Tuberculosis (TB), a chronic bacterial infection, causes more deaths worldwide than any other infectious disease. TB is spread through the air and usually infects the lungs, although other organs are sometimes involved. Some 1.7 billion people - one-third of the world's population - are infected with the predominant TB organism, Mycobacterium tuberculosis.

Most people infected with M. tuberculosis never develop active TB. However, in people with weakened immune systems, especially those infected with the human immunodeficiency virus (HIV, the cause of AIDS), TB organisms may overcome the body's defenses, multiply, and cause active disease. Each year, 8 million people worldwide develop active TB and 3 million die.

TB on the Rise in the United States

In the United States, TB has re-emerged as a serious public health problem. In 1993, a total of 25,287 active TB cases, in all 50 states and the District of Columbia, were reported to the Centers for Disease Control and Prevention (CDC), an increase of 14 percent since 1985. Thanks largely to improved public health control measures, this number decreased to 22,860 in 1995. In addition to those with active TB, however, an estimated 15 million people in the United States have latent TB infections and may develop active TB at some time in their lives.

Minorities are affected disproportionately by TB: 54 percent of active TB cases in 1995 were among African-American and Hispanic people, with an additional 17.5 percent found in Asians. In some sectors of U.S. society, TB rates now surpass those in the world's poorest countries. Among African-American men in New York City aged 35 to 44, for example, 315 out of 100,000 had active TB in 1993, many times the national average of 9.8 cases per 100,000 people.

Drug Resistance a Concern

With appropriate antibiotic therapy, TB usually can be cured. In recent years, however, drug-resistant cases of TB have increased dramatically.

Drug resistance results when patients fail to take their medicine consistently for the six to 12 months necessary to destroy all vestiges of M. tuberculosis. In some U.S. cities, more than 50 percent of patients - often homeless people, drug addicts, and others caught in poverty - fail to complete their prescribed course of TB therapy. One reason for this lack of compliance is that TB patients may feel better after only two to four weeks of treatment and stop taking their TB drugs, some of which have unpleasant side effects.

Resistance also may develop when patients are treated with too few drugs or with inadequate doses.

Particularly alarming is the increase in the number of people with multi-drug-resistant TB (MDR-TB), caused by M. tuberculosis strains resistant to two or more drugs. Even with treatment, the death rate for MDR-TB patients is 40 to 60 percent, the same as for TB patients who receive no treatment. For people coinfected with HIV and MDR-TB, the death rate may be as high as 80 percent. The time from diagnosis to death for some patients with MDR-TB and HIV may be only months as they are sometimes left with no treatment options.

Of all culture-positive TB cases in New York State in 1995, at least 13 percent were resistant to one or more antibiotic drugs. This figure is similar to that seen in an earlier national survey. At least 39 states reported drug-resistant cases of TB in 1995. In addition, CDC received numerous reports of outbreaks of MDR-TB in hospitals and prisons. During these outbreaks, MDR-TB has sometimes spread to hospital patients, health care workers, prisoners, and prison guards.

What Caused TB's Resurgence?

During the 19th century, TB claimed more lives in the United States than any other disease. Improvements in nutrition, housing, sanitation, and medical care in the first half of the 20th century dramatically reduced the number of cases and deaths. TB's decline hastened in the 1940s and 1950s with the introduction of the first effective antibiotic therapies for TB. By 1985, the number of cases had fallen to 22,201 in the United States, the lowest figure recorded in modern U.S. history.

In 1985, however, the decline ended and the number of active TB cases in the United States began to rise again. Several forces, often interrelated, were behind TB's resurgence:

• The HIV/AIDS epidemic. People with HIV are particularly vulnerable to reactivation of latent TB infections, as well as to disease caused by new TB infections. TB transmission occurs most frequently in crowded environments such as hospitals, prisons, and shelters where HIV-infected individuals make up a growing proportion of the population.

• Increased numbers of immigrants from countries with many cases of TB, many of whom live in crowded housing. Because of language and economic difficulties, many immigrants have limited access to health care and may not receive treatment.

• Increased poverty, injection drug use, and homelessness. TB transmission is rampant in crowded shelters and prisons where people weakened by poor nutrition, drug addiction, and alcoholism are exposed to M. tuberculosis. People in poor health, especially those infected with HIV, also are prone to reactivation of latent TB infections.

• Poor compliance with treatment regimens, especially among disadvantaged groups. Some of these people may remain contagious while others develop and pass on resistant strains of M. tuberculosis that are difficult to treat.

• Increased numbers of residents in long-term care facilities such as nursing homes. Immune function declines with age, and as patients live longer, many suffer recurrences of latent infections often acquired in early adulthood. As a result, other elderly people, especially those with weak immune systems, become newly infected with TB.

