Tuberculosis (TB) is a potentially serious infectious disease that primarily affects your

lungs. Tuberculosis is spread from person to person through tiny droplets released into
the air. Most people who become infected with the bacteria that cause tuberculosis
don't develop symptoms of the disease.

Despite advances in treatment, TB remains a major cause of illness and death

worldwide, especially in Africa and Asia. Every year tuberculosis kills almost 2 million
people. Since the 1980s, rates of TB have increased, fueled by the HIV/AIDS epidemic
and the emergence of drug-resistant strains of the TB bacteria.

Most cases of tuberculosis can be cured by taking a combination of medications for

several months or longer. It's important to complete your whole course of therapy.

Symptoms
By Mayo Clinic staff
Although your body may harbor the bacteria that cause tuberculosis, your immune
system often can prevent you from becoming sick. For this reason, doctors make a
distinction between:

 Latent TB. In this condition, you have a TB infection, but the bacteria remain in
your body in an inactive state and cause no symptoms. Latent TB, also called inactive
TB or TB infection, isn't contagious.

 Active TB. This condition makes you sick and can spread to others.

Signs and symptoms of active TB include:

 Unexplained weight loss

 Fatigue

 Fever

 Night sweats

 Chills

 Loss of appetite
 Tuberculosis usually attacks your lungs. Signs and symptoms of TB of the lungs
include:

 Coughing that lasts three or more weeks

 Coughing up blood

 Chest pain, or pain with breathing or coughing

Tuberculosis can also affect other parts of your body, including your kidneys, spine or
brain. When TB occurs outside your lungs, symptoms vary according to the organs
involved. For example, tuberculosis of the spine may give you back pain, and
tuberculosis in your kidneys might cause blood in your urine.

When to see a doctor

See your doctor if you have a fever, unexplained weight loss, night sweats and a
persistent cough. These are often signs of TB, but they can also result from other
medical problems. Your doctor can perform tests to help determine the cause. TB can
be diagnosed by your primary care doctor or by a doctor who specializes in lung
diseases (pulmonologist) or by an infectious disease specialist. If you don't have a
doctor, your local public health department can help.

Causes
By Mayo Clinic staff
Tuberculosis is caused by an organism called Mycobacterium tuberculosis. The bacteria
spread from person to person through microscopic droplets released into the air. This
can happen when someone with the untreated, active form of tuberculosis coughs,
speaks, sneezes, spits, laughs or sings. Rarely, a pregnant woman with active TB may
pass the bacteria to her unborn child.

Although tuberculosis is contagious, it's not especially easy to catch. You're much more
likely to get tuberculosis from a family member or close co-worker than from a
stranger. Most people with active TB who've had appropriate drug treatment for at least
two weeks are no longer contagious.

TB infection vs. active TB

If you breathe TB bacteria into your lungs, one of four things might happen:
 You don't become infected with TB. Your immune system immediately
destroys the germs and clears them from your body.

 You develop latent TB infection. The germs settle in your lungs and begin to
multiply. Within several weeks, however, your immune system successfully "walls off"
the bacteria in your lungs, much like a scab forming over a wound. The bacteria may
remain within these walls for years — alive, but in a dormant state. In this case,
you're considered to have TB infection and you'll test positive on a TB skin test. But
you won't have symptoms and won't transmit the disease to others.

 You develop active TB. If your immune defenses fail, TB bacteria begin to
exploit your immune system cells for their own survival. The bacteria move into the
airways in your lungs, causing large air spaces (cavities) to form. Filled with oxygen
— which the bacteria need to survive — the air spaces make an ideal breeding
ground for the bacteria. The bacteria may then spread from the cavities to the rest of
your lungs as well as to other parts of your body.

If you have active TB, you're likely to feel sick. Even if you don't feel sick, you can still
infect others. Without treatment, many people with active TB die. Those who survive
may develop long-term symptoms, such as chest pain and a cough with bloody sputum,
or they may recover and go into remission.

 You develop active TB years after the initial infection. After you've had
latent TB for years, the walled-off bacteria may suddenly begin multiplying again,
causing active TB, also known as reactivation TB. It's not always clear what triggers
this reactivation, but it most commonly happens after your immune system becomes
weakened. Your resistance may be lower because of aging, drug or alcohol abuse,
malnutrition, chemotherapy, prolonged use of prescription medications such as
corticosteroids or TNF inhibitors, and diseases such as HIV/AIDS.

Only about one in 10 people who have TB infection goes on to develop active TB. The
risk is greatest in the first two years after infection and is much higher if you have HIV
infection.

HIV and TB
Since the 1980s, the number of cases of tuberculosis has increased dramatically
because of the spread of HIV, the virus that causes AIDS. Tuberculosis and HIV have a
deadly relationship — each drives the progress of the other.
 Infection with HIV suppresses the immune system, making it difficult for the body to
control TB bacteria. As a result, people with HIV are many times more likely to get TB
and to progress from latent to active disease than are people who aren't HIV-positive.

TB is one of the leading causes of death among people with AIDS, especially outside the
United States.  One of the first indications of HIV infection may be the sudden onset of
TB, often in a site outside the lungs.

Drug-resistant TB
Another reason TB remains a major killer is the increase in drug-resistant strains of the
bacterium. Ever since the first antibiotics were used to fight TB 60 years ago, the germ
has developed the ability to survive attack, and that ability gets passed on to its
descendants. Drug-resistant strains of TB emerge when an antibiotic fails to kill all of
the bacteria it targets. The surviving bacteria become resistant to that particular drug
and frequently other antibiotics as well. Today, for each major TB medication, there's a
TB strain that resists its treatment.

The major cause of TB drug resistance is inadequate treatment, either because the
wrong drugs are prescribed or because people don't take their entire course of
medication.

There are two types of drug-resistant TB:

 Multidrug-resistant TB (MDR TB). This form of TB can't be killed by the two

most powerful antibiotics for TB, isoniazid and rifampin. Although MDR TB can be
successfully treated, it's much harder to combat than is regular TB and requires long-
term therapy — up to two years — with drugs that are very expensive and can cause
serious side effects. People with untreated MDR TB can transmit this serious type of
TB to others.

 Extensively drug-resistant TB (XDR TB). XDR TB is a less common form of

MDR TB in which the bacteria resist isoniazid and rifampin as well as most of the
alternative or second line drugs used to treat TB. XDR TB has shown up across the
world, including 49 cases in the United States between 1993 and 2006. Treatment for
XDR TB is challenging and lengthy and leads to serious side effects and a higher rate
of failure. Recently, the first cases of completely drug-resistant TB were reported —
the bacteria could not be killed by any available TB drug.

Risk factors
 By Mayo Clinic staff
Anyone can get tuberculosis, but certain factors increase your risk of the disease. These
factors include:

 Lowered immunity. A healthy immune system can often successfully fight TB

bacteria, but your body can't mount an effective defense if your resistance is low. A
number of factors can weaken your immune system. Having a disease that
suppresses immunity, such as HIV/AIDS, diabetes, end-stage kidney disease, certain
cancers or the lung disease silicosis, can reduce your body's ability to protect itself.
Your risk is also higher if you take corticosteroids, certain arthritis medications,
chemotherapy drugs or other drugs that suppress the immune system.

