Tuberculosis

Tuberculosis, MTB, or TB (short for tubercle bacillus),in the past also called phthisis, phthisis pulmonalis,or consumption, is a widespread, and in many casesfatal, infectious disease caused by various strains ofmycobacteria, usuallyMycobacterium tuberculosis.[1] Tu-berculosis typically attacks the lungs, but can also aectother parts of the body. It is spread through the air whenpeople who have an active TB infection cough, sneeze,or otherwise transmit respiratory uids through the air.[2]Most infections do not have symptoms, known as latenttuberculosis. About one in ten latent infections eventuallyprogresses to active disease which, if left untreated, killsmore than 50% of those so infected.The classic symptoms of active TB infection are a chroniccough with blood-tinged sputum, fever, night sweats, andweight loss (the latter giving rise to the formerly commonterm for the disease, consumption). Infection of otherorgans causes a wide range of symptoms. Diagnosis ofactive TB relies on radiology (commonly chest X-rays),as well as microscopic examination and microbiologicalculture of body uids. Diagnosis of latent TB relies on thetuberculin skin test (TST) and/or blood tests. Treatmentis dicult and requires administration of multiple antibi-otics over a long period of time. Social contacts are alsoscreened and treated if necessary. Antibiotic resistanceis a growing problem in multiple drug-resistant tubercu-losis (MDR-TB) infections. Prevention relies on screen-ing programs and vaccination with the bacillus Calmette-Gurin vaccine.One-third of the worlds population is thought to havebeen infected withM. tuberculosis,[3] with new infectionsoccurring in about 1% of the population each year.[4] In2007, an estimated 13.7 million chronic cases were ac-tive globally,[5] while in 2013, an estimated 9 million newcases occurred.[6] In 2013 there were between 1.3 and 1.5million associated deaths,[6][7] most of which occurred indeveloping countries.[8] The total number of tuberculo-sis cases has been decreasing since 2006, and new caseshave decreased since 2002.[8] The rate of tuberculosis indierent areas varies across the globe; about 80% of thepopulation inmanyAsian andAfrican countries tests pos-itive in tuberculin tests, while only 510% of the UnitedStates population tests positive.[1] More people in the de-veloping world contract tuberculosis because of a poorimmune system, largely due to high rates of HIV infec-tion and the corresponding development of AIDS.[9]

1 Signs and symptoms

TuberculosisSymptoms of

(Established) pulmonary tuberculosis Productive cough

Primary pulmonary tuberculosis

Structural abnormalities

Tuberculous pleuritis Chest pain

Miliary tuberculosis

Return of dormant tuberculosis Cough with increasing mucusCoughing up blood

Extrapulmonary tuberculosis

Lymph nodes

Genitourinary tractBone and joint sites

Meninges

Poor appetite

Common sites:

Fever

Dry cough

Weight loss

Night sweats

Gastrointestinal symptoms

Weakness

Grey lines = More specific

Colored lines = Overlapping

The main symptoms of variants and stages of tuberculosis aregiven,[10] with many symptoms overlapping with other variants,while others are more (but not entirely) specic for certain vari-ants. Multiple variants may be present simultaneously.

Tuberculosis may infect any part of the body, but mostcommonly occurs in the lungs (known as pulmonarytuberculosis).[11] Extrapulmonary TB occurs when tuber-culosis develops outside of the lungs, although extrapul-monary TB may coexist with pulmonary TB, as well.[11]

General signs and symptoms include fever, chills, nightsweats, loss of appetite, weight loss, and fatigue.[11] Sig-nicant nail clubbing may also occur.[12]

1.1 Pulmonary

If a tuberculosis infection does become active, itmost commonly involves the lungs (in about 90% ofcases).[9][13] Symptoms may include chest pain anda prolonged cough producing sputum. About 25%of people may not have any symptoms (i.e. theyremain asymptomatic).[9] Occasionally, people maycough up blood in small amounts, and in very rarecases, the infection may erode into the pulmonaryartery or a Rasmussens aneurysm, resulting in massivebleeding.[11][14] Tuberculosis may become a chronic ill-ness and cause extensive scarring in the upper lobes ofthe lungs. The upper lung lobes are more frequently af-fected by tuberculosis than the lower ones.[11] The reasonfor this dierence is not entirely clear.[1] It may be due ei-

1

2 2 CAUSES

ther to better air ow,[1] or to poor lymph drainage withinthe upper lungs.[11]

1.2 ExtrapulmonaryIn 1520% of active cases, the infection spreadsoutside the lungs, causing other kinds of TB.[15]These are collectively denoted as extrapulmonarytuberculosis.[16] Extrapulmonary TB occurs more com-monly in immunosuppressed persons and young children.In those with HIV, this occurs in more than 50% ofcases.[16] Notable extrapulmonary infection sites includethe pleura (in tuberculous pleurisy), the central nervoussystem (in tuberculous meningitis), the lymphatic system(in scrofula of the neck), the genitourinary system (inurogenital tuberculosis), and the bones and joints (in Pottdisease of the spine), among others. When it spreads tothe bones, it is also known as osseous tuberculosis.[17] aform of osteomyelitis.[1] Sometimes, bursting of a tuber-cular abscess through skin results in tuberculous ulcer.[18]An ulcer originating from nearby infected lymph nodes ispainless, slowly enlarging and has an appearance of washleather.[19] A potentially more serious, widespread formof TB is called disseminated TB, commonly known asmiliary tuberculosis.[11] Miliary TB makes up about 10%of extrapulmonary cases.[20]

