Self-Study Modules on Tuberculosis
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3: Diagnosis of Tuberculosis Infection and Disease
Diagnosis of TB Infection: The Tuberculin
The tuberculin skin test is used to determine whether a person has
TB infection. In this test, a substance called tuberculin is injected
into the skin. Tuberculin is protein derived from
tubercle bacilli that have been killed by heating. In most people
who have TB infection, the immune system will recognize the tuberculin
because it is similar to the tubercle bacilli that caused infection.
This will cause a reaction to the tuberculin. Tuberculin is used for
diagnosing TB infection; it is not a vaccine.
Tuberculin testing is useful for
Different types of tuberculin tests are available, such as the Mantoux
tuberculin skin test and the multiple-puncture test. The
Mantoux tuberculin skin test is the preferred type because it is the
- Examining a person who is not sick but who may have
TB infection,such as a person who has been exposed to
someone who has TB. In fact, the tuberculin skin test is the only
way to diagnose TB infection before the infection has progressed
to TB disease.
- Screening groups of people for TB infection
- Examining a person who has symptoms of TB disease
The Mantoux skin test is given by using a needle and syringe to inject
0.1 ml of 5 tuberculin units of liquid tuberculin
between the layers of the skin (intradermally), usually on the forearm
(Figure 3.1). A tuberculin unit is a standard strength of tuberculin.
The tuberculin used in the Mantoux skin test is also known as purified
protein derivative, or PPD. For this reason,
the tuberculin skin test is sometimes called a PPD skin
With the Mantoux skin test, the patient's arm is examined 48 to
72 hours after the tuberculin is injected. Most people with
TB infection have a positive reaction to the tuberculin.
The reaction is an area of induration (swelling
that can be felt) around the site of the injection. The diameter
of the indurated area is measured across the forearm (Figure 3.2);
erythema (redness) around the indurated area is
not measured, because the presence of erythema does not indicate
that a person has TB infection (Figure 3.3).
Figure 3.1 Giving the Mantoux tuberculin skin test. This
is a picture of the administration of the Mantoux skin test.
Figure 3.2 Only the induration is being measured. This is CORRECT.
This is a picture of the correct reading of the tuberculin skin
test when only the induration is measured.
Figure 3.3 The erythema is being measured. This is INCORRECT.
This is a picture of the incorrect reading of the tuberculin skin
test when the erythema is measured.
Multiple-puncture tests (for example, the Tine test) are done by
puncturing the skin of the forearm with a set of short prongs or
tines coated with tuberculin. Multiple-puncture tests are easy to
give, and they are convenient because they do not require a needle
and syringe. However, in the multiple-puncture test the amount of
tuberculin that actually enters the skin cannot be measured. Because
the amount of tuberculin can always be measured during a Mantoux
test, this type of test is more accurate, and it is the preferred
Positive reactions to multiple-puncture tests should always
be confirmed with a Mantoux test (except when there is
blistering at the site of the injection).
|Study Questions 3.1-3.2
3.1. What is
the tuberculin skin test used for?
3.2. How is the Mantoux tuberculin skin test given?
|Study Questions 3.3-3.5
3.3. With the
Mantoux skin test, when is the patient’s arm examined?
3.4. How is the induration measured?
3.5 Why is the Mantoux skin test preferable to multiple-puncture
Classifying the Reaction
Whether a reaction to the Mantoux tuberculin skin test is classified
as positive depends on the size of the induration and the person's
risk factors for TB (Table 3.1).
An induration of 5 or more millimeters is considered
a positive reaction for the following people:
- People with HIV infection
- Close contacts of people with infectious TB
- People with chest x-ray findings suggestive of previous TB disease
- People who inject illicit drugs and whose HIV status is unknown
An induration of 10 or more millimeters is considered
a positive reaction for the following people:
- People born in areas of the world where TB is common (foreign-born
- People who inject illicit drugs but who are known to be HIV
- Low-income groups with poor access to health care
- People who live in residential facilities (for example, nursing
homes or correctional facilities)
- People with medical conditions that appear to increase the risk
for TB (not including HIV infection), such as diabetes
- Children younger than 4 years old
- People in other groups likely to be exposed to TB, as identified
by local public health officials
An induration of 15 or more millimeters is considered
a positive reaction for people with no risk factors for TB. In most
cases, people who have a very small reaction or no reaction probably
do not have TB infection.
