Wikipedia

Tuberculosis

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Tuberculosis(TB), also known colloquially as the "white death",or historically asconsumption,[8]is aninfectious diseaseusually caused byMycobacterium tuberculosis(MTB)bacteria.[1]Tuberculosis generally affects thelungs,but it can also affect other parts of the body.[1]Most infections show no symptoms, in which case it is known aslatent tuberculosis.[1]Around 10% of latent infections progress to active disease that, if left untreated, kill about half of those affected.[1]Typical symptoms of active TB are chroniccoughwithblood-containingmucus,fever,night sweats,andweight loss.[1]Infectionof other organs can cause a wide range of symptoms.[9]

Tuberculosis
Other namesPhthisis, phthisis pulmonalis, consumption, great white plague
Chest X-rayof a person with advanced tuberculosis: Infection in both lungs is marked by white arrow-heads, and the formation of a cavity is marked by black arrows.
SpecialtyInfectious disease,pulmonology
SymptomsChronic cough,fever,cough with bloody mucus,weight loss[1]
CausesMycobacterium tuberculosis[1]
Risk factorsSmoking,HIV/AIDS[1]
Diagnostic methodCXR,culture,tuberculin skin test,QuantiFERON[1]
Differential diagnosisPneumonia,histoplasmosis,sarcoidosis,coccidioidomycosis[2]
PreventionScreening those at high risk, treatment of those infected,vaccinationwithbacillus Calmette-Guérin(BCG)[3][4][5]
TreatmentAntibiotics[1]
Frequency25% of people (latent TB)[6] 10.6 million (active TB)[7]
Deaths1.3 million (2022)[6]

Tuberculosis isspread from one person to the nextthrough the airwhen people who have active TB in their lungs cough, spit, speak, orsneeze.[1][10]People with latent TB do not spread the disease.[1]Active infection occurs more often in people withHIV/AIDSand in those whosmoke.[1]Diagnosisof active TB is based onchest X-rays,as well asmicroscopicexamination andcultureof bodily fluids.[11]Diagnosis of latent TB relies on thetuberculin skin test(TST) or blood tests.[11]

Prevention of TB involves screening those at high risk, early detection and treatment of cases, andvaccinationwith thebacillus Calmette-Guérin(BCG) vaccine.[3][4][5]Those at high risk include household, workplace, and social contacts of people with active TB.[4]Treatment requires the use of multipleantibioticsover a long period of time.[1]Antibiotic resistanceis a growing problem, with increasing rates ofmultiple drug-resistant tuberculosis(MDR-TB).[1]

In 2018, one quarter of the world's population was thought to have a latent infection of TB.[6]New infections occur in about 1% of the population each year.[12]In 2022, an estimated 10.6 million people developed active TB, resulting in 1.3 million deaths, making it the second leadingcause of death from an infectious diseaseafterCOVID-19.[7]As of 2018, most TB cases occurred in the WHO regions of South-East Asia (44%), Africa (24%), and the Western Pacific (18%), with more than 50% of cases being diagnosed in seven countries: India (27%), China (9%), Indonesia (8%), the Philippines (6%), Pakistan (6%), Nigeria (4%), and Bangladesh (4%).[13]By 2021, the number of new cases each year was decreasing by around 2% annually.[7][1]About 80% of people in many Asian and African countries test positive, while 5–10% of people in the United States test positive via the tuberculin test.[14]Tuberculosis has been present in humans sinceancient times.[15]

Video summary (script)

History

Main article:History of tuberculosis
AnEgyptian mummyin theBritish Museum– tubercular decay has been found in the spine.

Tuberculosis has existed sinceantiquity.[15]The oldest unambiguously detectedM. tuberculosisgives evidence of the disease in the remains of bison in Wyoming dated to around 17,000 years ago.[16]However, whether tuberculosis originated in bovines, then transferred to humans, or whether both bovine and human tuberculosis diverged from a common ancestor, remains unclear.[17]A comparison of thegenesofM. tuberculosis complex(MTBC) in humans to MTBC in animals suggests humans did not acquire MTBC from animals during animal domestication, as researchers previously believed. Both strains of the tuberculosis bacteria share a common ancestor, which could have infected humans even before theNeolithic Revolution.[18]Skeletal remains show some prehistoric humans (4000BC) had TB, and researchers have found tubercular decay in the spines ofEgyptianmummiesdating from 3000 to 2400 BC.[19]Genetic studies suggest the presence of TB inthe Americasfrom about AD 100.[20]

Before theIndustrial Revolution,folklore often associated tuberculosis withvampires.When one member of a family died from the disease, the other infected members would lose their health slowly. People believed this was caused by the original person with TB draining the life from the other family members.[21]

Identification

AlthoughRichard Mortonestablished the pulmonary form associated withtuberclesas a pathology in 1689,[22][23]due to the variety of its symptoms, TB was not identified as a single disease until the 1820s.Benjamin Martenconjectured in 1720 that consumptions were caused by microbes which were spread by people living close to each other.[24]In 1819,René Laennecclaimed that tubercles were the cause of pulmonary tuberculosis.[25]J. L. Schönleinfirst published the name "tuberculosis" (German:Tuberkulose) in 1832.[26][27]

Between 1838 and 1845, John Croghan, the owner ofMammoth Cavein Kentucky from 1839 onwards, brought a number of people with tuberculosis into the cave in the hope of curing the disease with the constant temperature and purity of the cave air; each died within a year.[28]Hermann Brehmer opened the first TBsanatoriumin 1859 in Görbersdorf (nowSokołowsko) inSilesia.[29]In 1865,Jean Antoine Villemindemonstrated that tuberculosis could be transmitted, via inoculation, from humans to animals and among animals.[30](Villemin's findings were confirmed in 1867 and 1868 byJohn Burdon-Sanderson.[31])

Robert Kochdiscovered the tuberculosis bacillus.

