Tuberculosis

If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases).[15][18] 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's aneurysm, resulting in massive bleeding.[9][19] 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.[20] These are collectively denoted as "extrapulmonary tuberculosis".[21] 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.[21] 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.[22]

Scanning electron micrograph of M. tuberculosis

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.[23] 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.[24] Mycobacteria have an outer membrane lipid bilayer.[25] 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.[26] 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.[27]

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][26] The most common acid-fast staining techniques are the Ziehl–Neelsen stain[28] and the Kinyoun stain, which dye acid-fast bacilli a bright red that stands out against a blue background.[29] Auramine-rhodamine staining[30] and fluorescence microscopy[31] are also used.

The M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canetti, and M. microti.[32] M. africanum is not widespread, but it is a significant cause of tuberculosis in parts of Africa.[33][34] M. bovis was once a common cause of tuberculosis, but the introduction of pasteurized milk has almost completely eliminated this as a public health problem in developed countries.[14][35] M. canetti is rare and seems to be limited to the Horn of Africa, although a few cases have been seen in African emigrants.[36][37] M. microti is also rare and is seen almost only in immunodeficient people, although its prevalence may be significantly underestimated.[38]

Other known pathogenic mycobacteria include M. leprae, M. avium, and M. kansasii. The latter two species are classified as "nontuberculous mycobacteria" (NTM). NTM cause neither TB nor leprosy, but they do cause lung diseases that resemble TB.[39]

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

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.[40] 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).[41]

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.[42] A person with active but untreated tuberculosis may infect 10–15 (or more) other people per year.[43] 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 virulence of the M. tuberculosis strain, the level of immunity in the uninfected person, and others.[44] 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.[42] 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.[45]

A number of factors make individuals more susceptible to TB infection and/or disease.[46]

The most important risk factor globally is HIV; 13% of those with TB are also infected with HIV.[47] This is a particular problem in sub-Saharan Africa, where rates of HIV are high.[48][49] Of those without HIV who are infected with tuberculosis, about 5–10% develop active disease during their lifetimes;[17] in contrast, 30% of those co-infected with HIV develop the active disease.[17]

Use of certain medications, such as corticosteroids and infliximab (an anti-αTNF monoclonal antibody), is another important risk factor, especially in the developed world.[15]

Other risk factors include: alcoholism,[15] diabetes mellitus (3-fold increased risk),[50] silicosis (30-fold increased risk),[51] tobacco smoking (2-fold increased risk),[52] indoor air pollution, malnutrition, young age,[46] recently acquired TB infection, recreational drug use, severe kidney disease, low body weight, organ transplant, head and neck cancer,[53] and genetic susceptibility[54] (of which the overall importance remains undefined[15]).

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 (children).[46]

Diagnosing active tuberculosis based only on signs and symptoms is difficult,[68] as is diagnosing the disease in those who have a weakened immune system.[69] A diagnosis of TB should, however, be considered in those with signs of lung disease or constitutional symptoms lasting longer than two weeks.[69] A chest X-ray and multiple sputum cultures for acid-fast bacilli are typically part of the initial evaluation.[69] Interferon-γ release assays and tuberculin skin tests are of little use in most of the developing world.[70][71] Interferon gamma release assays (IGRA) have similar limitations in those with HIV.[71][72]

A definitive diagnosis of TB is made by identifying M. tuberculosis in a clinical sample (e.g., sputum, pus, or a tissue biopsy). However, the difficult culture process for this slow-growing organism can take two to six weeks for blood or sputum culture.[73] Thus, treatment is often begun before cultures are confirmed.[74]

Nucleic acid amplification tests and adenosine deaminase testing may allow rapid diagnosis of TB.[68] These tests, however, are not routinely recommended, as they rarely alter how a person is treated.[74] Blood tests to detect antibodies are not specific or sensitive, so they are not recommended.[75]

Mantoux tuberculin skin test

The Mantoux tuberculin skin test is often used to screen people at high risk for TB.[69] Those who have been previously immunized with the Bacille Calmette-Guerin vaccine may have a false-positive test result.[76] The test may be falsely negative in those with sarcoidosis, 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.[74] These are not affected by immunization or most environmental mycobacteria, so they generate fewer false-positive results.[77] However, they are affected by M. szulgai, M. marinum, and M. kansasii.[78] IGRAs may increase sensitivity when used in addition to the skin test, but may be less sensitive than the skin test when used alone.[79]

