Tuberculosis (TB) remains a major global health concern, with a significant portion of the world’s population carrying the latent form of the infection. Latent TB infection means the bacteria are present in the body but are not actively causing disease or symptoms. Identifying these individuals is important because they are at risk of developing active, transmissible disease later on. Accurate diagnostic testing is necessary to identify those who carry the bacteria and could benefit from preventive treatment. This article examines the reliability of the modern blood test, focusing specifically on the likelihood of receiving a positive result when no infection is actually present.
Understanding the TB Blood Test
The modern method for detecting Mycobacterium tuberculosis infection is the Interferon-Gamma Release Assay (IGRA). This blood test measures the immune system’s reaction to proteins specific to the TB bacteria and requires only a single blood draw.
The basic mechanism relies on specialized white blood cells, called T-cells, which “remember” past exposure. When the blood sample is mixed with synthetic TB antigens (such as ESAT-6 and CFP-10), T-cells from an infected person release interferon-gamma. The test measures the quantity of this chemical messenger to determine if an infection has occurred.
The IGRA is an improvement over the older Tuberculin Skin Test (TST), especially for those who have received the Bacille Calmette-Guérin (BCG) vaccine. BCG vaccination, common in many countries, often causes false-positive results on the TST because it uses a related bacterial strain. Since the IGRA uses highly specific antigens not found in the BCG vaccine, its results are generally unaffected by prior vaccination.
Quantifying False Positives
The likelihood of a false-positive IGRA result is directly related to the test’s specificity, which is its ability to correctly identify people who do not have a TB infection. In low-risk populations, studies consistently show the specificity of available IGRA tests, such as QuantiFERON-TB Gold Plus and T-SPOT.TB, to be very high. This high specificity means the false positive rate is generally quite low.
In low-prevalence settings, where most people tested are truly uninfected, the specificity of these assays is often cited in the range of 97.8% to 99%. This means that for every 100 uninfected people tested, approximately one to two individuals may receive a false-positive result.
For example, pooled estimates for the specificity of the QuantiFERON-TB Gold Plus test are around 97.8%, while the T-SPOT.TB test is estimated at 98.1% in similar populations. These figures demonstrate that while the test is highly accurate, it is not perfect. The interpretation of a positive result must always take into account the individual’s actual risk factors, as the statistical likelihood of a result being false is higher when the risk of true infection is low.
Biological Factors Leading to Non-Infection Positives
While the IGRA is highly specific, false-positive results are often traceable to biological cross-reactivity or issues related to test processing. One major biological factor is exposure to Non-Tuberculous Mycobacteria (NTM), which are common in the environment and do not cause TB disease. Some NTM species share antigens with M. tuberculosis, specifically the ESAT-6 and CFP-10 proteins.
Exposure to these NTM strains can cause T-cells to react in the IGRA test. The immune system recognizes the shared antigen and releases interferon-gamma, leading to a positive result despite the absence of true TB bacteria. This cross-reactivity is a known limitation, though modern IGRAs are designed to minimize this effect.
Another source of error arises from the biological variability inherent in measuring an immune response, especially for results that fall close to the test’s cut-off threshold. These borderline or “gray zone” results are less reliable than clearly positive or negative results. A result near the cut-off may reflect transient immune activation or statistical noise rather than a stable infection.
Technical factors related to blood handling and laboratory processing also contribute to false positives. The sample must be processed within a specific time window (typically 8 to 30 hours) while the white blood cells are still viable. Errors such as delayed incubation or incorrect temperature can artificially affect the measured interferon-gamma levels, leading to an elevated immune signal and a positive outcome.
Next Steps After a Positive Result
A positive IGRA test result should never be interpreted in isolation, as it indicates only an immune response to the TB bacteria. The immediate next step is a comprehensive clinical evaluation to determine if the infection is latent or has progressed to active TB disease. This distinction is important because latent infection is asymptomatic and not contagious, while active TB requires immediate treatment and isolation.
The evaluation includes a thorough medical history review to assess risk factors, such as contact with active TB cases or travel to high-prevalence areas. A chest X-ray is mandatory to look for signs of lung damage consistent with active disease. If the X-ray suggests active disease or if the patient reports symptoms like a persistent cough or unexplained weight loss, further bacteriologic examinations, such as sputum samples, are necessary.
If the clinical evaluation rules out active disease, the positive IGRA result is interpreted as latent TB infection. In low-risk individuals with no known exposure, a low-level positive result may prompt a repeat IGRA or an alternative test to confirm the finding before treatment is initiated. The decision to treat is based on a clinical correlation, weighing the test result against the individual’s overall risk profile.