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Original research
Performance of QuantiFERON-TB Gold Plus assays in paediatric tuberculosis: a multicentre PTBNET study
  1. Danilo Buonsenso1,2,3,
  2. Antoni Noguera-Julian4,5,6,7,
  3. Rossana Moroni8,
  4. Angel Hernández-Bartolomé9,
  5. Nora Fritschi10,
  6. Laura Lancella11,
  7. Laura Cursi11,
  8. Aleix Soler-Garcia4,
  9. Renate Krüger12,
  10. Cornelia Feiterna-Sperling12,
  11. Michela Sali2,13,
  12. Andrea Lo Vecchio14,
  13. Sara Scarano14,
  14. Alicia Hernanz Lobo9,
  15. Maria Espiau15,
  16. Antonio Soriano-Arandes15,
  17. Benhur Sirvan Cetin16,
  18. Folke Brinkmann17,
  19. Iveta Ozere18,
  20. Fernando Baquero-Artigao7,19,20,
  21. Maria Tsolia21,
  22. Tiago Milheiro Silva22,
  23. Matilde Bustillo-Alonso23,
  24. Andrea Martín Nalda15,
  25. Margherita Mancini24,
  26. Anna Starshinova25,
  27. Nicole Ritz10,26,27,
  28. Svetlana Velizarova28,
  29. Laura Ferreras-Antolín29,
  30. Florian Götzinger30,
  31. Olga Bilogortseva31,32,
  32. Vira Chechenyeva31,32,
  33. Marc Tebruegge27,33,
  34. Begoña Santiago-García9
  35. ptbnet QFT-Plus study group
    1. 1Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
    2. 2Dipartimento di Scienze biotecnologiche di base, cliniche intensivologiche e perioperatorie – Sezione di Microbiologia, Università Cattolica del Sacro Cuore, Milano, Italy
    3. 3Center for Global Health Research and Studies, Università Cattolica del Sacro Cuore, Roma, Italia
    4. 4Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Unitat d'Infeccions, Servei de Pediatria, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
    5. 5Departament de Pediatria, Universitat de Barcelona, Barcelona, Spain
    6. 6Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Madrid, Spain
    7. 7Red de Investigación Translacional en Infectología Pediátrica, Madrid, Spain
    8. 8Direzione Scientifica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
    9. 9Paediatric Infectious Diseases Department, Gregorio Marañón University Hospital, Madrid, Spain. Gregorio Marañón Research Health Institute (IiSGM), Madrid, Spain. Centro de Investigación Biomédica en Red de Enfermedades Infecciosas {CIBER INFEC), Instituto de Salud Carlos III, Madrid, Spain
    10. 10Mycobacterial and Migrant Health Research Group, University of Basel Children’s Hospital Basel and Department of Clinical Research, University of Basel, Basel, Switzerland
    11. 11Paediatric Infectious Diseases Unit, Bambino Gesù Children Hospital, Rome, Italy
    12. 12Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin, Berlin, Germany
    13. 13Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Rome, Italy
    14. 14Department of Translational Medical Sciences, Pediatric Infectious Diseases Unit, University of Naples Federico II, Naples, Italy
    15. 15Paediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain
    16. 16Department of Pediatric Infectious Diseases, Erciyes University, Kayseri, Turkey
    17. 17Department of Paediatric Pulmonology, Children's Hospital, Ruhr-University, Bochum, Germany
    18. 18Riga Stradiņš University, Riga, Latvia
    19. 19Hospital Infantil La Paz, Madrid, Spain
    20. 20CIBERINFEC, ISCIII, Madrid, Spain
    21. 21Panagiotis & Aglaia Kyriakou Children's Hospital, Athens, Greece
    22. 22Hospital Dona Estefânia, Lisbon, Portugal
    23. 23Hospital Universitario Miguel Servet, Zaragoza, Spain
    24. 24Specialty School of Pediatrics, Alma Mater Studiorum, University of Bologna, Bologna, Italy
    25. 25St. Petersburg Scientific Research Institute of Phthisiopulmonology, St. Petersburg, Russian Federation
    26. 26Department of Paediatrics and Paediatric Infectious Diseases, Children’s Hospital Lucerne Lucerne Cantonal Hospital, Lucerne, Switzerland
    27. 27Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia
    28. 28Medical University Sofia, Sofia, Bulgaria
    29. 29Paediatric Infectious Diseases Unit, St. George's University Hospitals NHS Foundation Trust, London, UK
    30. 30Department of Paediatric and Adolescent Medicine, National Reference Centre for Childhood Tuberculosis, Klinik Ottakring, Vienna, Austria
    31. 31Ukraine. Department of Children Phthisiology, National Institution of Phthisiology and Pulmonology of National Academy of Medical sciences of Ukraine, Kiev, Ukraine
    32. 32Infectious diseases Centre «Clinic for treatment of children with HIV/AIDS» National Specialized Children's Hospital 'OKHMATDYT', Kiev, Ukraine
    33. 33Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
    1. Correspondence to Dr Marc Tebruegge, Department of Infection, Immunity, and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London, UK; m.tebruegge{at}ucl.ac.uk