For people who may be exposed to TB on the job
(such as health care workers and staff of nursing homes or correctional
facilities), the classification of the skin test reaction as positive
or negative depends on
- The size of the induration
- The employee's individual risk factors for TB
- The risk of exposure to TB in the person's job
Therefore, in facilities where the risk of exposure to TB is very
low, 15 or more millimeters of induration may be considered a positive
reaction for employees with no other risk factors for TB. In facilities
where TB patients receive care, 10 or more millimeters of induration
may be considered a positive reaction for employees with no other
risk factors for TB.
Most people who have a positive skin test reaction will have a
positive reaction if they are skin tested later in their lives,
regardless of whether they receive treatment. This is because the
tuberculin skin test detects the immune response to tuberculin,
not the presence of tubercle bacilli in the body (see
Diagnosis of TB Infection: The Tuberculin Skin Test).
|Study Questions 3.6-3.7
3.6. What two
factors are considered when classifying a skin test reaction
as positive or negative? What additional factor is considered
for people who may be exposed to TB on the job?
3.7. For which groups of people is 5 or more millimeters
of induration considered a positive reaction? Name four.
|Study Questions 3.8-3.9
3.8. For which
groups of people is 10 or more millimeters of induration
considered a positive reaction? Name seven.
3.9. For which group of people is 15 or more millimeters
of induration considered a positive reaction?
|Case Study 3.1
Which of the following
patients have a positive tuberculin skin test reaction?
- Mr. West, 36 years old, HIV infected, 08 mm of induration
- Mr. Hernandez, 26 years old, native of Mexico, 07 mm
- Ms. Jones, 56 years old, has diabetes, 12 mm of induration
- Mr. Sung, 79 years old, resident of a nursing home,
11 mm of induration
- Mr. Williams, 21 years old, no risk factors, 13 mm of
- Ms. Marcos, 42 years old, chest x-ray findings suggestive
of previous TB, 06 mm of induration
- Ms. Rayle, 50 years old, husband has pulmonary TB, 09
mm of induration
The skin test is a valuable tool, but it is not perfect. Several
factors can affect the skin test reaction. Two factors are infection
with nontuberculous mycobacteria (mycobacteria other than M.
tuberculosis) and vaccination with BCG. BCG (bacillus
Calmette-Guérin) is a vaccine for TB disease that is used in many
countries. However, it is rarely used in the United States because
studies have shown that it is not completely effective. People who
are infected with nontuberculous mycobacteria or who have been vaccinated
with BCG may have a positive reaction to the tuberculin skin test
even if they do not have TB infection. This is called a false-positive
There is NO RELIABLE WAY to distinguish a positive tuberculin reaction
caused by vaccination with BCG from a reaction caused by true TB
infection. However, the reaction is more likely to be due to
TB infection if any of the following are true:
- The reaction is large
- The person was vaccinated a long time ago
- The person comes from an area of the world where TB is common
- The person has been exposed to someone with infectious TB disease
- The person's family has a history of TB disease
People who have a positive reaction should be further evaluated
for TB disease, regardless of whether they were vaccinated with
|Study Questions 3.10-3.11
two factors that can cause false-positive reactions to the
tuberculin skin test.
3.11. Is there a reliable way to distinguish a positive
tuberculin reaction caused by vaccination with BCG from
a reaction caused by true TB infection?
|Case Study 3.2
A 30-year-old man who
recently immigrated from India is given a tuberculin skin
test and found to have 14 millimeters of induration. He
reports that he was vaccinated with BCG as a child. He also
says that his wife was treated for pulmonary TB disease
- Can you tell for sure whether this man has TB infection?
