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General Principles, Risk Factors, Diagnosis, and Treatment of Latent Tuberculosis

The early identification and diagnosis of cases of active tuberculosis are the keys to successful therapy without sequelae. Unfortunately diagnostic testing remains problematic, and maintaining a high index of suspicion continues to be crucial.

General Principles and Risk Factors of Latent Tuberculosis

Tuberculosis (TB) should be suspected not only in patients who have cough, sputum production, or hemoptysis, but also in patients without those symptoms who have unexplained weight loss, fever, night sweats, or fatigue.3952  Particularly close attention should be paid to individuals who have had contact with someone known to have TB, health care workers, individuals born in endemic countries, individuals who are or have been incarcerated, patients in chronic care facilities, homeless persons, individuals of low socioeconomic status, and abusers of illicit drugs and alcohol.

An estimated 10-15 million individuals in the United States have latent TB infection (LTBI).3953  Individuals with LTBI are asymptomatic, and the majority will not have any radiographic evidence of pulmonary TB. In most individuals with LTBI, the only evidence of disease is a positive tuberculin skin test. However, even this test is not always reliable in immunocompromised individuals, including those who are taking immunosuppressive medications. An alternative screening test, the QuantiFERON®-TB Gold blood test (QFT-G) (Cellestis Limited, Carnegie, Victoria, Australia) is now approved by the FDA.3915,  3954 

In approximately 95% of individuals, the TB remains latent for life (latent TB). Five percent of individuals will develop active TB following the initial infection,3861  and an additional 5% of the infected individuals will develop active TB later in life (reactivation TB).3877  However, the odds of reactivation are much higher in immunosuppressed individuals, including individuals treated with anti-tumor necrosis factor-α agents.3959 

Diagnosis of Latent Tuberculosis

Multiple tests are available for diagnosing latent tuberculosis.

Tuberculin Skin Testing

The tuberculin skin test using purified protein derivative (PPD) is the method routinely used for identifying latent TB infection (LTBI). This test is based on the development of a delayed-type hypersensitivity reaction to tubercular antigens in individuals with TB, latent or active. The standard test dose of a PPD preparation is 5 tuberculin units. The Mantoux (single-needle injection) method is preferable to the multiple-puncture tests. The reaction typically begins 5-6 hours after injection, and induration peaks at 48-72 hours.3956 

Administering the Tuberculin Skin Test

  • 0.1 mL of 5 tuberculin units of purified protein derivative (PPD) is administered intradermally on the forearm using a ¼- to ½-inch 27-gauge needle.

  • A 6- to 10-mm wheal should be produced if injection is performed properly.

  • Test should be read 48-72 hours after injection.

  • The diameter of induration (not erythema) should be measured to the long axis of the forearm and recorded in millimeters.3956 

Figure 916 – Administering the Tuberculin Skin Test

VIEW LARGER IMAGE

Centers for Disease Control (CDC). Administering the Tuberculin Skin Test. CDC website.http://www.cdc.gov/tb/pubs/slidesets/core/Chapter4/test7.htm. Accessed July 1, 2009.

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Reading and Interpreting the Tuberculin Skin Test

In order to interpret the tuberculin skin test (TST), familiarity with the sensitivity and specificity of the test, as well as with the predictive value of the test, is valuable.3946  False-negative–TST reactions may occur due to3958  :

  • Infections or recent live-virus vaccination

  • Overwhelming TB

  • Age (newborns, elderly)

  • Chronic renal failure

  • Low protein states

  • Diseases affecting lymphoid organs (lymphomas, chronic leukemia, sarcoidosis)

  • Drugs (corticosteroids and other immunosuppressants including anti-tumor necrosis factor-α agents

  • Poor TST administration technique or factors related to the tuberculin used (such as improper storage or misplacement of the test)

Figure 917 – Reading the Tuberculin Skin Test

VIEW LARGER IMAGE

Centers for Disease Control and Prevention (CDC). Reading the Tuberculin Skin Test [slide]. Available at: http://www.cdc.gov/tb/pubs/slidesets/core/Chapter4/test8.htm. Accessed July 1, 2009.

3958

Some figures may not display clearly when rendered as a PDF or printed. The reader is encouraged to visit www.medversation.com to view full-size versions.

