Tuberculosis and Mycobacteria

The main cause of TB is Mycobacterium tuberculosis, a small, aerobic, nonmotile bacillus. TB is widespread, deadly and causes the highest number of deaths worldwide. One third of the global population has latent TB infection. The bacteria usually attack the lungs. But, TB bacteria can attack any part of the body such as the kidney, spine, and brain.

 The M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria:

·         M. bovis: It 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.

·          M. africanum: It is not widespread, but it is a significant cause of tuberculosis in parts of Africa. 

·         M. canetti: It is rare and seems to be limited to the Horn of Africa, although a few cases have been seen in African emigrants. 

·         M. microti.  It is also rare and is seen almost only in immunodeficient people, although its prevalence may be significantly underestimated.

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 pulmonary diseases that resemble TB.

Tuberculosis epidemiology is the field that is concerned with the study of health and disease within populations and the various underlying factors that lead to these conditions, with a goal of preventing the spread of such future incidents of Tuberculosis epidemiology also involves the investigation of different patterns of disease within a population, in relation to which people are affected, the spatial distribution of affected people, and the temporal distribution of affected people (i.e. patterns of disease through time). It is thus considered the cornerstone of public health, productive medicine, and preventive medicine.

The genome of the H37Rv strain was published in 1998.^] Its size is 4 million base pairs, with 3959 genes; 40% of these genes have had their function characterised, with possible function postulated for another 44%. Within the genome are also six pseudogenes.

The genome contains 250 genes involved in fatty acid metabolism, with 39 of these involved in the polyketide metabolism generating the waxy coat. Such large numbers of conserved genes show the evolutionary importance of the waxy coat to pathogen survival. Bacteria isolated from the lungs of infected mice were shown to preferentially use fatty acids over carbohydrate substrates. M. tuberculosis can also grow on the lipid cholesterol as a sole source of carbon, and genes involved in the cholesterol use pathway(s) have been validated as important during various stages of the infection lifecycle of M. tuberculosis, especially during the chronic phase of infection when other nutrients are likely not available.

About 10% of the coding capacity is taken up by the PE/PPE gene families that encode acidic, glycine-rich proteins. These proteins have a conserved N-terminal motif, deletion of which impairs growth in macrophages and granulomas.

TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within endosomes of alveolar macrophages. Macrophages identify the bacterium as foreign and attempt to eliminate it by phagocytosis. During this process, the bacterium is enveloped by the macrophage and stored temporarily in a membrane-bound vesicle called a phagosome. The phagosome then combines with a lysosome to create a phagolysosome. In the phagolysosome, the cell attempts to use reactive oxygen species and acid to kill the bacterium. However, M. tuberculosis has a thick, waxy mycolic acid capsule that protects it from these toxic substances. M. tuberculosis is able to reproduce inside the macrophage and will eventually kill the immune cell.

 The primary site of infection in the lungs, known as the "Ghon focus", is generally located in either the upper part of the lower lobe, or the lower part of the upper lobe. Tuberculosis of the lungs may also occur via infection from the blood stream. This is known as a Simon focus and is typically found in the top of the lung. This hematogenous transmission can also spread infection to more distant sites, such as peripheral lymph nodes, the kidneys, the brain, and the bones. All parts of the body can be affected by the disease, though for unknown reasons it rarely affects the heart, skeletal muscles, pancreas, or thyroid.

Tuberculosis may infect any part of the body, but most commonly occurs in the lungs (known as pulmonary tuberculosis).Extrapulmonary TB occurs when tuberculosis develops outside of the lungs.

General signs and symptoms include fever, chills, night sweats, loss of appetite, weight loss, and fatigue. Significant nail clubbing may also occur.

Pulmonary

If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases). 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"). 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. 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. 

