Mycobacterium TB

The world's most deadly illness, killing over 10 billion people over the course of human history. Also known as the white death, tuberculosis is a respiratory illness that spreads through air and causes lung damage, bloody cough and death. Tuberculosis is spread from one person to the next through the air when people who have active TB in their lungs cough, spit, speak, or sneeze.[1][4] People with latent TB do not spread the disease.[1] A latent infection is more likely to become active in those with weakened immune systems.[1] There are two principal tests for TB: interferon-gamma release assay (IGRA) of a blood sample, and the tuberculin skin test.[1][6]

Prevention of TB involves screening those at high risk, early detection and treatment of cases, and vaccination with the bacillus Calmette-Guérin (BCG) vaccine.[7][8][9] Those at high risk include household, workplace, and social contacts of people with active TB.[8] Treatment requires the use of multiple antibiotics over a long period of time.[1]

Tuberculosis has been present in humans since ancient times.[10] In the 1800s, when it was known as consumption, it was responsible for an estimated quarter of all deaths in Europe.[11] The incidence of TB decreased during the 20th century with improvement in sanitation and efficient vaccination campaigns.[12] However, since the 1980s, antibiotic resistance has become a growing problem, with increasing rates of drug-resistant tuberculosis.[1][13] It is estimated that one quarter of the world's population have latent TB.[14] In 2024, TB is estimated to have newly infected 10.7 million people and caused 1.23 million deaths, making it the leading cause of death from an infectious disease.[1]

Tuberculosis has existed since antiquity.[15] Skeletal remains show some prehistoric humans (4000 BC) had TB, and researchers have found tubercular decay in the spines of Egyptian mummies dating from 3000 to 2400 BC.[16] Genetic studies suggest the presence of TB-like bacteria in Southern America from about AD 140.[17] Identification

Although Richard Morton established the pulmonary form associated with tubercles as a pathology in 1689,[18][19] due to the variety of its symptoms, TB was not identified as a single disease until the 1820s. Benjamin Marten conjectured in 1720 that consumptions were caused by microbes which were spread by people living close to each other.[20] In 1819, René Laennec claimed that tubercles were the cause of pulmonary tuberculosis.[21] J. L. Schönlein first published the name "tuberculosis" (German: Tuberkulose) in 1832.[22][23]

In 1865, Jean Antoine Villemin demonstrated that tuberculosis could be transmitted, via inoculation, from humans to animals and among animals.[24] Villemin's findings were confirmed in 1867 and 1868 by John Burdon-Sanderson.[25] Robert Koch discovered the tuberculosis bacillus.

Robert Koch identified and described the bacillus causing tuberculosis, M. tuberculosis, on 24 March 1882.[26][27] In 1905, he was awarded the Nobel Prize in Physiology or Medicine for this discovery.[28] 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.[11] In the 18th and 19th century, tuberculosis had become epidemic in Europe, showing a seasonal pattern.[29][30] 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]

Between 1838 and 1845, John Croghan, the owner of Mammoth Cave in 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.[31]

Hermann Brehmer opened the first TB sanatorium in 1859 in Görbersdorf (now Sokołowsko) in Silesia.[32] After TB was determined to be contagious, in the 1880s, it was put on a notifiable-disease list in Britain. Campaigns started to stop people from spitting in public places, and the infected poor were "encouraged" to enter sanatoria that resembled prisons. The sanatoria for the middle and upper classes offered excellent care and constant medical attention.[32] 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).[32]

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 the pasteurization process. Koch announced a glycerine extract 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.[33] World Tuberculosis Day is marked on 24 March each year, the anniversary of Koch's original scientific announcement. When the Medical Research Council formed in Britain in 1913, it initially focused on tuberculosis research.[34]

Albert Calmette and Camille Guérin achieved the first genuine success in immunization against tuberculosis in 1906, using attenuated bovine-strain tuberculosis. It was called bacille Calmette–Guérin (BCG). The BCG vaccine was first used on humans in 1921 in France,[35] but achieved widespread acceptance in the US, Great Britain, and Germany only after World War II.[36]

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 "pneumothorax technique", which involved collapsing an infected lung to "rest" it and to allow tuberculous lesions to heal.[37]

By the 1950s, mortality in Europe had decreased about 90%. Improvements in sanitation, vaccination, and other public-health measures began significantly reducing rates of tuberculosis even before the arrival of streptomycin and other antibiotics, although the disease remained a significant threat.[citation needed] Drug resistant tuberculosis

