Management of Indeterminate QuantiFERON-TB Gold Results
What an Indeterminate Result Means
An indeterminate QuantiFERON-TB Gold result provides no useful information about whether M. tuberculosis infection is present and requires risk-stratified follow-up testing. 1
An indeterminate result occurs due to either:
- High background interferon-gamma (IFN-γ) in the nil/negative control sample (indicating non-specific immune activation) 1
- Inadequate response to mitogen in the positive control (indicating impaired T-cell function, often associated with immunosuppression) 1, 2
The laboratory must report which type of control failure caused the indeterminate result, as this guides clinical interpretation. 1
Risk-Stratified Management Approach
High-Risk Patients Requiring Repeat Testing
For patients at increased likelihood of M. tuberculosis infection, perform either a repeat QFT-G with a newly obtained blood specimen OR administer a tuberculin skin test (TST). 3
High-risk patients include:
- Close contacts of persons with infectious TB disease 3
- Immunocompromised individuals (HIV-infected, TNF-α antagonist therapy, other immunosuppressive medications) 3
- Healthcare workers 3
- Individuals from TB-endemic countries 3
- Recent immigrants from high TB burden countries 3
When choosing TST as the alternative, consider that it can cause boosting of subsequent test results, requiring two-step testing protocols in serial testing settings. 1, 3
Low-Risk Patients
No further testing is necessary after an indeterminate QFT-G result in persons unlikely to have M. tuberculosis infection. 1, 3
If Active TB Disease is Suspected
When TB disease is clinically suspected, immediately perform additional diagnostic evaluations without waiting for QFT-G results. 1, 3
Required evaluations include:
- Chest radiography 1, 3
- Bacteriologic studies (sputum acid-fast bacilli smear and culture) 1, 3
- HIV serology 1, 3
- Additional tests as indicated by clinical presentation 1
The indeterminate QFT-G result should not delay or influence the selection of these diagnostic tests. 1
Repeat Testing Strategy
If repeating QFT-G:
- Use a newly obtained blood specimen, not the same sample 3
- Expect that 16-32% of repeat tests will remain indeterminate 2, 4
- When indeterminate results recur, they are typically the same type (same control failure) 4
Risk Factors for Indeterminate Results
Understanding these helps predict who may have persistent indeterminate results:
Positive control failure (low mitogen response) is associated with:
- Elderly patients 2
- Immunocompromised conditions 1, 2
- Lymphocytopenia 2, 5
- Hypoalbuminemia 2, 5
- Immunosuppressive drug therapy and longer treatment duration 5
- Decreased estimated glomerular filtration rate 5
- Age <10 years, female sex, Asian race, and US-born status 4
Negative control failure (high nil/background IFN-γ) is associated with:
- Hispanic ethnicity 4
- Foreign-born status 4
- Active TB disease with high antigen burden (rare but reported in miliary TB) 6
Critical Pitfalls to Avoid
- Never follow a positive QFT-G with a TST – this provides no added value 3
- Never delay evaluation for active TB disease while awaiting or repeating QFT-G results 1, 3
- Never assume an indeterminate result means "negative" – it provides no information about infection status 1
- Be cautious in elderly and immunocompromised patients – the probability of obtaining determinate results on repeat testing may be low 2
- Consider that indeterminate results in miliary TB can occur with either high or low IFN-γ production, even with lymphocytopenia 6
When Repeat Testing Yields Determinate Results
Among those who undergo repeat QFT-G testing:
- Approximately 64% will test negative 4
- Approximately 4% will test positive 4
- Approximately 32% will have a second indeterminate result 4
If the repeat test is positive or if clinical suspicion remains high despite negative repeat testing, proceed with chest radiography and evaluation for latent TB infection treatment as appropriate for the patient's risk category. 3