Latent Tuberculosis — Strategies for Early Intervention

Leake, John A.D., MD, MPH
Medical Director
Infectious Diseases
Quest Diagnostics
San Juan Capistrano, CA Also by this Author 

About one-third of the world's population has latent tuberculosis (LTBI).1 Those infected with LTBI have a lifetime risk of 10% of developing active TB.1 In the United States it is estimated that there are 10 to 15 million with LTBI.2

Dr. John Leake, Medical Director, Infectious Diseases, Quest Diagnostics, discusses the importance and challenge of identifying those with LTBI and reviews approaches to enable timely intervention in those exhibiting no clinical signs of TB.

Defining Latent Tuberculosis

“Latent tuberculosis (LTBI) is infection with TB, as detected by skin tests or interferon gamma release assay (IGRA), in the absence of signs or symptoms, such as fever, weight loss, night sweats, or cough, together with a negative chest x-ray,” says Dr. Leake. “Latent TB is a very significant global health problem, affecting around a third of people worldwide, of whom 1 in 10 will develop active disease.1 This represents a challenge for healthcare providers in all countries, particularly due to the ever-increasing level of international travel. In the United States about 10,000 new cases of active TB were reported in 2013,3 and it is estimated 10 to 15 million people in the U.S. have LTBI.”2

Identifying those with LTBI

The Centers for Disease Control and Prevention (CDC) recommends TB testing for those at high risk of infection.4 These include foreign-born immigrants and their families; people whose immune systems are liable to be inadequate to fight against TB, such as those who have uncontrolled HIV or who are receiving new biologic therapies such as the TNF inhibitors; people who are in contact with those with active TB, such as household contacts; people who live or work in institutional settings where TB is more common (prisons, homeless shelters, some nursing homes); and those with symptoms compatible with TB.4 It is now also recommended that all college students are screened for TB risk factors and testing performed on those identified as high risk.5

Testing for TB – Skin Test

“The historic standard test has been the tuberculin skin test (TST), also referred to as the purified protein derivative or PPD,” says Dr. Leake. “This test is based on the placement of intradermal antigens from TB organisms, which generate a delayed type hypersensitivity immune response in people who are infected. The test is read after 48 or 72 hours, so this requires another office visit.”

“There are several shortcomings of this test,” continues Dr. Leake. “Firstly, the technology is not very specific.  Environmental mycobacteria, like Mycobacterium avium- intracellulare (MAI), can cross react and cause false positive tests. The TB vaccine that many people received in many regions of the world, the BCG (bacille Calmette-Guérin) vaccine, can cause these reactions. The technical aspect of the test is also suboptimal. In addition to the need for a return visit, it's not always evident whether or not a result is positive. In assessing the skin reaction some healthcare providers focus on the size or redness of the induration on the forearm, when it’s really the firmness of the induration that is the hallmark of a positive reaction. This leads to an overestimation of positive reactions. Correctly placing this mixture intradermally can also be a challenge - sometimes it is placed subcutaneously, which can cause a more allergic reaction as opposed to a genuine delayed-type hypersensitivity response.”

Newer Generation of Testing - Interferon-Gamma Release Assays

“The newer generation blood tests, interferon-gamma release assays (IGRAs), are much more convenient.  They provide a result within one to two days without the need for the patient to come back,” notes Dr. Leake. Other advantages of IGRA tests compared with the TST are increased specificity and no false-positive test result due to prior BCG vaccination. The CDC recommends that the IGRA test may be used as an alternative to the TST in most cases, and states that it’s preferred to the TST for those who have received BCG and for people with historically poor follow-up TST return rates.4 While TST is currently preferred over IGRAs for testing children less than 5 years of age, many pediatric infectious disease experts feel that IGRAs are likely to be reliable from as young as 2 years of age.4

Like the TST, IGRAs rely on the human immune response to tuberculosis to diagnose latent infection as opposed to detecting the organism directly. White blood cells from most people who have been infected with Mycobacterium tuberculosis will release interferon-gamma (IFN-γ) when mixed with antigens derived from M. tuberculosis. “Since these tests require an intact immune response, they may not be as accurate in severely immunocompromised patients, or if the immune system is generating IFN-γ for an unrelated reason which could lead to a false positive result,” says Dr. Leake.

Test Reliability

“Another advantage of the IGRA test platform,” continues Dr. Leake, “is that it gives an indication on the reliability of the result.  For example, for the Quantiferon IGRA assay, there are three possible results - positive, negative or indeterminate. There's a positive control and a negative control, and if one of those doesn't have a correct result then you have to call the test indeterminate. With a positive result you can be confident that it’s a true positive in a way that’s not possible with the TST, since the latter test has a high rate of false positives, while the specificity of the IGRA approaches 100%.  With a positive IGRA result, one can be confident that the patient's blood reacted to the TB antigens and also reacted appropriately to the control antigens that should induce IFN-γ production, while at the same time having little to no reaction to a negative control (saline).  Such data allow one to interpret  the validity of IGRAs more convincingly than TSTs in which a positive result may be due to BCG or environmental mycobacteria.”

Evaluating “Inappropriate” Results

“Before LTBI testing, we should consider a patient’s likelihood that they have TB risk factors,” says Dr. Leake. “In fact, one take-home message on this topic is that people at extremely low risk or no risk for TB really should not be tested, as a rule.  In these cases a higher proportion of tests are likely to be false positive results which may well lead to unnecessary evaluation (at the very least, chest radiographs) and therapy.  In such instances, or in high-risk patients, it may be advisable to test with a different methodology (e.g., TST after IGRA) to “break the tie” with the first test. With an IGRA indeterminate result, it may also sometimes be helpful to repeat the test, as the first test may have been performed sub-optimally – for example, the blood sample may not have been incubated properly or the tubes not shaken adequately.”

An Art and a Science

“The diagnosis of latent TB using laboratory tests is still an art as well as a science,” concludes Dr. Leake. “It combines assessments of the patient’s epidemiological risk and likelihood of developing active disease. While no diagnostic test for LTBI is perfect, the new generation of IGRAs do at least provide more information, even when they're indeterminate. They’re also more practical for many patients and clinics, since they do not require a return visit. I think the general trend is toward embracing the newer platforms and that over the next decade we'll probably do less skin testing, including in young children.”




  1. World Health Organization. Tuberculosis Fact Sheet No.104.

  2. Bennett DE, Courval JM, Onorato I et al. Prevalence of tuberculosis infection in the United States population: the national health and nutrition examination survey, 1999-2000. Am J Respir Crit Care Med. 2008 Feb 1;177(3):348-55. Epub 2007 Nov 7.

  3. CDC. Reported Tuberculosis in the United States, 2013. Atlanta, GA: U.S. Department of Health and Human Services, CDC, October 2014. Accessed 4th March, 2015.

  4. Centers for Disease Control and Prevention. Tuberculosis Fact Sheet.  Accessed 4th March, 2015

  5. Tuberculosis Screening and Targeted Testing of College and University Students. American College Health Association