The TB Organism

TB is caused by repeated exposure to airborne droplets contaminated with M. tuberculosis, a rod-shaped bacterium. The TB bacterium also is known as the tubercle bacillus. (A small fraction of cases are caused by related bacteria, M. africanum and M. bovis.)

M. tuberculosis, like other mycobacteria, has an unusual cell wall, a waxy coat comprised of fatty molecules whose structure and function are not well known. This cell wall appears to allow M. tuberculosis to survive in its preferred environment: inside immune cells called macrophages, which ordinarily degrade pathogens with enzymes. The coat of M. tuberculosis also renders it impermeable to many common drugs.

Biologists call M. tuberculosis and other mycobacteria "acid fast" bacteria because their fatty cell walls prevent the cells from being decolorized by acid solutions after staining during diagnostic tests.

Several factors make M. tuberculosis a difficult organism to study in the laboratory, hampering TB research. The bacteria multiply very slowly, only once every 24 hours, and take a month to form a colony. By comparison, other bacteria such as E. coli form colonies within eight hours. TB bacilli tend to form clumps, which makes working with them and counting them difficult. Most daunting, M. tuberculosis, a dangerous, airborne organism, can be studied only in laboratories that have specialized safety equipment.

Transmission

TB is primarily an airborne disease. The disease is not likely to be transmitted through personal items belonging to those with TB, such as clothing, bedding, or other items they have touched. Adequate ventilation is the most important measure to prevent the transmission of TB.

Because most infected people expel relatively few bacilli, transmission of TB usually occurs only after prolonged exposure to someone with active TB. On average, people have a 50 percent chance of becoming infected with TB if they spend eight hours a day for six months or 24 hours a day for two months working or living with someone with active TB, researchers have estimated.

People are most likely to be contagious when their sputum contains bacilli, when they cough frequently and when the extent of their lung disease, as revealed by a chest x-ray, is great. TB is spread from person to person in microscopic droplets - droplet nuclei - expelled from the lungs when a TB sufferer coughs, sneezes, speaks, sings, or laughs. Only people with active disease are contagious.

Droplet nuclei are tiny and may remain in the air for prolonged periods, ready to be inhaled. They are small enough to bypass the natural defenses of upper respiratory passages, such as hairs in the nose or the hairlike cilia in the bronchial tubes. Infection begins when the bacilli reach the tiny air sacs of the lungs known as alveoli, where they multiply within macrophages.

People who have been treated with appropriate drugs for at least two weeks usually are not infectious.

Infection

The site of initial infection is usually the alveoli - the balloonlike sacs at the ends of the small air passages in the lungs known as bronchioles. In the alveoli, white blood cells called macrophages ingest the inhaled M. tuberculosis bacilli.

Some of the bacilli may be killed immediately; others may multiply within the macrophages. Infrequently, but especially in HIV-infected people and in children, the bacilli spread to other sites in the body. This dissemination sometimes results in life-threatening meningitis and other problems.

During the two to eight weeks after initial infection in people with intact immune systems, macrophages present pieces of the bacilli, displayed on their cell surfaces, to another type of white blood cell - the T cell. When stimulated, T cells release an elaborate array of chemical signals. Once this response, called cell-mediated hypersensitivity, is established, a person's T cells usually will respond to the tuberculin skin test (PPD test) and produce a characteristic red welt.

Some of the T-cell signals produce inflammatory reactions; other signals recruit and activate specialized cells to kill bacilli and wall-off infected macrophages in tiny, hard grayish capsules known as tubercles.

From then on the body's immune system maintains a standoff with the infection, sometimes for years. In the tubercles, TB bacilli may persist within macrophages, but further multiplication and spread of M. tuberculosis are confined. Most people undergo complete healing of their initial infection, and the tubercles calcify and lose their viability. A positive TB skin test, and in some cases a chest x-ray, may provide the only evidence of the infection.

If, however, the body's resistance is low because of aging, infections such as HIV, malnutrition, or other factors, the bacilli may break out of the tubercles in the alveoli and lead to active disease.

Active Disease

On the average, people infected with M. tuberculosis have a 10 percent chance of developing active TB at some time in their lives. The risk of developing active disease is greatest in the first year after infection, but active disease sometimes does not occur until many years later.

Active TB usually results from the spread of bacilli from the alveoli through the bloodstream or lymphatic system to other sites, usually elsewhere in the lungs or local lymph nodes. In 15 percent of cases, the bacilli cause disease in other regions, such as the skin, kidneys, bones, or reproductive and urinary systems.

