médica Portuguesa]]|date=Jan–Feb 2011|volume=24|issue=1|pages=145–54|pmid=21672452}}</ref> as is diagnosing the disease in those who are immunosuppressed.<ref name=Clinic2009>{{cite journal|last=Escalante|first=P|title=In the clinic. Tuberculosis|journal=Annals of Internal Medicine|date=2 June 2009|volume=150|issue=11|pages=ITC61–614; quiz ITV616|pmid=19487708|doi=10.7326/0003-4819-150-11-200906020-01006}}</ref> A diagnosis of TB should, however, be considered in those with signs of lung disease or [[constitutional symptoms]] lasting longer than two weeks.<ref name=Clinic2009/> A [[chest X-ray]] and multiple [[sputum culture]]s for [[acid-fast bacilli]] are typically part of the initial evaluation.<ref name=Clinic2009/> Interferon-γ release assays and tuberculin skin tests are of little use in the developing world.<ref>{{cite journal|last=Metcalfe|first=JZ |author2=Everett, CK |author3=Steingart, KR |author4=Cattamanchi, A |author5=Huang, L |author6=Hopewell, PC |author7=Pai, M|title=Interferon-γ release assays for active pulmonary tuberculosis diagnosis in adults in low- and middle-income countries: systematic review and meta-analysis|journal=The Journal of Infectious Diseases|date=15 November 2011|volume=204 Suppl 4|pages=S1120–9|pmid=21996694|doi=10.1093/infdis/jir410|pmc=3192542|issue=suppl_4}}</ref><ref name="Sester 100–11">{{cite journal|last=Sester|first=M |author2=Sotgiu, G |author3=Lange, C |author4=Giehl, C |author5=Girardi, E |author6=Migliori, GB |author7=Bossink, A |author8=Dheda, K |author9=Diel, R |author10=Dominguez, J |author11=Lipman, M |author12=Nemeth, J |author13=Ravn, P |author14=Winkler, S |author15=Huitric, E |author16=Sandgren, A |author17=Manissero, D |title=Interferon-γ release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis|journal=The European Respiratory Journal|date=January 2011|volume=37|issue=1|pages=100–11|pmid=20847080|doi=10.1183/09031936.00114810}}</ref> [[Interferon gamma release assay]]s (IGRA) have similar limitations in those with HIV.<ref name="Sester 100–11"/><ref>{{cite journal|last=Chen|first=J|author2=Zhang, R |author3=Wang, J |author4=Liu, L |author5=Zheng, Y |author6=Shen, Y |author7=Qi, T |author8=Lu, H |title=Interferon-gamma release assays for the diagnosis of active tuberculosis in HIV-infected patients: a systematic review and meta-analysis|journal=PLoS ONE|year=2011|volume=6|issue=11|pages=e26827|pmid=22069472|doi=10.1371/journal.pone.0026827|pmc=3206065|editor1-last=Vermund|editor1-first=Sten H}} {{open access}}</ref>
-A definitive diagnosis of TB is made by identifying ''M. tuberculosis'' in a clinical sample (e.g., sputum, [[pus]], or a [[Tissue (biology)|tissue]] [[biopsy]]). However, the difficult culture process for this slow-growing organism can take two to six weeks for blood or sputum culture.<ref>{{cite book|last=Diseases|first=Special Programme for Research & Training in Tropical|title=Diagnostics for tuberculosis: global demand and market potential.|year=2006|publisher=World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases|location=Geneva|isbn=978-92-4-156330-7|pages=36|url=https://books.google.com/books?id=CFPpcCef4yQC&pg=PA36}}</ref> Thus, treatment is often begun before cultures are confirmed.<ref name=NICE2011/>
+A definitive diagnosis of TB is made by identifying ''M. tuberculosis'' in a clinical sample (e.g., sputum, [[pus]], or a [[Tissue (biology)|tissue]] [[biopsy]]). However, the difficult culture process for this slow-growing organism can take two to six weeks for blood or sputum culture.<ref>{{cite book|last=Diseases|first=Special Programme for Research & Training in Tropical|title=Diagnostics for tuberculosis: global demand and market potential.|year=2006|publisher=World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases|location=Geneva|isbn=978-92-4-156330-7|pages=36|url=https://books.google.com/books?id=CFPpcCef4yQC&pg=PA36|deadurl=no|archiveurl=https://web.archive.org/web/20150906202315/https://books.google.com/books?id=CFPpcCef4yQC&pg=PA36|archivedate=6 September 2015|df=dmy-all}}</ref> Thus, treatment is often begun before cultures are confirmed.<ref name=NICE2011/>
 [[Nucleic acid amplification test]]s and [[adenosine deaminase]] testing may allow rapid diagnosis of TB.<ref name=DiagP2011/> These tests, however, are not routinely recommended, as they rarely alter how a person is treated.<ref name=NICE2011/> Blood tests to detect antibodies are not [[sensitivity and specificity|specific or sensitive]], so they are not recommended.<ref>{{cite journal|last=Steingart|first=KR |author2=Flores, LL |author3=Dendukuri, N |author4=Schiller, I |author5=Laal, S |author6=Ramsay, A |author7=Hopewell, PC |author8=Pai, M|title=Commercial serological tests for the diagnosis of active pulmonary and extrapulmonary tuberculosis: an updated systematic review and meta-analysis|journal=PLOS Medicine|date=August 2011|volume=8|issue=8|pages=e1001062|pmid=21857806|doi=10.1371/journal.pmed.1001062|pmc=3153457|editor1-last=Evans|editor1-first=Carlton}} {{open access}}</ref>
@@ Line 118: / Line 118: @@
 {{Main article|Latent tuberculosis}}
 [[File:Mantoux tuberculin skin test.jpg|thumb|[[Mantoux test|Mantoux tuberculin skin test]]]]
-The [[Mantoux test|Mantoux tuberculin skin test]] is often used to screen people at high risk for TB.<ref name=Clinic2009/> Those who have been previously immunized may have a false-positive test result.<ref name=Rothel_2005>{{cite journal|vauthors=Rothel J, Andersen P |title=Diagnosis of latent ''Mycobacterium tuberculosis'' infection: is the demise of the Mantoux test imminent?|journal=Expert Rev Anti Infect Ther |volume=3 |issue=6 |pages=981–93 |year=2005|pmid = 16307510|doi = 10.1586/14787210.3.6.981}}</ref> The test may be falsely negative in those with [[sarcoidosis]], [[Hodgkin's lymphoma]], [[malnutrition]], and most notably, active tuberculosis.<ref name=Robbins/> Interferon gamma release assays, on a blood sample, are recommended in those who are positive to the Mantoux test.<ref name=NICE2011>{{NICE|117|Tuberculosis|2011}}</ref> These are not affected by immunization or most [[environmental mycobacteria]], so they generate fewer [[false-positive]] results.<ref>{{cite journal|vauthors=Pai M, Zwerling A, Menzies D |title=Systematic Review: T-Cell–based Assays for the Diagnosis of Latent Tuberculosis Infection: An Update |journal=Ann. Intern. Med. |volume=149 |issue=3 |pages=1–9 |year=2008 |pmid=18593687 |pmc=2951987|doi=10.7326/0003-4819-149-3-200808050-00241}}</ref> However, they are affected by ''M. szulgai'', ''M. marinum'', and ''M. kansasii''.<ref>{{cite book|last=Jindal|first=editor-in-chief SK|title=Textbook of Pulmonary and Critical Care Medicine|publisher=Jaypee Brothers Medical Publishers|location=New Delhi|isbn=978-93-5025-073-0|pages=544|url=https://books.google.com/books?id=rAT1bdnDakAC&pg=PA544|year=2011}}</ref> IGRAs may increase sensitivity when used in addition to the skin test, but may be less sensitive than the skin test when used alone.<ref>{{cite journal|last=Amicosante|first=M|author2=Ciccozzi, M |author3=Markova, R |title=Rational use of immunodiagnostic tools for tuberculosis infection: guidelines and cost effectiveness studies|journal=The new microbiologica|date=April 2010|volume=33|issue=2|pages=93–107|pmid=20518271}}</ref>
+The [[Mantoux test|Mantoux tuberculin skin test]] is often used to screen people at high risk for TB.<ref name=Clinic2009/> Those who have been previously immunized may have a false-positive test result.<ref name=Rothel_2005>{{cite journal|vauthors=Rothel J, Andersen P |title=Diagnosis of latent ''Mycobacterium tuberculosis'' infection: is the demise of the Mantoux test imminent?|journal=Expert Rev Anti Infect Ther |volume=3 |issue=6 |pages=981–93 |year=2005|pmid = 16307510|doi = 10.1586/14787210.3.6.981}}</ref> The test may be falsely negative in those with [[sarcoidosis]], [[Hodgkin's lymphoma]], [[malnutrition]], and most notably, active tuberculosis.<ref name=Robbins/> Interferon gamma release assays, on a blood sample, are recommended in those who are positive to the Mantoux test.<ref name=NICE2011>{{NICE|117|Tuberculosis|2011}}</ref> These are not affected by immunization or most [[environmental mycobacteria]], so they generate fewer [[false-positive]] results.<ref>{{cite journal|vauthors=Pai M, Zwerling A, Menzies D |title=Systematic Review: T-Cell–based Assays for the Diagnosis of Latent Tuberculosis Infection: An Update |journal=Ann. Intern. Med. |volume=149 |issue=3 |pages=1–9 |year=2008 |pmid=18593687 |pmc=2951987|doi=10.7326/0003-4819-149-3-200808050-00241}}</ref> However, they are affected by ''M. szulgai'', ''M. marinum'', and ''M. kansasii''.<ref>{{cite book|last=Jindal|first=editor-in-chief SK|title=Textbook of Pulmonary and Critical Care Medicine|publisher=Jaypee Brothers Medical Publishers|location=New Delhi|isbn=978-93-5025-073-0|pages=544|url=https://books.google.com/books?id=rAT1bdnDakAC&pg=PA544|year=2011|deadurl=no|archiveurl=https://web.archive.org/web/20150906185238/https://books.google.com/books?id=rAT1bdnDakAC&pg=PA544|archivedate=6 September 2015|df=dmy-all}}</ref> IGRAs may increase sensitivity when used in addition to the skin test, but may be less sensitive than the skin test when used alone.<ref>{{cite journal|last=Amicosante|first=M|author2=Ciccozzi, M |author3=Markova, R |title=Rational use of immunodiagnostic tools for tuberculosis infection: guidelines and cost effectiveness studies|journal=The new microbiologica|date=April 2010|volume=33|issue=2|pages=93–107|pmid=20518271}}</ref>
 ==Prevention==
@@ Line 127: / Line 127: @@
 The only available [[vaccine]] as of 2011 is [[Bacillus Calmette-Guérin]] (BCG).<ref name=McS2011>{{cite journal|last=McShane|first=H|title=Tuberculosis vaccines: beyond bacille Calmette–Guérin|journal=Philosophical transactions of the Royal Society of London. Series B, Biological sciences|date=12 October 2011|volume=366|issue=1579|pages=2782–9|pmid=21893541|doi=10.1098/rstb.2011.0097|pmc=3146779}}</ref> In children it decreases the risk of getting the infection by 20% and the risk of infection turning into disease by nearly 60%.<ref>{{cite journal|last1=Roy|first1=A|last2=Eisenhut|first2=M|last3=Harris|first3=RJ|last4=Rodrigues|first4=LC|last5=Sridhar|first5=S|last6=Habermann|first6=S|last7=Snell|first7=L|last8=Mangtani|first8=P|last9=Adetifa|first9=I|last10=Lalvani|first10=A|last11=Abubakar|first11=I|title=Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis.|journal=BMJ (Clinical research ed.)|date=Aug 5, 2014|volume=349|pages=g4643|pmid=25097193|doi=10.1136/bmj.g4643|pmc=4122754}}</ref>
-It is the most widely used vaccine worldwide, with more than 90% of all children being [[vaccinated]].<ref name=Lancet11/> The immunity it induces decreases after about ten years.<ref name=Lancet11/> As tuberculosis is uncommon in most of Canada, the United Kingdom, and the United States, BCG is administered to only those people at high risk.<ref>{{cite web|url=http://www.cdc.gov/tb/topic/vaccines/|title=Vaccine and Immunizations: TB Vaccine (BCG)|publisher =Centers for Disease Control and Prevention|year=2011|accessdate=26 July 2011}}</ref><ref>{{cite web|title=BCG Vaccine Usage in Canada – Current and Historical|url=http://www.phac-aspc.gc.ca/tbpc-latb/bcgvac_1206-eng.php|work=Public Health Agency of Canada|accessdate=30 December 2011|date=September 2010}}</ref><ref name=UK06>{{cite journal|last=Teo|first=SS|author2=Shingadia, DV |title=Does BCG have a role in tuberculosis control and prevention in the United Kingdom?|journal=Archives of Disease in Childhood|date=June 2006|volume=91|issue=6|pages=529–31|pmid=16714729|pmc= 2082765|doi=10.1136/adc.2005.085043 }}</ref> Part of the reasoning against the use of the vaccine is that it makes the [[tuberculin skin test]] falsely positive, reducing the test's use in screening.<ref name=UK06/> A number of new vaccines are currently in development.<ref name=Lancet11/>
