Latent Tuberculosis Infection: A Guide for Primary Health Care Providers

Return to Table of Contents

Diagnosis of Latent TB Infection

The diagnosis of LTBI is based on information gathered from the medical history, TST or IGRA result, chest radiograph, physical examination, and in certain circumstances, sputum examinations. The presence of TB disease must be excluded before treatment for LTBI is initiated (i.e., waiting for culture results if specimens are obtained) because failure to do so may result in inadequate treatment and development of drug resistance (see Table 1).

CDC discourages use of diagnostic tests for LTBI among individuals and populations at low risk for infection with M. tuberculosis. Despite CDC recommendations to the contrary, testing is sometimes done to meet administrative or legal requirements for groups who are not considered to have an increased possibility of infection in the absence of other factors cited above, such as persons meeting entrance requirements for certain schools and workplaces.

Table 1: Differentiating Between LTBI and TB Disease

LTBI No symptoms or physical findings suggestive of TB disease Positive TST or IGRA result Chest radiograph normal If done, respiratory specimens are  smear and culture negative

TB Disease Symptoms may include one or more of the following: fever, cough, chest pain, weight loss, night sweats, hemoptysis, fatigue, and decreased appetite. TST or IGRA result usually positive Chest radiograph is usually abnormal. However, may be normal in persons with advanced immunosuppression or extrapulmonary disease. Respiratory specimens are usually smear or culture positive. However, may be negative in persons with extrapulmonary disease or minimal or early pulmonary disease.

Tests for TB Infection

Tuberculin Skin Test (TST)

The tuberculin skin test (TST) is used to determine if a person is infected with M. tuberculosis. The skin test is administered intradermally using the Mantoux technique by injecting 0.1ml 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 a trained health care professional. For more information about tuberculin skin testing, visit the CDC website for additional resources (see Resources) and refer to Appendix C.

Key Points

• The TST should not be performed on a person who has written documentation of either a previous positive TST result or treatment for TB disease.
• Patients or family members should never measure TST results; this should only be done by a trained health care professional.
• Interpretation of the TST result is the same for persons who have had BCG vaccination.
• A TST that was not measured and recorded in mm of induration must be repeated.

Classification of Tuberculin Skin Test Reactions

A TST reaction of ≥5 mm of induration is considered positive in

• HIV-infected persons
• Recent contacts of a person with infectious TB disease
• Persons with fibrotic changes on chest radiograph consistent with prior TB
• Organ transplant recipients
• Persons who are immunosuppressed for other reasons (e.g., 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 countries
• 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 TST reaction of ≥15 mm of induration is considered positive in

• Persons with no known risk factors for TB

Although skin testing activities should be conducted only among at-risk groups, certain individuals may be required to have testing for employment or school attendance independent of risk. CDC and ATS do not recommend an approach independent of risk assessment.

Interferon–Gamma Release Assays (IGRAs)

IGRAs are used to determine if a person is infected with M. tuberculosis. The Quantiferon^®-TB Gold test (QFT-G), Quantiferon^®-TB Gold In-Tube test (QFT-GIT), and T-SPOT.^®-TB are blood tests that measure a person’s immune reactivity to specific mycobacterial antigens. Specimens are mixed with peptides that simulate antigens derived from M. tuberculosis and controls. In a person infected with M. tuberculosis, the white blood cells recognize the simulated antigens and release interferon-gamma (IFN-γ); results are based on the amount of IFN-γ released.

Key Points

• Advantages of IGRAs include the following:
  • Requires a single patient visit
  • Does not cause booster phenomenon
  • Less subject to reader bias than TST
  • Unaffected by BCG and most environmental mycobacteria
• Limitations of IGRAs include the following:
  • Blood sample must be processed within 8-16 hours
  • Limited data exist on use in groups such as children younger than 5 years of age, persons recently exposed to TB, immunocompromised persons, and those who will be tested repeatedly (serial testing)

Selecting a Test to Detect TB Infection

• IGRAs are the preferred method of testing for:
  • Groups of people who have a poor rates of returning to have TST read
  • Persons who have received BCG vaccine
• TST is the preferred method for testing for:
  • Children under the age of 5 years
• Either TST or IGRA may be used without preference for other groups that are tested for LTBI.
• Key Point
  Routine testing with both TST and IGRAs is NOT recommended.

