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)-alpha 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-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 one 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, 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-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.