Tuberculosis: Difference between revisions

Tuberculosis
Tuberculosis
Specialty	Infectious diseases, pulmonology
Frequency	0.043—0.045% (Suriname), 0.00033—0.00053% (Iceland), 0.077—0.079% (Ecuador), -0.99—1.01% (Norway), -0.00088—0.00112% (France), 0.0029% (United States of America), 0.0028%

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Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis.^[1] Tuberculosis usually attacks the lungs but can also affect other parts of the body. It is spread through the air when people who have an active MTB infection cough, sneeze, or otherwise transmit their saliva through the air.^[2] Most infections in humans result in an asymptomatic, latent infection, and about one in ten latent infections eventually progress to active disease, which, if left untreated, kills more than 50% of those infected.

The classic symptoms are a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss (the last giving rise to the formerly prevalent colloquial term "consumption"). Infection of other organs causes a wide range of symptoms. Diagnosis relies on radiology (commonly chest X-rays), a tuberculin skin test, blood tests, as well as microscopic examination and microbiological culture of bodily fluids. Treatment is difficult and requires long courses of multiple antibiotics. Social contacts are also screened and treated if necessary. Antibiotic resistance is a growing problem in (extensively) multi-drug-resistant tuberculosis. Prevention relies on screening programs and vaccination, usually with Bacillus Calmette-Guérin vaccine.

One third of the world's population is thought to have been infected with M. tuberculosis,^[3]^[4] and new infections occur at a rate of about one per second.^[3] In 2007 there were an estimated 13.7 million chronic active cases,^[5] and in 2010 8.8 million new cases, and 1.45 million deaths, mostly in developing countries.^[6] The absolute number of tuberculosis cases has been decreasing since 2006 and new cases since 2002.^[6] In addition, more people in the developing world contract tuberculosis because their immune systems are more likely to be compromised due to higher rates of AIDS.^[7] The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5–10% of the U.S. population test positive.^[1]

Signs and symptoms

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

Pulmonary

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

Extrapulmonary

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

Constitutional

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

Causes

Mycobacterium

The main cause of TB is, Mycobacterium tuberculosis, a small aerobic non-motile bacillus or less commonly the closely related Mycobacterium bovis.^[10] The high lipid content of this pathogen accounts for many of its unique clinical characteristics.^[13] It divides every 16 to 20 hours, an extremely slow rate compared with other bacteria, which usually divide in less than an hour.^[14] Since MTB has a cell wall but lacks a phospholipid outer membrane, it is classified as a Gram-positive bacterium. However, if a Gram stain is performed, MTB either stains very weakly Gram-positive or does not retain dye as a result of the high lipid and mycolic acid content of its cell wall.^[15] MTB can withstand weak disinfectants and survive in a dry state for weeks. In nature, the bacterium can grow only within the cells of a host organism, but M. tuberculosis can be cultured in the laboratory.^[16]

Using histological stains on expectorate samples from phlegm (also called sputum), scientists can identify MTB under a regular microscope. Since MTB retains certain stains after being treated with acidic solution, it is classified as an acid-fast bacillus (AFB).^[1]^[15] The most common acid-fast staining technique, the Ziehl-Neelsen stain, dyes AFBs a bright red that stands out clearly against a blue background. Other ways to visualize AFBs include an auramine-rhodamine stain and fluorescent microscopy.

The M. tuberculosis complex includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canetti, and M. microti.^[17] M. africanum is not widespread, but in parts of Africa it is a significant cause of tuberculosis.^[18]^[19] M. bovis was once a common cause of tuberculosis, but the introduction of pasteurized milk has largely eliminated this as a public health problem in developed countries.^[1]^[20] M. canetti is rare and seems to be limited to Africa, although a few cases have been seen in African emigrants.^[21] M. microti is mostly seen in immunodeficient people, although it is possible that the prevalence of this pathogen has been underestimated.^[22] Other known pathogenic mycobacteria include Mycobacterium leprae, Mycobacterium avium, and M. kansasii. The latter two are part of the nontuberculous mycobacteria (NTM) group. Nontuberculous mycobacteria cause neither TB nor leprosy, but they do cause pulmonary diseases resembling TB.^[23]

Risk factors

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

Mechanism

Transmission

When people with active pulmonary TB cough, sneeze, speak, sing, or spit, they expel infectious aerosol droplets 0.5 to 5 µm in diameter. A single sneeze can release up to 40,000 droplets.^[30] Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very low and inhaling fewer than ten bacteria may cause an infection.^[31]