+It is the most widely used vaccine worldwide, with more than 90% of all children being [[vaccinated]].<ref name=Lancet11/> The immunity it induces decreases after about ten years.<ref name=Lancet11/> As tuberculosis is uncommon in most of Canada, the United Kingdom, and the United States, BCG is administered to only those people at high risk.<ref>{{cite web|url=http://www.cdc.gov/tb/topic/vaccines/|title=Vaccine and Immunizations: TB Vaccine (BCG)|publisher=Centers for Disease Control and Prevention|year=2011|accessdate=26 July 2011|deadurl=no|archiveurl=https://web.archive.org/web/20111117140855/http://www.cdc.gov/tb/topic/vaccines/|archivedate=17 November 2011|df=dmy-all}}</ref><ref>{{cite web|title=BCG Vaccine Usage in Canada – Current and Historical|url=http://www.phac-aspc.gc.ca/tbpc-latb/bcgvac_1206-eng.php|work=Public Health Agency of Canada|accessdate=30 December 2011|date=September 2010|deadurl=no|archiveurl=https://web.archive.org/web/20120330042719/http://www.phac-aspc.gc.ca/tbpc-latb/bcgvac_1206-eng.php|archivedate=30 March 2012|df=dmy-all}}</ref><ref name=UK06>{{cite journal|last=Teo|first=SS|author2=Shingadia, DV |title=Does BCG have a role in tuberculosis control and prevention in the United Kingdom?|journal=Archives of Disease in Childhood|date=June 2006|volume=91|issue=6|pages=529–31|pmid=16714729|pmc= 2082765|doi=10.1136/adc.2005.085043 }}</ref> Part of the reasoning against the use of the vaccine is that it makes the [[tuberculin skin test]] falsely positive, reducing the test's use in screening.<ref name=UK06/> A number of new vaccines are currently in development.<ref name=Lancet11/>
 ===Public health===
-The World Health Organization declared TB a "global health emergency" in 1993,<ref name=Lancet11/> and in 2006, the Stop TB Partnership developed a [[Global Plan to Stop Tuberculosis]] that aimed to save 14 million lives between its launch and 2015.<ref>{{cite web|url=http://www.stoptb.org/global/plan/|title=The Global Plan to Stop TB|publisher=[[World Health Organization]]|year=2011|accessdate=13 June 2011}}</ref> A number of targets they set were not achieved by 2015, mostly due to the increase in HIV-associated tuberculosis and the emergence of multiple drug-resistant tuberculosis.<ref name=Lancet11/> A [[tuberculosis classification]] system developed by the [[American Thoracic Society]] is used primarily in public health programs.<ref>{{cite book|last=Warrell|first=ed. by D. J. Weatherall ... [4. + 5. ed.] ed. by David A.|title=Sections 1 – 10.|year=2005|publisher=Oxford Univ. Press|location=Oxford [u.a.]|isbn=978-0-19-857014-1|pages=560|url=https://books.google.com/books?id=EhjX517cGVsC&pg=PA560|edition=4. ed., paperback.}}</ref>
+The World Health Organization declared TB a "global health emergency" in 1993,<ref name=Lancet11/> and in 2006, the Stop TB Partnership developed a [[Global Plan to Stop Tuberculosis]] that aimed to save 14 million lives between its launch and 2015.<ref>{{cite web|url=http://www.stoptb.org/global/plan/|title=The Global Plan to Stop TB|publisher=[[World Health Organization]]|year=2011|accessdate=13 June 2011|deadurl=no|archiveurl=https://web.archive.org/web/20110612030924/http://www.stoptb.org/global/plan/|archivedate=12 June 2011|df=dmy-all}}</ref> A number of targets they set were not achieved by 2015, mostly due to the increase in HIV-associated tuberculosis and the emergence of multiple drug-resistant tuberculosis.<ref name=Lancet11/> A [[tuberculosis classification]] system developed by the [[American Thoracic Society]] is used primarily in public health programs.<ref>{{cite book|last=Warrell|first=ed. by D. J. Weatherall ... [4. + 5. ed.] ed. by David A.|title=Sections 1 – 10.|year=2005|publisher=Oxford Univ. Press|location=Oxford [u.a.]|isbn=978-0-19-857014-1|pages=560|url=https://books.google.com/books?id=EhjX517cGVsC&pg=PA560|edition=4. ed., paperback.|deadurl=no|archiveurl=https://web.archive.org/web/20150906210011/https://books.google.com/books?id=EhjX517cGVsC&pg=PA560|archivedate=6 September 2015|df=dmy-all}}</ref>
 ==Management==
 {{Main article|Tuberculosis management}}
-Treatment of 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 hinders the entry of drugs and makes many antibiotics ineffective.<ref>{{cite journal |vauthors=Brennan PJ, Nikaido H |title=The envelope of mycobacteria |journal=Annu. Rev. Biochem. |volume=64 |pages=29–63 |year=1995 |pmid=7574484 |doi=10.1146/annurev.bi.64.070195.000333}}</ref> The two antibiotics most commonly used are [[isoniazid]] and [[rifampicin]], and treatments can be prolonged, taking several months.<ref name=CDCcourse/> Latent TB treatment usually employs a single antibiotic,<ref name=Latent2011/> while active TB disease is best treated with combinations of several antibiotics to reduce the risk of the bacteria developing [[antibiotic resistance]].<ref name=Lancet11/> People with latent infections are also treated to prevent them from progressing to active TB disease later in life.<ref name=Latent2011>{{cite journal|last=Menzies|first=D |author2=Al Jahdali, H |author3=Al Otaibi, B|title=Recent developments in treatment of latent tuberculosis infection|journal=The Indian journal of medical research|date=March 2011|volume=133|pages=257–66|pmid=21441678|pmc=3103149|issue=3}}</ref> [[Directly observed therapy]], i.e., having a health care provider watch the person take their medications, is recommended by the WHO in an effort to reduce the number of people not appropriately taking antibiotics.<ref>{{cite book |author1=Arch G. |author2=III Mainous |title=Management of Antimicrobials in Infectious Diseases: Impact of Antibiotic Resistance |publisher=Humana Press |location=Totowa, N.J.|year=2010 |pages=69 |isbn=1-60327-238-0 |oclc= |url=https://books.google.com/books?id=hwVFAPLYznsC&pg=PA69}}</ref> The evidence to support this practice over people simply taking their medications independently is of poor quality.<ref name=Karumbi2015 /> There is no strong evidence indicating that directly observed therapy improves the number of people who were cured or the number of people who complete their medicine.<ref name=Karumbi2015>{{Cite journal|last=Karumbi|first=Jamlick|last2=Garner|first2=Paul|date=2015-05-29|title=Directly observed therapy for treating tuberculosis|url=|journal=The Cochrane Database of Systematic Reviews|volume=|issue=5|pages=CD003343|doi=10.1002/14651858.CD003343.pub4|issn=1469-493X|pmc=4460720|pmid=26022367|via=}}</ref> Moderate quality evidence suggests that there is also no difference if people are observed at home versus at a clinic, or by a family member versus a health care worker.<ref name=Karumbi2015 /> Methods to remind people of the importance of treatment and appointments may result in a small but important improvement.<ref>{{Cite journal|last=Liu|first=Qin|last2=Abba|first2=Katharine|last3=Alejandria|first3=Marissa M.|last4=Sinclair|first4=David|last5=Balanag|first5=Vincent M.|last6=Lansang|first6=Mary Ann D.|date=2014-11-18|title=Reminder systems to improve patient adherence to tuberculosis clinic appointments for diagnosis and treatment|url=|journal=The Cochrane Database of Systematic Reviews|volume=|issue=11|pages=CD006594|doi=10.1002/14651858.CD006594.pub3|issn=1469-493X|pmc=4448217|pmid=25403701|via=}}</ref>
+Treatment of 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 hinders the entry of drugs and makes many antibiotics ineffective.<ref>{{cite journal |vauthors=Brennan PJ, Nikaido H |title=The envelope of mycobacteria |journal=Annu. Rev. Biochem. |volume=64 |pages=29–63 |year=1995 |pmid=7574484 |doi=10.1146/annurev.bi.64.070195.000333}}</ref> The two antibiotics most commonly used are [[isoniazid]] and [[rifampicin]], and treatments can be prolonged, taking several months.<ref name=CDCcourse/> Latent TB treatment usually employs a single antibiotic,<ref name=Latent2011/> while active TB disease is best treated with combinations of several antibiotics to reduce the risk of the bacteria developing [[antibiotic resistance]].<ref name=Lancet11/> People with latent infections are also treated to prevent them from progressing to active TB disease later in life.<ref name=Latent2011>{{cite journal|last=Menzies|first=D |author2=Al Jahdali, H |author3=Al Otaibi, B|title=Recent developments in treatment of latent tuberculosis infection|journal=The Indian journal of medical research|date=March 2011|volume=133|pages=257–66|pmid=21441678|pmc=3103149|issue=3}}</ref> [[Directly observed therapy]], i.e., having a health care provider watch the person take their medications, is recommended by the WHO in an effort to reduce the number of people not appropriately taking antibiotics.<ref>{{cite book |author1=Arch G. |author2=III Mainous |title=Management of Antimicrobials in Infectious Diseases: Impact of Antibiotic Resistance |publisher=Humana Press |location=Totowa, N.J. |year=2010 |pages=69 |isbn=1-60327-238-0 |oclc= |url=https://books.google.com/books?id=hwVFAPLYznsC&pg=PA69 |deadurl=no |archiveurl=https://web.archive.org/web/20150906215558/https://books.google.com/books?id=hwVFAPLYznsC&pg=PA69 |archivedate=6 September 2015 |df=dmy-all }}</ref> The evidence to support this practice over people simply taking their medications independently is of poor quality.<ref name=Karumbi2015 /> There is no strong evidence indicating that directly observed therapy improves the number of people who were cured or the number of people who complete their medicine.<ref name=Karumbi2015>{{Cite journal|last=Karumbi|first=Jamlick|last2=Garner|first2=Paul|date=2015-05-29|title=Directly observed therapy for treating tuberculosis|url=|journal=The Cochrane Database of Systematic Reviews|volume=|issue=5|pages=CD003343|doi=10.1002/14651858.CD003343.pub4|issn=1469-493X|pmc=4460720|pmid=26022367|via=}}</ref> Moderate quality evidence suggests that there is also no difference if people are observed at home versus at a clinic, or by a family member versus a health care worker.<ref name=Karumbi2015 /> Methods to remind people of the importance of treatment and appointments may result in a small but important improvement.<ref>{{Cite journal|last=Liu|first=Qin|last2=Abba|first2=Katharine|last3=Alejandria|first3=Marissa M.|last4=Sinclair|first4=David|last5=Balanag|first5=Vincent M.|last6=Lansang|first6=Mary Ann D.|date=2014-11-18|title=Reminder systems to improve patient adherence to tuberculosis clinic appointments for diagnosis and treatment|url=|journal=The Cochrane Database of Systematic Reviews|volume=|issue=11|pages=CD006594|doi=10.1002/14651858.CD006594.pub3|issn=1469-493X|pmc=4448217|pmid=25403701|via=}}</ref>
 ===New onset===
@@ Line 143: / Line 143: @@
 ===Medication resistance===
-Primary resistance occurs when a person becomes infected with a resistant strain of TB. A person with fully susceptible [[Mycobacterium tuberculosis|MTB]] may develop secondary (acquired) resistance during therapy because of inadequate treatment, not taking the prescribed regimen appropriately (lack of compliance), or using low-quality medication.<ref name=OBrien>{{cite journal |author=O'Brien R |title=Drug-resistant tuberculosis: etiology, management and prevention |journal=Semin Respir Infect |volume=9 |issue=2 |pages=104–12 |year=1994|pmid = 7973169}}</ref> Drug-resistant TB is a serious public health issue in many developing countries, as its treatment is longer and requires more expensive drugs. MDR-TB is defined as resistance to the two most effective first-line TB drugs: rifampicin and isoniazid. [[Extensively drug-resistant tuberculosis|Extensively drug-resistant TB]] is also resistant to three or more of the six classes of second-line drugs.<ref name="MMWR2006">{{cite journal |title=Emergence of ''Mycobacterium tuberculosis'' with extensive resistance to second-line drugs—worldwide, 2000–2004 |journal=MMWR Morb Mortal Wkly Rep |volume=55 |issue=11 |pages=301–5 |year=2006 |url=http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5511a2.htm|pmid = 16557213 |author=Centers for Disease Control and Prevention (CDC)}}</ref> [[Totally drug-resistant tuberculosis|Totally drug-resistant TB]] is resistant to all currently used drugs.<ref name=TR2012>{{cite web|title=Totally Resistant TB: Earliest Cases in Italy |url=https://www.wired.com/wiredscience/2012/01/tdr-first-italy/|author=Maryn McKenna|date=12 January 2012|accessdate=12 January 2012|publisher=[[Wired (magazine)|Wired]]}}</ref> It was first observed in 2003 in Italy,<ref>{{cite journal|last1=Migliori|first1=G.B.|last2=De Iaco|first2=G.|last3=Besozzi|first3=G.|last4=Centis|first4=R.|last5=Cirillo|first5=D.M.|title=First tuberculosis cases in Italy resistant to all tested drugs|journal=Euro Surveillance|date=May 17, 2007|volume=12|issue=5|page=E070517.1.|pmid=17868596}}</ref> but not widely reported until 2012,<ref name=TR2012/><ref>{{cite web|title=Totally Drug-Resistant TB: a WHO consultation on the diagnostic definition and treatment options|url=http://www.who.int/tb/challenges/xdr/Report_Meeting_totallydrugresistantTB_032012.pdf?ua=1|website=who.int|publisher=World Health Organization|accessdate=25 March 2016}}</ref> and has also been found in Iran and India.<ref name="EIU 2014"/><ref>{{cite journal|last1=Velayati|first1=A.A.|last2=Masjedi|first2=M.R.|last3=Farnia|first3=P.|last4=Tabarsi|first4=P.|last5=Ghanavi|first5=J.|last6=Ziazarifi|first6=A.H.|last7=Hoffner|first7=S.E.|title=Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran|journal=Chest|date=August 2009|volume=136|issue=2|pages=420–425|doi=10.1378/chest.08-2427|pmid=19349380}}</ref> [[Bedaquiline]] is tentatively supported for use in multiple drug-resistant TB.<ref>{{cite web|title=Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis|url=http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6209a1.htm?s_cid=rr6209a1_x}}</ref>
