NIAID Backgrounder - April 1993
National Institute of Allergy and Infectious Diseases

Most people infected with M. tuberculosis never develop active TB. However, in persons with weakened immune systems, especially those infected with the human immunodeficiency virus (HIV, the cause of AIDS), TB organisms may overcome the body's defense, 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 1991, a total of 26,283 active TB case, in all 50 states, were reported to the Centers for Disease Control and Prevention, an increase of 18 percent since 1985. In addition to those with active TB, an estimated 15 million people in the United States have latent TB infections and may develop active TB as some time in their life

Minorities are affected disproportionately by TB: more than 56 percent of active TB cases in 1991 were among Hispanic and Black persons. In some sectors of U.S. society, TB rates now surpass those in the world's poorest countries. Young black men in New York City, for example, suffer 345 active cases per 100,000, many times the national average of 10 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 persons, 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 persons 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 persons 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.

One-third of all TB cases in New York in 1991 were resistant to one or more antibiotic drugs. At least 36 states, plus Puerto rico and the District of Columbia, reported drug-resistant cases of TB in 1991. In 1990 and 1991 the Centers for Disease Control received 13 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 Has 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 tuberculosis. 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 since 1989 the number of active TB cases in the United States has been on the rise. Several forces, often interrelated, are behind TB's resurgence:

- The HIV/AIDS epidemic. Persons 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 persons weakened by poor nutrition, drug addiction and alcoholism are exposed to M. tuberculosis. Persons 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 persons 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 f 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 persons, 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 most important measure to prevent the transmission of TB.

Because most infected persons 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 suffer coughs, sneezes, speaks, sings, or laughs. Only persons 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 by pass the natural defenses of upper respiratory passages, such as hair 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.

Persons 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 persons 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 persons 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 is confined. Most persons undergo complete healing of their initial infection and the tubercles calcify and lose their viability. A positive TB skin test, and in some case 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, persons 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 lung 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 may be vague and go unnoticed by the affected individual: weight loss, fever, night sweats and loss of appetite.

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 persons with previous exposure to TB will test positive on the tuberculin test, as will some people exposed to related mycobacteria. An important exception is persons 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 disease, 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 4 weeks. An additional two to three weeks usually are needed to determine the drug susceptibility of the organism.

Advances in Diagnosis

Recently, NIAID-supported researchers have developed an experimental test that uses polymerase chain reaction to speed the diagnosis of TB from four weeks to 2 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. Standard test often require three weeks to determine drug sensitivity, making treatment decisions difficult.

Treatment of Active Disease

The death rate of untreated patients is between 40 and 60 percent. With appropriate antibiotics, however, 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, physician and other health workers. 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 treatments. 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. Patient education is essential, and many doctors opt for supervised, directly observed therapy (DOT). Therapy for 18 months to two years may be necessary, and patients often received 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 persons in close contact with infected persons 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 over the age of 35, suffer INH-related hepatitis. Rifampin for one year is recommended for close contacts of patients with INH- resistant TB organism.

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

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

- Persons with a positive tuberculin skin test and an abnormal chest-ray compatible with inactive TB ( (lesions caused by prior disease);

- Persons whose skin test has recently converted from negative to positive;

- Persons with a positive skin test reaction who also have a special medical condition known to increase the risk of TB (e.g., HIV infection, diabetes mellitus) or who are on corticosteroid therapy;

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

- Injection drug users who have positive skin test reactions.

In addition, persons under the age of 35 in the following groups should be considered for preventive therapy if they have a positive skin test reaction:

- Foreign-born persons from countries where TB is common

- Medically underserved low income groups, especially Blacks, Hispanics and Native Americans and

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

Health care workers with frequent contact with TB patients or involved with high-risk procedures such as those that induce coughing should have a skin test every 6 months.

Hospitals and clinics caring for high risk population can take precautions to prevent the spread of TB. All patients should be taught to cover their mouths and noses when coughing or sneezing. UV 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. 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 persons who have received the BCG vaccine, thus limiting the effectiveness of the PPD skin test for the identification of new infections. Because of the limitation of BCG, more effective vaccines are needed.

