MYCO BACTERIUM TUBERCULOSIS

Tuberculosis

Tuberculosis or TB (short for tubercles bacillus) is a common and often deadly infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis in humans. Tuberculosis usually attacks the lungs but can also affect other parts of the body. It is spread through the air when people who have the disease cough, sneeze, or spit. Most infections in humans result in an asymptomatic, latent infection, and about one in ten latent infections eventually progresses to active disease, which, if left untreated, kills more than 50% of its victims.
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. 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 be infected with M. tuberculosis, and new infections occur at a rate of about one per second. The proportion of people who become sick with tuberculosis each year is stable or falling worldwide but, because of population growth, the absolute number of new cases is still increasing. In 2007 there were an estimated 13.7 million chronic active cases, 9.3 million new cases, and 1.8 million deaths, mostly in developing countries. In addition, more people in the developed world contract tuberculosis because their immune systems are more likely to be compromised due to higher exposure to immunosuppressive drugs, substance abuse, or AIDS. 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 US population test positive.

Signs and symptoms

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

Scanning electron micrograph of Mycobacterium tuberculosis

Phylogenetic tree of the genus Mycobacterium.

When the disease becomes active, 75% of the cases are pulmonary TB, that is, TB in the lungs. Symptoms include chest pain, coughing up blood, and a productive, prolonged cough for more than three weeks. Systemic symptoms include fever, chills, night sweats, appetite loss, weight loss, pallor, and fatigue.
 Tuberculosis also has a specific odour attached to it, this has led to trained animals being used to vet samples as a method of early detection
In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB, collectively denoted extrapulmonary tuberculosis. This occurs more commonly in immunosuppressed persons and young children. Extrapulmonary infection sites include the pleura in tuberculosis pleurisy, the central nervous system in meningitis, the lymphatic system in scrofula of the neck, the genitourinary system in urogenital tuberculosis, and bones and joints in Pott's disease of the spine. An especially serious form is disseminated TB, more commonly known as miliary tuberculosis. Extrapulmonary TB may co-exist with pulmonary TB as well.

Causes

The primary cause of TB, Mycobacterium tuberculosis (MTB), is a small aerobic non-motile bacillus. High lipid content of this pathogen accounts for many of its unique clinical characteristics. It divides every 16 to 20 hours, an extremely slow rate compared with other bacteria, which usually divide in less than an hour. (For example, one of the fastest-growing bacteria is a strain of E. coli that can divide roughly every 20 minutes.) 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 due to the high lipid & mycolic acid content of its cell wall. 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 vitro.
 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][14] 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. M. africanum is not widespread, but in parts of Africa it is a significant cause of tuberculosis. 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. M. canetti is rare and seems to be limited to Africa, although a few cases have been seen in African emigrants. M. microti is mostly seen in immunodeficient people, although it is possible that the prevalence of this pathogen has been underestimated.
 Other known pathogenic mycobacteria include Mycobacterium leprae, Mycobacterium marinum, Mycobacterium avium and M. kansasii. The last two are part of the nontuberculous mycobacteria (NTM) group. Nontuberculous mycobacteria cause neither TB nor leprosy, but they do cause pulmonary diseases resembling TB.

