Tuberculosis

: image is invalid or non-existent

Tuberculosis Classification & external resources
Chest X-ray of a patient suffering from tuberculosis
ICD-10	A15.-A19.
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 or Tuberculosis) is a common and deadly infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis. Tuberculosis most commonly attacks the lungs (as pulmonary TB) but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, bones, joints and even the skin. Other mycobacteria such as Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, and Mycobacterium microti can also cause tuberculosis, but these species do not usually infect healthy adults.Raviglione MC, O\'Brien RJ (2004). "Tuberculosis", in Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Isselbacher KJ, eds.: Harrison\'s Principles of Internal Medicine, 16th ed., McGraw-Hill Professional, 953–66. DOI:10.1036/0071402357. ISBN 0071402357. 

Over one-third of the world\'s population has been exposed to the TB bacterium, and new infections occur at a rate of one per second.World Health Organization (WHO). Tuberculosis Fact sheet N°104 - Global and regional incidence. March 2006, Retrieved on 6 October 2006. Not everyone infected develops the full-blown disease; asymptomatic, latent TB infection is most common. However, one in ten latent infections will progress to active TB disease, which, if left untreated, kills more than half of its victims.

In 2004, mortality and morbidity statistics included 14.6 million chronic active TB cases, 8.9 million new cases, and 1.6 million deaths, mostly in developing countries. In addition, a rising number of people in the developed world are contracting tuberculosis because their immune systems are compromised by immunosuppressive drugs, substance abuse, or HIV/AIDS.

The rise in HIV infections and the neglect of TB control programs have enabled a resurgence of tuberculosis.Iademarco MF, Castro KG (2003). "Epidemiology of tuberculosis". Seminars in respiratory infections 18 (4): 225-40. PMID 14679472.  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. (2006) "Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs—worldwide, 2000–2004". MMWR Morb Mortal Wkly Rep 55 (11): 301-5. PMID 16557213.  TB incidence varies widely, even in neighboring countries, apparently because of differences in health care systems.Sobero R, Peabody J (2006). "Tuberculosis control in Bolivia, Chile, Colombia and Peru: why does incidence vary so much between neighbors?". Int J Tuberc Lung Dis 10 (11): 1292–5. PMID 17131791.  The World Health Organization 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.World Health Organization (WHO). Stop TB Partnership. Retrieved on 3 October 2006.

Contents 1 Other names 2 Symptoms 3 Bacterial species 3.1 Evolution 4 Transmission 5 Pathogenesis 6 Diagnosis 7 Progression 8 Treatment 9 Prevention 9.1 Vaccines 10 Epidemiology 11 History 11.1 Folklore 11.2 Study and treatment 12 Infection of other animals 13 See also 14 References 15 Further reading 16 External links

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 (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.Tuberculosis Encyclopedia Britannica, 11th ed.Rudy\'s List of Archaic Medical Terms English Glossary of Archaic Medical Terms, Diseases and Causes of Death. Accessed 09 Oct 06 Miliary tuberculosis – now commonly known as disseminated TB– occurs when the infection invades the circulatory system resulting in lesions which have the appearance of millet seeds on X-ray.Disseminated tuberculosis NIH Medical Encyclopedia. Accessed 09 Oct 06

Symptoms

Further information: Tuberculosis classification

When the disease becomes active, 75% of the cases are pulmonary TB. 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 often a tendency to fatigue very easily.

In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB more common in immunosuppressed persons and young children. Extrapulmonary infection sites include the pleura, 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. Although extrapulmonary TB is not contagious, it may co-exist with pulmonary TB, which is contagious.Centers for Disease Control and Prevention (CDC), Division of Tuberculosis Elimination. Core Curriculum on Tuberculosis: What the Clinician Should Know. 4th edition (2000). Updated Aug 2003.

Bacterial species

Main article: Mycobacterium tuberculosis

Scanning electron micrograph of Mycobacterium tuberculosis

The primary cause of TB , Mycobacterium tuberculosis (M. TB), is an aerobic bacterium that divides every 16 to 20 hours, an extremely slow rate compared with other bacteria, which usually divide in less than an hour.Cox R (2004). "Quantitative relationships for specific growth rates and macromolecular compositions of Mycobacterium tuberculosis, Streptomyces coelicolor A3(2) and Escherichia coli B/r: an integrative theoretical approach". Microbiology 150 (Pt 5): 1413–26. PMID 15133103.  (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.Madison B (2001). "Application of stains in clinical microbiology.". Biotech Histochem 76 (3): 119-25. PMID 11475314.  MTB is a small rod-like bacillus that 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.Parish T, Stoker N (1999). "Mycobacteria: bugs and bugbears (two steps forward and one step back)". Mol Biotechnol 13 (3): 191–200. PMID 10934532. 

