A Three-Way Comparison of Tuberculin Skin Testing, QuantiFERON-TB Gold and T-SPOT.TB in Children

BACKGROUND: There are limited data comparing the performance of the two commercially available interferon gamma (IFN-gamma) release assays (IGRAs) for the diagnosis of tuberculosis (TB) in children. We compared QuantiFERON-TB gold In Tube (QFT-IT), T-SPOT.TB and the tuberculin skin test (TST) in children at risk for latent TB infection or TB disease. METHODS AND FINDINGS: The results of both IGRAs were compared with diagnosis assigned by TST-based criteria and assessed in relation to TB contact history. Results from the TST and at least one assay were available for 96 of 100 children. Agreement between QFT-IT and T-SPOT.TB was high (93% agreement, kappa = 0.83). QFT-IT and T-SPOT.TB tests were positive in 8 (89%) and 9 (100%) children with suspected active TB disease. There was moderate agreement between TST and either QFT-IT (75%, kappa = 0.50) or T-SPOT.TB (75%, kappa = 0.51). Among 38 children with TST-defined latent TB infection, QFT-IT gold and T-SPOT.TB assays were positive in 47% and 39% respectively. Three TST-negative children were positive by at least one IGRA. Children with a TB contact were more likely than children without a TB contact to have a positive IGRA (QFT-IT LR 3.9; T-SPOT.TB LR 3.9) and a positive TST (LR 1.4). Multivariate linear regression analysis showed that the magnitude of both TST induration and IGRA IFN-gamma responses was significantly influenced by TB contact history, but only the TST was influenced by age. CONCLUSIONS: Although a high level of agreement between the IGRAs was observed, they are commonly discordant with the TST. The correct interpretation of a negative assay in a child with a positive skin test in clinical practice remains challenging and highlights the need for longitudinal studies to determine the negative predictive value of IGRAs

Investigations.

*<p>Done routinely at the Community Health Centre at the time.</p

Visa Medical Examination and Pre-departure Medical Screening (PDMS) [31].

*<p>There is variation in the timing of the visa medical examination, and uptake of PDMS and screening may be limited, especially for children. The full PDMS is used in Thailand (the port of departure for most of this cohort). A short form of PDMS is also used in some ports of departure, which is an assessment of ‘fitness to fly’.</p

Prevalence of health issues by age group.

*<p>Low and high defined by reference range for age/gender. Although a proportion of the population may have results outside a reference range if it is defined according to a normal distribution; and reference ranges will not be specific to this group; in practice, most results outside the reported reference range require at least clinical assessment, and may require treatment, hence the results are reported using the reference ranges of the pathology provider.</p>†<p>Defined by titre ≥1: 32.</p>‡<p>Faecal pathogens were any one of <i>Giardia intestinalis</i>, <i>Entamoeba histolytica/dispar</i>, <i>Cyclospora cayetanensis</i>, Hookworm, <i>Trichuris trichiuria</i>, <i>Taenia spp</i>, <i>Strongyloides stercoralis</i>, <i>Enterobius vermicularis</i>, <i>Ascaris lumbricoides</i>.</p>Ş<p>Defined by being Hepatitis B cAb positive where sAb was detected.</p

Age and gender of Karen refugee cohort.

<p>Age and gender of Karen refugee cohort.</p

Venn diagram depicting agreement between tuberculin skin test, QuantiFERON-TB gold In Tube and T-SPOT.<i>TB</i> results for all children (n = 100).

<p>Venn diagram depicting agreement between tuberculin skin test, QuantiFERON-TB gold In Tube and T-SPOT.<i>TB</i> results for all children (n = 100).</p

Results of QuantiFERON-TB gold in-Tube and T-SPOT.<i>TB</i> assays in each diagnostic category.

*<p>3 inadequate PBMC; 1 cross contamination.</p>†<p>1 high nil control; 2 inadequate mitogen control.</p>‡<p>3 high nil control; 4 inadequate PBMC; 2 technical; 1 cross contamination.</p>§<p>1 inadequate PBMC; 1 cross contamination.</p>‖<p>1 inadequate mitogen control; 1 high nil control.</p>**<p>3 inadequate PBMC; 1 technical; 1 high nil control.</p

Relationship between results of QuantiFERON-TB gold In Tube and T-SPOT.<i>TB</i> assays and TST induration diameter in the 46 children with a positive tuberculin skin test (38 with TST-defined latent TB infection and 8 with TB disease).

<p>The broken line indicates a TST induration of 15 mm. QFT = QuantiFERON-TB gold In Tube, T-Sp = T-SPOT.<i>TB</i> assays, Indet = Indeterminate, TST = tuberculin skin test.</p