Management of Indeterminate QuantiFERON‑TB Gold Results (CDC Recommendations)

Interpretation of an Indeterminate Result

An indeterminate QuantiFERON‑TB Gold (QFT‑G) result provides no useful information about the presence of Mycobacterium tuberculosis infection and therefore requires risk‑stratified follow‑up testing. 1
Indeterminate results arise from high background interferon‑γ (IFN‑γ) in the nil/negative control, reflecting non‑specific immune activation. 2
Indeterminate results also arise from inadequate response to the mitogen positive control, indicating impaired T‑cell function that is often linked to immunosuppression. 2
The laboratory must specify which control failure (high nil or low mitogen) caused the indeterminate result, as this guides subsequent clinical interpretation. 2

In persons unlikely to have TB infection, no further testing is required after an indeterminate QFT‑G result. 2

For patients at increased likelihood of infection, clinicians may repeat QFT‑G with a newly drawn blood specimen or perform a tuberculin skin test (TST).
When TST is chosen as the alternative, be aware that TST can boost subsequent test results, necessitating a two‑step testing protocol in serial testing settings. 2

If clinical suspicion for active TB disease exists, additional diagnostic evaluations must be initiated immediately, without awaiting QFT‑G results. 2
Required evaluations include:
- Chest radiography,
- Sputum acid‑fast bacilli smear and culture,
- HIV serology, and
- Any other tests indicated by the clinical presentation. 2
An indeterminate QFT‑G result must not delay or influence the selection of these diagnostic investigations. 2

Positive‑control failure (low mitogen response) is associated with immunocompromised conditions (e.g., HIV infection, use of TNF‑α antagonists, other immunosuppressive therapies). 2

Do not delay evaluation for active TB disease while awaiting or repeating QFT‑G results. 2
Do not interpret an indeterminate result as “negative”; it conveys no information about infection status. 1

All facts are derived from CDC (MMWR Recommendations and Reports) guidance and are supported by the cited references.

High-risk patients, including close contacts of persons with infectious TB disease, immunocompromised individuals, healthcare workers, and individuals from TB-endemic countries, should receive either a repeat QFT-G test with a new blood specimen or a tuberculin skin test (TST) after an indeterminate QuantiFERON-TB Gold test result, as recommended by the Centers for Disease Control and Prevention (CDC) 3
The CDC recommends that low-risk patients require no further testing after an indeterminate QFT-G result 3, 4

When TB disease is clinically suspected, additional diagnostic evaluations, including chest radiography, bacteriologic studies, and HIV serology, should be performed immediately, as recommended by the CDC 3, 5, 6

Laboratories should report the specific reason for the indeterminate result to guide clinical interpretation, according to the CDC 3, 4

If repeating the QFT-G test, a newly obtained blood specimen should be used rather than retesting the same sample, as recommended by the CDC 3, 4
The CDC advises considering the need for two-step testing when using TST as an alternative test, due to the potential for boosting of subsequent test results 3, 4

The CDC recommends against following a positive QFT-G test with a TST, as it provides no added value, but notes that TST remains a valid alternative option for indeterminate results 3, 4