How to manage a patient with a low positive Tuberculosis (TB) test result but a negative Quantiferon TB Plus test?

From the Guidelines

A patient with a low positive tuberculosis skin test (TST) but negative Quantiferon TB Plus test should generally not receive treatment for latent tuberculosis infection (LTBI) unless they have specific risk factors. This discrepancy often represents either a false-positive TST due to prior BCG vaccination or non-tuberculous mycobacterial exposure, or a false-negative Quantiferon result. For most patients, clinical monitoring is appropriate without medication. However, if the patient is immunocompromised, has recent TB exposure, or has radiographic findings suggestive of TB, treatment for LTBI may be warranted despite the negative Quantiferon. The standard LTBI treatment regimen is isoniazid 300mg daily for 6-9 months, rifampin 600mg daily for 4 months, or isoniazid 900mg plus rifapentine 900mg weekly for 12 weeks (3HP regimen) 1. Before initiating any treatment, a chest X-ray should be performed to rule out active TB disease. The discordance between these tests occurs because the TST measures delayed-type hypersensitivity to tuberculin antigens, while Quantiferon measures interferon-gamma release from T-cells in response to specific TB antigens. Interferon-gamma release assays like Quantiferon are generally more specific than TST, particularly in BCG-vaccinated individuals, making them valuable in resolving ambiguous TST results.

Some key points to consider in the management of this patient include:

• The patient's risk factors for TB infection and progression to active disease
• The results of the TST and Quantiferon tests, including the magnitude of the interferon-gamma response
• The presence of symptoms or signs suggestive of active TB disease
• The results of the chest X-ray and any other diagnostic tests performed. According to the guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection, a single positive IGRA or TST result should not be taken as reliable evidence of M. tuberculosis infection in healthy persons who have a low likelihood of infection 1. In such situations, the likelihood of M. tuberculosis infection and of disease progression should be reassessed, and the initial test results should be confirmed. Repeat testing, with either the initial test or a different test, may be considered on a case-by-case basis.

In persons with discordant test results, decisions about medical or public health management require individualized judgment in assessing the quality and magnitude of each test result, the probability of infection, the risk for disease if infected, and the risk for a poor outcome if disease occurs 1. The performance characteristics of the QFT-Plus test have not been evaluated in immune-compromised patients, patients taking immunosuppressive drugs, pregnant women, and individuals younger than 18 years of age, and caution is warranted when evaluating QFT-Plus results from patients who have clinical conditions such as diabetes, silicosis, chronic renal failure, and hematological disorders.

From the FDA Drug Label

The performance characteristics of the QFT-Plus test has not been evaluated in immune compromised patients, patients taking immunosuppressive drugs, pregnant women, and individuals younger than 18 years of age. Caution is warranted when evaluating QFT-Plus results from patients who have clinical conditions such as diabetes, silicosis, chronic renal failure, and hematological disorders (e.g., leukemia and lymphomas), or those with other specific malignancies (e.g.,carcinoma of the head or neck and lung). A POSITIVE result suggests that M. tuberculosis complex infection is likely. This test will detect interferon gamma responses from individuals infected with M. tuberculosis, M. kansasii, M. szulgai, and M. marinum but not from BCG-vaccinated individuals without disease or risk for latent TB infections. The magnitude of the interferon gamma level does not correlate with the stage or degree of infection, level of immune responsiveness, or the likelihood of progressing to active disease. This test should not be used as the sole means for diagnosing or excluding active or latent tuberculosis.

The patient has a low positive Tuberculosis (TB) test result but a negative Quantiferon TB Plus test.

• The low positive TB test result may be a false positive in the absence of risk factors for infection.
• The negative Quantiferon TB Plus test suggests that M. tuberculosis complex infection is unlikely. Given the conflicting results, confirmatory repeat testing on a new specimen is recommended, as per ATS/IDSA/CDC Clinical Practice Guidelines (2017) 2. It is also important to consider the patient's medical history and risk factors for tuberculosis infection when interpreting the test results. Clinical judgment should be used to determine the best course of action for this patient.

From the Research

Management of Low Positive Tuberculosis Test Result with Negative Quantiferon TB Plus Test

• The patient has a low positive TB test result but a negative Quantiferon TB Plus test, which can be challenging to interpret 3, 4.
• According to the ATS/IDSA/CDC Clinical Practice Guidelines (2017), confirmatory repeat testing on a new specimen is recommended for low positive TB test results.
• The Quantiferon TB Plus test has not been evaluated in certain patient populations, such as immune compromised patients, patients taking immunosuppressive drugs, pregnant women, and individuals younger than 18 years of age.
• Studies have shown that false-negative results can occur in patients with certain risk factors, such as immunosuppressant diseases, lower platelet, protein, and albumin levels, and advanced age 3, 5.
• The test variability of the QuantiFERON-TB gold in-tube assay has been reported, with a substantial number of patients having discordant results on repeat testing 6.
• The effects of prophylaxis on QuantiFERON TB-2G responses have been studied, and it was found that the responses significantly declined after treatment of latent tuberculosis infection (LTBI) 7.

Considerations for Interpretation

• The results of the TB test and Quantiferon TB Plus test should be interpreted cautiously, taking into account the patient's clinical history, risk factors, and other laboratory results.
• The possibility of false-positive or false-negative results should be considered, and repeat testing may be necessary to confirm the diagnosis.
• The patient's risk factors, such as immunosuppressant diseases, advanced age, or malignancy, should be taken into account when interpreting the test results 3, 5.
• The test results should not be used as the sole means for diagnosing or excluding active or latent tuberculosis, and other diagnostic tests and clinical evaluations should be considered.