Sollai et al. BMC Infectious Diseases 2014, 14(Suppl 1):S6 http://www.biomedcentral.com/1471-2334/14/S1/S6 REVIEW Open Access Systematic review and meta-analysis on the utility of Interferon-gamma release assays for the diagnosis of Mycobacterium tuberculosis infection in children: a 2013 update S Sollai†, L Galli†, M de Martino*†, E Chiappini*† Abstract Background: Previous meta-analyses regarding the performance of interferon-gamma release assays (IGRAs) for tuberculosis diagnosis in children yielded contrasting results, probably due to different inclusion/exclusion criteria. Methods: We systematically searched PubMed, EMBASE and Cochrane databases and calculated pooled estimates of sensitivities and specificities of QuantiFERON-TB Gold In Tube (QFT-G-IT), T-SPOT.TB, and tuberculin skin test (TST). Several sub-analysis were performed: stratification by background (low income vs. high income countries); including only microbiological confirmed TB cases; including only studies performing a simultaneous three-way comparison of the three tests, and including immunocompromised children. Results: Overall, 31 studies (6183 children) for QFT-G-IT, 14 studies (2518 children) for T-SPOT.TB and 34 studies (6439 children) for TST were included in the analyses. In high income countries QFT-G-IT sensitivity was 0.79 (95% IC: 0.75-0.82) considering all the studies, 0.78 (95%CI:0.70-0.84) including only studies performing a simultaneous three-way comparison and 0.86 (95%IC 0.81-0.90) considering only microbiologically confirmed studies. In the same analyses T-SPOT.TB sensitivity was 0.67 (95%IC 0.62-0.73); 0.76 (95%CI: 0.68 to 0.83); and 0.79 (95%IC 0.69-0.87), respectively. In low income countries QFT-G-IT pooled sensitivity was significantly lower: 0.57 (95%IC:0.52-0.61), considering all the studies, and 0.66 (95%IC 0.55-0.76) considering only microbiologically confirmed cases; while T-SPOT.TB sensitivity was 0.61 (95%IC 0.57-0.65) overall, but reached 0.80 (95%IC 0.73-0.86) in microbiologically confirmed cases. In microbiologically confirmed cases TST sensitivity was similar: 0.86 (95%IC 0.79-0.91) in high income countries, and 0.74 (95%IC 0.68-0.80) in low income countries. Higher IGRAs specificity with respect to TST was observed in high income countries (97-98% vs. 92%) but not in low income countries (85-93% vs. 90%). Conclusions: Both IGRAs showed no better performance than TST in low income countries. Background needed. Nevertheless, infiltrate measurement may be Diagnosis of paediatric tuberculosis infection remains a operator-dependent [1-4]. Interferon gamma release challenging issue. Tuberculin skin test (TST) has several assays (IGRAs), including the commercially available ® limitations: sensitivity may be influenced by the child’s assays QuantiFERON -TB Gold (QFT-G; Cellestis, ® age and immunologic status, bacille Calmette-Guérin Australia), QuantiFERON -TB Gold In-Tube (QTF-G- ® (BCG) vaccination or non-tuberculosis mycobacterium- IT, Cellestis, Australia), and the T-SPOT TB (T-SPOT , infections; in case of repeated tests a booster effect can Oxford Immunotec Ltd. UK), have been extensively used occur and a double access to a health care facility is for the diagnosis of tuberculosis infection in adults. IGRAs allow detection of circulating T-cells responsive to specific Mycobacterium tuberculosis antigens, which are * Correspondence: [email protected]; [email protected] absent in BCG and many non-tuberculosis mycobacteria, † Contributed equally Department of Health Sciences, Meyer Children University Hospital, and displayed similar sensitivity and higher specificity than University of Florence, Florence, Italy © 2014 Sollai et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sollai et al. BMC Infectious Diseases 2014, 14(Suppl 1):S6 Page 2 of 11 http://www.biomedcentral.com/1471-2334/14/S1/S6 TST in adults (table 1) [5-12]. However, IGRA perfor- data and assessment of study quality are reported in Addi- mance in paediatric populations is still under debate and tional file 1. In particular only studies evaluating Quanti- ® caution is recommended for their use and interpretation FERON -TB Gold In-Tube (QTF-G-IT, Cellestis, ® in children [13]. Some authors reported a sub-optimal Australia), and/or T-SPOT TB (T-SPOT , Oxford Immu- IGRA sensitivity