Tuberculosis (TBC)

Tuberculosis is a contagious infection caused by an airborne bacterium, Mycobacterium tuberculosis. Tuberculosis usually affects the lungs, although it can attack almost any organ in the body. Other mycobacteria (such as Mycobacterium bovis or Mycobacterium africanum) occasionally can cause a similar disease.
Tuberculosis has been a serious public health problem for a long time. In the 1800s, the disease was responsible for more than 30% of all deaths in Europe. With the advent of antituberculosis antibiotics in the 1940s, the battle against tuberculosis seemed to be won. Unfortunately- because of factors such as inadequate public health resources, reduced immune response due to AIDS, the development of drug resistance, and extreme poverty in many parts of the world-tuberculosis continues to be a deadly disease. Worldwide, there are 8 million new cases of symptomatic tuberculosis and 3 million deaths from the disease every year. It is believed that one third of all the people in the world have a dormant (latent) tuberculosis infection, although
only about 5 to 10% progress to active tuberculosis disease.
In the developed countries, tuberculosis has been more common among older people, whereas it is a disease of young adults in poorer countries. Of the cases reported in 2000, 22% involved people older than age 65. There were more cases among older people because they were more likely to have acquired the infection in an era when tuberculosis was more common. As the body's immune system weakens with age, dormant bacteria become reactivated.
Fortunately, the incidence of tuberculosis among older people is declining because each generation entering old age has a lower rate of latent infection. Because tuberculosis has existed in Europe longer than anywhere else, people of European descent are somewhat more resistant to the disease than people whose ancestors lived in parts of the world where tuberculosis was introduced more recently. Additionally, people in these groups tend to be poorer, live in crowded conditions, and have less access to medical care-all conditions that are conducive to the spread of tuberculosis.

Diseases Resembling Tuberculosis
Many types of mycobacteria exist; many can cause infections that produce symptoms similar to tuberculosis. The most common are a group known as Mycobacterium avium complex (MAC). Although these mycobacteria are common, they generally cause infection only in people with a weakened immune system or with lungs that have been damaged by prolonged smoking, an old tuberculosis infection, bronchitis, emphysema, or other diseases. Similar to tuberculosis, a MAC infection primarily affects the lungs but may also attack the lymph nodes, bones, skin, and other tissues. Unlike tuberculosis, a MAC infection cannot be passed from one person to another.
The infection usually develops slowly. The first symptoms include coughing and spitting up mucus. As the infection progresses, the person may regularly spit up blood and have trouble breathing. A chest x-ray may or may not reveal an infection. A laboratory analysis of sputum taken from an infected person is needed to distinguish the infection from tuberculosis.
In people with AIDS or other diseases that weaken the immune system, MAC infection can spread throughout the body. Symptoms include a fever, anemia, blood disorders, diarrhea, and stomach pain. MAC infection of the lymph nodes may develop in children, generally those between the ages of 1 and 5 years. The infection is usually caused by eating soil or drinking water that is contaminated with the mycobacteria. Antibiotics do not usually cure the infection, but the infected lymph nodes can be removed by surgery.
MAC infections were very difficult to treat until recently, because the bacteria were resistant to most of the antibiotics effective against tuberculosis. Newer antibiotics, such as clarithromycin and azithromycin- which do not work in tuberculosis- have been found to be effective against MAC when used in combination with ethambutol and rifabutin.
Other mycobacteria grow in swimming pools and even in home aquariums and can cause skin disorders. These infections may clear up without treatment. However, people with chronic infections usually need treatment with tetracycline, clarithromycin, or another antibiotic for 3 to 6 months. Another type of mycobacteria, Mycobacterium fortuitum, can infect wounds and artificial body parts, such as a mechanical heart valve or breast implant. Antibiotics and surgical removal of the infected areas usually cure the infection.