People with prolonged, frequent, or intense contact are at particularly high risk of becoming infected, with an estimated 22% infection rate. A person with active but untreated tuberculosis can infect 10–15 other people per year.^[3] Others at risk include people in areas where TB is common, people who inject illicit drugs, residents and employees of high-risk congregate settings, medically under-served and low-income populations, high-risk racial or ethnic minority populations, children exposed to adults in high-risk categories, those who are immunocompromised by conditions such as HIV/AIDS, people who take immunosuppressant drugs, and health care workers serving these high-risk clients.^[32]

Transmission can only occur from people with active—not latent—TB.^[1] The probability of transmission from one person to another depends upon the number of infectious droplets expelled by a carrier, the effectiveness of ventilation, the duration of exposure, and the virulence of the M. tuberculosis strain.^[33] The chain of transmission can be broken by isolating people with active disease and starting effective anti-tuberculous therapy. After two weeks of such treatment, people with non-resistant active TB generally cease to be contagious. If someone does become infected, then it will take three to four weeks before the newly infected person can transmit the disease to others.^[34]

Pathogenesis

About 90% of those infected with Mycobacterium tuberculosis have asymptomatic, latent TB infection (sometimes called LTBI), with only a 10% lifetime chance that a latent infection will progress to TB disease.^[1] However, if untreated, the death rate for these active TB cases is more than 50%.^[3]

TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within the endosomes of alveolar macrophages.^[1]^[35] The primary site of infection in the lungs is called the Ghon focus, and is generally located in either the upper part of the lower lobe, or the lower part of the upper lobe.^[1] Simon foci may also be present. Bacteria are picked up by dendritic cells, which do not allow replication, although these cells can transport the bacilli to local (mediastinal) lymph nodes. Further spread is through the bloodstream to other tissues and organs where secondary TB lesions can develop in other parts of the lung (particularly the apex of the upper lobes), peripheral lymph nodes, kidneys, brain, and bone.^[1]^[36] All parts of the body can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid.^[37]

Tuberculosis is classified as one of the granulomatous inflammatory conditions. Macrophages, T lymphocytes, B lymphocytes, and fibroblasts are among the cells that aggregate to form granulomas, with lymphocytes surrounding the infected macrophages. The granuloma prevents dissemination of the mycobacteria and provides a local environment for interaction of cells of the immune system. Bacteria inside the granuloma can become dormant, resulting in a latent infection. Another feature of the granulomas of human tuberculosis is the development of abnormal cell death (necrosis) in the center of tubercles. To the naked eye this has the texture of soft white cheese and is termed caseous necrosis.^[38]

If TB bacteria gain entry to the bloodstream from an area of damaged tissue they spread through the body and set up many foci of infection, all appearing as tiny white tubercles in the tissues. This severe form of TB disease is most common in infants and the elderly and is called miliary tuberculosis. People with this disseminated TB have a fatality rate near 100% if untreated. However, if treated early, the fatality rate is reduced to about 10%.^[39]

In many people the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis.^[38] Affected tissue is replaced by scarring and cavities filled with cheese-like white necrotic material. During active disease, some of these cavities are joined to the air passages bronchi and this material can be coughed up. It contains living bacteria and can therefore spread the infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.^[38]

Diagnosis

Tuberculosis is diagnosed definitively by identifying the causative organism (Mycobacterium tuberculosis) in a clinical sample (for example, sputum or pus). When this is not possible, a probable—although sometimes inconclusive^[2]—diagnosis may be made using imaging (X-rays or scans), a tuberculin skin test (Mantoux test),^[2] or a, Interferon Gamma Release Assay (IGRA).

The main problem with tuberculosis diagnosis is the difficulty in culturing this slow-growing organism in the laboratory (it may take 4 to 12 weeks for blood or sputum culture). A complete medical evaluation for TB must include a medical history, a physical examination, a chest X-ray, microbiological smears, and cultures. It may also include a tuberculin skin test, a serological test. The interpretation of the tuberculin skin test depends upon the person's risk factors for infection and progression to TB disease, such as exposure to other cases of TB or immunosuppression.^[33]

New TB tests have been developed that are fast and accurate. These include polymerase chain reaction assays for the detection of bacterial DNA.^[40] One such molecular diagnostics test gives results in 100 minutes and is currently being offered to 116 low- and middle-income countries at a discount with support from WHO and the Bill and Melinda Gates foundation.^[41]

Another such test, which was approved by the FDA in 1996, is the amplified mycobacterium tuberculosis direct test (MTD, Gen-Probe). This test yields results in 2.5 to 3.5 hours, and it is highly sensitive and specific when used to test smears positive for acid-fast bacilli (AFB).^[42]