- What factors make it more likely that this man's positive
reaction is due to TB infection?
Some people have a negative reaction to the tuberculin skin test
even though they have TB infection. These are called false-negative
reactions. False-negative reactions may be due to
- Recent TB infection (within the past 10 weeks)
- Very young age (younger than 6 months old)
The most common cause of false-negative reactions is anergy.
Anergy is the inability to react to skin tests because of a
weakened immune system. Many conditions, such as HIV infection,
cancer, or severe TB disease itself, can weaken the immune system
and cause anergy. HIV infection is a main cause of anergy.
Because of their risk for anergy and their risk for TB, HIV-infected
people may be tested for anergy if they have a negative reaction
to the tuberculin skin test. Anergy testing is done by giving
skin tests using two substances other than tuberculin. The recommended
substances for anergy testing are mumps, Candida (a type
of fungus), or tetanus extracts. Most healthy people will have a
skin test reaction to one or more of these substances.
People who do not react to any of the substances, including tuberculin,
after 48 to 72 hours (that is, people who have less than 3 millimeters
of induration to all of the skin tests), are considered anergic.
People who have a reaction (3 or more millimeters of induration)
to any of the substances are NOT anergic. If a person being evaluated
for anergy has a reaction of 5 or more millimeters of induration
to tuberculin, he or she is considered to have TB infection, regardless
of the reaction to the other substances.
Another cause of false-negative reactions is recent TB infection
(infection within the past 10 weeks). It takes 2 to 10 weeks after
TB infection for the body's immune system to be able to react to
tuberculin. Therefore, after TB has been transmitted, it takes 2
to 10 weeks before TB infection can be detected by the tuberculin
skin test. For this reason, close contacts of someone with infectious
TB disease who have a negative reaction to the tuberculin skin test
should be retested 10 weeks after the last time they were in contact
with the person who has TB disease.
A third cause of false-negative reactions is very young age.
Because their immune systems are not yet fully developed, children
younger than 6 months old may have a false-negative reaction
to the tuberculin skin test.
A false-positive reaction or a false-negative reaction may occur
when the tuberculin skin test is given incorrectly or the results
are not measured properly. False-positive and false-negative reactions
to the tuberculin skin test are summarized in Table 3.2.
Any patient with symptoms of TB should be evaluated for TB disease,
regardless of his or her skin test reaction. In fact, people
with symptoms of TB should be evaluated for TB disease right away,
at the same time that the tuberculin skin test is given. The symptoms
of pulmonary TB disease include coughing, pain in the chest when
breathing or coughing, and coughing up sputum (phlegm from
deep in the lungs) or blood. The general symptoms of TB disease
(pulmonary or extrapulmonary) include weight loss, fatigue, malaise,
fever, and night sweats. The diagnosis of TB disease is discussed
in more detail in the next section of this module.
False-Positive and False-Negative Reactions to the Tuberculin Skin
|Type of Reaction
||People at Risk
||Action to Take*
||People infected with nontuberculous mycobacteria
||Evaluate for TB disease if person has TB symptoms
||People vaccinated with BCG
||Assess likelihood of true TB infection (see
five factors under False-Positive
||HIV-infected people, other people with weakened
||May do anergy testing
|Recent TB infection
||People infected with M. tuberculosis within
the past 10 weeks
||Retest 10 weeks after exposure to TB ended
|Very young age
||Children younger than 6 months old
||Retest when child is 6 months old and 10 weeks
after exposure to TB ended
* Any patient with symptoms of TB should be evaluated for TB disease,
regardless of his or her skin test reaction.
|Study Questions 3.12-3.14
three factors that can cause false-negative reactions to
the tuberculin skin test.
3.13. What is anergy?
3.14. How is anergy testing done?
|Study Questions 3.15-3.16
TB has been transmitted, how long does it take before TB
infection can be detected by the tuberculin skin test?