A few years after the first antibiotic treatment for TB in 1943, some strains of the TB bacteria developed resistance to the standard drugs (streptomycin, para-aminosalicylic acid, and isoniazid).[38] Between 1970 and 1990, there were numerous outbreaks of drug-resistant tuberculosis involving strains resistant to two or more drugs; these strains are called multi-drug resistant TB (MDR-TB).[38] The resurgence of tuberculosis, caused in part by drug resistance and in part by the HIV pandemic, resulted in the declaration of a global health emergency by the World Health Organization (WHO) in 1993.[39][40]

Treatment of MDR-TB requires treatment with second-line drugs, which in general are less effective, more toxic and more expensive than first-line drugs.[41] Treatment regimes can run for two years, compared to the six months of first-line drug treatment.[42][43] Signs and symptoms The main symptoms of variants and stages of tuberculosis are given,[44] with many symptoms overlapping with other variants, while others are more, but not entirely, specific for certain variants. Multiple variants may be present simultaneously. Tuberculosis of the lip, secondary to open pulmonary TB

There is a popular misconception that tuberculosis is purely a disease of the lungs that manifests as coughing.[45] Tuberculosis may infect many organs, even though it most commonly occurs in the lungs (known as pulmonary tuberculosis).[5] Extrapulmonary TB occurs when tuberculosis develops in organs other than the lungs; it may coexist with pulmonary TB.[5]

General signs and symptoms include fever, chills, night sweats, loss of appetite, weight loss, and fatigue.[5] Latent tuberculosis Main article: Latent tuberculosis

The majority of individuals with TB infection show no symptoms, a state known as inactive or latent tuberculosis.[4] This condition is not contagious, and can be detected by the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA); other tests should be conducted to eliminate the possibility of active TB.[46] Without treatment, an estimated 5% to 15% of cases will progress into active TB during the person's lifetime.[46] Pulmonary

If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases).[10][47] Symptoms may include chest pain, a prolonged cough producing sputum which may be bloody, tiredness, temperature, loss of appetite, wasting and general malaise.[10][48] In very rare cases, the infection may erode into the pulmonary artery or a Rasmussen aneurysm, resulting in massive bleeding.[5][49]

Tuberculosis may cause extensive scarring of the lungs, which persists after successful treatment of the disease. Survivors continue to experience chronic respiratory symptoms such as cough, sputum production, and shortness of breath.[50][51] 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 a weakened immune system and young children. In those with HIV, this occurs in more than 50% of cases.[53] Notable extrapulmonary infection sites include the pleura (in tuberculous pleurisy), the central nervous system (in tuberculous meningitis), the lymphatic system (in scrofula of the neck), the genitourinary system (in urogenital tuberculosis), and the bones and joints (in Pott disease of the spine), among others. A potentially more serious, widespread form of TB is called "disseminated tuberculosis"; it is also known as miliary tuberculosis.[5] Miliary TB currently makes up about 10% of extrapulmonary cases.[54]

Symptoms of extrapulmonary TB usually include the general signs and symptoms as above, with additional symptoms related to the part of the body which is affected.[55] Urogenital tuberculosis, however, typically presents differently, as this manifestation most commonly appears decades after the resolution of pulmonary symptoms. Most patients with chronic urogenital TB do not have pulmonary symptoms at the time of diagnosis. Urogenital tuberculosis most commonly presents with urinary 'storage symptoms' such as increased frequency and/or urgency of urination, flank pain, hematuria, and nonspecific symptoms such as fever and malaise.[56] Causes Mycobacteria Main article: Mycobacterium tuberculosis Scanning electron micrograph of M. tuberculosis

The main cause of TB is Mycobacterium tuberculosis (MTB), a small, aerobic, nonmotile bacillus.[5] It divides every 16 to 20 hours, which is slow compared with other bacteria, which usually divide in less than an hour.[57] Mycobacteria have a complex, lipid-rich cell envelope, with the high lipid content of the outer membrane acting as a robust barrier contributing to their drug resistance.[58][59] If a Gram stain is performed, MTB either stains very weakly "Gram-positive" or does not retain dye as a result of the high lipid and mycolic acid content of its cell wall.[60] MTB can withstand weak disinfectants and survive in a dry state for weeks. In nature, the bacterium can grow only within the cells of a host organism, but M. tuberculosis can be cultured in the laboratory.[61]

