Guide for Primary Health Care Providers: Targeted
Tuberculin Testing and Treatment of Latent Tuberculosis Infection
Diagnosis of Latent TB Infection
The diagnosis of LTBI is based on information gathered from TST
or QFT results, chest radiographs, physical examination, and, in
certain circumstances, sputum examinations. The presence of TB disease
must be ruled out before treatment for LTBI is initiated (i.e.,
waiting for culture results if specimens are obtained) because failure
to rule out TB may result in inadequate treatment and development
of drug resistance (see Table 3).
Differentiating Between LTBI and TB Disease
- No symptoms or physical findings suggestive of disease
- Positive TST or QFT
- Chest radiograph negative for active disease
- Symptoms may include one or more of the following:
fever, cough, chest pain, weight loss, night sweats, hemoptysis,
fatigue, and decreased appetite
- Chest radiograph may be abnormal
- Respiratory specimens may be smear or culture positive
- TST or QFT usually positive
Testing for Latent TB Infection
Tuberculin Skin Test (TST)
The tuberculin skin test (TST) detects individuals infected
with M. tuberculosis. The skin test is administered intradermally
using the Mantoux technique by injecting 0.1 ml of 5 TU purified
protein derivitive (PPD) solution. If a person is infected, a delayed-type
hypersensitivity reaction is detectable 2–8 weeks after infection.
The reading and interpretation of TST reactions should be conducted
within 48 to 72 hours of administration by trained health care professionals.
For more information about tuberculin skin testing, consult the
CDC Mantoux Tuberculin Skin Test video and wall chart (see Resources
and refer to Appendix C).
- The TST should not be performed on a person who has a documented
history of either a positive TST result or treatment for TB disease.
- TST results should only be read and interpreted by a trained
health care professional. Patients or family members should not
be relied upon to measure TST results.
- TB disease must be ruled out before initiating treatment for
LTBI to prevent inadequate treatment of TB disease.
and Quantiferon®-TB Gold Test (QFT)
The Quantiferon®-TB test and Quantiferon®-TB
Gold test (QFT) are blood tests that measure a person’s immune
reactivity to M. tuberculosis. Blood specimens are mixed
with antigens and incubated for 16–24 hours. In a person with LTBI,
the blood cells recognize the tuberculin antigen and release interferon-gamma
(IFN-γ); results are based on the proportion of IFN-γ
released. The first generation QFT (Quantiferon®-TB test)
was approved by the U.S. Food and Drug Administration (FDA) in 2001.
The second generation test (Quantiferon®-TB Gold test)
was approved by the FDA in 2005.
- Requires a single patient visit
- Does not cause booster phenomenon
- Less subject to reader bias than TST
- Blood sample must be processed in 12 hours
QFT is recommended for
- Initial and serial testing for those at increased risk for LTBI
CDC discourages use of diagnostic tests for LTBI among populations
at low risk for infection with M. tuberculosis. However,
initial testing is occasionally performed among certain population
groups for surveillance purposes or where cases of infectious TB
disease might result in extensive transmission to highly susceptible
populations, including the following:
- Initial and serial testing of persons who are at low risk for
LTBI, but whose future activity places them at increased risk
- Testing of those who are not considered to have an increased
possibility of infection, such as persons meeting entrance requirements
for certain schools and workplaces.
QFT is not currently recommended for
- Screening of pregnant women, children under the age of 17, or
persons with clinical conditions that increase the risk of progression
- Confirmation of TST results
- Diagnosis of M. avium-complex disease
Refer to the CDC website for the most current information on the
use of QFT: http://www.cdc.gov/tb.
Special Considerations in Testing for Latent
The BCG (bacillus Calmette-Guerin) vaccine is currently
used in many parts of the world where TB is common to protect infants
and young children from serious, life-threatening disease, specifically
miliary TB and TB meningitis. The World Health Organization (WHO)
recommends BCG vaccination once in infancy in TB endemic countries.
The question of the effect of BCG vaccine on TST results often causes
confusion. TST reactivity caused by BCG vaccine generally wanes
with the passage of time, but periodic skin testing may prolong
(boost) reactivity in vaccinated persons. However, there is no reliable
skin test method for distinguishing between vaccine-related reactions
and reactions caused by mycobacterial infections. Quantiferon®-TB
Gold test, which uses M. tuberculosis specific antigens,
is designed to not cross react with BCG and may cause less false
positive reactions. A history of BCG vaccine is not a contraindication
for tuberculin skin testing or treatment for LTBI in persons with
positive TST results. TST reactions should be interpreted regardless
of BCG vaccination history.
The risk of progression from LTBI to TB disease is 7% to
10% each year for those with both LTBI and HIV infection.
Those with LTBI and who are HIV negative only have a 10% risk over
HIV infected persons may have a compromised ability to react to
the TST, but should be tested for LTBI as soon as their HIV status
becomes known. A negative TST reaction does not rule out LTBI. Annual
repeat testing should be considered for HIV-infected persons who
are TST-negative on initial evaluation and who belong to populations
in which a substantial risk for exposure to M. tuberculosis exists.