+Primary resistance occurs when a person becomes infected with a resistant strain of TB. A person with fully susceptible [[Mycobacterium tuberculosis|MTB]] may develop secondary (acquired) resistance during therapy because of inadequate treatment, not taking the prescribed regimen appropriately (lack of compliance), or using low-quality medication.<ref name=OBrien>{{cite journal |author=O'Brien R |title=Drug-resistant tuberculosis: etiology, management and prevention |journal=Semin Respir Infect |volume=9 |issue=2 |pages=104–12 |year=1994|pmid = 7973169}}</ref> Drug-resistant TB is a serious public health issue in many developing countries, as its treatment is longer and requires more expensive drugs. MDR-TB is defined as resistance to the two most effective first-line TB drugs: rifampicin and isoniazid. [[Extensively drug-resistant tuberculosis|Extensively drug-resistant TB]] is also resistant to three or more of the six classes of second-line drugs.<ref name="MMWR2006">{{cite journal |title=Emergence of ''Mycobacterium tuberculosis'' with extensive resistance to second-line drugs—worldwide, 2000–2004 |journal=MMWR Morb Mortal Wkly Rep |volume=55 |issue=11 |pages=301–5 |year=2006 |url=http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5511a2.htm |pmid=16557213 |author=Centers for Disease Control and Prevention (CDC) |deadurl=no |archiveurl=https://web.archive.org/web/20170522030229/https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5511a2.htm |archivedate=22 May 2017 |df=dmy-all }}</ref> [[Totally drug-resistant tuberculosis|Totally drug-resistant TB]] is resistant to all currently used drugs.<ref name=TR2012>{{cite web|title=Totally Resistant TB: Earliest Cases in Italy|url=https://www.wired.com/wiredscience/2012/01/tdr-first-italy/|author=Maryn McKenna|date=12 January 2012|accessdate=12 January 2012|publisher=[[Wired (magazine)|Wired]]|deadurl=no|archiveurl=https://web.archive.org/web/20120114214156/http://www.wired.com/wiredscience/2012/01/tdr-first-italy/|archivedate=14 January 2012|df=dmy-all}}</ref> It was first observed in 2003 in Italy,<ref>{{cite journal|last1=Migliori|first1=G.B.|last2=De Iaco|first2=G.|last3=Besozzi|first3=G.|last4=Centis|first4=R.|last5=Cirillo|first5=D.M.|title=First tuberculosis cases in Italy resistant to all tested drugs|journal=Euro Surveillance|date=May 17, 2007|volume=12|issue=5|page=E070517.1.|pmid=17868596}}</ref> but not widely reported until 2012,<ref name=TR2012/><ref>{{cite web|title=Totally Drug-Resistant TB: a WHO consultation on the diagnostic definition and treatment options|url=http://www.who.int/tb/challenges/xdr/Report_Meeting_totallydrugresistantTB_032012.pdf?ua=1|website=who.int|publisher=World Health Organization|accessdate=25 March 2016|deadurl=no|archiveurl=https://web.archive.org/web/20161021151601/http://www.who.int/tb/challenges/xdr/Report_Meeting_totallydrugresistantTB_032012.pdf?ua=1|archivedate=21 October 2016|df=dmy-all}}</ref> and has also been found in Iran and India.<ref name="EIU 2014"/><ref>{{cite journal|last1=Velayati|first1=A.A.|last2=Masjedi|first2=M.R.|last3=Farnia|first3=P.|last4=Tabarsi|first4=P.|last5=Ghanavi|first5=J.|last6=Ziazarifi|first6=A.H.|last7=Hoffner|first7=S.E.|title=Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran|journal=Chest|date=August 2009|volume=136|issue=2|pages=420–425|doi=10.1378/chest.08-2427|pmid=19349380}}</ref> [[Bedaquiline]] is tentatively supported for use in multiple drug-resistant TB.<ref>{{cite web|title=Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug-Resistant Tuberculosis|url=http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6209a1.htm?s_cid=rr6209a1_x|deadurl=no|archiveurl=https://web.archive.org/web/20140104204359/http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6209a1.htm?s_cid=rr6209a1_x|archivedate=4 January 2014|df=dmy-all}}</ref>
-XDR-TB is a term sometimes used to define ''extensively resistant'' TB, and constitutes one in ten cases of MDR-TB. Cases of XDR TB have been identified in more than 90% of countries.<ref name="EIU 2014">{{cite journal|title=Ancient enemy, modern imperative – A time for greater action against tuberculosis|url=http://www.economistinsights.com/healthcare/analysis/ancient-enemy-modern-imperative|website=Economist Insights|publisher=The Economist Group|accessdate=1 August 2014|date=30 June 2014|author= Paul Kielstra|editor=Zoe Tabary}}</ref>
+XDR-TB is a term sometimes used to define ''extensively resistant'' TB, and constitutes one in ten cases of MDR-TB. Cases of XDR TB have been identified in more than 90% of countries.<ref name="EIU 2014">{{cite journal|title=Ancient enemy, modern imperative – A time for greater action against tuberculosis|url=http://www.economistinsights.com/healthcare/analysis/ancient-enemy-modern-imperative|website=Economist Insights|publisher=The Economist Group|accessdate=1 August 2014|date=30 June 2014|author=Paul Kielstra|editor=Zoe Tabary|deadurl=no|archiveurl=https://web.archive.org/web/20140731145650/http://www.economistinsights.com/healthcare/analysis/ancient-enemy-modern-imperative|archivedate=31 July 2014|df=dmy-all}}</ref>
 ==Prognosis==
-[[File:Tuberculosis world map - DALY - WHO2004.svg|thumb|upright=1.4|left|[[Age adjustment|Age-standardized]] [[disability-adjusted life year]]s caused by tuberculosis per 100,000&nbsp;inhabitants in 2004.<ref>{{cite web|url=http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |title=WHO Disease and injury country estimates |year=2004 |work=World Health Organization |accessdate=11 November 2009}}</ref>
+[[File:Tuberculosis world map - DALY - WHO2004.svg|thumb|upright=1.4|left|[[Age adjustment|Age-standardized]] [[disability-adjusted life year]]s caused by tuberculosis per 100,000&nbsp;inhabitants in 2004.<ref>{{cite web |url=http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |title=WHO Disease and injury country estimates |year=2004 |work=World Health Organization |accessdate=11 November 2009 |deadurl=no |archiveurl=https://web.archive.org/web/20091111101009/http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |archivedate=11 November 2009 |df=dmy-all }}</ref>
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-Roughly one-third of the world's population has been infected with ''M. tuberculosis'',<ref name=WHO2012data/> with new infections occurring in about 1% of the population each year.<ref name=WHO2002/> However, most infections with ''M. tuberculosis'' do not cause TB disease,<ref name=CDC>{{cite web|publisher=[[Centers for Disease Control]]|url=http://www.cdc.gov/tb/publications/factsheets/general/LTBIandActiveTB.htm|title=Fact Sheets: The Difference Between Latent TB Infection and Active TB Disease|date=20 June 2011|accessdate=26 July 2011}}</ref> and 90–95% of infections remain asymptomatic.<ref name=Book90/> In 2012, an estimated 8.6 million chronic cases were active.<ref>{{cite web|title=Global tuberculosis report 2013|url=http://www.who.int/tb/publications/global_report/en/index.html|work=World Health Organization|year=2013}}</ref> In 2010, 8.8 million new cases of TB were diagnosed, and 1.20–1.45 million deaths occurred, most of these occurring in [[Developing nation|developing countries]].<ref name=WHO2011/><ref name=Loz2012>{{cite journal|last=Lozano|first=R|title=Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010|journal=Lancet|date=15 December 2012|volume=380|issue=9859|pages=2095–128|pmid=23245604|doi=10.1016/S0140-6736(12)61728-0|hdl=10536/DRO/DU:30050819}}</ref> Of these 1.45 million deaths, about 0.35&nbsp;million occur in those also infected with HIV.<ref name=WHO2011Control>{{cite web|title=Global Tuberculosis Control 2011 |url=http://www.who.int/tb/publications/global_report/2011/gtbr11_full.pdf |work=World Health Organization |accessdate=15 April 2012 |deadurl=yes |archiveurl=https://web.archive.org/web/20120617064025/http://www.who.int/tb/publications/global_report/2011/gtbr11_full.pdf |archivedate=17 June 2012 |df= }}</ref>
+Roughly one-third of the world's population has been infected with ''M. tuberculosis'',<ref name=WHO2012data/> with new infections occurring in about 1% of the population each year.<ref name=WHO2002/> However, most infections with ''M. tuberculosis'' do not cause TB disease,<ref name=CDC>{{cite web|publisher=[[Centers for Disease Control]]|url=http://www.cdc.gov/tb/publications/factsheets/general/LTBIandActiveTB.htm|title=Fact Sheets: The Difference Between Latent TB Infection and Active TB Disease|date=20 June 2011|accessdate=26 July 2011|deadurl=no|archiveurl=https://web.archive.org/web/20110804005502/http://www.cdc.gov/tb/publications/factsheets/general/LTBIandActiveTB.htm|archivedate=4 August 2011|df=dmy-all}}</ref> and 90–95% of infections remain asymptomatic.<ref name=Book90/> In 2012, an estimated 8.6 million chronic cases were active.<ref>{{cite web|title=Global tuberculosis report 2013|url=http://www.who.int/tb/publications/global_report/en/index.html|work=World Health Organization|year=2013|deadurl=no|archiveurl=https://web.archive.org/web/20061212123736/http://www.who.int/tb/publications/global_report/en/index.html|archivedate=12 December 2006|df=dmy-all}}</ref> In 2010, 8.8 million new cases of TB were diagnosed, and 1.20–1.45 million deaths occurred, most of these occurring in [[Developing nation|developing countries]].<ref name=WHO2011/><ref name=Loz2012>{{cite journal|last=Lozano|first=R|title=Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010|journal=Lancet|date=15 December 2012|volume=380|issue=9859|pages=2095–128|pmid=23245604|doi=10.1016/S0140-6736(12)61728-0|hdl=10536/DRO/DU:30050819}}</ref> Of these 1.45 million deaths, about 0.35&nbsp;million occur in those also infected with HIV.<ref name=WHO2011Control>{{cite web|title=Global Tuberculosis Control 2011 |url=http://www.who.int/tb/publications/global_report/2011/gtbr11_full.pdf |work=World Health Organization |accessdate=15 April 2012 |deadurl=yes |archiveurl=https://web.archive.org/web/20120617064025/http://www.who.int/tb/publications/global_report/2011/gtbr11_full.pdf |archivedate=17 June 2012 |df= }}</ref>
 Tuberculosis is the second-most common cause of death from infectious disease (after those due to HIV/AIDS).<ref name=ID10/> The total number of tuberculosis cases has been decreasing since 2005, while new cases have decreased since 2002.<ref name=WHO2011/> China has achieved particularly dramatic progress, with about an 80% reduction in its TB mortality rate between 1990 and 2010.<ref name=WHO2011Control/> The number of new cases has declined by 17% between 2004 and 2014.<ref name="EIU 2014"/> Tuberculosis is more common in developing countries; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5–10% of the US population test positive.<ref name=Robbins/> Hopes of totally controlling the disease have been dramatically dampened because of a number of factors, including the difficulty of developing an effective vaccine, the expensive and time-consuming diagnostic process, the necessity of many months of treatment, the increase in HIV-associated tuberculosis, and the emergence of drug-resistant cases in the 1980s.<ref name=Lancet11/>