Screening

Mantoux tuberculin skin tests are often used for routine screening of high risk individuals.^[43] Currently, latent infection is diagnosed in a non-immunized person by a tuberculin skin test, which yields a delayed hypersensitivity type response to an extract made from M. tuberculosis.^[1] Those immunized for TB or with past-cleared infection will respond with delayed hypersensitivity parallel to those currently in a state of infection, so the test must be used with caution, particularly with regard to persons from countries where TB immunization is common.^[44] Tuberculin tests have the disadvantage of producing false negatives, especially when the person is co-morbid with sarcoidosis, Hodgkins lymphoma, malnutrition, or most notably active tuberculosis disease.^[1] The newer interferon release assays (IGRAs) such as T-SPOT.TB and QuantiFERON-TB Gold In Tube overcome many of these problems. IGRAs are in vitro blood tests that are more specific than the skin test. IGRAs detect the release of interferon gamma in response to mycobacterial proteins such as ESAT-6.^[45] These are not affected by immunization or environmental mycobacteria, so generate fewer false positive results.^[46] There is also evidence that IGRAs are more sensitive than the skin test.^[47]

Prevention

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

Vaccines

The only currently available vaccine as of 2011 is Bacillus Calmette-Guérin (BCG) which while effective against disseminated disease in childhood, confers inconsistent protection against pulmonary disease.^[48] It is the most widely used vaccine worldwide with more than 90% of children vaccinated.^[7] However the immunity that it induces, decreases after about ten years.^[7] As tuberculosis is uncommon in most of Canada, the United Kingdom and the United States, BCG is only administered to people at high risk.^[49]^[50]^[51] Part of the reason against the use of vaccine is that it makes the tuberculin skin test falsely positive and thus of no use in screening.^[51] A number of new vaccines are in development.^[7]

Public health

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

Treatment

Treatment for TB uses antibiotics to kill the bacteria. Effective TB treatment is difficult, due to the unusual structure and chemical composition of the mycobacterial cell wall, which makes many antibiotics ineffective and hinders the entry of drugs.^[53] The two antibiotics most commonly used are isoniazid and rifampicin and treatments can be prolonged.^[33] Latent TB treatment usually uses a single antibiotic, while active TB disease is best treated with combinations of several antibiotics, to reduce the risk of the bacteria developing antibiotic resistance.^[54] People with latent infections are treated to prevent them from progressing to active TB disease later in life.

New onset

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

Recurrent disease

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

Medication resistance

Primary resistance occurs in persons infected with a resistant strain of TB. A person with fully susceptible TB develops secondary resistance (acquired resistance) during TB therapy because of inadequate treatment, not taking the prescribed regimen appropriately, or using low-quality medication.^[54] Drug-resistant TB is a public health issue in many developing countries, as treatment is longer and requires more expensive drugs. Multi-drug-resistant tuberculosis (MDR-TB) is defined as resistance to the two most effective first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB (XDR-TB) is also resistant to three or more of the six classes of second-line drugs.^[55] Totally drug-resistant TB (TDR-TB), which was first observed in 2003 in Italy, but not widely reported until 2012, is resistant to all currently-used drugs.^[56]

Prognosis

Progression from TB infection to TB disease occurs when the TB bacilli overcome the immune system defenses and begin to multiply. In primary TB disease—1–5% of cases—this occurs soon after infection.^[1] However, in the majority of cases, a latent infection occurs that has no obvious symptoms.^[1] These dormant bacilli can produce tuberculosis in 2–23% of these latent cases, often many years after infection.^[57]

The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In people co-infected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year.^[1] Studies utilizing DNA fingerprinting of M. tuberculosis strains have shown that reinfection contributes more substantially to recurrent TB than previously thought,^[58] with estimates that it might account for more than 50% in areas where TB is common.^[59] The chance of death from a case of tuberculosis is about 4%.^[7]

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 prevalence of TB per 100,000 people was highest in sub-Saharan Africa, and was also relatively high in Asia.^[61]

Roughly a third of the world's population has been infected with M. tuberculosis, and new infections occur at a rate of one per second.^[3] However, not all infections with M. tuberculosis cause TB disease and many infections are asymptomatic.^[63] In 2007 there were an estimated 13.7 million chronic active cases,^[5] and in 2010, 8.8 million new cases, and 1.45 million deaths, mostly in developing countries.^[6] The absolute number of tuberculosis cases has been decreasing since 2005 and new cases since 2002.^[6] China has achieved particularly dramatic progress, with an 80 percent decline in its TB mortality rate.^[64] The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5–10% of the U.S. population test positive.^[1] Tuberculosis is the world's greatest infectious killer of women of reproductive age and the leading cause of death among people with HIV/AIDS.^[65] This is due to the fact that worldwide, women have a larger burden from poverty, ill-health, malnutrition and disease than men. Tuberculosis results in more deaths among women than all causes of maternal mortality combined, and more than 900 million women are infected with TB worldwide. It also kills more young people and adults than any other known infectious disease.^[66]