How Infection Develops
With most infectious diseases (such as strep throat or pneumonia), a person becomes sick right after the microorganism enters the body and is noticeably ill within 1 or 2 weeks. Tuberculosis does not follow this pattern.
Stages of Infection: Except for very young children, few people become sick immediately after tuberculosis bacteria enter their body (primary infection). Many tuberculosis bacteria that enter the lungs are immediately killed by the body's defenses. Those that survive are captured inside white blood cells called macrophages. The captured bacteria can remain alive inside these cells in a dormant state for many years, walled off inside tiny scars (latent infection). In 90 to 95% of cases, the bacteria never cause any further problem, but in about 5 to 10% of infected people they start to multiply (active disease). It is in this active phase that an infected person actually becomes sick and can spread the disease.
More than half the time, activation of dormant bacteria happens within the first 2 years, but it may not occur for a very long time. Doctors do not always know why the dormant bacteria become active, but it often occurs when the person's immune system becomes impaired-for example, from very advanced age, the use of corticosteroids, or AIDS. Like many infectious diseases, tuberculosis spreads more quickly and is much more dangerous in people who have a weakened immune system. For such people (including the very young, the very old, and those who are also infected with HIV), tuberculosis can be life threatening.
Transmission of Infection: Mycobacterium tuberculosis can live only in people; it cannot be carried by animals, insects, soil, or other nonliving objects. A person can be infected with tuberculosis only from another person who has active disease. Touching someone who has the disease does not spread it, because the bacteria are transmitted only through the air. Mycobacterium bovis, a bacterium that can live in animals, is an exception. In developing
countries, children become infected with it by drinking unpasteurized milk from infected cattle.
People with active tuberculosis in their lungs contaminate the air with bacteria when they cough, sneeze, or even speak. These bacteria can stay in the air for several hours. If another person breathes them in, that person may become infected. People who have latent disease or tuberculosis that is not in their lungs do not spread bacteria into the air and cannot transmit the infection.
Progression and Spread of Infection: The progression of tuberculosis from latent infection to active disease varies greatly. For example, tuberculosis often progresses more rapidly in blacks and Native Americans than in whites because of inherited differences in resistance. Impaired immunity also plays a role. Progression to an active disease is far more likely and much faster
in people with AIDS. A person with AIDS who becomes infected with Mycobacterium tuberculosis has a 50% chance of developing active tuberculosis within 2 months and a 5 to 10% chance of developing active disease each year thereafter.
In people with a fully functioning immune system, active tuberculosis is usually limited to the lungs (pulmonary tuberculosis) . Tuberculosis that affects other parts of the body (extrapulmonary tuberculosis) comes from pulmonary tuberculosis that has spread through the blood. As in the lungs, the infection may not cause disease, but the bacteria may remain dormant in a very small scar. Latent organisms in these scars can reactivate later in life, leading to symptoms in the organs involved. In pregnant women, the tuberculosis bacteria may spread to the fetus and cause disease; however, such congenital tuberculosis is uncommon.

Symptoms and Complications
Cough is the most common symptom of tuberculosis. Because the disease comes on slowly, an infected person at first may blame the cough on smoking, a recent episode of flu, or asthma. The cough may produce a small amount of green or yellow sputum in the morning. Eventually, the sputum may be streaked with blood, although large amounts of blood are rare.
Another symptom is awakening in the night drenched with a cold sweat. Sometimes there is so much sweat that the person has to change nightclothes or even the bed sheets. However, these night sweats are not specific to tuberculosis. Along with the cough and night sweats, the person feels generally unwell, with decreased energy and appetite. Weight loss often occurs after the illness has been present for a while. Rapidly developing shortness of breath along with chest pain may signal the presence of air (pneumothorax) or fluid (pleural effusion) in the space between the lungs and the chest wall. About one third of tuberculosis infections first show up as a pleural effusion. Eventually, many people with untreated tuberculosis develop shortness of breath as the infection spreads in the lungs.
In a new tuberculosis infection, the bacteria may travel from the lungs to the lymph nodes that drain the lungs. If the body's natural defenses can control the infection, it goes no further, and the bacteria become dormant. However, very young children have weaker defenses and these lymph nodes may become large enough to compress the bronchial tubes, causing a brassy cough and possibly a collapsed lung. Occasionally, bacteria spread up the lymph channels to the lymph nodes in the neck. An infection in these lymph nodes may break through the skin and discharge pus.
The kidneys and lymph nodes are probably the most common sites for tuberculosis that develops outside the lungs (extrapulmonary tuberculosis) . It can also affect the bones, brain, abdominal cavity, membrane around the heart (pericardium) , joints (especially weight-bearing joints, such as the hips and knees), and reproductive organs. Tuberculosis in these areas can be
difficult to diagnose.
The symptoms of extrapulmonary tuberculosis are vague, usually with fatigue, poor appetite, intermittent fevers, sweats, and possibly weight loss. Sometimes the infection causes pain or discomfort, depending on the area involved, but not always.
Tuberculosis that infects the tissues covering the brain (tuberculous meningitis) is life threatening. In the United States and other developed countries, tuberculous meningitis most commonly occurs among older people. In developing countries, tuberculous meningitis is most common among children from birth to age 5. Symptoms include fever, constant headache, neck stiffness, nausea, and drowsiness that can lead to coma. Tuberculosis also may infect the brain itself, forming a mass called a tuberculoma. The tuberculoma may cause symptoms such as headaches, seizures, or muscle weakness.
Tuberculous pericarditis is tuberculosis affecting the pericardium. This infection causes the pericardium to thicken and sometimes leak fluid into the space between the pericardium and the heart. This limits the heart's ability to pump and causes swollen neck veins and difficulty breathing. Intestinal tuberculosis occurs mainly in developing countries. This infection may not produce any symptoms but can produce abnormal growth of tissue, which may be mistaken for cancer, at the infected area.