Robert Kochidentified and described the bacillus causing tuberculosis,M. tuberculosis,on 24 March 1882.[32][33]In 1905, he was awarded theNobel Prize in Physiology or Medicinefor this discovery.[34]

Development of treatments

In Europe, rates of tuberculosis began to rise in the early 1600s to a peak level in the 1800s, when it caused nearly 25% of all deaths.[35]In the 18th and 19th century,tuberculosis had become epidemic in Europe,showing a seasonal pattern.[36][37]Tuberculosis caused widespread public concern in the 19th and early 20th centuries as the disease became common among the urban poor. In 1815, one in four deaths in England was due to "consumption". By 1918, TB still caused one in six deaths in France.[citation needed]

After TB was determined to be contagious, in the 1880s, it was put on anotifiable-diseaselist in Britain. Campaigns started to stop people from spitting in public places, and the infected poor were "encouraged" to entersanatoriathat resembled prisons. The sanatoria for the middle and upper classes offered excellent care and constant medical attention.[29]What later became known as theAlexandra Hospital for Children with Hip Disease(tuberculous arthritis) was opened in London in 1867.[38]Whatever the benefits of the "fresh air" and labor in the sanatoria, even under the best conditions, 50% of those who entered died within five years (c.1916).[29]

Robert Koch did not believe the cattle and human tuberculosis diseases were similar, which delayed the recognition of infected milk as a source of infection. During the first half of the 1900s, the risk of transmission from this source was dramatically reduced after the application of thepasteurizationprocess. Koch announced aglycerineextract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it "tuberculin". Although it was not effective, it was later successfully adapted as a screening test for the presence of pre-symptomatic tuberculosis.[39]World Tuberculosis Dayis marked on 24 March each year, the anniversary of Koch's original scientific announcement. When theMedical Research Councilformed in Britain in 1913, it initially focused on tuberculosis research.[40]

Albert CalmetteandCamille Guérinachieved the first genuine success in immunization against tuberculosis in 1906, using attenuated bovine-strain tuberculosis. It was calledbacille Calmette–Guérin(BCG). The BCG vaccine was first used on humans in 1921 in France,[41]but achieved widespread acceptance in the US, Great Britain, and Germany only after World War II.[42]

By the 1950s mortality in Europe had decreased about 90%.[43]Improvements in sanitation, vaccination, and other public-health measures began significantly reducing rates of tuberculosis even before the arrival ofstreptomycinand other antibiotics, although the disease remained a significant threat.[43]In 1946, the development of the antibiotic streptomycin made effective treatment and cure of TB a reality. Prior to the introduction of this medication, the only treatment was surgical intervention, including the "pneumothoraxtechnique ", which involved collapsing an infected lung to" rest "it and to allow tuberculous lesions to heal.[44]

Current reemergence

Because of the emergence ofmultidrug-resistant tuberculosis(MDR-TB), surgery has been re-introduced for certain cases of TB infections. It involves the removal of infected chest cavities ( "bullae" ) in the lungs to reduce the number of bacteria and to increase exposure of the remaining bacteria to antibiotics in the bloodstream.[45]Hopes of eliminating TB ended with the rise ofdrug-resistantstrains in the 1980s. The subsequent resurgence of tuberculosis resulted in the declaration of a global health emergency by the World Health Organization (WHO) in 1993.[46]

Signs and symptoms

The main symptoms of variants and stages of tuberculosis are given,[47]with many symptoms overlapping with other variants, while others are more, but not entirely, specific for certain variants. Multiple variants may be present simultaneously.

There is a popular misconception that tuberculosis is purely a disease of the lungs that manifests ascoughing.[48]Tuberculosis may infect many organs, even though it most commonly occurs in the lungs (known as pulmonary tuberculosis).[9]Extrapulmonary TB occurs when tuberculosis develops outside of the lungs, although extrapulmonary TB may coexist with pulmonary TB.[9]

General signs and symptoms include fever,chills,night sweats,loss of appetite,weight loss, andfatigue.[9]Significantnail clubbingmay also occur.[49]

Pulmonary

If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases).[15][50]Symptoms may includechest painand a prolonged cough producing sputum. About 25% of people may not have any symptoms (i.e., they remain asymptomatic).[15]Occasionally, people maycough up bloodin small amounts, and in very rare cases, the infection may erode into thepulmonary arteryor aRasmussen aneurysm,resulting in massive bleeding.[9][51]Tuberculosis may become a chronic illness and cause extensive scarring in the upper lobes of the lungs. The upper lung lobes are more frequently affected by tuberculosis than the lower ones.[9]The reason for this difference is not clear.[14]It may be due to either better air flow,[14]or poorlymphdrainage within the upper lungs.[9]

Extrapulmonary

Main article:Extrapulmonary tuberculosis

In 15–20% of active cases, the infection spreads outside the lungs, causing other kinds of TB.[52]These are collectively denoted as extrapulmonary tuberculosis.[53]Extrapulmonary TB occurs more commonly in people with aweakened immune systemand young children. In those with HIV, this occurs in more than 50% of cases.[53]Notable extrapulmonary infection sites include thepleura(in tuberculous pleurisy), thecentral nervous system(intuberculous meningitis), thelymphatic system(inscrofulaof the neck), thegenitourinary system(inurogenital tuberculosis), and thebonesand joints (inPott diseaseof the spine), among others. A potentially more serious, widespread form of TB is called "disseminated tuberculosis"; it is also known asmiliary tuberculosis.[9]Miliary TB currently makes up about 10% of extrapulmonary cases.[54]

Causes

Mycobacteria

Main article:Mycobacterium tuberculosis
Scanning electron micrographofM. tuberculosis

