Tuberculosis (TB) remains a significant global health concern, and accurate, timely diagnosis is crucial for effective control and treatment. While the tuberculin skin test has been a long-standing method, TB blood tests, also known as interferon-gamma release assays (IGRAs), offer a modern alternative with distinct advantages. This article delves into the background, benefits, limitations, and proper utilization of TB blood tests in diagnosing TB infection, particularly relevant in adult populations.
Understanding the TB Blood Test
The foundation of the TB blood test lies in the body’s immune response to Mycobacterium tuberculosis, the bacteria responsible for TB. These tests, known as interferon-gamma release assays (IGRAs), analyze a patient’s blood sample when exposed to synthetic peptides mirroring antigens from TB bacteria. These specific antigens are carefully selected; they are present in the M. tuberculosis complex, which includes M. bovis, but importantly, they are absent from the Bacille Calmette-Guérin (BCG) vaccine and most other types of mycobacteria.
When an individual is infected with TB bacteria, their immune system typically develops a specific immunity within six to eight weeks. During a TB blood test, certain white blood cells in an infected person’s blood will recognize and react to these simulated TB antigens by releasing interferon-gamma (IFN-γ). The test’s core function is to measure the level of this IFN-γ response. Control substances are incorporated into the test process. These controls serve as vital benchmarks, helping to validate the test results and establish a baseline level of IFN-γ for each individual being tested.
Currently, two TB blood tests have received the U.S. Food and Drug Administration (FDA) approval and are readily available in the United States:
- QuantiFERON®-TB Gold Plus (QFT-Plus)
- T-SPOT®.TB test (T-Spot)
QFT-Plus vs. T-Spot: Key Differences
While both QFT-Plus and T-Spot tests detect TB infection by measuring IFN-γ, they differ in several aspects:
| Characteristics | QFT-Plus | T-Spot |
|---|---|---|
| Processing Time | Within 16 hours (whole blood) | Within 8 to 32 hours (blood cells) |
| M. tuberculosis Antigens | ESAT-6 and CFP-10 | ESAT-6 and CFP-10 |
| Measurement | IFN-γ Concentration | Number of IFN-γ Producing Cells (spots) |
| Possible Results | Positive, Negative, Indeterminate | Positive, Negative, Invalid, Borderline |
Advantages of TB Blood Tests Over Skin Tests
TB blood tests offer several advantages compared to the traditional tuberculin skin test, primarily enhancing convenience and accuracy:
Key Benefits
- Single Patient Visit: A significant advantage of TB blood tests is that they only require one patient visit to complete the testing process. This is in contrast to the TB skin test, which necessitates a return visit for reading and interpretation, improving patient compliance and reducing logistical hurdles.
- No Booster Phenomenon: Unlike the TB skin test, TB blood tests do not trigger the booster phenomenon. The booster effect can occur when a person who was previously infected with TB but whose skin test reaction has waned receives a skin test years later, resulting in a falsely boosted reaction. TB blood tests avoid this issue, providing more reliable results in individuals who have had prior TB exposure or BCG vaccination.
- Reduced Bias and Error: TB skin tests are prone to subjective interpretation and technical errors in placement and reading. TB blood tests, being laboratory-based assays, minimize these biases and errors, leading to more objective and consistent results.
- Rapid Results: Results from TB blood tests are typically available within 24 hours after the blood sample reaches the laboratory, facilitating quicker diagnosis and initiation of appropriate treatment or preventive measures.
- Unaffected by BCG Vaccine: The BCG vaccine, used in many countries to prevent childhood TB, can cause false-positive reactions in TB skin tests, complicating interpretation, especially in vaccinated populations. TB blood tests are not affected by prior BCG vaccination, enhancing their specificity in BCG-vaccinated individuals. They are also generally unaffected by most nontuberculosis mycobacteria, further improving accuracy.