 Close contact with someone with infectious TB. In general, you must spend
an extended period of time with someone with untreated, active TB to become
infected yourself. You're more likely to catch the disease from a family member,
roommate, friend or close co-worker.

 Country of origin. People from regions with high rates of TB — especially sub-
Saharan Africa, India, China, the islands of Southeast Asia and Micronesia, and parts
of the former Soviet Union — are more likely to develop TB. In the United States,
more than half the people with TB were born in a different country. Among these, the
most common countries of origin were Mexico, the Philippines, India and Vietnam.

 Age. Older adults are at greater risk of TB because normal aging or illness may
weaken their immune systems. They're also more likely to live in nursing homes,
where outbreaks of TB can occur.

 Substance abuse. Long-term drug or alcohol use weakens your immune

system and makes you more vulnerable to TB.

 Malnutrition. A poor diet or one too low in calories puts you at greater risk of
TB.

 Lack of medical care. If you are on a low or fixed income, live in a remote
area, have recently immigrated to the United States or are homeless, you may lack
access to the medical care needed to diagnose and treat TB.

 Living or working in a residential care facility. People who live or work in

prisons, immigration centers or nursing homes are all at risk of TB. That's because
the risk of the disease is higher anywhere there is overcrowding and poor ventilation.
 Living in a refugee camp or shelter. Weakened by poor nutrition and ill
health and living in crowded, unsanitary conditions, refugees are at especially high
risk of TB infection.

 Health care work. Regular contact with people who are ill increases your
chances of exposure to TB bacteria. Wearing a mask and frequent hand washing
greatly reduce your risk.

 International travel. As people migrate and travel widely, they may expose
others or be exposed to TB bacteria.

Complications
By Mayo Clinic staff
Without treatment, tuberculosis can be fatal. Drug-resistant strains of the disease are
more difficult to treat.

Untreated active disease typically affects your lungs, but it can spread to other parts of
the body through your bloodstream. Complications vary according to the location of TB
bacteria:

 Lung damage can occur if TB in your lungs (pulmonary TB) isn't diagnosed and
treated early.

 Severe pain, abscesses and joint destruction may result from TB that
infects your bones.

 Meningitis can occur if TB infects your brain and central nervous system.

 Miliary TB is TB that has spread throughout your entire body, a serious

complication.

Preparing for your appointment

By Mayo Clinic staff
If you suspect that you have tuberculosis, contact your family doctor, a general
practitioner or your state health department. You may be referred to an infectious
disease or lung specialist (pulmonologist).
 You can help your doctor by being prepared with as much information as possible.
Here's some information to help you get ready for your appointment.

What you can do

 Be aware of any pre-appointment restrictions. At the time you make the

appointment, be sure to ask if there's anything you need to do in advance. In
particular, ask if you should wear a face mask to your appointment.

 Write down any symptoms you're experiencing, including any that may
seem unrelated to the reason for which you scheduled the appointment.

 Write down key personal information, including your HIV status (if known),
country of origin, any recent travel outside the United States, contact with people
who may have tuberculosis, any past infection with TB, and any medical conditions or
diseases you have.

 Make a list of all medications, as well as any vitamins or supplements, that

you're taking.

 Take a family member or friend along, if possible. Sometimes it can be

difficult to absorb all the information provided during an appointment. Someone who
accompanies you may remember something that you missed or forgot.

 Write down questions to ask your doctor.

Your time with your doctor is limited, so preparing a list of questions ahead of time will
help you make the most of your time together. For TB, some basic questions to ask
your doctor include:

 What kinds of tests do I need?

 What is the best course of action?

 How long will my treatment last?

 What can I do to stay on track with my treatment?

 I have these other health conditions. How can I best manage them together?

 Are there any restrictions that I need to follow, especially with respect to
preventing the spread of infection?
 Should I see a specialist? What will that cost, and will my insurance cover it?

 Is there a generic alternative to the medicine you're prescribing me?

 Are there any brochures or other printed material that I can take with me? What
Web sites do you recommend?

 Will I work with a nurse or other health care provider to oversee my treatment?

 What are the side effects of my treatment?

In addition to the questions that you've prepared to ask your doctor, don't hesitate to
ask questions during your appointment at any time that you don't understand
something.

What to expect from your doctor

Your doctor is likely to ask you a number of questions. Being ready to answer them
may reserve time to go over points you want to spend more time on. Your doctor may
ask:

 When did you first begin experiencing symptoms?

 Have you been in contact with anyone who has TB?

 Were you born in another country, or have you traveled in another country?

 Have you ever had tuberculosis or a positive skin test in the past?

 What kind of work do you do?

 Do you use alcohol or recreational drugs?

 What is your typical diet?

 Do you have HIV infection or AIDS, cancer, diabetes or any other medical
condition?

Tests and diagnosis

By Mayo Clinic staff
If your doctor suspects TB, you will need a complete medical evaluation and tests for
TB infection.
 Skin test
The most commonly used diagnostic tool for TB is a simple skin test. Although there are
two methods, the Mantoux test is preferred because it's more accurate.

For the Mantoux test, a small amount of a substance called PPD tuberculin is injected
just below the skin of your inside forearm. You should feel only a slight needle prick.
Within 48 to 72 hours, a health care professional will check your arm for swelling at the
injection site, indicating a reaction to the injected material. A hard, raised red bump
(induration) means you're likely to have TB infection. The size of the bump determines
whether the test results are significant, based on your risk factors for TB.

The Mantoux test isn't perfect. A false-positive test suggests that you have TB when
you really don't. This is most likely to occur if you're infected with a different type of
mycobacterium other than the one that causes tuberculosis, or if you've recently been
vaccinated with the bacillus Calmette-Guerin (BCG) vaccine. This TB vaccine is seldom
used in the United States, but widely used in countries with high TB infection rates.

On the other hand, some people who are infected with TB — including children, older
people and people with AIDS — may have a delayed or no response to the Mantoux
test.

Blood tests
Blood tests may be used to confirm or rule out latent or active TB. These tests use
sophisticated technology to measure the immune system's reaction to Mycobacterium
tuberculosis. These tests are quicker and more accurate than is the traditional skin test.
They may be useful if you're at high risk of TB infection but have a negative response
to the Mantoux test, or if you received the BCG vaccine.

Further testing
If the results of a TB test are positive (referred to as "significant"), you may have
further tests to help determine whether you have active TB disease and whether it is a
drug-resistant strain.

These tests may include:

 Chest X-ray or CT scan. If you've had a positive skin test, your doctor is likely
to order a chest X-ray. In some cases, this may show white spots in your lungs where
your immune system has walled off TB bacteria. In others, it may reveal a nodule or
 cavities in your lungs caused by active TB. A computerized tomography (CT) scan,
which uses cross-sectional X-ray images, may show more subtle signs of disease.

 Culture tests. If your chest X-ray shows signs of TB, your doctor may take a
sample of your stomach secretions or sputum — the mucus that comes up when you
cough. The samples are tested for TB bacteria, and your doctor can have the results
of special smears in a matter of hours.

Samples may also be sent to a laboratory where they're examined under a microscope
as well as placed on a special medium that encourages the growth of bacteria (culture).
The bacteria that appear are then tested to see if they respond to the medications
commonly used to treat TB. Your doctor uses the results of the culture tests to
prescribe the most effective medications for you. Because TB bacteria grow very slowly,
traditional culture tests can take four to eight weeks.