-In 2007, the country with the highest estimated incidence rate of TB was [[Swaziland]], with 1,200 cases per 100,000 people. India had the largest total incidence, with an estimated 2.0 million new cases.<ref name=WHO2009-Epidemiology>{{cite book |title=Global tuberculosis control: epidemiology, strategy, financing |author=World Health Organization |year=2009 |isbn=978-92-4-156380-2 |chapter=Epidemiology|chapterurl=http://who.int/entity/tb/publications/global_report/2009/pdf/chapter1.pdf |pages=6–33}}</ref> In developed countries, tuberculosis is less common and is found mainly in urban areas. Rates per 100,000 people in different areas of the world were: globally 178, Africa 332, the Americas 36, Eastern Mediterranean 173, Europe 63, Southeast Asia 278, and Western Pacific 139 in 2010.<ref name=WHO2011Control/> In Canada and Australia, tuberculosis is many times more common among the [[aboriginal peoples]], especially in remote areas.<ref>{{cite journal|last=FitzGerald|first=JM|author2=Wang, L |author3=Elwood, RK |title=Tuberculosis: 13. Control of the disease among aboriginal people in Canada|journal=Canadian Medical Association Journal |date=8 February 2000|volume=162|issue=3|pages=351–5|pmid=10693593|pmc=1231016}}</ref><ref>{{cite book |author1=Quah, Stella R. |author2=Carrin, Guy |author3=Buse, Kent |author4=Kristian Heggenhougen |title=Health Systems Policy, Finance, and Organization |publisher=Academic Press |location=Boston |year=2009 |pages=424 |isbn=0-12-375087-3 |oclc= |url=https://books.google.com/books?id=IEXUrc0tr1wC&pg=PA424}}</ref> In the United States [[Native Americans in the United States|Native Americans]] have a fivefold greater mortality from TB,<ref>{{cite book |author= Anne-Emanuelle Birn |title= Textbook of International Health: Global Health in a Dynamic World |year=2009 |pages=261 |isbn= 9780199885213 |url=https://books.google.com/books?id=2XBB4-eYGZIC&pg=PT261  |doi= |accessdate=}}</ref> and racial and ethnic minorities accounted for 84% of all reported TB cases.<ref>{{cite web|author=Centers for Disease Control and Prevention|url=http://www.cdc.gov/tb/statistics/surv/surv2012/slides/surv12.htm|title=CDC Surveillance Slides 2012 – TB}}</ref>
+In 2007, the country with the highest estimated incidence rate of TB was [[Swaziland]], with 1,200 cases per 100,000 people. India had the largest total incidence, with an estimated 2.0 million new cases.<ref name=WHO2009-Epidemiology>{{cite book |title=Global tuberculosis control: epidemiology, strategy, financing |author=World Health Organization |year=2009 |isbn=978-92-4-156380-2 |chapter=Epidemiology|chapterurl=http://who.int/entity/tb/publications/global_report/2009/pdf/chapter1.pdf |pages=6–33}}</ref> In developed countries, tuberculosis is less common and is found mainly in urban areas. Rates per 100,000 people in different areas of the world were: globally 178, Africa 332, the Americas 36, Eastern Mediterranean 173, Europe 63, Southeast Asia 278, and Western Pacific 139 in 2010.<ref name=WHO2011Control/> In Canada and Australia, tuberculosis is many times more common among the [[aboriginal peoples]], especially in remote areas.<ref>{{cite journal|last=FitzGerald|first=JM|author2=Wang, L |author3=Elwood, RK |title=Tuberculosis: 13. Control of the disease among aboriginal people in Canada|journal=Canadian Medical Association Journal |date=8 February 2000|volume=162|issue=3|pages=351–5|pmid=10693593|pmc=1231016}}</ref><ref>{{cite book |author1=Quah, Stella R. |author2=Carrin, Guy |author3=Buse, Kent |author4=Kristian Heggenhougen |title=Health Systems Policy, Finance, and Organization |publisher=Academic Press |location=Boston |year=2009 |pages=424 |isbn=0-12-375087-3 |oclc= |url=https://books.google.com/books?id=IEXUrc0tr1wC&pg=PA424 |deadurl=no |archiveurl=https://web.archive.org/web/20150906220918/https://books.google.com/books?id=IEXUrc0tr1wC&pg=PA424 |archivedate=6 September 2015 |df=dmy-all }}</ref> In the United States [[Native Americans in the United States|Native Americans]] have a fivefold greater mortality from TB,<ref>{{cite book |author= Anne-Emanuelle Birn |title= Textbook of International Health: Global Health in a Dynamic World |year= 2009 |pages= 261 |isbn= 9780199885213 |url= https://books.google.com/books?id=2XBB4-eYGZIC&pg=PT261 |doi=  |accessdate=  |deadurl= no |archiveurl= https://web.archive.org/web/20150906213750/https://books.google.com/books?id=2XBB4-eYGZIC&pg=PT261 |archivedate= 6 September 2015 |df= dmy-all }}</ref> and racial and ethnic minorities accounted for 84% of all reported TB cases.<ref>{{cite web|author=Centers for Disease Control and Prevention|url=http://www.cdc.gov/tb/statistics/surv/surv2012/slides/surv12.htm|title=CDC Surveillance Slides 2012 – TB|deadurl=no|archiveurl=https://web.archive.org/web/20131109150519/http://www.cdc.gov/tb/statistics/surv/surv2012/slides/surv12.htm|archivedate=9 November 2013|df=dmy-all}}</ref>
-The rates of TB varies with age. In Africa, it primarily affects adolescents and young adults.<ref>{{cite web|author=World Health Organization |url=http://www.who.int/tb/publications/global_report/2006/pdf/full_report_correctedversion.pdf |title=Global Tuberculosis Control Report, 2006 – Annex 1 Profiles of high-burden countries |format=PDF |accessdate=13 October 2006 |deadurl=yes |archiveurl=https://web.archive.org/web/20090726124358/http://www.who.int/tb/publications/global_report/2006/pdf/full_report_correctedversion.pdf |archivedate=26 July 2009 |df= }}</ref> However, in countries where incidence rates have declined dramatically (such as the United States), TB is mainly a disease of older people and the immunocompromised (risk factors are listed above).<ref name=Robbins/><ref>{{cite web|author=Centers for Disease Control and Prevention|url=http://www.cdc.gov/nchstp/tb/pubs/slidesets/surv/surv2005/default.htm|title=2005 Surveillance Slide Set|date=12 September 2006|accessdate=13 October 2006}}</ref>
+The rates of TB varies with age. In Africa, it primarily affects adolescents and young adults.<ref>{{cite web|author=World Health Organization |url=http://www.who.int/tb/publications/global_report/2006/pdf/full_report_correctedversion.pdf |title=Global Tuberculosis Control Report, 2006 – Annex 1 Profiles of high-burden countries |format=PDF |accessdate=13 October 2006 |deadurl=yes |archiveurl=https://web.archive.org/web/20090726124358/http://www.who.int/tb/publications/global_report/2006/pdf/full_report_correctedversion.pdf |archivedate=26 July 2009 |df= }}</ref> However, in countries where incidence rates have declined dramatically (such as the United States), TB is mainly a disease of older people and the immunocompromised (risk factors are listed above).<ref name=Robbins/><ref>{{cite web|author=Centers for Disease Control and Prevention|url=http://www.cdc.gov/nchstp/tb/pubs/slidesets/surv/surv2005/default.htm|title=2005 Surveillance Slide Set|date=12 September 2006|accessdate=13 October 2006|deadurl=no|archiveurl=https://web.archive.org/web/20061123122326/http://www.cdc.gov/nchstp/tb/pubs/slidesets/surv/surv2005/default.htm|archivedate=23 November 2006|df=dmy-all}}</ref>
 Worldwide, 22 "high-burden" states or countries together experience 80% of cases as well as 83% of deaths.<ref name="EIU 2014"/>
@@ Line 192: / Line 192: @@
 Tuberculosis has been present in humans since [[Ancient history|antiquity]].<ref name=Lancet11/> The earliest unambiguous detection of ''M. tuberculosis'' involves evidence of the disease in the remains of bison in Wyoming dated to around 17,000 years ago.<ref>{{cite journal |author=Rothschild BM |title=Mycobacterium tuberculosis complex DNA from an extinct bison dated 17,000 years before the present |journal=Clin. Infect. Dis. |volume=33 |issue=3 |pages=305–11 |date=August 2001 |pmid=11438894 |doi=10.1086/321886 |url=http://www.journals.uchicago.edu/cgi-bin/resolve?CID001531 |name-list-format=vanc|author2=Martin LD |author3=Lev G |display-authors=3 |last4=Bercovier |first4=Helen |last5=Bar‐Gal |first5=Gila Kahila |last6=Greenblatt |first6=Charles |last7=Donoghue |first7=Helen |last8=Spigelman |first8=Mark |last9=Brittain |first9=David}}</ref> However, whether tuberculosis originated in bovines, then was transferred to humans, or whether it diverged from a common ancestor, is currently unclear.<ref>{{cite journal |author=Pearce-Duvet J |title=The origin of human pathogens: evaluating the role of agriculture and domestic animals in the evolution of human disease |journal=Biol Rev Camb Philos Soc |volume=81 |issue=3 |pages=369–82 |year=2006|pmid = 16672105 |doi=10.1017/S1464793106007020}}</ref> A comparison of the [[gene]]s of ''M. tuberculosis'' complex (MTBC) in humans to MTBC in animals suggests humans did not acquire MTBC from animals during animal domestication, as was previously believed. Both strains of the tuberculosis bacteria share a common ancestor, which could have infected humans even before the [[Neolithic Revolution]].<ref>{{cite journal|last=Comas|first=I|author2=Gagneux, S |title=The past and future of tuberculosis research|journal=PLoS Pathogens|date=October 2009|volume=5|issue=10|pages=e1000600|pmid=19855821|doi=10.1371/journal.ppat.1000600|pmc=2745564|editor1-last=Manchester|editor1-first=Marianne}}</ref> Skeletal remains show prehistoric humans (4000 [[Common Era|BC]]) had TB, and researchers have found tubercular decay in the spines of [[Egypt]]ian [[mummy|mummies]] dating from 3000–2400 BC.<ref>{{cite journal |vauthors=Zink A, Sola C, Reischl U, Grabner W, Rastogi N, Wolf H, Nerlich A |title=Characterization of Mycobacterium tuberculosis Complex DNAs from Egyptian Mummies by Spoligotyping |journal=J Clin Microbiol |volume=41 |issue=1 |pages=359–67 |year=2003 |pmid=12517873 |doi=10.1128/JCM.41.1.359-367.2003 |pmc=149558}}</ref> Genetic studies suggest TB was present in [[the Americas]] from about 100 AD.<ref>{{cite journal |vauthors=Konomi N, Lebwohl E, Mowbray K, Tattersall I, Zhang D |title=Detection of Mycobacterial DNA in Andean Mummies |journal=J Clin Microbiol |volume=40 |issue=12 |pages=4738–40 |year=2002 |pmid=12454182 |doi=10.1128/JCM.40.12.4738-4740.2002 |pmc=154635}}</ref>
-Before the [[Industrial Revolution]], folklore often associated tuberculosis with [[vampire]]s. When one member of a family died from it, the other infected members would lose their health slowly. People believed this was caused by the original person with TB draining the life from the other family members.<ref name=sledzik>{{cite journal |last=Sledzik |first=Paul S. |author2=Nicholas Bellantoni  |date=June 1994 |title=Bioarcheological and biocultural evidence for the New England vampire folk belief |journal=American Journal of Physical Anthropology |volume=94 |issue=2 |pages=269–274 |doi=10.1002/ajpa.1330940210 |url=http://www.yorku.ca/kdenning/+++2150%202007-8/sledzik%20vampire.pdf |format=PDF|pmid=8085617 }}</ref>
+Before the [[Industrial Revolution]], folklore often associated tuberculosis with [[vampire]]s. When one member of a family died from it, the other infected members would lose their health slowly. People believed this was caused by the original person with TB draining the life from the other family members.<ref name=sledzik>{{cite journal |last=Sledzik |first=Paul S. |author2=Nicholas Bellantoni |date=June 1994 |title=Bioarcheological and biocultural evidence for the New England vampire folk belief |journal=American Journal of Physical Anthropology |volume=94 |issue=2 |pages=269–274 |doi=10.1002/ajpa.1330940210 |url=http://www.yorku.ca/kdenning/+++2150%202007-8/sledzik%20vampire.pdf |format=PDF |pmid=8085617 |deadurl=no |archiveurl=https://web.archive.org/web/20170218082115/http://www.yorku.ca/kdenning/+++2150%202007-8/sledzik%20vampire.pdf |archivedate=18 February 2017 |df=dmy-all }}</ref>
-Although the pulmonary form associated with [[tubercle (anatomy)|tubercles]] was established as a pathology by [[Dr Richard Morton|Richard Morton]] in 1689,<ref name="WhoNamedIt-Calmette">{{WhoNamedIt|doctor|2413|Léon Charles Albert Calmette}}</ref><ref name="MedHist1970-Trail">{{cite journal |author=Trail RR |title=Richard Morton (1637–1698) |journal=Med Hist |volume=14 |issue=2 |pages=166–74 |date=April 1970 |pmid=4914685 |pmc=1034037 |doi=10.1017/S0025727300015350 }}</ref> due to the variety of its symptoms, TB was not identified as a single disease until the 1820s. It was not named "tuberculosis" until 1839, by [[Johann Lukas Schönlein|J. L. Schönlein]].<ref>''Zur Pathogenie der Impetigines. Auszug aus einer brieflichen Mitteilung an den Herausgeber''. [Müller's] ''Archiv für Anatomie, Physiologie und wissenschaftliche Medicin''. 1839, page 82.</ref> During 1838–1845, Dr. John Croghan, the owner of [[Mammoth Cave]], brought a number of people with tuberculosis into the cave in the hope of curing the disease with the constant temperature and purity of the cave air; they died within a year.<ref>[http://edition.cnn.com/2004/TRAVEL/DESTINATIONS/02/26/mammoth.cave.ap/index.html Kentucky: Mammoth Cave long on history.] ''[[CNN]]''. 27 February 2004. Accessed 8 October 2006.</ref> Hermann Brehmer opened the first TB [[sanatorium]] in 1859 in Görbersdorf (now [[Sokołowsko]]), [[Silesia]].<ref name =sanatoria>{{cite journal |author=McCarthy OR |title=The key to the sanatoria |journal=J R Soc Med |volume=94 |issue=8 |pages=413–7 |date=August 2001 |pmid=11461990 |pmc=1281640 |url=http://www.jrsm.org/cgi/pmidlookup?view=long&pmid=11461990}}</ref>
