Tuberculosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2]; João André Alves Silva, M.D. [3]

Tuberculosis has been detected for a long time. The earliest unambiguous detection of Mycobacterium tuberculosis was in the remains of bison, dated 18,000 BC.^[1] However, whether tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor, is unclear.^[2] Through history tuberculosis has had many names including phthisis and Wasting disease, which were mostly derived from its symptoms. Robert Koch identified the Mycobacterium tuberculosis 1882. In the 19th and early 20th centuries, tuberculosis was considered an endemic disease of the urban poor and a public healthcare issue. In 1946, the development of the antibiotic streptomycin made the cure possible. In the 1980s, the drug-resistant strains appeared increasingly eliminating the hope of cure.

TB was present in prehistoric humans and the evidence of infection was found in the skeletal remains 4000 BC, in addition to the spines of mummies showing tubercular decay from 3000-2400 BC.^[4] Phthisis is a Greek term for tuberculosis; around 460 BC. In terms of Hippocrates point of view,  phthisis was the most widespread disease of the time involving fever and coughing up blood, which was almost always fatal.^[5] TB was present in South America for about 2,000 years evidenced by some genetic studies.^[6] In South America, the earliest evidence of tuberculosis was linked to the Paracas-Caverna culture (circa 750 BC to circa 100 AD).^[7]

Egyptian mummies, that dates back to 2400 BC, showed skeletal deformities characteristic of tuberculosis of spine (Pott’s lesions) and those findings were documented clearly in early Egyptian art.^[8]

In the Ancient Greece TB was identified and named Phtisis. Hippocrates recognized it as a fatal disease especially for young adults. Isocrates was the first to suggest that TB is considered an infectious disease, while Aristotle suggested its contagious in oxes and pigs.^[9]

Along time ago, Since tuberculosis was similar to the idea of consumption of the infected patients with fever, hemoptysis, pallor, and severe wasting, tuberculosis was called consumption. Other names are:^{[10][11][10][12]}

• Phthisis (Greek for consumption)
• Phthisis pulmonalis
• Scrofula (in adults) – TB of the lymphatic system, resulting in swollen cervical lymph nodes
• Tabes mesenterica – TB of the abdomen
• Lupus vulgaris – TB of the skin
• Wasting disease
• White plague – due to paleness of the sufferers
• King’s evil – as people had a false belief that that scrofula would heal by the king’s touch
• Pott’s disease – TB of the spine
• Miliary tuberculosis – also called disseminated TB, occurs when the infection spreads in the blood stream, resulting in lesions in multiple organs with the appearance of millet seeds on x-ray.

tuberculosis was sometimes considered as as vampirism before the industrial revolution. When one family member died from it, the other members became infected and died slowly. People had a false belief that this occurs because the first victim drains the life from the other family members. Moreover, people who had TB had symptoms such as red, swollen eyes (which also causes photosensitivity), pale skin and hemoptysis that are similar to what people knew about vampires. This suggested the idea that the only way for the afflicted to replenish this loss of blood was by sucking blood.^[13] people also attributed it to being forced, nightly, to attend fairy revels, so that the victim wasted away due to lack of rest.^[14] Similarly, but rarely, it was attributed to the victims being ‘hagridden’ – being transformed into horses by witches (hags) to travel to their nightly meetings leading to lack of rest.^[14]

In the 19th century. Many people believed TB caused a sensation of euphoria called ”Spes phthisica” or ”hope of the consumptive”. It was believed that artists affected with TB had bursts of creativity with TB progression. It was also believed that TB sufferers were having a final burst of energy just before their death that made women more beautiful and men more creative.^[15]

In 1020s, Ibn Sina (Avicenna), with his book The Canon of Medicine, was the first physician to identify pulmonary tuberculosis as a contagious disease and suggest that it could spread through contact with soil and water.^[16][17] He developed the method of quarantine to reduce the spread of tuberculosis.^[18]

Although Dr Richard Morton established that the pulmonary form was associated with ‘tubercles’ in 1689,^[19][20] due to the variation of its symptoms, TB was not identified as a single disease until the 1820s and was not named ‘tuberculosis‘ until 1839 by J. L. Schönlein.^[21] During the years 1838-1845, Dr. John Croghan, the owner of Mammoth Cave, brought some tuberculosis sufferers into the cave to treat them with the constant temperature and purity of the cave air; however, they died within a year.^[22] The first TB sanatorium opened in 1859 in Görbersdorf, Germany (today Sokołowsko, Poland) by Hermann Brehmer.^[23]

Hermann Lebert published his project Traite Pratique des Maladies Scrofuleuses et Tuberculeuses in 1849, reporting that the TB or “King’s evil” was a childhood disease that can affect multiple body’s sites such as skin, eyes, ears, joints, and bones, causing ulceration and suppuration.^[24]

Robert Koch identified and deascribed the bacillus causing tuberculosis, Mycobacterium tuberculosis, on March 24, 1882 for which He received the Nobel Prize in physiology or medicine in 1905.^[25] Koch did not identify that bovine (cattle) and human tuberculosis were the same infection, which delayed considering infected milk as a source of infection. Later on, this source was eliminated by the process of milk pasteurization. Koch identified a glycerine extract of the tubercle bacilli as in 1890, calling it ‘tuberculin’. It was not accurate, but was later adapted as a test for pre-symptomatic tuberculosis.^[26]

The first achievement in tuberculosis immunization was ‘BCG’ (Bacillus of Calmette and Guerin) that was developed from attenuated bovine-strain tuberculosis by Albert Calmette and Camille Guerin in 1906. The BCG vaccine was first used on humans in 1921 in France, and after World War II, BCG received approval in the USA, Great Britain, and Germany.

