Week 4

“Tuberculosis”

Tuberculosis (TB), infectious disease that is caused by the tubercle bacillus,

Mycobacterium tuberculosis. In most forms of the disease, the bacillus spreads slowly and
widely in the lungs, causing the formation of hard nodules (tubercles) or large cheeselike masses
that break down the respiratory tissues and form cavities in the lungs. Blood vessels also can be
eroded by the advancing disease, causing the infected person to cough up bright red blood.

During the 18th and 19th centuries, tuberculosis reached near-epidemic proportions in the
rapidly urbanizing and industrializing societies of Europe and North America. Indeed,
“consumption,” as it was then known, was the leading cause of death for all age groups in the
Western world from that period until the early 20th century, at which time improved healthand
hygiene brought about a steady decline in its mortality rates. Since the 1940s, antibiotic
drugs have reduced the span of treatment to months instead of years, and drug therapy has done
away with the old TB sanatoriums where patients at one time were nursed for years while the
defensive properties of their bodies dealt with the disease.

Today, in less-developed countries where population is dense and hygienic standards

poor, tuberculosis remains a major fatal disease. The prevalence of the disease has increased in
association with the HIV/AIDS epidemic; an estimated one out of every four deaths from
tuberculosis involves an individual coinfected with HIV. In addition, the successful elimination
of tuberculosis as a major threat to public health in the world has been complicated by the rise of
new strains of the tubercle bacillus that are resistant to conventional antibiotics. Infections with
these strains are often difficult to treat and require the use of combination drug therapies,
sometimes involving the use of five different agents.

The tubercle bacillus is a small, rod-shaped bacterium that is extremely hardy; it can
survive for months in a state of dryness and can also resist the action of mild disinfectants.
Infection spreads primarily by the respiratory route directly from an infected person who
discharges live bacilli into the air. Minute droplets ejected by sneezing, coughing, and even
talking can contain hundreds of tubercle bacilli that may be inhaled by a healthy person. There
the bacilli become trapped in the tissues of the body, are surrounded by immune cells, and finally
are sealed up in hard, nodular tubercles.

A tubercle usually consists of a centre of dead cells and tissues, cheeselike (caseous) in
appearance, in which can be found many bacilli. This centre is surrounded by radially arranged
phagocytic (scavenger) cells and a periphery containing connective tissuecells. The tubercle thus
forms as a result of the body’s defensive reaction to the bacilli. Individual tubercles are
microscopic in size, but most of the visible manifestations of tuberculosis, from barely visible
nodules to large tuberculous masses, are conglomerations of tubercles.
 In otherwise healthy children and adults, the primary infection often heals without
causing symptoms. The bacilli are quickly sequestered in the tissues, and the infected person
acquires a lifelong immunity to the disease. A skin test taken at any later time may reveal the
earlier infection and the immunity, and a small scar in the lung may be visible by X-ray. In this
condition, sometimes called latent tuberculosis, the affected person is not contagious. In some
cases, however, sometimes after periods of time that can reach 40 years or more, the original
tubercles break down, releasing viable bacilli into the bloodstream.

From the blood the bacilli create new tissue infections elsewhere in the body, most
commonly in the upper portion of one or both lungs. This causes a condition known
as pulmonary tuberculosis, a highly infectious stage of the disease. In some cases the infection
may break into the pleural space between the lung and the chest wall, causing a pleural effusion,
or collection of fluid outside the lung. Particularly among infants, the elderly, and
immunocompromised adults (organ transplant recipients or AIDS patients, for example), the
primary infection may spread through the body, causing miliary tuberculosis, a highly fatal form
if not adequately treated.

In fact, once the bacilli enter the bloodstream, they can travel to almost any organ of the
body, including the lymph nodes, bones and joints, skin, intestines, genital organs, kidneys, and
bladder. An infection of the meninges that cover the brain causes tuberculous meningitis; before
the advent of specific drugs, this disease was always fatal, though most affected people now
recover.

The onset of pulmonary tuberculosis is usually insidious, with lack of energy, weight

loss, and persistent cough. These symptoms do not subside, and the general health of the patient
deteriorates. Eventually, the cough increases, the patient may have chest pain from pleurisy, and
there may be blood in the sputum, an alarming symptom. Fever develops, usually with drenching
night sweats.