3.16. What should be done if a patient has a negative skin
test reaction but has symptoms of TB disease?
|Case Study 3.3
Mr. Bell comes to the
TB clinic for a tuberculin skin test. He believes that he
has been exposed to TB, and he knows he is at high risk
for TB because he is HIV infected. He is given a tuberculin
skin test, and his reaction is read 48 hours later as 0
millimeters of induration.
- What are three ways to interpret this result?
TB Screening Programs and Two-Step Testing
Many residential facilities, health care facilities, and other
settings have TB screening programs. This means that employees
and residents are periodically given tuberculin skin tests. The
purposes of the screening program are to
- Identify people who have TB infection and possibly TB disease,
so that they can be given treatment as needed
- Determine whether TB is being transmitted in the facility
In a TB screening program, employees or residents are skin tested
when they start their job or enter the facility. This is called
the baseline skin test. If they have a negative
skin test reaction, they may be retested at regular intervals thereafter.
(For most employees, repeat testing should be done at least once
Employees or residents whose skin test reaction converts from negative
to positive between screening intervals have probably become infected
with M. tuberculosis. These skin test conversions
may indicate that TB is being transmitted in the facility. People
with skin test conversions are at high risk of developing TB disease
because they were infected with M. tuberculosis relatively
recently (within the past 2 years). (See
Module 1, Transmission and Pathogenesis of Tuberculosis.) In
order to detect TB transmission and identify people who have skin
test conversions, accurate information must be obtained for every
employee's baseline skin test, as well as for additional skin tests.
One factor that can affect the accuracy of the baseline skin test
is the booster phenomenon. The booster phenomenon
happens because in some people who have TB infection, the ability
to react to tuberculin lessens over time. When these people are
skin tested many years after they became infected with M. tuberculosis,
they may have a negative reaction. However, if they are tested again
within a year of the first test, they may have a positive reaction.
This is because the first skin test "jogged the memory"
of the immune system, boosting its ability to
react to tuberculin. It may appear that these people were infected
between the first and second skin tests (recent TB infection). Actually,
the second, positive reaction is a boosted reaction
(due to TB infection that occurred a long time ago). The booster
phenomenon occurs mainly among older adults. The booster phenomenon
is illustrated in Figure 3.4.
Figure 3.4 The booster phenomenon. This is a flow chart depicting
the booster phenomenon.
The booster phenomenon can present a problem in TB screening programs.
This is because a negative reaction to the baseline skin test, followed
by a positive reaction to a subsequent skin test that is given up
to a year later, may be caused by either
- Recent TB infection in a person who was NOT infected at the
time of the baseline skin test, or
- A boosted reaction in a person who WAS infected at the time
of the baseline skin test
To avoid misinterpretation, a strategy has been
developed for telling the difference between boosted reactions and
reactions caused by recent infection. This strategy, called
two-step testing, means that if a person has a negative
reaction to an initial skin test, he or she is given a second test
1 to 3 weeks later.
- If the reaction to the second test is positive,
it probably is a boosted reaction (due to TB
infection that occurred a long time ago).
- If the reaction to the second test is negative,
the person is considered uninfected. In this
person, a positive reaction to a skin test given later on will
probably be due to recent infection.
Thus, because it provides accurate information about each employee's
baseline skin test reaction, two-step testing is used in many TB
screening programs for skin testing employees when they start their
job. In particular, two-step testing is often used in hospitals
and nursing homes. The procedure for two-step testing is shown in
Figure 3.5 Two-step testing. This is a flow chart depicting
|Study Questions 3.17-3.20
is the booster phenomenon?
3.18. What is the purpose of two-step testing?
3.19. In what type of situation is two-step testing used?
3.20. How is two-step testing done?
|Case Study 3.4
Ms. Wilson is a 60-year-old
nurse. When she started a job at the local hospital, she
was given a tuberculin skin test, her first test in 25 years.
Her reaction was read 48 hours later as 0 millimeters of
induration. Six months later, she was retested as part of
the TB screening program in the unit where she works. Her
skin test reaction was read 48 hours later as 11 millimeters
- What are two ways to interpret this result?