2 Causes

2.1 MycobacteriaMain article: Mycobacterium tuberculosisThe main cause of TB is Mycobacterium tuberculosis, a

Scanning electron micrograph of M. tuberculosis

small, aerobic, nonmotile bacillus.[11] The high lipid con-tent of this pathogen accounts for many of its unique clin-

ical characteristics.[21] It divides every 16 to 20 hours,which is an extremely slow rate compared with other bac-teria, which usually divide in less than an hour.[22] My-cobacteria have an outer membrane lipid bilayer.[23] If aGram stain is performed, MTB either stains very weaklyGram-positive or does not retain dye as a result of thehigh lipid and mycolic acid content of its cell wall.[24]MTB can withstand weak disinfectants and survive in adry state for weeks. In nature, the bacterium can growonly within the cells of a host organism, but M. tubercu-losis can be cultured in the laboratory.[25]

Using histological stains on expectorated samples fromphlegm (also called sputum), scientists can identifyMTB under a regular (light) microscope. Since MTB re-tains certain stains even after being treated with acidic so-lution, it is classied as an acid-fast bacillus (AFB).[1][24]The most common acid-fast staining techniques are theZiehlNeelsen stain, which dyes AFBs a bright red thatstands out clearly against a blue background,[26] and theauramine-rhodamine stain followed by uorescence mi-croscopy.[27]

The M. tuberculosis complex (MTBC) includes fourother TB-causing mycobacteria: M. bovis,M. africanum,M. canetti, and M. microti.[28] M. africanum is notwidespread, but it is a signicant cause of tuberculosisin parts of Africa.[29][30] M. bovis was once a commoncause of tuberculosis, but the introduction of pasteurizedmilk has largely eliminated this as a public health prob-lem in developed countries.[1][31] M. canetti is rare andseems to be limited to the Horn of Africa, although a fewcases have been seen in African emigrants.[32][33] M. mi-croti is also rare and is mostly seen in immunodecientpeople, although the prevalence of this pathogen has pos-sibly been signicantly underestimated.[34]

Other known pathogenic mycobacteria include M. lep-rae, M. avium, and M. kansasii. The latter two speciesare classied as "nontuberculous mycobacteria" (NTM).NTM cause neither TB nor leprosy, but they do causepulmonary diseases that resemble TB.[35]

2.2 Risk factors

Main article: Risk factors for tuberculosis

A number of factors make people more susceptible toTB infections. The most important risk factor glob-ally is HIV; 13% of all people with TB are infected bythe virus.[8] This is a particular problem in sub-SaharanAfrica, where rates of HIV are high.[36][37] Of peoplewithout HIV who are infected with tuberculosis, about510% develop active disease during their lifetimes;[12]in contrast, 30% of those coinfected with HIV developthe active disease.[12]

Tuberculosis is closely linked to both overcrowding andmalnutrition, making it one of the principal diseases of

3.1 Transmission 3

poverty.[9] Those at high risk thus include: people whoinject illicit drugs, inhabitants and employees of localeswhere vulnerable people gather (e.g. prisons and home-less shelters), medically underprivileged and resource-poor communities, high-risk ethnic minorities, childrenin close contact with high-risk category patients, andhealth-care providers serving these patients.[38]

Chronic lung disease is another signicant risk factor.Silicosis increases the risk about 30-fold.[39] Those whosmoke cigarettes have nearly twice the risk of TB com-pared to nonsmokers.[40]

Other disease states can also increase the risk of de-veloping tuberculosis. These include alcoholism[9] anddiabetes mellitus (three-fold increase).[41]

Certain medications, such as corticosteroids andiniximab (an anti-TNF monoclonal antibody), arebecoming increasingly important risk factors, especiallyin the developed world.[9]

Also a genetic susceptibility element exists,[42] for whichthe overall importance remains undened.[9]

3 Mechanism

Public health campaigns in the 1920s tried to halt the spread ofTB.

3.1 Transmission

When people with active pulmonary TB cough, sneeze,speak, sing, or spit, they expel infectious aerosol droplets0.5 to 5.0 m in diameter. A single sneeze can releaseup to 40,000 droplets.[43] Each one of these droplets maytransmit the disease, since the infectious dose of tubercu-losis is very small (the inhalation of fewer than 10 bacteriamay cause an infection).[44]

People with prolonged, frequent, or close contact withpeople with TB are at particularly high risk of becom-ing infected, with an estimated 22% infection rate.[45] Aperson with active but untreated tuberculosis may infect1015 (or more) other people per year.[3] Transmissionshould occur from only people with active TB thosewith latent infection are not thought to be contagious.[1]The probability of transmission from one person to an-other depends upon several factors, including the num-ber of infectious droplets expelled by the carrier, the ef-fectiveness of ventilation, the duration of exposure, thevirulence of theM. tuberculosis strain, the level of immu-nity in the uninfected person, and others.[46] The cascadeof person-to-person spread can be circumvented by ef-fectively segregating those with active (overt) TB andputting them on anti-TB drug regimens. After about twoweeks of eective treatment, subjects with nonresistantactive infections generally do not remain contagious toothers.[45] If someone does become infected, it typicallytakes three to four weeks before the newly infected per-son becomes infectious enough to transmit the disease toothers.[47]