At the new sites, the body's immune defenses kill many bacilli, but immune cells and local tissue die as well. The dead cells and tissue form granulomas with the consistency of soft cheese, where the bacilli survive but do not flourish. The early symptoms of active TB can include weight loss, fever, night sweats, and loss of appetite, or they may be vague and go unnoticed by the affected individual.

As more lung tissue is destroyed and the granulomas expand, cavities in the lungs develop, and sometimes break into larger airways called bronchi. This allows large numbers of bacilli to spread when patients cough. As the disease progresses, the granulomas may liquefy, perhaps as a result of enzymes secreted by the body's own immune cells. This creates a rich medium in which the bacilli multiply rapidly and spread, creating further lesions and the characteristic chest pain, cough, and, when a blood vessel is eroded, bloody sputum.

Most patients do not suffer shortness of breath until the lungs are extensively damaged by the formation of cavities. Symptoms of TB involving areas other than the lungs vary, depending upon the organ affected.

Diagnosing TB

The tuberculin skin test, also known as the Mantoux test, can identify most people infected with tubercle bacilli six to eight weeks after initial exposure. A substance called purified protein derivative (PPD) is injected under the skin of the forearm and examined about 48 to 72 hours later. If a red welt forms around the injection site, the person may have been infected with M. tuberculosis, but doesn't necessarily have active disease. Most people with previous exposure to TB will test positive on the tuberculin test, as will some people exposed to related mycobacteria. An important exception is people with severely weakened immune systems, such as those with HIV.

If a person has a significant reaction to the tuberculin skin test, additional methods can determine if the individual has active TB. This is sometimes difficult because TB can mimic other diseases, such as pneumonia, lung abscesses, tumors, and fungal infections, or occur along with them. In making a diagnosis, doctors rely on symptoms and other physical signs, a person's history of exposure to TB, and x-rays that may show evidence of TB infection, usually in the form of cavities or lesions in the lungs.

The physician also will take sputum and other samples, because a positive bacteriologic culture of M. tuberculosis is essential to confirm the diagnosis and determine which drugs will work against the strain of TB the patient carries. Because M. tuberculosis grows very slowly, the laboratory diagnosis requires approximately four weeks. An additional two to three weeks usually are needed to determine the drug susceptibility of the organism, making treatment decisions difficult.

Advances in Diagnosis

Recently, researchers supported by the National Institute of Allergy and Infectious Diseases (NIAID) as well as other investigators developed tests that use nucleic acid amplification to speed the diagnosis of TB from four weeks to two days. Another test in development uses luminescent chemicals from the firefly to determine, in 24 to 48 hours, which drugs can kill the TB strain a patient carries.

Treatment of Active Disease

The death rate for untreated TB patients is between 40 and 60 percent. With appropriate antibiotics, however, people with drug-susceptible cases of TB can be cured more than 90 percent of the time.

Successful management of TB depends on close cooperation between the patient and physicians and other health care workers. Patient education is essential, and many doctors opt for supervised, directly observed therapy (DOT). Treatment usually combines the drugs isoniazid (INH) and rifampin, which are given for at least six months, and pyrazinamide, which is used only in the first two months of treatment. This treatment is referred to as short-course chemotherapy. A fourth drug, ethambutol, sometimes is added if a physician suspects that drug-resistant organisms are present.

Therapy for MDR-TB

Treatment for MDR-TB often requires the use of a second line of TB drugs, all of which can produce serious side effects. Therapy for 18 months to two years may be necessary, and patients often receive three drugs, one as an injection, after drug susceptibility testing.

Prevention

TB is largely a preventable disease. In the United States, prevention has focused on identifying infected individuals early - especially those who run the highest risk of developing active disease - and treating them with drugs in a program of directly observed therapy.

INH prevents the disease in most people in close contact with infected people or who are infected with the tubercle bacilli but who do not have active TB. The drug is given daily for six to 12 months and strict patient compliance in taking medication is essential to prevent drug-resistant strains from emerging. Adverse reactions to INH are rare, although a small percentage of patients, especially those older than 35, suffer INH-related hepatitis. Rifampin for one year is recommended for close contacts of patients with INH-resistant TB organisms.

In the United States, people with any of the following risk factors should be considered for preventive therapy, regardless of age, if they have not been previously treated for TB:

• Close contacts of people with newly diagnosed infectious TB; (In addition, children and adolescents who react negatively to the PPD test, but who have been in close contact with infectious people within the past three months should be considered for preventive therapy. Therapy should continue until a second skin test is done 12 weeks after their first contact with an infectious person.)