In the lung, the lesionconsists of a collection of dead cells in which tubercle bacilli may
be seen. This lesion may erode a neighbouring bronchus or blood vessel, causing the patient to
cough up blood (hemoptysis). Tubercular lesions may spread extensively in the lung, causing
large areas of destruction, cavities, and scarring. The amount of lung tissue available for the
exchange of gases in respiration decreases, and if untreated the patient will die from failure of
ventilation and general toxemia and exhaustion.

The diagnosis of pulmonary tuberculosis depends on finding tubercle bacilli in the

sputum, in the urine, in gastric washings, or in the cerebrospinal fluid. The primary method used
to confirm the presence of bacilli is a sputum smear, in which a sputum specimen is smeared
onto a slide, stained with a compound that penetrates the organism’s cell wall, and examined
under a microscope. If bacilli are present, the sputum specimen is cultured on a special medium
to determine whether the bacilli are M. tuberculosis. An X-ray of the lungs may show typical
shadows caused by tubercular nodules or lesions. The prevention of tuberculosis depends on
good hygienic and nutritional conditions and on the identification of infected patients and their
early treatment.

A vaccine, known as BCG vaccine, is composed of specially weakened tubercle bacilli.

Injected into the skin, it causes a local reaction, which confers some immunity to infection by M.
tuberculosis for several years. It has been widely used in some countries with success; its use in
young children in particular has helped to control infection in the developing world.

The main hope of ultimate control, however, lies in preventing exposure to infection, and
this means treating infectious patients quickly, possibly in isolation until they are noninfectious.
In many developed countries, individuals at risk for tuberculosis, such as health care workers, are
regularly given a skin test (see tuberculin test) to show whether they have had a primary
infection with the bacillus.

Today, the treatment of tuberculosis consists of drug therapy and methods to prevent the
spread of infectious bacilli. Historically, treatment of tuberculosis consisted of long periods,
often years, of bed rest and surgical removal of useless lungtissue. In the 1940s and ’50s
several antimicrobial drugs were discovered that revolutionized the treatment of patients with
tuberculosis. As a result, with early drug treatment, surgery is rarely needed.

The most commonly used antituberculosis drugs are isoniazid and rifampicin (rifampin).

These drugs are often used in various combinations with other agents, such
as ethambutol, pyrazinamide, or rifapentine, in order to avoid the development of drug-resistant
bacilli. Patients with strongly suspected or confirmed tuberculosis undergo an initial treatment
period that lasts two months and consists of combination therapy with isoniazid, rifampicin,
ethambutol, and pyrazinamide. These drugs may be given daily or two times per week.

The patient is usually made noninfectious quite quickly, but complete cure requires
continuous treatment for another four to nine months. The length of the continuous treatment
period depends on the results of chest X-rays and sputum smears taken at the end of the two-
month period of initial therapy. Continuous treatment may consist of once daily or twice weekly
doses of isoniazid and rifampicin or isoniazid and rifapentine.

If a patient does not continue treatment for the required time or is treated with only one
drug, bacilli will become resistant and multiply, making the patient sick again. If subsequent
treatment is also incomplete, the surviving bacilli will become resistant to several drugs.
Multidrug-resistant tuberculosis (MDR TB) is a form of the disease in which bacilli have become
resistant to isoniazid and rifampicin. MDR TB is treatable but is extremely difficult to cure,
typically requiring two years of treatment with agents known to have more severe side effects
than isoniazid or rifampicin.
 Extensively drug-resistant tuberculosis (XDR TB) is a rare form of MDR TB. XDR TB is
characterized by resistance to not only isoniazid and rifampin but also a group of bactericidal
drugs known as fluoroquinolones and at least one aminoglycoside antibiotic, such as kanamycin,
amikacin, or capreomycin. Aggressive treatment using five different drugs, which are selected
based on the drug sensitivity of the specific strain of bacilli in a patient, has been shown to be
effective in reducing mortality in roughly 50 percent of XDR TB patients. In addition, aggressive
treatment can help prevent the spread of strains of XDR TB bacilli.