3.2 Pathogenesis

Microscopy of tuberculous epididymitis. H&E stain

About 90% of those infected with M. tuberculosis haveasymptomatic, latent TB infections (sometimes calledLTBI),[48] with only a 10% lifetime chance that the la-tent infection will progress to overt, active tuberculousdisease.[49] In those with HIV, the risk of developing ac-tive TB increases to nearly 10% a year.[49] If eective

4 4 DIAGNOSIS

treatment is not given, the death rate for active TB casesis up to 66%.[3]

TB infection begins when the mycobacteria reach thepulmonary alveoli, where they invade and replicate withinendosomes of alveolar macrophages.[1][50] Macrophagesidentify the bacterium as foreign and attempt to elimi-nate it by phagocytosis. During this process, the entirebacterium is enveloped by the macrophage and storedtemporarily in a membrane-bound vesicle called a phago-some. The phagosome then combines with a lysosome tocreate a phagolysosome. In the phagolysosome, the cellattempts to use reactive oxygen species and acid to kill thebacterium. However, M. tuberculosis has a thick, waxymycolic acid capsule that protects it from these toxic sub-stances. M. tuberculosis actually reproduces inside themacrophage and will eventually kill the immune cell.The primary site of infection in the lungs, known as the"Ghon focus", is generally located in either the upperpart of the lower lobe, or the lower part of the upperlobe.[1] Tuberculosis of the lungs may also occur via in-fection from the blood stream. This is known as a Simonfocus and is typically found in the top of the lung.[51]This hematogenous transmission can also spread infec-tion to more distant sites, such as peripheral lymph nodes,the kidneys, the brain, and the bones.[1][52] All parts ofthe body can be aected by the disease, though for un-known reasons it rarely aects the heart, skeletal muscles,pancreas, or thyroid.[53]

Tuberculosis is classied as one of the granulomatousinammatory diseases. Macrophages, T lymphocytes,B lymphocytes, and broblasts aggregate to formgranulomas, with lymphocytes surrounding the infectedmacrophages. When other macrophages attack the in-fected macrophage, they fuse together to form a giantmultinucleated cell in the alveolar lumen. The granulomamay prevent dissemination of the mycobacteria and pro-vide a local environment for interaction of cells of the im-mune system.[54] However more recent evidence suggeststhat the bacteria use the granulomas to avoid destructionby the hosts immune system. Macrophages and dendriticcells in the granulomas are unable to present antigen tolymphocytes; thus the immune response is suppressed.[55]Bacteria inside the granuloma can become dormant, re-sulting in latent infection. Another feature of the granulo-mas is the development of abnormal cell death (necrosis)in the center of tubercles. To the naked eye, this hasthe texture of soft, white cheese and is termed caseousnecrosis.[54]

If TB bacteria gain entry to the blood stream from an areaof damaged tissue, they can spread throughout the bodyand set up many foci of infection, all appearing as tiny,white tubercles in the tissues.[56] This severe form of TBdisease, most common in young children and those withHIV, is called miliary tuberculosis.[57] People with thisdisseminated TB have a high fatality rate even with treat-ment (about 30%).[20][58]

In many people, the infection waxes and wanes. Tissuedestruction and necrosis are often balanced by healingand brosis.[54] Aected tissue is replaced by scarringand cavities lled with caseous necrotic material. Dur-ing active disease, some of these cavities are joined tothe air passages bronchi and this material can be coughedup. It contains living bacteria, so can spread the infection.Treatment with appropriate antibiotics kills bacteria andallows healing to take place. Upon cure, aected areasare eventually replaced by scar tissue.[54]

4 DiagnosisMain article: Tuberculosis diagnosis

M. tuberculosis (stained red) in sputum

4.1 Active tuberculosis

Diagnosing active tuberculosis based merely on signs andsymptoms is dicult,[59] as is diagnosing the disease inthose who are immunosuppressed.[60] A diagnosis of TBshould, however, be considered in those with signs of lungdisease or constitutional symptoms lasting longer thantwo weeks.[60] A chest X-ray and multiple sputum cul-tures for acid-fast bacilli are typically part of the initialevaluation.[60] Interferon- release assays and tuberculinskin tests are of little use in the developing world.[61][62]IGRA have similar limitations in those with HIV.[62][63]

A denitive diagnosis of TB is made by identifying M.tuberculosis in a clinical sample (e.g., sputum, pus, or atissue biopsy). However, the dicult culture process forthis slow-growing organism can take two to six weeks forblood or sputum culture.[64] Thus, treatment is often be-gun before cultures are conrmed.[65]

5.2 Public health 5

Nucleic acid amplication tests and adenosine deaminasetesting may allow rapid diagnosis of TB.[59] These tests,however, are not routinely recommended, as they rarelyalter how a person is treated.[65] Blood tests to detectantibodies are not specic or sensitive, so they are notrecommended.[66]