Tuberculosis: A Disease of Many Organs
Site Infection & Symptoms of Complications
Abdominal cavity: Fatigue, swelling, slight tenderness, appendicitis- like pain
Bladder: Painful urination, blood in urine
Bones: Swelling, minimal pain
Brain: Fever, headache, nausea, drowsiness; coma and brain damage if untreated
Pericardium (the membrane around the heart): Fever, enlarged neck veins, shortness of breath
Joints: Arthritis-like symptoms
Kidneys: Kidney damage, infection around the kidneys
Lymph nodes: Painless, red swelling; may drain pus
Men Reproductive organs: Lump in scrotum
Women Reproductive organs: Sterility
Spine: Pain, leading to collapsed vertebrae and leg paralysis

Diagnosis
Sometimes the first indication of tuberculosis is an abnormal chest x-ray or positive tuberculin skin test (also known as a Mantoux test or PPD for purified protein derivative), because these tests are often done as routine screening tests. When a person has symptoms that suggest tuberculosis, a chest x-ray is taken, a tuberculin skin test is performed, and a sputum sample is sent to the laboratory. The sputum sample is examined under a microscope to look for tuberculosis bacteria and used to grow the bacteria in a culture. The microscopic examination is much faster than a culture but is less accurate. Cultures do not provide results for many weeks because tuberculosis bacteria grow slowly.
Chest x-ray findings in tuberculosis often resemble those from other diseases, so the diagnosis may depend on the results of the tuberculin skin test and examination of sputum for Mycobacterium tuberculosis. Although a tuberculin skin test is one of the most useful tests for diagnosing tuberculosis, it indicates only that an infection by the bacteria has occurred some time in the past. It does not reveal whether the infection is currently active. False-positive results can occur because of an infection with one of the close, generally harmless, relatives of tuberculosis or by recent vaccination against tuberculosis.
Sputum usually provides an adequate sample from the lung, but occasionally a doctor may use an instrument called a bronchoscope to inspect the bronchial tubes and obtain samples of mucus or lung tissue. This procedure is most often performed when other diseases, such as lung cancer, are suspected.
When symptoms indicate the possibility of tuberculous meningitis, a doctor may need to perform a spinal tap to obtain a sample of spinal fluid for analysis. Because tuberculosis bacteria are hard to find in spinal fluid, and cultures usually take weeks, the sample is often sent for a test called polymerase chain reaction (PCR), which can detect tiny amounts of the bacteria's DNA. Although test results are available quickly, a doctor generally begins antibiotic therapy on the mere suspicion of tuberculous meningitis to prevent death and minimize brain damage.

The Tuberculin Skin Test
A tuberculin skin test is performed by injecting a small amount of protein derived from tuberculosis bacteria between the layers of the skin, usually on the forearm. About 2 days later, the injection site is checked and measured: swelling that feels firm to the touch and is larger than a certain size indicates a positive result. Redness around the site without swelling is not positive. Some people who are very ill or who have a weakened immune system may not respond to the skin test even if they are infected with tuberculosis.

What Is Miliary Tuberculosis?
A potentially life-threatening type of tuberculosis may result when a large number of the bacteria spread throughout the body by way of the bloodstream. This infection is called miliary tuberculosis because the millions of tiny lesions formed are the size of millet, the small round seeds in bird food. Symptoms of miliary tuberculosis can be vague and difficult to identify;
they include weight loss, fever, chills, weakness, general discomfort, and difficulty in breathing. Involvement of the bone marrow may cause severe anemia and other blood abnormalities, suggesting leukemia. An intermittent release of bacteria into the bloodstream from a hidden lesion may cause a fever that comes and goes, with gradual wasting of the body.