The US Preventive Services Task Force (USPSTF) has recommended screening people who are at high risk for latent tuberculosis with either tuberculin skin tests or interferon-gamma release assays.[80] While some have recommend testing health care workers, evidence of benefit for this is poor as of 2019.[81] The Centers for Disease Control and Prevention (CDC) stopped recommending yearly testing of health care workers without known exposure in 2019.[82]

The only available vaccine as of 2011 is Bacillus Calmette-Guérin (BCG).[83] In children it decreases the risk of getting the infection by 20% and the risk of infection turning into active disease by nearly 60%.[84]

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.[85][86][87] 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.[87] Several vaccines are being developed.[15]

Intradermal MVA85A Vaccine in addition to BCG injection is not effective in preventing tuberculosis.[88]

The World Health Organization (WHO) declared TB a "global health emergency" in 1993,[15] 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.[89] 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] A tuberculosis classification system developed by the American Thoracic Society is used primarily in public health programs.[90]

The benefits and risks of giving anti-tubercular drugs in those exposed to MDR-TB is unclear.[91]

Latent TB is treated with either isoniazid or rifampin alone, or a combination of isoniazid with either rifampicin or rifapentine.[94][95][96]

The treatment takes three to nine months depending on the medications used.[44][94][97][96] People with latent infections are treated to prevent them from progressing to active TB disease later in life.[98]

Education or counselling may improve the latent tuberculosis treatment completion rates.[99]

The recommended treatment of new-onset pulmonary tuberculosis, as of 2010, is six months of a combination of antibiotics containing rifampicin, isoniazid, pyrazinamide, and ethambutol for 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.[100] There is also no evidence to support shorter anti-tubeculosis treatment regimen when compared to 6 months treatment regimen.[101]

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

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.[102] The evidence to support this practice over people simply taking their medications independently is of poor quality.[103] 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.[103] 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.[103] Methods to remind people of the importance of treatment and appointments may result in a small but important improvement.[104] 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.[105] 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.[106]

Primary resistance occurs when a person becomes infected with a resistant strain of TB. A person with fully susceptible MTB may develop secondary (acquired) resistance during therapy because of inadequate treatment, not taking the prescribed regimen appropriately (lack of compliance), or using low-quality medication.[107] 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.[108] Totally drug-resistant TB is resistant to all currently used drugs.[109] It was first observed in 2003 in Italy,[110] but not widely reported until 2012,[109][111] and has also been found in Iran and India.[112][113] Bedaquiline is tentatively supported for use in multiple drug-resistant TB.[114]

XDR-TB is a term sometimes used to define extensively resistant TB, and constitutes one in ten cases of MDR-TB. Cases of XDR TB have been identified in more than 90% of countries.[112] There is some efficacy for linezolid to treat those with XDR-TB but side effects and discontinuation of medications were common.[115]

For those with known rifampicin or MDR-TB, Genotype® MTBDRsl Assay performed on culture isolates or smear positive specimens may be useful to detect second-line anti-tubercular drug resistance.[116]

Tuberculosis is closely linked to both overcrowding and malnutrition, making it one of the principal diseases 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.[132]

The rate of TB varies with age. In Africa, it primarily affects adolescents and young adults.[133] However, in countries where incidence rates have declined dramatically (such as the United States), TB is mainly a disease of older people and the immunocompromised (risk factors are listed above).[14][134] Worldwide, 22 "high-burden" states or countries together experience 80% of cases as well as 83% of deaths.[112]

In Canada and Australia, tuberculosis is many times more common among the aboriginal peoples, especially in remote areas.[135][136] Factors contributing to this include higher prevalence of predisposing health conditions and behaviours, and overcrowding and poverty. In some Canadian aboriginal groups, genetic susceptibility may play a role.[46]

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.[46]

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 a number of 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 the Medical Research Council was formed in Britain in 1913 its initial focus was tuberculosis research.[137]

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.[124]

Russia has achieved particularly dramatic progress with decline in its TB mortality rate—from 61.9 per 100,000 in 1965 to 2.7 per 100,000 in 1993;[138][139] however, mortality rate increased to 24 per 100,000 in 2005 and then recoiled to 11 per 100,000 by 2015.[140]

China has achieved particularly dramatic progress, with about an 80% reduction in its TB mortality rate between 1990 and 2010.[124] The number of new cases has declined by 17% between 2004 and 2014.[112]

In 2007, the country with the highest estimated incidence rate of TB was Eswatini, with 1,200 cases per 100,000 people. In 2017, the country with the highest estimated incidence rate as a % of the population was Lesotho, with 665 cases per 100,000 people.[141]

As of 2017, India had the largest total incidence, with an estimated 2 740 000 cases.[141] According to the World 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.[142][143] In India a major proportion of tuberculosis patient 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 [144]