 Other tests. Testing called nuclear acid amplification (NAA) can detect genes
associated with drug resistance in Mycobacterium tuberculosis. This test is generally
available only in developed countries.

A test used primarily in developing countries is called the microscopic-observation drug-

susceptibility (MODS) assay. It can detect the presence of TB bacteria in sputum in as
little as seven days. Additionally, the test can identify drug-resistant strains of the TB
bacteria.

What if my test is negative?

Having little or no reaction to the Mantoux test usually means that you're not infected
with TB bacteria. But in some cases it's possible to have TB infection in spite of a
negative test. Reasons for a false-negative test include:

 Recent TB infection. It can take eight to 10 weeks after you've been infected
for your body to react to a skin test. If your doctor suspects that you've been tested
too soon, you may need to repeat the test in a few months.

 Severely weakened immune system. If your immune system is compromised

by an illness, such as AIDS, or by corticosteroid or chemotherapy drugs, you may not
respond to the Mantoux test, even though you're infected with TB. Diagnosing TB in
HIV-positive people is further complicated because many symptoms of AIDS are
similar to TB symptoms.
 Vaccination with a live virus. Vaccines that contain a live virus, such as the
measles or smallpox vaccine, can interfere with a TB skin test.

 Overwhelming TB disease. If your body has been overwhelmed with TB

bacteria, it may not be able to mount enough of a defense to respond to the skin
test.

 Improper testing. Sometimes the PPD tuberculin may be injected too deeply
below the surface of your skin. In that case, any reaction you have may not be
visible. Be sure that you're tested by someone skilled in administering TB tests.

Diagnosing TB in children
It's harder to diagnose TB in children than in adults. Children may swallow sputum,
rather than coughing it out, making it harder to take culture samples. And infants and
young children may not react to the skin test. For these reasons, tests from an adult
who is likely to have been the cause of the infection may be used to help diagnose TB
in a child.

Treatments and drugs

By Mayo Clinic staff
Medications are the cornerstone of tuberculosis treatment. But treating TB takes much
longer than treating other types of bacterial infections. Normally, you take antibiotics
for at least six to nine months to destroy the TB bacteria. The exact drugs and length of
treatment depend on your age, overall health, possible drug resistance, the form of TB
(latent or active) and its location in the body.

Several promising new TB drugs are in development, and some may become available
within the next 10 years.

Treating TB infection (latent TB)

If tests show that you have TB infection but not active disease, your doctor may
recommend preventive drug therapy to destroy bacteria that might become active in
the future. You're likely to receive a daily or twice-a-week dose of the TB medication
isoniazid. For treatment to be effective, you usually take isoniazid for nine months.
Long-term use of isoniazid can cause side effects, including the life-threatening liver
disease hepatitis. For this reason, your doctor will monitor you closely while you're
taking isoniazid. During treatment, avoid using acetaminophen (Tylenol, others) and
avoid or limit alcohol use. Both increase your risk of liver damage.
 Treating active TB disease
If you're diagnosed with active TB, you're likely to begin taking four medications —
isoniazid, rifampin (Rifadin), ethambutol (Myambutol) and pyrazinamide. This regimen
may change if tests later show some of these drugs to be ineffective. Even so, you'll
continue to take several medications. Depending on the severity of your disease and
whether the bacteria are drug-resistant, one or two of the four drugs may be stopped
after a few months. You may be hospitalized for the first two weeks of therapy or until
tests show that you're no longer contagious.

Sometimes the drugs may be combined in a single tablet such as Rifater, which
contains isoniazid, rifampin and pyrazinamide. This makes your treatment less
complicated while ensuring that you get all the drugs needed to completely destroy TB
bacteria. Another drug that may make treatment easier is rifapentine (Priftin), which is
taken just once a week during the last four months of therapy, in combination with
other drugs.

Medication side effects

Side effects of TB drugs aren't common, but can be serious when they do occur. All TB
medications can be highly toxic to your liver. Rifampin can also cause severe flu-like
signs and symptoms — fever, chills, muscle pain, nausea and vomiting. When taking
these medications, call your doctor immediately if you experience any of the following:

 Nausea or vomiting

 Loss of appetite

 A yellow color to your skin (jaundice)

 Dark urine

 A fever that lasts three or more days and has no obvious cause

 Tenderness or soreness in your abdomen

 Blurred vision or colorblindness

Treating drug-resistant TB
Multidrug-resistant TB (MDR TB) can't be cured by the two major TB drugs, isoniazid
and rifampin. Extensive drug-resistant TB (XDR TB) is resistant to those drugs as well
as three or more of the second line TB drugs. Treating these resistant forms of TB is far
more costly than is treating nonresistant TB.
Treatment of drug-resistant TB requires taking a "cocktail" of at least four drugs,
including first line medications that are still effective and several second line
medications, for 18 months to two years or longer. Even with treatment, many people
with these types of TB may not survive. If treatment is successful, you may need
surgery to remove areas of persistent infection or repair lung damage.

Treating people who have HIV/AIDS

HIV-positive people are especially likely to develop active TB, and drug-resistant forms
of the disease are especially dangerous for them. What's more, the most powerful AIDS
drugs (antiretroviral therapy) interact with rifampin and other drugs used to treat TB,
reducing the effectiveness of both types of medications.

To avoid interactions, people living with both HIV and TB may stop taking antiretroviral
therapy while they complete a short course of TB therapy that includes rifampin. Or
they may be treated with a TB regimen in which rifampin is replaced with another drug
that's less likely to interfere with AIDS medications. In such cases, doctors carefully
monitor the response to therapy, and the duration and type of regimen may change
over time.

Treating children and pregnant women

Treating TB in children is largely the same as treating adults, except that ethambutol is
not used for young children because of the possible side effect of vision problems.
Instead of ethambutol, children may take streptomycin.

For pregnant women with active TB, initial treatment often involves three drugs —
isoniazid, rifampin and ethambutol. Pyrazinamide isn't recommended because its effect
on the unborn baby isn't known. Some second line TB medications also aren't
recommended.

Completing treatment is essential

After a few weeks, you won't be contagious and you may start to feel better. It might
be tempting to stop taking your TB drugs. But it is crucial that you finish the full course
of therapy and take the medications exactly as prescribed by your doctor. Stopping
treatment too soon or skipping doses can allow the bacteria that are still alive to
become resistant to those drugs, leading to TB that is much more dangerous and
difficult to treat. Drug-resistant strains of TB can quickly become fatal, especially if your
immune system is impaired.
 In an effort to help people stick with their treatment, a program called directly observed
therapy (DOT) is recommended. In this approach, a nurse or other health care
professional administers your medication so that you don't have to remember to take it
on your own. Sometimes clinics provide incentives, such as food coupons or
transportation, for people to show up for their appointments.

Prevention
By Mayo Clinic staff
In general, TB is preventable. From a public health standpoint, the best way to control
TB is to diagnose and treat people with TB infection before they develop active disease
and to take careful precautions with people hospitalized with TB. But there also are
measures you can take on your own to help protect yourself and others:

 Keep your immune system healthy. Eat plenty of healthy foods including
fruits and vegetables, get enough sleep, and exercise at least 30 minutes a day most
days of the week to keep your immune system in top form.

