engleski

Tuberculosis disease in children and adolescents on therapy with anti-tumor necrosis factor-alpha agents: a collaborative, multi-centre ptbnet study

Background In adults, anti-tumor-necrosis-factor (TNF)-α therapy is associated with progression of latent tuberculosis infection (LTBI) to tuberculosis (TB) disease. The existing paediatric data are very limited. Methods Retrospective multi-centre study within the Paediatric Tuberculosis Network European Trials Group, capturing patients <18 years who developed TB disease during anti-TNF-α therapy. Results Sixty-six tertiary healthcare institutions providing care for children with TB participated. Nineteen cases were identified ; Crohn´s disease (n=8 ; 42%) and juvenile idiopathic arthritis (n=6 ; 32%) were the commonest underlying conditions. Immune-based TB screening (tuberculin skin test and/or interferon-gamma release assay) was performed in 15 patients before commencing anti-TNF-α therapy, but only identified one LTBI case ; 13 patients were already receiving immunosuppressants at the time of screening. The median interval between starting anti-TNF-α therapy and TB diagnosis was 13.1 (IQR:7.1-20.3) months. All cases presented with severe disease, predominately miliary TB (n=14 ; 78%). One case was diagnosed post-mortem. TB was microbiologically confirmed in 15 cases (79%). The median duration of anti-TB treatment was 50 (IQR:46-66) weeks. Five of 15 (33%) cases who had completed TB treatment had long-term sequelae. Conclusions The data indicate that LTBI screening is frequently false-negative in this patient population, likely due to immunosuppressants impairing test performance. Therefore, patients with immune-mediated diseases should be screened for LTBI at the point of diagnosis, before commencing immunosuppressive medication. Children on anti-TNF-α therapy are prone to severe TB disease, and significant long-term morbidity. Those observations underscore the need for robust LTBI screening programs in this high- risk patient population, even in low TB prevalence settings.

Tuberculosis ; anti-TNF-alpha ; reactivation ; miliary tuberculosis ; children

Acknowledgements: The authors thank Dr Nicola Ruperto, from Istituto G. Gaslini in Genova, for kindly sharing data from the Paediatric Rheumatology International Trials Organisation (PRINTO) study. The authors also thank all ptbnet members who reported to the study team in March 2019 (OSM 2): Australia: Nigel Curtis, Paola Villanueva, Ben Marais, Phil Britton, Julia Clark; Austria: Julia Pichler, Anna Zschocke, Matthias Bogyi; Belgium: Alexandra Dreesman, Françoise Mouchet; Bulgaria: Svetlana Velizarova; Croatia: Ivan Pavic; Denmark: Ulrika Nygaard, Anja Pulsen; Finland: Antti Kontturi, Eeva Salo; France: Katarina Chadelat; Germany: Renate Krüger, Stephanie Thee, Frank Ahrens, Michael Barker, Theodor Zimmermann, Ulf Schulze-Sturm, Petra Kaiser-Labusch; Greece: Maria Tsolia; Iran: Oxana Mansour Ghanaie; Italy: Danilo Buonsenso, Andrea Lo Vecchio; Lithuania: Inga Ivaskeviciene; Moldova: Valentina Vilc; Norway: Anastasios Smyrnaios; Romania: Adriana Sorete Arbore; Russian Federation: Anna Starshinova; Slovakia: Ivan Solovic; Slovenia: Uros Krivec, Malena Aldeco; Spain: María Espiau, Antoni Soriano-Arandes, Olaf Neth, Begoña Santiago, David Gómez-Pastrana, Daniel Blázquez, Mati