The rise in HIV infections and the neglect of TB control programs have enabled a resurgence of tuberculosis.^[67] The emergence of drug-resistant strains has also contributed to this new epidemic with, from 2000 to 2004, 20% of TB cases being resistant to standard treatments and 2% resistant to second-line drugs.^[55] The rate at which new TB cases occur varies widely, even in neighbouring countries, apparently because of differences in health care systems.^[68]

In 2007, the country with the highest estimated incidence rate of TB was Swaziland, with 1200 cases per 100,000 people. India had the largest total incidence, with an estimated 2.0 million new cases.^[5] In developed countries, tuberculosis is less common and is mainly an urban disease. In the United Kingdom, the national average was 15 per 100,000 in 2007, and the highest incidence rates in Western Europe were 30 per 100,000 in Portugal and Spain. These rates compared with 98 per 100,000 in China and 48 per 100,000 in Brazil. In the United States, the overall tuberculosis case rate was 4 per 100,000 persons in 2007.^[61] In Canada, tuberculosis is still endemic in some rural areas.^[69]

The incidence of TB varies with age. In Africa, TB primarily affects adolescents and young adults.^[70] However, in countries where TB has gone from high to low incidence, such as the United States, TB is mainly a disease of older people, or of the immunocompromised.^[1]^[71]

History

Tuberculosis has been present in humans since antiquity.^[7] The earliest unambiguous detection of Mycobacterium tuberculosis is in the remains of bison dated 17,000 years before the present.^[72] However, whether tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor, is currently unclear.^[73] Although, there is evidence following a comparative genomic approach of MTBC in humans to MTBC in animals that suggests that humans did not acquire MTBC from animals during animal domestication as previously believed. Both strains of the tuberculosis bacteria are shown to share a common ancestor, which could have infected humans as early as the Neolithic transition.^[74] Skeletal remains show prehistoric humans (4000 BCE) had TB, and researchers have found tubercular decay in the spines of Egyptian mummies dating from 3000-2400 BCE.^[75] Phthisis is a Greek term for consumption; around 460 BCE, Hippocrates identified phthisis as the most widespread disease of the times involving coughing up blood and fever, which was almost always fatal.^[76] Genetic studies suggest that TB was present in The Americas from about the year 100 CE.^[77]

Before the Industrial Revolution, folklore often associated tuberculosis with vampires. When one member of a family died from it, the other members that were infected would lose their health slowly. People believed that this was caused by the original victim draining the life from the other family members.^[78]

Although it was established that the pulmonary form was associated with 'tubercles' by Dr Richard Morton in 1689,^[79]^[80] due to the variety of its symptoms, TB was not identified as a single disease until the 1820s and was not named 'tuberculosis' until 1839 by J. L. Schönlein.^[81] During the years 1838–1845, Dr. John Croghan, the owner of Mammoth Cave, brought a number of tuberculosis sufferers 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.^[82] Hermann Brehmer opened the first TB sanatorium in 1859 in Sokołowsko, Poland.^[83]

Dr. Robert Koch discovered the tuberculosis bacilli.

The bacillus causing tuberculosis, Mycobacterium 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.^[84] Koch did not believe that bovine (cattle) and human tuberculosis were similar, which delayed the recognition of infected milk as a source of infection. Later, this source was eliminated by the pasteurization process. Koch announced a glycerine extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it 'tuberculin'. It was not effective, but was later adapted as a test for pre-symptomatic tuberculosis.^[85]

Albert Calmette and Camille Guerin achieved the first genuine success in immunizing against tuberculosis in 1906, using attenuated bovine-strain tuberculosis. It was called 'BCG' (Bacillus of Calmette and Guerin). The BCG vaccine was first used on humans in 1921 in France,^[86] but it wasn't until after World War II that BCG received widespread acceptance in the USA, Great Britain, and Germany.^[87]

Tuberculosis caused the most widespread public concern in the 19th and early 20th centuries as an endemic disease of the urban poor. In 1815, one in four deaths in England was of consumption; by 1918 one in six deaths in France were still caused by TB. After the establishment in the 1880s that the disease was contagious, TB was made a notifiable disease in Britain; there were campaigns to stop 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.^[83] Whatever the purported benefits of the fresh air and labor in the sanatoria, even under the best conditions, 50% of those who entered were dead within five years (1916).^[83]

The promotion of Christmas Seals began in Denmark during 1904 as a way to raise money for tuberculosis programs. It expanded to the United States and Canada in 1907–1908 to help the National Tuberculosis Association (later called the American Lung Association).