Risk factors

Persons with silicosis have an approximately 30-fold greater risk for developing TB. Silica particles irritate the respiratory system, causing immunogenic responses such as phagocytosis, which, as a consequence, results in high lymphatic vessel deposits. It is this interference and blockage of macrophage function that increases the risk of tuberculosis. Persons with chronic renal failure and also on hemodialysis have an increased risk: 10–25 times greater than the general population. Persons with diabetes mellitus have a risk for developing active TB that is two to four times greater than persons without diabetes mellitus, and this risk is likely greater in persons with insulin-dependent or poorly controlled diabetes. Other clinical conditions that have been associated with active TB include gastrectomy with attendant weight loss and malabsorption, jejunoileal bypass, renal and cardiac transplantation, carcinoma of the head or neck, and other neoplasms (e.g., lung cancer, lymphoma, and leukemia).
 Given that silicosis greatly increases the risk of tuberculosis, more research about the effect of various indoor or outdoor air pollutants on the disease would be necessary. Some possible indoor sources of silica include paint, concrete and Portland cement. Crystalline silica is found in concrete, masonry, sandstone, rock, paint, and other abrasives. The cutting, breaking, crushing, drilling, grinding, or abrasive blasting of these materials may produce fine silica dust. It can also be in soil, mortar, plaster, and shingles. When you wear dusty clothing at home or in your car, you may be carrying silica dust that your family will breathe.
Low body weight is associated with risk of tuberculosis as well. A body mass index (BMI) below 18.5 increases the risk by 2—3 times. On the other hand, an increase in body weight lowers the risk. Patients with diabetes mellitus are at increased risk of contracting tuberculosis, and they have a poorer response to treatment, possibly due to poorer drug absorption.
 Other conditions that increase risk include the sharing of needles among IV drug users; recent TB infection or a history of inadequately treated TB; chest X-ray suggestive of previous TB, showing fibrotic lesions and nodules; prolonged corticosteroid therapy and other immunosuppressive therapy; Immunocompromised patients (30-40% of AIDS patients in the world also have TB) hematologic and reticuloendothelial diseases, such as leukemia and Hodgkin's disease; end-stage kidney disease; intestinal bypass; chronic malabsorption syndromes; vitamin D deficiency; and low body weight.
Twin studies in the 1940s showed that susceptibility to TB was heritable. If one of a pair of twins got TB, then the other was more likely to get TB if he was identical than if he was not. These findings were more recently confirmed by a series of studies in South Africa. Specific gene polymorphisms in IL12B have been linked to tuberculosis susceptibility.
Some drugs, including rheumatoid arthritis drugs that work by blocking tumor necrosis factor-alpha (an inflammation-causing cytokine), raise the risk of activating a latent infection due to the importance of this cytokine in the immune defense against TB.

Mechanism

Transmission

When people suffering from active pulmonary TB cough, sneeze, speak, or spit, they expel infectious aerosol droplets 0.5 to 5 µm in diameter. A single sneeze can release up to 40,000 droplets. 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.
 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. Others at risk include people in areas where TB is common, people who inject drugs using unsanitary needles, 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, patients immunocompromised by conditions such as HIV/AIDS, people who take immunosuppressant drugs, and health care workers serving these high-risk clients.
 Transmission can only occur from people with active — not latent — TB. 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. The chain of transmission can, therefore, be broken by isolating patients 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 at least 21 days, or three to four weeks, before the newly infected person can transmit the disease to others. TB can also be transmitted by eating meat infected with TB. Mycobacterium bovis causes TB in cattle.

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.
 However, if untreated, the death rate for these active TB cases is more than 50%.TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within the endosomes of alveolar macrophages. 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. 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. All parts of the body can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid.
 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 a granuloma, with lymphocytes surrounding the infected macrophages. The granuloma functions not only to prevent dissemination of the mycobacteria, but also provides a local environment for communication of cells of the immune system. Within the granuloma, T lymphocytes secrete cytokines such as interferon gamma, which activates macrophages to destroy the bacteria with which they are infected. Cytotoxic T cells can also directly kill infected cells, by secreting perforin and granulysin.
Importantly, bacteria are not always eliminated within the granuloma, but can become dormant, resulting in a latent infection.Another feature of the granulomas of human tuberculosis is the development of abnormal cell death, also called necrosis, in the center of tubercles. To the naked eye this has the texture of soft white cheese and was termed caseous necrosis.

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. Patients with this disseminated TB have a fatality rate near 100% if untreated. However, If treated early, the fatality rate is reduced to near 10%.
In many patients the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis. 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 pass on infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.
If untreated, infection with Mycobacterium tuberculosis can become lobar pneumonia.

 Diagnosis

Mycobacterium tuberculosis (stained red) in sputum

Tuberculosis is diagnosed definitively by identifying the causative organism (Mycobacterium tuberculosis) in a clinical sample (for example, sputum or pus). When this is not possible, a probable - although sometimes inconclusive - diagnosis may be made using imaging (X-rays or scans) and/or a tuberculin skin test (Mantoux test).
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.

