Why is my TB-IGRA Result Indeterminate? Comparing AdvanSure, QFT-Plus, and T-SPOT.TB
Why is my TB-IGRA Result Indeterminate? Comparing AdvanSure, QFT-Plus, and T-SPOT.TB
Interferon-Gamma Release Assays (IGRA) are essential tools for screening latent tuberculosis infection (LTBI). However, clinicians often encounter an “Indeterminate” result, which can be frustrating to interpret.
In this article, we will break down the causes of indeterminate results, compare the performance of AdvanSure TB-IGRA, QFT-Plus, and T-SPOT.TB, and discuss the best clinical approach for retesting.
1. What Does an “Indeterminate” Result Actually Mean?
An indeterminate result is not a negative result. It simply means the test could not be interpreted due to one of two technical reasons:
A. High Background (Nil) Level
- Cause: The “Nil” tube (negative control) shows abnormally high IFN-$\gamma$ levels.
- Clinical Factors: Acute infections, systemic inflammation, autoimmune diseases, or heterophile antibodies.
- Outcome: Non-specific IFN-$\gamma$ production makes it impossible to distinguish a true TB-specific response.
B. Low Mitogen (Positive Control) Response
- Cause: The patient’s immune cells fail to respond to a non-specific stimulant (PHA/Mitogen).
- Clinical Factors: Immunosuppression (steroids, chemotherapy, HIV, ESRD), lymphopenia, advanced age, or technical errors (delayed incubation/improper storage).
- Outcome: The test is invalid because the patient’s immune system is too weak to provide a reliable signal.
2. Comparison of Leading IGRA Assays
While all three assays target M. tuberculosis specific antigens (ESAT-6 and CFP-10), their methodologies and indeterminate rates differ significantly.
| Feature | QFT-Plus | AdvanSure TB-IGRA | T-SPOT.TB |
| Method | ELISA (Whole Blood) | ELISA (Whole Blood) | ELISPOT (Isolated PBMCs) |
| Sensitivity | 80–90% | 85–90% | ~95% (Highest) |
| Indeterminate Rate | 3–8% | 2–6% | 1–3% (Lowest) |
| Best for… | General Screening | General/Clinical Use | Immunocompromised Patients |
■ QuantiFERON-TB Gold Plus (QFT-Plus)
The most widely used assay. However, it is sensitive to blood handling and has higher indeterminate rates in patients with low lymphocyte counts.
■ AdvanSure TB-IGRA
A popular ELISA-based assay in Korea. Recent studies suggest it offers performance comparable to QFT-Plus, with some reports showing slightly lower indeterminate rates due to its optimized processing.
■ T-SPOT.TB (The Gold Standard for Sensitivity)
T-SPOT.TB uses an ELISPOT technique where peripheral blood mononuclear cells (PBMCs) are isolated and counted before testing.
- Key Advantage: By normalizing the number of lymphocytes, it maintains high sensitivity even in patients with lymphopenia (HIV, organ transplant, or cancer patients).
3. Clinical Approach to Indeterminate Results
If you receive an indeterminate report, follow this diagnostic algorithm:
- For Immunocompromised Patients: If QFT or AdvanSure returns indeterminate, switch to T-SPOT.TB. Its ability to adjust for cell counts makes it far more reliable in this population.
- For General Patients: A 4-week wait followed by a retest (using the same or a different assay) is often sufficient to resolve technical or transient issues.
- In Suspected Active TB: Remember that IGRA is not a diagnostic tool for active disease. Prioritize Chest X-ray/CT, Sputum AFB smear/culture, and TB-PCR (e.g., Xpert MTB/RIF).
Conclusion
An indeterminate IGRA result is a call for further clinical investigation, not a sign of “no infection.” Understanding the strengths of ELISPOT (T-SPOT) versus ELISA (QFT/AdvanSure) allows for a more personalized and accurate screening strategy, especially for vulnerable patients.
Have you encountered persistent indeterminate results in your clinic? Share your experience or questions in the comments below.
📚 Selected References
- Kim SY et al. Performance of AdvanSure TB-IGRA Compared with QuantiFERON-TB Gold Plus. Tuberc Respir Dis. 2021.
- Lee SH et al. Comparison of IGRA assays including T-SPOT.TB in immunocompromised patients. Clin Infect Dis. 2019.
- Pai M et al. Interferon-$\gamma$ release assays in clinical practice. Lancet Infect Dis. 2014.