Limitations to Consider
Despite their advantages, TB blood tests also have certain limitations:
Potential Drawbacks
- Blood Sample Processing Time: TB blood tests require blood samples to be processed within a specific timeframe, ranging from 8 to 32 hours after collection, depending on the test type. This necessitates efficient sample handling and laboratory logistics.
- Accuracy Concerns: Errors in blood collection, transportation, or test execution and interpretation can compromise the accuracy of TB blood tests, potentially leading to false results. Strict adherence to standardized procedures and quality control measures are essential to maintain test reliability.
- Turnaround Time Variability: While generally faster than skin tests overall result availability can still vary, taking several days depending on the laboratory and clinic’s processing times and workflow. This turnaround time should be considered in clinical decision-making and patient management.
- Cost Factor: TB blood tests may be more expensive than TB skin tests, which could be a factor in resource-limited settings or for large-scale screening programs. Cost-effectiveness analyses should be considered when choosing between testing methods, especially in public health contexts.
Guiding Test Selection
When deciding to use a TB blood test, healthcare providers should consider several factors to ensure appropriate test utilization. Consulting the FDA-approved product labeling for the specific IGRA being used is crucial for detailed information on test characteristics, precautions, and result interpretation guidelines.
The Centers for Disease Control and Prevention (CDC) offers valuable resources to aid healthcare providers in discussions with patients about TB testing and treatment. Current recommendations emphasize TB blood tests as the preferred method for TB infection testing, particularly in:
- Individuals who have received the BCG vaccine, where skin test interpretation is complicated.
- People who may face challenges returning for the reading and interpretation of a TB skin test, improving follow-through and diagnostic completion.
When considering a TB blood test for a patient, factors such as age and vaccination history should be taken into account.
Age Considerations
Current CDC guidelines generally recommend the TB skin test as the primary method for children under 5 years old. However, it’s important to note that expert opinions vary, and some clinicians do utilize TB blood tests even in younger children. Healthcare providers may find it helpful to consult guidance from the American Academy of Pediatrics (AAP) for specific recommendations on TB blood test use in pediatric populations. Practical considerations, such as obtaining a sufficient blood sample volume, can sometimes pose challenges when testing very young children with TB blood tests.
Vaccination History
Vaccination status, particularly regarding live virus vaccines, can impact TB test timing and interpretation.
Live Virus Vaccination
Vaccinations with live viruses, such as measles, mumps, rubella, oral polio, varicella, and yellow fever vaccines, can potentially interfere with TB blood test reactions, leading to inaccurate results. For individuals scheduled to undergo TB blood testing, it is recommended that testing be performed:
- On the same day as live-virus vaccination, or
- At least one month after the administration of the live-virus vaccine to avoid potential interference.
Other Vaccinations
Vaccination with inactivated viruses, in contrast to live virus vaccines, does not interfere with TB blood test reactions. Importantly, COVID-19 vaccination should not be delayed due to TB infection testing needs. TB blood tests are not anticipated to affect the safety or effectiveness of COVID-19 vaccines. Therefore, TB blood testing can be conducted conveniently before, during, or after a COVID-19 vaccination appointment.
Prior TB History
TB blood tests, like TB skin tests, are not recommended for individuals with documented evidence of a previous positive TB test result (either blood test or skin test) or a history of TB disease treatment. In most cases, individuals who have had a positive TB test will continue to test positive. Repeat TB blood tests in such individuals are unlikely to provide additional clinical value and are generally not indicated.
Performing the TB Blood Test
Proper TB blood test administration is crucial for accurate and reliable results. Healthcare providers should receive adequate training on TB blood test procedures. Adhering to the manufacturer’s instructions is essential. Key steps include:
- Laboratory Confirmation: Verify testing arrangements with a qualified laboratory. Note that laboratory service availability may vary, with some laboratories offering only one type of TB blood test or none at all.
- Sample Delivery Arrangements: Coordinate the timely delivery of blood samples to the laboratory within the laboratory’s specified timeframe to ensure testing of viable blood cells.
