Tuberculosis
Definition of Tuberculosis
Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis typically attacks the lungs, but can also affect other parts of the body. It is spread through the air when people who have an active TB infection cough, sneeze, or otherwise transmit their saliva through the air. Most infections are asymptomatic and latent, but about one in ten latent infections eventually progresses to active disease which, if left untreated, kills more than 50% of those so infected.
The classic symptoms of active TB infection are a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss (the latter giving rise to the formerly prevalent term “consumption”). Infection of other organs causes a wide range of symptoms. Diagnosis of active TB relies on radiology (commonly chest X-rays), as well as microscopic examination and microbiological culture of body fluids. Diagnosis of latent TB relies on the tuberculin skin test (TST) and/or blood tests. Treatment is difficult and requires administration of multiple antibiotics over a long period of time. Social contacts are also screened and treated if necessary. Antibiotic resistance is a growing problem in multiple drug-resistant tuberculosis (MDR-TB) infections. Prevention relies on screening programs and vaccination with the bacillus Calmette–Guérin vaccine.
Many strains of tuberculosis resist the drugs most used to treat the disease. People with active tuberculosis must take several types of medications for many months to eradicate the infection and prevent development of antibiotic resistance.
Cause of Tuberculosis
Mycobacteria
The main cause of TB is Mycobacterium tuberculosis, 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. 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.
Using histological stains on expectorated samples from phlegm (also called “sputum”), scientists can identify MTB under a regular (light) microscope. Since MTB retains certain stains even after being treated with acidic solution, it is classified as an acid-fast bacillus (AFB). The most common acid-fast staining techniques are the Ziehl–Neelsen stain, which dyes AFBs a bright red that stands out clearly against a blue background, and the auramine-rhodamine stain followed by fluorescence microscopy.
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 largely 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 mostly seen in immunodeficient people, although the prevalence of this pathogen has possibly been 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.
Signs and Symptoms of Tuberculosis
About 5–10% of those without HIV, infected with tuberculosis, develop active disease during their lifetimes. In contrast, 30% of those coinfected with HIV develop active disease. 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. Extrapulmonary TB may coexist with pulmonary TB as well. General signs and symptoms include fever, chills, night sweats, loss of appetite, weight loss, and fatigue, and significant finger 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, resulting in massive bleeding (Rasmussen’s aneurysm). 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 entirely clear. It may be due either to better air flow, or to poor lymph drainage within the upper lungs.
Extrapulmonary
In 15–20% of active cases, the infection spreads outside the respiratory organs, 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’s 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” TB, commonly known as miliary tuberculosis. Miliary TB makes up about 10% of extrapulmonary cases.
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 TB cases are infected by the virus. This is a particular problem in sub-Saharan Africa, where rates of HIV are high. 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 clients. Chronic lung disease is another significant risk factor – with silicosis increasing the risk about 30-fold. Those who smoke cigarettes have nearly twice the risk of TB than nonsmokers. Other disease states can also increase the risk of developing tuberculosis, including alcoholism and diabetes mellitus (threefold increase). Certain medications, such as corticosteroids and infliximab (an anti-αTNF monoclonal antibody) are becoming increasingly important risk factors, especially in the developed world. There is also a genetic susceptibility, for which overall importance remains undefined.
Diagnosis of Tuberculosis
Active Tuberculosis
Diagnosing active tuberculosis based merely 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. Interferon-γ release assays and tuberculin skin tests are of little use in the developing world. 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
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, or most notably, in those who truly do have 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.
Prevention from Tuberculosis
Tuberculosis prevention and control efforts primarily rely 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.
Vaccines
The only currently available vaccine as of 2011 is bacillus Calmette–Guérin (BCG) which, while it is effective against disseminated disease in childhood, confers inconsistent protection against contracting pulmonary TB. Nevertheless, it is the most widely used vaccine worldwide, with more than 90% of all children being vaccinated. However, 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 only administered to people at high risk. Part of the reasoning arguing against the use of the vaccine is that it makes the tuberculin skin test falsely positive, and therefore, of no use in screening. 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 aims to save 14 million lives between its launch and 2015. A number of targets they have set are not likely to be achieved by 2015, mostly due to the increase in HIV-associated tuberculosis and the emergence of multiple drug-resistant tuberculosis (MDR-TB). A tuberculosis classification system developed by the American Thoracic Society is used primarily in public health programs.
Treatment of Tuberculosis
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. 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. 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 to which antibiotics it is sensitive 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 TB 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, which was first observed in 2003 in Italy, but not widely reported until 2012, is resistant to all currently used drugs.