4.2 Latent tuberculosis

Mantoux tuberculin skin test

The Mantoux tuberculin skin test is often used to screenpeople at high risk for TB.[60] Those who have been previ-ously immunized may have a false-positive test result.[67]The test may be falsely negative in those with sarcoidosis,Hodgkins lymphoma, malnutrition, or most notably, inthose who truly do have active tuberculosis.[1] Interferongamma release assays (IGRAs), on a blood sample, arerecommended in those who are positive to the Man-toux test.[65] These are not aected by immunization ormost environmental mycobacteria, so they generate fewerfalse-positive results.[68] However, they are aected byM.szulgai,M. marinum, andM. kansasii.[69] IGRAs may in-crease sensitivity when used in addition to the skin test,but may be less sensitive than the skin test when usedalone.[70]

5 PreventionTuberculosis prevention and control eorts primarilyrely on the vaccination of infants and the detectionand appropriate treatment of active cases.[9] The WorldHealth Organization has achieved some success with im-proved treatment regimens, and a small decrease in casenumbers.[9]

5.1 Vaccines

The only available vaccine as of 2011 is bacillusCalmette-Gurin (BCG).[71] In children it decreases therisk of getting the infection by 20% and the risk of infec-tion turning into disease by nearly 60%.[72]

It is the most widely used vaccine worldwide, with morethan 90% of all children being vaccinated.[9] The immu-nity it induces decreases after about ten years.[9] As tu-berculosis is uncommon in most of Canada, the UnitedKingdom, and the United States, BCG is administered toonly those people at high risk.[73][74][75] Part of the rea-soning arguing against the use of the vaccine is that itmakes the tuberculin skin test falsely positive, so is of nouse in screening.[75] A number of new vaccines are cur-rently in development.[9]

5.2 Public healthThe World Health Organization declared TB a globalhealth emergency in 1993,[9] and in 2006, the Stop TBPartnership developed a Global Plan to Stop Tuberculosisthat aims to save 14 million lives between its launch and2015.[76] A number of targets they have set are not likelyto be achieved by 2015, mostly due to the increase inHIV-associated tuberculosis and the emergence of mul-tiple drug-resistant tuberculosis.[9] A tuberculosis classi-cation system developed by the American Thoracic So-ciety is used primarily in public health programs.[77]

6 ManagementMain article: Tuberculosis management

Treatment of TB uses antibiotics to kill the bacteria. Ef-fective TB treatment is dicult, due to the unusual struc-ture and chemical composition of the mycobacterial cellwall, which hinders the entry of drugs and makes manyantibiotics ineective.[78] The two antibiotics most com-monly used are isoniazid and rifampicin, and treatmentscan be prolonged, taking several months.[46] Latent TBtreatment usually employs a single antibiotic,[79] while ac-tive TB disease is best treated with combinations of sev-eral antibiotics to reduce the risk of the bacteria develop-ing antibiotic resistance.[9] People with latent infectionsare also treated to prevent them from progressing to activeTB disease later in life.[79] Directly observed therapy, i.e.,having a health care provider watch the person take theirmedications, is recommended by the WHO in an eortto reduce the number of people not appropriately takingantibiotics.[80] The evidence to support this practice overpeople simply taking their medications independently ispoor.[81] Methods to remind people of the importance oftreatment do, however, appear eective.[82]

6.1 New onsetThe recommended treatment of new-onset pulmonarytuberculosis, as of 2010, is six months of a combi-nation of antibiotics containing rifampicin, isoniazid,pyrazinamide, and ethambutol for the rst two months,

6 8 EPIDEMIOLOGY

and only rifampicin and isoniazid for the last fourmonths.[9] Where resistance to isoniazid is high, etham-butol may be added for the last four months as analternative.[9]

6.2 Recurrent diseaseIf tuberculosis recurs, testing to determine to which an-tibiotics it is sensitive is important before determiningtreatment.[9] If multiple drug-resistant TB is detected,treatment with at least four eective antibiotics for 18 to24 months is recommended.[9]

6.3 Medication resistancePrimary resistance occurs when a person becomes in-fected with a resistant strain of TB. A person with fullysusceptible TB may develop secondary (acquired) resis-tance during therapy because of inadequate treatment,not taking the prescribed regimen appropriately (lack ofcompliance), or using low-quality medication.[83] Drug-resistant TB is a serious public health issue in many de-veloping countries, as its treatment is longer and requiresmore expensive drugs. MDR-TB is dened as resistanceto the two most eective rst-line TB drugs: rifampicinand isoniazid. Extensively drug-resistant TB is also re-sistant to three or more of the six classes of second-linedrugs.[84] Totally drug-resistant TB is resistant to all cur-rently used drugs.[85] It was rst observed in 2003 in Italy,but not widely reported until 2012,[85] and has also beenfound in Iran and India.[86] Bedaquiline is tentatively sup-ported for use in multiple drug-resistant TB.[87]

XDR-TB is a term sometimes used to dene extensivelyresistant TB, and constitutes one in ten cases of MDR-TB. Cases of XDR TB have been identied in more than90% of countries.[86]

7 Prognosis

Age-standardized death from tuberculosis per 100,000 inhabi-tants in 2004.[88]

Progression from TB infection to overt TB disease oc-curs when the bacilli overcome the immune system de-fenses and begin to multiply. In primary TB disease

(some 15% of cases), this occurs soon after the initialinfection.[1] However, in the majority of cases, a latentinfection occurs with no obvious symptoms.[1] These dor-mant bacilli produce active tuberculosis in 510% ofthese latent cases, often many years after infection.[12]