The main cause of TB isMycobacterium tuberculosis(MTB), a small,aerobic,nonmotilebacillus.[9]The highlipidcontent of thispathogenaccounts for many of its unique clinical characteristics.[55]Itdividesevery 16 to 20 hours, which is an extremely slow rate compared with other bacteria, which usually divide in less than an hour.[56]Mycobacteria have anouter membranelipid bilayer.[57]If aGram stainis performed, MTB either stains very weakly "Gram-positive" or does not retain dye as a result of the high lipid andmycolic acidcontent of its cell wall.[58]MTB can withstand weakdisinfectantsand survive in adry statefor weeks. In nature, the bacterium can grow only within the cells of ahostorganism, butM. tuberculosiscan be culturedin the laboratory.[59]

Usinghistologicalstains onexpectoratedsamples fromphlegm(also called sputum), scientists can identify MTB under a microscope. Since MTB retains certain stains even after being treated with acidic solution, it is classified as anacid-fast bacillus.[14][58]The most common acid-fast staining techniques are theZiehl–Neelsen stain[60]and theKinyoun stain,which dye acid-fast bacilli a bright red that stands out against a blue background.[61]Auramine-rhodamine staining[62]andfluorescence microscopy[63]are also used.

TheM. tuberculosiscomplex(MTBC) includes four other TB-causingmycobacteria:M. bovis,M. africanum,M. canettii,andM. microti.[64]M. africanumis not widespread, but it is a significant cause of tuberculosis in parts of Africa.[65][66]M. boviswas once a common cause of tuberculosis, but the introduction ofpasteurized milkhas almost eliminated this as a public health problem in developed countries.[14][67]M. canettiiis rare and seems to be limited to theHorn of Africa,although a few cases have been seen in African emigrants.[68][69]M. microtiis also rare and is seen almost only in immunodeficient people, although itsprevalencemay be significantly underestimated.[70]

Other known pathogenic mycobacteria includeM. leprae,M. avium,andM. kansasii.The latter two species are classified as "nontuberculous mycobacteria"(NTM) or atypical mycobacteria. NTM cause neither TB norleprosy,but they do cause lung diseases that resemble TB.[71]

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

Transmission

When people with active pulmonary TB cough, sneeze, speak, sing, or spit, they expel infectiousaerosoldroplets 0.5 to 5.0μmin diameter. A single sneeze can release up to 40,000 droplets.[72]Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very small (the inhalation of fewer than 10 bacteria may cause an infection).[73]

Risk of transmission

People with prolonged, frequent, or close contact with people with TB are at particularly high risk of becoming infected, with an estimated 22% infection rate.[74]A person with active but untreated tuberculosis may infect 10–15 (or more) other people per year.[75]Transmission should occur from only people with active TB – those with latent infection are not thought to be contagious.[14]The probability of transmission from one person to another depends upon several factors, including the number of infectious droplets expelled by the carrier, the effectiveness of ventilation, the duration of exposure, thevirulenceof theM. tuberculosisstrain,the level of immunity in the uninfected person, and others.[76]

The cascade of person-to-person spread can be circumvented by segregating those with active ( "overt" ) TB and putting them on anti-TB drug regimens. After about two weeks of effective treatment, subjects withnonresistantactive infections generally do not remain contagious to others.[74]If someone does become infected, it typically takes three to four weeks before the newly infected person becomes infectious enough to transmit the disease to others.[77]

Risk factors

Main article:Risk factors for tuberculosis

A number of factors make individuals more susceptible to TB infection and/or disease.[78]

Active disease risk

The most important risk factor globally for developing active TB is concurrent HIV infection; 13% of those with TB are also infected with HIV.[79]This is a particular problem insub-Saharan Africa,where HIV infection rates are high.[80][81]Of those without HIV infection who are infected with tuberculosis, about 5–10% develop active disease during their lifetimes;[49]in contrast, 30% of those co-infected with HIV develop the active disease.[49]

Use of certain medications, such ascorticosteroidsandinfliximab(an anti-αTNF monoclonal antibody), is another important risk factor, especially in thedeveloped world.[15]

Other risk factors include:alcoholism,[15]diabetes mellitus(3-fold increased risk),[82]silicosis(30-fold increased risk),[83]tobacco smoking(2-fold increased risk),[84]indoor air pollution,malnutrition, young age,[78]recently acquired TB infection, recreational drug use, severe kidney disease, low body weight, organ transplant, head and neck cancer,[85]andgenetic susceptibility[86](the overall importance of genetic risk factors remains undefined[15]).

Infection susceptibility

Tobacco smoking increases the risk of infections (in addition to increasing the risk of active disease and death). Additional factors increasing infection susceptibility include young age.[78]

Pathogenesis

Robert Carswell's illustration of tubercle[87]

About 90% of those infected withM. tuberculosishaveasymptomatic,latent TB infections (sometimes called LTBI),[88]with only a 10% lifetime chance that the latent infection will progress to overt, active tuberculous disease.[89]In those with HIV, the risk of developing active TB increases to nearly 10% a year.[89]If effective treatment is not given, the death rate for active TB cases is up to 66%.[75]

Microscopy of tuberculous epididymitis.H&Estain

TB infection begins when the mycobacteria reach thealveolar air sacsof the lungs, where they invade and replicate withinendosomesof alveolarmacrophages.[14][90][91]Macrophages identify the bacterium as foreign and attempt to eliminate it byphagocytosis.During this process, the bacterium is enveloped by the macrophage and stored temporarily in a membrane-bound vesicle called a phagosome. The phagosome then combines with a lysosome to create a phagolysosome. In the phagolysosome, the cell attempts to usereactive oxygen speciesand acid to kill the bacterium. However,M. tuberculosishas a thick, waxymycolic acidcapsule that protects it from these toxic substances.M. tuberculosisis able to reproduce inside the macrophage and will eventually kill the immune cell.