+Although the pulmonary form associated with [[tubercle (anatomy)|tubercles]] was established as a pathology by [[Dr Richard Morton|Richard Morton]] in 1689,<ref name="WhoNamedIt-Calmette">{{WhoNamedIt|doctor|2413|Léon Charles Albert Calmette}}</ref><ref name="MedHist1970-Trail">{{cite journal |author=Trail RR |title=Richard Morton (1637–1698) |journal=Med Hist |volume=14 |issue=2 |pages=166–74 |date=April 1970 |pmid=4914685 |pmc=1034037 |doi=10.1017/S0025727300015350 }}</ref> due to the variety of its symptoms, TB was not identified as a single disease until the 1820s. It was not named "tuberculosis" until 1839, by [[Johann Lukas Schönlein|J. L. Schönlein]].<ref>''Zur Pathogenie der Impetigines. Auszug aus einer brieflichen Mitteilung an den Herausgeber''. [Müller's] ''Archiv für Anatomie, Physiologie und wissenschaftliche Medicin''. 1839, page 82.</ref> During 1838–1845, Dr. John Croghan, the owner of [[Mammoth Cave]], brought a number of people with tuberculosis into the cave in the hope of curing the disease with the constant temperature and purity of the cave air; they died within a year.<ref>[http://edition.cnn.com/2004/TRAVEL/DESTINATIONS/02/26/mammoth.cave.ap/index.html Kentucky: Mammoth Cave long on history.] {{webarchive|url=https://web.archive.org/web/20060813140746/http://edition.cnn.com/2004/TRAVEL/DESTINATIONS/02/26/mammoth.cave.ap/index.html |date=13 August 2006 }} ''[[CNN]]''. 27 February 2004. Accessed 8 October 2006.</ref> Hermann Brehmer opened the first TB [[sanatorium]] in 1859 in Görbersdorf (now [[Sokołowsko]]), [[Silesia]].<ref name =sanatoria>{{cite journal |author=McCarthy OR |title=The key to the sanatoria |journal=J R Soc Med |volume=94 |issue=8 |pages=413–7 |date=August 2001 |pmid=11461990 |pmc=1281640 |url=http://www.jrsm.org/cgi/pmidlookup?view=long&pmid=11461990}}</ref>
 [[File:RobertKoch.jpg|upright|thumb|left|Robert Koch discovered the tuberculosis bacillus.]]
-The bacillus causing tuberculosis, ''M. tuberculosis'', was identified and described on 24 March 1882 by [[Robert Koch]]. He received the [[Nobel Prize in physiology or medicine]] in 1905 for this discovery.<ref>[[Nobel Foundation]]. [http://nobelprize.org/nobel_prizes/medicine/laureates/1905/ The Nobel Prize in Physiology or Medicine 1905.] Accessed 7 October 2006.</ref> Koch did not believe the bovine (cattle) and human tuberculosis diseases were similar, which delayed the recognition of infected milk as a source of infection. Later, the risk of transmission from this source was dramatically reduced by the invention of the [[pasteurization]] process. Koch announced a [[glycerine]] extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it "tuberculin". While it was not effective, it was later successfully adapted as a screening test for the presence of pre-symptomatic tuberculosis.<ref>{{cite journal |author=Waddington K |title=To stamp out "So Terrible a Malady": bovine tuberculosis and tuberculin testing in Britain, 1890–1939 |journal=Med Hist |volume=48 |issue=1 |pages=29–48 |date=January 2004 |pmid=14968644 |pmc=546294 |doi=10.1017/S0025727300007043 }}</ref> The [[World Tuberculosis Day]] was established on 24 March for this reason.
+The bacillus causing tuberculosis, ''M. tuberculosis'', was identified and described on 24 March 1882 by [[Robert Koch]]. He received the [[Nobel Prize in physiology or medicine]] in 1905 for this discovery.<ref>[[Nobel Foundation]]. [http://nobelprize.org/nobel_prizes/medicine/laureates/1905/ The Nobel Prize in Physiology or Medicine 1905.] {{webarchive|url=https://web.archive.org/web/20061210184150/http://nobelprize.org/nobel_prizes/medicine/laureates/1905/ |date=10 December 2006 }} Accessed 7 October 2006.</ref> Koch did not believe the bovine (cattle) and human tuberculosis diseases were similar, which delayed the recognition of infected milk as a source of infection. Later, the risk of transmission from this source was dramatically reduced by the invention of the [[pasteurization]] process. Koch announced a [[glycerine]] extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it "tuberculin". While it was not effective, it was later successfully adapted as a screening test for the presence of pre-symptomatic tuberculosis.<ref>{{cite journal |author=Waddington K |title=To stamp out "So Terrible a Malady": bovine tuberculosis and tuberculin testing in Britain, 1890–1939 |journal=Med Hist |volume=48 |issue=1 |pages=29–48 |date=January 2004 |pmid=14968644 |pmc=546294 |doi=10.1017/S0025727300007043 }}</ref> The [[World Tuberculosis Day]] was established on 24 March for this reason.
 [[Albert Calmette]] and [[Camille Guérin]] achieved the first genuine success in immunization against tuberculosis in 1906, using attenuated bovine-strain tuberculosis. It was called [[BCG vaccine|bacille Calmette–Guérin]] (BCG). The BCG vaccine was first used on humans in 1921 in France,<ref name=Bonah>{{cite journal |author=Bonah C |title=The 'experimental stable' of the BCG vaccine: safety, efficacy, proof, and standards, 1921–1933 |journal=Stud Hist Philos Biol Biomed Sci |volume=36 |issue=4 |pages=696–721 |year=2005 |pmid=16337557|doi=10.1016/j.shpsc.2005.09.003}}</ref> but received widespread acceptance in the US, Great Britain, and Germany only after World War II.<ref name=Comstock>{{cite journal |author=Comstock G |title=The International Tuberculosis Campaign: a pioneering venture in mass vaccination and research |journal=Clin Infect Dis |volume=19 |issue=3 |pages=528–40 |year=1994|pmid=7811874 |doi=10.1093/clinids/19.3.528}}</ref>
-Tuberculosis caused widespread public concern in the 19th and early 20th centuries as the disease became common among the urban poor. In 1815, one in four deaths in England was due to "consumption". By 1918, one in six deaths in France was still caused by TB. After TB was determined to be contagious, in the 1880s, it was put on a [[List of notifiable diseases|notifiable disease]] list in Britain; campaigns were started to stop people from spitting in public places, and the infected poor were "encouraged" to enter [[sanatorium|sanatoria]] that resembled prisons (the sanatoria for the middle and upper classes offered excellent care and constant medical attention).<ref name =sanatoria/> Whatever the benefits of the "fresh air" and labor in the sanatoria, even under the best conditions, 50% of those who entered died within five years (c. 1916).<ref name =sanatoria/> When the [[Medical Research Council (UK)|Medical Research Council]] was formed in Britain in 1913, its initial focus was tuberculosis research.<ref>{{cite book|last=editor|first=Caroline Hannaway,|title=Biomedicine in the twentieth century: practices, policies, and politics|year=2008|publisher=IOS Press|location=Amsterdam|isbn=978-1-58603-832-8|pages=233|url=https://books.google.com/books?id=o5HBxyg5APIC&pg=PA233}}</ref>
+Tuberculosis caused widespread public concern in the 19th and early 20th centuries as the disease became common among the urban poor. In 1815, one in four deaths in England was due to "consumption". By 1918, one in six deaths in France was still caused by TB. After TB was determined to be contagious, in the 1880s, it was put on a [[List of notifiable diseases|notifiable disease]] list in Britain; campaigns were started to stop people from spitting in public places, and the infected poor were "encouraged" to enter [[sanatorium|sanatoria]] that resembled prisons (the sanatoria for the middle and upper classes offered excellent care and constant medical attention).<ref name =sanatoria/> Whatever the benefits of the "fresh air" and labor in the sanatoria, even under the best conditions, 50% of those who entered died within five years (c. 1916).<ref name =sanatoria/> When the [[Medical Research Council (UK)|Medical Research Council]] was formed in Britain in 1913, its initial focus was tuberculosis research.<ref>{{cite book|last=editor|first=Caroline Hannaway,|title=Biomedicine in the twentieth century: practices, policies, and politics|year=2008|publisher=IOS Press|location=Amsterdam|isbn=978-1-58603-832-8|pages=233|url=https://books.google.com/books?id=o5HBxyg5APIC&pg=PA233|deadurl=no|archiveurl=https://web.archive.org/web/20150907185226/https://books.google.com/books?id=o5HBxyg5APIC&pg=PA233|archivedate=7 September 2015|df=dmy-all}}</ref>
 <!-- Effective management -->
-In Europe, rates of tuberculosis began to rise in the early 1600s to a peak level in the 1800s, when it caused nearly 25% of all deaths.<ref>{{cite book|last=Bloom|first=editor, Barry R.|title=Tuberculosis: pathogenesis, protection, and control|year=1994|publisher=ASM Press|location=Washington, D.C.|isbn=978-1-55581-072-6}}</ref> By the 1950s, mortality in Europe had decreased about 90%.<ref name=Per2010>{{cite book|last=Persson|first=Sheryl|title=Smallpox, Syphilis and Salvation: Medical Breakthroughs That Changed the World|year=2010|publisher=ReadHowYouWant.com|isbn=978-1-4587-6712-7|pages=141|url=https://books.google.com/books?id=-W7ch1d6JOoC&pg=PA141}}</ref> Improvements in sanitation, vaccination, and other public health measures began significantly reducing rates of tuberculosis even before the arrival of [[streptomycin]] and other antibiotics, although the disease remained a significant threat.<ref name=Per2010/> In 1946, the development of the antibiotic [[streptomycin]] made effective treatment and cure of TB a reality. Prior to the introduction of this medication, the only treatment was surgical intervention, including the "[[pneumothorax]] technique", which involved collapsing an infected lung to "rest" it and allow tuberculous lesions to heal.<ref>{{cite book|last=Shields|first=Thomas|title=General thoracic surgery|year=2009|publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins|location=Philadelphia|isbn=978-0-7817-7982-1|pages=792|url=https://books.google.com/books?id=bVEEHmpU-1wC&pg=PA792|edition=7th}}</ref>
+In Europe, rates of tuberculosis began to rise in the early 1600s to a peak level in the 1800s, when it caused nearly 25% of all deaths.<ref>{{cite book|last=Bloom|first=editor, Barry R.|title=Tuberculosis: pathogenesis, protection, and control|year=1994|publisher=ASM Press|location=Washington, D.C.|isbn=978-1-55581-072-6}}</ref> By the 1950s, mortality in Europe had decreased about 90%.<ref name=Per2010>{{cite book|last=Persson|first=Sheryl|title=Smallpox, Syphilis and Salvation: Medical Breakthroughs That Changed the World|year=2010|publisher=ReadHowYouWant.com|isbn=978-1-4587-6712-7|pages=141|url=https://books.google.com/books?id=-W7ch1d6JOoC&pg=PA141|deadurl=no|archiveurl=https://web.archive.org/web/20150906192102/https://books.google.com/books?id=-W7ch1d6JOoC&pg=PA141|archivedate=6 September 2015|df=dmy-all}}</ref> Improvements in sanitation, vaccination, and other public health measures began significantly reducing rates of tuberculosis even before the arrival of [[streptomycin]] and other antibiotics, although the disease remained a significant threat.<ref name=Per2010/> In 1946, the development of the antibiotic [[streptomycin]] made effective treatment and cure of TB a reality. Prior to the introduction of this medication, the only treatment was surgical intervention, including the "[[pneumothorax]] technique", which involved collapsing an infected lung to "rest" it and allow tuberculous lesions to heal.<ref>{{cite book|last=Shields|first=Thomas|title=General thoracic surgery|year=2009|publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins|location=Philadelphia|isbn=978-0-7817-7982-1|pages=792|url=https://books.google.com/books?id=bVEEHmpU-1wC&pg=PA792|edition=7th|deadurl=no|archiveurl=https://web.archive.org/web/20150906212146/https://books.google.com/books?id=bVEEHmpU-1wC&pg=PA792|archivedate=6 September 2015|df=dmy-all}}</ref>
 <!-- Current reemergence -->
@@ Line 216: / Line 216: @@
 ''Phthisis'' (Φθισις) is a Greek word for consumption, an old term for pulmonary tuberculosis;<ref name=Cha1998/> around 460 BCE, [[Hippocrates]] described phthisis as a disease of dry seasons.<ref>{{cite web|title=Hippocrates 3.16 Classics, MIT |url=http://classics.mit.edu/Hippocrates/aphorisms.mb.txt |accessdate=15 December 2015 |deadurl=unfit |archiveurl=https://web.archive.org/web/20050211173218/http://classics.mit.edu/Hippocrates/aphorisms.mb.txt |archivedate=11 February 2005 }}</ref> The abbreviation "TB" is short for ''tubercle [[Bacillus (shape)|bacillus]]''.