In the United States, concern about the spread of tuberculosis played a role in the movement to prohibit public spitting except into spittoons.

In Europe, deaths from TB fell from 500 out of 100,000 in 1850 to 50 out of 100,000 by 1950. Improvements in public health were reducing tuberculosis even before the arrival of antibiotics, although the disease remained a significant threat to public health, such that when the Medical Research Council was formed in Britain in 1913 its initial focus was tuberculosis research.^[88]

It was not until 1946 with the development of the antibiotic streptomycin that effective treatment and cure became possible. Prior to the introduction of this drug, the only treatment besides sanatoria were surgical interventions, including the pneumothorax technique—collapsing an infected lung to "rest" it and allow lesions to heal—a technique that was of little benefit and was largely discontinued by the 1950s.^[89] The emergence of multidrug-resistant TB has again introduced surgery as part of the treatment for these infections. Here, surgical removal of chest cavities will reduce the number of bacteria in the lungs, as well as increasing the exposure of the remaining bacteria to drugs in the bloodstream, and is therefore thought to increase the effectiveness of the chemotherapy.^[90]

Hopes of completely eliminating the disease were dashed following the rise of drug-resistant strains in the 1980s. For example, tuberculosis cases in Britain, numbering around 50,000 in 1955, had fallen to around 5,500 in 1987, but in 2000 there were over 7,000 confirmed cases.^{[citation needed]} Due to the elimination of public health facilities in New York and the emergence of HIV, there was a resurgence in the late 1980s.^[91] The number of those failing to complete their course of drugs is high. NY had to cope with more than 20,000 "unnecessary" TB-patients with multidrug-resistant strains (resistant to, at least, both Rifampin and Isoniazid). The resurgence of tuberculosis resulted in the declaration of a global health emergency by the World Health Organization in 1993.^[92]

In other animals

Tuberculosis can be carried by mammals; domesticated species, such as cats and dogs, are generally free of tuberculosis, but wild animals may be carriers. In some places, regulations aiming to prevent the spread of TB restrict the ownership of novelty pets; for example, the U.S. state of California forbids the ownership of pet gerbils.^[93]

Mycobacterium bovis causes TB in cattle. An effort to eradicate bovine tuberculosis from the cattle and deer herds of New Zealand is under way. It has been found that herd infection is more likely in areas where infected vector species such as Australian brush-tailed possums come into contact with domestic livestock at farm/bush borders.^[94] Controlling the vectors through possum eradication and monitoring the level of disease in livestock herds through regular surveillance are seen as a "two-pronged" approach to ridding New Zealand of the disease.

In both the Republic of Ireland and Northern Ireland, badgers have been identified as a vector species for the transmission of bovine tuberculosis. As a result, the government in both regions has mounted an active campaign of eradication of the species in an effort to reduce the incidence of the disease. Badgers have been culled primarily by snaring and gassing. It remains a contentious issue, with proponents and opponents of the scheme citing their own studies to support their position.^[95]^[96]^[97]

Research

epicfailure!!!!!!!!!!!!!!! Several new vaccines to prevent TB infection are being developed, among others by Aeras and TBVI. The first recombinant tuberculosis vaccine, Mtb72F, entered clinical trials in the United States in 2004, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).^[98]^[99] A 2005 study showed that a DNA TB vaccine given with conventional chemotherapy can accelerate the disappearance of bacteria as well as protect against re-infection in mice; it may take four to five years to be available in humans.^[100] Another TB vaccine, MVA85A, is currently in phase II trials in South Africa,^[101] and is based on a genetically modified vaccinia virus. Many other strategies are also being used to develop novel vaccines,^[102] including both subunit vaccines (fusion molecules composed of two recombinant proteins delivered in an adjuvant) such as Hybrid-1, HyVac4, or M72, and recombinant adenoviruses such as Ad35.^[103]^[104]^[105]^[106] Some of these vaccines can be effectively administered without needles, making them preferable for areas where HIV is common.^[107] All of these vaccines have been successfully tested in humans and are now in extended testing in TB-endemic regions. To encourage further discovery, researchers and policymakers are promoting new economic models of vaccine development including prizes, tax incentives, and advance market commitments.^[108]^[109]

An experimental vaccine, with positive results in mouse models, may be effective not only in preventing infection, but also in eradicating the infection once it has been established.^[110] A tuberculosis vaccine aimed at sterile Mtb eradication should be able to target latent Mtb as well as Mtb that causes early-stage tuberculosis.^[111] The vaccine is a combination of antigens Ag85B and ESAT-6 as well as the protein Rv2660c. Ag85B and ESAT-6 together form the vaccine Hybrid-1, while Rv2660c is a protein that is expressed even in late-stage infections, when protein transcription is generally reduced. The novel combination of Ag85B, ESAT-6, and Rv2660c allows for both short- and long-term protection as a result of the continued expression of target proteins. The new vaccine, currently referred to as H56, works by promoting a polyfunctional CD4+ T cell response against tuberculosis protein components.^[110] Phase I clinical trials began in Cape Town, South Africa, in December 2011.^[112]^{[needs update]}

A number of groups including the Mycobacterium Tuberculosis Structural Genomics Consortium and The Tuberculosis Vaccine Initiative (TBVI) are involved with research.