Treatment
A number of antibiotics are effective against tuberculosis. But because tuberculosis bacteria are very slow-growing, the antibiotics must be taken for a long time-usually for 6 months or longer. Treatment must be continued long after the person feels completely well; otherwise, the disease tends to relapse because it was not fully eliminated.
Most people find it difficult to remember to take their drugs every day for such a long time. Other people, for various reasons, discontinue treatment as soon as they feel better. Because of these problems, many experts recommend that people with tuberculosis receive their drugs from a health care worker. This is called Directly Observed Therapy (DOT). Because DOT ensures that the person takes every dose, DOT treatments are often shorter, and the drugs are usually given just 2 or 3 times per week.
To treat tuberculosis, two or more antibiotics with different mechanisms of action are always given, because treatment with only one drug can leave behind a few bacteria resistant to that drug. With most other bacteria, this would not be enough to cause a relapse, but people treated with only one drug develop tuberculosis resistant to that drug. A third and fourth drug are usually used during the initial, intensive phase of treatment to shorten the duration of treatment and to ensure success even if drug resistance exists at the outset.
The most commonly used antibiotics are isoniazid, rifampin, pyrazinamide, streptomycin, and ethambutol. Isoniazid causes liver injury in 1 person in 10,000, resulting in nausea, vomiting, and jaundice. Rifampin also may injure the liver, particularly when combined with isoniazid. These effects go away when the person discontinues the drug. Pyrazinamide also causes liver injury and sometimes gout. Streptomycin can damage the nerves of the inner ear, producing dizziness and slight hearing loss. Ethambutol sometimes affects the optic nerve, causing blurred vision and decreased color perception. However, 95% of the people with tuberculosis successfully complete therapy and are cured with these drugs and do not experience any serious side effects.
There are many different combinations and dose schedules for these drugs. Isoniazid, rifampin, and pyrazinamide may be contained in the same capsule, reducing the number of pills a person has to take each day and reducing the chance of developing drug resistance.
Surgery to remove a portion of the lung is seldom needed if the person faithfully follows the drug treatment plan. However, surgery is sometimes needed for very drug-resistant infections and to drain pus from wherever it has accumulated. When tuberculous pericarditis causes significant
restriction of the motion of the heart, the pericardium may need to be removed surgically. A tuberculoma in the brain may need to be surgically removed.

Prevention
There are two aspects of prevention: stopping the spread of disease and treating early infection before it becomes active disease. Because tuberculosis bacteria are airborne, good ventilation with fresh air lowers the concentration of bacteria and limits their spread. Also, a germicidal ultraviolet light can be used to kill airborne tuberculosis bacteria in places where people at risk are gathered, such as homeless shelters, jails, and hospital and emergency department waiting areas. Since tuberculosis is transmitted only by people with active disease, early recognition and treatment of active disease is one of the best ways to stop it from spreading. People with active tuberculosis should cough into a tissue to reduce the spread of bacteria, and they should remain in isolation until they are no longer coughing. After only a few days of treatment with the correct antibiotics, a person is less likely to spread the disease and usually does not need to be isolated for longer than a week or two. However, if a person works with people who are at high risk (such as young children or people with AIDS), repeated analyses of sputum samples may be needed to determine when there is no danger of transmission of the infection. Also, people who continue to cough during treatment, fail to take their drugs properly, or have drug-resistant tuberculosis may need to be isolated longer so that they do not spread the disease.
The second aspect of prevention consists of treating people with a positive tuberculin skin test who are not yet ill. The drug isoniazid is very effective at stopping the infection before it becomes active disease. It is given daily for 6 to 9 months. Newer, shorter treatments use rifampin plus pyrazinamide daily for 2 months or rifampin alone daily for 4 months.
Preventive therapy definitely benefits younger people who have a positive tuberculin skin test. It also is likely to help older people at high risk for tuberculosis (for example, people whose tuberculin skin test result recently changed from negative to positive, people who have been recently exposed, or those with a weakened immune system). The risk of toxicity from the antibiotics in older adults with long-standing dormant (latent) disease may be greater than the risk of developing tuberculosis.
A person with a positive tuberculin skin test who becomes infected with HIV is at very high risk of developing active infection; similarly, a person who takes corticosteroids has a greatly increased risk of activation of latent tuberculosis. Thus, such people usually need treatment of latent tuberculosis infection.
In much of the developing world, a vaccine called BCG is used to prevent development of serious complications, such as meningitis, in people who are at high risk of becoming infected with Mycobacterium tuberculosis. The value of BCG is the subject of debate, and the vaccine continues to be used only in countries where the likelihood of contracting tuberculosis is very high.
Research is under way to develop a more effective vaccine. About 10% of people who have received BCG at birth have a positive reaction to the tuberculin skin test 15 years later, even if they are not infected with tuberculosis bacteria. However, it is common for people vaccinated at birth to incorrectly attribute a positive PPD reaction later in life to having received BCG. In most countries, tuberculosis is stigmatized and many people are reluctant to believe they have even latent infection, much less active disease.
(Merck)