Based on considerations of sensitivity, specificity, and prevalence of TB in different groups and on risk for developing active infection, different amounts of induration in different populations have been recommended for defining a positive tuberculin reaction.3946 

Individuals in the highest risk categories for development of active TB following initial infection with Mycobacterium tuberculosis are defined as having a positive reaction if they have ≥5 mm of induration. These individuals include the following3959,  3956  :

  • HIV-positive patients

  • Individuals who have had recent contact with TB patients

  • Fibrotic changes on chest radiograph consistent with prior TB (untreated)

  • Patients with organ transplants and other immunosuppressed patients (receiving the equivalent of 15 mg/day of prednisone for 1 month or more)

  • Patients receiving or planning to receive anti-tumor necrosis factor-α agents6090,  3956 

Individuals at intermediate risk for development of active TB following initial infection with M tuberculosis are defined as having a positive reaction when ≥10 mm of induration is present, and include the following individuals:

  • Recent (within the last 5 years) immigrants from high prevalence countries, such as areas of eastern Europe, Latin America, Asia, and Africa

  • Intravenous drug users who are HIV-negative or have an unknown HIV status

  • Residents and employees of high-risk congregate settings, such as

    • Hospitals and other health care facilities

    • Prisons and jails

    • Long-term facilities for the elderly such as nursing homes

    • Residential facilities for patients with AIDS

    • Homeless shelters

  • Mycobacterial laboratory personnel

  • Individuals with clinical conditions that place them at high risk for active disease, such as

    • Diabetes mellitus

    • Silicosis

    • Chronic renal failure

    • Hematologic disorders such as leukemias and lymphomas

    • Other specific malignancies (such as carcinoma of the head or neck and lung)

    • Weight loss of >10% of ideal body weight

    • Gastrectomy

    • Jejunoileal bypass

  • Children younger than 4 years of age

  • Infants, children, and adolescents exposed to adults at high risk for active TB

Finally, individuals at low risk (i.e., those with no risk factors) for development of TB following initial infection with M tuberculosis are considered to have a positive reaction if ≥15 mm of induration is present.

Bacillus Calmette-Guérin and Tuberculin Skin Test

A history of Bacillus Calmette-Guérin (BCG) vaccination with or without BCG scar should not influence the interpretation of tuberculin skin test (TST) as described above. Tuberculin skin testing is not contraindicated in patients who have received BCG.3960 

In any BCG-vaccinated person whose skin test reaction is ≥10mm, latent TB infection (LTBI) diagnosis and treatment for LTBI should be considered, particularly if any of the following circumstances are present3961  :

  • Was in contact of another person with infectious TB

  • Was born or has resided in a high TB prevalence country

  • Is continually exposed to populations where TB prevalence is high

Booster Testing and the Tuberculin Skin Test

Booster testing of patients in order to increase the sensitivity of tuberculin skin test for latent TB infection (LTBI) is not recommended as this would also decrease the specificity for LTBI, especially in areas of low TB prevalence and high Bacillus Calmette-Guérin vaccination.3962 

Other Tests for Latent Tuberculosis: QuantiFERON®-TB Gold and the Interferon-γ Release-Based Assays

QuantiFERON®-TB Gold test and T-SPOT TB assay (Oxford Immunotec, Oxford, United Kingdom) tests measure the release of interferon γ (INF-γ) induced by incubation of whole blood (QFT) or peripheral blood mononuclear cells (T-SPOT TB) with two M tuberculosis proteins.3915,  3954  Both proteins are present in purified protein derivative (PPD) but absent in all Bacillus Calmette-Guérin (BCG) vaccine preparations and environmental mycobacteria with the exception of M kansasii, M marinum, and M szulgai. The tests are unaffected by the tested individual’s BCG vaccination status—in other words, a prior BCG vaccination will not give a positive test. In this regard, the test can be used to differentiate a positive PPD due to BCG vaccination from a positive PPD due to latent TB infection (LTBI). However, the Centers for Disease Control and Prevention’s recommendation is that any adult with a positive PPD, regardless of BCG status, be considered to have LTBI.

The QFT assay uses an enzyme-linked immunosorbent assay to measure INF-γ and T-SPOT TB uses an enzyme-linked immunospot assay. Results are typically available in 24-48 hours. INF-γ release-based assays should have greater specificity than tuberculin skin testing; however, in the absence of a gold standard for LTBI, the sensitivity and specificity cannot be directly measured. The clinical applicability, value, and limitations of INF-γ release-based assays are still unclear with respect to immunocompromised individuals (e.g., dialytic, transplantation, and those on immunosuppressant drugs), children, patients with exposure or infection with nontuberculous mycobacteria, in countries endemic for TB, and in patients with radiographs suggesting prior TB infection.3915,  3954 

Treatment of Latent Tuberculosis

The current treatment recommendations for latent TB infection (LTBI) were published in 2003 and recently updated in 2006. Treatment is generally with isoniazid (INH) for a total of 9 months. This is the preferred regimen published in the updated statement by the American Thoracic Society and the Centers for Disease Control and Prevention. See .3886,  3895,  3967,  3967  Children should be given 9 months of therapy. Therapy can be given twice per week if it is directly observed.3964 

There are alternative options available if an individual is INH-resistant or multidrug-resistant, but it is recommended that a TB expert be consulted in these cases (see Fig.921). Isoniazid (INH) for 6 months or rifampin (RIF) for a total of 4 months is an alternative. Guidelines were issued against the general use of RIF and pyrazinamide (PZA) due to adverse events. 3966 

Figure 921 – Treatment of Latent Tuberculosis Recommendations


Centers for Disease Control and Prevention (CDC). Treatment options for latent tuberculosis infection. CDC website.http://www.cdc.gov/tb/pubs/tbfactsheets/treatmentLTBI.htm. Last updated June 1, 2009. Accessed July 1, 2009.

