Douwe H. Visser

Impact of drug resistance on clinical outcome in children with tuberculous meningitis

Background: Tuberculous meningitis (TBM) is associated with delayed diagnosis and poor outcome in children. This study investigated the impact of drug resistance on clinical outcome in children with TBM. Methods: All children (0–13 years) were included if admitted to Tygerberg Children’s Hospital, Cape Town, South Africa, from January 2003 to April 2009 with a diagnosis of either confirmed TBM, or probable TBM with mycobacterial isolation from a site other than cerebrospinal fluid. Mycobacterial samples underwent drug susceptibility testing to rifampin and isoniazid. Children were treated with isoniazid, rifampin, pyrazinamide and ethionamide according to local guidelines. Results: One hundred twenty-three children were included; 13% (16 of 123) had any form of drug resistance, and 4% (5 of 123) had multidrug-resistant tuberculosis. Time from start of symptoms to appropriate treatment was longer in children with any drug resistance (median: 31 days versus 9 days; P = 0.001). In multivariable analysis, young age (P = 0.013) and multidrug-resistant tuberculosis (adjusted odds ratio: 12.4 [95% confidence interval: 1.17–132.3]; P = 0.037) remained risk factors for unfavorable outcome, and multidrug-resistant tuberculosis remained a risk for death (adjusted odds ratio: 63.9 [95% confidence interval: 4.84–843.2]; P = 0.002). We did not detect any difference in outcome between those with isolates resistant to only isoniazid and those with fully susceptible strains (adjusted odds ratio: 0.22 [confidence interval: 0.03–1.87]; P = 0.17). Conclusion: Multidrug-resistant TBM in children has poor clinical outcome and is associated with death. We did not find any difference in the outcomes between children with isoniazid monoresistant TBM and those with drug-susceptible TBM. One explanation could be the local treatment regimen. Further investigation of this regimen is indicated.

Host Immune Response to Tuberculous Meningitis

BACKGROUND Tuberculous meningitis (TBM) is a severe complication of tuberculosis predominantly affecting young children. Early treatment is vital to prevent morbidity and mortality, emphasizing the importance of early diagnosis. The lack of sensitive methods for early diagnosis is the most common cause of delay. Attempts have been made to develop simplified tests for tuberculosis, but their diagnostic power remains poor. The clinical picture of TBM is mainly driven by the hosts immune response to Mycobacterium tuberculosis; therefore, identification of disease-specific biomarkers may have diagnostic and therapeutic value and improve our understanding of its pathogenesis. METHODS We investigated disease-specific biomarkers of childhood TBM in a cohort of children aged 3 months-13 years with symptoms and signs suggestive of meningitis. Cerebrospinal fluid (CSF) and serum from 56 patients with and 55 patients without TBM were assessed for 28 soluble mediators. RESULTS Unsupervised hierarchical clustering analysis revealed a disease-specific pattern of biomarkers for TBM relative to other types of meningitis. A biomarker-based diagnostic prediction model for childhood TBM based on CSF concentrations of interleukin 13 (cutoff value, 37.26 pg/mL), vascular endothelial growth factor (cutoff value, 42.92 pg/mL), and cathelicidin LL-37 (cutoff value, 3221.01 pg/mL) is presented with a sensitivity of 0.52 and a specificity of 0.95. CONCLUSIONS These data highlight the potential of biosignatures in the hosts CSF for diagnostic applications and for improving our understanding of the pathogenesis of TBM to discover strategies to prevent immunopathological sequelae.

Improved diagnosis of childhood tuberculous meningitis using more than one nucleic acid amplification test.

BACKGROUND Early treatment is critical to reducing tuberculous meningitis (TBM) related morbidity and mortality. Diagnosis based on cerebrospinal fluid (CSF) culture is impractical due to slow turnaround times, while microscopy has poor sensitivity. Enhanced detection methods are essential to guide early treatment initiation, especially in vulnerable young children. METHODS We assessed the diagnostic accuracy of the GenoType(®) MTBDRplus and Xpert(®) MTB/RIF assays on CSF collected from paediatric meningitis suspects prospectively enrolled at Tygerberg Hospital, Cape Town, South Africa. Fluorescent auramine-O microscopy, liquid culture for Mycobacterium tuberculosis, GenoType and Xpert assays were performed on all CSF samples. RESULTS Of 101 meningitis suspects, 55 were diagnosed with TBM and 46 served as non-TBM controls. Using a pre-defined TBM case definition as reference standard, sensitivities and specificities were 4% and 100% for fluorescent microscopy, 22% and 100% for culture, 33% and 98% for GenoType, 26% and 100% for Xpert, 22% and 100% for microscopy and culture combined and 49% and 98% for GenoType and Xpert combined. Culture, GenoType and Xpert combined performed best, with 56% sensitivity and 98% specificity. CONCLUSION Although commercial nucleic-acid amplification tests performed on CSF revealed incrementally improved diagnostic accuracy, providing rapid microbiological confirmation, they cannot serve as a rule-out test.

