Detecting Tuberculosis Infection in HIV-infected Children: A Study of Diagnostic Accuracy, Confounding and Interaction

Background: Accurate identification of Mycobacterium tuberculosis infection in young and HIV-infected children could guide delivery of preventive therapy, improve resource utilization and help prevent tuberculosis. Methods: We assessed the performance of the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) for identifying M. tuberculosis infection in South African children presenting for outpatient care. Tuberculosis contact was quantified using a standardized measure of M. tuberculosis exposure. Logistic regression assessed the association among test positivity, age, nutritional and HIV status, while controlling for M. tuberculosis exposure, bacille Calmette-Guerin vaccination and prior tuberculosis treatment. Results: Among 250 (130 HIV infected) children (age 0.25-14.6 years, median 39 months), the proportion positive for each test varied: 34% (TST), 21% (T-SPOT. TB) and 25% (QuantiFERON-TB Gold In-Tube). IGRAs were more likely to be positive in HIV-uninfected compared with HIV-infected children; TST positivity did not differ between these groups. Agreement between tests was good-to-excellent in HIV-uninfected children and poor-to-good in HIV-infected children. In adjusted models, TST and T-SPOT. TB were positively associated with age; this effect varied by HIV status. The QuantiFERON-TB Gold In-Tube was negatively associated with chronic malnutrition; this effect varied by HIV status. Because 93% of children had received bacille Calmette-Guerin, we could not assess the contribution of bacille Calmette-Guerin to false-positive TST results. Conclusions: Our findings indicate that the TST and IGRAs perform similarly for the detection of M. tuberculosis infection in well-nourished HIV-uninfected children, but test performance is differentially affected by chronic malnutrition, HIV infection and age. Similar to TST interpretation, clinicians and researchers should interpret IGRAs in children with caution taking age, nutritional and HIV status into consideration.