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Performance of Tuberculin Skin Tests and Interferon-γ Release Assays in Children Younger Than 5 years

Velasco-Arnaiz, Eneritz, MDa,b; Soriano-Arandes, Antoni, MD, PhDc; Latorre, Irene, PhDd; Altet, Neus, MD, PhDc; Domínguez, José, PhDd; Fortuny, Clàudia, MD, PhDa,b,e,f; Monsonís, Manuel, MDg; Tebruegge, Marc, MD, MRCPCH, DTM&H, MSc, PhDh,i,j,k,*; Noguera-Julian, Antoni, MD, PhDa,b,e, f,*

The Pediatric Infectious Disease Journal: March 23, 2018 - Volume Publish Ahead of Print - Issue - p
doi: 10.1097/INF.0000000000002015
Original Studies: PDF Only

Background: Available data to assess the optimal diagnostic approach in infants and pre-school children at risk of tuberculosis (TB) are limited.

Methods: We conducted a prospective observational study in children younger than 5 years undergoing assessment with both tuberculin skin tests (TST) and QuantiFERON-TB Gold In-Tube® (QFT-GIT) assays at two tertiary TB Units in Barcelona, Spain.

Results: 383 children were included. One of 304 participants considered uninfected developed active TB during follow-up (median [IQR]: 47 [30;48] months), compared with none of 40 participants with latent TB infection (follow-up since completion of anti-TB treatment: 42 [32;45] months). Overall test agreement between TST and QFT-GIT was moderate (κ=0.551), but very good in children screened after TB contact (κ=0.801) and in BCG-unvaccinated children (κ=0.816). Discordant results (16.8%, all TST+/QFT-GIT negative) were mainly observed in new-entrant screening and in BCG-vaccinated children. Children with indeterminate QFT-GIT results were on average younger than those with determinate results (median age: 12 versus 30 months; p<0.001). The sensitivity of TSTs and QFT-GIT assays in children with confirmed active TB was 100% (95%CI: 79.4-100%) and 93.7% (95%CI: 69.8-99.8%), respectively. In patients with latent TB infection or active TB there was no correlation between age and antigen-stimulated interferon-gamma responses (r=-0.044, p=0.714).

Conclusions: In young BCG-unvaccinated children with recent TB contact a dual testing strategy using TST and QFT-GIT in parallel may not be necessary. However, TST+/QFT-GIT negative discordance is common, and it remains uncertain if this constellation indicates TB infection or not. In active TB, QFT-GIT assays do not perform better than TSTs.

aMalalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria. Unitat d´Infeccions, Servei de Pediatria. Institut de Recerca Pediàtrica Hospital Sant Joan de Déu; Barcelona, Spain. bDepartament de Pediatria, Universitat de Barcelona; Barcelona, Spain. cInstitut Català de la Salut. Unitat de Tuberculosi Hospital Universitari Vall d’Hebrón-Drassanes. Barcelona, Spain. dInstitut d’Investigació Germans Trias i Pujol. CIBER Enfermedades Respiratorias. Universitat Autònoma de Barcelona. Badalona, Spain. eCIBER de Epidemiología y Salud Pública (Ciberesp, Spain). fRed de Investigación Transalacional en Infectología Pediátrica (RITIP, Spain). gServei de Microbiologia. Hospital Sant Joan de Déu. Barcelona, Spain. hAcademic Unit of Clinical and Experimental Sciences, Faculty of Medicine & Global Health Research Institute, University of Southampton, Southampton, United Kingdom. iDepartment of Paediatric Infectious Diseases & Immunology, Evelina London Children’s Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK, United Kingdom. jGreat Ormond Street Hospital Institute of Child Health, University College London, London, UK. kDepartment of Paediatrics, The University of Melbourne, Parkville, Australia.

* Both authors share credit for senior authorship.

Conflicts of Interest and Source of Funding: Dr. Tebruegge has received QuantiFERON-TB Gold assays at reduced cost for related research projects from the manufacturer (Cellestis/Qiagen). The manufacturer had no influence on the study design, data interpretation, writing of the manuscript or decision to submit the data for publication. The remaining authors have no potential conflicts of interest to disclose.

Dr. Domínguez is funded by the Miguel Servet program of the Instituto de Salud Carlos III (Spain). This research was partially supported by different grants from the Instituto de Salud Carlos III (PI 13/01546, PI 13/01740 and ICI14/00228), integrated in the Plan Nacional de I+D+I and co-funded by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER). Dr. Tebruegge was supported by a Clinical Lectureship provided by the UK National Institute for Health Research and funding provided by the Technology Strategy Board/Innovate U.K.

Acknowledgements: The authors thank the patients and their families for kindly agreeing to take part in this study.

Address correspondence to (and address for reprints): Antoni NOGUERA-JULIAN, MD, PhD, Passeig de Sant Joan de Déu 2, 08950 Esplugues de Llobregat, Barcelona (Spain), e-mail address:, Phone number: +34 93 280 40 00; fax number: +34 93 203 39 59

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