Tuberculosis, or ‘consumption’ was considered an endemic disease of the urban poor and a public healthcare issue. In 1815, one in four deaths in England was of consumption; by 1918 one in six deaths in France were still caused by TB. In the 20th century, the number of deaths due to TB was 100 million people.^[27] After the establishment in the 1880s that the disease was contagious, TB was reported as a notifiable disease in Britain.^[23]

In the United States, concern about the spread of tuberculosis played a role in the movement to prohibit public spitting except into spittoons.

In Europe, deaths from TB decreased from 500 out of 100,000 in 1850 to 50 out of 100,000 by 1950. public health improvements had an impact regarding decreasing tuberculosis cases even before the development of antibiotics, but the disease was still representing a significant harm to public health.^[28]

In 1946, the development of the antibiotic streptomycin made the cure possible. Before the discovery of this drug, the only treatment besides sanatoria were surgical interventions, such as the pneumothorax technique – in the form of collapsing an infected lung to rest it and allow lesions to heal – which was of little benefit and was largely stopped by the 1950s.^[29] The emergence of multidrug-resistant TB has again introduced surgery as part of the treatment for these infections. Here, surgical removal of lung cavities will reduce the number of bacteria in the lungs, as well as increase the exposure of the remaining bacteria to drugs in the bloodstream, which is thought to increase the effectiveness of the chemotherapy.^[30]

In the 1980s, the drug-resistant strains appeared increasingly eliminating the hope of cure. For example, tuberculosis cases in Britain, numbering around 117,000 in 1913, had fallen to around 5,000 in 1987, but cases increased again, reaching 6,300 in 2000 and 7,600 cases in 2005.^[31] As a result of the elimination of public health facilities in New York and the emergence of HIV, there was another TB resurgence in the late 1980s.^[32]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2]; João André Alves Silva, M.D. [3]

Tuberculosis can be classified into 6 main categories according to exposure, symptoms, and diagnostic testing. The classification ranges from Class 0, in people with no previous exposure to TB and negative tuberculin skin testing and/or interferon-gamma release assay (2 methods of screening for TB), to Class 3 for active TB infection and Class 5 for suspected TB infection based on signs and symptoms of the disease. The U.S. Citizenship and Immigration Services has also designed a special classification for immigrants and refugees according to the risk of infection.

Below is a table of the current classification system of tuberculosis (TB), according to its pathogenesis:^[1]

Based on the U.S. Citizenship and Immigration Services, developed by the Centers for Disease Control and Prevention (CDC), tuberculosis for immigrants and refugees s classified into the following categories: ^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2]; João André Alves Silva, M.D. [3]

Synonyms and keywords: M. Tuberculosis

Mycobacterium tuberculosis is the bacterium responsible for tuberculosis. M. tuberculosis is an obligate aerobe, non-encapsulated, non-motile, acid-fast bacillus. . M. tuberculosis is one of the Mycobacterium tuberculosis complex, which also includes bacteria, such as M. bovis and M. africanum. The bacterium has a very slow rate of replication, and its genetic variations account for the different strains and the growing drug resistance. M. tuberculosis has tropism for different kinds of human cells, with preference for cells of the lung. The main natural reservoir for M. tuberculosis are Human beings; however, the bacteria can also infect other species.

Cellular organisms; bacteria; Actinobacteria; Actinobacteria; Actinobacteridae; Actinomycetales; Corynebacterineae; Mycobacteriaceae; Mycobacterium; Mycobacterium tuberculosis complex; M. tuberculosis^[3]

• Mycobacterium tuberculosis belongs to the Mycobacterium tuberculosis complex. This complex includes M. tuberculosis, M. bovis, M. africanum, M. canetti, and M. microti.^[4]

• M. tuberculosis is an obligate aerobe, non-encapsulated, non-motile, acid-fast bacillus.
• Its shape is slender, straight or slightly curved bacillus with rounded ends.
• It can be present singly, in pairs or in small groups or clumps.
• It cannot form spores.
• It favors tissues with high oxygen levels.
• Due to the high lipid and mycolic acid content of its cell wall, It stains weakly gram-positive or does not retain the dye.
• Microscopic examination of sputum samples cannot differentiate it from other acid-fast bacteria, such as Nocardia spp.^[4]
• M. tuberculosis divides every 15-20 hours which is considered an extremely low rate of division. This feature, in addition to its ability to remain latent for long time, are responsible for the long treatment duration needed.^[4]
• It can withstand dryness for weeks and also weak disinfectants.

• Genetic variations in the M. tuberculosis genome lead to important phenotypical changes. As a result, there are several variable strains of the bacteria, six of which have particular geographical distribution. Three strains, the Beijing family, strain W and the W-like strains, were reported to be associated with higher incidence of multi-drug resistance.^[5][6]

There is no particular tissue tropism for M. tuberculosis and it can infect almost all human tissues. However, M. tuberculosis prefers tissues with high levels of oxygen , hence, pulmonary tuberculosis has the highest rate. ^[4]

The main natural reservoir for M. tuberculosis are Human beings; however, the bacteria can also infect other species.^[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2]; Alejandro Lemor, M.D. [3]

Pulmonary tuberculosis should be distinguished from other diseases that cause cough, hemoptysis, fever, night sweat, and weight loss such as: bacterial pneumonia, atypical pneumonia, brucellosis, bronchogenic carcinoma, sarcoidosis, and Hodgkin lymphoma.

Pulmonary tuberculosis must be distinguished from other cavitary lung lesions.