Table 2: Interpretation of IGRA Results

IGRA test	Results reported as:
QuantiFERON® - TB Gold	Positive, negative, indeterminate
QuantiFERON® - TB Gold In-Tube	Positive, negative, indeterminate
T-SPOT®.TB	Positive, negative, indeterminate, borderline
Note: Laboratory should provide both quantitative and qualitative test results

 

Special Considerations in Testing for TB Infection

BCG Vaccine
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 that BCG vaccine be administered during infancy in TB endemic countries. BCG vaccination is not recommended in the U.S. 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. 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.

IGRAs use M. tuberculosis specific antigens that do not cross react with BCG and therefore, do not cause false positive reactions in BCG recipients.

HIV Infection
The risk of progression from LTBI to TB disease is 7% to 10% each year for those with both LTBI and untreated HIV infection. Those with LTBI and who are HIV negative only have a 10% risk over their lifetime.

HIV-infected persons should be tested for LTBI as soon as their HIV status becomes known. A negative TST or IGRA result does not exclude LTBI as they may have a compromised ability to react to tests for TB infection. Annual testing should be considered for HIV-infected persons who are TST or IGRA negative on initial evaluation and who have a risk for exposure to M. tuberculosis. Because the usefulness of anergy testing in HIV-infected individuals or others has not been demonstrated, it is not recommended.

After the initiation of antiretroviral therapies (ART), repeat testing for LTBI is recommended in HIV-infected persons previously known to have negative TST or IGRA results as immune reconstitution may result in restoration of immune response.

Booster Phenomenon
Some people infected with M. tuberculosis 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 may be tested periodically (e.g., health care workers).  If the first TST result in the two-step baseline testing is positive, consider that the person is infected and evaluate and treat the person accordingly. If the first test result is negative, the TST should be repeated in 1–3 weeks. If the second test result is positive, consider that the person is infected and evaluate and treat the person accordingly; if both steps are negative, consider the person uninfected and classify the TST as negative at baseline testing (see Figure 1).

When IGRAs are used for serial testing, there is no need for a second test because boosting does not occur.

Figure 1: Two-Step Tuberculin Skin Test (TST) Method

1st TST	Negative	Repeat TST in 1–3 weeks
2nd TST	Negative	Person probably does not have infection
	Positive	Boosted reaction due to infection in the past

Contacts

• For contacts of a person with infectious TB disease, retesting in 8–10 weeks is indicated when the initial TST or IGRA result is negative.
• Children under the age of 5 years and immunosuppressed persons (e.g., HIV infected) who have a negative results should have a chest radiograph. If normal, treatment should be started for LTBI and another test performed 8–10 weeks after contact has ended.
• If a repeat test result is positive, treatment should be continued. If it is negative, treatment can usually be discontinued. However, for some contacts at very high risk a full course of LTBI treatment may be recommended even in the absence of a positive TST or IGRA result. Consult with your local TB control program about the management of such contacts.
• In contact investigations, retesting is not called two-step testing. The second test is needed to determine if infection occurred but was too early in onset to be detected at the time of the first test.
• If testing is repeated, the same type of test (TST or IGRA) should be used.

Pregnancy

• Test only if specific risk factors are present.
• If a TST or IGRA reaction is positive, obtain a chest radiograph using proper shielding.

Other Diagnostic Considerations

Chest Radiograph
Chest radiographs help differentiate between LTBI and pulmonary TB disease in individuals with positive tests for TB infection. The following guidelines are recommended:

• Order a chest radiograph as part of a medical evaluation for a person who has a positive TST or IGRA result.
• A chest radiograph is also indicated in the absence of a positive test result for TB infection 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 the health care provider’s judgment.
• Persons with nodular or fibrotic lesions consistent with old TB are high-priority candidates for treatment.
• Persons with calcified granulomas only are not at increased 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 positive test results for TB infection and either an abnormal chest radiograph or the presence of respiratory symptoms (even when the chest radiograph is normal).

Physical Examination and Medical History
Physical examination and medical history, which includes obtaining information about  previous positive results of a test for TB, previous treatment for LTBI or TB disease, and a risk assessment for liver disease, are indicated for an individual with positive test results. Written documentation of a previously positive TST or IGRA result is required; a patient’s verbal history is not sufficient. Appendix D provides an example of a documentation form.