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Tuberculosis t2-+bur-kyu-!lO-sus

by Edward A. Nardell, MD

Tuberculosis is a contagious infection caused by the airborne bacteria Mycobacterium tuberculosis.

  • Tuberculosis is spread only when people breathe air contaminated by a person who has active disease.

  • Cough is the most common symptom, but people may also have night sweats, feel generally unwell, and, if tuberculosis affects other organs, have various other symptoms.

  • The diagnosis usually involves a tuberculin skin test or a blood test, a chest x-ray, and examination and culture of a sputum sample.

  • Two or more antibiotics are always given to reduce the chances of bacterial resistance.

  • Early diagnosis and treatment plus isolation of people with active disease until they have responded to treatment help prevent tuberculosis from spreading.

Tuberculosis usually affects the lungs, although it can affect almost any organ in the body. Other related bacteria (called mycobacteria), such as Mycobacterium bovis or Mycobacterium africanum, can occasionally cause a similar disease.

Tuberculosis has been a serious public health problem for a long time. In the 1800s, the disease caused more than 30% of all deaths in Europe. With the advent of antituberculosis antibiotics in the late 1940s, the battle against tuberculosis seemed to be won. However—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, as the following statistics from 2006 show:

  • There were 9.2 million new cases of symptomatic tuberculosis and 3 million deaths from the disease. The number of new cases varies widely by country, age, race, sex, and socioeconomic status.

  • Of the 9.2 million new cases, about 3 million occurred in Africa, 3 million in Southeast Asia, and about 2 million in the Western Pacific region.

  • India and China reported the largest total number of new cases, but South Africa had the highest rate of new cases in the world, with 940 new cases per 100,000 people.

About one third of all the people in the world are thought to have a dormant (latent) tuberculosis infection, although only about 5 to 10% of these infections progress to active tuberculosis.

In the United States, the rate of new cases has decreased 10-fold since 1953 (when national reporting for tuberculosis first began). In 2007, 13,293 cases (about 4.4 cases per 100,000 people) were reported. However, there is a wide range of incidence, from 10.2 per 100,000 people in Washington, DC to 0.4 per 100,000 in Wyoming. Over half of new cases occurred in people born outside the United States in areas where tuberculosis is relatively common (such as Africa, Southeast Asia, or Latin America). In the United States, US-born blacks, the homeless, people in jails and prisons, and other disenfranchised minorities are much more likely to be infected. The rate of new cases among these high-risk groups is likely to be almost as high as that in areas of the world where tuberculosis is relatively common.

Did You Know...

  • Tuberculosis caused 3 million deaths worldwide in 2006.

In developing countries, tuberculosis is a disease of young adults. In the United States and other developed countries, tuberculosis has traditionally been more common among older people. More cases have occurred among older people because they were more likely to have acquired the infection in an era when tuberculosis was more common. Moreover, the body’s immune system weakens as people age, allowing inactive (dormant) bacteria to become reactivated. However, the incidence of tuberculosis among older people is declining because fewer people in each generation entering old age have inactive (latent) infection. Because the number of new cases among people born outside the United States is increasing, the age profile of tuberculosis infection in the United States is getting younger.

How Infection Develops

With most infectious diseases (such as strep throat or pneumonia), people become sick right after the microorganism enters the body and are noticeably ill within 1 or 2 weeks. Tuberculosis does not follow this pattern.

Stages of Infection

There are several stages:

  • Primary infection

  • Latent infection

  • Active disease

Except for very young children and people with a weakened immune system, few people become sick immediately after tuberculosis bacteria enter their body (this stage is called primary infection). In most cases, tuberculosis bacteria that enter the lungs are immediately killed by the body’s defenses. Bacteria that survive are engulfed by white blood cells called macrophages. The engulfed bacteria can remain alive inside these cells in a dormant state for many years, walled off inside collections of cells that form tiny scars (this stage is called latent infection). In 90 to 95% of cases, the bacteria never cause any further problems, but in about 5 to 10% of infected people, they eventually start to multiply and cause active disease. At this stage, infected people actually become sick and can spread the disease.