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. 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. Tuberculin tests have the disadvantage of producing false negatives, especially when the patient is co-morbid with sarcoidosis, Hodgkins lymphoma, malnutrition, or most notably active tuberculosis disease. The newer interferon release assays (IGRAs) 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.These are not affected by immunization or environmental mycobacteria, so generate fewer false positive results.There is also evidence that the T-SPOT.TB IGRA is more sensitive than the skin test.
New TB tests have been developed that are fast and accurate. These include polymerase chain reaction assays for the detection of bacterial DNA. One such molecular diagnostics text gives results in 100 minutes and is being currently offered to 116 low and middle-income countries at a discount with support from WHO and the Bill and Melinda Gates foundation.

Prevention

Map showing the 22 high-burden countries (HBC) that according to WHO account for 80% of all new TB cases arising each year. The Global Plan is especially aimed at these countries.

TB prevention and control takes two parallel approaches. In the first, people with TB and their contacts are identified and then treated. Identification of infections often involves testing high-risk groups for TB. In the second approach, children are vaccinated to protect them from TB. No vaccine is available that provides reliable protection for adults. However, in tropical areas where the levels of other species of mycobacteria are high, exposure to nontuberculous mycobacteria gives some protection against TB.

The World Health Organization (WHO) declared TB a global health emergency in 1993, and the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aims to save 14 million lives between 2006 and 2015. Since humans are the only host of Mycobacterium tuberculosis, eradication would be possible. This goal would be helped greatly by an effective vaccine.

Vaccines

Many countries use Bacillus Calmette-Guérin (BCG) vaccine as part of their TB control programmes, especially for infants. According to the WHO, this is the most often used vaccine worldwide, with 85% of infants in 172 countries immunized in 1993. One country that notably does not widely administer BCG is the United States, where TB is rather uncommon. BCG was the first vaccine for TB and developed at the Pasteur Institute in France between 1905 and 1921. However, mass vaccination with BCG did not start until after World War II.^[ The protective efficacy of BCG for preventing serious forms of TB (e.g. meningitis) in children is greater than 80%; its protective efficacy for preventing pulmonary TB in adolescents and adults is variable, ranging from 0 to 80%.In South Africa, the country with the highest prevalence of TB, BCG is given to all children under age three. However, BCG is less effective in areas where mycobacteria are less prevalent; therefore BCG is not given to the entire population in these countries. In the USA, for example, BCG vaccine is not recommended except for people who meet specific criteria:
 Infants or children with negative skin test results who are continually exposed to untreated or ineffectively treated patients or will be continually exposed to multidrug-resistant TB.

• Healthcare workers considered on an individual basis in settings in which a high percentage of MDR-TB patients has been found, transmission of MDR-TB is likely, and TB control precautions have been implemented and were not successful.

BCG provides some protection against severe forms of pediatric TB, but has been shown to be unreliable against adult pulmonary TB, which accounts for most of the disease burden worldwide. Currently, there are more cases of TB on the planet than at any other time in history and most agree there is an urgent need for a newer, more effective vaccine that would prevent all forms of TB—including drug resistant strains—in all age groups and among people with HIV.
Several new vaccines to prevent TB infection are being developed. The first recombinant tuberculosis vaccine rBCG30, entered clinical trials in the United States in 2004, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). 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. A very promising TB vaccine, MVA85A, is currently in phase II trials in South Africa by a group led by Oxford University, and is based on a genetically modified vaccinia virus. Many other strategies are also being used to develop novel vaccines, 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. Some of these vaccines can be effectively administered without needles, making them preferable for areas where HIV is very common. 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. January 2011: Statens Serum Institute in Denmark has announced in the journal Nature Medicine that there are a new vaccine can fight tuberculosis before and after infection. It has been applied in mice successfully.^[79]

Screening

Mantoux tuberculin skin tests are often used for routine screening of high risk individuals.
Interferon-γ release assays are blood tests used in the diagnosis of some infectious diseases. There are currently two interferon-γ release assays available for the diagnosis of tuberculosis:

• QuantiFERON-TB Gold (licensed in US, Europe and Japan); and
• T-SPOT.TB, a form of ELISPOT (licensed in Europe).