The risk of reactivation increases with immunosuppres-sion, such as that caused by infection with HIV. In peoplecoinfected withM. tuberculosis and HIV, the risk of reac-tivation increases to 10% per year.[1] Studies using DNAngerprinting of M. tuberculosis strains have shown re-infection contributes more substantially to recurrent TBthan previously thought,[89] with estimates that it mightaccount for more than 50% of reactivated cases in areaswhere TB is common.[90] The chance of death from a caseof tuberculosis is about 4% as of 2008, down from 8% in1995.[9]

8 EpidemiologyMain article: Epidemiology of tuberculosisRoughly one-third of the worlds population has been

0

10

100

1000

In 2007, the prevalence of TB per 100,000 people was highest insub-Saharan Africa, and was also relatively high in Asia.[91]

infected with M. tuberculosis,[3] with new infections oc-curring in about 1% of the population each year.[4]However, most infections with M. tuberculosis do notcause TB disease,[92] and 9095% of infections re-main asymptomatic.[48] In 2012, an estimated 8.6 mil-lion chronic cases were active.[93] In 2010, 8.8 millionnew cases of TB were diagnosed, and 1.201.45 milliondeaths occurred, most of these occurring in developingcountries.[8][94] Of these 1.45 million deaths, about 0.35million occur in those also infected with HIV.[95]

Tuberculosis is the second-most common cause ofdeath from infectious disease (after those due toHIV/AIDS).[11] The total number of tuberculosis caseshas been decreasing since 2005, while new cases havedecreased since 2002.[8] China has achieved particularlydramatic progress, with about an 80% reduction in itsTB mortality rate between 1990 and 2010.[95] The num-ber of new cases has declined by 17% between 20042014.[86] Tuberculosis is more common in developingcountries; about 80% of the population in many Asianand African countries test positive in tuberculin tests,while only 510% of the US population test positive.[1]

7Hopes of totally controlling the disease have been dra-matically dampened because of a number of factors, in-cluding the diculty of developing an eective vaccine,the expensive and time-consuming diagnostic process,the necessity ofmanymonths of treatment, the increase inHIV-associated tuberculosis, and the emergence of drug-resistant cases in the 1980s.[9]

In 2007, the country with the highest estimated incidencerate of TB was Swaziland, with 1,200 cases per 100,000people. India had the largest total incidence, with an es-timated 2.0 million new cases.[5] In developed countries,tuberculosis is less common and is found mainly in ur-ban areas. Rates per 100,000 people in dierent areasof the world were: globally 178, Africa 332, the Amer-icas 36, Eastern Mediterranean 173, Europe 63, South-east Asia 278, and Western Pacic 139 in 2010.[95] InCanada and Australia, tuberculosis is many times morecommon among the aboriginal peoples, especially in re-mote areas.[96][97] In the United States Native Americanshave a vefold greater mortality from TB,[98] and racialand ethnic minorities accounted for 84% of all reportedTB cases.[99]

The rates of TB varies with age. In Africa, it primarily af-fects adolescents and young adults.[100] However, in coun-tries where incidence rates have declined dramatically(such as theUnited States), TB ismainly a disease of olderpeople and the immunocompromised (risk factors arelisted above).[1][101] Worldwide, 22 high-burden statesor countries together experience 80% of cases as well as83% of deaths.[86]

9 HistoryMain article: History of tuberculosisTuberculosis has been present in humans since

Egyptian mummy in the British Museum tubercular decay hasbeen found in the spines of Egyptian mummies.

antiquity.[9] The earliest unambiguous detection of M.tuberculosis involves evidence of the disease in the re-mains of bison inWyoming dated to around 17,000 years

ago.[102] However, whether tuberculosis originated inbovines, then was transferred to humans, or whether it di-verged from a common ancestor, is currently unclear.[103]A comparison of the genes of M. tuberculosis complex(MTBC) in humans toMTBC in animals suggests humansdid not acquire MTBC from animals during animal do-mestication, as was previously believed. Both strains ofthe tuberculosis bacteria share a common ancestor, whichcould have infected humans as early as the Neolithic Rev-olution.[104]

Skeletal remains show prehistoric humans (4000 BC) hadTB, and researchers have found tubercular decay in thespines of Egyptian mummies dating from 30002400BC.[105] Genetic studies suggest TB was present in theAmericas from about 100 AD.[106]

Phthisis is a Greek word for consumption, an old term forpulmonary tuberculosis;[107] around 460 BC, Hippocratesidentied phthisis as the most widespread disease of thetimes. It was said to involve fever and the coughing up ofblood, which was almost always fatal.[108]

Before the Industrial Revolution, folklore often associ-ated tuberculosis with vampires. When one member ofa family died from it, the other infected members wouldlose their health slowly. People believed this was causedby the original person with TB draining the life from theother family members.[109]

Although the pulmonary form associated with tubercleswas established as a pathology by Dr Richard Morton in1689,[110][111] due to the variety of its symptoms, TB wasnot identied as a single disease until the 1820s. It was notnamed tuberculosis until 1839, by J. L. Schnlein.[112]

During 18381845, Dr. John Croghan, the owner ofMammoth Cave, brought a number of people with tu-berculosis into the cave in the hope of curing the diseasewith the constant temperature and purity of the cave air;they died within a year.[113] Hermann Brehmer openedthe rst TB sanatorium in 1859 in Grbersdorf (nowSokoowsko), Silesia.[114]

