Management of Indeterminate QuantiFERON-TB Gold Test Results

Introduction to Indeterminate Results

For patients with indeterminate QuantiFERON-TB Gold (QFT-G) test results, the optimal management approach is to repeat QFT-G testing with a newly obtained blood specimen or administer a tuberculin skin test (TST), with the decision based on the patient's risk factors for TB infection, as recommended by the Centers for Disease Control and Prevention (CDC) 1
Indeterminate QFT-G results provide no useful information regarding the likelihood of Mycobacterium tuberculosis infection, and can occur due to high background levels of interferon-gamma in the nil sample or inadequate response to mitogen (often associated with immunosuppression) 1

Recent contact with infectious TB cases, birth or residence in high TB-incidence countries, immunocompromised status, abnormal chest radiograph consistent with prior TB, and age (very young or elderly patients have higher rates of indeterminate results) are risk factors for indeterminate QFT-G results, although specific associations may vary 1

If clinical suspicion for TB disease exists, proceed with additional diagnostic evaluations without delay, including chest radiography, bacteriologic studies, and HIV testing, as advised by the CDC 1
Consider chest radiography to rule out active TB disease, and don't delay diagnostic evaluation for suspected TB disease while awaiting QFT-G results 1

Repeat testing is recommended, either repeat QFT-G or administer TST, based on individual patient risk factors for TB infection, with the TB Gold test having higher specificity than the tuberculin skin test (TST) for detecting Mycobacterium tuberculosis infection, due to the use of specific M. tuberculosis antigens (ESAT-6 and CFP-10) 1
If repeat QFT-G is positive, evaluate for TB disease before diagnosing latent TB infection (LTBI), and if repeat QFT-G is negative, no further evaluation is needed in most cases 1
Don't assume an indeterminate result rules out TB infection, as it provides no useful information regarding infection status, and consider laboratory reports on the reason for indeterminate results (high nil vs. low mitogen) to guide clinical decision-making 1
Technical factors, including improper handling or processing of blood specimens, can cause false positives, with blood needing to be incubated with test antigens within 12 hours of collection, as reported by 2, 1

QFT-G test results should be interpreted as follows:
Strong predictors of true positive QFT-G results include abnormal chest radiograph consistent with healed TB, TST induration ≥16mm, and birth in a high TB-incidence country, as recommended by the American Thoracic Society (ATS) and CDC 1

Individuals with severely immunocompromised status or children <5 years with recent TB exposure should be considered for treatment for latent TB infection (LTBI) regardless of test results, as per the CDC recommendations 1
Certain populations, such as cancer patients (e.g., hematologic malignancies, head and neck squamous cell carcinoma, and lung cancer), should be considered for targeted LTBC screening, according to the American Thoracic Society (ATS), CDC, and Infectious Diseases Society of America (IDSA) 3
For individuals with increased risk for LTBI, such as recent immigrants, injection-drug users, and residents/employees of prisons and jails, positive QFT alone is sufficient to recommend LTBI treatment, based on clinical judgment and perceived risk, as per the CDC 4
A dual testing approach (IGRA and TST) may increase detection sensitivity in high-risk individuals, and both tests should be performed before initiating immunotherapy or intensive chemotherapy, as recommended by the ATS, CDC, and IDSA 3, 2

Individuals with low mitogen response (<0.5 IU/mL) may indicate immunosuppression, which is more common in advanced cancer or individuals receiving immunosuppressive therapy, with a recommended targeted LTBC screening approach for high-risk individuals 3, 5
Indeterminate QFT-G results provide no useful information regarding the likelihood of M. tuberculosis infection and should not be used to rule out TB infection, with consideration given to chest radiography to rule out active TB disease, according to the CDC guidelines 1