The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG’s effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.
Background Subclinical tuberculosis (TB) is well recognized and defined as a disease state with absent or non-recognized symptoms. The study identifies factors associated with subclinical TB and diagnostic strategies in a low-burden, high-resource country. Methods Data was collected between December 2013 to November 2019 through the Swiss Pediatric Surveillance Unit (SPSU). Children with culture/molecular confirmed TB, or who were treated with ≥3 anti-mycobacterial drugs, were included. Results A total of 138 (80%) children with TB disease were included in the final analysis, of which 43 (31%) were subclinical. The median age of children with subclinical compared to symptomatic TB was 3.7(IQR 2.2 to 7) and 9.7(IQR 2.7 to 14.3) years, respectively (p=0.003). The cause of investigation for TB was recorded in 31/43 (72.1%) of children with subclinical TB, and included contact exposure in 25 (80.6%). In children with subclinical TB, diagnosis was made by a combination of the following abnormal/confirming results: culture/molecular + immunodiagnostic + chest radiography in 12 (27.9%), immunodiagnostic + chest radiography in 19 (44.2%), culture/molecular + chest radiography in 2 (4.7%), culture + immunodiagnostic in 1 (2.3%), chest radiography only in 8 (18.6%) and immunodiagnostic only in 1 (2.3%) case. Conclusion A notable proportion of children with TB had subclinical disease. This highlights the importance of non-symptom-based TB case finding in exposed children and refugees from high-TB-prevalence settings. TB screening in these asymptomatic children should therefore include a combination of immunodiagnostic testing and imaging followed by culture and molecular testing
RationaleIn 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).ObjectivesThis 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.MethodsMulticentre, 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 results1001 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.TBin 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.TB77.6% (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).ConclusionsThe 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.
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