Pulmonary tuberculosis must be distinguished from other cavitary lung lesions.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[3]; João André Alves Silva, M.D. [4], Dima Nimri, M.D. [5], Tarek Nafee, M.D. [6]

In 2019, about 8,920 TB cases were documented in the US with an incidence of 2.7 cases/100,000 persons. This represented a decrease by 1.1% from 2018. In 2015, about 10.4 million people developed symptomatic TB and 1.8 million died from the disease. In 2014, approximately 9,421 cases were documented in the United States, with an incidence of 3.0 cases/100 000 persons. Since 1990, there has been a decrease in the mortality rate . TB is more prevalent in older men. Racial and ethnic minorities have a higher prevalence of TB than non-Hispanic whites. Coinfection with HIV is an important leading cause of death in TB. In 2015, 60% of the worldwide TB cases were in 6 countries: South Africa, Indonesia, China, Pakistan, India, and Nigeria. The WHO reported 24 other high-burden TB countries including Bangladesh, Korea, Columbia, Cambodia, Congo, Brazil, Ethiopia, Myanmar, Philippines, Thailand, Liberia, Vietnam, Kenya, Central Africa, Russia, Angola, Zimbabwe, Namibia, Mozambique, Tanzania, Sierra Leone, Zambia, Papua New Guinea, and Lesotho.^[1]

• Worldwide, in 2018, there were approximately 10 million individuals with incident TB and about 1.5 million TB-related deaths.
  • Approximately 862,000 of these cases were in patients coinfected with HIV ^[12]
• Worldwide, in 2015, approximately 10.4 million people had symptomatic TB.^[2][3]

• 1.17 million of these cases occurred were in patients coinfected with HIV.^[2][3]

• Worldwide, in 2015, about 1.8 million people died from TB.^[2][3]

• 400,000 of these cases were in patients coinfected with HIV.^[2][3]

• In the United States, in 2014, approximately 9,421 cases were reported with an incidence of 3.0 cases/100 000 persons.^[2][3]

• Over 95% of TB deaths occur in low- and middle-income countries, and it is among the top three causes of death for women aged 15 to 44.
• The TB death rate dropped 45% between 1990 and 2012.
• In 2015, 3 million lives were saved by the global TB response.

• 
  Incidence of All Forms of TB in 2015. – WHO 2016 TB Report)^[1]
• 
  Trend in TB incidence from 2000 to 2015. – WHO 2016 TB Report)^[1]
• 
  TB mortality trends (2000-2015) – WHO 2016 TB Report)^[1]
• 
  TB Global Mortality in 2015. – WHO 2016 TB Report)^[1]
• 
  Image 5 – TB is in the top 10 causes of death in 2015. – WHO 2016 TB Report)^[1]
• 
  Trends in Estimated Incident Tuberculosis 2000-2018 (TB)[1]

The following global regional trends in TB incidence are observed from 2000 to 2015:

Immunosuppression secondary to HIV is strongly associated with incidence of TB and its subsequent complications. Tuberculosis contributes to a considerable proportion of HIV/AIDS related deaths.

• 
  Incidence of TB and HIV in 2015 – WHO 2016 TB Report)^[1]
• 
  Trend in TB and HIV mortality (2000-2015) – WHO 2016 TB Report)^[1]
• 
  Estimated TB and HIV deaths in 2015 – WHO 2016 TB Report)^[1]

In 2015, 60% of the worldwide TB cases were reported in six countries:

• The incidence of tuberculosis was reported as 834 per 100,000 of the general population.^[1]
• The mortality rate of tuberculosis (excluding HIV-TB coinfection) was reported as 46 per 100,000 of the general population.^[1]

• The incidence of tuberculosis was reported as 395 per 100,000 of the overall population.^[1]
• The mortality rate of tuberculosis (excluding HIV–TB coinfection) was reported as 40 per 100,000 of the overall population.^[1]

• The incidence of tuberculosis was reported as 322 per 100,000 of the general population.^[1]
• The mortality rate of tuberculosis (excluding HIV–TB coinfection) was reported as 99 per 100,000 of the general population.^[1]

• The incidence of tuberculosis was reported as 270 per 100,000 of the general population.^[1]
• The mortality rate of tuberculosis (excluding HIV-TB coinfection) was reported as 23 per 100,000 of the general population.^[1]

• The incidence of tuberculosis was reported as 217 per 100,000 of the general population.^[1]
• The mortality rate of tuberculosis (excluding HIV-TB coinfection) was reported as 36 per 100,000 of the general population.^[1]

• The incidence of tuberculosis was reported as 67 per 100,000 of the general population.^[1]
• The mortality rate of tuberculosis (excluding HIV-TB coinfection) was reported as 2.6 per 100,000 of the general population.^[1]

TB resurge occurred in the mid-1980s since when the number of cases steadily increased with a peak occurred in 1992. Following this peak, the number of reported TB cases has decreased annually. The year of 2014 represented the twenty-second year of decline in the reported TB cases in the United States since that peak. In 2014, approximately a total number of 9,421 cases were reported in the 50 states and the District of Columbia (DC). This was considered a decline of 1.5% from 2013. The number of TB cases per 100,000 in 2013 and 2014 was at a stable rate of 3.0.^[1]

In 2014, TB cases in most age groups decreased by approximately 70% from the 1993 values. Below is the comparison between the case rates (per 100 000 persons) of these two years, according to different ages:^[4]

Depending on the age of the patient, tuberculosis may have different clinical manifestations, progression, and prognosis:^{[6][7][8][9][7][10]}

