Stephanie Thee1, Robindra Basu Roy2, Daniel Blázquez-Gamero3, Lola Falcón-Neyra4, Olaf Neth4, Antoni Noguera-Julian5,6,7,8, Cristina Lillo3, Luisa Galli9,10, Elisabetta Venturini9,10, Danilo Buonsenso11, Florian Götzinger12, Nuria Martinez-Alier13, Svetlana Velizarova14, Folke Brinkmann15, Steven B Welch16, Maria Tsolia17, Begoña Santiago-Garcia18, Ralph Schilling19,20, Marc Tebruegge13,21,22, Renate Krüger1. 1. Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Centre, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. 2. Clinical Research Department, London School of Hygiene & Tropical Medicine, London, United Kingdom. 3. Pediatric Infectious Diseases Unit, Hospital Universitario, Universidad Complutense de Madrid, Instituto de Investigación Hospital Universitario, RITIP, Madrid, Spain. 4. Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Seville (IBIS), Seville, Spain. 5. Malalties Infeccioses i Resposta Inflamatòria Sistèmica en Pediatria, Institut de Recerca Sant Joan de Déu, Barcelona, Spain. 6. Departament de Pediatria, Universitat de Barcelona, Barcelona, Spain. 7. CIBER de Epidemiología y Salud Pública, CIBERESP, Madrid, Spain. 8. Red de Investigación Translacional en Infectología Pediátrica, RITIP, Madrid, Spain. 9. Department of Health Sciences, University of Florence, Florence, Italy. 10. Pediatric Infectious Disease Unit, Meyer Children's University Hospital, Florence, Italy. 11. Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCC S, Rome, Italy. 12. Department of Pediatrics and Adolescent Medicine, National Reference Centre for Childhood Tuberculosis, Klinik Ottakring, Vienna, Austria. 13. Department of Pediatric Infectious Diseases & Immunology, Evelina London Children's Hospital, Guy's and St. Thomas's NHS Foundation Trust, London, United Kingdom. 14. Department of Pulmonary Diseases, Medical University, Hospital for Lung Diseases "St. Sofia," Sofia, Bulgaria. 15. Department of Pediatric Pulmonology, Ruhr University Bochum, Bochum, Germany. 16. Birmingham Chest Clinic and Heartlands Hospital, University Hospitals Birmingham, Birmingham, United Kingdom. 17. Second Department or Paediatrics, National and Kapodistrian University of Athens, School of Medicine, P. and A. Kyriakou Children's Hospita l, Athens, Greece. 18. Department of Pediatric Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain. Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain Red de Investigación Translacional en Infectología Pediátrica (RITIP), Madrid, Spain. 19. Institute of Biometry and Clinical Epidemiology, Charité-Universitätsmedizin Berlin, Germany. 20. Institute for Social Medicine, Epidemiology and Health Economics, Charité-Universitätsmedizin Berlin, Germany. 21. Department of Paediatrics, Royal Children's Hospital Melbourne, University of Melbourne, Melbourne, Australiaand. 22. Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
Abstract
BACKGROUND: Currently, data on treatment, outcome, and prognostic factors in children with tuberculous meningitis (TBM) in Europe are limited. To date, most existing data on TBM originate from adult studies, or studies conducted in low-resource settings. METHODS: We designed a multicenter, retrospective study involving 27 pediatric healthcare institutions in 9 European countries via an established pediatric TB research network, before and after the 2014 revision of World Health Organization (WHO) dosing recommendations. RESULTS: Of 118 children, 39 (33.1%) had TBM grade 1, 68 (57.6%) grade 2, and 11 (9.3%) grade 3. Fifty-eight (49.1%) children received a standard 4-drug treatment regimen; other commonly used drugs included streptomycin, prothionamide, and amikacin. Almost half of the patients (48.3%; 56/116) were admitted to intensive care unit, with a median stay of 10 (interquartile range [IQR] 4.5-21.0) days. Of 104 children with complete outcome data, 9.6% (10/104) died, and only 47.1% (49/104) recovered fully. Main long-term sequelae included spasticity of 1 or more limbs and developmental delay both in 19.2% (20/104), and seizure disorder in 17.3% (18/104). Multivariate regression analyses identified microbiological confirmation of TBM, the need for neurosurgical intervention, and mechanical ventilation as risk factors for unfavorable outcome. CONCLUSIONS: There was considerable heterogeneity in the use of TB drugs in this cohort. Despite few children presenting with advanced disease and the study being conducted in a high-resource setting, morbidity and mortality were high. Several risk factors for poor outcome were identified, which may aid prognostic predictions in children with TBM in the future.
BACKGROUND: Currently, data on treatment, outcome, and prognostic factors in children with tuberculous meningitis (TBM) in Europe are limited. To date, most existing data on TBM originate from adult studies, or studies conducted in low-resource settings. METHODS: We designed a multicenter, retrospective study involving 27 pediatric healthcare institutions in 9 European countries via an established pediatric TB research network, before and after the 2014 revision of World Health Organization (WHO) dosing recommendations. RESULTS: Of 118 children, 39 (33.1%) had TBM grade 1, 68 (57.6%) grade 2, and 11 (9.3%) grade 3. Fifty-eight (49.1%) children received a standard 4-drug treatment regimen; other commonly used drugs included streptomycin, prothionamide, and amikacin. Almost half of the patients (48.3%; 56/116) were admitted to intensive care unit, with a median stay of 10 (interquartile range [IQR] 4.5-21.0) days. Of 104 children with complete outcome data, 9.6% (10/104) died, and only 47.1% (49/104) recovered fully. Main long-term sequelae included spasticity of 1 or more limbs and developmental delay both in 19.2% (20/104), and seizure disorder in 17.3% (18/104). Multivariate regression analyses identified microbiological confirmation of TBM, the need for neurosurgical intervention, and mechanical ventilation as risk factors for unfavorable outcome. CONCLUSIONS: There was considerable heterogeneity in the use of TB drugs in this cohort. Despite few children presenting with advanced disease and the study being conducted in a high-resource setting, morbidity and mortality were high. Several risk factors for poor outcome were identified, which may aid prognostic predictions in children with TBM in the future.