Tuberculosis (TB) screening identifies individuals infected with the bacteria Mycobacterium tuberculosis, even if they do not show symptoms. Screening uses either the traditional skin test or modern blood tests, known as Interferon-Gamma Release Assays (IGRAs). While the goal is a clear positive or negative result to guide treatment, results can occasionally return as “indeterminate.” An indeterminate result means the test could not be reliably interpreted because the testing process failed its internal quality checks. This outcome does not indicate infection but necessitates further investigation.
Understanding the Indeterminate Designation
The indeterminate designation applies only to blood-based Interferon-Gamma Release Assays (IGRAs), such as QuantiFERON and T-Spot. These tests measure the release of interferon-gamma by T-cells when exposed to specific TB antigens. An indeterminate result signifies that the internal test controls, designed to ensure T-cell function and low background signal, did not perform as expected.
The IGRA includes a Negative Control (Nil control) and a Positive Control, which uses a mitogen to stimulate T-cells broadly. Indeterminate results occur if T-cells fail to respond to the mitogen (Positive Control failure) or if the background interferon-gamma level in the Nil control is too high (Negative Control failure). Positive Control failure suggests the T-cells cannot produce an adequate immune response. High readings in the Negative Control indicate high background immune activity that interferes with accurate measurement.
Technical and Sample-Related Causes
Indeterminate results often stem from issues outside the patient’s body, related to sample collection, handling, or laboratory processing. T-cell viability in the blood sample is paramount for a valid result. Poor phlebotomy technique, such as collecting an inadequate volume of blood, can incorrect the ratio of blood to reagents, leading to a failed test.
The timing of sample processing is a significant technical factor. Because the test relies on living T-cells, delaying processing reduces the cells’ ability to respond during incubation, often causing Positive Control failure. The blood must be incubated within a specific window, typically 8 to 16 hours after collection, to maintain high cell viability. Errors in storage, such as temperature fluctuations during transport, further compromise T-cell function. Less commonly, technical failures within the assay itself, such as equipment malfunction or reagent issues, can also cause an indeterminate outcome.
Immunological Factors and Patient Status
If the failure is not technical, the cause is usually an inadequate immune response from the patient. This is the most complex reason and almost always results from a failed Positive Control, meaning the T-cells could not produce a strong interferon-gamma response to the mitogen. The most common underlying factor is severe immunosuppression, which compromises the overall number or function of T-cells.
Conditions causing T-cell impairment significantly increase the likelihood of an indeterminate result. These include advanced Human Immunodeficiency Virus (HIV) infection and treatment with immunosuppressive medications like high-dose corticosteroids or anti-TNF-alpha agents. Other chronic illnesses compromise the systemic immune function necessary for the test, such as chronic renal disease, severe lymphopenia (low overall lymphocyte count), and hypoalbuminemia. Extreme ages, particularly the very young and the elderly, also show a higher incidence of indeterminate results, reflecting an immune system that is either undeveloped or senescent. In these cases, the indeterminate result signals a depressed immune status that warrants clinical attention.
Required Follow-Up and Re-testing Protocols
An indeterminate result requires a carefully considered follow-up plan, as it provides no useful information about the presence of Mycobacterium tuberculosis infection. The most common approach is to repeat the IGRA test using a newly collected blood sample, often after four to eight weeks. Retesting allows time for temporary issues, such as a recent mild viral infection or transient immunosuppression, to resolve, increasing the chance of a clear result.
If the repeat IGRA test is also indeterminate, alternative testing methods should be considered. Switching to a Tuberculin Skin Test (TST) is an option, though TST also has limitations in immunocompromised patients. A comprehensive clinical evaluation is mandatory, regardless of the re-testing strategy. This assessment should consider the patient’s risk factors for TB exposure, current symptoms, and potentially include a chest X-ray to rule out active TB disease.