Chest photofluorography has been used in the past for mass screening for tuberculosis.

Treatment

Treatment for TB uses antibiotics to kill the bacteria. Effective TB treatment is difficult, due to the unusual structure and chemical composition of the mycobacterial cell wall, which makes many antibiotics ineffective and hinders the entry of drugs. The two antibiotics most commonly used are rifampicin and isoniazid. However, instead of the short course of antibiotics typically used to cure other bacterial infections, TB requires much longer periods of treatment (around 6 to 24 months) to entirely eliminate mycobacteria from the body. 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. People with latent infections are treated to prevent them from progressing to active TB disease later in life.
Drug-resistant tuberculosis is transmitted in the same way as regular TB. Primary resistance occurs in persons infected with a resistant strain of TB. A patient 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. 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.
 The DOTS (Directly Observed Treatment Short-course) strategy of tuberculosis treatment recommended by WHO was based on clinical trials done in the 1970s by Tuberculosis Research Centre, Chennai, India. The country in which a person with TB lives can determine what treatment they receive. This is because multidrug-resistant tuberculosis is resistant to most first-line medications, the use of second-line antituberculosis medications is necessary to cure the patient. However, the price of these medications is high; thus poor people in the developing world have no or limited access to these treatments.

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.However, in the majority of cases, a latent infection occurs that has no obvious symptoms. These dormant bacilli can produce tuberculosis in 2–23% of these latent cases, often many years after infection. The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In patients co-infected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year.
Studies utilizing DNA fingerprinting of M. tuberculosis strains have shown that reinfection contributes more substantially to recurrent TB than previously thought, with between 12% and 77% of cases attributable to reinfection (instead of reactivation).

Age-standardized death from tuberculosis per 100,000 inhabitants in 2004. no data

  ≤ 10

  10-25

  25-50

  50-75

  75-100

  100-250

  250-500

  500-750

  750-1000

  1000-2000

  2000-3000

  ≥ 3000

In 2007, the prevalence of TB per 100,000 people was highest in sub-Saharan Africa, and was also relatively high in Asia.

Annual number of new reported TB cases. Data from WHO.

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. However, not all infections with M. tuberculosis cause TB disease and many infections are asymptomatic. In 2007, an estimated 13.7 million people had active TB disease, with 9.3 million new cases and 1.8 million deaths; the annual incidence rate varied from 363 per 100,000 in Africa to 32 per 100,000 in the Americas. Tuberculosis is the world's greatest infectious killer of women of reproductive age and the leading cause of death among people with HIV/AIDS.
 The rise in HIV infections and the neglect of TB control programs have enabled a resurgence of tuberculosis. 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. The rate at which new TB cases occur varies widely, even in neighboring countries, apparently because of differences in health care systems.
 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. The Philippines ranks fourth in the world for the number of cases of tuberculosis and has the highest number of cases per head in Southeast Asia. Almost two thirds of Filipinos have tuberculosis, and up to an additional five million people are infected yearly. 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. In Canada tuberculosis is still endemic in some rural areas.
The incidence of TB varies with age. In Africa, TB primarily affects adolescents and young adults. 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. There are a number of known factors that make people more susceptible to TB infection: worldwide the most important of these is HIV. Co-infection with HIV is a particular problem in Sub-Saharan Africa, due to the high incidence of HIV in these countries.^[102][103] Smoking more than 20 cigarettes a day also increases the risk of TB by two to four times. Diabetes mellitus is also an important risk factor that is growing in importance in developing countries. Other disease states that increase the risk of developing tuberculosis are Hodgkin lymphoma, end-stage renal disease, chronic lung disease, malnutrition, and alcoholism.
Diet may also modulate risk. For example, among immigrants in London from the Indian subcontinent, vegetarian Hindu Asians were found to have an 8.5 fold increased risk of tuberculosis, compared to Muslims who ate meat and fish daily. Although a causal link is not proved by this data, this increased risk could be caused by micronutrient deficiencies: possibly iron, vitamin B12 or vitamin D. Further studies have provided more evidence of a link between vitamin D deficiency and an increased risk of contracting tuberculosis.^[109][110] Globally, the severe malnutrition common in parts of the developing world causes a large increase in the risk of developing active tuberculosis, due to its damaging effects on the immune system. Along with overcrowding, poor nutrition may contribute to the strong link observed between tuberculosis and poverty.
Prisoners, especially in poor countries, are particularly vulnerable to infectious diseases such as HIV/AIDS and TB. Prisons provide a conditions that allow TB to spread rapidly, due to overcrowding, poor nutrition and a lack of health services. Since the early 1990s, TB outbreaks have been reported in prisons in many countries in Eastern Europe. The prevalence of TB in prisons is much higher than among the general population – in some countries as much as 40 times higher.

