What is the follow-up for an indeterminate Quantiferon (Interferon-Gamma Release Assay) TB test result?

Follow-Up for Indeterminate QuantiFERON-TB Test

For patients with indeterminate QuantiFERON results, the follow-up approach depends entirely on their risk level: high-risk patients should receive either a repeat QFT test with a new blood specimen or a tuberculin skin test (TST), while low-risk patients require no further testing. 1

Risk-Stratified Management Algorithm

High-Risk Patients (Require Additional Testing)

High-risk patients include the following groups and should undergo further evaluation 1:

• Close contacts of persons with infectious TB disease 1
• Immunocompromised individuals (including those on immunosuppressive therapy, HIV-positive patients, or those with autoimmune diseases) 1, 2
• Healthcare workers with occupational exposure 1
• Individuals from TB-endemic countries 1

For these high-risk patients, you have two options 3, 1:

1. Repeat the QFT test with a newly obtained blood specimen (not the same sample) 1
2. Administer a TST as an alternative 3, 1

Low-Risk Patients (No Further Testing Needed)

Patients without recognized risk factors for M. tuberculosis infection require no additional testing after an indeterminate result. 3, 1

When Active TB Disease is Suspected

If TB disease is clinically suspected based on symptoms or presentation, do not wait for repeat testing—immediately proceed with diagnostic evaluation including chest radiography, bacteriologic studies, and HIV serology. 3, 1 These evaluations should be performed before or simultaneously with any repeat QFT testing and should not be delayed while awaiting results 3.

Understanding Why Results Are Indeterminate

The laboratory should report the specific reason for the indeterminate result, which typically falls into two categories 3:

• High background levels of interferon-gamma in the nil (negative control) sample 3
• Inadequate response to mitogen (positive control failure) 3, 4

Inadequate mitogen response is strongly associated with immunosuppressive conditions and is the most common cause (occurring in approximately 89% of indeterminate results) 3, 4.

Clinical Factors Associated with Indeterminate Results

Be aware that certain patient characteristics significantly increase the likelihood of indeterminate results 4, 2, 5:

• Severe lymphocytopenia (8.8-fold increased odds) 2
• Elderly patients 4
• Chronic renal disease (2.8-fold increased odds) 2
• Autoimmune diseases (2.5-fold increased odds) 2
• Chronic lung disease (3.2-fold increased odds) 2
• Hypoalbuminemia 4, 5
• Bedridden status 5

Success Rate of Repeat Testing

When repeating the QFT test in patients with indeterminate results, expect variable success rates 4, 6:

• Only 17% of repeat tests may yield determinate results in elderly or severely immunocompromised patients 4
• However, 88% of indeterminate results can be resolved when using T-SPOT.TB as an alternative IGRA test, particularly if performed within 30 days 6
• The likelihood of obtaining a determinate result on repeat testing is lower in elderly and immunocompromised patients, so careful consideration is needed before pursuing this strategy 4

Important Considerations for TST as Alternative

If you choose TST as the follow-up test for an indeterminate QFT result 3, 1:

• Consider the potential for TST boosting and the need for two-step testing in settings that conduct serial testing 3, 1
• Remember that TST should never be used to follow up a positive QFT result (only for indeterminate results), as it provides no added value in that scenario 7, 1

Critical Pitfall to Avoid

Never perform a TST after a positive QFT result—this has no clinical utility. 7, 1 TST is only appropriate as an alternative test for indeterminate results, not for confirming positive results.

Treatment Decisions Despite Indeterminate Results

In certain high-risk scenarios, treatment should be considered even without a definitive test result 3:

• When the rate of M. tuberculosis transmission to other contacts was high 3
• When a false-negative result is suspected due to medical conditions affecting immune response 3
• Treatment decisions should incorporate all available epidemiologic, historic, clinical, physical, and diagnostic information, including findings from contact investigations 3, 7