In the United States Native Americans have a fivefold greater mortality from TB,[145] and racial and ethnic minorities accounted for 84% of all reported TB cases.[146]

In the United States, the overall tuberculosis case rate was 3 per 100,000 persons in 2017.[141] In Canada, tuberculosis is still endemic in some rural areas.[147]

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

• 
  Number of new cases of tuberculosis per 100,000 people in 2016.[148]
• 
  Tuberculosis deaths per million persons in 2012
• 
  Tuberculosis deaths by region, 1990 to 2017.[149]

Tuberculosis has been known by many names from the technical to the familiar.[177] Phthisis (Φθισις) is a Greek word for consumption, an old term for pulmonary tuberculosis;[8] around 460 BCE, Hippocrates described phthisis as a disease of dry seasons.[178] The abbreviation "TB" is short for tubercle bacillus. "Consumption" was the most common nineteenth century English word for the disease. The Latin root "con" meaning "completely" is linked to "sumere" meaning "to take up from under."[179] In The Life and Death of Mr Badman by John Bunyan, the author calls consumption "the captain of all these men of death."[180] "Great white plague" has also been used.[177]

Painting The Sick Child by Edvard Munch, 1885–86, depicts the illness of his sister Sophie, who died of tuberculosis when Edvard was 14; his mother too died of the disease.

Tuberculosis was for centuries associated with poetic and artistic qualities among those infected, and was also known as "the romantic disease".[177][181] Major artistic figures such as the poets John Keats, Percy Bysshe Shelley, and Edgar Allan Poe, the composer Frédéric Chopin,[182] the playwright Anton Chekhov, the novelists Franz Kafka, Katherine Mansfield,[183] Charlotte Brontë, Fyodor Dostoevsky, Thomas Mann, W. Somerset Maugham,[184] George Orwell,[185] and Robert Louis Stevenson, and the artists Alice Neel,[186] Jean-Antoine Watteau, Elizabeth Siddal, Marie Bashkirtseff, Edvard Munch, Aubrey Beardsley and Amedeo Modigliani either 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.[187][188][189]

Tuberculosis formed an often-reused theme in literature, as in Thomas Mann's The Magic Mountain, set in a sanatorium;[190] in music, as in Van Morrison's song "T.B. Sheets";[191] in opera, as in Puccini's La bohème and Verdi's La Traviata;[189] in art, as in Monet's painting of his first wife Camille on her deathbed;[192] and in film, such as the 1945 The Bells of St. Mary's starring Ingrid Bergman as a nun with tuberculosis.[193]

The World Health Organization (WHO), the Bill 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.[194][195][196] 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.[194][197] Many resource-poor places as of 2011 have access to only sputum microscopy.[198]

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. Programs such as the Revised National Tuberculosis Control Program are working to reduce TB levels among people receiving public health care.[199][200]

A 2014 the EIU-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."[112]

Slow progress has led to frustration, expressed by the executive director of the Global 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."[112] 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.[112] The government of Brazil provides universal TB-care, which reduces this problem.[112] Conversely, falling rates of TB-infection may not relate to the number of programs directed at reducing infection rates but may be tied to increased level of education, income, and health of the population.[112] Costs of the disease, as calculated by the World Bank in 2009 may exceed US$150 billion per year in "high burden" countries.[112] Lack of progress eradicating the disease may also be due to lack of patient follow-up – as among the 250M rural migrants in China.[112]

There is insufficient data to show that active contact tracing helps to improve case detection rates for tuberculosis.[201] Interventions such as house-to-house visits, educational leaflets, mass media strategies, educational sessions may increase tuberculosis detection rates in short-term.[202] There is no study that compare new method of contact tracing such as social network analysis with existing contact tracing methods.[203]

Slow progress in preventing the disease may in part be due to stigma associated with TB.[112] 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 in Africa, AIDS.[112] Such stigmatization may be both real and perceived; for example, in Ghana individuals with TB are banned from attending public gatherings.[204]

Stigma towards TB may result in delays in seeking treatment,[112] lower treatment compliance, and family members keeping cause of death secret[204] – allowing the disease to spread further.[112] In contrast, in Russia stigma was associated with increased treatment compliance.[204] TB stigma also affects socially marginalized individuals to a greater degree and varies between regions.[204]

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.[204] Some studies have shown TB education programs to be effective in decreasing stigma, and may thus be effective in increasing treatment adherence.[204] 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.[204] 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.[112] A greater understanding of the social and cultural dimensions of tuberculosis may also help with stigma reduction.[205]