The bacillus causing tuberculosis, M. tuberculosis, wasidentied and described on 24 March 1882 by RobertKoch. He received the Nobel Prize in physiology ormedicine in 1905 for this discovery.[115] Koch did notbelieve the bovine (cattle) and human tuberculosis dis-eases were similar, which delayed the recognition of in-fected milk as a source of infection. Later, the risk oftransmission from this source was dramatically reducedby the invention of the pasteurization process. Kochannounced a glycerine extract of the tubercle bacilli asa remedy for tuberculosis in 1890, calling it tuber-culin. While it was not eective, it was later success-fully adapted as a screening test for the presence of pre-symptomatic tuberculosis.[116]

Albert Calmette and Camille Gurin achieved the rstgenuine success in immunization against tuberculosis in1906, using attenuated bovine-strain tuberculosis. It was

8 10 SOCIETY AND CULTURE

Dr. Robert Koch discovered the tuberculosis bacillus.

called bacille CalmetteGurin (BCG). The BCG vac-cine was rst used on humans in 1921 in France,[117] butreceived widespread acceptance in the US, Great Britain,and Germany only after World War II.[118]

Tuberculosis caused the most widespread public concernin the 19th and early 20th centuries as an endemic diseaseof the urban poor. In 1815, one in four deaths in Englandwas due to consumption. By 1918, one in six deaths inFrance was still caused by TB. After TB was determinedto be contagious, in the 1880s, it was put on a notiabledisease list in Britain; campaigns were started to stop peo-ple from spitting in public places, and the infected poorwere encouraged to enter sanatoria that resembled pris-ons (the sanatoria for the middle and upper classes of-fered excellent care and constant medical attention).[114]Whatever the (purported) benets of the fresh air andlabor in the sanatoria, even under the best conditions,50% of those who entered died within ve years (circa1916).[114]

In Europe, rates of tuberculosis began to rise in the early1600s to a peak level in the 1800s, when it caused nearly25% of all deaths.[119] By the 1950s, mortality had de-creased nearly 90%.[120] Improvements in public healthbegan signicantly reducing rates of tuberculosis evenbefore the arrival of streptomycin and other antibiotics,although the disease remained a signicant threat to pub-lic health such that when the Medical Research Councilwas formed in Britain in 1913, its initial focus was tuber-culosis research.[121]

In 1946, the development of the antibiotic streptomycinmade eective treatment and cure of TB a reality. Priorto the introduction of this drug, the only treatment (ex-cept sanatoria) was surgical intervention, including the"pneumothorax technique, which involved collapsing aninfected lung to rest it and allow tuberculous lesions toheal.[122]

Because of the emergence of MDR-TB, surgery has beenre-introduced as an option within the generally acceptedstandard of care in treating TB infections. Current sur-gical interventions involve removal of pathological chestcavities (bullae) in the lungs to reduce the number ofbacteria and to increase the exposure of the remainingbacteria to drugs in the bloodstream, thereby simultane-ously reducing the total bacterial load and increasing theeectiveness of systemic antibiotic therapy.[123]

Hopes of completely eliminating TB (cf. smallpox) fromthe population were dashed after the rise of drug-resistantstrains in the 1980s. The subsequent resurgence of tuber-culosis resulted in the declaration of a global health emer-gency by the World Health Organization in 1993.[124]

10 Society and culture

10.1 Public health eorts

The World Health Organization, Bill and Melinda GatesFoundation, and US government are subsidizing a fast-acting diagnostic tuberculosis test for use in low- andmiddle-income countries.[125][126][127] In addition to be-ing fast-acting, the test can determine if there is resis-tance to the antibiotic rifampicin which may indicatemulti-drug resistant tuberculosis and is accurate in thosewho are also infected with HIV.[125][128] Many resource-poor places as of 2011 only have access to sputummicroscopy.[129]

India had the highest total number of TB cases world-wide in 2010, in part due to poor disease managementwithin the private and public health care sector.[130] Pro-grams such as the Revised National Tuberculosis ControlProgram are working to reduce TB levels amongst peoplereceiving public health care.[131][132]

A2014 the EIU-healthcare report that the need to addressapathy and urging for increased funding. The report citesamong others Lucica Ditui "[TB] is like an orphan. It hasbeen neglected even in countries with a high burden andoften forgotten by donors and those investing in healthinterventions.[86]

Slow progress has led to frustration, expressed by exec-utive director of the Global Fund to Fight AIDS, Tuber-culosis and Malaria Mark Dybul: we have the toolsto end TB as a pandemic and public health threat on theplanet, but we are not doing it.[86] Several internationalorganizations are pushing for more transparency in treat-

9ment, and more countries are implementing mandatoryreporting of cases to the government, although adher-ence is often sketchy. Commercial treatment-providersmay at times overprescribe second-line drugs as well assupplementary treatment, promoting demands for fur-ther regulations.[86] The government of Brazil providesuniversal TB-care, which reduces this problem.[86] Con-versely falling rates of TB-infection may not relate to thenumber of programs directed at reducing infection rates,but may be tied to increased level of education, incomeand health of the population.[86] Costs of the disease, ascalculated by the World Bank in 2009 may exceed 150billion USD per year in high burden countries.[86] Lackof progress eradicating the diseasemay also be due to lackof patient follow-up as among the 250M rural migrantsin China.[86]