Using certain histological techniques 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).Madison B (2001). "Application of stains in clinical microbiology". Biotech Histochem 76 (3): 119-25. PMID 11475314.  The most common 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 3 other TB-causing mycobacteria: M. bovis, M. africanum and M. microti. The first two only very rarely cause disease in immunocompetent people. On the other hand, although M. microti is not usually pathogenic, it is possible that the prevalence of M. microti infections has been underestimated.Niemann S, Richter E, Dalügge-Tamm H, Schlesinger H, Graupner D, Königstein B, Gurath G, Greinert U, Rüsch-Gerdes S (2000). "Two cases of Mycobacterium microti derived tuberculosis in HIV-negative immunocompetent patients". Emerg Infect Dis 6 (5): 539-42. PMID 10998387. 

Other known pathogenic mycobacteria include Mycobacterium leprae, 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. (1997) "Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Medical Section of the American Lung Association". Am J Respir Crit Care Med 156 (2 Pt 2): S1–25. PMID 9279284. 

Evolution

During its evolution, 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.Rao K, Kauser F, Srinivas S, Zanetti S, Sechi L, Ahmed N, Hasnain S (2005). "Analysis of genomic downsizing on the basis of region-of-difference polymorphism profiling of Mycobacterium tuberculosis patient isolates reveals geographic partitioning". J Clin Microbiol 43 (12): 5978–82. PMID 16333085. 

Transmission

Further information: Transmission (medicine)

When people suffering from active pulmonary TB cough, sneeze, speak, kiss, or spit, they expel infectious aerosol droplets 0.5 to 5 µm in diameter. A single sneeze, for instance, can release up to 40,000 droplets.Cole E, Cook C (1998). "Characterization of infectious aerosols in health care facilities: an aid to effective engineering controls and preventive strategies". Am J Infect Control 26 (4): 453-64. PMID 9721404.  Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very low and the inhalation of just a single bacterium can cause a new infection.Nicas M, Nazaroff WW, Hubbard A (2005). "Toward understanding the risk of secondary airborne infection: emission of respirable pathogens". J Occup Environ Hyg 2 (3): 143–54. PMID 15764538. 

Tuberculosis is spread by aerosols created by coughing or sneezing.

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 illicit drugs (especially when sharing 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.Griffith D, Kerr C (1996). "Tuberculosis: disease of the past, disease of the present". J Perianesth Nurs 11 (4): 240-5. PMID 8964016. 

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.Causes of Tuberculosis. Mayo Clinic (2006-12-21). Retrieved on 2007-10-19.

Pathogenesis

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%.Onyebujoh, Phillip and Rook, Graham A. W. World Health Organization Disease Watch: Focus: Tuberculosis. December 2004. Accessed 07 October 2006.

TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within alveolar macrophages.Houben E, Nguyen L, Pieters J (2006). "Interaction of pathogenic mycobacteria with the host immune system". Curr Opin Microbiol 9 (1): 76–85. PMID 16406837.  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 apices, peripheral lymph nodes, kidneys, brain, and bone.Herrmann J, Lagrange P (2005). "Dendritic cells and Mycobacterium tuberculosis: which is the Trojan horse?". Pathol Biol (Paris) 53 (1): 35–40. PMID 15620608.  All parts of the body can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid.Agarwal R, Malhotra P, Awasthi A, Kakkar N, Gupta D (2005). "Tuberculous dilated cardiomyopathy: an under-recognized entity?". BMC Infect Dis 5 (1): 29. PMID 15857515. 

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.Kaufmann S (2002). "Protection against tuberculosis: cytokines, T cells, and macrophages". Ann Rheum Dis 61 Suppl 2: ii54-8. PMID 12379623.  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 center of tubercles. To the naked eye this has the texture of soft white cheese and was termed caseous necrosis.Grosset J (2003). "Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary". Antimicrob Agents Chemother 47 (3): 833-6. PMID 12604509. 

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.Kim J, Park Y, Kim Y, Kang S, Shin J, Park I, Choi B (2003). "Miliary tuberculosis and acute respiratory distress syndrome". Int J Tuberc Lung Dis 7 (4): 359-64. PMID 12733492. 