The primary site of infection in the lungs, known as theGhon focus,is generally located in either the upper part of the lower lobe, or the lower part of theupper lobe.[14]Tuberculosis of the lungs may also occur via infection from the blood stream. This is known as aSimon focusand is typically found in the top of the lung.[92]This hematogenous transmission can also spread infection to more distant sites, such as peripheral lymph nodes, the kidneys, the brain, and the bones.[14][93]All parts of the body can be affected by the disease, though for unknown reasons it rarely affects theheart,skeletal muscles,pancreas,orthyroid.[94]

Tuberculosis is classified as one of thegranulomatousinflammatory diseases.Macrophages,epithelioid cells,T lymphocytes,B lymphocytes,andfibroblastsaggregate to form granulomas, withlymphocytessurrounding the infected macrophages. When other macrophages attack the infected macrophage, they fuse together to form a giant multinucleated cell in the alveolar lumen. The granuloma may prevent dissemination of the mycobacteria and provide a local environment for interaction of cells of the immune system.[95]

However, more recent evidence suggests that the bacteria use the granulomas to avoid destruction by the host's immune system. Macrophages anddendritic cellsin the granulomas are unable to present antigen to lymphocytes; thus the immune response is suppressed.[96]Bacteria inside the granuloma can become dormant, resulting in latent infection. Another feature of the granulomas is the development of abnormal cell death (necrosis) in the center oftubercles.To the naked eye, this has the texture of soft, white cheese and is termedcaseous necrosis.[95]

If TB bacteria gain entry to the blood stream from an area of damaged tissue, they can spread throughout the body and set up many foci of infection, all appearing as tiny, white tubercles in the tissues.[97]This severe form of TB disease, most common in young children and those with HIV, is called miliary tuberculosis.[98]People with this disseminated TB have a high fatality rate even with treatment (about 30%).[54][99]

In many people, the infection waxes and wanes. Tissue destruction and necrosis are often balanced by healing andfibrosis.[95]Affected tissue is replaced by scarring and cavities filled with caseous 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 thus can spread the infection. Treatment with appropriateantibioticskills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.[95]

Diagnosis

Main article:Diagnosis of tuberculosis
M. tuberculosis(stained red) insputum

Active tuberculosis

Diagnosing active tuberculosis based only on signs and symptoms is difficult,[100]as is diagnosing the disease in those who have a weakened immune system.[101]A diagnosis of TB should, however, be considered in those with signs of lung disease orconstitutional symptomslasting longer than two weeks.[101]Achest X-rayand multiplesputum culturesforacid-fast bacilliare typically part of the initial evaluation.[101]Interferon-γ release assays(IGRA) and tuberculin skin tests are of little use in most of the developing world.[102][103]IGRA have similar limitations in those with HIV.[103][104]

A definitive diagnosis of TB is made by identifyingM. tuberculosisin a clinical sample (e.g., sputum,pus,or atissuebiopsy). However, the difficult culture process for this slow-growing organism can take two to six weeks for blood or sputum culture.[105]Thus, treatment is often begun before cultures are confirmed.[106]

Nucleic acid amplification testsandadenosine deaminasetesting may allow rapid diagnosis of TB.[100]Blood tests to detect antibodies are notspecific or sensitive,so they are not recommended.[107]

Latent tuberculosis

Main article:Latent tuberculosis
A Mantoux tuberculin skin test

TheMantoux tuberculin skin testis often used to screen people at high risk for TB.[101]Those who have been previously immunized with the Bacille Calmette-Guerin vaccine may have a false-positive test result.[108]The test may be falsely negative in those withsarcoidosis,Hodgkin's lymphoma,malnutrition,and most notably, active tuberculosis.[14]Interferon gamma release assays,on a blood sample, are recommended in those who are positive to the Mantoux test.[106]These are not affected by immunization or mostenvironmental mycobacteria,so they generate fewerfalse-positiveresults.[109]However, they are affected byM. szulgai,M. marinum,andM. kansasii.[110]IGRAs may increase sensitivity when used in addition to the skin test, but may be less sensitive than the skin test when used alone.[111]

TheUS Preventive Services Task Force(USPSTF) has recommended screening people who are at high risk for latent tuberculosis with either tuberculin skin tests orinterferon-gamma release assays.[112]While some have recommend testing health care workers, evidence of benefit for this is poor as of 2019.[113]TheCenters for Disease Control and Prevention(CDC) stopped recommending yearly testing of health care workers without known exposure in 2019.[114]

Prevention

A tuberculosis public health campaign in Ireland, 1905

Tuberculosis prevention and control efforts rely primarily on the vaccination of infants and the detection and appropriate treatment of active cases.[15]TheWorld Health Organization(WHO) has achieved some success with improved treatment regimens, and a small decrease in case numbers.[15]Some countries have legislation to involuntarily detain or examine those suspected to have tuberculosis, orinvoluntarily treatthem if infected.[115]

Vaccines

Main articles:Tuberculosis vaccinesandBCG vaccine

The only availablevaccineas of 2021isbacillus Calmette-Guérin(BCG).[116][117]In children it decreases the risk of getting the infection by 20% and the risk of infection turning into active disease by nearly 60%.[118][119]

It is the most widely used vaccine worldwide, with more than 90% of all children being vaccinated.[15]The immunity it induces decreases after about ten years.[15]As tuberculosis is uncommon in most of Canada, Western Europe, and the United States, BCG is administered to only those people at high risk.[120][121][122]Part of the reasoning against the use of the vaccine is that it makes the tuberculin skin test falsely positive, reducing the test's usefulness as a screening tool.[122]Several vaccines are being developed.[15]

Intradermal MVA85A vaccine in addition to BCG injection is not effective in preventing tuberculosis.[123]

Public health

Public health campaigns which have focused on overcrowding, public spitting and regular sanitation (including hand washing) during the 1800s helped to either interrupt or slow spread which when combined with contact tracing, isolation and treatment helped to dramatically curb the transmission of both tuberculosis and other airborne diseases which led to theelimination of tuberculosisas a major public health issue in most developed economies.[124][125]Other risk factors which worsened TB spread such as malnutrition were also ameliorated, but since the emergence ofHIVa new population of immunocompromised individuals was available for TB to infect.

