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: Mashal Awais, M.D.[2]; Alejandro Lemor, M.D. [3]; Marjan Khan M.B.B.S.[4]

Tuberculosis screening is performed using a mantoux tuberculin skin test, also known as a tuberculin skin test or a PPD. This test is done by intradermal injection of a small amount of a purified protein derivative (PPD) of the tuberculosis bacterium then observing the reaction in the following days.

• The Mantoux tuberculin skin test (TST) is primarily used to evaluate a person whether they are infected with Mycobacterium tuberculosis.

• The TST is done by intradermal injection 0.1 ml of tuberculin purified protein derivative (PPD) into the inner surface of the forearm. The injection is done using a tuberculin syringe, with the needle bevel facing upward. In case of a correct injection, it produces a pale elevation of the skin (wheal) 6 to 10 mm in diameter.

• The reaction is read between 48 and 72 hours after administration. If the patient does not return within 72 hours, another TST should be rescheduled.

• The induration (palpable, raised, hardened area, or swelling) should be measured in millimeters not the erythema (redness), and the diameter of the indurated area is measured across the forearm (perpendicular to the long axis).

• The only contraindication for TST is in persons who had any severe reaction (e.g., necrosis, blistering, anaphylactic shock, or ulcerations) to another previous TST.

• TST is not contraindicated for any other individuals, including infants, children, pregnant women, HIV-infected patients, or individuals who received BCG vaccination.

• In some individuals with with previous M. tuberculosis infection, the reaction to tuberculin can wane over time, so if TST is done years after infection, it may yield false-negative reaction. However, the TST may activate the immune system, leading to a positive, or boosted reaction to the following tests. Doing a second TST after an initial negative TST reaction, that is known as two-step testing, is preferred especially for healthcare workers or nursing home residents (retested periodically).

Interpretation of TST is based on on two elements:

• Measurement of the induration in millimeters.
• The individual’s risk of being infected with TB and also of progression to disease if infected.

• According to CDC, HIV screening is recommended for all TB patients after the patient notification that testing will be done unless the patient defers (i.e., opt-out screening). This includes patients with TB disease and with latent TB infection.
• HIV testing is also recommended for individuals who are suspected of having TB disease, patients with latent TB infection, and contacts of TB patients.
• Prevention counseling and separate written consent for HIV testing are no longer necessary.
• These recommendations are effective for eliminating missed opportunities for HIV screening and reducing significant barriers to HIV testing in health care settings by:

• Using opt-out HIV screening.
• Annually screening persons at high risk for HIV.
• No need for separate written consent for HIV testing.
• No need for prevention counseling for HIV screening.

• Opt-out screening refers to performing HIV testing after informing the patient that the test will be done, and despite being declined by the patient, it is strongly recommended. Assent is inferred unless the patient defers HIV testing.

• The early identification of Mycobacterium tuberculosis infection is a complex issue regarding the control and prevention of TB.^[3]
• Over several years, the tuberculin skin test (TST) was the most commonly used test for the diagnosis of TB infection due to its low cost and convenience in most countries.^[4]
• However, PPD testing has several disadvantages, including low specificity in individuals who received the Bacillus Calmette-Guerin (BCG) vaccination.^[5]
• In the last decade, interferon gamma release assays (IGRAs) have been used to detect Latent Tuberculosis.^[6]
• Interferon-gamma release assays (IGRAs) are immunodiagnostics techniques that measure interferon-gamma (IFN-γ) released by T-cells in response to Mycobacterium tuberculosis-specific antigen.^[7]
• There are two commercial in vitro IGRAs; including the QuantiFERON-TB Gold In-Tube (QFT-GIT) test and T-SPOT.TB that have been used for for the early detection of M. tuberculosis infection.^[7]
• QuantiFERON-TB Gold includes proteins that are almost exclusively found in mycobacterium tuberculosis.^[8]
• The QuantiFERON-TB Gold In-Tube test (QFT-GIT) assay measures the IFN-γ serum concentration following stimulation by specific TB antigens.^[8]
• The Quantiferon Gold test is used on a large scale in developed countries.^[6]
• The ability of QFT-GIT will be to monitor the response to anti-tuberculosis treatment is not fully-understood.^[9]

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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 complications are pulmonary and extra-pulmonary. Moreover, they include severe parenchymal, vascular, pleural and chest wall complications. The pulmonary complications of tuberculosis include pneumonia, pleural effusions, bronchiectasis, cavitations, and lymphadenopathy. The hematogenous spread of infection resuts in miliary tuberculosis. Without effective medical therapy, 1/3 of patients with active tuberculosis die within 1 year of diagnosis, and more than 50% die during the first 5 years. However, M. tuberculosis infections carry a good prognosis if diagnosed early and treated effectively.