 Get tested regularly. Experts advise people who have a high risk of TB to get a
skin test once a year. This includes people with HIV or other conditions that weaken
the immune system, people who live or work in a prison or nursing home, health care
workers, people from countries with high rates of TB, and others in high-risk groups.

 Consider preventive therapy. If you test positive for latent TB infection, your
doctor will likely advise you to take medications to reduce your risk of developing
active TB. Vaccination with BCG isn't recommended for general use in the United
States, because it isn't very effective in adults and it causes a false-positive result on
a Mantoux skin test. But the vaccine is often given to infants in countries where TB is
more common. Vaccination can prevent severe TB in children. Researchers are
working on developing a more effective TB vaccine.

 Finish your entire course of medication. This is the most important step you
can take to protect yourself and others from TB. When you stop treatment early or
skip doses, TB bacteria have a chance to develop mutations that allow them to
survive the most potent TB drugs. The resulting drug-resistant strains are much more
deadly and difficult to treat.

To help keep your family and friends from getting sick if you have active TB:
 Stay home. Don't go to work or school or sleep in a room with other people
during the first few weeks of treatment for active TB.

 Ensure adequate ventilation. Open the windows whenever possible to let in

fresh air.

 Cover your mouth. It takes two to three weeks of treatment before you're no
longer contagious. During that time, be sure to cover your mouth with a tissue
anytime you laugh, sneeze or cough. Put the dirty tissue in a bag, seal it and throw it
away. Also, wearing a mask when you're around other people during the first three
weeks of treatment may help lessen the risk of transmission.

 Coping and support

 By Mayo Clinic staff
 Undergoing treatment for TB is a complicated and lengthy process. But the only
way to cure the disease is to stick with your treatment. You may find it helpful
to have your medication given by a nurse or other health care professional so
that you don't have to remember to take it on your own. In addition, try to
maintain your normal activities and hobbies and stay connected with family and
friends.
 Keep in mind that your physical health can affect your mental health. Denial,
anger and frustration are normal when you must deal with something difficult
and unexpected. At times, you may need more tools to deal with these or other
emotions. Professionals, such as therapists or behavioral psychologists, can
help you develop positive coping strategies.

INTRODUCTION

Pulmonary tuberculosis is an infectious disease caused by

slow- growing bacteria that resembles a fungus,
Myobacterium tuberculosis, which is usually spread from
person to person by droplet nuclei through the air. The
lung is the usual infection site but the disease can occur
elsewhere in the body. Typically, the bacteria from lesion
(tubercle) in the alveoli. The lesion may heal, leaving scar
tissue; may continue as an active granuloma, heal, then
reactivate or may progress to necrosis, liquefaction,
sloughing, and cavitation of lung tissue. The initial lesion
may disseminate bacteria directly to adjacent tissue, through the blood stream, the lymphatic
system, or the bronchi.

Most people who become infected do not develop clinical illness because the body’s immune
system brings the infection under control. However, the incidence of tuberculosis (especially
drug resistant varieties) is rising. Alcoholics, the homeless and patients infected with the human
immunodeficiency virus (HIV) are especially at risk. Complications of tuberculosis include
pneumonia, pleural effusion, and extrapulmonary disease.

ANATOMY AND PHYSIOLOGY

UPPER RESPIRATORY TRACT

Respiration is defined in two ways. In common usage, respiration refers to the act of breathing,
or inhaling and exhaling. Biologically speaking, respiration strictly means the uptake of oxygen
by an organism, its use in the tissues, and the release of carbon dioxide. By either definition,
respiration has two main functions: to supply the cells of the body with the oxygen needed for
metabolism and to remove carbon dioxide formed as a waste product from metabolism. This
lesson describes the components of the upper respiratory tract.

The upper respiratory tract conducts air from outside the body to the lower respiratory tract and
helps protect the body from irritating substances. The upper respiratory tract consists of the
following structures:
The nasal cavity, the mouth, the pharynx, the epiglottis, the larynx, and the upper trachea. The
oesophagus leads to the digestive tract.

One of the features of both the upper and lower respiratory tracts is the mucociliary apparatus
that protects the airways from irritating substances, and is composed of the ciliated cells and
mucus-producing glands in the nasal epithelium. The glands produce a layer of mucus that traps
unwanted particles as they are inhaled. These are swept toward the posterior pharynx, from
where they are either swallowed, spat out, sneezed, or blown out.

Air passes through each of the structures of the upper respiratory tract on its way to the lower
respiratory tract. When a person at rest inhales, air enters via the nose and mouth. The nasal
cavity filters, warms, and humidifies air. The pharynx or throat is a tube like structure that
connects the back of the nasal cavity and mouth to the larynx, a passageway for air, and the
esophagus, a passageway for food. The pharynx serves as a common hallway for the respiratory
and digestive tracts, allowing both air and food to pass through before entering the appropriate
passageways.

The pharynx contains a specialised flap-like structure called the epiglottis that lowers over the
larynx to prevent the inhalation of food and liquid into the lower respiratory tract.

The larynx, or voice box, is a unique structure that contains the vocal cords, which are essential
for human speech. Small and triangular in shape, the larynx extends from the epiglottis to the
trachea. The larynx helps control movement of the epiglottis. In addition, the larynx has
specialised muscular folds that close it off and also prevent food, foreign objects, and secretions
such as saliva from entering the lower respiratory tract

LOWER RESPIRATORY TRACT

The lower respiratory tract begins with the trachea, which is just below the larynx. The trachea,
or windpipe, is a hollow, flexible, but sturdy air tube that contains C-shaped cartilage in its walls.
The inner portion of the trachea is called the lumen.

The first branching point of the respiratory tree occurs at the lower end of the trachea, which
divides into two larger airways of the lower respiratory tract called the right bronchus and left
bronchus. The wall of each bronchus contains substantial amounts of cartilage that help keep the
airway open. Each bronchus enters a lung at a site called the hilum. The bronchi branch
sequentially into secondary bronchi and tertiary bronchi.

The tertiary bronchi branch into the bronchioles. The bronchioles branch several times until they
arrive at the terminal bronchioles, each of which subsequently branches into two or more
respiratory bronchioles.

The respiratory bronchiole leads into alveolar ducts and alveoli. The alveoli are bubble-like,
elastic, thin-walled structures that are responsible for the lungs’ most vital function: the exchange
of oxygen and carbon dioxide.
Each structure of the lower respiratory tract, beginning with the trachea, divides into smaller
branches. This branching pattern occurs multiple times, creating multiple branches. In this way,
the lower respiratory tract resembles an “upside-down” tree that begins with one trachea “trunk”
and ends with more than 250 million alveoli “leaves”. Because of this resemblance, the lower
respiratory tract is often referred to as the respiratory tree.

In descending order, these generations of branches include:

 trachea
 right bronchus and left bronchus
 secondary bronchi
 tertiary bronchi
 bronchioles
 terminal bronchioles
 respiratory bronchioles
 alveoli

THE LUNGS

The thoracic cage, or ribs, and the diaphragm bound the thoracic cavity. There are two lungs that
occupy a significant portion of this cavity.
The diaphragm is a broad, dome-shaped muscle that separates the thoracic and abdominal
cavities and generates most of the work of breathing. The inter-costal muscles, located between
the ribs, also aid in respiration. The internal intercostal muscles lie close to the lungs and are
covered by the external intercostal muscles.