In 1995, in part to prevent the development and spread of MDR TB, the World Health
Organization began encouraging countries to implement a compliance program called directly
observed therapy (DOT). Instead of taking daily medication on their own, patients are directly
observed by a clinician or responsible family member while taking larger doses twice a week.
Although some patients consider DOT invasive, it has proved successful in controlling
tuberculosis.

Despite stringent control efforts, however, drug-resistant tuberculosis remained a serious

threat in the early 21st century. In 2009, for example, researchers reported the emergence
of extremely drug-resistant tuberculosis (XXDR-TB), also known as totally drug-resistant
tuberculosis (TDR-TB), in a small subset of Iranian patients. This form of the disease, which had
also been detected in Italy (in 2003) and India (in 2011), is resistant to all first- and second-line
antituberculosis drugs.

The above discussion of tuberculosis relates to the disease caused by M. tuberculosis.
Another species, M. bovis, is the cause of bovine tuberculosis. M. bovis is transmitted
among cattle and some wild animals through the respiratory route, and it is also excreted in milk.
If the milk is ingested raw, M. bovis readily infects humans. The bovine bacillus may be caught
in the tonsils and may spread from there to the lymph nodes of the neck, where it causes
caseation of the node tissue (a condition formerly known as scrofula). The node swells under the
skin of the neck, finally eroding through the skin as a chronic discharging ulcer.

From the gastrointestinal tract, M. bovis may spread into the bloodstream and reach any
part of the body. It shows, however, a great preference for bones and joints, where it causes
destruction of tissue and eventually gross deformity. Tuberculosis of the spine, or Pott disease, is
characterized by softening and collapse of the vertebrae, often resulting in a hunchback
deformity. Pasteurization of milk kills tubercle bacilli, and this, along with the systematic
identification and destruction of infected cattle, has led to the disappearance of bovine
tuberculosis in humans in many countries.

The AIDS epidemic has given prominence to a group of infectious agents known

variously as nontuberculosis mycobacteria, atypical mycobacteria, and mycobacteria other than
tuberculosis (MOTT). This group includes such Mycobacterium species as M. avium (or M.
avium-intracellulare), M. kansasii, M. marinum, and M. ulcerans. These bacilli have long been
known to infect animals and humans, but they cause dangerous illnesses of the lungs, lymph
nodes, and other organs only in people whose immune systems have been weakened. Among
AIDS patients, atypical mycobacterial illnesses are common complications of HIV infection.
Treatment is attempted with various drugs, but the prognosis is usually poor owing to the AIDS
patient’s overall condition.

Evidence that M. tuberculosis and humans have long coexisted comes primarily from
studies of bone samples collected from a Neolithic human settlement in the eastern
Mediterranean. Genetic evidence gathered from these studies indicates that roughly 9,000 years
ago there existed a strain of M. tuberculosis similar to strains present in the 21st century.
Evidence of mycobacterial infection has also been found in the mummified remains of ancient
Egyptians, and references to phthisis, or “wasting,” occur in the writings of the Greek
physician Hippocrates.

In the medical writings of Europe through the Middle Ages and well into the industrial
age, tuberculosis was referred to as phthisis, the “white plague,” or consumption—all in
reference to the progressive wasting of the victim’s health and vitality as the disease took its
inexorable course. The cause was assumed to be mainly constitutional, either the result of an
inherited disposition or of unhealthy or dissolute living. In the first edition of Encyclopædia
Britannica (1768), it was reported that a tendency to develop “consumption of the lungs” could
tragically be expected in people who were fine, delicate, and precocious:

This is known from a view of the tender and fine vessels, and of the slender make of the
whole body, a long neck, a flat and narrow thorax, depressed scapulæ; the blood of a bright red,
thin, sharp, and hot; the skin transparent, very white and fair, with a blooming red in the cheeks;
the wit quick, subtle, and early ripe with regard to the age, and a merry chearful disposition.

Based on the stage of the disease, treatments included regular bloodletting, administration
of expectorants and purgatives, healthful diet, exercise such as vigorous horseback riding, and, in
the grim final stages, opiates. The view that tuberculosis might be a contagious disease also had
its adherents, but it was not until 1865 that Jean Antoine Villemin, an army doctor in Paris,
showed that it could be transmitted from tuberculous animals to healthy animals by inoculation.