The term M. tuberculosis complex describes a genetically related group of Mycobacterium species that can cause tuberculosis in humans or other animals. It includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canettii, and M. microti.[62] M. bovis causes bovine TB and was once a common cause of human TB, but the introduction of pasteurized milk has almost eliminated this as a public health problem in developed countries.[63][64] M. africanum is not widespread, but it is a significant cause of human TB in parts of Africa.[65][66] M. canettii is rare and seems to be limited to the Horn of Africa, although a few cases have been seen in African emigrants.[67][68] M. microti appears to have a natural reservoir in small rodents such as mice and voles, but can infect larger mammals. It is rare in humans and is seen almost only in immunodeficient people, although its prevalence may be significantly underestimated.[69][70]

There are other known mycobacteria which cause lung disease resembling TB. M. avium complex is an environmental microorganism found in soil and water sources worldwide, which tends to present as an opportunistic infection in immunocompromised people.[71][72] The natural reservoir of M. kansasii is unknown, but it has been found in tap water; it is most likely to infect humans with lung disease or who smoke.[73] These two species are classified as "nontuberculous mycobacteria".[74] Public health campaigns in the 1920s tried to halt the spread of TB. Transmission

Tuberculosis spreads through the air when people with active pulmonary TB cough, sneeze, speak, or sing, releasing tiny airborne droplets containing the bacteria. Anyone nearby can breathe in these droplets and become infected. The droplets can remain airborne and infective for several hours, and are more likely to persist in poorly ventilated areas.[75] Risk factors Main article: Risk factors for tuberculosis

Risk factors for TB include exposure to droplets from people with active TB and environmental-related and health-condition related factors that decrease a person's immune system response such as HIV or taking immunosuppressant medications.[76] Close contact

Prolonged, frequent, or close contact with people who have active TB is a high high risk factor for becoming infected; this group includes health care workers and children where a family member is infected.[77][78] Transmission is most likely to occur from only people with active TB – those with latent infection are not thought to be contagious.[63] Environmental risk factors which put a person at closer contact with infective droplets from a person infected with TB are overcrowding, poor ventilation, or close proximity to a potentially infective person.[79][80] Immunodeficiencies

The most important risk factor globally for developing active TB is concurrent human immunodeficiency virus (HIV) infection; in 2023, 6.1% of those becoming infected with TB were also infected with HIV.[81] Sub-Saharan Africa has a particularly high burden of HIV-associated TB.[1] Of those without HIV infection who are infected with tuberculosis, about 5–15% develop active disease during their lifetimes;[46] in contrast, 30% of those co-infected with HIV develop the active disease.[82] People living with HIV are estimated 16 times more likely to fall ill with TB than people without HIV; TB is the leading cause of death among people with HIV.[1]

Another important risk factor is use of medications which suppress the immune system. These include (but are not limited to), chemotherapy; medication after an organ transplant; and medication for lupus or rheumatoid arthritis.[76][83] Other risk factors include: heavy alcohol use, diabetes mellitus, silicosis, tobacco smoking, recreational drug use, severe kidney disease, head and neck cancer, and low body weight.[76][84] Children, especially those under age five, have undeveloped immune systems and are at higher risk.[84]

Environmental factors which weaken the body's protective mechanisms and may put a person at additional risk of contracting TB include air pollution, exposure to smoke (including tobacco smoke), and exposure (often occupational) to dust or particulates.[79] Pathogenesis The spleen in a patient with miliary tuberculosis showing granulomas (tubercles)

TB infection begins when a M. tuberculosis bacterium, inhaled from the air, penetrates the lungs and reaches the alveoli. Here it encounters an alveolar macrophage, a cell which is part of the body's immune system, which attempts to destroy it.[85] However, M. tuberculosis is able to neutralise and colonise the macrophage, leading to persistent infection.[85]

The defence mechanism of the macrophage begins when a foreign body, such as a bacterial cell, binds to receptors on the surface of the macrophage. The macrophage then stretches itself around the bacterium and engulfs it.[86] Once inside this macrophage, the bacterium is trapped in a compartment called a phagosome; the phagosome subsequently merges with a lysosome to form a phagolysosome.[87] The lysosome is an organelle which contains digestive enzymes; these are released into the phagolysosome and kill the invader.[88]

The M. tuberculosis bacterium is able to subvert the normal process by inhibiting the development of the phagosome and preventing it from fusing with the lysosome.[87] The bacterium is able to survive and replicate within the phagosome; it will eventually destroy its host macrophage, releasing progeny bacteria which spread the infection.[85]