TB and HIV Infection

The World Health Organization (WHO) estimates that 4.4 million people worldwide are coinfected with TB and HIV. By the year 2000, TB will claim one million lives annually among the HIV-infected, the WHO projects. In the United States, an estimated 100,000 HIV-infected persons also carry M. Tuberculosis, according to the 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, persons coinfected with TB and HIV develop active TB at a rate of about eight percent each year. By comparison, otherwise healthy individuals infected with M. tuberculosis have a 10 percent lifetime risk of developing active TB. Persons with HIV also are at greater risk of having a new infection progress directly to active disease.

MDR-TB in persons 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 persons 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, a decision to begin anti-TB therapy in HIV+ persons suspected of having active TB must often be made 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 50 research projects related to TB. Another six NIAID TB projects are funded through the National Vaccine Program. In FY 1993, NIAID will devote an estimated $20.6 million to TB research, a nearly six-fold increase since 1991.

In addition, NIAID recently formulated a comprehensive research agenda, with plans for increased support for:

- 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 will draw on the Institute's expertise in immunology and microbiology, as well as the capabilities in drug and vaccine development honed as part of the AIDS research efforts.

NIAID Research Agenda for Tuberculosis

NIAID, the lead institute for tuberculosis (TB) research at the National Institute of Health, supports more than 50 research projects related to TB. Another six NIAID TB projects are funded through the National Vaccine Program. In FY 1993, NIAID will devote an estimated $20.6 million to TB research, a nearly six-fold increase since 1991.

In addition, NIAID recently formulated a comprehensive research agenda, with plans for increased support for:

- 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 will draw on the Institute's expertise in immunology and microbiology, as well as the capabilities in drug and vaccine development honed as part of the AIDS research effort.

Basic Research

To develop effective therapies and vaccines for TB, much more must be learned about how mycobacterium tuberculosis causes disease and how the body responds to infection. To facilitate this research, NIAID recently funded an initiative to supply researchers with purified research materials. In addition, NIAID has requested grant applications, to be funded in FY 1993, for research that will complement ongoing projects.

Under construction on the NIH campus is a state-of-the- art facility that will allow researchers to safely conduct research with multi-drug-resistant strains of M. tuberculosis. This facility will serve as a resource for both intramural and extramural scientist.

Research plans

- Determine the basic mechanisms of drug resistance to M. tuberculosis infection.

- Identify and characterize the mechanisms by which M. tuberculosis causes disease and the factors that influence it virulence.

- Determine the immunologic and biologic factors associated with or responsible for latency and reactivation of M. tuberculosis infection.

- Develop improved culture and animal model systems to support basic and applied research on TB.

Diagnosis of TB

Active TB is diagnosed by evaluating clinical signs and symptoms, chest x-ray findings, and evidence of M. tuberculosis in sputum or biopsy specimens. A culture of M. tuberculosis and determination of drug sensitivity can take six weeks or longer, delaying treatment and impeding control efforts. In addition, the TB skin test is now the only means of detecting persons with latent infection. In immunosuppressed persons, such as those infected with HIV, this test often yields unreliable results.

Research plans

- Add TB skin testing to existing U.S. and international AIDS studies to determine the relationship between TB skin test reactivity and immunologic status.

- Develop and evaluate test for rapid diagnosis of active TB and determine drug susceptibility patterns in populations with compromised or intact immune systems.

TB Drug Development

TB outbreaks in the United States cannot be fully controlled unless improved therapies against active TB, particularly multi-drug-resistant TB (MDR-TB), are developed. Currently, many patients do not consistently take their TB drugs for the necessary six to nine months (18 to 24 months for MDR-TB), leading to the development of multi-drug resistant organisms. New drugs or new ways to deliver standard drugs are needed.

For persons latently infected with M. Tuberculosis, especially those at high risk such as person with HIV, optimal preventive regimens are needed.