    Abstract

    Rationale In 2016, a new interferon-gamma release assay (IGRA) was introduced, QuantiFERON-TB Gold Plus (QFT-Plus), claimed to have improved sensitivity in active tuberculosis (TB).

    Objectives This study aimed to determine the performance of QFT-Plus, compared with previous generation IGRAs and the tuberculin skin test (TST), in children with TB in Europe.

    Methods Multicentre, ambispective cohort study within the Paediatric Tuberculosis Network European Trials Group (ptbnet), a dedicated paediatric TB research network comprising >300 members, capturing TB cases <18 years-of-age diagnosed between January 2009 and December 2019.

    Measurements and main results 1001 TB cases from 16 countries were included (mean age (IQR) 5.6 (2.4–12.1) years). QFT-Plus was performed in 358, QFT Gold in-Tube (QFT-GIT) in 600, T-SPOT.TB in 58 and TST in 636 cases. The overall test sensitivities were: QFT-Plus 83.8% (95% CI 80.2% to 87.8%), QFT-GIT 85.5% (95% CI 82.7% to 88.3%), T-SPOT.TB 77.6% (95% CI 66.9% to 88.3%) and TST (cut-off ≥10 mm) 83.3% (95% CI 83.3% to 86.2%). There was a trend for tests to have lower sensitivity in patients with miliary and/or central nervous system (CNS) TB (73.1%, 70.9%, 63.6% and 43.5%, respectively), and in immunocompromised patients (75.0%, 59.6%, 45.5% and 59.1%, respectively).

    Conclusions The results indicate that the latest generation IGRA assay, QFT-Plus, does not perform better than previous generation IGRAs or the TST in children with TB disease. Overall, tests performed worse in CNS and miliary TB, and in immunocompromised children. None of the tests evaluated had sufficiently high sensitivity to be used as a rule-out test in children with suspected TB.

    • Tuberculosis

    Data availability statement

    Data are available on reasonable request.

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    Data availability statement

    Data are available on reasonable request.

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    Footnotes

    • DB and AN-J are joint first authors.

    • Twitter @surf4children, @tonisoriano66

    • Correction notice This article has been corrected since it was published Online First. Changes have been made to some affiliations and the funding statement. Minor changes have also been applied to the tables and text.