In 2012, there were 410,000 total deaths in women as a result of TB in the United States, 160,000 of them were HIV-positive. Out of the total TB deaths among HIV-positive people, 50% were women.^[2][3] TB rates tend to increase with age, ranging from a low rate of less than 1 per 100,000 in children aged 5 – 14 to a high rate of 6.9 per 100,000 in men aged 65 years and older. With age increasing, the case rate increases faster in men than in women; the rates in men aged 45 years and older were approximately more than double the case rate in women of the same age.^[2][3]

The highest TB rates was reported in Asians, a decline from 29.9 per 100,000 persons in 2003 to 17.8 in 2014.^[2][11]

The disproportionate burden of TB in minorities is due to many factors. In persons who were born in countries where TB is endemic, the disease can be a result of an acquired infection in their country of origin. Unequal distribution of TB risk factors, such as HIV infection, leads to increased TB exposure or to an increased risk of developing TB after infection with with M. tuberculosis.^[2]

• Image 7 shows that TB rates are decreasing by race/ethnicity in the last 12 years.^[5]

• Image 8 shows that above the age of 5, there is an increased risk of TB with age across all racial and ethnic groups. The case rates were higher in minority racial and ethnic groups than in non-Hispanic whites and were highest in Asians, Native Hawaiians and Other Pacific Islanders, especially in the adult age groups.^[5]

• Image 9 shows that in 2014, 85% of all reported TB cases occurred in racial and ethnic minorities, whereas 13% of cases occurred in non-Hispanic whites. Persons reporting two or more races accounted for 2% of all cases^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2]; João André Alves Silva, M.D. [3]

The risk factors for developing tuberculosis include: living or traveling to endemic areas for TB, elderly people and infants, immunosuppression, history of frequent or prolonged contact with infected patients, IV drug users, smoking, bad hygiene, and poor nutrition. In addition, the risk factors for multidrug-resistant TB include: non-adherence to treatment regimen, inadequate treatment for that bacterial strain, and contact with patients with multidrug-resistant TB.

Primary TB, which represents 1-5% cases, occurs after infection. However, most of the cases occur with latent infection which is asymptomatic. The dormant bacilli can cause tuberculosis in 2 to 23% of the latent cases, usually several years following the primary infection.^[1] The risk of reactivation is much higher with immunosuppression, such as HIV. In patients with HIV coinfection, the risk of reactivation increases reaching up to 10% per year.

The following are risk factors for active TB:^[2][3]

• Living or traveling to endemic areas (Sub-saharan African, Russia, India, Pakistan, China)
• Elderly
• Infants
• IV drug users
• Immunosuppression:

• AIDS
• Diabetes
• Silicosis
• Malignancy, such as head and neck cancers

• Hematologic and reticuloendothelial disease, such as leukemia and Hodgkin’s disease

• End-stage kidney disease
• History of gastrectomy
• Malabsorption syndrome

• Or those taking medications, such as:

• Chemotherapy
• Immunosuppressive medications, such as prolonged corticosteroid therapy, tumor necrosis factor-alpha blockers^[4]
• Tocilizumab

The risk of contracting TB increases in cases where there is:^[2]

• Frequent or prolonged contact with people who have TB
• Poor nutrition
• Smoking
• Bad hygiene

The following factors may increase the rate of TB infection in a population:^[2]

• Chest X-ray with evidence of previous TB disease (fibrotic lesions and nodules)
• Increased number of HIV infections
• Increased number of homeless people
• The appearance of drug-resistant strains of TB

• Treatment with the following drugs have been reported with increased risk of reactivation of latent tuberculosis.

• Adalimumab
• Alemtuzumab
• Belatacept
• Certolizumab pegol
• Canakinumab
• Etanercept
• Fluocortolone
• Golimumab
• Infliximab
• Rilonacept
• Ruxolitinib
• Saxagliptin
• Teriflunomide
• Tocilizumab
• Tofacitinib
• Vedolizumab

Drug resistance is more common in people who:^[5]

• Do not take their TB medicine regularly
• Do not take all of their TB medicine as told by their doctor or nurse
• Develop TB disease again, after having taken TB medicine in the past
• Come from areas of the world where drug-resistant TB is common
• Have spent time with someone known to have drug-resistant TB disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Joseph Nasr, M.D.[2]; Mashal Awais, M.D.[3]; Alejandro Lemor, M.D. [4]; Marjan Khan M.B.B.S.[5]

Tuberculosis (TB) screening is the risk-based identification of asymptomatic persons who may have Mycobacterium tuberculosis infection and who would benefit from further evaluation and treatment of latent tuberculosis infection (LTBI). Screening is performed using either the Mantoux tuberculin skin test (TST) or an interferon-gamma release assay (IGRA). Neither TST nor IGRA distinguishes LTBI from active TB disease, and neither test should be used to monitor response to treatment.^[1][2]

Screening should be targeted to persons at increased risk for TB infection or increased risk of progression from LTBI to active disease. Universal testing of low-risk populations is not recommended because the positive predictive value is poor when pretest probability is low, and false-positive results may lead to unnecessary radiography, follow-up testing, and treatment.^[3][1]

The United States Preventive Services Task Force recommends screening for LTBI in asymptomatic adults aged 18 years or older who are at increased risk for TB infection.^[3] The CDC and specialty guidelines also recommend testing selected children, contacts, healthcare personnel, and immunocompromised persons based on exposure risk and risk of progression.^[1][4]

Conditions such as diabetes mellitus, chronic kidney disease, low body weight, smoking, gastrectomy, and head or neck cancer increase risk of progression once infection is present, but they are not usually independent indications for LTBI testing without epidemiologic exposure risk.^[2]