The lungs are cone-shaped organs that are soft, spongy and normally pink. The lungs cannot
expand or contract on their own, but their softness allows them to change shape in response to
breathing. The lungs rely on expansion and contraction of the thoracic cavity to actually generate
inhalation and exhalation. This process requires contraction of the diaphragm.

To facilitate the movements associated with respiration, each lung is enclosed by the pleura, a
membrane consisting of two layers, the parietal pleura and the visceral pleura.

The parietal pleura comprise the outer layer and are attached to the chest wall. The visceral
pleura are directly attached to the outer surface of each lung. The two pleural layers are separated
by a normally tiny space called the pleural cavity. A thin film of serous or watery fluid called
pleural fluid lines and lubricates the pleural cavity. This fluid prevents friction and holds the
pleural surfaces together during inhalation and exhalation.

PREDISPOSING FACTORS

1. Malnutrition
2. Overcrowding
3. Alcoholism
4. Ingestion of infected cattle
5. Virulence
6. Over fatigue

SIGNS AND SYMPTOMS

1. Productive Cough – yellowish in color

2. Low fever
3. Night sweats
4. Dyspnea
5. Anorexia, general body malaise, weight loss
6. Chest/back pain
7. Hemoptysis

PATHOPHYSIOLOGY
TB results from infection by any of the TB complex mycobacteria, including Mycobacterium
tuberculosis, M bovis, M africanum, M microti, and M canetti.5

TB can be divided into primary, progressive-primary, and postprimary forms on the basis of the
natural history of the disease. Postprimary TB results from either reactivation of a latent primary
infection or, less commonly, from the repeat infection of a previously sensitized host. The term
“postprimary” is preferred to “reactivation” when referring to the clinical diagnosis because
firmly distinguishing recurrence from an antecedent infection is impossible in most cases.
Approximately 10% of all infected patients are likely to develop reactivation, and the risk is
highest within the first 2 years or during periods of immunosuppression.

The major determinants of the type and extent of TB disease are the patient’s age and immune
status, the virulence of the organism, and the mycobacterial load. Postprimary TB is typically a
disease of adolescence and adulthood that results from reactivation of an initially contained
infection by a TB complex mycobacterium. Pulmonary reactivation usually occurs in the apical
and posterior segments of the upper lobes or in the superior segments of the lower lobes.This
distribution may be related to the higher oxygen tension or the reduced perfusion and lymphatic
clearance in these lung segments.

DIAGNOSTIC EVALUATION

 Sputum smear – detection of the acid fast bacilli in stained smears is the first bacteriologic clue
of TB. Obtain first morning sputum on 3 consecutive days.
 Sputum culture – a positive culture for M. tuberculosis confirms a diagnosis of TB.
 Chest X-ray – to determine presence and extent of disease.
 Tuberculin skin test (purified protein derivative or Mantoux test) – inoculation of tubercle
bacillus extract (tuberculin) into the intradermal layer of the inner aspect of the forearm.
 Nonspecific screening test – such as multiple puncture tests (tine test), should not be used to
determine if a person is infected.
MEDICATION

 A combination of drugs to which the organisms are susceptible is given to destroy viable
bacilli as rapidly as possible and to protect against the emergence of drug resistant
organism.

 Current recommended regimen of uncomplicated, previously untreated pulmonary

tuberculosis is an initial phase of 2 months of bacterial drugs, including isoniazid (INH),
rifampin ( Rifadin), pyrazinamide (PZA), and ethambutol (EMB). This regimen should be
followed until the results of drug susceptibility studies are available, unless there is little
possibilityn of drug resistance.

a. If drug susceptibility results are known and organism is fully susceptible, ethambutol
does not need to be included.

b. For children whose visual acuity cannot be monitored, ethambutol is not normally
recommended except with increased likelihood of isoniazid resistance or if the child
has upper lobe infiltration and or cavity formation of TB.
 c. Due to increasing frequency of global streptomycin reistance, streptomycin is not
considered interchangeable with ethambutol unless organism is known to be
susceptible to streptomycin.

ScienceDaily (July 15, 2008) — People with diabetes mellitus are at increased
risk of developing active tuberculosis (TB), according to an analysis published
in PLoS Medicine.

See Also:

Health & Medicine

 Diabetes
 Hormone Disorders
 Wounds and Healing
 Tuberculosis
 Chronic Illness
 Health Policy

Reference

 Diabetes mellitus type 2

 Blood sugar
 Diabetic diet
 Diabetes mellitus type 1

Searching for research over the past four decades containing data on the relationship
between diabetes and TB, Christie Jeon and Megan Murray of the Harvard School of
Public Health identified 13 studies involving more than 1.7 million participants, including
17,698 cases of TB.

Combining the data from cohort studies in particular, the researchers calculated that
diabetes increases the risk of active TB by about a factor of three.

A three-fold increased risk suggests that diabetes may already be responsible for more
than 10% of TB cases in India and China. If these findings are replicated in other
countries, global TB control might benefit from special attention to people with diabetes
when identifying and treating latent TB.
Increased efforts to diagnose and treat diabetes might also decrease the global burden
of TB, which kills about 1.6 million people each year.

Type 2 Diabetes and the Risk of Tuberculosis

From Debra Manzella, R.N., former About.com Guide

Updated February 02, 2009

About.com Health's Disease and Condition content is reviewed by our Medical Review Board

See More About:

 diabetes complications
 chronic illness
 tuberculosis

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People who have type 2 diabetes might be at greater risk for contracting tuberculosis (TB) than people
who don't have diabetes, according to recent research from the University of Texas School of Public
Health Brownsville Regional Campus (UTSPH).

A press release from UTSPH outlines results from 3 new studies:

 Type 2 diabetes, especially Type 2 diabetes involving chronic high blood sugar, is associated
with altered immune response to TB, and this was particularly marked in patients with chronically
high blood sugar.
 Patients with diabetes and TB take longer to respond to anti-TB treatment.
 Patients with active tuberculosis and Type 2 diabetes are more likely to have multi-drug
resistant TB.

There has been a known link between tuberculosis and diabetes for several years. In 1997, a study
from Columbia University appeared in the American Journal of Public Health, which named diabetes as
a risk factor for tuberculosis.

With the results of these new studies from UTSPH, Joseph B. McCormick, M.D., regional dean, is
quoted as saying, "It opens a door to doing something about it," said McCormick, the university's
James H. Steele Professor. "We can educate physicians and offer more TB screenings. We have an
opportunity to make sure patients are diagnosed correctly and that there is no delay in diagnosis."

What can you do, as a person with diabetes, to protect yourself from a disease like
tuberculosis?

 Keep good control of your blood sugar levels. The risk of tuberculosis goes up when
hyperglycemia is uncontrolled.
 Because TB is an airborne disease it is difficult to protect yourself from it. If an infected person
coughs, sneezes or otherwise expels respiratory secretions into the air, it places others at risk for
inhaling the droplets and contracting the disease. Places that are over-crowded with little
ventilation are more likely to contribute to the spread of TB.

There is a vaccine, called the BCG vaccine, that is used for TB prevention in developing countries, but
it is usually given at birth. When used in adults, it doesn't have a good success rate and can even
interfere with the results of a TB test.

If you have diabetes and a chronic cough, ask to be tested for tuberculosis, especially if you have
recently been to, or live in, an area where the rate of tuberculosis is high.