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

For more details on this topic, see Tuberculosis diagnosis.

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 delayed hypersensitivity parallel to those currently in a state of infection and thus the test must be used with caution, particularly with regard to persons from countries where TB immunization is common.Rothel J, Andersen P (2005). "Diagnosis of latent Mycobacterium tuberculosis infection: is the demise of the Mantoux test imminent?". Expert Rev Anti Infect Ther 3 (6): 981-93. PMID 16307510.  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.Nahid P, Pai M, Hopewell P (2006). "Advances in the diagnosis and treatment of tuberculosis". Proc Am Thorac Soc 3 (1): 103-10. PMID 16493157.  Rapid and inexpensive 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. However, in the majority of cases, a latent infection occurs that has no obvious symptoms. These dormant bacilli can produce tuberculosis in 2 to 23% of these latent cases, often many years after infection.Parrish N, Dick J, Bishai W (1998). "Mechanisms of latency in Mycobacterium tuberculosis". Trends Microbiol 6 (3): 107-12. PMID 9582936.  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 due to the lifestyle 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 malabsorption syndromes; or low body weight.

Twin studies in the 1950\'s showed that the course of TB infection was highly dependent on the genetics of the patient. At that time, it was rare that one identical twin would die and the other live.New Scientist, 16 June 2007 [1]

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.Mutlu G, Mutlu E, Bellmeyer A, Rubinstein I (2006). "Pulmonary adverse events of anti-tumor necrosis factor-alpha antibody therapy". Am J Med 119 (8): 639-46. PMID 16887405. 

Treatment

For more details on this topic, see Tuberculosis treatment.

Treatment for TB uses antibiotics to kill the bacteria. 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 12 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.O\'Brien R (1994). "Drug-resistant tuberculosis: etiology, management and prevention". Semin Respir Infect 9 (2): 104-12. PMID 7973169.  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. (2003) "Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States, 2003". MMWR Morb Mortal Wkly Rep 52 (31): 735-9. PMID 12904741. 

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.

In ancient times, available treatments focused more on dietary parameters. 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".Pliny the Elder, Natural History, quoted at Naphtali Lewis, Meyer Reinhold. Roman Civilization. While these particular remedies haven\'t been tested scientifically, it has been demonstrated that malnourished mice receiving a 2% protein diet suffer far higher mortality from tuberculosis than those receiving 20% protein receiving the same infectious challenge dose, and the progressively fatal course of the illness could be reversed by restoring the mice to the normal diet.John Chan, Yu Tian, Kathryn E. Tanakadagger, Ming S. Tsang, Keming Yu, Padmini Salgame, Dinah Carroll, Yvonne Kress, Rachel Teitelbaum, and Barry R. Bloom (1996-12-10). "Effects of protein calorie malnutrition on tuberculosis in mice". Proc Natl Acad Sci U S A 93 (25): 14857-61.  Moreover, statistics for immigrants in South London reveal an 8.5 fold increased risk of tuberculosis in (primarily Hindu Asian) lacto vegetarians, who frequently suffer protein malnutrition, compared to those of similar cultural backgrounds who ate meat and fish daily. (1995-02) "Vegetarian diet as a risk factor for tuberculosis in immigrant south London Asians". Thorax 50 (2): 175-80. 

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.Fine P, Floyd S, Stanford J, Nkhosa P, Kasunga A, Chaguluka S, Warndorff D, Jenkins P, Yates M, Ponnighaus J (2001). "Environmental mycobacteria in northern Malawi: implications for the epidemiology of tuberculosis and leprosy". Epidemiol Infect 126 (3): 379-87. PMID 11467795. 

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.Bonah C (2005). "The \'experimental stable\' of the BCG vaccine: safety, efficacy, proof, and standards, 1921–1933". Stud Hist Philos Biol Biomed Sci 36 (4): 696–721. PMID 16337557.  However, mass vaccination with BCG did not start until after World War II.Comstock G (1994). "The International Tuberculosis Campaign: a pioneering venture in mass vaccination and research". Clin Infect Dis 19 (3): 528-40. PMID 7811874.  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%.Bannon M (1999). "BCG and tuberculosis". Arch Dis Child 80 (1): 80-3. PMID 10325767. 

In South Africa, the country with the highest prevalence of TB, BCG is given to all children under the age of three.WHO/UNICEF Review of National Immunization Coverage 1980–2005: South Africa (PDF). World Health Organization (August 2006). Retrieved on 2007-06-08. 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 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.

