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Tuberculosis in Children

Systematic Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pediatr. | doi: 10.3389/fped.2019.00208

Risk factors for indeterminate interferon-gamma release assay for the diagnosis of tuberculosis in children – a systematic review and meta-analysis

  • 1Faculty of Medicine, Universität Basel, Switzerland
  • 2Mycobacterial Research Laboratory, Universitätskinderklinik Basel, Switzerland
  • 3School of Health Professions, Zurich University of Applied Sciences, Switzerland
  • 4Paediatric Infectious Diseases and Vaccinology Unit, Universitätskinderklinik Basel, Switzerland
  • 5UCL Great Ormond Street Institute of Child Health, University College London, United Kingdom
  • 6Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Australia
  • 7Department of Paediatrics Infectious Diseases and Immunology, Evelina London Children's Hospital, United Kingdom
  • 8Mycobacterial Research laboratory, Paediatric Infectious Diseases and Vaccinology Unit, Universitätskinderklinik Basel, Switzerland
  • 9Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Australia

Interferon-gamma release assays (IGRA) are well-established immunodiagnostic tests for tuberculosis (TB) in adults. In children these tests are associated with higher rates of false-negative and indeterminate results. Age is presumed to be one factor influencing cytokine release and therefore test performance. The aim of this study was to systematically review factors associated with indeterminate IGRA results in paediatric patients.
Systematic literature review guided by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) searching PubMed, EMBASE and Web of Science. Studies reporting results of at least one commercially available IGRA (QuantiFERON-TB, T-SPOT.TB) in paediatric patient groups were included. Random effects meta-analysis was used to assess proportions of indeterminate IGRA results. Heterogeneity was assessed using the I2 value. Risk differences were calculated for studies comparing QuantiFERON-TB and T-SPOT.TB in the same study. Meta-regression was used to further explore the influence of study level variables on heterogeneity.
Of 1293 articles screened, 133 studies were included in the final analysis. These assessed QuantiFERON-TB only in 77.4% (103/133), QuantiFERON-TB and T-SPOT.TB in 15.8% (21/133), and T-SPOT.TB only in 6.8% (9/133) resulting in 155 datasets including 107,418 participants. Overall 4% of IGRA results were indeterminate, and T-SPOT.TB (0.03, 95% CI 0.02-0.05) and QuantiFERON-TB assays (0.05, 95% CI 0.04-0.06) showed similar proportions of indeterminate results; pooled risk difference was 0.01 (95% CI -0.03 to 0.00). Significant differences with lower proportions of indeterminate assays with T-SPOT.TB compared to QuantiFERON-TB were only seen in subgroup analyses of studies performed in Africa and in non-HIV-infected immunocompromised patients. Meta-regression confirmed lower proportions of indeterminate results for T-SPOT.TB compared to QuantiFERON-TB only among studies that reported results from non-HIV-infected immunocompromised patients (p<0.001).
On average indeterminate IGRA results occur in 1 in 25 tests performed. Overall, there was no difference in the proportion of indeterminate results between both commercial assays. However, our findings suggest that in patients in Africa and/or patients with immunocompromising conditions other than HIV infection the T-SPOT.TB assay appears to produce fewer indeterminate results.

Keywords: IGRA, clinical studies, Tuberculosis, Latent, paeditarics, risk difference, T cell response, QuantiFERON, T-SPOT .TB ®

Received: 14 Nov 2018; Accepted: 08 May 2019.

Edited by:

Dimitri Van Der Linden, Cliniques Universitaires Saint-Luc, Belgium

Reviewed by:

Anna Starshinova, Saint Petersburg State University, Russia
Delane Shingadia, Great Ormond Street Hospital, United Kingdom
Tea Nieminen, Helsinki Children's Hospital, Finland  

Copyright: © 2019 Meier, Volken, Geiger, Heininger, Tebruegge and Ritz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Nicole Ritz, Universität Basel, Faculty of Medicine, Basel, CH-4001, Switzerland,