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External links

Tuberculosis at Curlie
"Tuberculosis (TB)". Centers for Disease Control. Retrieved 6 April 2011.
"Tuberculosis (TB)". UK Health Protection Agency. Retrieved 6 April 2011.

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[Robbins-1] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q 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.{{cite book}}: CS1 maint: multiple names: authors list (link)

[AP-2] Konstantinos A (2010). "Testing for tuberculosis". Australian Prescriber. 33 (1): 12–18.

[WHO2004data-3] "Tuberculosis Fact sheet N°104". World Health Organization. November 2010. Retrieved 26 July 2011.

[4] Jasmer RM, Nahid P, Hopewell PC (2002). "Clinical practice. Latent tuberculosis infection" (PDF). N. Engl. J. Med. 347 (23): 1860–6. doi:10.1056/NEJMcp021045. PMID 12466511.{{cite journal}}: CS1 maint: multiple names: authors list (link), which cites Dolin PJ, Raviglione MC, Kochi A (1994). "Global tuberculosis incidence and mortality during 1990-2000". Bull World Health Organ. 72 (2): 213–20. PMC 2486541. PMID 8205640.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[WHO2009-Epidemiology-5] World Health Organization (2009). "Epidemiology". Global tuberculosis control: epidemiology, strategy, financing. pp. 6–33. ISBN 9789241563802. {{cite book}}: |access-date= requires |url= (help); External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help)

[WHO2011-6] "The sixteenth global report on tuberculosis" (PDF). 2011.

[Lancet11-7] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t Lawn, SD (2 July 2011). "Tuberculosis". Lancet. 378 (9785): 57–72. doi:10.1016/S0140-6736(10)62173-3. PMID 21420161. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[8] Schiffman G (15 January 2009). "Tuberculosis Symptoms". eMedicineHealth.

[Pet2005-9] .], edited by Peter G. Gibson ; section editors, Michael Abramson ... [et (2005). Evidence-based respiratory medicine (1. publ. ed.). Oxford: Blackwell. p. 321. ISBN 9780727916051. {{cite book}}: |first= has generic name (help)CS1 maint: multiple names: authors list (link)

[ID10-10] ^ ^a ^b ^c ^d ^e ^f ^g ^h 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 978-0443068393. {{cite book}}: |first= has generic name (help)CS1 maint: multiple names: authors list (link)

[11] Golden MP, Vikram HR (2005). "Extrapulmonary tuberculosis: an overview". American family physician. 72 (9): 1761–8. PMID 16300038.

