The Quantiferon-TB Gold Plus (QFT-Plus) test is a modern blood test designed to identify latent tuberculosis infection (LTBI), which occurs when a person is infected with Mycobacterium tuberculosis but shows no symptoms. This interferon-gamma release assay (IGRA) is an important tool used in clinical settings to prevent the progression to active tuberculosis disease. It is often preferred over the older tuberculin skin test, especially for individuals who have received the BCG vaccine, because it is generally more specific. The QFT-Plus test determines if the body’s T-cells have previously encountered TB-specific proteins. While results are typically positive (latent infection) or negative (no infection), a third outcome, the “indeterminate” result, requires understanding the test’s internal quality checks.
How the Test Controls Work
The reliability of a QFT-Plus result depends on the successful function of its internal controls, which are built into the blood collection tubes. These controls ensure the test is working correctly for the specific blood sample. The “Nil” control serves as the negative control. This tube contains no stimulating antigens and measures the baseline amount of interferon-gamma (IFN-γ) released by the patient’s blood cells without specific stimulation. This background level of IFN-γ must be low for the test to be valid; if it is too high, it indicates non-specific reactivity that could mask a true result.
The “Mitogen” control functions as the positive control. This tube contains a substance known to stimulate T-cells non-specifically, prompting them to release a large amount of IFN-γ. This control checks the responsiveness of the patient’s immune system. A robust IFN-γ response confirms that the patient’s T-cells are capable of producing IFN-γ and that the sample was handled and incubated correctly. This proves the immune cells are functional enough to react to the TB antigens if an infection were present. The validity of any result relies entirely on both the Nil and Mitogen controls performing within a defined range.
Decoding the Indeterminate Result
An indeterminate result means the QFT-Plus test failed its internal quality checks and is invalid; it cannot be interpreted as positive or negative for LTBI. This outcome signifies that the laboratory cannot determine if the patient is infected with M. tuberculosis. The indeterminate designation indicates an underlying problem with the sample or the patient’s immune response, not a diagnostic finding itself.
This lack of a clear result typically occurs in one of two ways. The first is when the Nil control value is excessively high, indicating elevated background IFN-γ levels. A high Nil value suggests non-specific stimulation or a large amount of IFN-γ already present, making it impossible to accurately measure the increase caused by the TB antigens.
The second, and more common, cause is a low Mitogen control value. A low Mitogen response means the patient’s T-cells failed to produce the expected amount of IFN-γ when stimulated. If the immune cells cannot react to the Mitogen, they may also fail to react to the TB antigens, potentially missing a true latent infection. This risk of a false negative is why the test is rendered indeterminate.
Primary Reasons for Control Failure
The root causes of an indeterminate result are split between issues related to the patient’s health and the technical handling of the sample. Patient factors often involve immune system compromise, which directly affects the Mitogen control’s ability to elicit a strong response. Immunosuppression, whether caused by disease or medication, is a frequent reason for a low Mitogen value.
Conditions such as HIV infection, certain cancers, or the use of immunosuppressive drugs like corticosteroids can suppress T-cell function. These factors reduce the number or activity of T-cells, making them unable to produce the necessary IFN-γ response to the Mitogen stimulant. Extremes of age, particularly in very elderly patients, can also be associated with a less responsive immune system and a higher chance of Mitogen control failure.
Low lymphocyte counts in the blood, related to various diseases or treatments, are directly linked to an insufficient Mitogen response. If there are not enough T-cells in the sample, the overall IFN-γ production will be too low to meet the test’s validity criteria. A low Mitogen result is often a reflection of the patient’s overall immune status at the time of the blood draw.
Technical factors, on the other hand, often contribute to a high Nil control result or a general failure in cell viability. Improper blood collection, such as inadequate mixing of the blood with the tube components, can cause cells to clump or lyse, leading to non-specific background activity.
A time delay between the blood draw and the start of the sample’s incubation in the laboratory is another frequent technical cause. The blood sample must begin incubation at 37°C within a specific timeframe, typically 16 hours, to keep the T-cells viable and responsive. If the sample is stored for too long or at incorrect temperatures, the T-cells may lose their ability to function, resulting in a failed Mitogen control or a high Nil value from cell breakdown. These technical issues suggest a problem with the sample itself, not necessarily the patient’s immune status.
Necessary Follow-up Actions
Receiving an indeterminate QFT-Plus result requires consultation with a healthcare provider to determine the best course of action. The initial step is often to repeat the QFT-Plus test using a new blood sample. Strict attention must be paid to proper collection and laboratory processing to rule out technical errors, as repeating the test may resolve the inconclusive result.
If the repeat test is also indeterminate, especially if the Mitogen control remains low, the patient’s clinical status and potential causes, such as immunosuppression, must be evaluated. If the underlying cause of immune suppression cannot be reversed or is ongoing, an alternative diagnostic method may be considered. Providers may recommend the Tuberculin Skin Test (TST) as an alternative screening tool, though its use in BCG-vaccinated or immunosuppressed individuals has limitations. The decision to pursue further testing or treatment must ultimately be based on the patient’s individual risk factors for M. tuberculosis infection, including exposure history.