Management of Indeterminate QuantiFERON-Gold Results
For patients with increased likelihood of M. tuberculosis infection and an indeterminate QuantiFERON-Gold result, repeat testing with either a new QuantiFERON-Gold sample or perform a tuberculin skin test (TST); for those unlikely to have infection, no further testing is necessary. 1
Risk-Stratified Approach
The next step depends critically on the patient's risk profile for M. tuberculosis infection:
High-Risk Patients (Repeat Testing Recommended)
Perform a second test—either repeat QuantiFERON-Gold with a new blood specimen or administer a TST in patients with: 1
- Recent contact with infectious TB cases
- Immunosuppressive conditions (HIV infection, pharmacological immunosuppression, severe lymphopenia) 1, 2
- Plans to initiate anti-TNF or other biologic therapy 3
- Origin from or prolonged stay in TB-endemic areas
- Severe illness requiring hospitalization 2, 4
Important timing consideration: If repeating QuantiFERON-Gold after an indeterminate result, performing the T-SPOT.TB test within 30 days resolves 84.8% of indeterminate results, compared to lower resolution rates with delayed testing. 5
Low-Risk Patients (No Further Testing)
No additional testing is necessary for persons unlikely to have M. tuberculosis infection after an indeterminate result. 1
Understanding Indeterminate Results
Common Causes to Review
Laboratories should report why the result was indeterminate: 1
- Low mitogen response (most common—accounts for 96% of indeterminate results) 2, 4
- High background IFN-γ in the nil sample 1
Clinical Factors Associated with Indeterminate Results
Be aware that indeterminate results are significantly more common in: 2, 6, 4
- Severe COVID-19 infection (OR 3.9) 2
- Hospitalized patients (OR 3.9) 2, 4
- Pharmacological immunosuppression (OR 1.7) 2
- Severe lymphopenia (OR 1.7) 2, 4
- Anemia (OR 1.9) 2
- Hypoalbuminemia (OR 6.81) 4
- Female sex (OR 1.64) 4
Clinical pearl: In severely ill COVID-19 patients, over 60% demonstrate inability to produce measurable IFN-γ when stimulated with mitogen, making QuantiFERON-Gold testing unreliable in this population. 6
Practical Testing Considerations
If Choosing TST as Second Test
Consider that TST can cause boosting, which complicates interpretation in settings requiring serial testing. 1 Two-step testing protocols may be needed for baseline establishment in serial testing programs. 1
If Repeating QuantiFERON-Gold
- Use a new blood specimen 1
- Repeat testing yields another indeterminate result in 42% of cases 4
- Ensure proper sample collection by trained phlebotomists (non-phlebotomist collection increases indeterminate results 3-fold) 4
Alternative: T-SPOT.TB Test
For patients with indeterminate QuantiFERON-Gold results, the T-SPOT.TB provides definitive results in 87.6% of cases when performed within 30 days. 5 This resolves 80 negative and 40 positive results among indeterminate cases. 5
Special Circumstances
If Active TB Disease is Suspected
Do not delay diagnostic evaluation while awaiting or repeating QuantiFERON-Gold results. 1 Proceed immediately with: 1
- Chest radiography
- Bacteriologic studies (sputum microscopy, culture, PCR)
- HIV serology
- Additional testing based on clinical presentation
Timing Considerations for Severely Ill Patients
Postpone QuantiFERON-Gold testing until clinical condition improves in patients with severe acute illness, as indeterminate results are highly prevalent (10% overall, higher in hospitalized patients) and reflect deficient IFN-γ responses rather than true infection status. 2, 6, 4
Window Period Contacts
For contacts requiring window period prophylaxis (children <5 years or severely immunocompromised persons exposed to highly contagious TB), repeat testing should occur 8-10 weeks after exposure ends, regardless of initial indeterminate result. 1
Key Pitfalls to Avoid
- Do not assume an indeterminate result provides any information about infection likelihood—it is a failed test, not a negative result. 1
- Do not perform QuantiFERON-Gold testing in severely ill hospitalized patients when it can be deferred, as the indeterminate rate approaches 20% in this population. 4
- Do not repeat testing in low-risk individuals simply because the result was indeterminate—this wastes resources without improving patient outcomes. 1