More than half the time, dormant bacteria reactivate within the first 2 years after the primary infection, but they may not reactivate for a very long time, even decades. Usually, doctors do not know why the dormant bacteria reactivate, but reactivation is more likely to occur when the person’s immune system becomes impaired—for example, from very advanced age, infection with the human immunodeficiency virus (HIV), the use of corticosteroids, or the use of some of the new prescription anti-inflammatory drugs such as adalimumab, etanercept, and infliximab. Like many infectious diseases, tuberculosis spreads more quickly and is much more dangerous in people who have a weakened immune system. For such people, tuberculosis can be life threatening. In the United States, about 10% of people with tuberculosis die of the disease or a related condition. In parts of the world where tuberculosis is common, the mortality is much higher.

Transmission of Infection

Mycobacterium tuberculosis can live only in people. These bacteria are not normally carried by animals, insects, soil, or other nonliving objects. People can be infected with tuberculosis only from a person who has active disease. Touching someone who has the disease does not spread it because the bacteria are spread almost exclusively through the air. Mycobacterium bovis, which can live in animals, is an exception. In developing countries, children become infected with it by drinking unpasteurized milk from infected cattle. In developed countries, this type of tuberculosis is no longer a problem because cattle are tested for tuberculosis and milk is pasteurized.

Did You Know...

  • People with active tuberculosis often contaminate the air when they cough, sneeze, or even talk.

People with active tuberculosis in their lungs often 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. Thus, people who have contact with a person who has active tuberculosis (such as family members or health care practitioners who treat such a person) are at increased risk of getting the infection. People who have latent infection or tuberculosis that is not in their lungs do not expel bacteria into the air and cannot spread the infection.

Progression and Spread of Infection

The progression of tuberculosis from latent infection to active disease varies greatly. Progression to active disease is far more likely and much faster in people with HIV infection and other conditions (including use of drugs) that weaken the immune system. If people with AIDS become infected with Mycobacterium tuberculosis, they have a 5 to 10% chance of developing active disease each year. In contrast, people who have latent tuberculosis but do not have AIDS have only a 5 to 10% chance of developing active disease during their lifetime.

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 from the lungs through the blood. As in the lungs, the infection may not cause disease, but the bacteria may remain dormant in a very small scar. Dormant bacteria in these scars can reactivate later in life, leading to symptoms related to the organs involved.

In pregnant women, tuberculosis bacteria may spread to the fetus and cause disease (called congenital tuberculosis). However, such cases are extremely uncommon.

Tuberculosis: A Disease of Many Organs

Site of Infection

Symptoms or Complications

Abdominal cavity

Fatigue, swelling, slight tenderness, and appendicitis-like pain

Bladder

Painful urination and blood in urine

Bones (mainly in children)

Swelling and minimal pain

Brain

Fever, headache, nausea, drowsiness, and, if untreated, coma and brain damage

Pericardium (the membrane around the heart)

Fever, enlarged neck veins, and shortness of breath

Joints

Arthritis-like symptoms

Kidneys

Kidney damage and infection around the kidneys

Lymph nodes

Painless, red and swollen lymph nodes, which may drain pus

Reproductive organs in men

Lump in the scrotum

Reproductive organs in women

Sterility

Spine

Pain, leading to collapsed vertebrae and leg paralysis

Symptoms and Complications

Pulmonary Tuberculosis

Cough is the most common symptom of tuberculosis. Because the disease develops slowly, infected people at first may blame the cough on smoking, a recent episode of flu, the common cold, 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.

People may awaken in the night and be drenched with a cold sweat, with or without fever. Sometimes there is so much sweat that people have to change nightclothes or even the bed sheets. However, tuberculosis does not always cause night sweats, and many other conditions can cause night sweats.

People also feel generally unwell, with decreased energy and appetite. Weight loss often occurs after they have been ill for a while.

Rapidly developing shortness of breath plus chest pain may signal the presence of air (pneumothorax—see Pneumothorax) or fluid (pleural effusion) in the space between the lungs and the chest wall (see Pleural Effusion). About one third of tuberculosis infections first show up as pleural effusion. Eventually, many people with untreated tuberculosis develop shortness of breath as the infection spreads in the lungs.

Extrapulmonary Tuberculosis

The kidneys and lymph nodes are probably the most common sites for tuberculosis that develops outside the lungs. Tuberculosis 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.

Symptoms of extrapulmonary tuberculosis are vague, usually with fatigue, poor appetite, intermittent fevers, sweats, and possibly weight loss. Sometimes the infection causes pain, discomfort, a collection of pus (abscess), or other symptoms, depending on the area involved:

  • Lymph nodes: 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 in them, 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 vessels to the lymph nodes in the neck. An infection in lymph nodes in the neck may break through the skin and discharge pus.

