TB Spot Test After Negative TST and Indeterminate QuantiFERON Gold
Yes, repeat testing with either a new QuantiFERON Gold specimen or a TB spot test (T-SPOT.TB) is necessary for high-risk patients with a negative TST and indeterminate QuantiFERON Gold result. 1, 2
Risk-Stratified Approach to Management
The decision to pursue additional testing depends critically on the patient's TB risk profile:
High-Risk Patients Requiring Repeat Testing
Repeat testing is mandatory for patients in any of these categories 1, 2:
- Close contacts of persons with infectious TB disease - highest priority group
- Immunocompromised individuals (HIV-infected, on immunosuppressive therapy, organ transplant recipients)
- Healthcare workers with ongoing TB exposure risk
- Individuals from TB-endemic countries
- Children aged <5 years
- Patients with medical conditions increasing progression risk (diabetes, chronic kidney disease, silicosis, malignancy)
For these high-risk patients, the CDC recommends either repeating the QuantiFERON test with a newly obtained blood specimen or performing a tuberculin skin test 1, 2, 3
Low-Risk Patients Requiring No Further Testing
No additional testing is needed for patients without identifiable TB risk factors after an indeterminate result 1, 2
Understanding Why the Result Was Indeterminate
Indeterminate results occur for two specific reasons 1:
- Inadequate mitogen response (IFN-γ ≤0.5 IU/mL in positive control) - suggests impaired T-cell function
- High background IFN-γ (>8 IU/mL in nil control) - suggests non-specific immune activation
Indeterminate results are significantly more common in immunocompromised populations, occurring in 21.4% of immunocompromised patients versus 9.6% of immunocompetent patients 4. These results are associated with anemia, lymphocytopenia, hypoproteinemia, and hypoalbuminemia 4
Repeat Testing Strategy
For QuantiFERON Repeat Testing
Always use a newly obtained blood specimen - never retest the same sample 1, 2, 3
For T-SPOT.TB Testing
The T-SPOT.TB may be preferable in immunocompromised patients as it has fewer indeterminate results (5.8% for T-SPOT.TB versus higher rates for QuantiFERON in some studies) 5. The T-SPOT.TB uses an ELISPOT method that may perform better when lymphocyte counts are low 4
For TST as Alternative
If using TST as the repeat test, consider two-step testing in serial testing settings due to potential TST boosting 1, 2
Critical Pitfall: When Active TB Disease is Suspected
Do not delay diagnostic evaluation while awaiting repeat testing if clinical suspicion for active TB exists 1, 2. Immediately perform:
- Chest radiography
- Bacteriologic studies (sputum AFB smear and culture)
- HIV serology
Neither IGRAs nor TST can distinguish latent TB infection from active TB disease 3
Special Considerations in Immunocompromised Patients
In immunocompromised patients on biologics (particularly anti-TNF therapy), the British Society of Gastroenterology recommends screening with interferon-gamma release assays rather than TST because TST has a high false-negative rate due to anergy 3. In one study, 83% of patients on steroids or immunomodulators were anergic to TST versus 43% not on these therapies 3
Consider empiric LTBI treatment in close contacts with high transmission risk or patients at high risk for progression to active disease, even without confirmatory testing 1. Treatment decisions should incorporate all epidemiologic, historical, clinical, and diagnostic information 1, 6
The Role of Both Tests Together
For immunocompromised patients, using both TST and IGRA may maximize screening efficacy 4. When the initial test is negative but risk remains high, a positive result from a second test increases detection sensitivity 3. However, multiple negative results from any combination of tests cannot exclude M. tuberculosis infection 3