Treatment and Outcome in Children With Tuberculous Meningitis: A Multicenter Pediatric Tuberculosis Network European Trials Group Study.

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.

Performance of immune-based and microbiological tests in children with tuberculosis meningitis in Europe: a multicentre Paediatric Tuberculosis Network European Trials Group (ptbnet) study.

INTRODUCTION: Tuberculous meningitis (TBM) is often diagnostically challenging. Only limited data exist on the performance of interferon-γ release assays (IGRA) and molecular assays in children with TBM in routine clinical practice, particularly in the European setting. METHODS: Multicentre, retrospective study involving 27 healthcare institutions providing care for children with tuberculosis (TB) in nine European countries. RESULTS: Of 118 children included, 54 (45.8%) had definite, 38 (32.2%) probable and 26 (22.0%) possible TBM; 39 (33.1%) had TBM grade 1, 68 (57.6%) grade 2 and 11 (9.3%) grade 3. Of 108 patients who underwent cranial imaging 90 (83.3%) had at least one abnormal finding consistent with TBM. At the 5-mm cut-off the tuberculin skin test had a sensitivity of 61.9% (95% CI 51.2-71.6%) and at the 10-mm cut-off 50.0% (95% CI 40.0-60.0%). The test sensitivities of QuantiFERON-TB and T-SPOT.TB assays were 71.7% (95% CI 58.4-82.1%) and 82.5% (95% CI 58.2-94.6%), respectively (p=0.53). Indeterminate results were common, occurring in 17.0% of QuantiFERON-TB assays performed. Cerebrospinal fluid (CSF) cultures were positive in 50.0% (95% CI 40.1-59.9%) of cases, and CSF PCR in 34.8% (95% CI 22.9-43.7%). In the subgroup of children who underwent tuberculin skin test, IGRA, CSF culture and CSF PCR simultaneously, 84.4% had at least one positive test result (95% CI 67.8%-93.6%). CONCLUSIONS: Existing immunological and microbiological TB tests have suboptimal sensitivity in children with TBM, with each test producing false-negative results in a substantial proportion of patients. Combining immune-based tests with CSF culture and CSF PCR results in considerably higher positive diagnostic yields, and should therefore be standard clinical practice in high-resource settings.

Severe combined immunodeficiency--an update.

Severe combined immunodeficiencies (SCIDs) are a group of inherited disorders responsible for severe dysfunctions of the immune system. These diseases are life-threatening when the diagnosis is made too late; they are the most severe forms of primary immunodeficiency. SCID patients often die during the first two years of life if appropriate treatments to reconstitute their immune system are not undertaken. Conventionally, SCIDs are classified according either to the main pathway affected by the molecular defect or on the basis of the specific immunologic phenotype that reflects the stage where the blockage occurs during the differentiation process. However, during the last few years many new causative gene alterations have been associated with unusual clinical and immunological phenotypes. Many of these novel forms of SCID also show extra-hematopoietic alterations, leading to complex phenotypes characterized by a functional impairment of several organs, which may lead to a considerable delay in the diagnosis. Here we review the biological and clinical features of SCIDs paying particular attention to the most recently identified forms and to their unusual or extra-immunological clinical features.