What to do next for a patient with a positive Interferon Gamma Release Assay (IGRA) result, followed by a negative result, and a normal Chest X-ray (CXR)?

Management of Discordant IGRA Results in Low-Risk Patients

In a healthy patient with low risk for tuberculosis infection who has discordant IGRA results (first positive, second negative) and a normal chest X-ray, the initial positive result should be considered a false positive and no treatment for latent tuberculosis infection is warranted. 1

Risk Assessment Framework

The critical first step is determining the patient's risk profile for M. tuberculosis infection and progression to active disease:

• Low-risk patients include those without known TB exposure, not from high-incidence countries, no immunosuppression, and no occupational risk 1
• In low-risk populations, false-positive IGRA results are common because the low prevalence of true infection increases the likelihood that any positive result is spurious 1

Interpretation of Discordant Results

For patients at low risk for both infection and progression, requiring both tests to be positive increases the likelihood that results reflect true infection rather than false positivity. 1

The CDC guidelines explicitly address this scenario:

• When the initial IGRA is positive in healthy persons with low risk, a confirmatory second test should be performed 1
• If the second test is negative, the patient should be considered not infected 1
• An acceptable alternative is to assume the initial positive result is false without additional testing, given the low risk 1

Understanding IGRA Variability

IGRAs have significant inherent variability that explains discordant results:

• Intrasubject discordance rates range from 4-22% depending on the assay and response strength 2
• Results near cutoff thresholds are particularly prone to spurious fluctuations between positive and negative 2
• Frequent conversions and reversions occur during serial testing that are largely unexplained and nonspecific 2

Clinical Management Algorithm

No further evaluation or treatment is needed when:

• Patient has low risk for TB infection and progression 1
• Chest X-ray is normal (excludes active disease) 1
• Second IGRA is negative (discordant with initial positive) 1

Additional evaluation would only be warranted if:

• The patient had high-risk features (HIV infection, immunosuppression, recent close contact with active TB, symptoms suggestive of TB) 1
• Chest X-ray showed abnormalities 1
• Clinical suspicion remained high despite negative second test 1

Key Pitfalls to Avoid

Do not treat based on a single positive IGRA in low-risk patients. The 2017 ATS/IDSA/CDC guidelines specifically recommend confirmatory testing when the initial test is positive in persons unlikely to be infected, and only considering the patient infected if both tests are positive 1

Do not repeat IGRA testing after treatment or use it to monitor response. IGRAs should not be used as biomarkers of treatment response, as persistent positivity does not indicate failure and conversion to negative does not confirm success 2

Avoid unnecessary testing of low-risk individuals in the first place. Steps should be taken to minimize misleading testing of persons at low risk for infection 1

Documentation and Follow-Up

• Document the risk assessment showing low probability of infection 1
• Explain to the patient that the discordant results most likely represent a false-positive initial test 1
• No routine follow-up testing is needed unless new TB exposure occurs or risk factors develop 1
• Educate about TB symptoms to report if they develop in the future 1