Symptoms of tuberculosis include:

 Cough
 Chest pain
 Coughing up blood or bloody sputum
 Nausea
 Fatigue
 Weakness
 Rapid weight loss
 Fever
 Night sweats
 Background
 Tuberculosis (TB) remains a major cause of mortality in developing countries, and in these
countries diabetes prevalence is increasing rapidly. Diabetes increases the risk of TB. Our aim
was to assess the potential impact of diabetes as a risk factor for incident pulmonary
tuberculosis, using India as an example.
 Methods
 We constructed an epidemiological model using data on tuberculosis incidence, diabetes
prevalence, population structure, and relative risk of tuberculosis associated with diabetes. We
evaluated the contribution made by diabetes to both tuberculosis incidence, and to the
difference between tuberculosis incidence in urban and rural areas.
 Results
 In India in 2000 there were an estimated 20.7 million adults with diabetes, and 900,000
incident adult cases of pulmonary tuberculosis. Our calculations suggest that diabetes
accounts for 14.8% (uncertainty range 7.1% to 23.8%) of pulmonary tuberculosis and 20.2%
(8.3% to 41.9%) of smear-positive (i.e. infectious) tuberculosis.
 We estimate that the increased diabetes prevalence in urban areas is associated with a 15.2%
greater smear-positive tuberculosis incidence in urban than rural areas – over a fifth of the
estimated total difference.
 Conclusion
 Diabetes makes a substantial contribution to the burden of incident tuberculosis in India, and
the association is particularly strong for the infectious form of tuberculosis. The current
diabetes epidemic may lead to a resurgence of tuberculosis in endemic regions, especially in
urban areas. This potentially carries a risk of global spread with serious implications for
tuberculosis control and the achievement of the United Nations Millennium Development
Goals.
 Background
 Tuberculosis remains a leading cause of death globally. In 2005 there were an estimated 8.8
million new cases of tuberculosis worldwide, with 1.9 million of those occurring in India[1].
Incidence of tuberculosis is greatest among those with conditions impairing immunity[2], such
as human immunodeficiency virus (HIV) infection and diabetes. The consequences of
mismanagement of tuberculosis in a patient with diabetes can be severe, but there are simple
and immediate opportunities for improving treatment success and reducing mortality.
 The global burden of diabetes is increasing, and recent estimates highlight the importance of
this disease in India. There were an estimated 20–30 million people in India with diabetes in
2000 (estimates vary with study methodology) [3,4], and projections suggest prevalence will
rise to almost 80 million people by 2030[4]. It is possible that in areas of high diabetes
prevalence the impact of this diabetes epidemic[4] on tuberculosis could be as great as that of
HIV[5], and the spread of HIV is one of the main reasons why targets set by the Stop TB
Partnership (within the framework of the Millennium Development Goals) will not be met in
several regions, at least at current rates of progress[6]. However, the overall importance of
diabetes as a risk factor for tuberculosis is still largely unknown, although a recent analysis in
Mexico concluded that, in the population studied, 25% of pulmonary tuberculosis was
attributable to diabetes[5].
 Our objective was to estimate the population-level impact of diabetes on the incidence of
pulmonary tuberculosis in India. We chose India as an illustrative example because of its large
population size, the availability of relatively good data on both diabetes and tuberculosis, and
because the latter indicate that both these conditions are major public health problems there.
We also aimed to evaluate the contribution made by diabetes to the higher tuberculosis
incidence in urban compared with rural populations.
 Methods
 Epidemiological data
 Data were extracted from the sources below, as summarised in Table 1. Analyses were limited
to the adult population aged 25 years and over, as estimates of diabetes prevalence and the
 relative risks of incident tuberculosis associated with diabetes were available for this age
group only.
 Table 1. Summary of epidemiological data used to evaluate the importance of
diabetes as a risk factor for tuberculosis in India in 2000 for adults aged 25 years and
over
 Diabetes Prevalence
 Several sources of diabetes prevalence data are available for India [3,7,11]; however, we
used data from the Prevalence of Diabetes in India Study (PODIS)[3], as it was the largest
study and the only one to ascertain urban and rural prevalences separately. PODIS is a
population-based study of 18,363 participants (9,008 men, 9,355 women) aged ≥ 25 years in
77 centres throughout India. As PODIS reported no sex difference in crude diabetes
prevalence, we applied the same age-specific prevalence estimates to men and women.
 Numbers of diabetes cases in India were estimated by multiplying age-specific diabetes
prevalence estimates from PODIS by the age- and sex-specific United Nations population
estimates for India in 2000[12].
 Tuberculosis Incidence
 Tuberculosis case-notification data are routinely sent to the World Health Organization from
the Revised National Tuberculosis Control Programme (RNTCP) in India. As the programme
does not yet detect all new TB cases arising each year, the distribution of reported smear-
positive cases by age and sex was used with the WHO crude estimate[1] (all ages, both sexes)
of smear-positive tuberculosis incidence in India in 2000 to calculate the total number of
smear-positive cases by age and sex. The percentage of new smear-positive cases occurring in
each age/sex group was calculated by dividing the RNTCP-reported number of cases in each
group by the total reported incidence.
 RNTCP notifications only include information on age and sex for smear-positive cases. Age-
and sex-specific incidences of total pulmonary tuberculosis (smear-positive plus smear-
negative) were therefore calculated from the estimates for smear-positive incidences
calculated previously. We adjusted for the difference in age distribution of smear-negative and
smear-positive tuberculosis incidence by dividing the age- and sex-specific smear-positive
incidence estimates by the age-specific ratios of smear-positive to total pulmonary
tuberculosis[13]. We then calculated the overall incidence of total pulmonary tuberculosis in
the population using the WHO estimate for total tuberculosis incidence in the population
(smear-positive, smear-negative and extra-pulmonary)[1] and estimating that 20% of
incident tuberculosis is extrapulmonary [14-16]. The adjusted age- and sex-specific incidences
were then each multiplied by the ratio of the WHO-estimated crude incidence to the sum of
the individual incidences, to ensure that the sum of the age- and sex-specific incidences was
equal to the overall WHO crude incidence estimate.
 Relative risk for tuberculosis associated with diabetes
 We obtained age-specific relative risks for the association between diabetes and incident
tuberculosis (for total pulmonary tuberculosis and smear-positive tuberculosis separately)
from a study of 814,713 Korean civil servants[17]. As separate age-specific relative risks were
not reported for men and women, we applied the same estimates to both sexes.
 This is the only large-scale prospective study quantifying the diabetes-associated risk of
incident tuberculosis (reactivation was excluded by baseline chest x-ray) within a single
population. The only study we found at the time of undertaking the analyses which had been
undertaken in India had a small sample size and was cross-sectional in design, so was less
precise and could not account for temporal associations and does not provide age specific
relative risk estimates,[18] Recently a case control study of risk factors for TB has been
 published from India in which known diabetes was ascertained by questionnaire[19], but this
only provides a single, all ages, estimate of relative risk.
 Population
 Age- and sex-specific estimates of the resident Indian population in 2000 were obtained from
UN World Population Prospects, 2004 revision[12].
 Statistical calculations
 Estimates of diabetes prevalence, tuberculosis incidence and the relative risk of tuberculosis
incidence associated with diabetes were applied to age- and sex-specific estimates of the
Indian population to calculate the Attributable Fraction (Population)[20] (see below). We
calculated crude estimates of the AF(P) using data for tuberculosis incidence and diabetes
prevalence for the overall population, as well as estimates stratified by age and sex. The
published 95% confidence intervals for the relative risks were used to derive upper and lower
bounds for the AF(P) estimates.
 We estimated the proportion of tuberculosis attributable to diabetes among those with
diabetes using the Attributable Fraction (Exposed)[20] (see below) for smear-positive and
total pulmonary tuberculosis. Age-adjusted relative risks and 95% confidence intervals were
calculated using Mantel-Haenszel methods.
 Attributable fractions: definitions and formulae
 We used the following definitions and formulae for attributable fractions.
 Attributable Fraction (Population)
 The proportion by which the incidence rate of the outcome of interest (here, incident
tuberculosis) in the entire population would theoretically be reduced if the exposure of interest
(here, diabetes) were eliminated.