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).National Institute of Allergy and Infectious Diseases (NIAID).First U.S. Tuberculosis Vaccine Trial in 60 Years Begins. National Institutes of Health News 26 January 2004. Retrieved on 19 October 2007. 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.Ha S, Jeon B, Youn J, Kim S, Cho S, Sung Y (2005). "Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis". Gene Ther 12 (7): 634-8. PMID 15690060.  A very promising TB vaccine, MVA85A, is currently in phase II trials in South Africa by a group led by Oxford University,Ibanga H, Brookes R, Hill P, Owiafe P, Fletcher H, Lienhardt C, Hill A, Adegbola R, McShane H (2006). "Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design". Lancet Infect Dis 6 (8): 522-8. PMID 16870530.  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.Webber, David and Kremer, Michael. Stimulating Industrial R&D for Neglected Infectious Diseases: Economic Perspectives (PDF). Bulletin of the World Health Organization 79(8), 2001, pp. 693–801.Barder, Owen; Kremer, Michael; Williams, Heidi. "Advance Market Commitments: A Policy to Stimulate Investment in Vaccines for Neglected Diseases," The Economists\' Voice, Vol. 3 (2006) Issue 3.

Epidemiology

Annual number of new reported TB cases. Data from WHO.World Health Organization (WHO). Global tuberculosis control - surveillance, planning, financing WHO Report 2006. Retrieved on 13 October 2006.

World TB incidence. Cases per 100,000; Red = >300, orange = 200–300; yellow = 100–200; green 50–100 and grey <50. Data from WHO, 2005.World Health Organization (WHO). Global tuberculosis control - surveillance, planning, financing WHO Report 2006. Retrieved on 13 October 2006.

According to the World Health Organization (WHO), nearly 2 billion people—one–third of the world\'s population—have been exposed to the tuberculosis pathogen.National Institute of Allergy and Infectious Diseases (NIAID). [2] 26 October 2005. Retrieved on 3 October 2006. "According to the World Health Organization (WHO), nearly 2 billion people, one-third of the world\'s population, have TB." Annually, 8 million people become ill with tuberculosis, and 2 million people die from the disease worldwide.Centers for Disease Control. Fact Sheet: Tuberculosis in the United States. 17 March 2005, Retrieved on 6 October 2006. 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.Stop TB Partnership. London tuberculosis rates now at Third World proportions. PR Newswire Europe Ltd. 4 December 2002. Retrieved on 3 October 2006.

In 2005, the country with the highest estimated incidence of TB was Swaziland, with 1262 cases per 100,000 people. India has the largest number of infections, with over 1.8 million cases. Global tuberculosis control: surveillance, planning, financing. WHO report 2007. Geneva, World Health Organization (WHO/HTM/TB/2007.376) 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;Notification rates of tuberculosis: by NHS Regional Office area, 1990-2001: Regional Trends 37 Office for National Statistics Retrieved on 13 October 2006. 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.World Health Organization (WHO). Global Tuberculosis Control Report, 2006 - Annex 1 Profiles of high-burden countries. (PDF) Retrieved on 13 October 2006. 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.Centers for Disease Control and Prevention (CDC). 2005 Surveillance Slide Set. (September 12, 2006) Retrieved on 13 October 2006.

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.Chaisson RE, Martinson NA (2008). "Tuberculosis in Africa—combating an HIV-driven crisis". N Engl J Med 358 (11): 1089–1092.  Smoking more than 20 cigarettes a day also increases the risk of TB by two- to four-times.Davies PDO, Yew WW, Ganguly D, et al. (2006). "Smoking and tuberculosis: the epidemiological association and pathogenesis". Trans R Soc Trop Med Hyg 100: 291–8. PMID 16325875. Jha P, Jacob B, Gajalakshmi V, et al. (2008). "A nationally representative case–control study of smoking and death in India". N Engl J Med 358 (11): 1137–1147.  Diabetes mellitus is also an important risk factor that is growing in importance in developing countries.Restrepo BI (2007). "Convergence of the tuberculosis and diabetes epidemics: renewal of old acquaintances". Clin Infect Dis 45: 436–8. 