Extrapulmonary

In 15–20% cases, the infection spreads outside the lungs, causing other kinds of TB. These are collectively denoted as "extrapulmonary tuberculosis". Extrapulmonary TB occurs more commonly in immunosuppressed persons and young children. In those with HIV, this occurs in more than 50% of cases. 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. When it spreads to the bones, it is also known as "osseous tuberculosis", a form of osteomyelitis. Sometimes, bursting of a tubercular abscess through skin results in tuberculous ulcer.  An ulcer originating from nearby infected lymph nodes is painless, slowly enlarging and has an appearance of "wash leather". A potentially more serious, widespread form of TB is called "disseminated tuberculosis", also known as miliary tuberculosis. Miliary TB makes up about 10% of extrapulmonary cases.

If tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases).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"). 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. 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. The reason for this difference is not clear. It may be due either to better air flow, or to poor lymph drainage within the upper lungs. Chronic obstructive pulmonary disease

Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis (MTB). Tuberculosis generally affects the lungs, but can also affect other parts of the body. Most infections do not have symptoms, known as latent tuberculosis. About 10% of latent infections progress to active disease which, if left untreated, kills about half of those infected. The classic symptoms of active TB are a chronic cough with blood-containing sputum, fever, night sweats, and weight loss. The historical term "consumption" came about due to the weight loss. Infection of other organs can cause a wide range of symptoms.

Track09: TB and HIV co-infection

TB and HIV co-infection is when people have both HIV infection, and also either latent or active TB disease. When someone has both HIV and TB each disease speeds up the progress of the other. In addition to HIV infection speeding up the progression from latent to active TB, TB bacteria also accelerate the progress of HIV infection. TB also occurs earlier in the course of HIV infection than many other opportunistic infections. The risk of death in co-infected individuals is also twice that of HIV infected individuals without TB, even when CD4 cell count and antiretroviral therapy are taken into account.

Providing HIV antiretroviral therapy and anti TB drug treatment together

The provision of HIV antiretroviral therapy and anti TB drug treatment at the same time involves a number of potential difficulties including:

·         Cumulative drug toxicities

·         Drug – drug interactions

·         A high pill burden

·         The Immune Reconstitution Inflammatory Syndrome (IRIS)

Diagnosis of TB should be considered with signs of lung disease or constitutional symptoms lasting longer than 2 weeks.  A chest X-ray and multiple sputum cultures for acid-fast bacilli are typically part of the initial evaluation. Interferon-γ release assays and tuberculin skin tests are of little use in the developing world. 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. Thus, treatment is often begun before cultures are confirmed. Nucleic acid amplification tests and adenosine deaminase testing may allow rapid diagnosis of TB. These tests, however, are not routinely recommended, as they rarely alter how a person is treated. Blood tests to detect antibodies are not specific or sensitive, so they are not recommended.

The Mantoux tuberculin skin test is often used to screen people at high risk for TB. Those who have been previously immunized may have a false-positive test result. The test may be falsely negative in those with sarcoidosis, Hodgkin's lymphoma, malnutrition, and most notably, active tuberculosis. Interferon gamma release assays (IGRAs), on a blood sample, are recommended in those who are positive to the Mantoux test. These are not affected by immunization or most environmental mycobacteria, so they generate fewer false-positive results. However, they are affected by M. szulgai, M. marinum, and M. kansasii. IGRAs may increase sensitivity when used in addition to the skin test, but may be less sensitive than the skin test when used alone.

Clinical trials are concerned with diagnoses and Treatment. The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) is an increasing global health problem. Recent advances in the development of new drugs and regimens provide hope that well tolerated, effective, and shorter-duration treatments for tuberculosis (TB) will become available.