History

Tubercular decay has been found in the spines of Egyptian mummies. Pictured: Egyptian mummy in the British Museum

Tuberculosis has been present in humans since antiquity. The earliest unambiguous detection of Mycobacterium tuberculosis is in the remains of bison dated 18,000 years before the present. Whether tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor infecting a different species, is currently unclear. However, it is clear that M. tuberculosis is not directly descended from M. bovis, which seems to have evolved relatively recently.

 Skeletal remains from a Neolithic Settlement in the Eastern Mediterranean show prehistoric humans (7000 BC) had TB, and tubercular decay has been found in the spines of mummies from 3000–2400 BC. Phthisis is a Greek term for tuberculosis; around 460 BC, Hippocrates identified phthisis as the most widespread disease of the times involving coughing up blood and fever, which was almost always fatal. In South America, the earliest evidence of tuberculosis is associated with the Paracas-Caverna culture (circa 750 BC to circa 100 AD). Skeletal remains from prehistoric North America indicate that the disease was so common that "virtually every member of these late prehistoric communities had primary exposure to tuberculosis."

Other names

In the past, tuberculosis has been called consumption, because it seemed to consume people from within, with a bloody cough, fever, pallor, and long relentless wasting. Other names included phthisis (Greek for consumption) and phthisis pulmonalis; scrofula (in adults), affecting the lymphatic system and resulting in swollen neck glands; tabes mesenterica, TB of the abdomen and lupus vulgaris, TB of the skin; wasting disease; white plague, because sufferers appear markedly pale; king's evil, because it was believed that a king's touch would heal scrofula; and Pott's disease, or gibbus of the spine and joints.

Miliary tuberculosis—now commonly known as disseminated TB—occurs when the infection invades the circulatory system, resulting in millet-like seeding of TB bacilli in the lungs as seen on an X-ray. TB is also called Koch's disease, after the scientist Robert Koch.

Folklore

Before the Industrial Revolution, tuberculosis may sometimes have beenregarded as vampirism. 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. Furthermore, people who had TB exhibited symptoms similar to what people considered to be vampire traits. People with TB often have symptoms such as red, swollen eyes (which also creates a sensitivity to bright light), pale skin, extremely low body heat, a weak heart and coughing blood, suggesting the idea that the only way for the afflicted to replenish this loss of blood was by sucking blood. Another folk belief told that the affected individual was being forced, nightly, to attend fairy revels, so that the victim wasted away owing to lack of rest; this belief was most common when a strong connection was seen between the fairies and the dead.Similarly, but less commonly, it was attributed to the victims being "hagridden"—being transformed into horses by witches (hags) to travel to their nightly meetings, again resulting in a lack of rest.
TB was romanticized in the nineteenth century. Many people believed TB produced feelings of euphoria referred to as Spes phthisica ("hope of the consumptive"). It was believed that TB sufferers who were artists had bursts of creativity as the disease progressed. It was also believed that TB sufferers acquired a final burst of energy just before they died that made women more beautiful and men more creative. In the early 20th century, some believed TB to be caused by masturbation.