Source control in the US

Main article:Source control (respiratory disease) § Source control during TB Outbreaks
NIOSHguidelines for TB, with focus onrespiratorsunder the old30 CFR 11,replaced in1995(Wikisource link)

During theHIV/AIDS epidemic in the US,up to 35% of those affected by TB were also infected by HIV.[126]Handling of TB-infected patients in US hospitals was known to create airborne TB that could infect others, especially in unventilated spaces.[127]

Multiple US agencies rolled out new public health rules as a result of the TB spread: theCDCbrought in new guidelines mandatingHEPAfilters andHEPA respirators,[128]NIOSHpushed through new 42 CFR 84 respirator regulations in 1995 (like theN95),[129]andOSHAcreated a proposed rule for TB in 1997, a result of pressure from groups like theLabor Coalition to Fight TB in the Workplace.[130][131]

However, in 2003, OSHA dropped their proposed TB rules, citing a decline of TB in the US, and public disapproval.[132]

Worldwide campaigns

The World Health Organization (WHO) declared TB a "global health emergency" in 1993,[15]and in 2006, the Stop TB Partnership developed aGlobal Plan to Stop Tuberculosisthat aimed to save 14 million lives between its launch and 2015.[133]A number of targets they set were not achieved by 2015, mostly due to the increase in HIV-associated tuberculosis and the emergence of multiple drug-resistant tuberculosis.[15]Atuberculosis classificationsystem developed by theAmerican Thoracic Societyis used primarily in public health programs.[134]In 2015, it launched the End TB Strategy to reduce deaths by 95% and incidence by 90% before 2035. The goal of tuberculosis elimination is being hampered by the lack of rapid testing, short and effective treatment courses, andcompletely effective vaccines.[135]

The benefits and risks of giving anti-tubercular drugs to those exposed to MDR-TB is unclear.[136]Making HAART therapy available to HIV-positive individuals significantly reduces the risk of progression to an active TB infection by up to 90% and can mitigate the spread through this population.[137]

Management

Main article:Management of tuberculosis
Tuberculosisphototherapy treatmentinKuopio,Finland,1934

Treatment of TB uses antibiotics to kill the bacteria. Effective TB treatment is difficult, due to the unusual structure and chemical composition of the mycobacterialcell wall,which hinders the entry of drugs and makes many antibiotics ineffective.[138]

Active TB is best treated with combinations of several antibiotics to reduce the risk of the bacteria developingantibiotic resistance.[15]The routine use ofrifabutininstead ofrifampicinin HIV-positive people with tuberculosis is of unclear benefit as of 2007.[139]

Acetylsalicylic acid (aspirin) at a dose of 100 mg per day has been shown to improve clinical signs and symptoms, reduce cavitary lesions, lower inflammatory markers, and increase the rate of sputum-negative conversion in patients with pulmonary tuberculosis.[140]

Latent TB

Latent TB is treated with eitherisoniazidorrifampinalone, or a combination of isoniazid with either rifampicin or rifapentine.[141][142][143]

The treatment takes three to nine months depending on the medications used.[76][141][144][143]People with latent infections are treated to prevent them from progressing to active TB disease later in life.[145]

Education or counselling may improve the latent tuberculosis treatment completion rates.[146]

New onset

The recommended treatment of new-onset pulmonary tuberculosis, as of 2010,is six months of a combination of antibiotics containing rifampicin, isoniazid,pyrazinamide,andethambutolfor the first two months, and only rifampicin and isoniazid for the last four months.[15]Where resistance to isoniazid is high, ethambutol may be added for the last four months as an alternative.[15]Treatment with anti-TB drugs for at least 6 months results in higher success rates when compared with treatment less than 6 months, even though the difference is small. Shorter treatment regimen may be recommended for those with compliance issues.[147]There is also no evidence to support shorter anti-tuberculosis treatment regimens when compared to a 6-month treatment regimen.[148]However, results presented in 2020 from an international, randomized, controlled clinical trial indicate that a four-month daily treatment regimen containing high-dose, or "optimized", rifapentine with moxifloxacin (2PHZM/2PHM) is as safe and effective as the existing standard six-month daily regimen at curing drug-susceptible tuberculosis (TB) disease.[149]

Recurrent disease

If tuberculosis recurs, testing to determine which antibiotics it is sensitive to is important before determining treatment.[15]Ifmultiple drug-resistant TB(MDR-TB) is detected, treatment with at least four effective antibiotics for 18 to 24 months is recommended.[15]

Medication administration

Directly observed therapy,i.e., having a health care provider watch the person take their medications, is recommended by the World Health Organization (WHO) in an effort to reduce the number of people not appropriately taking antibiotics.[150]The evidence to support this practice over people simply taking their medications independently is of poor quality.[151]There is no strong evidence indicating that directly observed therapy improves the number of people who were cured or the number of people who complete their medicine.[151]Moderate quality evidence suggests that there is also no difference if people are observed at home versus at a clinic, or by a family member versus a health care worker.[151]

Methods to remind people of the importance of treatment and appointments may result in a small but important improvement.[152]There is also not enough evidence to support intermittent rifampicin-containing therapy given two to three times a week has equal effectiveness as daily dose regimen on improving cure rates and reducing relapsing rates.[153]There is also not enough evidence on effectiveness of giving intermittent twice or thrice weekly short course regimen compared to daily dosing regimen in treating children with tuberculosis.[154]

Medication resistance

Primary resistance occurs when a person becomes infected with a resistant strain of TB. A person with fully susceptibleMTBmay develop secondary (acquired) resistance during therapy because of inadequate treatment, not taking the prescribed regimen appropriately (lack of compliance), or using low-quality medication.[155]Drug-resistant TB is a serious public health issue in many developing countries, as its treatment is longer and requires more expensive drugs. MDR-TB is defined as resistance to the two most effective first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB is also resistant to three or more of the six classes of second-line drugs.[156]Totally drug-resistant TB is resistant to all currently used drugs.[157]It was first observed in 2003 in Italy,[158]but not widely reported until 2012,[157][159]and has also been found in Iran and India.[160]There is some efficacy forlinezolidto treat those with XDR-TB but side effects and discontinuation of medications were common.[161][162]Bedaquilineis tentatively supported for use in multiple drug-resistant TB.[163]