Two test categories are used for LTBI screening: the TST and IGRAs. Both detect immune sensitization to M. tuberculosis antigens. Neither test can determine whether infection is latent or active.^[1][2]

The Mantoux tuberculin skin test is performed by intradermal injection of 0.1 mL of purified protein derivative (PPD; 5 tuberculin units) into the volar surface of the forearm. A properly placed test produces a 6-10 mm wheal. The result is read 48-72 hours later by measuring the transverse diameter of induration, not erythema, in millimeters.^[1][7]

The only absolute contraindication to TST is a prior severe reaction, such as necrosis, blistering, ulceration, or anaphylaxis, after a previous TST. TST is not contraindicated in pregnancy, infants, children, persons with HIV infection, or persons who received BCG vaccine.^[7]

• 
  Mantoux tuberculin skin test placement. Image from the CDC Public Health Image Library.
• 
  Tuberculin skin test reading. Image from the CDC Public Health Image Library.
• 
  Tuberculin skin test reaction. Image from the CDC Public Health Image Library.

TST interpretation depends on both the measured induration and the patient’s risk of TB infection or progression to active disease.^[1][7]

Interferon-gamma release assays measure interferon-gamma release by T cells after stimulation with M. tuberculosis-specific antigens, including ESAT-6 and CFP-10. These antigens are absent from BCG strains and most nontuberculous mycobacteria, giving IGRAs higher specificity than TST in BCG-vaccinated persons.^[1][2]

Two FDA-approved IGRAs are used in the United States:

The 2023 USPSTF evidence review reported sensitivity of 89% for QuantiFERON-TB Gold Plus (95% CI, 84%-94%) and 90% for T-SPOT.TB (95% CI, 87%-92%). Reported specificity was 98% for QuantiFERON-TB Gold Plus (95% CI, 95%-99%) based on one study, and approximately 95%-97% for T-SPOT.TB based on two studies.^[9] Indeterminate or invalid IGRA results occur in a minority of tests and should prompt repeat testing or use of an alternate test, depending on clinical context.^[1]

The choice between TST and IGRA depends on age, BCG vaccination history, likelihood of return for TST reading, immune status, test availability, and local practice.^[1]

Two-step TST is used to establish a baseline in persons who will undergo serial TST testing and who have not had a TST within the previous 1-2 years. Remote TB infection, prior BCG vaccination, or nontuberculous mycobacterial exposure may produce waning immune reactivity, so the first TST may boost the immune response and make a later TST appear falsely converted.^[1][11]

If the first TST is negative, a second TST is placed 1-3 weeks later. If the second test is negative, the person is considered uninfected at baseline. If the second test is positive, this is interpreted as boosting rather than new infection.^[11]

Two-step testing is recommended when TST is used for baseline testing in healthcare personnel, selected residents of congregate facilities, and travelers who will undergo serial TST testing. Two-step testing is unnecessary when using an IGRA.^[5][11]

Borderline or low-positive IGRA results may have limited reproducibility, especially in low-risk populations. When testing is performed despite low pretest probability, confirmatory testing is recommended after an initial positive result.^[1]

All persons with HIV infection should be evaluated for LTBI at the time of HIV diagnosis, regardless of epidemiologic risk.^[6] Either TST or IGRA may be used; IGRA is preferred in BCG-vaccinated persons. TST is positive at ≥5 mm in persons with HIV.^[6]

Progressive immunodeficiency reduces the sensitivity of both TST and IGRA. Persons with HIV who initially test negative during advanced immunosuppression should be retested after immune reconstitution on antiretroviral therapy if they remain at risk.^[6] Annual retesting is recommended for persons with ongoing exposure risk.^[6]

In a U.S. prospective study of persons with HIV, T-SPOT.TB had the highest specificity and positive predictive value, whereas QFT-GIT had higher sensitivity than TST. These data support guideline statements that test performance varies with immune status and that no single test is clearly preferred for all persons with HIV.^[6]

Children should be tested only when they have risk factors for TB infection or progression. Testing should not be performed routinely in low-risk children.^[10]

The ATS/IDSA/CDC guideline suggests TST rather than IGRA in healthy children younger than 5 years, whereas the American Academy of Pediatrics supports IGRAs in children aged 2 years or older, especially if BCG-vaccinated.^[1][10] This creates a practical pediatric cutoff discrepancy: CDC TST interpretation tables use children younger than 4 years in the ≥10 mm threshold group, while AAP guidance often uses younger than 5 years when discussing high-risk pediatric testing considerations.^[7][10] In exposed young children, a negative initial test does not exclude recent infection; repeat testing 8-10 weeks after last exposure is required.^[10]

TST is not contraindicated during pregnancy. Either TST or IGRA may be used when risk factors for TB infection or progression are present.^[7] Screening should not be delayed when the pregnant patient has recent exposure, HIV infection, or other major risk factors for progression.