Without proper medical therapy, 1/3 of patients with active tuberculosis die within 1 year of the diagnosis, and more than 50% during the first 5 years. The 5-year mortality rate in patients with a positive sputum smear test for M. tuberculosis is 65%. Patients who survive the 5 years have probability of 60% of spontaneous remission. ^[1]

Primary tuberculosis occurs soon after infection with M. tuberculosis and differs from clinical illness. In endemic areas, primary TB is usually observed at a young age. Primary TB may be completely asymptomatic, or iinvolves mild symptoms, such as fever, cough, and chest pain, due to pleurisy. Some patients can have other symptoms, such as erythema nodosum in the lower limbs and phlyctenulosis. The initial lesion (Ghon focus) often resolves spontaneously, becoming a calcified nodule that may be identified on the chest X-Ray. Pleuritic chest pain usually occurs as a result of the pleural reaction to the underlying Ghon focus.^[1]

The progression of primary TB is more rapidly in patients with impaired immunity and in children. Progression of primary tuberculosis results in the enlargement of the Ghon focus. The disease may have the following manifestations:^[1]

• Pleural effusion – results from invasion of the pleural space by M. tuberculosis. Usually occurs with subpleural focus of infection.
• Cavitation – results from progressive enlargement of the Ghon focus and necrosis of its center.
• Lymphadenopathy – the dissemination of M. tuberculosis from the lungs to lymph leads to the enlargement of lymph nodes particularly the paratracheal and perihilar lymph nodes.
• Airway obstruction – presents with shortness of breath and wheezing. Usually occurs as a result of severe enlargement of the lymph nodes, compressing the airways resulting in distal collapse, partial obstruction, or hyperinflation.
• Pneumonia – results from rupture and leakage of lymph node content into the airways.
• Bronchiectasis – results from progressive pneumonia that damages a specific segment of the lung, or an entire lobe, leading to bronchiectasis.

Primary infection leads to dissemination of M. tuberculosis through the blood. With impaired immune response, miliary tuberculosis may occur resulting in the formation of granulomatous lesions in several organs.^[1]

Also known as “adult-type” or “post-primary tuberculosis”. May result from recent infection with M. tuberculosis, or from the reactivation of an endogenous focus containing the latent form of the infection. Without effective medical therapy, approximately 1/3 of patients die within months of disease onset. Of the remaining 2/3, some can develop spontaneous remission, while others experience a chronic infection with severe symptoms. The survivors may have fibrotic and calcified lesions, and cavitations in some areas of the lungs, that can be detected later on a chest X-Ray.^[1]

The onset of illness is insidious and nonspecific, and the symptoms include:

• Fever
• Night sweats
• Weakness
• Malaise
• Anorexia
• Weight loss
• Cough (90% cases) – nonproductive at the outset, more frequent during the morning, that gradually progresses to productive cough, with purulent sputum, with occasional streaks of blood
• Hemoptysis (20-30% cases) may occur in the following cases:

• Rupture of a blood vessel on a cavity wall leads to severe hemoptysis
• Rupture of a pulmonary artery aneurysm adjacent or within a tuberculous cavity (Rasmussen’s aneurysm)
• Formation of an aspergilloma in a lung cavity

• Pleuritic chest pain
• Dyspnea (in severe disease)
• ARDS

Tuberculosis may be localized to the lungs, or affects other organs of the body. Pulmonary TB can result in permanent damage of the lungs and affected organs. According to the pulmonary, or extrapulmonary nature of the lesions, the possible complications may include:^[3][4]

• If untreated, active TB is often fatal. According to studies performed in several countries, 1/3 of the untreated patients died within 1 year after the diagnosis, while > 50% died within the first 5 years. However, with early diagnosis and adequate treatment, these patients have a good prognosis.^[1]
• Symptoms of uncomplicated TB usually improve after 2-3 weeks of treatment initiation.^[4]
• Improvements in the chest X-ray require several weeks to months to be noted.^[4]