XDR-TB is a term sometimes used to defineextensively resistantTB, and constitutes one in ten cases of MDR-TB. Cases of XDR TB have been identified in more than 90% of countries.[160]

For those with known rifampicin or MDR-TB, molecular tests such as the Genotype MTBDRsl Assay (performed on culture isolates or smear positive specimens) may be useful to detect second-line anti-tubercular drug resistance.[164][165]

Prognosis

Age-standardizeddisability-adjusted life yearscaused by tuberculosis per 100,000 inhabitants, 2004.[166]

Progression from TB infection to overt TB disease occurs when the bacilli overcome the immune system defenses and begin to multiply. In primary TB disease (some 1–5% of cases), this occurs soon after the initial infection.[14]However, in the majority of cases, alatent infectionoccurs with no obvious symptoms.[14]These dormant bacilli produce active tuberculosis in 5–10% of these latent cases, often many years after infection.[49]

The risk of reactivation increases withimmunosuppression,such as that caused by infection with HIV. In people coinfected withM. tuberculosisand HIV, the risk of reactivation increases to 10% per year.[14]Studies usingDNA fingerprintingofM. tuberculosisstrains have shown reinfection contributes more substantially to recurrent TB than previously thought,[167]with estimates that it might account for more than 50% of reactivated cases in areas where TB is common.[168]The chance of death from a case of tuberculosis is about 4% as of 2008,down from 8% in 1995.[15]

In people with smear-positive pulmonary TB (without HIV co-infection), after 5 years without treatment, 50–60% die while 20–25% achieve spontaneous resolution (cure). TB is almost always fatal in those with untreated HIV co-infection and death rates are increased even with antiretroviral treatment of HIV.[169]

Epidemiology

Roughly one-quarter of the world's population has been infected withM. tuberculosis,[6]with new infections occurring in about 1% of the population each year.[12]However, most infections withM. tuberculosisdo not cause disease,[170]and 90–95% of infections remain asymptomatic.[88]In 2012, an estimated 8.6 million chronic cases were active.[171]In 2010, 8.8 million new cases of tuberculosis were diagnosed, and 1.20–1.45 million deaths occurred (most of these occurring indeveloping countries).[79][172]Of these, about 0.35 million occur in those also infected with HIV.[173]In 2018, tuberculosis was the leading cause of death worldwide from a single infectious agent.[174]The total number of tuberculosis cases has been decreasing since 2005, while new cases have decreased since 2002.[79]

Tuberculosis[clarification needed]incidence is seasonal, with peaks occurring every spring and summer.[175][176][177][178]The reasons for this are unclear, but may be related to vitamin D deficiency during the winter.[178][179]There are also studies linking tuberculosis to different weather conditions like low temperature, low humidity and low rainfall. It has been suggested that tuberculosis incidence rates may be connected toclimate change.[180]

At-risk groups

Tuberculosis is closely linked to both overcrowding andmalnutrition,making it one of the principaldiseases of poverty.[15]Those at high risk thus include: people who inject illicit drugs, inhabitants and employees of locales where vulnerable people gather (e.g., prisons and homeless shelters), medically underprivileged and resource-poor communities, high-risk ethnic minorities, children in close contact with high-risk category patients, and health-care providers serving these patients.[181]

The rate of tuberculosis varies with age. In Africa, it primarily affects adolescents and young adults.[182]However, in countries where incidence rates have declined dramatically (such as the United States), tuberculosis is mainly a disease of the elderly andimmunocompromised(risk factors are listed above).[14][183]Worldwide, 22 "high-burden" states or countries together experience 80% of cases as well as 83% of deaths.[160]

In Canada and Australia, tuberculosis is many times more common among theIndigenous peoples,especially in remote areas.[184][185]Factors contributing to this include higher prevalence of predisposing health conditions and behaviours, and overcrowding and poverty. In some Canadian Indigenous groups, genetic susceptibility may play a role.[78]

Socioeconomic status (SES) strongly affects TB risk. People of low SES are both more likely to contract TB and to be more severely affected by the disease. Those with low SES are more likely to be affected by risk factors for developing TB (e.g., malnutrition, indoor air pollution, HIV co-infection, etc.), and are additionally more likely to be exposed to crowded and poorly ventilated spaces. Inadequate healthcare also means that people with active disease who facilitate spread are not diagnosed and treated promptly; sick people thus remain in the infectious state and (continue to) spread the infection.[78]

Geographical epidemiology

The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many African, Caribbean, South Asian, and eastern European countries test positive in tuberculin tests, while only 5–10% of the U.S. population test positive.[14]Hopes of totally controlling the disease have been dramatically dampened because of many factors, including the difficulty of developing an effective vaccine, the expensive and time-consuming diagnostic process, the necessity of many months of treatment, the increase in HIV-associated tuberculosis, and the emergence of drug-resistant cases in the 1980s.[15]

In developed countries, tuberculosis is less common and is found mainly in urban areas. 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 theMedical Research Councilwas formed in Britain in 1913 its initial focus was tuberculosis research.[186]

In 2010, rates per 100,000 people in different areas of the world were: globally 178, Africa 332, the Americas 36, Eastern Mediterranean 173, Europe 63, Southeast Asia 278, and Western Pacific 139.[173]

In 2023, tuberculosis overtookCOVID-19as the leading cause of infectious disease-related deaths globally, according to aWorld Health Organization.[187]Around 8.2 million people were newly diagnosed with TB last year, allowing them access to treatment—a record high since WHO’s tracking began in 1995 and an increase from 7.5 million cases in 2022.[188]The report highlights ongoing obstacles in combating TB, including severe funding shortages that hinder efforts toward eradication. Although TB-related deaths decreased slightly to 1.25 million in 2023 from 1.32 million in 2022, the overall number of new cases rose marginally to an estimated 10.8 million.

