Blood Tests for Tuberculosis
By Philip R. Fischer, MD, DTM&H
Dr. Fischer is Professor of Pediatrics, Department of Pediatric & Adolescent Medicine, Mayo Clinic, Rochester, MN.
Dr. Fischer reports no financial relationships relevant to this field of study.
Synopsis: As with skin tests, interferon gamma release assays using blood samples now serve as useful aids in diagnosing tuberculosis (TB) infection. Still, these tests must also be used and interpreted in view of the clinical situation, including age, immune status, and potential tuberculosis exposures of any given patient.
Source: Mazurek GH, Jereb J, Vernon A, et al. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection United States 2010. Morbid Mortal Wkly Rep 2010;59:RR5:1-25.
During the past decade, blood tests have been developed to diagnose infection with Mycobacterium tuberculosis. With advancements in techniques, new test products are now available. In June 2010, the Centers for Disease Control and Prevention reviewed the scientific and clinical evidence behind these tests and published new guidelines for their use.
Tuberculosis continues to be a major problem in both global health and travel medicine. Approximately two billion people are currently infected with Mycobacterium tuberculosis. Each year, nine million people develop active tuberculosis (TB), and two million people die from TB. Travel medicine practitioners often are called upon to screen asymptomatic travelers and immigrants for tuberculosis, and even to provide accurate diagnostic testing for symptomatic individuals. This issue is especially relevant in long-term travelers, those involved in health care within developing countries, and in contacts of known tuberculosis patients.1
For most of the past century, specific screening for infection with Mycobacterium tuberculosis was limited to the tuberculin skin test (Mantoux, Purified Protein Derivative, PPD). Now, for nearly a decade, blood tests have been possible.
Tuberculosis skin tests are based on the identification of an immune-mediated intradermal reaction to a combination of antigens from Mycobacterium tuberculosis and other non-tuberculosis mycobacteria, including antigens found in the Bacille Calmette-Guerin (BCG) vaccine. The new blood tests are designed to be more specific for actual Mycobacterium tuberculosis. They are based on an interferon gamma releasing in vitro reaction of a patient's fresh blood to a collection of Mycobacterium tuberculosis-specific antigens. The QuantiFERON-TB test was put into practice in the United States at 2001 but had limited specificity and was withdrawn from the commercial market in 2005. The QuantiFERON-TB Gold test entered general use in 2005 and was more specifically based on reactions to discrete Mycobacterium tuberculosis antigens. Since then, two other tests have been developed and used the QuantiFERON-TB Gold In-Tube test in 2007 and the T-Spot TB test in 2008. Each of these tests is intended to be an aid in the diagnosis of Mycobacterium tuberculosis infection, but careful clinical interpretation and usage of the results are necessary.
There is still no "gold standard" for the diagnosis of latent or culture-negative TB infection. Comparative studies performed in a variety of population groups, however, show that the commercially available interferon gamma release assays are 88% (T-Spot) to 99% (QuantiFERON-TB Gold In-Tube) specific; skin testing was 85-86% specific in similar populations. Interferon gamma releasing assay results do not seem to be affected by previous BCG vaccination, but results of these tests do seem to fluctuate over time. There is some evidence that interferon gamma releasing assays are more sensitive than skin tests in identifying recent infection. The interferon gamma releasing assay tests do seem accurate in identifying infected individuals who are more likely to go on to develop active disease.
So, what considerations are important for travel medicine providers who want to test for TB? First, the new tests can be used when TB screening is indicated. The tests are especially appropriate when the patient is unable or unlikely to return and have the skin test read by a qualified professional in a timely fashion. Second, the new blood-based tests can be preferable when the patient has previously received BCG vaccine. The positive blood test would be more likely than a positive skin test to represent actual Mycobacterium tuberculosis infection in this setting and could more specifically identify individuals for whom latent TB treatment would actually be helpful. Third, it should be remembered that neither the TB skin test nor the blood tests distinguish between latent infection and active disease. Thorough evaluation and subsequent therapy are indicated for anyone with a positive screening test. And, since the sensitivity of all TB tests is less than 100%, a negative test does not preclude additional evaluation in a patient with symptoms suggestive of TB.
Pediatric data about TB blood tests are limited. Preschool age children are more likely than older children to develop active TB disease and severe forms of infection. This suggests that TB immunity varies with age. Similarly, blood from young children might respond less vigorously to interferon gamma stimulation tests. Until further data are available, caution should be exercised when interpreting interferon gamma release assay results, especially negative ones, in children younger than 5 years of age. At the same time, however, there are new data suggesting that the QuantiFERON-TB Gold In-Tube assay is more reliable than a TB skin test for identifying children who are at risk of progressing to active TB disease.2
Immunocompromised travelers might respond differently to these tests than do their immunocompetent counterparts. Nonetheless, some studies suggest that these tests are 80% sensitive in HIV-positive patients a similar sensitivity to that of the TB skin test. As previously reported in Travel Medicine Advisor, blood tests might do better than skin tests in determining which patients with inflammatory disease under consideration for anti-tumor necrosis factor-alpha therapy should first receive treatment for latent TB.3
TB skin tests do not "convert" to positivity exactly at the time of a new infection. Typically, skin tests are done three months following an international trip with concern for exposure in an asymptomatic traveler so as to allow time for an adequate immune response to develop. There is some evidence that the blood-based tests become positive more quickly than do skin tests, but there are no conclusive data, as yet, to guide the timing of earlier blood test screening for new latent TB infections.
Thus, multiple new blood tests are available to diagnose TB infection. These tests offer advantages over TB skin testing in some settings and yield more specific results than skin testing in BCG-vaccinated patients. These tests seem to be at least as good as skin tests in immunocompetent and immunocompromised adult patients, but these tests are incompletely studied in young children.
References
- Chen LH. TB in travelers: US reports and IGRA for screening. Travel Medicine Advisor 2009;1 68-70.
- Diel R, Loddenkemper R, Niemann S, Meywald-Walter K, Nienhaus A. Negative and positive predictive value of a whole-blood IGRA for developing active TB an update. Am J Respir Crit Care Med 2010;Aug 27 (e-pub ahead of print). PMID 20802162
- Kemper CA. TB screening before anti-TNF-alpha therapy. Travel Medicine Advisor 2010;20:15-16.
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