Management of Indeterminate QuantiFERON Gold Plus Results
For patients with indeterminate QuantiFERON Gold Plus results, management depends on TB risk stratification: high-risk patients require repeat testing with either a new QFT-Plus specimen or tuberculin skin test (TST), while low-risk patients need no further testing. 1
Risk-Stratified Management Algorithm
High-Risk Patients (Require Additional Testing)
High-risk patients who warrant repeat testing include: 1
- Close contacts of persons with infectious TB disease 1
- Immunocompromised individuals (HIV infection, immunosuppressive therapy including TNF-α antagonists, organ transplant recipients, high-dose corticosteroids ≥15 mg prednisone daily) 2
- Healthcare workers with ongoing TB exposure risk 1
- Individuals from TB-endemic countries 1
- Children aged <5 years (higher risk for progression to severe disease) 2
- Patients with medical conditions increasing progression risk (silicosis, diabetes, chronic renal failure, hematologic malignancies, head/neck/lung cancer) 2
Low-Risk Patients (No Further Testing Required)
Patients without identifiable TB risk factors require no additional testing after an indeterminate result. 2, 1
Understanding Indeterminate Results
Indeterminate results occur due to two specific patterns: 2
- Inadequate mitogen response (IFN-γ ≤0.5 IU/mL in positive control) - suggests immunosuppression or lymphocyte dysfunction 2
- High background IFN-γ (>8 IU/mL in nil control) - indicates nonspecific immune activation 2
Laboratories must report the specific reason for the indeterminate result, as this guides clinical interpretation and management decisions. 2, 1
Repeat Testing Strategy for High-Risk Patients
Option 1: Repeat QFT-Plus
- Use a newly obtained blood specimen (not the same sample) 1
- Optimal timing: within 30 days of initial test for best resolution rate (84.8% success) 3
- Consider T-SPOT.TB as alternative IGRA if second QFT-Plus remains indeterminate (resolves 87.6% of indeterminate cases) 3
Option 2: Tuberculin Skin Test
- Valid alternative for indeterminate QFT-Plus results 2, 1
- Consider two-step testing in serial testing settings due to TST boosting potential 2, 1
- TST may be preferred in patients with suspected immunosuppression causing inadequate mitogen response 2
When Active TB Disease is Suspected
If clinical suspicion for active TB exists, do not delay diagnostic evaluation while awaiting repeat testing. Immediately perform: 2, 1
- Chest radiography 2, 1
- Bacteriologic studies (sputum AFB smear and culture) 2, 1
- HIV serology 2, 1
- Additional studies as clinically indicated 2
An indeterminate IGRA result does not exclude active TB disease in symptomatic patients. 2
Risk Factors Associated with Indeterminate Results
Recent research identifies specific predictors of indeterminate results: 4
- Lymphopenia (absolute lymphocyte count <1.15 × 10⁹ cells) 4
- Hypoalbuminemia 4
- Decreased estimated glomerular filtration rate 4
- Immunosuppressive drug therapy (particularly duration of treatment) 4
- Lower CD4+ T cell counts (<467.7-478.5 × 10⁶ cells) 5
Critical Pitfalls to Avoid
Never follow a positive QFT-Plus with a TST - this provides no added value and wastes resources. 6, 1 However, TST remains appropriate for indeterminate results in high-risk patients. 1
Do not assume indeterminate results mean negative - in high-risk patients, indeterminate results require the same cautious approach as if testing had not been performed. 2
Avoid using the same blood specimen for repeat testing - always obtain a fresh sample if repeating QFT-Plus. 1
Special Considerations in Immunocompromised Patients
Indeterminate results are more common in immunocompromised populations (up to 21% in some studies). 2 In patients receiving long-term immunosuppressive therapy, QFT-Plus may detect more latent TB infections than older QFT versions. 5
For patients with sustained lymphocytopenia, high IFN-γ production can still occur despite low lymphocyte counts, particularly in disseminated TB, making interpretation complex. 7 Clinical context remains paramount in these cases.
Treatment Decisions After Indeterminate Results
For high-risk patients with indeterminate results who cannot be retested or have persistently indeterminate results, treatment decisions should incorporate all epidemiologic, historical, clinical, and diagnostic information. 6 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. 2