The actual infectious agent, the tubercle bacillus, was discovered and identified in 1882
by the German physician Robert Koch. By that time the cultural status of the disease was
assured. As summarized by Dr. J.O. Affleck of the University of Edinburgh, Scotland, in the
ninth edition of Encyclopædia Britannica(1885), “Few diseases possess such sad interest for
humanity as consumption, both on account of its widespread prevalenceand its destructive
effects, particularly among the young.” Causing as much as one-quarter of all deaths in Europe,
arising with particular frequency among young adults between the ages of 18 and 35, and
bringing on a lingering, melancholydecline characterized by loss of body weight, skin pallor, and
sunken yet luminous eyes, tuberculosis was enshrined in literature as the “captain of death,” the
slow killer of youth, promise, and genius.

Prominent artists who died of consumption in the 19th century included the English
poet John Keats, the Polish composer Frédéric Chopin, and all of the Brontë sisters
(Charlotte, Emily, and Anne); in the early 20th century they were followed by the Russian
playwright Anton Chekhov, the Italian painter Amedeo Modigliani, and the German writer Franz
Kafka. Without a clear understanding of the bacterium that caused the disease, little could be
done for its victims except to isolate them in sanitariums, where cleanliness and fresh air were
thought to help the body’s natural defenses to stop or at least slow the progress of the disease.

Preventive inoculation against tuberculosis, in which live but attenuated tubercle bacilli

are used as a vaccine, was introduced in France in 1921 by bacteriologists Albert
Calmetteand Camille Guérin. The strain designated BCG (Bacillus Calmette-Guérin), of bovine
origin, became attenuated while growing on culture media containing bile. After its introduction
by Calmette, large numbers of children were vaccinated in France, elsewhere in Europe, and in
South America; after 1930 the vaccine was used on an extensive scale. In 1943–44 the
Ukrainian-born microbiologist Selman A. Waksman and his associates, working at Rutgers
University, New Jersey, U.S., discovered the potent antimicrobial agent streptomycin in
the growth medium of the soil microorganism Streptomycesgriseus.

In 1944–45 veterinarian W.H. Feldman and physician H.C. Hinshaw, working at

the Mayo Clinic in Minnesota, demonstrated its specific effect in inhibiting tuberculosis in both
animals and people. Wide clinical use of streptomycin promptly followed, eventually in
combination with other drugs to attack resistant bacilli.

In 1952 a great advance was made with the successful testing of isoniazid in the United
States and Germany. Isoniazid is the most important drug in the history of chemotherapy for
tuberculosis; other drugs were brought out in following years, pyrazinamide in 1954, ethambutol
in 1962, and rifampicin in 1963. By this time the industrialized countries were already seeing the
health benefits of economic improvement, better sanitation, more widespread education, and
particularly the establishment of public health practice, including specific measures for
tuberculosis control.

The rate of deaths from tuberculosis in England and Wales dropped from 190 per
100,000 population in 1900 to 7 per 100,000 in the early 1960s. In the United States during the
same time period, it dropped from 194 per 100,000 to approximately 6 per 100,000. In the
popular mind, tuberculosis was then a disease of the past, of the indigent, and of the Third
World.

However, in the mid-1980s the number of deaths caused by tuberculosis began to rise
again in developed countries. The disease’s resurgence was attributed in part
to complacenthealth care systems, increased immigration of people from regions where
tuberculosis was prevalent, and the spread of HIV. In addition, throughout the 1990s the number
of cases of tuberculosis increased in Africa. Global programs such as the Stop TB Partnership,
which was established in 2000, have worked to increase awareness of tuberculosis and to make
new and existing treatments available to people living in developing countries most affected by
the disease.

In the early 2000s, as a result of the rapid implementation of global efforts to combat the
disease, the epidemic in Africa slowed and incidence rates stabilized. Despite a leveling off of
per capita incidence of tuberculosis, the global number of new cases continued to rise, due to
population growth, especially in regions of Africa, Southeast Asia, and the eastern
Mediterranean. The mortality rate from tuberculosis remains between 1.6 million and 2 million
deaths per year.

What’s the Treatment for Tuberculosis?

With the proper treatment, tuberculosis (TB, for short) is almost always curable.