Russia

Russia has achieved particularly dramatic progress with a decline in its TB mortality rate—from 61.9 per 100,000 in 1965 to 2.7 per 100,000 in 1993;[189][190]however, mortality rate increased to 24 per 100,000 in 2005 and then recoiled to 11 per 100,000 by 2015.[191]

China

China has achieved particularly dramatic progress, with about an 80% reduction in its TB mortality rate between 1990 and 2010.[173]The number of new cases has declined by 17% between 2004 and 2014.[160]

Africa

In 2007, the country with the highest estimated incidence rate of TB wasEswatini,with 1,200 cases per 100,000 people. In 2017, the country with the highest estimatedincidence rateas a % of the population wasLesotho,with 665 cases per 100,000 people.[192]

In South Africa, 54,200 people died in 2022 from TB. The incidence rate was 468 per 100,000 people; in 2015, this was 988 per 100,000. The total incidence was 280,000 in 2022; in 2015, this was 552,000.[193]

India

As of 2017, India had the largest total incidence, with an estimated 2,740,000 cases.[192]According to theWorld Health Organization(WHO), in 2000–2015, India's estimated mortality rate dropped from 55 to 36 per 100,000 population per year with estimated 480 thousand people died of TB in 2015.[194][195]In India a major proportion of tuberculosis patients are being treated by private partners and private hospitals. Evidence indicates that the tuberculosis national survey does not represent the number of cases that are diagnosed and recorded by private clinics and hospitals in India.[196]

North America

In Canada, tuberculosis was endemic in some rural areas as of 1998.[197]The tuberculosis case rate in Canada in 2021 was 4.8 per 100,000 persons. The rates were highest among Inuit (135.1 per 100,000), First Nations (16.1 per 100,000) and people born outside of Canada (12.3 per 100,000).[198]

In the United States,Native Americanshave a fivefold greater mortality from TB,[199]and racial and ethnic minorities accounted for 88% of all reported TB cases.[200]The overall tuberculosis case rate in the United States was 2.9 per 100,000 persons in 2023, representing a 16% increase in cases compared to 2022.[200]

In 2024, Long Beach, California authorized apublic health emergencyin response to a localoutbreakof TB.[201]

Western Europe

In 2017, in the United Kingdom, the national average was 9 per 100,000 and the highest incidence rates inWestern Europewere 20 per 100,000 in Portugal.

  • Number of new cases of tuberculosis per 100,000 people, 2016.[202]
  • Tuberculosis deaths per million persons, 2012
  • Tuberculosis deaths by region, 1990 to 2017.[203]

Society and culture

Names

Tuberculosis has been known by many names from the technical to the familiar.[204]Phthisis(φθίσις) is the Greek word for consumption, an old term for pulmonary tuberculosis;[8]around 460 BCE,Hippocratesdescribed phthisis as a disease of dry seasons.[205]The abbreviationTBis short fortuberclebacillus.Consumptionwas the most common nineteenth century English word for the disease, and was also in use well into the twentieth century. The Latin rootconmeaning 'completely' is linked tosumeremeaning 'to take up from under'.[206]InThe Life and Death of Mr BadmanbyJohn Bunyan,the author calls consumption "the captain of all these men of death."[207]"Great white plague" has also been used.[204]

Art and literature

PaintingThe Sick ChildbyEdvard Munch,1885–1886, depicts the illness of his sister Sophie, who died of tuberculosis when Edvard was 14; his mother also died of the disease.
Main article:Cultural depictions of tuberculosis

Tuberculosis was for centuries associated withpoeticandartisticqualities among those infected, and was also known as "the romantic disease".[204][208]Major artistic figures such as the poetsJohn Keats,Percy Bysshe Shelley,andEdgar Allan Poe,the composerFrédéric Chopin,[209]the playwrightAnton Chekhov,the novelistsFranz Kafka,Katherine Mansfield,[210]Charlotte Brontë,Fyodor Dostoevsky,Thomas Mann,W. Somerset Maugham,[211]George Orwell,[212]andRobert Louis Stevenson,and the artistsAlice Neel,[213]Jean-Antoine Watteau,Elizabeth Siddal,Marie Bashkirtseff,Edvard Munch,Aubrey BeardsleyandAmedeo Modiglianieither had the disease or were surrounded by people who did. A widespread belief was that tuberculosis assisted artistic talent. Physical mechanisms proposed for this effect included the slight fever and toxaemia that it caused, allegedly helping them to see life more clearly and to act decisively.[214][215][216]

Tuberculosis formed an often-reused theme inliterature,as inThomas Mann'sThe Magic Mountain,set in asanatorium;[217]inmusic,as inVan Morrison's song "T.B. Sheets";[218]inopera,as inPuccini'sLa bohèmeandVerdi'sLa Traviata;[216]inart,as inMunch's painting of his ill sister;[219]and infilm,such as the 1945The Bells of St. Mary'sstarringIngrid Bergmanas a nun with tuberculosis.[220]

Public health efforts

Further information:Elimination of tuberculosis

In 2014, the WHO adopted the "End TB" strategy which aims to reduce TB incidence by 80% and TB deaths by 90% by 2030.[221]The strategy contains a milestone to reduce TB incidence by 20% and TB deaths by 35% by 2020.[222]However, by 2020 only a 9% reduction in incidence per population was achieved globally, with the European region achieving 19% and the African region achieving 16% reductions.[222]Similarly, the number of deaths only fell by 14%, missing the 2020 milestone of a 35% reduction, with some regions making better progress (31% reduction in Europe and 19% in Africa).[222]Correspondingly, also treatment, prevention and funding milestones were missed in 2020, for example only 6.3 million people were started on TB prevention short of the target of 30 million.[222]