10.2 Stigma

Slow progress in preventing the diseasemay in part be dueto stigma associated with TB.[86] Stigma may be due tothe fear of transmission from aected individuals. Thisstigma may additionally arise due to links between TBand poverty, and in Africa, AIDS.[86] Such stigmatizationmay be both real and perceived, for example; in Ghanaindividuals with TB are banned from attending publicgatherings.[133]

Stigma towards TB may result in delays in seekingtreatment,[86] lower treatment compliance, and familymembers keeping cause of death secret[133] allow-ing the disease to spread further.[86] At odds is Russia,where stigma was associated with increased treatmentcompliance.[133] TB stigma also aects socially marginal-ized individuals to a greater degree and varies betweenregions.[133]

One way to decrease stigma may be through the promo-tion of TB clubs, where those infected may share ex-periences and oer support, or through counseling.[133]Some studies have shown TB education programs to beeective in decreasing stigma, and may thus be eec-tive in increasing treatment adherence.[133] Despite this,studies on relationship between reduced stigma and mor-tality are lacking as of 2010, and similar eorts to de-crease stigma surrounding AIDS have been minimallyeective.[133] Some have claimed the stigma to be worsethan the disease, and healthcare providers may uninten-tionally reinforce stigma, as those with TB are often per-ceived as dicult or otherwise undesirable.[86]

11 ResearchThe BCG vaccine has limitations, and research to developnew TB vaccines is ongoing.[134] A number of poten-tial candidates are currently in phase I and II clinical tri-als.[134] Two main approaches are being used to attempt

to improve the ecacy of available vaccines. One ap-proach involves adding a subunit vaccine to BCG, whilethe other strategy is attempting to create new and betterlive vaccines.[134] MVA85A, an example of a subunit vac-cine, currently in trials in South Africa, is based on a ge-netically modied vaccinia virus.[135] Vaccines are hopedto play a signicant role in treatment of both latent andactive disease.[136]

To encourage further discovery, researchers and pol-icymakers are promoting new economic models ofvaccine development, including prizes, tax incentives,and advance market commitments.[137][138] A numberof groups, including the Stop TB Partnership,[139] theSouth African Tuberculosis Vaccine Initiative, and theAeras Global TB Vaccine Foundation, are involved withresearch.[140] Among these, the Aeras Global TB Vac-cine Foundation received a gift of more than $280 mil-lion (US) from the Bill and Melinda Gates Foundation todevelop and license an improved vaccine against tubercu-losis for use in high burden countries.[141][142]

A number of medications are being studied for multidrug resistant tuberculosis including: bedaquiline anddelamanid.[143] Bedaquiline received U.S. Food and DrugAdministration (FDA) approval in late 2012.[144] Thesafety and eectiveness of these new agents are still un-certain, because they are based on the results of a rela-tively small studies.[143][145] However, existing data sug-gest that patients taking bedaquiline in addition to stan-dard TB therapy are ve times more likely to die thanthose without the new drug,[146] which has resulted inmedical journal articles raising health policy questionsabout why the FDA approved the drug and whether nan-cial ties to the company making bedaquiline inuencedphysicians support for its use [145][147]

12 Other animalsMycobacteria infect many dierent animals, includingbirds,[148] rodents,[149] and reptiles.[150] The subspeciesMycobacterium tuberculosis, though, is rarely present inwild animals.[151] An eort to eradicate bovine tuber-culosis caused by Mycobacterium bovis from the cat-tle and deer herds of New Zealand has been relativelysuccessful.[152] Eorts in Great Britain have been lesssuccessful.[153][154]

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14 External links Tuberculosis at DMOZ Tuberculosis (TB)". Centers for Disease Control. Tuberculosis (TB)". UK Health ProtectionAgency.