in children [14], but this finding has not notec Ltd. UK) in comparison to TST were included while been confirmed by others [8]. Five meta-analyses have pre- studies using QFT-G were excluded. viously assessed IGRA sensitivity and specificity in chil- dren but reported pooled estimates largely differ (Table 1) Statistical methods [1,5,9-11]. Such discordances may be due to different For each included study, we computed and calculated sen- inclusion/exclusion criteria and, thus, different characteris- sitivity or specificity (and 95% CIs) and summarized the tics of the study populations (i.e. proportion of immuno- results in forest plots. Random-effects meta-analysis was ® compromised/HIV infected and/or young children performed using MetaDiSc , Meta-analysis of Diagnostic included). The setting is also relevant. IGRA performance and Screening tests, Version 1.4 [15]. Studies were is influenced by the child’s immunologic status, which, in weighted by total sample size to pool estimates of sensitiv- turn, may be impaired by several conditions commonly ity and specificity across the studies. Chi-square test was observed in low income countries, such as malnutrition, used to evaluate the presence of statistically significant het- HIV-infection, and elminthiasis [1-3]. Hereby, we report erogeneity across studies, whose variance proportion attri- results of an updated meta-analysis regarding IGRA per- butable to between studies heterogeneity was expressed formance in children, focusing on settings, age, and immu- calculating the I2 statistic. nologic status of the study children. Results Methods For the analysis of sensitivity, 31 studies (20 conducted in A literature search using multiple keywords and standar- high income countries and 11 in low income countries) for dized terminology in Medline, EMBASE and Cochrane QFT-G-IT, including 6183 children [3,16-44], 14 studies databases dating back to their inception up to and through (9 conducted in high income countries and 5 conducted June 7th, 2013, as summarized in Additional file 1, in low income countries for T-SPOT.TB including appendix 1. Inclusion and exclusion criteria, extraction of 2518 children [10,14,16,18,19,22,23,37,39,45-48,50] and Table 1 Sensitivity and specificity of Interferon-gamma release assays (IGRAs) and tuberculin skin test (TST) in the previous published meta-analyses [1,5-12] TST QFN-G-IT T-SPOT.TB Population Number of Author, year of studies publication considered Sensitivity 0.70 (95%CI 0.67-0.72) 0.81 (95%CI 0.78-0.89) 0.84 (95%CI 0.81-0.87) Adults 124 Diel, 2010 0.77 (95%CI 0.71-0.82) 0.78 (95% CI 73-82) 0.90 (95%CI 0.86-0.93) Adults 20 Pai, 2008 0.80 (95%CI 0.75-0.91) 0.81 (95CI 0.78-0.84) Adults 27 Sester, 2010 0.80 (95%CI 0.70-0.90) 0.83(95%CI 0.75-0.92) 0.84(95%CI 0.63-1.00) Children 32 Mandalakas, 2011 0.71(95%CI 0.67-0.75) 0.70 (95%CI 0.65-0.75) 0.62 (95%CI 0.57-0.67) Children 16 Sun, 2011 0.82(95%CI 0.72-0.93) 0.79 (95%CI 0.70-0.89) 0.74 (95%CI 0.59-0.90) Children 11 Chiappini, 2012 0.77 (95%CI 0.64-0.73) Adults and 11 Dheda, 2009 Children 0.66 (95%IC 0.53-0.78) Children 6 Machingaidze, 2011 0.71 (95%CI 0.65-0.74) 0.76 (95%CI 0.70-0.83) 0.88 (95%CI 0.81-0.95) Adults and 58 Menzies, 2007 Children Specificity 0.99 (95%CI 0.98-1.00) 0.86 (95%CI 0.81-0.90) Adults 124 Diel, 2010 0.59 (95%CI 0.46-0.73) 0.96 (95%CI 94-98) 0.93 (95%CI 0.86-1.00) Adults 20 Pai, 2008 0.82 (95%CI 0.70-0.91) 0.82 (95%CI 0.78-0.86) Adults 27 Sester, 2010 0.85 (95%CI 0.69-1.00) 0.91 (95% CI 0.78-1.00) 0.94 (95%CI 0.87-1.00) Children 32 Mandalakas, 2011 0.56 (95% CI 0.50-0.61) 1.00 (95%CI 0.84-1.00) 0.90 (95%CI 0.86-0.93) Children 16 Sun, 2011 0.83 (95%CI 0.74-0.92) 0.95 (95%CI 0.93-0.97) 0.96 (95%CI 0.95-1.00) Children 8 Chiappini, 2012 0.66 (95%CI 0.46-0.86) 0.97 (95%CI 0.96-0.99) 0.92 (95%CI 0.86-0.99) Adults and 58 Menzies, 2007 Children Sollai et al. BMC Infectious Diseases 2014, 14(Suppl 1):S6 Page 3 of 11 http://www.biomedcentral.com/1471-2334/14/S1/S6 34 studies (18 studies conducted in high income countries In this analysis sensitivity of the three test was similar and 16 studies conducted in low income countries) for (0.81 (95%CI: 0.76-0.85) for QFT-G-IT, 0.80 (95%CI: 0.74- TST including 6439 children [14,17-35,37-43,45-47,49,50] 0.84) for T-SPOT.TB, and 0.79 (95%CI: 0.75-0.83) for TST.