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Tuberculosis

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

   CAPTION: Tuberculosis
   Classifications and external resources

   Chest X-ray of a patient with advanced pulmonary tuberculosis
     ICD- 10   A 15.- A 19.
     ICD- 9    010- 018
      OMIM     607948
   DiseasesDB  8515
   MedlinePlus 000077 000624
    eMedicine  med/2324  emerg/618 radio/411
   MeSH        C01.252.410.040.552.846

   Tuberculosis (abbreviated as TB for Tubercle Bacillus) is a common and
   deadly infectious disease caused by the bacterium Mycobacterium
   tuberculosis, which most commonly affects the lungs ( pulmonary TB) but
   can also affect the central nervous system, lymphatic system,
   circulatory system, genitourinary system, bones and joints.

   Over a half of the world's population now has the TB bacterium in their
   bodies and new infections are occurring at a rate of one per second.
   Not everyone who is infected develops the disease and asymptomatic
   latent TB infection is most common. However, one in ten latent
   infections will progress to active TB disease which, if left untreated,
   will kill more than half of its victims. In 2004, 14.6 million people
   had active TB and there were 8.9 million new cases and 1.7 million
   deaths, mostly in developing countries. A rising number of people in
   the developed world contract tuberculosis because their immune systems
   are compromised by immunosuppressive drugs, substance abuse, or
   HIV/AIDS.

   The rise in HIV infection levels and the neglect of TB control programs
   have caused a resurgence of tuberculosis, and drug-resistant strains of
   TB are also emerging. The World Health Organization declared TB a
   global health emergency in 1993, and the Stop TB Partnership proposed a
   Global Plan to Stop Tuberculosis which aims to save 14 million lives
   between 2006 and 2015.

Other names

   In the past, tuberculosis was 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, 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 of the spine and joints. Miliary TB is an archaic term that is
   still occasionally used, and is when the infection invades the
   circulatory system resulting in x-ray lesions with the appearance of
   millet seeds. This form of TB is now more commonly named disseminated
   TB.

Symptoms

   In the patients where TB becomes an active disease, 75% of these cases
   affect the lungs, where the disease is called pulmonary TB. Symptoms
   include a productive, prolonged cough of more than three weeks
   duration, chest pain, and coughing up blood. Systemic symptoms include
   fever, chills, night sweats, appetite loss, weight loss, and easy
   fatigability.

   When the infection spreads out of the lungs, extrapulmonary sites
   include the pleura, central nervous system in (meningitis), lymphatic
   system in ( scrofula of the neck), genitourinary system in urogenital
   tuberculosis, and bones and joints in Pott's disease of the spine. An
   especially serious form is disseminated, or miliary tuberculosis.
   Extrapulmonary forms are more common in immunosuppressed persons and in
   young children. Infectious pulmonary TB may co-exist with
   extrapulmonary TB, which is not contagious.

Bacterial species

   Scanning electron micrograph of Mycobacterium tuberculosis.
   Enlarge
   Scanning electron micrograph of Mycobacterium tuberculosis.

   The cause of tuberculosis, Mycobacterium tuberculosis (MTB), is a
   slow-growing aerobic bacterium that divides every 16 to 20 hours; this
   is extremely slow compared to other bacteria that have division times
   measured in minutes. In contrast, one of the fastest growing bacteria
   is a strain of E. coli that can divide roughly every 20 minutes. As MTB
   only has one phospholipid outer membrane, it is classified as a
   Gram-positive bacteria. However, if a Gram stain is performed, MTB
   either stains very weakly Gram-positive, or does not retain dye, due to
   the high lipid content of its cell wall. MTB is a small rod-like
   bacillus which can withstand weak disinfectants and can survive in a
   dry state for weeks. Normally, the bacteria can only grow within a host
   organism, so in vitro culture of M. tuberculosis took a long time to
   develop, but is now a routine laboratory procedure.

   MTB is identified microscopically by its staining characteristics: it
   retains certain stains after being treated with acidic solution, and is
   thus classified as an " acid-fast bacillus" or AFB. In the most common
   staining technique, the Ziehl-Neelsen stain, AFB are stained a bright
   red which stands out clearly against a blue background. Acid-fast
   bacilli can also be visualized by fluorescent microscopy, and by an
   auramine-rhodamine stain.

   The M. tuberculosis complex includes 3 other mycobacteria which can
   cause tuberculosis: M. bovis, M. africanum and M. microti. The first
   two are very rare causes of disease in immunocompetent people, and M.
   microti is not usually pathogenic, although it is possible that the
   prevalence of M. microti infections has been underestimated. Other
   pathogenic mycobacteria are known, such as Mycobacterium leprae,
   Mycobacterium avium and M. kansasii. The last two are part of the group
   defined as Nontuberculous mycobacteria (NTM). Nontuberculous
   mycobacteria are mycobacteria that are not part of the M. tuberculosis
   complex, and do not cause leprosy, but do cause pulmonary diseases
   resembling tuberculosis.

