Immune Sensitization to Mycobacterium tuberculosis Among Young Children with and without Tuberculosis

Identification of young children with Mycobacterium tuberculosis (Mtb) infection is critical to curb pediatric morbidity and mortality. The optimal test to identify young children with Mtb infection remains controversial. Using a tuberculosis (TB) household contact (HHC) study design among 130 Ugandan children less than 5 years of age with Mtb exposure, this study was conducted to determine the following: (1) the prevalence of Mtb immune sensitization in young children heavily exposed to TB using both the tuberculin skin test (TST) and QuantiFERON Gold Plus (QFT-Plus) interferon gamma release assay, and to examine the concordance of these two tests; and (2) the diagnostic accuracy of TST and QFT-plus for confirmed and unconfirmed TB in young children. Prevalence of Mtb immune sensitization was determined using TST at both 5 mm and 10 mm thresholds for positivity; manufacturer's thresholds were utilized to establish QFT-Plus positivity. Concordance analysis between TST and QFT-Plus results was performed, including correlation between QFT-Plus tube TB.1 and tube TB.2. The sensitivity and specificity of TST and QFT-Plus for confirmed and unconfirmed TB was determined, and a logistic regression model was utilized to estimate the odds of TB. A 5 mm TST threshold identified the most children with Mtb sensitization (49.2%) and had moderate agreement with QFT-Plus (Cohen's Kappa 0.59). The odds of TB were two times higher among children with a positive TST using a 5 mm threshold. Concordance between 10 mm TST threshold and QFT-Plus was substantial (Cohen's Kappa 0.65), with higher concordance observed among older children (2-5 years). The QFT-Plus tube TB.1 and tube TB.2 results were highly correlated. Positive TST using a 5 mm threshold demonstrated the highest sensitivity for TB (60%), whereas QFT-Plus testing demonstrated the highest specificity (72%). Overall, our findings support that among a population of young, BCG-vaccinated children with heavy household exposure to TB, the TST using a 5 mm threshold identified more children with evidence of Mtb immune sensitization, and children with TB disease, than the QFT-Plus. These findings are highly relevant for children who are TB HHCs in endemic settings, and most at risk for TB following an exposure. We recommend that TST testing continue to be performed to assess for Mtb sensitization in young, TB-exposed children in TB-endemic settings to both prioritize provision of preventive therapy and to aide in diagnosis of pediatric TB.