 where Pe is the prevalence of the exposure and RR is the relative risk for the outcome of
interest.
 Attributable Fraction (Exposed)
 The proportion by which the incidence rate of the outcome of interest (here, incident
tuberculosis) in the exposed population would theoretically be reduced if the exposure of
interest (here, diabetes) were eliminated.


 where RR is the relative risk for the outcome of interest.
 Urban/rural distribution
 We aimed to estimate the contribution made by diabetes to the higher tuberculosis incidence
observed in urban as compared with rural populations. We approached this by calculating the
theoretical urban and rural tuberculosis incidences which would be expected from the
distribution of diabetes prevalence and the diabetes-associated relative risk for developing
tuberculosis. This initially required partitioning tuberculosis incidence across the populations
with and without diabetes. We defined the equation:
 TBT = [TBND × RR × PDIA] + [TBND × (1 - PDIA)],
 where TBT is the total tuberculosis incidence rate, TB ND is tuberculosis incidence in the sub-
population without diabetes, RR is the relative risk of incident tuberculosis for diabetes, and
PDIA is the prevalence of diabetes. This equation was used to estimate tuberculosis incidence in
the populations with and without diabetes by solving mathematically for TB ND. Tuberculosis
incidence in the population with diabetes is TBND × RR. Theoretical urban and rural tuberculosis
 incidences were then calculated using the equation above with the urban and rural diabetes
prevalences reported by PODIS[3]. For comparison, urban and rural tuberculosis incidences
were also calculated using recent measurements of the annual risk of tuberculosis
infection[21] and Styblo's equation[22], which has been shown to be applicable within
India[23].
 Prevalence of diabetes among tuberculosis patients
 The prevalence of diabetes among people with tuberculosis was estimated by calculating the
number of tuberculosis cases in the populations with and without diabetes, and hence the
percentage of cases with diabetes. Numbers of tuberculosis cases were calculated by
multiplying age-specific estimates of tuberculosis incidence and of diabetic and non-diabetic
population size. Age-specific tuberculosis incidences in the populations with and without
diabetes were estimated using the same methods described under Urban/rural distribution.
 All calculations were carried out in Microsoft Excel 2003.
 Results
 In India in 2000 there were an estimated 481,573,000 people over the age of 25 (12). Among
these, 4.3% (20,707,639) had diabetes (3), and 939,064 developed pulmonary tuberculosis,
of which 575,900 were smear-positive and hence infectious (Table 1).
 Population impact of diabetes on tuberculosis
 We estimate that diabetes accounted for 14.8% (7.1% to 23.8% – upper and lower bounds
based on relative risk 95% confidence intervals) of incident pulmonary tuberculosis in India in
2000, equating to 139,000 (67,000 to 224,000) cases. We estimated the proportion of
incident smear-positive tuberculosis due to diabetes to be 20.2% (8.3% to 41.9%), or
116,000 (48,000 to 241,000) cases (Table 2).
 Table 2. Fraction of tuberculosis attributable to diabetes in India in 2000 in the adult
population aged 25 years and over
 In the sub-population of the estimated 20.7 million adults with diabetes in India, our
calculations indicate that diabetes accounts for 80.5% (39.9% to 93.7%) of the 172,000
annual incident cases of pulmonary tuberculosis, and 85.9% (65.9% to 94.2%) of the 135,000
cases of smear-positive (i.e. infectious) tuberculosis (Table 3).
 Table 3. Proportion of tuberculosis attributable to diabetes in the subpopulation of
people with diabetes
 Urban/Rural differences
 Our calculations suggest that the increased prevalence of diabetes in urban areas is associated
with a 15.2% greater smear-positive tuberculosis incidence and a 10.8% greater total
pulmonary tuberculosis incidence in urban compared with rural areas. We estimate that the
incidence of smear-positive tuberculosis in urban areas is in fact 69.2% greater than that in
rural areas, from calculations using measurements of the annual risk of tuberculosis infection,
suggesting that diabetes accounts for approximately a fifth of the total difference.
 Prevalence of diabetes among tuberculosis patients
 We predict that in India 18.4% (12.5% to 29.9%) of people with pulmonary tuberculosis (both
smear-positive and smear-negative) have diabetes, and that in the smear-positive group
diabetes prevalence is 23.5% (12.1% to 44%).
 Discussion
 Our findings suggest that a substantial proportion of incident tuberculosis in India is
attributable to diabetes;14.8% of pulmonary tuberculosis and 20.2% of smear-positive – i.e.
infectious – tuberculosis. They also suggest that diabetes is present in 18.4% of adults in
India with pulmonary tuberculosis and in 23.5% of those with smear-positive tuberculosis,
 despite a national adult diabetes prevalence of 4.3%. This result is comparable to that of a
recent study in Mexico, which found a diabetes prevalence of 35% among tuberculosis
patients in a district with an adult diabetes prevalence of 5.3%[5].
 Estimates of the urban/rural distribution of the annual risk of tuberculosis infection suggest
that, on average, smear-positive tuberculosis incidence in India is 69.2% higher in urban
compared with rural areas. Crowded living conditions in urban districts are one possible factor.
However, the increased prevalence of diabetes in urban areas may also play a role – according
to our calculations, diabetes is responsible for the urban incidence of smear-positive
tuberculosis being 15.2% greater than that in rural areas, or approximately a fifth of the total
difference. Our results suggest therefore that the increased diabetes prevalence associated
with the rapid urbanization taking place in India has important implications for tuberculosis
control.
 Our findings are subject to the general caveats applied to attributable risk estimates, for
example that we assume a causal association, that other risk factors for tuberculosis are
equally distributed across those with and without diabetes, and that those made more
susceptible to infection by diabetes are fully exposed to the tuberculosis risk. One underlying
risk factor for tuberculosis that may not be equally distributed between those with and without
diabetes in India is poverty. Consistent with this a recent case control study from India of risk
factors for TB found a univariate odds ratio of 1.8 for previously diagnosed diabetes, which
strengthened to 2.44 when controlling for other risk factors, including low socio economic
status[19]. However, even allowing for an uneven distribution in other risk factors between
those with and without diabetes our attributable risk estimates may well be conservative
because our prevalence figures for diabetes are conservative. A large study measuring the
prevalence of diabetes in urban areas in India reported that 12.1% of adults had diabetes[10],
compared with an urban prevalence of 5.6% found by the study used in our calculations[3].
Recalculating the Attributable Fraction (Population) using this higher value suggests that in
urban areas this could be as high as 33.3% (7.4% to 64.2%) for pulmonary tuberculosis and
42.5% (19.0% to 66.2%) for smear-positive tuberculosis. Additionally, we have not
considered the contribution to tuberculosis risk from hyperglycaemia below the diabetic
threshold. Published data on the association between non-diabetic hyperglycaemia and
tuberculosis are rare. However, a recent case control study from Indonesia[24] reported an
odds ratio for the risk of tuberculosis associated with impaired fasting glucose (4.2, 95% CIs
1.5–11.7) as similar to that for diabetes (4.7, 2.7 – 8.1). The prevalence of impaired fasting
glucose and of impaired glucose tolerance tend to be similar to or higher than the prevalence
of diabetes[8,10], and thus the overall impact of hyperglycaemia may be even higher than our
estimates presented here suggest. Population-level measures for managing hyperglycaemia
