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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, in which case it is 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.[4] Infection of other organs can cause a wide range of symptoms.

Tuberculosis is spread through the air when people who have active TB in their lungs cough, spit, speak, or sneeze. People with latent TB do not spread the disease. Active infection occurs more often in people with HIV/AIDS and in those who smoke. Diagnosis of active TB is based on chest X-rays, as well as microscopic examination and culture of body fluids. Diagnosis of latent TB relies on the tuberculin skin test (TST) or blood tests.

Prevention of TB involves screening those at high risk, early detection and treatment of cases, and vaccination with the bacillus Calmette-Guérin vaccine. Those at high risk include household, workplace, and social contacts of people with active TB. Treatment requires the use of multiple antibiotics over a long period of time. Antibiotic resistance is a growing problem with increasing rates of multiple drug-resistant tuberculosis (MDR-TB).

One-third of the world's population is thought to be infected with TB. New infections occur in about 1% of the population each year. In 2014, there were 9.6 million cases of active TB which resulted in 1.5 million deaths. More than 95% of deaths occurred in developing countries. The number of new cases each year has decreased since 2000. About 80% of people in many Asian and African countries test positive while 5–10% of people in the United States population tests positive by the tuberculin test. Tuberculosis has been present in humans since ancient times.

Signs and Symptoms

The main symptoms of variants and stages of tuberculosis are given, with many symptoms overlapping with other variants, while others are more (but not entirely) specific for certain variants. Multiple variants may be present simultaneously.
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, although extrapulmonary TB may coexist with pulmonary TB.

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. The reason for this difference is not clear. It may be due to either better air flow, or poor lymph drainage within the upper lungs.

Extrapulmonary

In 15–20% of active cases, the infection spreads outside the lungs, causing other kinds of TB. These are collectively denoted as "extrapulmonary tuberculosis".[19] 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. Spread to lymph nodes is the most common. An ulcer originating from nearby infected lymph nodes may occur and is painless, slowly enlarging and has an appearance of "wash leather". When it spreads to the bones, it is known as "osseous tuberculosis", a form of osteomyelitis. A potentially more serious, widespread form of TB is called "disseminated tuberculosis", also known as miliary tuberculosis. Miliary TB currently makes up about 10% of extrapulmonary cases.

Using histological stains on expectorated samples from phlegm (also called "sputum"), scientists can identify MTB under a microscope. Since MTB retains certain stains even after being treated with acidic solution, it is classified as an acid-fast bacillus. The most common acid-fast staining techniques are the Ziehl–Neelsen stain[29] and the Kinyoun stain, which dye acid-fast bacilli a bright red that stands out against a blue background. Auramine-rhodamine staining and fluorescence microscopy are also used.

The M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canetti, and M. microti. M. africanum is not widespread, but it is a significant cause of tuberculosis in parts of Africa. M. bovis was once a common cause of tuberculosis, but the introduction of pasteurized milk has almost completely eliminated this as a public health problem in developed countries. M. canetti is rare and seems to be limited to the Horn of Africa, although a few cases have been seen in African emigrants. M. microti 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.

Risk factors

Main article: Risk factors for tuberculosis
A number of factors make people more susceptible to TB infections. The most important risk factor globally is HIV; 13% of all people with TB are infected by the virus. This is a particular problem in sub-Saharan Africa, where rates of HIV are high. Of people without HIV who are infected with tuberculosis, about 5–10% develop active disease during their lifetimes; in contrast, 30% of those coinfected with HIV develop the active disease.

Tuberculosis is closely linked to both overcrowding and malnutrition, making it one of the principal diseases of poverty. Those at high risk thus include: people who inject illicit drugs, inhabitants and employees of locales where vulnerable people gather (e.g. prisons and homeless shelters), medically underprivileged and resource-poor communities, high-risk ethnic minorities, children in close contact with high-risk category patients, and health-care providers serving these patients.

Chronic lung disease is another significant risk factor. Silicosis increases the risk about 30-fold. Those who smoke cigarettes have nearly twice the risk of TB compared to nonsmokers.

Other disease states can also increase the risk of developing tuberculosis. These include alcoholism and diabetes mellitus (three-fold increase).