In the next stage of infection, macrophages, epithelioid cells, lymphocytes and fibroblasts aggregate to form a granuloma, which surrounds and isolates the infected macrophages.[85] This does not destroy the tuberculosis bacilli, but contains them, preventing spread of the infection to other parts of the body. They are nevertheless able to survive within the granuloma.[85][89] In tuberculosis, the granuloma contains necrotic tissue at its centre, and appears as a small white nodule, also known as a tubercle, from which the disease derives its name.[90]

Granulomas are most common in the lung, but they can appear anywhere in the body. As long as the infection is contained within granulomas, there are no outward symptoms and the infection is latent.[90] However, if the immune system is unable to control the infection, the disease can progress to active TB, which can cause significant damage to the lungs and other organs.[89]

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.[91] This severe form of TB disease, most common in young children and those with HIV, is called miliary tuberculosis.[92] People with this disseminated TB have a high fatality rate even with treatment (about 30%).[54][93]

In many people, the infection waxes and wanes. Tissue destruction and necrosis are often balanced by healing and fibrosis.[94] 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 appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.[94] Diagnosis Main article: Diagnosis of tuberculosis M. tuberculosis (stained red) in sputum

Diagnosis of tuberculosis is often difficult. Symptoms manifest slowly, and are generally non-specific, e.g. cough, fatigue, fever which could be caused by a number of other factors.[95] The conclusive test for pulmonary TB is a bacterial culture taken from a sample of sputum, but this is slow to give a result, and does not detect latent TB. Extra-pulmonary TB infection can affect the kidneys, spine, brain, lymph nodes, or bones - a sample cannot easily be obtained for culture.[96] Tests based on the immune response are sensitive but are likely to give false negatives in those with weak immune systems such as very young patients and those coinfected with HIV. Another issue affecting diagnosis in many parts of the world is that TB infection is most common in resource-poor settings where sophisticated laboratories are rarely available.[97][98]

A diagnosis of TB should be considered in those with signs of lung disease or constitutional symptoms lasting longer than two weeks.[99] Diagnosis of TB, whether latent or active, starts with medical history and physical examination. Subsequently a number of tests can be performed to refine the diagnosis:[100] A chest X-ray and multiple sputum cultures for acid-fast bacilli are typically part of the initial evaluation.[99] Mantoux test The Mantoux skin test consists of an injection of a small quantity of PPD tuberculin just below the skin on the forearm.

The Mantoux tuberculin skin test is often used to screen people at high risk for TB such as health workers or close contacts of TB patients, who may not display symptoms of infection.[99] In the Mantoux test, a small quantity of tuberculin antigen is injected intradermally on the forearm.[101][102] The result of the test is read after 48 to 72 hours. A person who has been exposed to the bacteria would be expected to mount an immune response; the reaction is read by measuring the diameter of the raised area.[103] Vaccination with Bacille Calmette-Guerin (BCG) may result in a false-positive result. Several factors may lead to false negatives; these include HIV infection, some viral illnesses, and overwhelming TB disease.[104][105] Interferon-Gamma Release Assay

The Interferon Gamma Release Assay (IGRA) is recommended in those who are positive to the Mantoux test.[106] This test mixes a blood sample with antigenic material derived from the TB bacterium. If the patient has developed an immune response to a TB infection, white blood cells in the sample will release interferon-gamma (IFN-γ), which can be measured.[107] This test is more reliable than the Mantoux test, and does not give a false positive after BCG vaccination;[107] however it may give a positive result in case of infection by the related bacteria M. szulgai, M. marinum, and M. kansasii.[108] Chest radiograph

In active pulmonary TB, infiltrates (opaque areas) or scarring are visible in the lungs on a chest X-ray. Infiltrates are suggestive but not necessarily diagnostic of TB. Other lung diseases can mimic the appearance of TB; and this test will not detect extrapulmonary infection or a recent infection.[109] Microbiological studies A close-up of Mycobacterium tuberculosis in a culture medium

A definitive diagnosis of tuberculosis can be made by detecting Mycobacterium tuberculosis organisms in a specimen taken from the patient (most often sputum, but may also be pus, cerebrospinal fluid, biopsied tissue, etc.).[95] The specimen is examined by fluorescence microscopy.[110] The bacterium is slow growing so a cell culture may take several weeks to yield a result.[111] Other tests

Nucleic acid amplification tests (NAAT) and adenosine deaminase testing may allow rapid diagnosis of TB.[112][113] In December 2010, the World Health Organization endorsed the Xpert MTB/RIF system (a NAAT) for diagnosis of tuberculosis in endemic countries.[114]

Blood tests to detect antibodies are not specific or sensitive, so they are not recommended.[115]

Polymerase chain reaction testing of urine for Mycobacterium tuberculosis is often required for the diagnosis of urogenital tuberculosis and may also be used to diagnose tuberculosis in biopsy samples from tissues. It is highly sensitive and specific with good turnaround time.[56] Prevention

The main strategies to prevent infection with TB are treatment of both active and latent TB, as well as vaccination of children who are at risk.[10]

Although latent TB is not infective, it should be treated in order to prevent its development into active pulmonary TB, which is infective.[116] 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 with nonresistant active infections generally do not remain contagious to others; however it is important to complete the full course of treatment which is usually six months.[117][78] Vaccines Main articles: Tuberculosis vaccines and BCG vaccine

The only available vaccine as of 2021 is bacillus Calmette-Guérin (BCG).[118][119] In areas where tuberculosis is not common, only children at high risk are typically immunized, while suspected cases of tuberculosis are individually tested for and treated.[120] In countries where tuberculosis is common, one dose is recommended in healthy babies as soon after birth as possible.[120] A single dose is given by intradermal injection. Administered to children under 5, it decreases the risk of getting the infection by 20% and the risk of infection turning into active disease by nearly 60%.[121][122] It is not effective if administered to adults.[123] Public health A tuberculosis public health campaign in Ireland, 1905

The first International Congress on Tuberculosis was held at Berlin in 1899. It was known by this time that tuberculosis was caused by a bacillus, thought to be passed by phlegm coughed up by a sick person, dried into dust and then inhaled by a healthy person.[124] Milk was known to be an important means of infection.[124] Means of prevention included free ventilation of houses and wholesome and abundant food. Milk should be boiled, and meat should be carefully inspected, or else the cattle tested for infection. Cures for the disease included abundant food, particularly of a fatty nature, and life in the open air.[125]

TB was made a notifiable disease in Britain; there were campaigns to stop spitting in public places, and the infected poor were pressured to enter sanatoria that resembled prisons.[126] In the United States, concern about the spread of tuberculosis played a role in the movement to prohibit public spitting except into spittoons. Worldwide campaigns Royal Navy sailors being screened for tuberculosis (1940) Further information: Elimination of tuberculosis

The World Health Organization (WHO) declared TB a "global health emergency" in 1993,[10] and in 2006, the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aimed to save 14 million lives between its launch and 2015.[127] A number of targets they set were not achieved by 2015, mostly due to the increase in HIV-associated tuberculosis and the emergence of multi-drug resistant tuberculosis.[10]

In 2014, the WHO adopted the "End TB" strategy which aims to reduce TB incidence by 80% and TB deaths by 90% by 2030.[128] The strategy contains a milestone to reduce TB incidence by 20% and TB deaths by 35% by 2020.[129] 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.[129] 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).[129] 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.[129]

The goal of tuberculosis elimination is being hampered by the lack of rapid testing, short and effective treatment courses, and completely effective vaccines.[130] Management Main article: Management of tuberculosis Tuberculosis phototherapy treatment in Kuopio, 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 mycobacterial cell wall, which hinders the entry of drugs and makes many antibiotics ineffective.[131] Latent TB

People with latent infections are treated to prevent them from progressing to active TB disease later in life.[132] Treatment comprises a course of one or more of isoniazid, rifampin (also known as rifampicin) and rifapentine; the treatment regimen may last for between 3 and 9 months.[133][134] Completing treatment is crucial to eliminate the bacteria completely, prevent recurrence, and avoid the development of drug resistance.[135][136] New onset

Active TB is best treated with combinations of several antibiotics to reduce the risk of the bacteria developing antibiotic resistance.[10] The recommended treatment of new-onset pulmonary tuberculosis is a combination of antibiotics comprising rifampicin, isoniazid, pyrazinamide, and ethambutol for the first two months, followed by four months of only rifampicin and isoniazid; a total of six months.[10][137] If the symptoms do not improve, further testing is necessary to establish if the infection is drug-resistant, and the treatment regime should be adjusted if necessary.[10][138] Recurrent disease Tuberculosis has existed since antiquity.[15] Skeletal remains show some prehistoric humans (4000 BC) had TB, and researchers have found tubercular decay in the spines of Egyptian mummies dating from 3000 to 2400 BC.[16] Genetic studies suggest the presence of TB-like bacteria in Southern America from about AD 140.[17] Identification