Management of Indeterminate QuantiFERON Gold Plus Results

Risk-Stratified Management Algorithm

The Centers for Disease Control and Prevention recommends that high-risk patients, including close contacts of persons with infectious TB disease, immunocompromised individuals, healthcare workers with ongoing TB exposure risk, individuals from TB-endemic countries, children aged <5 years, and patients with medical conditions increasing progression risk, require repeat testing with either a new QFT-Plus specimen or tuberculin skin test (TST) 1, 2, 3
The Centers for Disease Control and Prevention suggests that low-risk patients without identifiable TB risk factors require no additional testing after an indeterminate result 4, 1

Indeterminate results occur due to inadequate mitogen response (IFN-γ ≤0.5 IU/mL in positive control) or high background IFN-γ (>8 IU/mL in nil control), and laboratories must report the specific reason for the indeterminate result to guide clinical interpretation and management decisions 5, 4, 1

The American Thoracic Society recommends using a newly obtained blood specimen for repeat QFT-Plus testing 1
The Centers for Disease Control and Prevention suggests considering two-step testing with TST in serial testing settings due to TST boosting potential 4, 1

The Centers for Disease Control and Prevention recommends immediately performing chest radiography, bacteriologic studies, and HIV serology if clinical suspicion for active TB exists, without delaying diagnostic evaluation while awaiting repeat testing 4, 1

The Centers for Disease Control and Prevention notes that indeterminate results are more common in immunocompromised populations, and treatment decisions should incorporate all epidemiologic, historical, clinical, and diagnostic information 6, 7, 4, 3
The Centers for Disease Control and Prevention suggests considering empiric LTBI treatment in close contacts with high transmission risk or patients at high risk for progression to active disease, even without confirmatory testing 4, 3

The CDC recommends repeat testing with either a new QuantiFERON Gold specimen or a TB spot test for high-risk patients, including healthcare workers with ongoing TB exposure risk, individuals from TB-endemic countries, children aged <5 years, and patients with medical conditions increasing progression risk, such as diabetes, chronic kidney disease, silicosis, and malignancy 8
The CDC also recommends repeat testing for patients who are close contacts of persons with infectious TB disease, immunocompromised individuals, including those with HIV infection, on immunosuppressive therapy, or organ transplant recipients, although this is not directly cited, the MMWR Recommendations and Reports guideline is applicable to these groups as well 8

If clinical suspicion for active TB exists, the CDC recommends immediate diagnostic evaluation, including chest radiography, bacteriologic studies, and HIV serology, without delaying for repeat testing 8
Neither IGRAs nor TST can distinguish latent TB infection from active TB disease, according to the MMWR Recommendations and Reports 8, 9

The British Society of Gastroenterology recommends screening with interferon-gamma release assays rather than TST for immunocompromised patients on biologics, particularly anti-TNF therapy, due to the high false-negative rate of TST 10
In immunocompromised patients, using both TST and IGRA may maximize screening efficacy, according to the MMWR Recommendations and Reports 8