-"Consumption" was the most common nineteenth century English word for the disease. The Latin root "con" meaning "completely" is linked to "sumere" meaning "to take up from under."<ref>{{cite book|last1=Caldwell|first1=Mark|title=The Last Crusade|date=1988|publisher=Macmillan|location=New York|isbn=0689118104|page=21}}</ref> In The Life and Death of Mr. Badman by [[John Bunyan]], the author calls consumption "the captain of all these men of death."<ref>{{cite book|last1=Bunyan|first1=John|date=1808|title=The Life and Death of Mr. Badman|url=https://books.google.com/books?id=TAYDAAAAQAAJ&q=tence&dq=related:HARVARDHWKHFR&lr=&source=gbs_word_cloud_r#v=onepage&q=captain&f=false|page=244|location=London|publisher=W. Nicholson|via=Google Books|accessdate=28 September 2016}}</ref>
+"Consumption" was the most common nineteenth century English word for the disease. The Latin root "con" meaning "completely" is linked to "sumere" meaning "to take up from under."<ref>{{cite book|last1=Caldwell|first1=Mark|title=The Last Crusade|date=1988|publisher=Macmillan|location=New York|isbn=0689118104|page=21}}</ref> In The Life and Death of Mr. Badman by [[John Bunyan]], the author calls consumption "the captain of all these men of death."<ref>{{cite book|last1=Bunyan|first1=John|date=1808|title=The Life and Death of Mr. Badman|url=https://books.google.com/books?id=TAYDAAAAQAAJ&q=tence&dq=related:HARVARDHWKHFR&lr=&source=gbs_word_cloud_r#v=onepage&q=captain&f=false|page=244|location=London|publisher=W. Nicholson|via=Google Books|accessdate=28 September 2016|deadurl=no|archiveurl=https://web.archive.org/web/20170910150141/https://books.google.com/books?id=TAYDAAAAQAAJ&q=tence&dq=related%3AHARVARDHWKHFR&lr=&source=gbs_word_cloud_r#v=onepage&q=captain&f=false|archivedate=10 September 2017|df=dmy-all}}</ref>
 ===Public health efforts===
-The [[World Health Organization]], [[Bill and Melinda Gates Foundation]], and US government are subsidizing a fast-acting diagnostic tuberculosis test for use in low- and middle-income countries.<ref name=PressRelease2012/><ref name=Xpert2011>{{cite journal|last=Lawn|first=SD|author2=Nicol, MP |title=Xpert® MTB/RIF assay: development, evaluation and implementation of a new rapid molecular diagnostic for tuberculosis and rifampicin resistance|journal=Future microbiology|date=September 2011|volume=6|issue=9|pages=1067–82|pmid=21958145|doi=10.2217/fmb.11.84|pmc=3252681}}</ref><ref>{{cite news|url=https://www.reuters.com/article/idUSTRE6B71RF20101208 |title=WHO says Cepheid rapid test will transform TB care |work= Reuters | date=8 December 2010}}</ref> In addition to being fast-acting, the test can determine if there is resistance to the antibiotic rifampicin which may indicate multi-drug resistant tuberculosis and is accurate in those who are also infected with HIV.<ref name=PressRelease2012>{{cite web|title=Public-Private Partnership Announces Immediate 40 Percent Cost Reduction for Rapid TB Test|url=http://www.who.int/tb/features_archive/GeneXpert_press_release_final.pdf|work=World Health Organization|format=pdf|date=6 August 2012}}</ref><ref>{{cite web|title=The Stop TB Partnership, which operates through a secretariat hosted by the World Health Organization (WHO) in Geneva, Switzerland.|url=http://www.stoptb.org/wg/gli/assets/documents/map/XpertPublications.pdf|author=STOPTB|format=pdf|date=5 April 2013}}</ref> Many resource-poor places as of 2011 have access to only sputum microscopy.<ref>{{cite journal|last=Lienhardt|first=C|author2=Espinal, M |author3=Pai, M |author4=Maher, D |author5=Raviglione, MC |title=What research is needed to stop TB? Introducing the TB Research Movement|journal=PLOS Medicine|date=November 2011|volume=8|issue=11|pages=e1001135|pmid=22140369|doi=10.1371/journal.pmed.1001135|pmc=3226454}}</ref>
+The [[World Health Organization]], [[Bill and Melinda Gates Foundation]], and US government are subsidizing a fast-acting diagnostic tuberculosis test for use in low- and middle-income countries.<ref name=PressRelease2012/><ref name=Xpert2011>{{cite journal|last=Lawn|first=SD|author2=Nicol, MP |title=Xpert® MTB/RIF assay: development, evaluation and implementation of a new rapid molecular diagnostic for tuberculosis and rifampicin resistance|journal=Future microbiology|date=September 2011|volume=6|issue=9|pages=1067–82|pmid=21958145|doi=10.2217/fmb.11.84|pmc=3252681}}</ref><ref>{{cite news |url=https://www.reuters.com/article/idUSTRE6B71RF20101208 |title=WHO says Cepheid rapid test will transform TB care |work=Reuters |date=8 December 2010 |deadurl=no |archiveurl=https://web.archive.org/web/20101211140847/http://www.reuters.com/article/idUSTRE6B71RF20101208 |archivedate=11 December 2010 |df=dmy-all }}</ref> In addition to being fast-acting, the test can determine if there is resistance to the antibiotic rifampicin which may indicate multi-drug resistant tuberculosis and is accurate in those who are also infected with HIV.<ref name=PressRelease2012>{{cite web|title=Public-Private Partnership Announces Immediate 40 Percent Cost Reduction for Rapid TB Test|url=http://www.who.int/tb/features_archive/GeneXpert_press_release_final.pdf|work=World Health Organization|format=pdf|date=6 August 2012|deadurl=no|archiveurl=https://web.archive.org/web/20131029234310/http://www.who.int/tb/features_archive/GeneXpert_press_release_final.pdf|archivedate=29 October 2013|df=dmy-all}}</ref><ref>{{cite web|title=The Stop TB Partnership, which operates through a secretariat hosted by the World Health Organization (WHO) in Geneva, Switzerland.|url=http://www.stoptb.org/wg/gli/assets/documents/map/XpertPublications.pdf|author=STOPTB|format=pdf|date=5 April 2013|deadurl=no|archiveurl=https://web.archive.org/web/20140124041952/http://www.stoptb.org/wg/gli/assets/documents/map/XpertPublications.pdf|archivedate=24 January 2014|df=dmy-all}}</ref> Many resource-poor places as of 2011 have access to only sputum microscopy.<ref>{{cite journal|last=Lienhardt|first=C|author2=Espinal, M |author3=Pai, M |author4=Maher, D |author5=Raviglione, MC |title=What research is needed to stop TB? Introducing the TB Research Movement|journal=PLOS Medicine|date=November 2011|volume=8|issue=11|pages=e1001135|pmid=22140369|doi=10.1371/journal.pmed.1001135|pmc=3226454}}</ref>
-India had the highest total number of TB cases worldwide in 2010, in part due to poor disease management within the private and public health care sector.<ref>{{cite journal|last=Mishra|first=G|title=Tuberculosis Prescription Practices In Private And Public Sector In India|journal=NJIRM|year=2013|volume=4|issue=2|pages=71–78|url=http://www.scopemed.org/?mno=36915}}</ref> Programs such as the [[Revised National Tuberculosis Control Program]] are working to reduce TB levels amongst people receiving public health care.<ref name="Bhargava">{{cite journal |author1=Anurag Bhargava |author2=Lancelot Pinto |author3=Madhukar Pai |title=Mismanagement of tuberculosis in India: Causes, consequences, and the way forward |journal=Hypothesis |volume=9 |issue=1 |pages=e7 |year=2011 |url=http://www.hypothesisjournal.com/?p=989 |doi=10.5779/hypothesis.v9i1.214}}</ref><ref>{{cite journal|last=Amdekar|first=Y|title=Changes in the management of tuberculosis|journal=Indian journal of pediatrics|date=July 2009|volume=76|issue=7|pages=739–42|pmid=19693453|doi=10.1007/s12098-009-0164-4}}</ref>
+India had the highest total number of TB cases worldwide in 2010, in part due to poor disease management within the private and public health care sector.<ref>{{cite journal|last=Mishra|first=G|title=Tuberculosis Prescription Practices In Private And Public Sector In India|journal=NJIRM|year=2013|volume=4|issue=2|pages=71–78|url=http://www.scopemed.org/?mno=36915|deadurl=no|archiveurl=https://web.archive.org/web/20130510025039/http://www.scopemed.org/?mno=36915|archivedate=10 May 2013|df=dmy-all}}</ref> Programs such as the [[Revised National Tuberculosis Control Program]] are working to reduce TB levels amongst people receiving public health care.<ref name="Bhargava">{{cite journal |author1=Anurag Bhargava |author2=Lancelot Pinto |author3=Madhukar Pai |title=Mismanagement of tuberculosis in India: Causes, consequences, and the way forward |journal=Hypothesis |volume=9 |issue=1 |pages=e7 |year=2011 |url=http://www.hypothesisjournal.com/?p=989 |doi=10.5779/hypothesis.v9i1.214 |deadurl=no |archiveurl=https://web.archive.org/web/20120425233108/http://www.hypothesisjournal.com/?p=989 |archivedate=25 April 2012 |df=dmy-all }}</ref><ref>{{cite journal|last=Amdekar|first=Y|title=Changes in the management of tuberculosis|journal=Indian journal of pediatrics|date=July 2009|volume=76|issue=7|pages=739–42|pmid=19693453|doi=10.1007/s12098-009-0164-4}}</ref>
 A 2014 the [[Economist Intelligence Unit|EIU]]-healthcare report that the need to address apathy and urging for increased funding. The report cites among others Lucica Ditui "[TB] is like an orphan. It has been neglected even in countries with a high burden and often forgotten by donors and those investing in health interventions."<ref name="EIU 2014"/>
@@ Line 237: / Line 237: @@
 The BCG vaccine has limitations, and research to develop new TB vaccines is ongoing.<ref name=VacRes2011>{{cite journal|last=Martín Montañés|first=C.|author2=Gicquel, B.|title=New tuberculosis vaccines|journal=Enfermedades infecciosas y microbiologia clinica|date=March 2011|volume=29 Suppl 1|pages=57–62|pmid=21420568|doi=10.1016/S0213-005X(11)70019-2}}</ref> A number of potential candidates are currently in [[clinical trial|phase I and II clinical trials]].<ref name=VacRes2011/> Two main approaches are being used to attempt to improve the efficacy of available vaccines. One approach involves adding a subunit vaccine to BCG, while the other strategy is attempting to create new and better live vaccines.<ref name=VacRes2011/> [[MVA85A]], an example of a subunit vaccine, currently in trials in South Africa, is based on a genetically modified [[vaccinia]] virus.<ref name=Ibanga_2006>{{cite journal |author1=Ibanga H. |author2=Brookes R. |author3=Hill P. |author4=Owiafe P. |author5=Fletcher H. |author6=Lienhardt C. |author7=Hill A. |author8=Adegbola R. |author9=McShane H. |title=Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design|journal=Lancet Infectious Diseases|volume=6|issue=8|pages=522–8|year=2006|doi=10.1016/S1473-3099(06)70552-7|pmid=16870530}}</ref> Vaccines are hoped to play a significant role in treatment of both latent and active disease.<ref>{{cite journal|author=Kaufmann S.H.|title=Future vaccination strategies against tuberculosis: Thinking outside the box|journal=Immunity|year=2010|volume=33|pages=567–77|pmid=21029966|doi=10.1016/j.immuni.2010.09.015|issue=4}}</ref>