Certain medications, such as corticosteroids and infliximab (an anti-αTNF monoclonal antibody), are becoming increasingly important risk factors, especially in the developed world.

Genetic susceptibility also exists, for which the overall importance remains undefined.

Mechanism

Public health campaigns in the 1920s tried to halt the spread of TB.
Transmission
When people with active pulmonary TB cough, sneeze, speak, sing, or spit, they expel infectious aerosol droplets 0.5 to 5.0 µm in diameter. A single sneeze can release up to 40,000 droplets. Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very small (the inhalation of fewer than 10 bacteria may cause an infection).

People with prolonged, frequent, or close contact with people with TB are at particularly high risk of becoming infected, with an estimated 22% infection rate. A person with active but untreated tuberculosis may infect 10–15 (or more) other people per year. Transmission should occur from only people with active TB – those with latent infection are not thought to be contagious. The probability of transmission from one person to another depends upon several factors, including the number of infectious droplets expelled by the carrier, the effectiveness of ventilation, the duration of exposure, the virulence of the M. tuberculosis strain, the level of immunity in the uninfected person, and others. The cascade of person-to-person spread can be circumvented by segregating those with active ("overt") TB and putting them on anti-TB drug regimens. After about two weeks of effective treatment, subjects with nonresistant active infections generally do not remain contagious to others. If someone does become infected, it typically takes three to four weeks before the newly infected person becomes infectious enough to transmit the disease to others.

Pathogenesis

Microscopy of tuberculous epididymitis. H&E stain
About 90% of those infected with M. tuberculosis have asymptomatic, latent TB infections (sometimes called LTBI), with only a 10% lifetime chance that the latent infection will progress to overt, active tuberculous disease. In those with HIV, the risk of developing active TB increases to nearly 10% a year. If effective treatment is not given, the death rate for active TB cases is up to 66%.

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.


Robert Carswell's illustration of tubercle
Tuberculosis is classified as one of the granulomatous inflammatory diseases. Macrophages, T lymphocytes, B lymphocytes, and fibroblasts aggregate to form granulomas, with lymphocytes surrounding the infected macrophages. When other macrophages attack the infected macrophage, they fuse together to form a giant multinucleated cell in the alveolar lumen. The granuloma may prevent dissemination of the mycobacteria and provide a local environment for interaction of cells of the immune system.[62] However, more recent evidence suggests that the bacteria use the granulomas to avoid destruction by the host's immune system. Macrophages and dendritic cells in the granulomas are unable to present antigen to lymphocytes; thus the immune response is suppressed.[63] Bacteria inside the granuloma can become dormant, resulting in latent infection. Another feature of the granulomas is the development of abnormal cell death (necrosis) in the center of tubercles. To the naked eye, this has the texture of soft, white cheese and is termed caseous necrosis.

If TB bacteria gain entry to the blood stream from an area of damaged tissue, they can spread throughout the body and set up many foci of infection, all appearing as tiny, white tubercles in the tissues. This severe form of TB disease, most common in young children and those with HIV, is called miliary tuberculosis. People with this disseminated TB have a high fatality rate even with treatment (about 30%).

In many people, the infection waxes and wanes. Tissue destruction and necrosis are often balanced by healing and fibrosis. Affected tissue is replaced by scarring and cavities filled with caseous necrotic material. During active disease, some of these cavities are joined to the air passages bronchi and this material can be coughed up. It contains living bacteria, so can spread the infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.

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

A definitive diagnosis of TB is made by identifying M. tuberculosis in a clinical sample (e.g., sputum, pus, or a tissue biopsy). However, the difficult culture process for this slow-growing organism can take two to six weeks for blood or sputum culture. 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.

Latent tuberculosis
Main article: Latent tuberculosis

Mantoux tuberculin skin test
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, 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.

Mycobacteria (Mycobacterium tuberculosis) : scanning electron micrograph of M. tuberculosis
The main cause of TB is Mycobacterium tuberculosis (MTB), a small, aerobic, nonmotile bacillus. The high lipid content of this pathogen accounts for many of its unique clinical characteristics. It divides every 16 to 20 hours, which is an extremely slow rate compared with other bacteria, which usually divide in less than an hour. Mycobacteria have an outer membrane lipid bilayer.[26] If a Gram stain is performed, MTB either stains very weakly "Gram-positive" or does not retain dye as a result of the high lipid and mycolic acid content of its cell wall. MTB can withstand weak disinfectants and survive in a dry state for weeks. In nature, the bacterium can grow only within the cells of a host organism, but M. tuberculosis can be cultured in the laboratory.

