Tuberculosis Disease In Children And Adolescents On Therapy With Antitumor Necrosis Factor-Alpha Agents: A Collaborative, Multicenter Paediatric Tuberculosis Network European Trials Group (Ptbnet) Study

Background. In adults, anti-tumor necrosis factor-alpha (TNF-alpha) therapy is associated with progression of latent tuberculosis (TB) infection (LTBI) to TB disease, but pediatric data are limited.Methods. Retrospective multicenter study within the Paediatric Tuberculosis Network European Trials Group, capturing patients <18 years who developed TB disease during anti-TNF-alpha 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-alpha therapy but only identified 1 LTBI case; 13 patients were already receiving immunosuppressants at the time of screening. The median interval between starting anti-TNF-alpha therapy and TB diagnosis was 13.1 (IQR, 7.1-20.3) months. All cases presented with severe disease, predominantly miliary TB (n = 14; 78%). One case was diagnosed postmortem. TB was microbiologically confirmed in 15 cases (79%). Me 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. 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-alpha 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.