Tuberculosis (TB) has been a disease affecting almost all parts of the world since ages. Lot many efforts came in the past for improving diagnosis and treatment. Also, an effective vaccine has been sought after for long. With the emergence of resistant strains of Mycobacterium tuberculosis, the causal organisms of tuberculosis, and complexities emerging due to other associated infections and disease conditions, there is a desperate need for further research input in the field. Be it the better medication and care or better resistance management, proper diagnostics holds the key to success. It has been observed that a high burden of the disease was accompanied by resource limitations and poor research set-up. The scenario remained like this for several decades. With the refreshed vision of resourceful countries and funding agencies, funding is being provided in many areas of research in tuberculosis diagnosis and treatment. This review has been written with an aim to bring forth the limitations of available methods in the field of diagnostics and making researchers aware about the changing scenario with better funding opportunities and support. The author visualizes an enthusiasm from all over the world for the development of better modalities and urges scientists to join the struggle at this very perfect time to take the challenge and come forward with innovations in this field.

Tuberculosis prevention and control efforts rely primarily on the vaccination of infants and the detection and appropriate treatment of active cases. The World Health Organization has achieved some success with improved treatment regimens, and a small decrease in case numbers. The US Preventive Services Task Force (USPSTF) recommends screening people who are at high risk for latent tuberculosis with either tuberculin skin tests or interferon-gamma release assays.

TB education is also necessary for the general public. The public needs to know basic information about TB for a number of reasons including reducing the stigma still associated with TB.

TB prevention consists of two main parts. The first part of TB prevention is to stop the transmission of TB from one adult to another. This is done through firstly, identifying people with active TB, and then curing them through the provision of drug treatment. With proper TB treatment someone with TB will very quickly not be infectious and so can no longer spread the disease to others. The second main part of TB prevention is to prevent people with latent TB from developing active, and infectious, TB disease.

TB disease can be treated by taking several drugs for 6 to 9 months.  There are 10 drugs currently approved by the U.S. Food and Drug Administration (FDA) for treating TB. Of the approved drugs, the first-line anti-TB agents that form the core of treatment regimens are: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Once the TB isolate is known to be fully susceptible, ethambutol (or streptomycin, if it is used as a fourth drug) can be discontinued.

 Directly observed therapy (DOT) is recommended for all patients. With DOT, patients on the above regimens can be switched to 2- to 3-times per week dosing after an initial 2 weeks of daily dosing. Patients on twice-weekly dosing must not miss any doses. Prescribe daily therapy for patients on self-administered medication.

Primary MDR-TB occurs in patients who have not previously been infected with TB but who become infected with a strain that is resistant to treatment. Acquired MDR-TB occurs in patients during treatment with a drug regimen that is not effective at killing the particular strain of TB with which they have been infected Treatment of MDR-TB requires treatment with second-line drugs, usually four or more anti-TB drugs for a minimum of 6 months, and possibly extending for 18–24 months if rifampin resistance has been identified in the specific strain of TB with which the patient has been infected.In general, second-line drugs are less effective, more toxic and much more expensive than first-line drugs. Under ideal program conditions, MDR-TB cure rates can approach 70%.

Systematic surveillance and tracking of drug-resistant TB helps in understanding the overall burden of the disease and can inform research and practice in diagnosis, treatment, and infection control. Speakers at the workshop described various approaches being taken to advance the tracking of drug-resistant TB in South Africa. This chapter summarizes those presentations. The first section reviews the use of genetic fingerprinting methodologies to understand the genotype and physiology of the various drug-resistant TB strains found in South Africa. The second section describes a clinical screening tool that has been developed to intensify TB case finding. The final section addresses the need for information systems to increase laboratory capacity.

Current tuberculosis (TB)-control methods, which do not include an adequate vaccine, do not effectively block transmission of TB.  Modelling studies show that mass vaccination campaigns using new vaccines could prevent 85.9 million new cases and 14.5 million deaths from 2015 through 2050 in southern Asia alone. After a dearth of many years, the development pipeline now includes 7 vaccine candidates that are being tested in humans. Two nonreplicating viral vectored vaccines have very recently entered the first phase IIb efficacy trial in infants (the first such trial in 80 years) and in human immunodeficiency virus-infected adults. Science is moving forward, but the scientific advancements need to be accompanied by political mobilization to ensure that the resources are available to develop, manufacture, and distribute the new vaccines and, thus, save millions of lives.