To add to ongoing projects, NIAID funded four new grants for tuberculosis drug development in September 1992.

Research plans

- Fund further meritorious grant proposals in the area of anti-TB drug development.

- Encourage pharmaceutical manufactures and academic researchers to develop and screen new compounds for anti-TB activity. Towards this end, NIAID has established a database of chemical structures and in vitro activity of compounds against M. tuberculosis to serve as a reference for design and synthesis of new drugs.

- Encourage pharmaceutical manufactures involved in AIDS drug development to review existing repositories of compounds for anti-TB activity.

- Expand existing National Cooperative Drug Discovery Group-Opportunistic Infections (NCDDG-OI) program to:

* Determine the basic mechanisms of the action of existing TB drug. * Identify new targets for TB drugs. * Identify new drugs that can rapidly kill or neutralize both actively growing and quiescent organisms

- Initiate new research to establish drug-screening capabilities and develop new animal models.

- Evaluate implantable formulations of isoniazid (INH) and other drugs. NIAID has formed an implantable INH Development Project Team to coordinate preclinical development of a sustained release formulation of INH.

Tuberculosis Clinical Trials

Five TB-related clinical trials for patients with HIV are supported by NIAID's Division of AIDS (DAIDS):

1) A comparison of treatment regimens of different duration, with and without the drug levofloxacin, in HIV-infected patients with active TB. The study also assesses the effectiveness of twice-weekly treatment, so called intermittent therapy. Intermittent therapy previously has been found effective in TB patients without HIV infection.

2) A comparison of the standard therapy for the prevention of TB--the drug isoniazid for one year--with a two-month course of treatment using the drugs pyrazinamide and rifampin. This study enrolls HIV-infective TB patients who have no symptoms of TB, but have a positive skin test.

3) An evaluation of a six-month course of isoniazid for the prevention of active TB in HIV-infected individuals suspected of being infected with M. tuberculosis, but who do not respond to the TB skin test because their immune systems are suppressed.

4) A study to determine patterns of drug-resistant TB among patients in AIDS clinical trials.

5) A study of the frequency of new TB infections among health care workers and volunteers at AIDS clinical trials site.

Studies in development for persons with HIV will evaluate new drugs and combinations of existing drugs for the management of both drug-sensitive TB and MDR-TB.

Research plans

- Integrate new anti-TB agents and cytokines into treatment regimens.

- Improve the rapidity of diagnosis and successful treatment of MDR-TB.

- Test improved delivery systems for anti-TB drugs.

- Evaluate existing drugs already approved for other indications. Such trials could be conducted in the existing network of NIAID AIDS clinical trials site.

Tuberculosis Vaccine Development

The TB vaccine used in some parts of the world, bacillus Calmette-Guerin (BCG) is variably effective across age groups and geographic areas. Because a person who has received BCG will usually test positive on the skin test, but may or may not actually be infected with M. tuberculosis, the use of BCG limits the reliability of the skin test.

In addition to 11 current research grants on tuberculosis vaccines, NIAID will fund additional grants in 1993.

Research plans

- Identify and characterize immunogenic components of M. tuberculosis. - Identify which immunogens elicit protective responses.

- Characterize protective responses.

- Develop animal models.

Tuberculosis Training

With the advent of effective antibiotic against TB in the 1940s and 1950s, many scientist and clinicians perceived TB as a problem that had been solved, and turned their attention to other areas. This has resulted in a critical shortage of physician-investigators and basic scientists actively involved in research M. tuberculosis.

NIAID recognizes the need for trained researchers to develop new diagnostic test, drugs and vaccines to meet present and future public health needs. By creating TB training programs for both new and established researchers, NIAID hopes to help rebuild the TB research community, draw new scientists and physicians into the field and stimulate new approaches that capitalize on the research advances of the last decade.

Tuberculosis Education and Outreach

With outbreaks of TB on the rise, educational materials on the disease and on how transmission can be prevented are needed. NIAID will develop materials targeted to both the general public and persons at high risk for acquiring the disease, such as persons with HIV and health care workers.

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

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