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

Mandalakas, Anna M. MD*†‡; van Wyk, Susan MD; Kirchner, H. Lester PhD§; Walzl, Gerhard MD, PhD; Cotton, Mark MD, PhD; Rabie, Helena MD; Kriel, Belinda NHD Med Tech; Gie, Robert P. FCP; Schaaf, H. Simon MD, PhD; Hesseling, Anneke C. MD, PhD

The Pediatric Infectious Disease Journal: March 2013 - Volume 32 - Issue 3 - p e111–e118
doi: 10.1097/INF.0b013e31827d77b7
HIV Reports

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-γ 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–Guérin 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–Guérin, we could not assess the contribution of bacille Calmette–Guérin 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.

From the *Department of Pediatrics, Section on Retrovirology and Global Health, Baylor College of Medicine; The Tuberculosis Initiative, Texas Children’s Hospital, Houston, TX; Department of Pediatrics and Child Health, Desmond Tutu TB Center, Stellenbosch University, Tygerberg, Cape Town, South Africa; §Division of Medicine, Geisinger Clinic, Danville, PA; Department of Molecular Biology and Human Genetics, Faculty of Health Sciences; and Department of Pediatrics and Child Health, Children’s Infectious Diseases Clinical Research Unit, Stellenbosch University, Tygerberg, Cape Town, South Africa.

Accepted for publication November 05, 2012.

Supported by the Thrasher Research Fund (02826-0). A.M. received salary support from the United States Department of State to serve as a Senior Fulbright Scholar to South Africa during the completion of this work. Funding sources played no role in project implementation, analysis or reporting. The cost of purchasing QFT tests was supported through the Foundation for Innovative New Diagnostics, Geneva. T.SPOT.TB tests and kits were purchased at a reduced rate from the manufacturer. Test manufacturers and their collaborators played no role in study design, implementation, analysis or the decision to publish this data. The authors have no other funding or conflicts of interest to disclose.

Address for correspondence: Anna Mandalakas, MD, Baylor College of Medicine, Texas Children’s Hospital, 1102 Bates St., FC-630, Houston, TX 77030. E-mail:

© 2013 Lippincott Williams & Wilkins, Inc.