Study and treatment

The study of tuberculosis, sometimes known as phthisiatry, dates back to The Canon of Medicine written by Ibn Sina (Avicenna) in the 1020s. He was the first physician to identify pulmonary tuberculosis as a contagious disease, the first to recognise the association with diabetes, and the first to suggest that it could spread through contact with soil and water Avicenna adopted, from the Greeks, the theory that epidemics are caused by pollution in the air (miasma, a noxious form of "bad air").He developed the method of quarantine in order to limit the spread of tuberculosis. In ancient times, treatments focused on sufferers' diets. Pliny the Elder described several methods in his Natural History: "wolf's liver taken in thin wine, the lard of a sow that has been fed upon grass, or the flesh of a she-ass taken in broth".
Although it was established that the pulmonary form was associated with "tubercles" by Dr Richard Morton in 1689,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.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. The first TB sanatorium opened in 1854 in Görbersdorf, Germany (today Sokołowsko, Poland) by Hermann Brehmer.
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. 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.
The first genuine success in immunizing against tuberculosis was developed from attenuated bovine-strain tuberculosis by Albert Calmette and Camille Guérin in 1906. It was called "BCG" (Bacillus of Calmette and Guérin). The BCG vaccine was first used on humans in 1921 in France, but it was not until after World War II that BCG received widespread acceptance in the USA, Great Britain, and Germany.
 Tuberculosis, or "consumption" as it was commonly known, 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. In the 20th century, tuberculosis killed an estimated 100 million people. 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 pressured to enter sanatoria that resembled prisons; the sanatoria for the middle and upper classes offered excellent care and constant medical attention. 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).

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. The disease remained such a significant threat to public health, that when the Medical Research Council was
 formed in Britain in 1913, its initial focus was tuberculosis research.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 bronchoscopy and suction as well as the pneumothorax or plombage technique — collapsing an infected lung to "rest" it and allow lesions to heal — a technique that was of little benefit and was mostly discontinued by the 1950s. 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. It is therefore thought to increase the effectiveness of the chemotherapy. ^[
Hopes that the disease could be completely eliminated have been dashed since the rise of drug-resistant strains in the 1980s. For example, tuberculosis cases in Britain, numbering around 117,000 in 1913, had fallen to around 5,000 in 1987, but cases rose again, reaching 6,300 in 2000 and 7,600 cases in 2005. Due to the elimination of public health facilities in New York and the emergence of HIV, there was a resurgence of TB in the late 1980s. The number of patients failing to complete their course of drugs is high. New York had to cope with more than 20,000 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 (WHO) in 1993. Every year, nearly half a million new cases of multidrug-resistant tuberculosis (MDR-TB) are estimated to occur worldwide.

Age

Tuberculosis has been around for millennia. The oldest known human remains showing signs of tuberculosis infection are 9,000 years old. During this period, M. tuberculosis has lost numerous coding and non-coding regions in its genome, losses that can be used to distinguish between strains of the bacteria. The implication is that M. tuberculosis strains differ geographically, so their genetic differences can be used to track the origins and movement of each strain.
A new species has recently been discovered for the first time in 20 years.

Pathophysiology

M. tuberculosis requires oxygen to grow. It does not retain any bacteriological stain due to high lipid content in its wall, and thus is neither Gram positive nor Gram negative; hence Ziehl-Neelsen staining, or acid-fast staining, is used. While Mycobacteria do not seem to fit the Gram-positive category from an empirical standpoint (i.e., they do not retain the crystal violet stain), they are classified as acid-fast Gram-positive bacteria due to their lack of an outer cell membrane.
 M. tuberculosis divides every 15–20 hours, which is extremely slow compared to other bacteria, which tend to have division times measured in minutes (Escherichia coli (E. coli) can divide roughly every 20 minutes). It is a small bacillus that can withstand weak disinfectants and can survive in a dry state for weeks. Its unusual cell wall, rich in lipids (e.g., mycolic acid), is likely responsible for this resistance and is a key virulence factor.
 When in the lungs, M. tuberculosis is taken up by alveolar macrophages, but they are unable to digest the bacterium. Its cell wall prevents the fusion of the phagosome with a lysosome. Specifically, M. tuberculosis blocks the bridging molecule, early endosomal autoantigen 1 (EEA1); however, this blockade does not prevent fusion of vesicles filled with nutrients. Consequently, the bacteria multiply unchecked within the macrophage. The bacteria also carried the UreC gene, which prevents acidification of the phagosome. The bacteria also evade macrophage-killing by neutralizing reactive nitrogen intermediates.
The ability to construct M. tuberculosis mutants and test individual gene products for specific functions has significantly advanced our understanding of the pathogenesis and virulence factors of M. tuberculosis. Many secreted and exported proteins are known to be important in pathogenesis.