may potentially be cost-effective simply in terms of their benefit to tuberculosis control.
 Limitations and strengths
 A consequence of using separate studies for the different estimates used in our calculations is
an inability to account for the inherent biases of each contributing study. However, so long as
each of the studies is independently valid, this does not invalidate our conclusions as long as
the assumptions involved are clearly understood.
 In deciding on which study to use for the relative risk estimates we searched thoroughly for
studies describing the association between tuberculosis and diabetes, and have critically
reviewed these studies elsewhere [25]. There is consistent evidence from a number of studies,
with different designs and from geographically diverse areas that diabetes is associated with
an increased risk of tuberculosis, with an overall increased risk around 1.5 to 8 times higher.
However, there are several limitations in the published studies, concerning in particular
 sample size, the case definitions used for diabetes and tuberculosis, the assessment and
control for potential confounders and the fact that most do not provide age specific relative
risks or odds ratios[25].
 We chose to use relative risk estimates from the study in Korea[17] for several reasons.
Firstly, the lack of robust studies reporting age specific relative risk estimates on the
association between diabetes and TB from India meant that we had to look elsewhere.
Secondly, the study from Korea is the only genuine prospective cohort study on this topic in
the past 20 years, and thirdly it is one of only two studies we found that provided age specific
relative risk estimates. In addition, based on chest X-rays at baseline the study was able
exclude reactivation of pulmonary TB and assess the association of diabetes with new cases. It
is, however, important to acknowledge the study's shortcomings. In particular the definition of
diabetes was based on unconventional glucose cut points (i.e. 150 mg/dl for fasting and 180
mg/dl post prandial – as opposed to 140 and 200 mg/dl respectively as recommended by
WHO at that time). In addition, the diagnosis of diabetes was based on glucose measurement
at one point in time, rather than repeated measurements to confirm the diagnosis. This is
common to virtually all epidemiological studies of diabetes but is likely to result in significant
misclassification of cases of diabetes due to a mixture of biological variation in blood glucose
levels and measurement error. It is likely that this led to an underestimate of the association
between diabetes and tuberculosis. The crude prevalence of diabetes was low, being 1.2% in
men and only 0.2% in women, and there were only 3 women with diabetes (out of 320) who
developed TB, and thus sex and age specific relative risk estimates were not available. A
further limitation is that there are likely to be underlying confounding factors that we have not
accounted for. One of these is smoking, which is implicated as a risk factor for both diabetes
and tuberculosis. Further work could include adjusting the diabetes-associated risk of
tuberculosis incidence for the effect of smoking.
 Nonetheless the study was large and well-structured, similar age specific relative risk
estimates were found by a group working in Mexico[5], and the physiological mechanisms
underlying diabetes-associated susceptibility are unlikely to vary between populations.
 Our finding that diabetes is more strongly related to smear positive than smear negative TB
reflects the greater relative risks of diabetes for this form of TB found in the study from Korea
(see table 1). This relatively greater association between diabetes and smear positive TB
compared to smear negative pulmonary TB, has been found in most, but not all, studies that
have addressed this issue [25]
 The strengths of our study are that the estimates used are taken from reliable, published
sources, chosen after a consideration of the available options, and we explore a new
hypothesis using a straightforward and transparent method. Further, our study represents the
first attempt we are aware of to quantify the population impact of diabetes on tuberculosis in
India.
 Implications
 Currently, the future impact of tuberculosis control programmes is predicted from knowledge
of the effects of chemotherapy and how it is modified by the HIV epidemic. The findings we
report indicate that diabetes also has a considerable effect on tuberculosis epidemiology, and
so it is important to adapt tuberculosis programme forecasts to incorporate additional risk
factors.
 The importance of the association between diabetes and tuberculosis is highlighted by the
immediate relevance to the UN Millennium Development Goals, as it offers opportunities for
reducing the death rate from tuberculosis, and improving its detection and treatment. It is
widely recognised that HIV makes a substantial contribution to the global tuberculosis crisis. It
 is also known that cooperation to target HIV and tuberculosis simultaneously is crucial for the
control of both diseases. In India, HIV accounts for 3.4% of adult tuberculosis incidence[2];
the proportion we estimate to be attributable to diabetes is 14.8%. The impact of diabetes on
tuberculosis is therefore already considerable, and the predictions of a diabetes epidemic
suggest this is likely to escalate.
 In the past, an association between tuberculosis and diabetes was widely accepted. Indeed,
half a century ago expert clinics were established for "tuberculous diabetics" and appeared to
be successful in reducing the otherwise high mortality rate[26]. Today, however, the potential
public health and clinical importance of this relationship seems to be largely ignored. For
example, national clinical and policy guidance in the UK on the control of tuberculosis does not
consider the relationship with diabetes[27]. The World Health Organization's new "Stop TB
Strategy" refers to the problem of TB in "high-risk groups" including people with diabetes[28],
but WHO has not yet made specific recommendations concerning the relationship between the
two conditions. The recently published international standards for TB care give only cursory
mention to diabetes [29,30]. There are, however, some guidelines, such as those from
American Thoracic Society[31], which explicitly recommend screening for latent tuberculosis in
patients with diabetes and a low threshold of investigation for tuberculosis in people with
diabetes with unexplained symptoms. There is a need for new research to guide policy and
practice in this area. This includes the need for robust studies of the association between the
two conditions, particularly from parts of the world such as India where diabetes is increasing
rapidly and TB remains highly endemic. There is evidence that people with TB and diabetes
have worse TB outcomes than those without diabetes[25]. For example, a study from
Indonesia found that people with diabetes are more than twice as likely to remain sputum
culture positive at the end of treatment[32]. The potential impact of diabetes on the success
of TB treatment and hence appropriate treatment strategies for those with the two diseases
deserves investigation in other parts of the world. Another area worthy of investigation is the
potential cost effectiveness of screening people with diabetes for TB in highly endemic areas
where diabetes is now common.
 Conclusion
 We have illustrated, using data from India, that diabetes makes a substantial contribution to
tuberculosis incidence. The current diabetes epidemic may lead to a resurgence of tuberculosis
in endemic regions, especially in urban areas. This has potentially serious implications for
tuberculosis control, and it must become a priority to use this knowledge to initiate focused
and coordinated action, including new research in parts of the world where diabetes is
epidemic and TB endemic to properly inform public health and clinical practice. It is time that
the "unhealthy partnership" [33]of tuberculosis and diabetes receives the attention it
deserves.