The 2019 National Tuberculosis Controllers Association and CDC recommendations changed the approach to healthcare personnel screening. Baseline screening is still recommended, but routine serial testing is no longer recommended in the absence of known exposure or ongoing transmission.^[5]

If baseline testing is positive in a healthcare worker who is asymptomatic and low risk, a second confirmatory test should be performed before chest radiography and LTBI diagnosis.^[5] Healthcare personnel with untreated LTBI should receive annual symptom screening.^[5]

HIV testing is recommended for all patients with suspected or confirmed TB disease and for persons diagnosed with LTBI or identified as TB contacts. Testing should be offered using an opt-out approach, meaning that testing is performed after the patient is informed unless the patient declines.^[12]

Separate written consent and prevention counseling are not required for HIV screening in healthcare settings unless required by local law.^[12]

In low-incidence settings such as the United States, chest radiography is used primarily after a positive TST or IGRA to exclude active pulmonary TB before diagnosing LTBI.^[1] A normal chest radiograph and absence of symptoms support LTBI rather than active pulmonary TB; abnormal radiography or TB symptoms require sputum testing for acid-fast bacilli smear, mycobacterial culture, and nucleic acid amplification testing.^[1]

In high-burden settings, chest radiography is also used for systematic screening for active pulmonary TB. Computer-aided detection (CAD) software can interpret digital chest radiographs for TB-suggestive abnormalities and has been conditionally recommended by WHO as an alternative to human readers in screening programs, although all positive screens require bacteriologic confirmation.^[13]

Recent prospective studies suggest that CAD-based chest radiography may improve screening throughput in high-burden settings, but thresholds, local prevalence, confirmatory testing capacity, and cost-effectiveness must be considered before implementation.^[14][15]

A positive TST or IGRA result requires clinical evaluation to exclude active TB disease before LTBI is diagnosed and treated.^[1][2]

• Screening low-risk persons, which increases false-positive results.
• Measuring erythema rather than induration when reading the TST.
• Using a single TST cutoff for all patients rather than risk-stratified thresholds.
• Using TST or IGRA to rule out active TB disease.
• Failing to perform chest radiography after a positive TST or IGRA.
• Treating a positive test as LTBI before excluding active TB disease.
• Ordering routine annual TB testing for all healthcare personnel despite the 2019 NTCA/CDC update.
• Using older QuantiFERON-TB Gold In-Tube language when QuantiFERON-TB Gold Plus is the current-generation assay.
• Using TST or IGRA to monitor response to anti-tuberculosis therapy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mashal Awais, M.D.[2];Sophia Saad, Associate Editor – WikiDoc [3] João André Alves Silva, M.D. [4] Template:Tuberculosis Natural History, complications, and prognosis

In the absence of treatment, approximately 5% to 15% of immunocompetent persons with LTBI progress to active TB disease over a lifetime, with estimates varying by source (ATS/IDSA/CDC diagnostic guideline estimates 4%–6%; USPSTF cites 5%–10%; NEJM review cites 5%–15%).^[1][2][3]

People with untreated HIV infection have an estimated annual risk of progression to TB disease of 3% to 16%.^[4]

Untreated active TB can progress over weeks to months with ongoing tissue destruction and increased transmission risk (for pulmonary disease). Pre-chemotherapy era systematic reviews provide the following estimates for HIV-negative individuals: untreated smear-positive pulmonary TB has a 10-year case fatality of approximately 70% (weighted mean), while culture-positive, smear-negative TB has an estimated 10-year case fatality of approximately 20%.^[5]

The average duration of untreated pulmonary TB from onset to cure or death is approximately 3 years, though Bayesian re-analysis estimates shorter duration for smear-positive disease (~1.6 years) and longer for smear-negative disease (~5.4 years). Natural recovery occurs in a substantial minority of untreated smear-positive cases.^[5][6]

In children (pre-treatment era), case fatality was 44% in those aged 0–4 years and 15% in those aged 5–14 years.^[7]

Common pulmonary complications include:

• Cavitation
• Hemoptysis (including massive hemoptysis; e.g., Rasmussen’s aneurysm)
• Pneumothorax
• Empyema
• Bronchiectasis / post-infectious airway disease
• Acute respiratory distress syndrome (ARDS) (uncommon; more likely with severe disseminated disease)^[8]

Miliary tuberculosis and other disseminated forms (hematogenous spread).^[9]

Site-specific complications may include neurologic disability from tuberculous meningitis, pericardial complications (effusion/constriction), skeletal deformity from spinal TB, and infertility/obstructive uropathy from genitourinary TB.

Risk factors associated with post-TB sequelae have been summarized in systematic review and meta-analysis.^[10]

Quantitative estimates of post-TB lung disease (PTLD) burden include: approximately 50% of pulmonary TB survivors have abnormal spirometry at or after treatment completion, with severe impairment in 10%–15%; bronchiectasis is observed in 35%–86% on imaging.^[11]

Chronic pulmonary aspergillosis (CPA) prevalence in TB survivors ranges from 7% to 23%, with residual cavitation being the strongest risk factor (annual incidence of new CPA ~6.5% in those with cavitation vs 0.2% without).^[12][13]

TB survivors have an estimated standardized mortality ratio of approximately 2.9 compared with the general population, with cardiovascular disease, cancer, and respiratory diseases among the leading causes of post-treatment death. Among post-treatment deaths, approximately 20% are attributable to cardiovascular disease. Post-TB excess mortality is highest in the first year after diagnosis (mortality rate ratio ~11) and declines progressively, reaching ~1.5 by year 10, but remains elevated for at least 14 years.^[14]

People with prior TB have an approximately 1.6-fold increased risk of all cancers and a 3.2-fold increased risk of lung cancer compared with controls.^[15]

Long-term sequelae after pulmonary TB (including cardiopulmonary impairment and chronic respiratory symptoms) are reviewed in narrative and European Respiratory Society publications.^[16][17]

Mortality differs substantially by drug susceptibility pattern in treated TB cohorts from high-burden countries.^[18]

TB in people with HIV has higher risk of disseminated and extrapulmonary disease and higher mortality, especially with advanced immunosuppression. The CD4+ T-lymphocyte count is the strongest predictor of TB-related mortality in people with HIV. Mortality with treatment is approximately 2.5% for HIV-negative individuals and approximately 14% for people with HIV.^[19][8]

Initiation of antiretroviral therapy (ART) during TB treatment reduces mortality by approximately 24% overall and reduces HIV disease progression by 34%.^[20]

Immune reconstitution inflammatory syndrome (IRIS) is a clinically important complication after ART initiation in TB-HIV co-infection; paradoxical TB-IRIS occurs in approximately 18% of patients starting ART.^[19]

TB meningitis carries the highest mortality of any TB form, with case fatality rates of approximately 20–30% in HIV-negative patients and up to 50% in HIV-positive patients, even with treatment. Mortality is strongly associated with MRC stage at presentation: stage I has the best prognosis, while stage III (GCS ≤10) carries the highest mortality. Survivors frequently have permanent neurologic sequelae.^[21][22]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Active tuberculosis will kill about two of every three people affected if left untreated. Treated tuberculosis has a mortality rate of less than 5% (or less in developed countries where intensive supportive measures are available).