Strain variation

M. tuberculosis Comes from the genus Mycobacterium,which is composed of approximately 100 recognized and proposed species. The most familiar of the species are Mycobacterium tuberculosis and Mycobacterium leprae(Leprosy). M. tuberculosis appears to be genetically diverse. A genetic diversity results in significant phenotypic differences between clinical isolates. M. tuberculosis exhibits a biogeographic population structure and different strain lineages are associated with different geographic regions. Phenotypic studies suggest that this strain variation never has implications for the development of new diagnostics and vaccines. Micro-evolutionary variation affects the relative fitness and transmission dynamics of antibiotic-resistant strains.

Hypervirulent strains

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

Microscopy

M. tuberculosis is characterized by caseating granulomas containing Langhans giant cells, which have a "horseshoe" pattern of nuclei. Organisms are identified by their red color on acid-fast staining.

Genome

The genome of the H37Rv strain was published in 1998. Its size is 4 million base pairs, with 3959 genes. 40% of these genes have had their function characterised, with possible function postulated for another 44%. Within the genome are also 6 pseudogenes.
The genome contains 250 genes involved in fatty acid metabolism, with 39 of these involved in the polyketide metabolism generating the waxy coat. Such large numbers of conserved genes shows the evolutionary importance of the waxy coat to pathogen survival.
10% of the coding capacity is taken up by 2 clustered gene families that encode acidic glycine rich proteins. These proteins have a conserved N-terminal motif, deletion of which impairs growth in macrophages and granulomas.
 Nine non-coding sRNAs have been characterised in M. tuberculosis with a further 56 predicted in a bioinformatics screen

Society and culture

Through its affecting important historical figures, tuberculosis has influenced particularly European history, and become a theme in art – mostly literature, music, and film.

Public health

Tuberculosis is one of the three primary diseases of poverty along with AIDS and malaria.^[160] The Global Fund to Fight AIDS, Tuberculosis and Malaria was started in 2002 to raise finances to address these infectious diseases. Globalization has led to increased opportunities for disease spread. A tuberculosis scare occurred in 2007 when Andrew Speaker flew on a transatlantic flight infected with multi-drug-resistant tuberculosis.
In the United States, the National Center for HIV, STD, and TB Prevention, as part of the Centers for Disease Control and Prevention (CDC), is responsible for public health surveillance and prevention research.

Notable victims

Research

The Mycobacterium Tuberculosis Structural Genomics Consortium is a global consortium of scientists conducting research regarding the diagnosis and treatment of tuberculosis. They are attempting to determine the 3-dimensional structures of proteins from M. Tuberculosis.

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.
Mycobacterium bovis causes TB in cattle. An effort to eradicate bovine tuberculosis from the cattle and deer herds of New Zealand is underway. It has been found that herd infection is more likely in areas where infected natural reservoir such as Australian brush-tailed possums come into contact with domestic livestock at farm/bush borders. 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 Ireland and the United Kingdom, badgers have been identified as one vector species for the transmission of bovine tuberculosis. As a result, governments have come under pressure from some quarters, primarily dairy farmers, to mount an active campaign of eradication of badgers in certain areas with the purpose of reducing the incidence of bovine TB. The effectiveness of culling on the incidence of TB in cattle is a contentious issue, with proponents and opponents citing their own studies to support their position. For instance, a study by an Independent Study Group on badger culling reported on 18 June 2007 that it was unlikely to be effective and would only make a “modest difference” to the spread of TB and that "badger culling cannot meaningfully contribute to the future control of cattle TB"; in contrast, another report concluded that this policy would have a significant impact. On 4 July 2008, the UK government decided against a proposed random culling policy.