-To encourage further discovery, researchers and policymakers are promoting new economic models of vaccine development, including prizes, tax incentives, and [[advance market commitments]].<ref>{{cite journal|author1=Webber D. |author2=Kremer M. |url=http://www.who.int/bulletin/archives/79(8)735.pdf|title=Stimulating Industrial R&D for Neglected Infectious Diseases: Economic Perspectives|journal=Bulletin of the World Health Organization|volume=79|issue=8|year=2001|pages=693–801}}</ref><ref>{{cite journal|author1=Barder O. |author2=Kremer M. |author3=Williams H. |url=http://www.bepress.com/ev/vol3/iss3/art1 |title=Advance Market Commitments: A Policy to Stimulate Investment in Vaccines for Neglected Diseases|journal=The Economists' Voice|volume=3|year=2006|issue=3|doi=10.2202/1553-3832.1144}}</ref> A number of groups, including the [[Stop TB Partnership]],<ref>{{cite book|last=Economic|first=Department of|title=Achieving the global public health agenda: dialogues at the Economic and Social Council|year=2009|publisher=United Nations|location=New York|isbn=978-92-1-104596-3|pages=103|url=https://books.google.com/books?id=VeF9dv74C4MC&pg=PA103|author2=Affairs, Social }}</ref> the South African Tuberculosis Vaccine Initiative, and the [[Aeras Global TB Vaccine Foundation]], are involved with research.<ref>{{cite book|last=Jong|first=[edited by] Jane N. Zuckerman, Elaine C.|title=Travelers' vaccines|year=2010|publisher=People's Medical Publishing House|location=Shelton, CT|isbn=978-1-60795-045-5|pages=319|url=https://books.google.com/books?id=BKRpWFEy66wC&pg=PA319|edition=2nd}}</ref> Among these, the Aeras Global TB Vaccine Foundation received a gift of more than $280 million (US) from the [[Bill and Melinda Gates Foundation]] to develop and license an improved vaccine against tuberculosis for use in high burden countries.<ref>{{Cite web|last=Bill and Melinda Gates Foundation Announcement |title=Gates Foundation Commits $82.9 Million to Develop New Tuberculosis Vaccines |date=12 February 2004 |url=http://www.globalhealth.org/news/article/4134 |deadurl=yes |archiveurl=https://web.archive.org/web/20091010163118/http://www.globalhealth.org/news/article/4134 |archivedate=10 October 2009 |df= }}</ref><ref>{{Cite web|last=Nightingale|first=Katherine|title=Gates foundation gives US$280 million to fight TB|date=19 September 2007|url=http://www.scidev.net/en/news/gates-foundation-gives-us280-million-to-fight-tb.html}}</ref>
+To encourage further discovery, researchers and policymakers are promoting new economic models of vaccine development, including prizes, tax incentives, and [[advance market commitments]].<ref>{{cite journal|author1=Webber D.|author2=Kremer M.|url=http://www.who.int/bulletin/archives/79(8)735.pdf|title=Stimulating Industrial R&D for Neglected Infectious Diseases: Economic Perspectives|journal=Bulletin of the World Health Organization|volume=79|issue=8|year=2001|pages=693–801|deadurl=no|archiveurl=https://web.archive.org/web/20070926012031/http://www.who.int/bulletin/archives/79(8)735.pdf|archivedate=26 September 2007|df=dmy-all}}</ref><ref>{{cite journal|author1=Barder O.|author2=Kremer M.|author3=Williams H.|url=http://www.bepress.com/ev/vol3/iss3/art1|title=Advance Market Commitments: A Policy to Stimulate Investment in Vaccines for Neglected Diseases|journal=The Economists' Voice|volume=3|year=2006|issue=3|doi=10.2202/1553-3832.1144|deadurl=yes|archiveurl=https://web.archive.org/web/20061105083659/http://www.bepress.com/ev/vol3/iss3/art1|archivedate=5 November 2006|df=dmy-all}}</ref> A number of groups, including the [[Stop TB Partnership]],<ref>{{cite book|last=Economic|first=Department of|title=Achieving the global public health agenda: dialogues at the Economic and Social Council|year=2009|publisher=United Nations|location=New York|isbn=978-92-1-104596-3|pages=103|url=https://books.google.com/books?id=VeF9dv74C4MC&pg=PA103|author2=Affairs, Social|deadurl=no|archiveurl=https://web.archive.org/web/20150906212013/https://books.google.com/books?id=VeF9dv74C4MC&pg=PA103|archivedate=6 September 2015|df=dmy-all}}</ref> the South African Tuberculosis Vaccine Initiative, and the [[Aeras Global TB Vaccine Foundation]], are involved with research.<ref>{{cite book|last=Jong|first=[edited by] Jane N. Zuckerman, Elaine C.|title=Travelers' vaccines|year=2010|publisher=People's Medical Publishing House|location=Shelton, CT|isbn=978-1-60795-045-5|pages=319|url=https://books.google.com/books?id=BKRpWFEy66wC&pg=PA319|edition=2nd|deadurl=no|archiveurl=https://web.archive.org/web/20150906203627/https://books.google.com/books?id=BKRpWFEy66wC&pg=PA319|archivedate=6 September 2015|df=dmy-all}}</ref> Among these, the Aeras Global TB Vaccine Foundation received a gift of more than $280 million (US) from the [[Bill and Melinda Gates Foundation]] to develop and license an improved vaccine against tuberculosis for use in high burden countries.<ref>{{Cite web|last=Bill and Melinda Gates Foundation Announcement |title=Gates Foundation Commits $82.9 Million to Develop New Tuberculosis Vaccines |date=12 February 2004 |url=http://www.globalhealth.org/news/article/4134 |deadurl=yes |archiveurl=https://web.archive.org/web/20091010163118/http://www.globalhealth.org/news/article/4134 |archivedate=10 October 2009 |df= }}</ref><ref>{{Cite web|last=Nightingale|first=Katherine|title=Gates foundation gives US$280 million to fight TB|date=19 September 2007|url=http://www.scidev.net/en/news/gates-foundation-gives-us280-million-to-fight-tb.html|deadurl=no|archiveurl=https://web.archive.org/web/20081201175618/http://www.scidev.net/en/news/gates-foundation-gives-us280-million-to-fight-tb.html|archivedate=1 December 2008|df=dmy-all}}</ref>
-A number of medications are being studied for multidrug-resistant tuberculosis, including [[bedaquiline]] and [[delamanid]].<ref name=Zumla2012>{{cite journal|last=Zumla|first=A|author2=Hafner, R |author3=Lienhardt, C |author4=Hoelscher, M |author5= Nunn, A |title=Advancing the development of tuberculosis therapy|journal=Nature Reviews. Drug Discovery|date=1 March 2012|volume=11|issue=3|pages=171–2|pmid=22378254|doi=10.1038/nrd3694}}</ref> Bedaquiline received U.S. [[Food and Drug Administration]] (FDA) approval in late 2012.<ref>{{cite news|title=J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB|url=https://www.bloomberg.com/news/2012-12-31/j-j-sirturo-wins-fda-approval-to-treat-drug-resistant-tb.html|accessdate=1 January 2013|newspaper=Bloombeg|date=31 December 2012}}</ref> The safety and effectiveness of these new agents are still uncertain, because they are based on the results of a relatively small studies.<ref name=Zumla2012/><ref name="Avorn 2013 1349–1350">{{cite journal|last=Avorn|first=J|title=Approval of a tuberculosis drug based on a paradoxical surrogate measure|journal=JAMA|date=April 2013|volume=309|issue=13|pages=1349–1350|doi=10.1001/jama.2013.623|pmid=23430122}}</ref> However, existing data suggest that patients taking bedaquiline in addition to standard TB therapy are five times more likely to die than those without the new drug,<ref name="US Food and Drug Administration website">{{cite web|last=US Food and Drug Administration.|title=Briefing Package: NDA 204–384: Sirturo|url=http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-%20InfectiveDrugsAdvisoryCommittee/UCM329258.pdf}}</ref> which has resulted in medical journal articles raising health policy questions about why the FDA approved the drug and whether financial ties to the company making bedaquiline influenced physicians' support for its use.<ref name="Avorn 2013 1349–1350"/><ref>{{cite journal|last=Zuckerman|first=Diana|author2=Jennifer Yttri |title=Antibiotics: When science and wishful thinking collide|journal=Health Affairs|date=January 2013|url=http://healthaffairs.org/blog/2013/01/25/antibiotics-when-science-and-wishful-thinking-collide/}}</ref>
+A number of medications are being studied for multidrug-resistant tuberculosis, including [[bedaquiline]] and [[delamanid]].<ref name=Zumla2012>{{cite journal|last=Zumla|first=A|author2=Hafner, R |author3=Lienhardt, C |author4=Hoelscher, M |author5= Nunn, A |title=Advancing the development of tuberculosis therapy|journal=Nature Reviews. Drug Discovery|date=1 March 2012|volume=11|issue=3|pages=171–2|pmid=22378254|doi=10.1038/nrd3694}}</ref> Bedaquiline received U.S. [[Food and Drug Administration]] (FDA) approval in late 2012.<ref>{{cite news|title=J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB|url=https://www.bloomberg.com/news/2012-12-31/j-j-sirturo-wins-fda-approval-to-treat-drug-resistant-tb.html|accessdate=1 January 2013|newspaper=Bloombeg|date=31 December 2012|deadurl=no|archiveurl=https://web.archive.org/web/20130104110903/http://www.bloomberg.com/news/2012-12-31/j-j-sirturo-wins-fda-approval-to-treat-drug-resistant-tb.html|archivedate=4 January 2013|df=dmy-all}}</ref> The safety and effectiveness of these new agents are still uncertain, because they are based on the results of a relatively small studies.<ref name=Zumla2012/><ref name="Avorn 2013 1349–1350">{{cite journal|last=Avorn|first=J|title=Approval of a tuberculosis drug based on a paradoxical surrogate measure|journal=JAMA|date=April 2013|volume=309|issue=13|pages=1349–1350|doi=10.1001/jama.2013.623|pmid=23430122}}</ref> However, existing data suggest that patients taking bedaquiline in addition to standard TB therapy are five times more likely to die than those without the new drug,<ref name="US Food and Drug Administration website">{{cite web|last=US Food and Drug Administration.|title=Briefing Package: NDA 204–384: Sirturo|url=http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-%20InfectiveDrugsAdvisoryCommittee/UCM329258.pdf|deadurl=no|archiveurl=https://web.archive.org/web/20140104212835/http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-%20InfectiveDrugsAdvisoryCommittee/UCM329258.pdf|archivedate=4 January 2014|df=dmy-all}}</ref> which has resulted in medical journal articles raising health policy questions about why the FDA approved the drug and whether financial ties to the company making bedaquiline influenced physicians' support for its use.<ref name="Avorn 2013 1349–1350"/><ref>{{cite journal|last=Zuckerman|first=Diana|author2=Jennifer Yttri|title=Antibiotics: When science and wishful thinking collide|journal=Health Affairs|date=January 2013|url=http://healthaffairs.org/blog/2013/01/25/antibiotics-when-science-and-wishful-thinking-collide/|deadurl=no|archiveurl=https://web.archive.org/web/20130210154447/http://healthaffairs.org/blog/2013/01/25/antibiotics-when-science-and-wishful-thinking-collide/|archivedate=10 February 2013|df=dmy-all}}</ref>
 ==Other animals==