The standard “short” course treatment for tuberculosis (TB), if it is active, is isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months. The patient is considered cured at six months (although there is still a relapse rate of 2 to 3%). For latent tuberculosis, the standard treatment is six to nine months of isoniazid alone.

If the organism is known to be fully sensitive, then treatment is with isoniazid, rifampicin, and pyrazinamide for two months, followed by isoniazid and rifampicin for four months. Ethambutol need not be used.

All first-line anti-tuberculous drug names have a standard three-letter and a single-letter abbreviation:

• streptomycin is STM or S,
• isoniazid is INH or H,
• rifampicin is RMP or R,
• ethambutol is EMB or E,
• pyrazinamide is PZA or Z.

The US commonly uses abbreviations and names that are not internationally recognised: rifampicin is called rifampin and abbreviated RIF; streptomycin is commonly abbreviated SM.

Drug regimens are similarly abbreviated in a standardised manner. The drugs are listed using their single letter abbreviations (in the order given above, which is roughly the order of introduction into clinical practice). A prefix denotes the number of months the treatment should be given for; a subscript denotes intermittent dosing (so ₃ means three times a week) and no subscript means daily dosing. Most regimens have an initial high-intensity phase, followed by a continuation phase (also called a consolidation phase or eradication phase): the high-intensity phase is given first, then the continuation phase, the two phases divided by a slash.

So,

2HREZ/4HR₃

means isoniazid, rifampicin, ethambutol, pyrazinamide daily for two months, followed by four months of isoniazid and rifampicin given three times a week.

These standard abbreviations are used in the rest of this article.

There are six classes of second-line drugs (SLDs) used for the treatment of TB. A drug may be classed as second-line instead of first-line for one of two possible reasons: it may be less effective than the first-line drugs (e.g., p-aminosalicylic acid); or, it may have toxic side-effects (e.g., cycloserine); or it may be unavailable in many developing countries (e.g., fluoroquinolones):

• aminoglycosides: e.g., amikacin (AK), kanamycin;
• polypeptides: e.g., capreomycin, viomycin, enviomycin;
• fluoroquinolones: e.g., ciprofloxacin (CIP), moxifloxacin (MXF);
• thioamides: e.g. ethionamide, prothionamide
• cycloserine (the only antibiotic in its class);
• p-aminosalicylic acid (PAS or P).

Other drugs that may be useful, but are not on the WHO list of SLDs:

• rifabutin
• macrolides: e.g., clarithromycin (CLR);
• linezolid (LZD);
• thioacetazone (T);
• thioridazine;
• arginine;
• vitamin D;
• R207910.

These drugs may be considered “third-line drugs” and are listed here either because they are not very effective (e.g., clarithromycin) or because their efficacy has not been proven (e.g., linezolid, R207910). Rifabutin is effective, but is not included on the WHO list because for most developing countries, it is impractically expensive.

Tuberculosis has been treated with combination therapy for over fifty years. Drugs are not used singly (except in latent TB or chemoprophylaxis), and regimens that use only single drugs result in the rapid development of resistance and treatment failure.^[1][2] The rationale for using multiple drugs to treat TB are based on simple probability. The frequency of spontaneous mutations that confer resistance to an individual drug are well known: 1 in 10⁷ for EMB, 1 in 10⁸ for STM and INH, and 1 in 10¹⁰ for RMP.^[3]

A patient with extensive pulmonary TB has approximately 10¹² bacteria in his body, and therefore will probably be harboring approximately 10⁵ EMB-resistant bacteria, 10⁴ STM-resistant bacteria, 10⁴ INH-resistant bacteria and 10² RMP-resistant bacteria. Resistance mutations appear spontaneously and independently, so the chances of him harbouring a bacterium that is spontaneously resistant to both INH and RMP is 1 in 10⁶, and the chances of him harbouring a bacterium that is spontaneously resistant to all four drugs is 1 in 10¹¹. This is, of course, an oversimplification, but it is a useful way of explaining combination therapy.

There are other theoretical reasons for supporting combination therapy. The different drugs in the regimen have different modes of action: INH and EMB are bacteriostatic (they stop the bacteria replicating, but do not kill them); RMP is bacteriocidal (it actually kills bacteria).

All TB regimens in use were 18 months or longer until the appearance of rifampicin. In 1953, the standard UK regimen was 3SPH/15PH or 3SPH/15SH₂. Between 1965 and 1970, EMB replaced PAS. RMP began to be used to treat TB in 1968 and the BTS study in the 1970s showed that 2HRE/7HR was efficacious. In 1984, a BTS study showed that 2HRZ/4HR was efficacious,^[4] with a relapse rate of less than 3% after two years.^[5] In 1995, with the recognition that INH resistance was increasing, the BTS recommended adding EMB or STM to the regimen: 2HREZ/4HR or 2SHRZ/4HR, which are the regimens currently recommended. The WHO also recommend a six month continuation phase of HR if the patient is still culture positive after 2 months of treatment (approximately 15% of patients with fully-sensitive TB) and for those patients who have extensive bilateral cavitation at the start of treatment.

