Use of T cell-based diagnosis of tuberculosis infection to optimize interpretation of tuberculin skin testing for child tuberculosis contacts.

BACKGROUND: Treatment of recent tuberculosis infection in children aged <2 years is essential, because of high risk of progression to disease, but diagnosis is hindered by the inaccuracy of the tuberculin skin test (TST). More-accurate T cell-based tests of infection could enhance diagnosis by optimizing interpretation of the TST results. METHODS: A total of 979 child tuberculosis contacts in Istanbul underwent the TST and enzyme-linked immunospot assay. Using enzyme-linked immunospot test results as a reference standard, we assessed the effect of age and bacille Calmette-Guérin (BCG) vaccination on the sensitivity and specificity of the TST, and we computed the optimal TST cutoff points, using receiver operating characteristic curves. RESULTS: With a TST cutoff point of >or=10 mm, the sensitivity of the TST was 66% for children aged <2 years, which was lower than that for older children (P= .006). Specificity was 75% for BCG-vaccinated children, compared with 92% for unvaccinated children (P= .001). Optimal cutoff points improved TST specificity for children with 1 BCG scar, with little loss of sensitivity. Despite the use of optimal cutoff points, TST sensitivity remained <70% for children aged <2 years, specificity remained <87% for BCG-vaccinated children aged >or=2 years, and overall accuracy was low for children with >1 BCG scar. CONCLUSIONS: Negative results of the TST cannot exclude tuberculosis infection for child tuberculosis contacts aged <2 years, which supports the use of preventive therapy regardless of the TST results for this age group. In children aged >or=2 years, the accuracy of the TST can be improved by adjustment of cutoff points for BCG-vaccinated children but remains poor for children with >1 BCG scar. This methodology can define optimal TST cutoff points for diagnosis of tuberculosis infection tailored to target populations.

Effect of BCG vaccination on risk of Mycobacterium tuberculosis infection in children with household tuberculosis contact: a prospective community-based study.

BACKGROUND: Little is known about factors that affect the risk of acquiring infection in children exposed to Mycobacterium tuberculosis. The effect of BCG vaccination has been difficult to ascertain because the tuberculin skin test (TST), until recently the only method for detecting M tuberculosis infection, does not reliably distinguish between tuberculosis infection and BCG vaccination. METHODS: We investigated risk factors for tuberculosis infection in 979 child household contacts of 414 adult index patients with sputum smear-positive pulmonary tuberculosis in Istanbul, Turkey. Children were aged up to 16 years (median 7, IQR 3-11) and 770 of 979 (79%) had a BCG scar. A T-cell-based enzyme-linked immunospot assay (ELISpot), which is not confounded by BCG vaccination, and TST were used to assess infection. Independent risk factors for infection were identified through multivariate analysis. FINDINGS: Amount of tuberculosis exposure within the household and age (a marker of tuberculosis exposure outside the household) were strongly associated with likelihood of infection as measured by both TST and ELISpot. ELISpot also identified absence of BCG scar as an independent risk factor for infection in tuberculosis-exposed children; BCG-vaccinated children had an odds ratio of 0.60 (95% CI 0.43-0.83, p=0.003) for tuberculosis infection, compared with unvaccinated children. INTERPRETATION: Contrary to the prevailing theory that BCG vaccination protects only against tuberculosis disease, our results suggest that the vaccine also protects against tuberculosis infection. This finding has important implications for our understanding of the biology of tuberculosis infection and development of improved tuberculosis vaccines.