Causes of Positive Mantoux with Negative IGRA
The most common cause of a positive Mantoux test with negative IGRA in an immunocompetent patient is prior BCG vaccination, which creates false-positive TST results due to cross-reactivity with antigens shared between BCG and the tuberculin PPD used in the Mantoux test. 1
Primary Causes in Order of Likelihood
BCG Vaccination (Most Common)
- BCG vaccination is the leading cause of TST-positive/IGRA-negative discordance because tuberculin PPD contains antigens present in BCG vaccine strains that trigger false-positive skin test reactions. 1
- IGRAs use M. tuberculosis-specific antigens (ESAT-6 and CFP-10) that are absent from BCG vaccine strains, eliminating this cross-reactivity and providing superior specificity. 1, 2
- TST and IGRA results correlate poorly in BCG-vaccinated populations, with the discordance primarily driven by false-positive TST results rather than true M. tuberculosis infection. 1
Nontuberculous Mycobacterial (NTM) Exposure
- Environmental exposure to certain nontuberculous mycobacteria can cause positive TST results through cross-reactive antigens in tuberculin PPD. 1
- IGRAs remain negative in most NTM exposures, though M. kansasii, M. szulgai, and M. marinum contain ESAT-6 and CFP-10 antigens that could theoretically cause false-positive IGRA results (rare in practice). 1
False-Positive TST in Low-Risk Populations
- In healthy persons with low probability of M. tuberculosis infection, a single positive TST result should not be considered reliable evidence of infection because false-positive results are more likely than true infection. 1
- The CDC recommends that in such low-risk individuals, the initial positive TST can be assumed to be false-positive without additional testing, or confirmation with IGRA should be performed. 1
Clinical Interpretation Algorithm
Step 1: Assess Pre-Test Probability
- Evaluate TB risk factors: immigration from high-prevalence countries, healthcare work, homeless shelter residence, correctional facility exposure, HIV infection, immunosuppression, or known TB contact. 1, 3
- In the absence of these risk factors, the positive predictive value of TST drops dramatically, making false-positive results more likely than true infection. 1
Step 2: Consider BCG History
- Document BCG vaccination history, particularly if received as a child or in countries with routine BCG programs. 4
- BCG vaccination received even decades earlier can cause persistent TST positivity without true M. tuberculosis infection. 1
Step 3: Apply the Two-Step Approach
- Several national guidelines (CDC, NICE, Swiss guidelines) recommend using IGRA to confirm positive TST results, particularly in BCG-vaccinated individuals. 1
- The negative IGRA in this scenario effectively rules out M. tuberculosis infection in an immunocompetent patient with high negative predictive value (99.7%). 5
Management Recommendation
No Treatment Required
- An immunocompetent patient with positive TST but negative IGRA and no TB risk factors does not require treatment for latent TB infection. 1, 4
- The negative IGRA has superior specificity and should be considered the definitive test result in this discordant scenario. 1, 2
- Treatment based solely on TST results in this context would represent overtreatment and unnecessary exposure to isoniazid hepatotoxicity risk. 1, 4
Confirm Active TB is Excluded
- Perform symptom assessment for cough, fever, night sweats, and weight loss. 3
- Obtain chest radiograph to exclude active pulmonary tuberculosis, as neither TST nor IGRA can distinguish latent infection from active disease. 1, 6
Important Caveats
When Discordance Requires Further Evaluation
- If the patient has significant TB exposure history or high-risk medical conditions (HIV, TNF-α antagonist therapy, recent transplant), consider repeat IGRA testing with a new blood sample to rule out indeterminate or borderline results. 1, 7
- Immunocompromised patients may have false-negative IGRAs due to impaired T-cell function, though this scenario specifies an immunocompetent patient. 8