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 ==Research==
-Several new vaccines to prevent TB infection are being developed, among others by [[Aeras]] and [[TBVI]]. The first [[genetic recombination|recombinant]] tuberculosis [[vaccine]], Mtb72F, entered [[clinical trial]]s in the United States in 2004, sponsored by the [[National Institute of Allergy and Infectious Diseases]] (NIAID).<ref>{{cite press release |title=First U.S. Tuberculosis Vaccine Trial in 60 Years Begins |publisher=[[National Institute of Allergy and Infectious Diseases]] |date=26 January 2004|url=http://www.nih.gov/news/pr/jan2004/niaid-26.htm |accessdate=27 September 2009}}</ref><ref>{{cite journal|pmid=15187142|year=2004|author=Skeiky YA, Alderson MR, Ovendale PJ, Guderian JA, Brandt L, Dillon DC, Campos-Neto A, Lobet Y, Dalemans W|title=Differential immune responses and protective efficacy induced by components of a tuberculosis polyprotein vaccine, Mtb72F, delivered as naked DNA or recombinant protein|volume=172|issue=12|pages=7618–28|journal=J Immunol|url=http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=15187142}}</ref> A 2005 study showed that a [[DNA vaccine|DNA TB vaccine]] given with conventional [[chemotherapy]] can accelerate the disappearance of bacteria as well as protect against re-infection in mice; it may take four to five years to be available in humans.<ref name=Ha_2005>{{cite journal |author=Ha S, Jeon B, Youn J, Kim S, Cho S, Sung Y|title=Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of ''Mycobacterium tuberculosis'' |journal=Gene Ther |volume=12 |issue=7 |pages=634–8 |year=2005|pmid = 15690060|doi = 10.1038/sj.gt.3302465}}</ref> Another TB vaccine, [[MVA85A]], is currently in [[clinical trial|phase II trials]] in South Africa,<ref name=Ibanga_2006>{{cite journal |author=Ibanga H, Brookes R, Hill P, Owiafe P, Fletcher H, Lienhardt C, Hill A, Adegbola R, McShane H |title=Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design |journal=Lancet Infect Dis |volume=6 |issue=8 |pages=522–8 |year=2006 |doi= 10.1016/S1473-3099(06)70552-7| pmid = 16870530}}</ref> and is based on a genetically modified [[vaccinia]] virus. Many other strategies are also being used to develop novel vaccines,<ref>{{cite journal |author=Doherty TM, Andersen P |year=2005 |title=Vaccines for Tuberculosis: Novel Concepts and Recent Progress |journal=[[Clinical Microbiology Reviews]] |volume=18 |issue=4 |pages=687–702|doi=10.1128/CMR.18.4.687-702.2005|pmc=1265910 |pmid=16223953 |last1=Doherty |first1=TM |last2=Andersen |first2=P}}</ref> including both [[Vaccination#Types of vaccinations|subunit vaccines]] (fusion molecules composed of two [[genetic recombination|recombinant]] proteins delivered in an [[Immunologic adjuvant|adjuvant]]) such as Hybrid-1, HyVac4, or M72, and recombinant [[adenovirus]]es such as Ad35.<ref>{{cite web|title=Vaccine Research – Tuberculosis|publisher=[[Statens Serum Institut]]|url=http://www.ssi.dk/sw13853.asp|accessdate=1 March 2009| archiveurl =http://web.archive.org/web/20070717164308/http://www.ssi.dk/sw13853.asp| archivedate = 17 July 2007}}</ref><ref>{{cite web|title=Statens Serum Institut (SSI), Intercell (ICLL), and Aeras Global Tuberculosis Vaccine Foundation (Aeras) announce the initiation of a clinical trial for a novel vaccine candidate|date=4 December 2007|publisher=[[Aeras Global TB Vaccine Foundation|Aeras]]|url=http://www.aeras.org/newscenter/news-detail.php?id=705|accessdate=1 March 2009}}</ref><ref>{{cite web|title=Vaccine Discovery&nbsp;— Overview|publisher=[[Aeras Global TB Vaccine Foundation|Aeras]]|url=http://www.aeras.org/our-approach/vaccine-development.php?discovery-overview|accessdate=1 March 2009}}</ref><ref>{{cite web|title=Tuberculosis Vaccine|publisher=[[Crucell]]|url=http://www.crucell.com/R_and_D-Clinical_Development-Tuberculosis_Vaccine|accessdate=1 March 2009}}</ref> Some of these vaccines can be effectively administered without needles, making them preferable for areas where HIV is common.<ref>{{cite journal|author=Dietrich J, Andersen C, Rappuoli R, Doherty TM, Jensen CG, Andersen P|title=Mucosal Administration of Ag85B-ESAT-6 Protects against Infection with ''Mycobacterium tuberculosis'' and Boosts Prior Bacillus Calmette-Guérin Immunity|journal=[[Journal of Immunology]]|year=2006|volume=177|pages=6353–60|url=http://www.jimmunol.org/cgi/reprint/177/9/6353.pdf|format=PDF|accessdate=1 March 2009|issue=9}}</ref> All of these vaccines have been successfully tested in humans and are now in extended testing in TB-endemic regions. 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|author=Webber D, 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|author=Barder O, Kremer M, 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>