16 15 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

15 Text and image sources, contributors, and licenses15.1 Text

Tuberculosis Source: http://en.wikipedia.org/wiki/Tuberculosis?oldid=650143680 Contributors: AxelBoldt, TwoOneTwo, Kpjas, Claude-Muncey, Eloquence, Mav, Koyaanis Qatsi, -- April, Alex.tan, Wayne Hardman, Andre Engels, Youssefsan, Danny, DWeir, Rmhermen,DavidLevinson, Zadcat, Rsabbatini, Camembert, Bernfarr, Someone else, Frecklefoot, Lir, Infrogmation, D, Michael Hardy, Vaughan,Zashaw, Fred Bauder, DopeshJustin, Gabbe, Sannse, Bjpremore, Kosebamse, Ihcoyc, Ahoerstemeier, Mac, Docu, Theresa knott, Snoyes,CatherineMunro, Angela, Den fjttrade ankan, JWSchmidt, Jdforrester, Aarchiba, Irmgard, Julesd, Salsa Shark, Glenn, Kimiko, Susurrus,Tristanb, Evercat, Danbirchall, Jengod, Ec5618, Popsracer, RodC, Guaka, Adam Bishop, Harris7, Viajero, Teresag, Fuzheado, Andrew-man327, Tb, Invalidname, Tpbradbury, Saltine, Dunning, Samsara, Thue, Raul654, MD87, Jeq, Rossumcapek, Chuunen Baka, Ke4roh,Dale Arnett, Korath, Jredmond, Gak, RedWolf, Donreed, Altenmann, Nurg, Chris Roy, Dukeofomnium, Auric, DHN, Mendalus, Hadal,Guy Peters, Hcheney, Xanzzibar, Dina, Carnildo, Tobias Bergemann, Alan Liefting, David Gerard, Marc Venot, Giftlite, Unother, DocWat-son42, Pretzelpaws, Nunh-huh, Cobaltbluetony, Tom harrison, Ferkelparade, Everyking, Alison, Michael Devore, Jfdwol, Andris, Raek-won, Bobblewik, Deus Ex, Ragib, Wmahan, Stevietheman, Andycjp, Jasper Chua, Nova77, Geni, Quadell, Antandrus, Bcameron54, Pi-otrus, Jossi, Exigentsky, SethTisue, 1297, Rdsmith4, Oneiros, Satori, Elektron, JulieADriver, Neutrality, Ukexpat, Jbinder, GreenReaper,Kate, Wikiti, Noisy, Discospinster, Rich Farmbrough, Guanabot, Supercoop, KittySaturn, Kdammers, Rsanchezsaez, Ardonik, Wk muri-ithi, Prateep, Paul August, SpookyMulder, Jayc12, Bender235, ESkog, Kaisershatner, FrankCostanza, Mashford, Calair, JoeSmack, Jarsyl,Petersam, Livajo, Nysalor, MBisanz, Sfahey, Izalithium, Mwanner, Chairboy, Ludek9, Diomidis Spinellis, EDGE, Liaody, Theshowme-canuck, Aloys, CDN99, Kerinth, Bobo192, Jpallan, Reinyday, Davidruben, .:Ajvol:., Brim, Elipongo, Adrian, Arcadian, Giraedata, BTouch, KBi, Kjkolb, Kundor, Cinnamon, XDarklytez, Chicago god, Stephen Bain, Orangemarlin, Petdance, DruidOfTheTalon, Jum-buck, Alansohn, Eric Kvaalen, Megan 189, Wouterstomp, Axl, Goldom, Ddlamb, Cdc, Bart133, Snowolf, Fasten, Wtmitchell, Grenavi-tar, Sciurin, Lerdsuwa, Ziddar, BlastOButter42, Bookandcoee, Dismas, TShilo12, Hijiri88, Abanima, Angr, Richard Arthur Norton(1958- ), Woohookitty, FeanorStar7, Percy Snoodle, Webwanderer56, Robwingeld, Pol098, Before My Ken, Colorajo, WadeSimMiser,Je3000, Burgher, Duncan.france, Fred J, Al E., Bbatsell, BlaiseFEgan, Wayward, Prashanthns, Bduttabaruah, Alan Canon, MarcoTolo,Fujitofu, Tslocum, Graham87, Cuvtixo, Deltabeignet, BD2412, Apayne, Canderson7, Sj, Kotukunui, Rjwilmsi, Markkawika, Koavf,Vary, Chochem, Bruce1ee, MZMcBride, SpNeo, SMC, Oblivious, Ligulem, Morbid-o, StephanieM, Brighterorange, The wub, Double-Blue, GregAsche, AySz88, Rangek, Ninuor, FlaBot, RobertG, Ground Zero, Wikidgood, Mishuletz, Apollo the Archer, DrG, RexNL,Gurch, Pgiii, Jagjag, Stevenfruitsmaak, Preslethe, McDogm, Dothefandango, Imnotminkus, Butros, Chobot, DVdm, Guliolopez, Antiuser,Adoniscik, Gwernol, Zentropa, Banaticus, YurikBot, Wavelength, Madmotet, Spaceriqui, Phantomsteve, RussBot, Spaully, Pigman, ChrisCapoccia, Epolk, Bhumburg, Wikinick, Hydrargyrum, Stephenb, Jeus, Shell Kinney, Gaius Cornelius, CambridgeBayWeather, Eleassar,Pseudomonas, Wimt, Ritchy, Draeco, NawlinWiki, Boneheadmx, Dialectric, Chick Bowen, Joel7687, Harksaw, Joelr31, BirgitteSB, Mc-cready, Unmake, Dfgarcia, Raven4x4x, Froth, Aaron Schulz, Deckiller, Samir, John Sheu, Psy guy, Rcinda1, Galar71, Bob247, Tetracube,Ke6jjj, WAS 4.250, FF2010, Mike Serfas, Blurble, Lt-wiki-bot, Encephalon, Nikkimaria, , Punkymonkey987, SMcCandlish,Skedaddle, Colin, Petri Krohn, GraemeL, Vicarious, Back ache, Willtron, MartinUK, JLaTondre, Arundhati bakshi, Spliy, TooPotato,Curpsbot-unicodify, MagneticFlux, Paul D. 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15.2 Images 17

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18 15 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

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Signs and symptomsPulmonaryExtrapulmonary

CausesMycobacteriaRisk factors

MechanismTransmissionPathogenesis

DiagnosisActive tuberculosisLatent tuberculosis

PreventionVaccinesPublic health

ManagementNew onsetRecurrent diseaseMedication resistance

PrognosisEpidemiologyHistorySociety and culturePublic health effortsStigma

ResearchOther animalsReferencesExternal linksText and image sources, contributors, and licensesTextImagesContent license