The World Health Organization (WHO), theBill and Melinda Gates Foundation,and the U.S. government are subsidizing a fast-acting diagnostic tuberculosis test for use in low- and middle-income countries as of 2012.[223][224][225]In addition to being fast-acting, the test can determine if there is resistance to the antibiotic rifampicin which may indicate multi-drug resistant tuberculosis and is accurate in those who are also infected with HIV.[223][226]Many resource-poor places as of 2011have access to only sputum microscopy.[227]

India had the highest total number of TB cases worldwide in 2010, in part due to poor disease management within the private and public health care sector.[228]Programs such as theRevised National Tuberculosis Control Programare working to reduce TB levels among people receiving public health care.[229][230]

A 2014EIU-healthcare report finds there is a need to address apathy and urges for increased funding. The report cites among others Lucica Ditui "[TB] is like an orphan. It has been neglected even in countries with a high burden and often forgotten by donors and those investing in health interventions."[160]

Slow progress has led to frustration, expressed by the executive director of theGlobal Fund to Fight AIDS, Tuberculosis and Malaria– Mark Dybul: "we have the tools to end TB as a pandemic and public health threat on the planet, but we are not doing it."[160]Several international organizations are pushing for more transparency in treatment, and more countries are implementing mandatory reporting of cases to the government as of 2014, although adherence is often variable. Commercial treatment providers may at times overprescribe second-line drugs as well as supplementary treatment, promoting demands for further regulations.[160]

The government of Brazil provides universal TB care, which reduces this problem.[160]Conversely, falling rates of TB infection may not relate to the number of programs directed at reducing infection rates but may be tied to an increased level of education, income, and health of the population.[160]Costs of the disease, as calculated by theWorld Bankin 2009 may exceed US$150 billion per year in "high burden" countries.[160]Lack of progress eradicating the disease may also be due to lack of patient follow-up – as among the 250 millionrural migrants in China.[160]

There is insufficient data to show that active contact tracing helps to improve case detection rates for tuberculosis.[231]Interventions such as house-to-house visits, educational leaflets, mass media strategies, educational sessions may increase tuberculosis detection rates in short-term.[232]There is no study that compares new methods of contact tracing such as social network analysis with existing contact tracing methods.[233]

Stigma

Slow progress in preventing the disease may in part be due tostigmaassociated with TB.[160]Stigma may be due to the fear of transmission from affected individuals. This stigma may additionally arise due to links between TB and poverty, and inAfrica, AIDS.[160]Such stigmatization may be both real and perceived; for example, in Ghana, individuals with TB are banned from attending public gatherings.[234]

Stigma towards TB may result in delays in seeking treatment,[160]lower treatment compliance, and family members keeping cause of death secret[234]– allowing the disease to spread further.[160]In contrast, in Russia stigma was associated with increased treatment compliance.[234]TB stigma also affects socially marginalized individuals to a greater degree and varies between regions.[234]

One way to decrease stigma may be through the promotion of "TB clubs", where those infected may share experiences and offer support, or through counseling.[234]Some studies have shown TB education programs to be effective in decreasing stigma, and may thus be effective in increasing treatment adherence.[234]Despite this, studies on the relationship between reduced stigma and mortality are lacking as of 2010,and similar efforts to decrease stigma surrounding AIDS have been minimally effective.[234]Some have claimed the stigma to be worse than the disease, and healthcare providers may unintentionally reinforce stigma, as those with TB are often perceived as difficult or otherwise undesirable.[160]A greater understanding of the social and cultural dimensions of tuberculosis may also help with stigma reduction.[235]

Research

See also:International Congress on Tuberculosis

The BCG vaccine has limitations and research to develop new TB vaccines is ongoing.[236]A number of potential candidates are currently inphase I and II clinical trials.[236][237]Two main approaches are used to attempt to improve the efficacy of available vaccines. One approach involves adding a subunit vaccine to BCG, while the other strategy is attempting to create new and better live vaccines.[236]MVA85A,an example of a subunit vaccine, is in trials in South Africa as of 2006, is based on a genetically modifiedvacciniavirus.[238]Vaccines are hoped to play a significant role in treatment of both latent and active disease.[239]

To encourage further discovery, researchers and policymakers are promoting new economic models of vaccine development as of 2006, including prizes, tax incentives, andadvance market commitments.[240][241]A number of groups, including theStop TB Partnership,[242]the South African Tuberculosis Vaccine Initiative, and the Aeras Global TB Vaccine Foundation, are involved with research.[243]Among these, the Aeras Global TB Vaccine Foundation received a gift of more than $280 million (US) from theBill and Melinda Gates Foundationto develop and license an improved vaccine against tuberculosis for use in high burden countries.[244][245]

In 2012 a new medication regimen was approved in the US for multidrug-resistant tuberculosis, usingbedaquilineas well as existing drugs. There were initial concerns about the safety of this drug,[246][247][248][249][250]but later research on larger groups found that this regimen improved health outcomes.[251]By 2017 the drug was used in at least 89 countries.[252]Another new drug isdelamanid,which was first approved by the European Medicines Agency in 2013 to be used in multidrug-resistant tuberculosis patients,[253]and by 2017 was used in at least 54 countries.[252]

Steroids add-on therapy has not shown any benefits for active pulmonary tuberculosis infection.[254]

Other animals

Mycobacteria infect many different animals, including birds,[255]fish, rodents,[256]and reptiles.[257]The subspeciesMycobacterium tuberculosis,though, is rarely present in wild animals.[258]An effort to eradicate bovine tuberculosis caused byMycobacterium bovisfrom the cattle and deer herds ofNew Zealandhas been relatively successful.[259]Efforts in Great Britain have been less successful.[260][261]

As of 2015,tuberculosis appears to be widespread among captiveelephantsin the US. It is believed that the animals originally acquired the disease from humans, a process calledreverse zoonosis.Because the disease can spread through the air to infect both humans and other animals, it is a public health concern affectingcircusesandzoos.[262][263]

See also

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