+epicfailure!!!!!!!!!!!!!!! Several new vaccines to prevent TB infection are being developed, among others by [[Aeras]] and [[TBVI]]. The first [[genetic recombination|recombinant]] tuberculosis [[vaccine]], Mtb72F, entered [[clinical trial]]s in the United States in 2004, sponsored by the [[National Institute of Allergy and Infectious Diseases]] (NIAID).<ref>{{cite press release |title=First U.S. Tuberculosis Vaccine Trial in 60 Years Begins |publisher=[[National Institute of Allergy and Infectious Diseases]] |date=26 January 2004|url=http://www.nih.gov/news/pr/jan2004/niaid-26.htm |accessdate=27 September 2009}}</ref><ref>{{cite journal|pmid=15187142|year=2004|author=Skeiky YA, Alderson MR, Ovendale PJ, Guderian JA, Brandt L, Dillon DC, Campos-Neto A, Lobet Y, Dalemans W|title=Differential immune responses and protective efficacy induced by components of a tuberculosis polyprotein vaccine, Mtb72F, delivered as naked DNA or recombinant protein|volume=172|issue=12|pages=7618–28|journal=J Immunol|url=http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=15187142}}</ref> A 2005 study showed that a [[DNA vaccine|DNA TB vaccine]] given with conventional [[chemotherapy]] can accelerate the disappearance of bacteria as well as protect against re-infection in mice; it may take four to five years to be available in humans.<ref name=Ha_2005>{{cite journal |author=Ha S, Jeon B, Youn J, Kim S, Cho S, Sung Y|title=Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of ''Mycobacterium tuberculosis'' |journal=Gene Ther |volume=12 |issue=7 |pages=634–8 |year=2005|pmid = 15690060|doi = 10.1038/sj.gt.3302465}}</ref> Another TB vaccine, [[MVA85A]], is currently in [[clinical trial|phase II trials]] in South Africa,<ref name=Ibanga_2006>{{cite journal |author=Ibanga H, Brookes R, Hill P, Owiafe P, Fletcher H, Lienhardt C, Hill A, Adegbola R, McShane H |title=Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design |journal=Lancet Infect Dis |volume=6 |issue=8 |pages=522–8 |year=2006 |doi= 10.1016/S1473-3099(06)70552-7| pmid = 16870530}}</ref> and is based on a genetically modified [[vaccinia]] virus. Many other strategies are also being used to develop novel vaccines,<ref>{{cite journal |author=Doherty TM, Andersen P |year=2005 |title=Vaccines for Tuberculosis: Novel Concepts and Recent Progress |journal=[[Clinical Microbiology Reviews]] |volume=18 |issue=4 |pages=687–702|doi=10.1128/CMR.18.4.687-702.2005|pmc=1265910 |pmid=16223953 |last1=Doherty |first1=TM |last2=Andersen |first2=P}}</ref> including both [[Vaccination#Types of vaccinations|subunit vaccines]] (fusion molecules composed of two [[genetic recombination|recombinant]] proteins delivered in an [[Immunologic adjuvant|adjuvant]]) such as Hybrid-1, HyVac4, or M72, and recombinant [[adenovirus]]es such as Ad35.<ref>{{cite web|title=Vaccine Research – Tuberculosis|publisher=[[Statens Serum Institut]]|url=http://www.ssi.dk/sw13853.asp|accessdate=1 March 2009| archiveurl =http://web.archive.org/web/20070717164308/http://www.ssi.dk/sw13853.asp| archivedate = 17 July 2007}}</ref><ref>{{cite web|title=Statens Serum Institut (SSI), Intercell (ICLL), and Aeras Global Tuberculosis Vaccine Foundation (Aeras) announce the initiation of a clinical trial for a novel vaccine candidate|date=4 December 2007|publisher=[[Aeras Global TB Vaccine Foundation|Aeras]]|url=http://www.aeras.org/newscenter/news-detail.php?id=705|accessdate=1 March 2009}}</ref><ref>{{cite web|title=Vaccine Discovery&nbsp;— Overview|publisher=[[Aeras Global TB Vaccine Foundation|Aeras]]|url=http://www.aeras.org/our-approach/vaccine-development.php?discovery-overview|accessdate=1 March 2009}}</ref><ref>{{cite web|title=Tuberculosis Vaccine|publisher=[[Crucell]]|url=http://www.crucell.com/R_and_D-Clinical_Development-Tuberculosis_Vaccine|accessdate=1 March 2009}}</ref> Some of these vaccines can be effectively administered without needles, making them preferable for areas where HIV is common.<ref>{{cite journal|author=Dietrich J, Andersen C, Rappuoli R, Doherty TM, Jensen CG, Andersen P|title=Mucosal Administration of Ag85B-ESAT-6 Protects against Infection with ''Mycobacterium tuberculosis'' and Boosts Prior Bacillus Calmette-Guérin Immunity|journal=[[Journal of Immunology]]|year=2006|volume=177|pages=6353–60|url=http://www.jimmunol.org/cgi/reprint/177/9/6353.pdf|format=PDF|accessdate=1 March 2009|issue=9}}</ref> All of these vaccines have been successfully tested in humans and are now in extended testing in TB-endemic regions. 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|author=Webber D, 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|author=Barder O, Kremer M, 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>
 An experimental vaccine, with positive results in mouse models, may be effective not only in preventing infection, but also in eradicating the infection once it has been established.<ref name="pmid21258338" /> A tuberculosis vaccine aimed at sterile ''Mtb'' eradication should be able to target latent ''Mtb'' as well as ''Mtb'' that causes early-stage tuberculosis.<ref>{{cite journal|author=Kaufmann SH|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>

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