- Blood Sample Collection: Collect the blood sample from the patient strictly following the test manufacturer’s detailed instructions. It’s important to recognize that blood collection and initial processing procedures differ between the two available TB blood tests (QFT-Plus and T-Spot).
- Follow-up Scheduling: Schedule a follow-up appointment for the patient to receive and discuss their test results.
- Evaluation and Treatment: Provide appropriate follow-up evaluation and treatment based on the TB blood test results and individual patient circumstances.
Interpreting Test Results
The interpretation of TB blood test results is test-specific:
QFT-Plus: Results are determined by quantifying the amount of IFN-γ released in response to TB antigens and control substances after blood incubation.
T-Spot: Results are based on comparing the number of IFN-γ producing cells (spots) after blood incubation with the same substances.
Laboratories should provide both qualitative and quantitative results:
- Qualitative Results:
- QFT-Plus: Reported as positive, negative, or indeterminate.
- T-Spot: Reported as positive, borderline, negative, or invalid.
- Quantitative Results: Numerical values reflecting responses to TB antigen and controls (nil and mitogen). While specific interpretive guidelines are lacking for quantitative IGRA results, they can be helpful in understanding qualitative results in individual cases, especially when considered alongside risk factors.
Understanding Result Categories
- Positive Result: A positive TB blood test result usually indicates TB infection. Further evaluation, including a chest radiograph, is necessary to rule out active TB disease.
- Negative Result: A negative result suggests TB infection is unlikely but cannot be entirely excluded, particularly in certain situations. A negative result may not definitively rule out TB infection, especially if the patient:
- Borderline, Indeterminate, or Invalid Results: These results (borderline for T-Spot, indeterminate for QFT-Plus, and invalid for T-Spot) indicate that the test did not yield useful information regarding TB infection likelihood. In such cases, repeating the TB blood test or performing a TB skin test may be considered to obtain a more conclusive result.
Test Accuracy Considerations
TB blood tests are generally highly accurate, but factors can influence their reliability, leading to false results.
False-Positive Results
False-positive TB blood test results can occur due to procedural errors during test execution or interpretation. Healthcare providers must strictly adhere to manufacturer’s instructions to minimize the risk of false-positive results.
False-Negative Results
False-negative results, where an individual is infected with TB bacteria but tests negative, can also occur.
False-negative TB blood test results can arise if TB infection occurred recently, within 8 weeks of testing. It typically takes 2 to 8 weeks post-TB infection for the immune system to mount a detectable response. For individuals who are contacts of persons with infectious TB disease and initially test negative, repeat testing 8 to 10 weeks after the last exposure is recommended to confirm the absence of infection.
Patients with advanced HIV infection (AIDS) or severe immunosuppression, such as sepsis, are also at higher risk of false-negative results due to compromised immune responses.
Other factors contributing to false-negative TB blood test results include:
- Improper blood sample collection techniques.
- Incorrect handling of blood collection tubes.
- Inaccurate assay performance in the laboratory.
Actions Following Test Results
For individuals with a positive TB blood test result or symptoms suggestive of TB disease, further evaluation for TB disease is essential. This evaluation includes:
- Chest radiograph.
- Bacteriologic examinations of sputum specimens, as appropriate.
If latent TB infection is diagnosed, effective short-course treatment regimens are available. Treatment for latent TB infection is highly effective, reducing the risk of progression to active TB disease by approximately 90%. State or local TB programs can provide valuable resources and guidance on latent TB infection management.
It is critical to emphasize that a negative TB blood test result does not definitively rule out active TB disease, particularly in patients with severe TB illness or HIV co-infection. Clinical judgment and further investigations are necessary in such cases.
Reporting Requirements
Both presumed and confirmed cases of active TB disease are reportable to the health department. Latent TB infection is also a reportable condition in certain states. Healthcare providers should consult their state TB program for specific reporting requirements in their jurisdiction.
Keep Reading: Clinical and Laboratory Diagnosis for Tuberculosis
Resources
Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection — United States, 2010