• People with positive tuberculin skin tests and abnormal chest x-rays compatible with inactive TB (lesions caused by prior disease);

• People whose skin test results have recently converted from negative to positive;

• People with positive skin test reactions who also have special medical conditions known to increase the risk of TB (e.g., HIV infection, diabetes mellitus) or who are on corticosteroid therapy;

• HIV-positive people or those suspected to be HIV-infected who now have, or had at any time in the past, positive skin test reactions, but who do not have active infection; and

• Injection drug users who have positive skin test reactions.

In addition, people younger than 35 in the following groups should be considered for preventive therapy if they have positive skin test reactions:

• Foreign-born people from countries where TB is common;

• People in medically underserved, low-income groups, especially African Americans, Hispanics, and Native Americans; and

• Residents of long-term care facilities such as prisons, nursing homes, and mental institutions.

Health care workers in frequent contact with TB patients or involved with high-risk procedures such as those that induce coughing should have a skin test every six months.

Hospitals and clinics caring for high-risk populations can take precautions to prevent the spread of TB. All patients should be taught to cover their mouths and noses when coughing or sneezing. Ultraviolet light can be used to sterilize the air, and negative pressure rooms and special filters are available, as are special respirators and masks, that filter out the droplet nuclei. Until they are no longer infectious, hospitalized TB patients should be isolated in rooms with controlled ventilation and air flow.

More Effective Vaccines are Needed

In those parts of the world where the disease is common, a vaccine composed of live, attenuated (weakened) mycobacteria from cows (M. bovis, called bacillus Calmette-Guerin [BCG]) is given to infants as part of the immunization program recommended by the World Health Organization (WHO). In infants, BCG prevents the spread of M. tuberculosis within the body, but does not prevent initial infection.

In adults, the effectiveness of BCG has varied widely in large-scale studies. In addition, positive skin test reactions occur in people who have received BCG vaccine, thus limiting the effectiveness of the PPD skin test to identify new infections. As a result, BCG is not recommended for general use in the United States. Because of BCG's limitations, more effective vaccines are needed.

TB and HIV Infection

WHO estimates that 4.4 million people worldwide are coinfected with TB and HIV. By the year 2000, TB will claim 1 million lives annually among the HIV-infected, WHO projects. In the United States, an estimated 100,000 HIV-infected people also carry M. tuberculosis, according to CDC.

TB frequently occurs early in the course of HIV infection, often months to years before other opportunistic infections such as Pneumocystis carinii pneumonia. TB may be the first indication that a person is HIV-infected, and often occurs in areas outside the lungs, particularly in the later stages of HIV disease.

In the United States, people coinfected with TB and HIV develop active TB at a rate of about 8 percent each year. By comparison, otherwise healthy individuals infected with M. tuberculosis have a 10 percent lifetime risk of developing active TB. People with HIV also are at greater risk of having a new infection progress directly to active disease.

MDR-TB in people coinfected with HIV appears to have a more rapid and deadly disease course than seen in patients with MDR-TB who are otherwise healthy.

Diagnosing TB in HIV-infected people is often difficult. These patients frequently have conditions that produce symptoms similar to those of TB, and may not react to the standard tuberculin skin test because their immune systems are suppressed. Although investigators have hypothesized that a two-stage TB skin test might be more reliable than a single-stage test in HIV-infected individuals, a recently completed NIAID study found this not to be the case.

X-rays, sputum smears and physical exams may also fail to provide an indication of TB infection in the HIV-infected. As a consequence, doctors must often decide to begin anti-TB therapy in HIV-infected people suspected of having active TB while waiting for the results of cultures of sputum or other specimens.

NIAID Research Agenda for Tuberculosis

NIAID, the lead institute for TB research at the National Institutes of Health, supports more than 100 research projects related to TB. In FY 1997, NIAID will devote an estimated $37 million to TB research.

NIAID has a comprehensive TB research agenda that supports the following:

• Studies of the epidemiology and natural history of TB.

• Basic research into the biology of TB.

• The development of new tools to diagnose TB.

• The development of new drugs or new ways to deliver standard drugs.

• Clinical trials of anti-TB therapies.

• The development of new vaccines to prevent TB.

• Training to increase the number of TB researchers.

• New ways to educate health care workers and the public about TB prevention.

This multi-disciplinary program draws on the Institute's expertise in immunology and microbiology, as well as its capabilities in drug and vaccine development honed as part of the research effort in AIDS and other infectious diseases.

NIAID, a component of the National Institutes of Health, supports research on AIDS, tuberculosis and other infectious diseases as well as allergies and immunology.

Prepared by:
Office of Communications
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892

Public Health Service
U.S. Department of Health and Human Services
March 1997