Because the usefulness of anergy testing in HIV-infected individuals
has not been demonstrated, it is not recommended.
After the initiation of highly active antiretroviral
therapies (HAART), repeat testing for LTBI is recommended in HIV-infected
persons previously known to have negative TST results as immune
reconstitution may result in restoration of TST reactivity.
Some people with LTBI may have a negative reaction to the
TST if many years have passed since they became infected. They may
have a positive reaction to a subsequent TST because the initial
test stimulates their ability to react to the test. This is commonly
referred to as the “booster effect” and may incorrectly be interpreted
as a skin test conversion (going from negative to positive). For
this reason, the “two-step method” is recommended at the time of
initial testing for individuals who will be tested periodically
(e.g., health care workers). If the first test result in the two-step
baseline testing is positive, consider that the person has LTBI
and evaluate and treat the person accordingly. If the first test
result is negative, the second step of the two-step baseline testing
should be repeated in 1–3 weeks. If the second test result is positive,
consider that the person has LTBI and evaluate and treat the person
accordingly; if both steps are negative, consider the person uninfected
and classify the TST as a negative baseline (see Figure 1).
Two-Step Tuberculin Skin Test (TST) Method
Note: A single step approach would be used for serial testing at baseline
with QFT because boosting does not occur with QFT.
||Repeat TST in 1–3 weeks
||Person probably does not have infection
||Boosted reaction due to infection in the past
- For contacts of an infectious TB case, retesting in 8–10
weeks is indicated when the initial TST result is negative.
- Children under the age of 5 years and immunosuppressed persons
(e.g., HIV infected) who have a negative TST result should be
treated and another TST performed 8–10 weeks after contact
- If a repeat TST result is positive, treatment should be continued.
If a repeat TST result is negative, treatment can be discontinued.
- Retesting is not called two-step testing. The second test is
needed in case infection occurred but was too early in onset at
the time of the first test.
- Pregnancy and the post partum period may affect the pathogenesis
of TB and may increase the risk of progression from infection
to TB disease.
- The TST has no adverse effects on the pregnant mother or fetus.
- Test only if specific risk factors are present, such as HIV
infection or recent contact with a person who has infectious TB.
- There is potential increased risk of hepatotoxicity during pregnancy
and the post- partum period.
- Consider delay of treatment 2–3 months post-partum unless
at higher risk (e.g., HIV infected, recent contact).
- If a TST reaction is positive, obtain a chest radiograph using
Classification of Tuberculin Skin Test Reactions
A TST reaction of ≥ 5 mm of
induration is considered positive in
- HIV-infected persons
- Recent contacts of infectious TB cases
- Persons with fibrotic changes on chest radiograph consistent
with prior TB
- Organ transplant recipients
- Those who are immunosuppressed for other reasons (taking
equivalent of ≥ 15 mg/day of prednisone for
1 month or more or those taking TNF-α antagonists
A TST reaction of ≥ 10 mm of induration
is considered positive in
- Recent immigrants (within last 5 years) from high-prevalence
- Injection drug users
- Residents or employees of high-risk congregate settings
(prisons, jails, long-term care facilities for the elderly,
hospitals and other health care facilities, residential
facilities for patients with AIDS, and homeless shelters)
- Mycobacteriology laboratory personnel
- Persons with clinical conditions previously mentioned
- Children younger than 4 years of age
- Infants, children, or adolescents exposed to adults at
high risk for TB disease
A tuberculin skin test reaction of ≥
15 mm of induration is considered positive in
- Persons with no risk factors for TB
Although skin testing programs should be conducted only among
high-risk groups, certain individuals may require testing
for employment or school attendance. An approach independent
of risk assessment is not recommended by CDC or ATS.
Other Diagnostic Considerations
Chest radiographs help differentiate between LTBI and pulmonary
TB disease in individuals with positive TST or QFT results. The
following guidelines are recommended:
- Order chest radiograph as part of a medical evaluation for a
person who has a positive TST or QFT
- A chest radiograph is also indicated in the absence of a positive
TST result when a person is a close contact of an infectious TB
patient and treatment for LTBI will be started (i.e., window prophylaxis
in a young child or immunocompromised person)
- Children less than 5 years of age should have both posterior-anterior
and lateral views
- All others should have at least posterior-anterior views
- Other views or additional studies should be done based on physician’s
- Persons with nodular or fibrotic lesions consistent with old
TB are high-priority candidates for treatment
- Persons with calcified granulomas only are low risk for progression
to TB disease
- Periodic follow-up radiographs are not indicated regardless
of whether treatment is completed except in unusual circumstances
(e.g., contacts to patients with MDR TB)
Sputum Examination for AFB Smear and Culture
Sputum examination is indicated for persons with a positive
TST or QFT result and either an abnormal chest radiograph or the
presence of respiratory symptoms (even when the chest radiograph
Physical Examination and Medical History
Physical examination and medical history, including previous
positive reactions and risk assessment for liver disease, are indicated
for positive skin test reactors. Written documentation of a previously
positive TST or QFT result is required; a patient’s verbal history
is not sufficient. Appendix D provides
an example of a documentation form.