  • Brain: 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 or people with a weakened immune system. 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 may also infect the brain itself, forming a mass called a tuberculoma. The tuberculoma may cause symptoms such as headaches, seizures, or muscle weakness.

  • Pericardium: In tuberculous pericarditis, the pericardium thickens and sometimes leaks fluid into the space between the pericardium and the heart. These effects limit the heart’s ability to pump and cause swollen neck veins and difficulty breathing. In parts of the world where tuberculosis is common, tuberculous pericarditis is a common cause of heart failure.

  • Intestine: Intestinal tuberculosis occurs mainly in developing countries. This infection may not cause any symptoms but can cause abnormal swelling of tissues in the abdomen. This swelling may be mistaken for cancer.

Diagnosis

Sometimes the first indication of tuberculosis is an abnormal chest x-ray or a positive tuberculin skin test (also known as a Mantoux test or PPD for purified protein derivative). These tests are often done as routine screening tests. For example, skin tests are done routinely for people who are at risk of tuberculosis because they

  • Live or work with people who have active disease (as an annual test)

  • Have just emigrated from areas where tuberculosis is common

  • Are starting to take a drug that may weaken the immune system and reactivate latent tuberculosis if present

When people have symptoms that suggest tuberculosis, the following may be done:

  • Chest x-ray

  • Tuberculin skin test

  • Examination and culture of a sputum sample

  • Blood tests

The sputum sample is examined under a microscope to look for tuberculosis bacteria and is used to grow the bacteria in a culture. Microscopic examination provides results much faster than a culture but is less accurate. It detects only about half the cases of tuberculosis identified by culture. However, traditional cultures do not provide results for many weeks because tuberculosis bacteria grow slowly. For this reason, treatment of people who may have tuberculosis is often begun while doctors wait for results of sputum examination and culture. A widely available culture test can routinely identify Mycobacterium tuberculosis growth within 21 days.

Newly available blood tests can confirm the presence of Mycobacterium tuberculosis within 24 hours. These tests appear to be at least as accurate as the tuberculin skin test, possibly more accurate. Other new tests can detect and identify genetic material of the bacteria in sputum in a few days. Genetic tests can also rapidly identify bacteria that are resistant to the usual drugs used to treat tuberculosis and thus can help doctors choose effective treatment. New tests that detect tuberculosis bacteria in sputum or urine are being developed.

Chest x-ray findings in tuberculosis often resemble those in other disorders, 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 indicate whether the infection is currently active. Results may also indicate tuberculosis when it is not present (false-positive results) because people have an infection with one of the close, generally harmless relatives of tuberculosis (see Diseases Resembling Tuberculosis) or have been recently vaccinated against tuberculosis. The new blood tests are not influenced by recent vaccination against the disease. However, like the tuberculin skin test, these tests indicate infection only—not whether the disease is active.

A sample of sputum is usually adequate, but occasionally a doctor needs to obtain a sample of lung fluid or tissue to make the diagnosis. An instrument called a bronchoscope is inserted through the mouth or nostril and into the airways. It is used to inspect the bronchial tubes and to obtain a sample of lung fluid or tissue. This procedure is most often done when other disorders, such as lung cancer, are suspected.

When symptoms suggest tuberculous meningitis, a doctor may need to do a spinal tap (lumbar puncture) to obtain a sample of spinal fluid for analysis. Because tuberculosis bacteria are hard to find in spinal fluid and because cultures usually take weeks, the polymerase chain reaction (PCR) technique may be used. It produces many copies of a gene, making identification of the bacteria’s DNA easier. Although test results are available quickly, doctors usually begin antibiotic therapy if they have any suspicion of tuberculous meningitis. Early treatment can prevent death and minimize brain damage.

Treatment

A number of antibiotics are effective against tuberculosis. But because tuberculosis bacteria are very slow-growing, antibiotics must be taken for a long time—usually for 6 months or longer. Treatment must be continued long after people feel completely well. Otherwise, the disease tends to recur 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, stop 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, who watches them take the pills. This approach is called directly observed therapy (DOT). Because DOT ensures that people take every dose, the drugs are often given for a shorter time and are usually given just 2 or 3 times per week.

Two or more antibiotics that work in different ways are always given because treatment with only one drug can leave behind a few bacteria resistant to that drug. With most other bacteria, a few bacteria would not be enough to cause a relapse, but people treated with only one drug soon 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, and ethambutol. Streptomycin is sometimes added to this regimen. All of these drugs have side effects, but 95% of people with tuberculosis are cured with these drugs and do not experience any serious side effects.