Transmission

   TB is spread by aerosol droplets expelled by people with the active
   disease of the lungs when they cough, sneeze, speak, or spit. These
   infectious droplets are 0.5 to 5 µm in diameter and about 40,000 can be
   produced by a single sneeze. People with prolonged, frequent, or
   intense contact are at highest risk of becoming infected, with an
   estimated 22% infection rate. A person with untreated, active
   tuberculosis can infect 10-15 other people per year. Others at risk
   include those from areas where TB is common, patients immunocompromised
   by conditions such as HIV/AIDS, residents and employees of high-risk
   congregate settings, health care workers who serve high-risk clients,
   medically underserved, low-income populations, high-risk racial or
   ethnic minority populations, children exposed to adults in high-risk
   categories, and people who inject illicit drugs.

   Transmission can only occur from people with active—not latent— TB
   disease. The probability of transmission from one person to another
   depends upon the quantity of the infectious droplets expelled by the
   patient, the effectiveness of ventilation, the duration of exposure,
   and the virulence of the Mycobacterium tuberculosis strain. The chain
   of transmission can therefore be broken by isolating patients with
   active disease and starting effective anti-tuberculous therapy.

Pathogenesis

   Mycobacterium tuberculosis (stained red) in sputum.
   Enlarge
   Mycobacterium tuberculosis (stained red) in sputum.

   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 alveolar macrophages. The
   primary site of infection in the lungs is called the Ghon focus.
   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
   the more distant tissues and organs where secondary TB lesions can
   develop in lung apexes, peripheral lymph nodes, kidneys, brain, and
   bone.

   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 (CD4+) secrete
   cytokines such as interferon gamma, which activates macrophages to
   destroy the bacteria with which they are infected. T lymphocytes (CD8+)
   can also directly kill infected cells.

   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
   cell death, also called necrosis, in the centre 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 of approximately 20%, even with intensive treatment.

   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.

Diagnosis

   Mantoux tuberculin skin test.
   Enlarge
   Mantoux tuberculin skin test.

   Tuberculosis can be a difficult disease to diagnose, due mainly to the
   difficulty in culturing this slow-growing organism in the laboratory. A
   complete medical evaluation for TB must include a medical history, a
   chest X-ray, and a physical examination. Tuberculosis radiology is used
   in the diagnosis of TB. It may also include a tuberculin skin test, a
   serological test, microbiological smears and cultures. 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 purified protein derivatives of M. tuberculosis. Those
   immunized for TB or with past-cleared infection will respond with
   parallel delayed hypersensitivity to those currently in a state of
   infection and thus must be used with caution, particularly with regard
   to persons from countries where TB immunization is common. New TB tests
   are being developed that offer the hope of cheap, fast and more
   accurate TB testing. These use polymerase chain reaction detection of
   bacterial DNA and antibody assays to detect the release of interferon
   gamma in response to mycobacteria. Rapid and cheap diagnosis will be
   particularly valuable in the developing world.

Progression

   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 to 5% of cases—this occurs soon after infection; in
   post-primary TB, secondary TB, or reactivation TB disease of dormant
   bacilli— 5 to 9% of cases—it occurs 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.

   Other conditions that increase risk include drug injection, mainly
   because of the life style of 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; diabetes mellitus; silicosis;
   prolonged corticosteroid therapy and other immunosuppressive therapy;
   head and neck cancers; hematologic and reticuloendothelial diseases,
   such as leukemia and Hodgkin's disease; end-stage kidney disease;
   intestinal bypass or gastrectomy; chronic mal-absorption syndromes; or
   low body weight.

   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.

Treatment

   Treatment for TB uses antibiotics to kill the bacteria. The two
   antibiotics most commonly used are rifampicin and isoniazid. However,
   these treatments are more difficult than the short courses of
   antibiotics used to cure most bacterial infections as long periods of
   treatment (around 6 to 12 months) are needed 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 these latent infections are treated
   to prevent them from progressing to active TB disease later in life.
   However, treatment using Rifampin and Pyrazinamide is not risk-free.
   The Centers for Disease Control and Prevention (CDC) notified
   healthcare professionals of revised recommendations against the use of
   rifampin plus pyrazinamide for treatment of latent tuberculosis
   infection, due to high rates of hospitalization and death from liver
   injury associated with the combined use of these drugs.

   Drug resistant tuberculosis is transmitted in the same way as regular
   TB. Primary resistance occurs in persons who are 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 TB (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.

