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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pediatr. | doi: 10.3389/fped.2019.00311

Identification of Mycobacterium tuberculosis infection in infants and children with partial discrimination between active disease and asymptomatic infection.

 Alexandra Dreesman1, 2, Violette Dirix1, Kaat Smits1,  Véronique Corbière1, Anne Van Praet1,  Sara Debulpaep3, Iris De Schutter4, Mariet-Karlijn Felderhof4,  Anne Malfroot4,  Mahavir Prof. Dr. Singh5,  Camille Locht6, 7,  Françoise Mouchet2 and  Françoise Mascart1, 8*
  • 1Laboratory of Vaccinology and Mucosal Immunology (LoVMI), Free University of Brussels, Belgium
  • 2Pediatric department, Hôpital Saint-Pierre, Belgium
  • 3Service de pédiatrie, Hôpital Saint-Pierre, Belgium
  • 4Depatment of Pediatric Pulmonology, Cystic Fibrosis Clinic and Pediatric Infectious Diseases, UZ Brussels, University Hospital Brussels, Belgium
  • 5LIONEX GmbH, Germany
  • 6Université Lille Nord de France, France
  • 7INSERM U8204 Centre d'infection et d'immunité de Lille (CIIL), France
  • 8Faculty of Medicine, Hôpital Erasme, Free University of Brussels, Belgium

Background:
Improved diagnostic tests are needed for the early identification of Mycobacterium tuberculosis-infected young children exposed to an active TB (aTB) index case. We aimed to compare the diagnostic accuracy of new blood-based tests to that of the tuberculin skin test (TST) for the identification of all infected children and for a potential differentiation between aTB and latent TB infection (LTBI).
Methods:
144 children exposed to a patient with aTB were included, and those who met all inclusion criteria (130/144) were classified in three groups based on results from classical investigations: non-infected (NI: n=69, 53%, median age 10 months), LTBI (n=28, 22%, median age 96 months), aTB disease (n=33, 25%, median age 24 months). The first whole blood assay consisted of a 7-days in vitro stimulation of blood with four different mycobacterial antigens (40µl/condition), followed by flow cytometric measurement of the proportions of blast cells appearing among lymphocytes as a result of their specific activation. Thresholds of positivity were determined by ROC curve analysis (results of NI children versus children with LTBI/aTB) in order to identify infected children in a first stage. Other cut-offs were determined to discriminate subgroups of infected children in a second step (results from children with aTB/LTBI). Analysis of blood monocytes and dendritic cell subsets was performed on 100 µl of blood for 25 of these children as a second test in a pilot study.
Results:
Combining the results of the blast-induced CD3+ T lymphocytes by Heparin-Binding Haemagglutinin and by Culture Filtrate Protein-10 identified all but one infected children (sensitivity 98.2% and specificity 86.9%compared to 93.4% and 100% for the TST). Further identification among infected children of those with aTB was best achieved by the results of blast-induced CD8+ T lymphocytes by purified protein derivative (sensitivity for localized aTB: 61.9%, specificity 96.3%), whereas the proportions of blood type 2 myeloid dendritic cells (mDC) were a hallmark of LTBI.
Conclusions:
New blood-based tests requiring a very small volume allow the accurate identification of M. tuberculosis-infected young children among exposed children and are promising to guide the clinical classification of children with aTB or LTBI.

Keywords: Mycobacterium tuberculosis, diagnosis, latent infection, active infection, Lymphoblasts, Fascia, Dendritic Cells, Children

Received: 28 Sep 2018; Accepted: 09 Jul 2019.

Edited by:

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

Reviewed by:

Robindra Basu Roy, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom
Petra Zimmermann, The University of Melbourne, Australia
Ulrich Von Both, Ludwig Maximilian University of Munich, Germany  

Copyright: © 2019 Dreesman, Dirix, Smits, Corbière, Van Praet, Debulpaep, De Schutter, Felderhof, Malfroot, Prof. Dr. Singh, Locht, Mouchet and Mascart. 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: Prof. Françoise Mascart, Free University of Brussels, Faculty of Medicine, Hôpital Erasme, Brussels, 1070, Belgium, Francoise.Mascart@erasme.ulb.ac.be