Doctors prescribe antibiotics to kill the bacteria that cause it. You’ll need to take them for
6 to 9 months. What medications you take and how long you’ll have to take them depends on
which works to eradicate your TB. Sometimes, antibiotics used to treat the disease don’t work.
Doctors call this "drug-resistant" TB. If you have this form of the disease, you may need to take
stronger medications for longer.

Treatment for Latent TB

There are two types of TB -- latent and active.

Depending on your risk factors, latent TB can re-activate and cause an active infection.
That’s why your doctor might prescribe medication to kill the inactive bacteria -- just in case.

These are the three treatment options:

Isoniazid (INH): This is the most common therapy for latent TB. You typically take an
isoniazid antibiotic pill daily for 9 months.

Rifampin : You take this antibiotic each day for 4 months. It’s an option if you have side
effects or contraindications to INH.

Isoniazid and rifapentine: You take both of these antibiotics once a week for 3 months
under your doctor’s supervision.

Treatment for Active TB

 If you have this form of the disease, you’ll need to take a number of antibiotics for 6 to 9
months. These four medications are most commonly used to treat it:

 Ethambutol
 Isoniazid
 Pyrazinamide
 Rifampin

Your doctor may order a test that shows which antibiotics will kill the TB strain. Based
on the results, you’ll take three or four medications for 2 months. Afterward, you’ll take two
medications for 4 to 7 months.

You’ll probably start to feel better after a few weeks of treatment. But only a doctor can
tell you if you’re still contagious. If you’re not, you may be able to go back to your daily routine.

Treatment for Drug-Resistant TB

If you have a TB strain that doesn’t respond to certain medications, you’ll need to see a
TB specialist.

What Is Tuberculosis?

Tuberculosis -- or TB, as it’s commonly called -- is a contagious infection that usually

attacks the lungs. It can also spread to other parts of the body, like the brain and spine. A type of
bacteria called Mycobacterium tuberculosis causes it.
In the 20th century, TB was a leading cause of death in the United States. Today, most
cases are cured with antibiotics. But it takes a long time. You have to take meds for at least 6 to 9
months.

Tuberculosis Symptoms

Tuberculosis Prevention

 Tuberculosis Treatment

If several types of medications don't do the job, you have what doctors call “multidrug-
resistant TB.” You’ll need to take a combination of medications for 20 to 30 months. They
include:

Antibiotics called fluoroquinolones

An injectable antibiotic, such as amikacin, kanamycin, and capreomycin

 Newer antibiotic treatments, such as linezolid and bedaquiline. These are given in
addition to other medications. Scientists are still studying these medicines.

A rare and serious type of the disease is called "extensively drug-resistant TB." This
means that many of the common medications -- including isoniazid, rifampin, fluoroquinolones,
and at least one of the antibiotics that are injected -- don't knock it out. Research shows that it
can be cured around 30% to 50% of the time.

Side Effects of Treatment

Tell your doctor right away if you have any of the following symptoms:

 Fever for 3 or more days

 Pain in the lower abdomen
 Itchiness or a rash
 Nausea, vomiting, or no appetite
 Yellowish skin or eyes
 Dark or brown urine
 Tingling, burning, or numbness of the hands and feet
 Fatigue
 Easy bruising or bleeding
 Bloody nose
 Dizziness

It’s important to take every dose of your antibiotics. Don’t stop, even if you feel better. If
you don’t kill all of the bacteria in your body, the remaining germs can adapt and become drug-
resistant.

To help you remember, your doctor may need to watch you take your medication. This is
called directly observed therapy. It’s recommended for treatment programs where you take
antibiotics a few times a week instead of every day.

Preventing the Spread of TB

If you have active TB of the lungs, you can infect other people. For that reason, your
doctor will tell you to stay home during the first few weeks of treatment, until you’re no longer
contagious. During that time, you should avoid public places and people with weakened immune
systems, like young children, the elderly, and people with HIV. You’ll have to wear a special
mask if you have visitors or need to go to the doctor’s office.
 If you go into public without a mask or don’t take your antibiotics properly, you may
become quarantined. That means you’ll live separately from people who don’t have the
infection, often in a clinic or hospital. People with dangerous strains, such as an extensively
drug-resistant TB, are also quarantined. The goal is to prevent the spread of the disease.