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.Rothschild B, Martin L, Lev G, Bercovier H, Bar-Gal G, Greenblatt C, Donoghue H, Spigelman M, Brittain D (2001). "Mycobacterium tuberculosis complex DNA from an extinct bison dated 17,000 years before the present". Clin Infect Dis 33 (3): 305-11. PMID 11438894.  However, whether tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor, is currently unclear.Pearce-Duvet J (2006). "The origin of human pathogens: evaluating the role of agriculture and domestic animals in the evolution of human disease". Biol Rev Camb Philos Soc 81 (3): 369-82. PMID 16672105.  Skeletal remains show prehistoric humans (4000 BC) had TB, and tubercular decay has been found in the spines of mummies from 3000-2400 BC.Zink A, Sola C, Reischl U, Grabner W, Rastogi N, Wolf H, Nerlich A (2003). "Characterization of Mycobacterium tuberculosis complex DNAs from Egyptian mummies by spoligotyping". J Clin Microbiol 41 (1): 359-67. PMID 12517873.  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.Hippocrates. Aphorisms. Accessed 07 October 2006. Genetic studies suggest that TB was present in South America for about 2,000 years.Konomi N, Lebwohl E, Mowbray K, Tattersall I, Zhang D (2002). "Detection of mycobacterial DNA in Andean mummies". J Clin Microbiol 40 (12): 4738–40. PMID 12454182.  In South America, the earliest evidence of tuberculosis is associated with the Paracas-Caverna culture (circa 750 BC to circa 100 AD)."South America: Prehistoric Findings". Memorias do Instituto Oswaldo Cruz, Vol. 98 (Suppl.I) January 2003. Retrieved on 2007-02-08.

Folklore

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.Sledzik P, Bellantoni N (1994). "Brief communication: bioarcheological and biocultural evidence for the New England vampire folk belief". Am J Phys Anthropol 94 (2): 269-74. PMID 8085617.  Another folk belief attributed it to 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.Katharine Briggs, An Encyclopedia of Fairies "Consumption" (Pantheon Books, 1976) p. 80. ISBN 0-394-73467-X 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 at the time believed TB produced feelings of euphoria referred to as "Spes phthisica" or "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 which made women more beautiful and men more creative.Lawlor, Clark. "Transatlantic Consumptions: Disease, Fame and Literary Nationalism in the Davidson Sisters, Southey, and Poe". Studies in the Literary Imagination, Fall 2003. Available at findarticles.com. Retrieved on 2007-06-08.

Study and treatment

The study of tuberculosis 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.Y. A. Al-Sharrah (2003), "The Arab Tradition of Medical Education and its Relationship with the European Tradition", Prospects 33 (4), Springer.George Sarton, Introduction to the History of Science.
(cf. Dr. A. Zahoor and Dr. Z. Haq (1997). Quotations From Famous Historians of Science, Cyberistan.) He developed the method of quarantine in order to limit the spread of tuberculosis.David W. Tschanz, MSPH, PhD (August 2003). "Arab Roots of European Medicine", Heart Views 4 (2).

Although it was established that the pulmonary form was associated with \'tubercles\' by Dr Richard Morton in 1689,Who Named It? Léon Charles Albert Calmette. Retrieved on 6 October 2006.Trail R (1970). "Richard Morton (1637–1698)". Med Hist 14 (2): 166-74. PMID 4914685.  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.Zur Pathogenie der Impetigines. Auszug aus einer brieflichen Mitteilung an den Herausgeber. [Müller’s] Archiv für Anatomie, Physiologie und wissenschaftliche Medicin. 1839, page 82. 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.Kentucky: Mammoth Cave long on history. CNN. 27 February 2004. Accessed 08 October 2006. The first TB sanatorium opened in 1859 in Görbersdorf, Germany (today Sokołowsko, Poland) by Hermann Brehmer.McCarthy OR (2001). "The key to the sanatoria". J R Soc Med 94 (8): 413-7. PMID 11461990. 

In regard to this claim, The Times for January 15, 1859, page 5, column 5, carries an advertisement seeking funds for the Bournemouth Sanatorium for Consumption, referring to the balance sheet for the past year, and offering an annual report to prospective donors, implying that this sanatorium was in existence at least in 1858.

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.Nobel Foundation. The Nobel Prize in Physiology or Medicine 1905. Accessed 07 October 2006. 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.Waddington K (2004). "To stamp out "so terrible a malady": bovine tuberculosis and tuberculin testing in Britain, 1890–1939". Med Hist 48 (1): 29–48. PMID 14968644. 

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. In the 20th century, tuberculosis killed an estimated 100 million people.Torrey EF and Yolken RH. 2005. Their bugs are worse than their bite. Washington Post, April 3, p. B01. 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

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