    • Collaborators Laura Minguell (Hospital Universitari Arnau de Vilanova. Lleida, Spain), Estrella Peromingo (Department of Paediatrics, Hospital Universitario Puerta del Mar, Cádiz, Spain), David Gomez Pastrana (Department of Paediatrics, Hospital Universitario de Jerez, Jerez de la Frontera, Spain), Tomas Pérez-Porcuna (Unitat de Salut Internacional, Departament de Pediatria, Fundació Recerca Mútua Terrassa, Atenció Primària, Hospital Universitari Mútua de Terrassa, Universitat de Barcelona, Terrassa, Spain), Beatriz Soto (Hospital Universitario de Getafe, Madrid, Spain), Elena Colino Gil (Department of Paediatrics, Complejo Hospitalario Universitario Insular Materno—Infantil de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain), Mercedes Herranz-Aguirre (Sección de Enfermedades Infecciosas Pediátricas, Servicio de Pediatría, Complejo Hospitalario de Navarra, Pamplona, Spain), Cesar Gavilan Martin (Servicio de Pediatría, Hospital Universitario San Juan de Alicante, Spain), Eva María López-Medina (Pediatric infectious Disease Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain), Christine Bell (Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK), Frances Child (Royal Manchester Children’s Hospital, UK), Inga Ivaškevičienė (Clinic of Children’s Diseases, Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania), Zulema Lobato (Department of Paediatrics, Hospital Sant Joan de Déu—Fundació Althaia, Manresa, Spain), Neus Rius (Hospital Universitari Sant Joan de Reus, Spain), Olga Calavia (Department of Paediatrics, Hospital Joan XXIII, Tarragona, Spain), Daniel Blázquez-Gamero (Pediatric Infectious Diseases Unit, Hospital Universitario 12 de Octubre, Madrid, Spain), Begoña Carazo (Pediatric Infectious Diseases Unit, Pediatrics Department, Hospital Materno Infantil de Málaga, Málaga, Spain), Maria Queralt Soler Campins (Department of Paediatrics, Consorci Sanitari de Terrassa, Terrassa, Spain), Cristina Calvo (Pediatric and Infectious Diseases Department Hospital Universitario La Paz, Madrid, Spain), Javier Korta Murua (Department of Paediatrics, Hospital Universitario Donostia, San Sebastián, Spain), Charlotte Buxbaum (Astrid Lindgren Children’s Hospital, Karolinska University Hospital Huddinge, Stockholm, Sweden), Ivan Pavić (Department of Paediatric Allergology, Pulmonology, Rheumatology and Clinical Immunology, Children’s Hospital Zagreb, Zagreb, Croatia), Cristina Alvarez (Department of Paediatrics, Hospital Universitario Marqués de Valdecillas, Santander, Spain), Elvira Cobo-Vazquez (Hospital Universitario Fundación de Alcorcón, Madrid, Spain), Beatriz Perez Gorricho (Pediatric Infectious Diseases Unit, Department of Pediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain), Sonia Rodriguez (Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain), Ana Menasalvas (Department of Paediatrics, Hospital Virgen de la Arrixaca, Murcia, Spain), Maria Isabel Garrote Llanos (Pediatric Infectious Diseases Department, Hospital Universitario de Basurto, Bilbao, Spain), Sara Berhard-Stirnemann (Department of Paediatrics, Cantonal Hospital Aarau Children’s Hospital, Aarau, Switzerland), Marie Rohr (Department of Paediatrics, Hôpitaux Universitaires de Genève, Geneva, Switzerland), Christa Relly (Division of Infectious Diseases and Hospital Epidemiology, University Children’s Hospital Zurich, Zurich, Switzerland), Lourdes Garcia Rodriguez (Pediatria, Hospital de Mataró—Consorci Sanitari del Maresme, Barcelona, Spain), Maria del Pozo (Pediatrics Department, Hospital General Universitario de Albacete, Albacete, Spain), Irene Rivero-Calle (Translational Pediatrics and Infectious Diseases Section, Hospital Clínico Universitario de Santiago de Compostela, Spain), Alfredo Tagarro (Pediatrics Department, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Madrid, Spain), Andrea Duppenthaler (Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland), Isabelle Rochat Guignard (Service of Paediatrics, Department of Woman, Mother, Child, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland), Michael Buettcher (Paediatric Infectious Diseases, Department of Paediatrics, Lucerne Children’s Hospital, Switzerland), Elizabeth Whittaker (Section of Paediatric Infectious Diseases, Imperial College, London, UK), Paddy McMaster (Department of Paediatric Infectious Diseases, Northern Care Alliance NHS Group, Manchester, UK), Verdiana Vigliano (Catholic University of Rome, Italy), Cristina Russo (Bambino Gesù Children Hospital, Rome, Italy).

    • Contributors DB, MT, BS-G, AN-J conceptualised the study, wrote the first draft and the last version of the manuscript. All authors contributed to methodology, data collection, revision of initial draft and final version of the manuscript. MT and BS-G are joint last authors. DB is the author acting as guarantor.

    • Funding AN-J was supported by “Subvencions per a la Intensificació de Facultatius Especialistes” (Departament de Salut de la Generalitat de Catalunya, Programa PERIS 2016-2020) [SLT008/18/00193]. AHL is funded by the Spanish Ministry of Science and Innovation—Instituto de Salud Carlos III and Fondos FEDER (Contrato Río Hortega CM20/00128).

    • Competing interests DB participated in a Qiagen advisory board meeting on the use of IGRAs in children <5 years of age. The manufacturers had no influence on the study design, data collection, analysis or interpretation, writing of the manuscript or the decision to submit the data for publication. BS-G and MT have received support from Cepheid for a project on molecular TB diagnostics unrelated to the study reported here. MT has received QuantiFERON-TB assays at reduced pricing or free of charge for TB diagnostics projects from the manufacturer (Cellestis/Qiagen) in the past, and has received support for conference attendance from Cepheid.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.