Prevention

   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. Unfortunately, no vaccine is available that provides reliable
   protection for adults. However, in tropical areas where the incidence
   of atypical mycobacteria is high, exposure to nontuberculous
   mycobacteria gives some protection against TB.

Vaccines

   Many countries use BCG vaccine as part of their TB control programs,
   especially for infants. This 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 from 0 to 80%.

   In South Africa, the country with the highest prevelance of TB, BCG is
   given to all children under the age of three. However, the
   effectiveness of BCG is lower 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 result 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 high percentage of MDR-TB patients has been found,
       transmission of MDR-TB is likely, and TB control precautions have
       been implemented and not successful.

   Several new vaccines to prevent TB infection are being developed. The
   first recombinant tuberculosis vaccine 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. The
   only TB vaccine currently in phase III trials is MVA85A, which is being
   trialed in South Africa by a group led by Oxford University, and is
   based on a genetically modified vaccinia virus. Because of the
   limitations of current vaccines, researchers and policymakers are
   promoting new economic models of vaccine development including prizes,
   tax incentives and advance market commitments.

Epidemiology

   Annual number of new reported TB cases. Data from WHO.
   Enlarge
   Annual number of new reported TB cases. Data from WHO.
   World TB incidence. Cases per 100,000; Red = >300, orange = 200-300;
   yellow = 100-200; green 50-100 and grey <50. Data from WHO, 2006.
   Enlarge
   World TB incidence. Cases per 100,000; Red = >300, orange = 200-300;
   yellow = 100-200; green 50-100 and grey <50. Data from WHO, 2006.

   According to the World Health Organization (WHO), nearly 2 billion
   people—one–third of the world's population—have tuberculosis. Annually,
   8 million people become ill with tuberculosis, and 2 million people die
   from the disease worldwide. In 2004, around 14.6 million people had
   active TB disease with 9 million new cases. The annual incidence rate
   varies from 356 per 100,000 in Africa to 41 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.

   In 2004, the country with the highest incidence of TB was South Africa,
   with 718 cases per 100,000 people. India has the largest number of
   infections, with over 1.8 million cases. In developed countries,
   tuberculosis is less common and is mainly an urban disease. In the
   United Kingdom, TB incidences range from 40 per 100,000 in London to
   less than 5 per 100,000 in the rural South West of England.; the
   national average is 13 per 100,000. The highest rates in Western Europe
   are in Portugal (42 per 100,000) and Spain (20 per 100,000). These
   rates compare with 113 per 100,000 in China and 64 per 100,000 in
   Brazil. In the United States, the overall tuberculosis case rate was
   4.9 per 100,000 persons in 2004.

   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 America, TB is mainly a disease of
   older people.

   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. Smoking more than
   20 cigarettes a day also increases the risk of TB by two- to
   four-times.

History

   Tubercular decay has been found in the spines of Egyptian mummies.
   Pictured: Egyptian mummy in the British Museum.
   Enlarge
   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 17,000 years before the present. However, whether
   tuberculosis originated in cattle and then transferred to humans, or
   diverged from a common ancestor, is currently unclear. Skeletal remains
   show prehistoric humans (4000 BCE) had TB, and tubercular decay has
   been found in the spines of Egyptian mummies from 3000-2400 BCE.
   Phthisis is a Greek term for tuberculosis; 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.
   Genetic studies suggest that TB was present in The Americas from about
   the year 100 CE.

   Before the Industrial Revolution, tuberculosis may sometimes have been
   regarded 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 and coughing blood,
   suggesting the idea that the only way for the afflicted to replenish
   this loss of blood was by sucking blood.

   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 1859 in
   Sokołowsko, Poland by Hermann Brehmer.
   Dr. Robert Koch discovered the tuberculosis bacilli.
   Enlarge
   Dr. Robert Koch discovered the tuberculosis bacilli.

   The bacillus causing tuberculosis, Mycobacterium tuberculosis, was
   identified and described on March 24, 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 Guerin in 1906. It was called 'BCG' ( Bacillus of Calmette
   and Guerin). The BCG vaccine was first used on humans in 1921 in
   France, but it wasn't 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. 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. 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).
   Public health campaigns tried to halt the spread of TB.
   Enlarge
   Public health campaigns tried to halt the spread of TB.

   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 1907-08 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.

   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. 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.

   Hope 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 50,000 in 1955, had
   fallen to around 5,500 in 1987, but in 2000 there were over 7,000
   confirmed cases. Due to the elimination of public health facilities in
   New York and the emergence of HIV, there was a resurgence in the late
   1980s. 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.

Infection of 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.

   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 vector species 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 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.

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