How to evaluate an indeterminate Quantiferon Gold (Interferon-Gamma Release Assay) result?

Evaluation of Indeterminate QuantiFERON-TB Gold Results

For patients with indeterminate QuantiFERON-TB Gold (QFT-G) results, repeat testing with either a new QFT-G specimen or a tuberculin skin test (TST) is recommended, with the decision based on the patient's likelihood of M. tuberculosis infection and underlying immune status. 1

Understanding Indeterminate Results

Indeterminate QFT-G results occur in approximately 3.5-10% of tests 2, 3 and can be caused by:

1. High background IFN-γ levels in the nil sample (negative control failure)
2. Inadequate response to mitogen (positive control failure) - accounts for approximately 89% of indeterminate results 3

The laboratory report should specify which of these scenarios has occurred, as this guides further management.

Evaluation Algorithm

Step 1: Determine the reason for indeterminate result

• If due to high background IFN-γ levels: May indicate immune hyperactivity or inflammatory conditions 4
• If due to inadequate mitogen response: Suggests immunosuppression 4

Step 2: Assess risk factors for indeterminate results

• Clinical factors:

  • Immunosuppressive conditions (HIV, cancer, especially hematologic malignancies) 4
  • Corticosteroid therapy (nearly 3x increased risk) 5
  • Hypoalbuminemia (<3.5 g/dL) (3.6x increased risk) 5
  • Advanced age 3
  • Lymphocytopenia 3
  • Elevated inflammatory markers (CRP >0.8 mg/dL, ESR >15 mm/hr) 5

• Technical factors:

  • Delayed incubation of blood samples (>6 hours) significantly increases indeterminate results 6
  • Improper specimen handling or processing 4

Step 3: Management based on TB risk assessment

For persons with HIGH likelihood of M. tuberculosis infection:

• Repeat QFT-G with a new blood specimen, or
• Perform TST 1
• Consider chest radiography to rule out active TB disease
• If the patient is severely immunocompromised or a child <5 years with recent TB exposure, consider treatment for LTBI regardless of test results 1

For persons with LOW likelihood of M. tuberculosis infection:

• No further testing is necessary after an indeterminate QFT-G result 1
• Document the indeterminate result and the clinical reasoning for not pursuing further testing

Important Considerations

• Indeterminate results provide no useful information regarding the likelihood of M. tuberculosis infection 1
• When repeat testing is performed, approximately 16-17% of initially indeterminate results will yield determinate results 3
• If TB disease is suspected clinically, do not delay additional diagnostic evaluations (chest radiography, bacteriologic studies, HIV testing) while awaiting QFT-G results 1
• In immunocompromised patients, both QFT-G and TST may have reduced sensitivity, so clinical judgment remains essential 4

Pitfalls to Avoid

1. Don't assume indeterminate equals negative: An indeterminate result should never be interpreted as indicating absence of infection
2. Don't ignore the reason for indeterminate results: The cause (high background vs. low mitogen) provides valuable clinical information
3. Don't delay processing: Ensure blood samples are processed within 12 hours of collection to reduce indeterminate results 6
4. Don't overlook technical factors: Improper specimen handling is a common cause of indeterminate results that can be corrected
5. Don't miss active TB: If clinical suspicion exists, proceed with full TB workup regardless of QFT-G results

By following this structured approach to evaluating indeterminate QFT-G results, clinicians can make appropriate decisions regarding the need for repeat testing or empiric treatment based on individual patient risk factors and clinical context.