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U.S. Department of Health and Human Services

  

Guide for Primary Health Care Providers: Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection
2005

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).

TABLE 3:
Differentiating Between LTBI and TB Disease

LTBI 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).

Key Points

  • 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.

Quantiferon®-TB Test 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.

QFT advantages:

  • Requires a single patient visit
  • Does not cause booster phenomenon
  • Less subject to reader bias than TST

QFT disadvantages:

  • 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 of exposure.
  • 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 to disease
  • 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 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 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.

HIV Infection
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 their lifetime.

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.

Booster Phenomenon
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).

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
Note: A single step approach would be used for serial testing at baseline with QFT because boosting does not occur with QFT.

Contacts

  • 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 has ended.
  • 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

  • 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 proper shielding.

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 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 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 Radiograph
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 judgment
  • 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 is normal).

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.

 


Released October 2008
Centers for Disease Control and Prevention
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
Division of Tuberculosis Elimination - http://www.cdc.gov/tb

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