Drugs Used to Treat Tuberculosis

Drug

Route

Side Effects

Isoniazid

By mouth

Liver injury in 1 person in 10,000, resulting in nausea, vomiting, and jaundice

Sometimes numbness in the limbs

Rifampin

By mouth

Liver injury, particularly when rifampin is combined with isoniazid (but the effects go away when people stop the drug)

Reddish orange discoloration of urine, tears, and sweat

Pyrazinamide

By mouth

Liver injury and sometimes gout

Ethambutol

By mouth

Sometimes blurred vision and decreased color perception (because the drug affects the optic nerve)

Streptomycin

By injection into a muscle

Dizziness and slight hearing loss (due to damage to nerves of the inner ear)

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 people have to take each day and reducing the chance of developing drug resistance. Unlike other antibiotics, those used to treat tuberculosis are usually taken all together, once a day.

Surgery to remove a portion of the lung is seldom needed if people faithfully follow the drug treatment plan. However, surgery is sometimes needed to treat very drug-resistant infections and to drain pus that has accumulated. When tuberculous pericarditis causes significant restriction of the heart’s motion, the pericardium may need to be removed surgically. A tuberculoma in the brain may need to be surgically removed.

Did You Know...

  • Treatment of tuberculosis must be continued long after people feel well.

Prevention

Prevention has two aspects: stopping the spread of infection and treating early infection before it becomes active disease.

Stopping the Spread

Because tuberculosis bacteria are airborne, good ventilation with fresh air lowers the concentration of bacteria and limits their spread. Also, germicidal ultraviolet lamps can be used to kill airborne tuberculosis bacteria in buildings where people at risk are gathered, such as homeless shelters, jails, and hospital and emergency department waiting areas. Health care workers who handle samples of infected tissue or interact with people who may be infected wear special masks, called respirators, to help protect them. No precautions are needed if people have no symptoms even if their skin or blood test for tuberculosis is positive.

People with active tuberculosis can help reduce the spread of bacteria by coughing into a tissue. Also, they should remain in isolation until they are responding to treatment and no longer coughing. After only a few days to weeks of treatment with the correct antibiotics, people are less likely to spread the disease. They usually do not need to be isolated for longer than 2 weeks. However, if infected people live or work 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 the danger of spreading the infection is past. Also, people who continue to cough during treatment, do not take their drugs as instructed, or have drug-resistant tuberculosis may need to be isolated longer so that they do not spread the disease.

Treating Early Infection

Because tuberculosis is spread 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 who have a positive tuberculin skin or blood test should be treated even if they are not yet ill. The antibiotic isoniazid is very effective at stopping the infection before it becomes active disease. It is given daily for 6 to 9 months. For some people, rifampin alone may be prescribed daily for 4 months. In some countries, isoniazid and rifampin are used together for 3 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 of tuberculosis (for example, if their skin or blood test recently changed from negative to positive, if they have been recently exposed, or if they have a weakened immune system). For older people with long-standing latent infection, the risk of toxicity from the antibiotics may be greater than the risk of developing tuberculosis. In such cases, doctors often consult an expert in the subject before they decide whether to use preventive therapy.

If people with a positive skin or blood test become infected with HIV, the risk of developing active infection is very high. Similarly, the risk is also high if people who have a latent infection take corticosteroids or other drugs that suppress the immune system (including some of the newer anti-inflammatory drugs). Such people usually need treatment of latent tuberculosis infection.

In much of the developing world, a vaccine called bacille Calmette-Guérin (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 debated, and the vaccine continues to be used only in countries where the likelihood of contracting tuberculosis is very high. The vaccine may have a role in protecting health care workers and others exposed to tuberculosis that is resistant to two or more drugs. 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, people vaccinated at birth often incorrectly attribute a positive skin test later in life to the BCG vaccine. In most countries, tuberculosis is stigmatized, and many people are reluctant to believe that they have even latent infection, much less active disease. The newer tuberculosis blood tests are not affected by BCG vaccination.

Resources In This Article

Drugs Mentioned In This Article

  • Generic Name
    Select Brand Names
  • ACHROMYCIN V
  • ZITHROMAX
  • MYCOBUTIN
  • MYAMBUTOL
  • BIAXIN
  • ENBREL
  • REMICADE
  • HUMIRA
  • RIFADIN, RIMACTANE
  • No US brand name
  • LANIAZID