-Mycobacteria infect many different animals, including birds,<ref>{{cite journal|last=Shivaprasad|first=H.L.|author2=Palmieri, C.|title=Pathology of mycobacteriosis in birds|journal=The Veterinary Clinics of North America. Exotic Animal Practice|date=January 2012|volume=15|issue=1|pages=41–55, v–vi|pmid=22244112|doi=10.1016/j.cvex.2011.11.004}}</ref> rodents,<ref>{{cite journal|last=Reavill|first=D.R.|author2=Schmidt, R.E.|title=Mycobacterial lesions in fish, amphibians, reptiles, rodents, lagomorphs, and ferrets with reference to animal models|journal=The Veterinary Clinics of North America. Exotic Animal Practice|date=January 2012|volume=15|issue=1|pages=25–40, v|pmid=22244111|doi=10.1016/j.cvex.2011.10.001}}</ref> and reptiles.<ref>{{cite journal|last=Mitchell|first=M.A.|title=Mycobacterial infections in reptiles|journal=The Veterinary Clinics of North America. Exotic Animal Practice|date=January 2012|volume=15|issue=1|pages=101–11, vii|pmid=22244116|doi=10.1016/j.cvex.2011.10.002}}</ref> The subspecies ''Mycobacterium tuberculosis'', though, is rarely present in wild animals.<ref>{{cite book|last=Wobeser|first=Gary A.|title=Essentials of disease in wild animals|year=2006|publisher=Blackwell Publishing|location=Ames, Iowa [u.a.]|isbn=978-0-8138-0589-4|pages=170|url=https://books.google.com/books?id=JgyS6fxVasYC&pg=PA170|edition=1st}}</ref> An effort to eradicate bovine tuberculosis caused by ''[[Mycobacterium bovis]]'' from the cattle and deer herds of [[New Zealand]] has been relatively successful.<ref>{{cite journal|last=Ryan|first=T.J.|author2=Livingstone, P.G.|author3=Ramsey, D.S.|author4=de Lisle, G.W.|author5=Nugent, G.|author6=Collins, D.M.|author7=Buddle, B.M.|title=Advances in understanding disease epidemiology and implications for control and eradication of tuberculosis in livestock: the experience from New Zealand|journal=Veterinary Microbiology|date=25 February 2006|volume=112|issue=2–4|pages=211–9|pmid=16330161|doi=10.1016/j.vetmic.2005.11.025}}</ref> Efforts in Great Britain have been less successful.<ref>{{cite journal|last=White|first=P.C.|author2=Böhm, M.|author3=Marion, G.|author4=Hutchings, M.R.|title=Control of bovine tuberculosis in British livestock: there is no 'silver bullet'|journal=Trends in Microbiology|date=September 2008|volume=16|issue=9|pages=420–7|pmid=18706814|doi=10.1016/j.tim.2008.06.005}}</ref><ref>{{cite journal|last=Ward|first=A.I.|author2=Judge, J.|author3=Delahay, R.J.|title=Farm husbandry and badger behaviour: opportunities to manage badger to cattle transmission of Mycobacterium bovis?|journal=Preventive veterinary medicine|date=1 January 2010|volume=93|issue=1|pages=2–10|pmid=19846226|doi=10.1016/j.prevetmed.2009.09.014}}</ref>
+Mycobacteria infect many different animals, including birds,<ref>{{cite journal|last=Shivaprasad|first=H.L.|author2=Palmieri, C.|title=Pathology of mycobacteriosis in birds|journal=The Veterinary Clinics of North America. Exotic Animal Practice|date=January 2012|volume=15|issue=1|pages=41–55, v–vi|pmid=22244112|doi=10.1016/j.cvex.2011.11.004}}</ref> rodents,<ref>{{cite journal|last=Reavill|first=D.R.|author2=Schmidt, R.E.|title=Mycobacterial lesions in fish, amphibians, reptiles, rodents, lagomorphs, and ferrets with reference to animal models|journal=The Veterinary Clinics of North America. Exotic Animal Practice|date=January 2012|volume=15|issue=1|pages=25–40, v|pmid=22244111|doi=10.1016/j.cvex.2011.10.001}}</ref> and reptiles.<ref>{{cite journal|last=Mitchell|first=M.A.|title=Mycobacterial infections in reptiles|journal=The Veterinary Clinics of North America. Exotic Animal Practice|date=January 2012|volume=15|issue=1|pages=101–11, vii|pmid=22244116|doi=10.1016/j.cvex.2011.10.002}}</ref> The subspecies ''Mycobacterium tuberculosis'', though, is rarely present in wild animals.<ref>{{cite book|last=Wobeser|first=Gary A.|title=Essentials of disease in wild animals|year=2006|publisher=Blackwell Publishing|location=Ames, Iowa [u.a.]|isbn=978-0-8138-0589-4|pages=170|url=https://books.google.com/books?id=JgyS6fxVasYC&pg=PA170|edition=1st|deadurl=no|archiveurl=https://web.archive.org/web/20150906172856/https://books.google.com/books?id=JgyS6fxVasYC&pg=PA170|archivedate=6 September 2015|df=dmy-all}}</ref> An effort to eradicate bovine tuberculosis caused by ''[[Mycobacterium bovis]]'' from the cattle and deer herds of [[New Zealand]] has been relatively successful.<ref>{{cite journal|last=Ryan|first=T.J.|author2=Livingstone, P.G.|author3=Ramsey, D.S.|author4=de Lisle, G.W.|author5=Nugent, G.|author6=Collins, D.M.|author7=Buddle, B.M.|title=Advances in understanding disease epidemiology and implications for control and eradication of tuberculosis in livestock: the experience from New Zealand|journal=Veterinary Microbiology|date=25 February 2006|volume=112|issue=2–4|pages=211–9|pmid=16330161|doi=10.1016/j.vetmic.2005.11.025}}</ref> Efforts in Great Britain have been less successful.<ref>{{cite journal|last=White|first=P.C.|author2=Böhm, M.|author3=Marion, G.|author4=Hutchings, M.R.|title=Control of bovine tuberculosis in British livestock: there is no 'silver bullet'|journal=Trends in Microbiology|date=September 2008|volume=16|issue=9|pages=420–7|pmid=18706814|doi=10.1016/j.tim.2008.06.005}}</ref><ref>{{cite journal|last=Ward|first=A.I.|author2=Judge, J.|author3=Delahay, R.J.|title=Farm husbandry and badger behaviour: opportunities to manage badger to cattle transmission of Mycobacterium bovis?|journal=Preventive veterinary medicine|date=1 January 2010|volume=93|issue=1|pages=2–10|pmid=19846226|doi=10.1016/j.prevetmed.2009.09.014}}</ref>
-{{As of|2015}}, tuberculosis appears to be widespread among captive [[elephant]]s in the US. It is believed that the animals originally acquired the disease from humans, a process called [[reverse zoonosis]]. Because the disease can spread through the air to infect both humans and other animals, it is a public health concern affecting [[circus]]es and [[zoo]]s.<ref name="Holt">{{cite web|last1=Holt|first1=Nathalia|title=The Infected Elephant in the Room|url=http://www.slate.com/blogs/wild_things/2015/03/24/elephant_tuberculosis_epidemic_zoo_and_circus_animals_passing_tb_to_humans.html|website=Slate|accessdate=2016-04-05|language=en-US|date=24 March 2015}}</ref><ref name="Mikota">{{cite web|last1=Mikota|first1=Susan K.|title=A Brief History of TB in Elephants|url=https://www.aphis.usda.gov/animal_welfare/downloads/elephant/A%20Brief%20History%20of%20TB%20in%20Elephants.pdf|website=APHIS|publisher=US Department of Agriculture|accessdate=2016-04-05}}</ref>
+{{As of|2015}}, tuberculosis appears to be widespread among captive [[elephant]]s in the US. It is believed that the animals originally acquired the disease from humans, a process called [[reverse zoonosis]]. Because the disease can spread through the air to infect both humans and other animals, it is a public health concern affecting [[circus]]es and [[zoo]]s.<ref name="Holt">{{cite web|last1=Holt|first1=Nathalia|title=The Infected Elephant in the Room|url=http://www.slate.com/blogs/wild_things/2015/03/24/elephant_tuberculosis_epidemic_zoo_and_circus_animals_passing_tb_to_humans.html|website=Slate|accessdate=2016-04-05|language=en-US|date=24 March 2015|deadurl=no|archiveurl=https://web.archive.org/web/20160414151050/http://www.slate.com/blogs/wild_things/2015/03/24/elephant_tuberculosis_epidemic_zoo_and_circus_animals_passing_tb_to_humans.html|archivedate=14 April 2016|df=dmy-all}}</ref><ref name="Mikota">{{cite web|last1=Mikota|first1=Susan K.|title=A Brief History of TB in Elephants|url=https://www.aphis.usda.gov/animal_welfare/downloads/elephant/A%20Brief%20History%20of%20TB%20in%20Elephants.pdf|website=APHIS|publisher=US Department of Agriculture|accessdate=2016-04-05|deadurl=no|archiveurl=https://web.archive.org/web/20161006125349/https://www.aphis.usda.gov/animal_welfare/downloads/elephant/A%20Brief%20History%20of%20TB%20in%20Elephants.pdf|archivedate=6 October 2016|df=dmy-all}}</ref>
 ==References==

Classification	D ICD-10: A15-A19 ICD-9-CM: 010–018 OMIM: 607948 MeSH: D014376 DiseasesDB: 8515
External resources	MedlinePlus: 000077 eMedicine: med/2324 emerg/618 radio/411 Patient UK: Tuberculosis Orphanet: 3389

v t e Tuberculosis
Symptoms, signs and associated conditions	Pulmonary tuberculosis Ghon focus / Ghon's complex Extrapulmonary tuberculosis Caseous necrosis Pott disease Canga's bead symptom Prosector's wart Lupus vulgaris Tuberculous lymphadenitis Tuberculous meningitis Miliary tuberculosis Latent tuberculosis Paronychia Giant multinucleated cell
Mycobacterium species	Mycobacterium africanum Mycobacterium bovis Mycobacterium caprae Mycobacterium tuberculosis
Tuberculosis diagnosis	Ziehl–Neelsen stain Auramine phenol stain Culture on Löwenstein–Jensen medium and/or MGIT Chest photofluorography GeneXpert MTB/RIF Interferon gamma release assay QuantiFERON T-SPOT.TB Microscopic Observation Drug Susceptibility assay Tuberculin Heaf test Mantoux test Tine test
Management (ATC code J04)	Isoniazid 4-Aminosalicylic acid Ethambutol Capreomycin Cycloserine Rifampicin Thioacetazone Streptomycin Bedaquiline Pyrazinamide Rifater
Vaccines	BCG vaccine Experimental M72/AS01E MVA85A RBCG30
Resistance	Multidrug-resistant tuberculosis Extensively drug-resistant tuberculosis Totally drug-resistant tuberculosis
History of tuberculosis	Manuel de Abreu Hermann Brehmer Albert Calmette Christopher Dye Marcos Espinal Friedrich Franz Friedmann Max Gerson Philip D'Arcy Hart F. R. G. Heaf George M. Heath Robert Koch Charles Mantoux Richard Morton Mario Raviglione Carl Rüedi Lucius Rüedi Madonna Swan Edward Livingston Trudeau
Organizations	Adirondack Cottage Sanitarium Campaign for Access to Essential Medicines Center for Global Infectious Disease Research Cure Cottages of Saranac Lake European and Developing Countries Clinical Trials Partnership Glen Lake Children's Camp Glen Lake Sanatorium Glenn Dale Hospital The Global Fund to Fight AIDS, Tuberculosis and Malaria Global Plan to Stop Tuberculosis International Congress on Tuberculosis International Union Against Tuberculosis and Lung Disease Millennium Foundation Mycobacterium Tuberculosis Structural Genomics Consortium National Jewish Health Phipps Institute for the Study, Treatment and Prevention of Tuberculosis Stop TB Partnership TB Alliance Unitaid
Other	Tuberculosis elimination 2007 tuberculosis scare Baumgarten-Tangl law CFP-10 ESAT-6 Iowa Cow War List of tuberculosis cases Plombage Preventorium Sanatorium Sunshine Way Tuberculosis classification Tuberculosis in China Tuberculosis in human culture Tuberculosis radiology Tygerberg score World Tuberculosis Day

v t e Diseases of poverty
Diseases of poverty	AIDS Malaria Tuberculosis Measles Pneumonia Diarrheal diseases Plague
Neglected diseases	Cholera Chagas disease African sleeping sickness Schistosomiasis Dracunculiasis River blindness Leishmaniasis Trachoma
Miscellaneous	Malnutrition Priority review voucher

Authority control databases
National	France BnF data Germany Israel United States Latvia Japan Czech Republic Croatia
Other	Historical Dictionary of Switzerland NARA