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Some figures may not display clearly when rendered as a PDF or printed. The reader is encouraged to visit www.medversation.com to view full-size versions.

This concludes the discussion of the topic Tuberculosis – Screening, Diagnosis, and Treatment. Information pertaining to an overview of infections and to infections with drug therapy are covered in separate topics. We encourage you to read other topics on the MEDVERSATION® website.

Content on this page was last reviewed on August 20, 2008.

Content on this page was last changed on March 19, 2009.

References:

3861.  Ellner JJ. Review: the immune response in human tuberculosis — implications for tuberculosis control. J Infect Dis. 1997;176(5):1351-1359.
3877.  Leung AN. Pulmonary tuberculosis: the essentials. Radiology. 1999;210(2):307-322.
3886.  Centers for Disease Control and Prevention (CDC); American Thoracic Society, CDC; Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep. 2003;52(RR-11):1-88.
3895.  Blumberg HM, Burman WJ, Chaisson RE, et al.; American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167(4):603-662.
3915.  Pai M, Riley LW, Colford JM. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis. 2004;4(12):761-776.
3946.  Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1376-1395.
3952.  Diagnosis of tuberculosis disease. Centers for Disease Control and Prevention website. http://www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250102.htm . Updated April 2006. Accessed July 1, 2009.
3953.  Taylor Z, Nolan CM, Blumberg HM; American Thoracic Society; Centers for Disease Control and Prevention (CDC); Infectious Diseases Society of America. Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Recomm Rep. 2005;54(RR-12):1-81.
3954.  Mori T, Sakatani M, Yamagishi F, et al. Specific detection of tuberculosis infection: an interferon-γ–based assay using new antigens. Am J Respir Crit Care Med. 2004;170(1):59-64.
3956.  Tuberculin skin testing. Centers for Disease Control and Prevention website. http://www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250140.htm . Updated April 2006. Accessed June 30, 2009.
3957.  Centers for Disease Control and Prevention (CDC). Administering the tuberculin skin test. CDC website. http://www.cdc.gov/tb/pubs/slidesets/core/Chapter4/test7.htm . Accessed July 1, 2009.
3958.  Centers for Disease Control and Prevention (CDC). Reading the tuberculin skin test. CDC website. http://www.cdc.gov/tb/pubs/slidesets/core/Chapter4/test8.htm . Accessed July 1, 2009.
3959.  Centers for Disease Control and Prevention. Tuberculosis associated with blocking agents against tumor necrosis factor-alpha—California, 2002-2003. MMWR Morb Mortal Wkly Rep. 2004;53(30):686-686.
3960.  The role of BCG vaccine in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 1996;45(RR-4):1-18.
3961.  Centers for Disease Control and Prevention (CDC). Bacillus Calmette-Guérin vaccination and tuberculin skin testing. CDC website. http://www.cdc.gov/tb/pubs/slidesets/core/Chapter9/bcg6.htm . Accessed July 1, 2009.
3962.  Winthrop KL, Siegel JN, Jereb J, Taylor Z, Iademarco MF. Tuberculosis associated with therapy against tumor necrosis factor alpha. Arthritis Rheum. 2005;52(10):2968-2974.
3964.  Centers for Disease Control and Prevention (CDC). Treatment of latent tuberculosis infection with isoniazid. CDC website. http://www.cdc.gov/tb/pubs/slidesets/core/Chapter6/treat5.htm . Accessed July 7, 2009.
3966.  Centers for Disease Control and Prevention. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection — United States, 2003. MMWR Morb Mortal Wkly Rep. 2003;52(31):725-739.
3967.  Centers for Disease Control and Prevention (CDC). Treatment of Latent Tuberculosis Infection (fact sheet). CDC website. http://www.cdc.gov/tb/publications/factsheets/treatment/treatmentLTBI.htm Updated June 1, 2009. Accessed July 1, 2009.
6090.  Centers for Disease Control and Prevention (CDC). Tuberculosis associated with blocking agents against tumor necrosis factor-alpha — California, 2002-2003. MMWR Morb Mortal Wkly Rep . 2004;53(30):683-686.
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