 

 

Prevention
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.

Vaccines
Main articles: Tuberculosis vaccines and BCG vaccine
The only available vaccine as of 2011 is Bacillus Calmette-Guérin (BCG). In children it decreases the risk of getting the infection by 20% and the risk of infection turning into disease by nearly 60%.

It is the most widely used vaccine worldwide, with more than 90% of all children being vaccinated. The immunity it induces decreases after about ten years. As tuberculosis is uncommon in most of Canada, the United Kingdom, and the United States, BCG is administered to only those people at high risk. Part of the reasoning against the use of the vaccine is that it makes the tuberculin skin test falsely positive, reducing the test's use in screening.[84] A number of new vaccines are currently in development.

Public health
The World Health Organization declared TB a "global health emergency" in 1993, and in 2006, the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aimed to save 14 million lives between its launch and 2015. A number of targets they set were not achieved by 2015, mostly due to the increase in HIV-associated tuberculosis and the emergence of multiple drug-resistant tuberculosis.[13] A tuberculosis classification system developed by the American Thoracic Society is used primarily in public health programs.

Management
Main article: Tuberculosis management
Treatment of TB uses antibiotics to kill the bacteria. Effective TB treatment is difficult, due to the unusual structure and chemical composition of the mycobacterial cell wall, which hinders the entry of drugs and makes many antibiotics ineffective.[87] The two antibiotics most commonly used are isoniazid and rifampicin, and treatments can be prolonged, taking several months. Latent TB treatment usually employs a single antibiotic, while active TB disease is best treated with combinations of several antibiotics to reduce the risk of the bacteria developing antibiotic resistance. People with latent infections are also treated to prevent them from progressing to active TB disease later in life. Directly observed therapy, i.e., having a health care provider watch the person take their medications, is recommended by the WHO in an effort to reduce the number of people not appropriately taking antibiotics. The evidence to support this practice over people simply taking their medications independently is poor.[90][needs update] Methods to remind people of the importance of treatment do, however, appear effective.

New onset
The recommended treatment of new-onset pulmonary tuberculosis, as of 2010, is six months of a combination of antibiotics containing rifampicin, isoniazid, pyrazinamide, and ethambutol for the first two months, and only rifampicin and isoniazid for the last four months. Where resistance to isoniazid is high, ethambutol may be added for the last four months as an alternative.

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

Medication resistance
Primary resistance occurs when a person becomes infected with a resistant strain of TB. A person with fully susceptible MTB may develop secondary (acquired) resistance during therapy because of inadequate treatment, not taking the prescribed regimen appropriately (lack of compliance), or using low-quality medication. Drug-resistant TB is a serious public health issue in many developing countries, as its treatment is longer and requires more expensive drugs. MDR-TB is defined as resistance to the two most effective first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB is also resistant to three or more of the six classes of second-line drugs. Totally drug-resistant TB is resistant to all currently used drugs. It was first observed in 2003 in Italy, but not widely reported until 2012,[ and has also been found in Iran and India. Bedaquiline is tentatively supported for use in multiple drug-resistant TB.

XDR-TB is a term sometimes used to define extensively resistant TB, and constitutes one in ten cases of MDR-TB. Cases of XDR TB have been identified in more than 90% of countries.

Progression from TB infection to overt TB disease occurs when the bacilli overcome the immune system defenses and begin to multiply. In primary TB disease (some 1–5% of cases), this occurs soon after the initial infection. However, in the majority of cases, a latent infection occurs with no obvious symptoms. These dormant bacilli produce active tuberculosis in 5–10% of these latent cases, often many years after infection.

The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In people coinfected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year.Studies using DNA fingerprinting of M. tuberculosis strains have shown reinfection contributes more substantially to recurrent TB than previously thought, with estimates that it might account for more than 50% of reactivated cases in areas where TB is common. The chance of death from a case of tuberculosis is about 4% as of 2008, down from 8% in 1995.