DOTS stands for “Directly Observed Therapy, Short-course” and is a major plank in the WHO global TB eradication programme. The WHO advises that all TB patients should have at least the first two months of their therapy observed (and preferably the whole of it observed): this means an independent observer watching tuberculosis patients swallow their anti-TB therapy. The independent observer is often not a healthcare worker and may be a shopkeeper or a tribal elder or similar senior person within that society. DOTS is used with intermittent dosing (thrice weekly or 2HREZ/4HR₃). Twice weekly dosing is effective^[6] but not recommended by the WHO, because there is no margin for error (accidentally omitting one dose per week results in once weekly dosing, which is ineffective).

Treatment with properly implemented DOTS has a success rate exceeding 95% and prevents the emergence of further multi-drug resistant strains of tuberculosis.

Some people recommend monthly surveillance until cultures convert to negative; this does not form any part of the UK or WHO recommendations for TB. If cultures are positive or symptoms do not resolve after three months of treatment, it is necessary to re-evaluate the patient for drug-resistant disease or nonadherence to drug regimen. If cultures do not convert to negative despite three months of therapy, consider initiating directly observed therapy.

Tuberculosis not affecting the lungs is called extra-pulmonary tuberculosis. Disease of the central nervous system is specifically excluded from this classification.

The UK and WHO recommendation is 2HREZ/4HR; the US recommendation is 2HREZ/7HR. There is good evidence from randomised-controlled trials to say that in tuberculous lymphadenitis^[7] and in TB of the spine,^[8][9][10] the six month regimen is equivalent to the nine month regimen; the US recommendation is therefore not supported by the evidence.

Up to 25% of patients with TB of the lymph nodes (TB lymphadenitis) will get worse on treatment before they get better and this usually happens in the first few months of treatment. A few weeks after starting treatment, lymph nodes often start to enlarge, and previously solid lymph nodes may become fluctuant. This should not be interpreted as failure of therapy and is a common reason for patients (and their physicians) to panic unnecessarily. With patience, two to three months into treatment the lymph nodes start to shrink again and re-aspiration or re-biopsy of the lymph nodes is unnecessary: if repeat microbiological studies are ordered, they will show the continued presence of viable bacteria with the same sensitivity pattern, which further adds to the confusion: physicians inexperienced in the treatment of TB will then often add second-line drugs in the belief that the treatment is not working. In these situations, all that is required is re-assurance. Steroids may be useful in resolving the swelling, especially if it is painful, but they are unnecessary. Additional antibiotics are unnecessary and the treatment regimen does not need to be lengthened.

Tuberculosis may affect the central nervous system (meninges, brain or spinal cord) in which case it is called TB meningitis, TB cerebritis, and TB myelitis respectively; the standard treatment is 12 months of drugs (2HREZ/10HR) and steroid are mandatory. Diagnosis is difficult as CSF culture is positive in less than half of cases, and therefore a large proportion of cases are treated on the basis of clinical suspicion alone. PCR of CSF does not significantly improve the microbiology yield; culture remains the most sensitive method and a minimum of 5 ml (preferably 20 ml) of CSF should be sent for analysis. TB cerebritis (or TB of the brain) may require brain biopsy in order to make the diagnosis, because the CSF is commonly normal: this is not always available and even when it is, some clinicians would debate whether it is justified putting a patient through such an invasive and potentially dangerous procedure when a trial of anti-TB therapy may yield the same answer; probably the only justification for brain biopsy is when drug-resistant TB is suspected. It is possible that shorter durations of therapy (e.g. six months) may be sufficient to treat TB meningitis, but no clinical trial has addressed this issue. The CSF of patients with treated TB meningitis is commonly abnormal even at 12 months;^[11] the rate of resolution of the abnormality bears no correlation with clinical progress or outcome,^[12] and is not an indication for extending or repeating treatment; repeated sampling of CSF by lumbar puncture to monitor treatment progress should therefore not be done.

Although TB meningitis and TB cerebritis are classified together, the experience of many clinicians is that their progression and response to treatment is not the same. TB meningitis usually responds well to treatment, but TB cerebritis may require prolonged treatment (up to two years) and the steroid course needed is often also prolonged (up to six months). Unlike TB meningitis, TB cerebritis often required repeated CT or MRI imaging of the brain to monitor progress.

CNS TB may be secondary to blood-borne spread: therefore some experts advocate the routine sampling of CSF in patients with miliary TB.^[13]

The anti-TB drugs that are most useful for the treatment of CNS TB are:

• INH (CSF penetration 100%)
• RMP (10–20%)
• EMB (25–50% inflamed meninges only)
• PZA (100%)
• STM (20% inflamed meninges only)
• LZD (20%)
• Cycloserine (80–100%)
• Ethionamide (100%)
• PAS (10–50%) (inflamed meninges only)

The use of steroids is routine in TB meningitis (see section below).

The usefulness of corticosteroids (e.g., prednisolone or dexamethasone) in the treatment is TB is proven for TB meningitis and TB pericarditis. The dose for TB meningitis is dexamethasone 8 to 12mg daily tapered off over six weeks (for those who prefer more precise dosing, please see Thwaites, 2004^[14]). The dose for pericarditis is prednisolone 60mg daily tapered off over four to eight weeks.

Steroids may be of temporary benefit in pleurisy, extremely advanced TB, and TB in children: