Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption,[8] is an infectious disease usually caused by Mycobacterium tuberculosis (MTB) bacteria.[1] Tuberculosis generally affects the lungs, but it can also affect other parts of the body.[1] Most infections show no symptoms, in which case it is known as latent 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 chronic cough with blood-containing mucus, fever, night sweats, and weight loss.[1] Infection of other organs can cause a wide range of symptoms.[9]
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][10] People with latent TB do not spread the disease.[1] Active infection occurs more often in people with HIV/AIDS and in those who smoke.[1] Diagnosis of active TB is based on chest X-rays, as well as microscopic examination and culture of body fluids.[11] Diagnosis of latent TB relies on the tuberculin skin test (TST) or blood tests.[11]
Prevention of TB involves screening those at high risk, early detection and treatment of cases, and vaccination with the bacillus 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 multiple antibiotics over a long period of time.[1] Antibiotic resistance is a growing problem, with increasing rates of multiple 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 leading cause of death from an infectious disease after COVID-19.[7] As of 2018, most TB cases occurred in the 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 since ancient times.[15]
Tuberculosis has existed since antiquity.[15] The oldest unambiguously detected M. tuberculosis gives 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 the genes of M. 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 the Neolithic Revolution.[18] 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.[19] Genetic studies suggest the presence of TB in the Americas from about AD 100.[20]
Before the Industrial Revolution, folklore often associated tuberculosis with vampires. 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]
Although Richard Morton established the pulmonary form associated with tubercles as 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 Marten conjectured in 1720 that consumptions were caused by microbes which were spread by people living close to each other.[24] In 1819, René Laennec claimed that tubercles were the cause of pulmonary tuberculosis.[25] J. L. Schönlein first published the name "tuberculosis" (German: Tuberkulose) in 1832.[26][27]
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.[28] Hermann Brehmer opened the first TB sanatorium in 1859 in Görbersdorf (now Sokołowsko) in Silesia.[29] In 1865, Jean Antoine Villemin demonstrated that tuberculosis could be transmitted, via inoculation, from humans to animals and among animals.[30] (Villemin's findings were confirmed in 1867 and 1868 by John Burdon-Sanderson.[31])
Robert Koch identified and described the bacillus causing tuberculosis, M. tuberculosis, on 24 March 1882.[32][33] In 1905, he was awarded the Nobel Prize in Physiology or Medicine for this discovery.[34]
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 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.[29] What later became known as the Alexandra 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 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.[39] 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.[40]
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,[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 of streptomycin and 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 "pneumothorax technique", which involved collapsing an infected lung to "rest" it and to allow tuberculous lesions to heal.[44]
Because of the emergence of multidrug-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 of drug-resistant strains 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]
There is a popular misconception that tuberculosis is purely a disease of the lungs that manifests as coughing.[48] However, 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, and fatigue.[9] Significant nail clubbing may also occur.[49]
If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases).[15][50] Symptoms may include chest pain and a prolonged cough producing sputum. About 25% of people may not have any symptoms (i.e., they remain asymptomatic).[15] Occasionally, people may cough up blood in small amounts, and in very rare cases, the infection may erode into the pulmonary artery or a Rasmussen 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 poor lymph drainage within the upper lungs.[9]
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.[9] Miliary TB currently makes up about 10% of extrapulmonary cases.[54]
The main cause of TB is Mycobacterium tuberculosis (MTB), a small, aerobic, nonmotile bacillus.[9] The high lipid content of this pathogen accounts for many of its unique clinical characteristics.[55] It divides every 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 an outer membrane lipid bilayer.[57] 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.[58] 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.[59]
Using histological stains on expectorated samples from phlegm (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 an acid-fast bacillus.[14][58] The most common acid-fast staining techniques are the Ziehl–Neelsen stain[60] and the Kinyoun stain, which dye acid-fast bacilli a bright red that stands out against a blue background.[61] Auramine-rhodamine staining[62] and fluorescence microscopy[63] are also used.
The M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canettii, and M. microti.[64] M. africanum is not widespread, but it is a significant cause of tuberculosis in parts of Africa.[65][66] M. bovis was once a common cause of tuberculosis, but the introduction of pasteurized milk has almost eliminated this as a public health problem in developed countries.[14][67] M. canettii is rare and seems to be limited to the Horn of Africa, although a few cases have been seen in African emigrants.[68][69] M. microti is also rare and is seen almost only in immunodeficient people, although its prevalence may be significantly underestimated.[70]
Other known pathogenic mycobacteria include M. leprae, M. avium, and M. kansasii. The latter two species are classified as "nontuberculous mycobacteria" (NTM) or atypical mycobacteria. NTM cause neither TB nor leprosy, but they do cause lung diseases that resemble TB.[71]
When people with active pulmonary TB cough, sneeze, speak, sing, or spit, they expel infectious aerosol droplets 0.5 to 5.0 μm in 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]
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, the