Tuberculosis (TB), a chronic bacterial infection, causes more
deaths worldwide than any other infectious disease. TB is spread
through the air and usually affects 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. 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 at some time in their lives.
Minorities are affected disproportionately by TB: 56 percent of
active TB cases in 1993 were among Hispanic and black people,
with an additional 14 percent found in Asians. In some sectors
of U.S. society, TB rates now surpass those in the world's poorest
countries. Black men in New York City aged 35 to 44, for example,
suffered 315 active cases per 100,000 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
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
Of all culture-positive TB cases in New York City in 1993, at
least 14 percent were resistant to one or more antibiotic drugs.
This figure is similar to that seen in an earlier national survey.
At least 30 states reported drug-resistant cases of TB in 1993.
In addition, the 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 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 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, are 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
- 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
- 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
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.
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.
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.
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 mac-rophages. 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
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.
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 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,
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.
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.
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 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. Standard tests often require three weeks to determine
drug sensitivity, making treatment decisions difficult.
Treatment of Active Disease
The death rate of untreated TB 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 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
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 receive three drugs, one as an
injection, after drug susceptibility testing.
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:
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.
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
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 for the identification of new infections.
Because of the limitations of BCG, more effective vaccines are
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 1 million lives annually among the HIV-infected,
the WHO projects. In the United States, an estimated 100,000 HIV-infected
people 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, 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,
a decision to begin anti-TB therapy in HIV-infected people 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 100 research projects related to
TB. In FY 1995, NIAID will devote an estimated $31 million to
TB research, a more than eight-fold increase since 1991.
In addition, NIAID recently formulated a comprehensive research
agenda, with plans for increased support for:
- 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
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, TB and other infectious diseases as well as
allergies and immunology. NIH is an agency of the U.S. Public
Health Service, U.S. Department of Health and Human Services.
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