Commercial nucleic acid amplification tests in tuberculous meningitis—a meta-analysis ☆ ☆☆

Although nucleic acid amplification tests (NAATs) promise a rapid, definitive diagnosis of tuberculous meningitis, the performance of first-generation NAATs was suboptimal and variable. We conducted a meta-analysis of studies published between 2003 and 2013, using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool to evaluate methodological quality. The diagnostic accuracy of newer commercial NAATs was assessed. Pooled estimates of diagnostic accuracy for commercial NAATs measured against a cerebrospinal fluid Mycobacterium tuberculosis culture-positive gold standard were sensitivity 0.64, specificity 0.98, and diagnostic odds ratio 64.0. Heterogeneity was limited; P value = 0.147 and I(2) = 33.85%. The Xpert MTB/RIF® test was evaluated in 1 retrospective study and 4 prospective studies, with pooled sensitivity 0.70 and specificity 0.97. The QUADAS-2 tool revealed low risk of bias, as well as low concerns regarding applicability. Heterogeneity was pronounced among studies of in-house tests. Commercial NAATs proved to be highly specific with greatly reduced heterogeneity compared to in-house tests. Sub-optimal sensitivity remains a limitation.

Seasonal variation in the incidence rate of tuberculous meningitis is associated with sunshine hours

Tuberculous meningitis (TBM) is a severe complication of tuberculosis and occurs mainly during early childhood. The incidence rate of TBM varies with season, and serum vitamin D levels, which are dependent on sunlight, might play a role. We studied the association between TBM incidence rate and hours of sunshine in Cape Town, South Africa and found a significant association between the incidence rate of TBM and hours of sunshine 3 months earlier (incidence rate ratio per 100 sunshine hours 0·69, 95% confidence interval 0·54-0·88, P = 0·002). The association supports the hypothesis that vitamin D might play a role in the pathophysiology of TBM. Further prospective studies in which vitamin D status is measured are necessary to determine causality.

Lipoarabinomannan enzyme-linked immunosorbent assay for early diagnosis of childhood tuberculous meningitis.

SETTING Tuberculous meningitis (TBM) is a severe complication of tuberculosis (TB) predominantly affecting young children. Early initiation of treatment is important to prevent morbidity and mortality associated with TBM, emphasising the importance of early diagnosis. Among the most promising new methods for diagnosing TB are antigen-detection assays based on the detection of lipoarabinomannan (LAM). OBJECTIVE To evaluate the diagnostic value of a commercial, antigen-capture enzyme-linked immunosorbent assay (ELISA) test based on the detection of LAM in urine for the early diagnosis of TBM in children. METHOD A cross-sectional study in which urine samples from paediatric patients with suspected TBM attending the Tygerberg Childrens Hospital, Cape Town, South Africa, were tested for LAM. RESULTS Complete data were available for 50 of 56 patients with suspected TBM. TBM was diagnosed in 21 (42%) patients and excluded in 29 (58%). The LAM ELISA had a sensitivity of 4.8% and a specificity of 93.1%. Serial measurements in the first 2 weeks after treatment initiation did not improve test performance. CONCLUSION We have shown that urinary LAM detection was of little value for the diagnosis of TBM in a cohort of paediatric patients with suspected TBM.

Solar ultraviolet B exposure and global variation in tuberculosis incidence: an ecological analysis

Epidemiological evidence supports vitamin D deficiency as a risk factor for tuberculosis. Differences in solar ultraviolet B (UV-B) exposure, the major source of vitamin D, might therefore partially explain global variation in tuberculosis incidence. In a global country-based ecological study, we explored the correlation between vitamin D-proxies, such as solar UV-B exposure, and other relevant variables with tuberculosis incidence, averaged over the period 2004–2013. Across 154 countries, annual solar UV-B exposure was associated with tuberculosis incidence. Tuberculosis incidence in countries in the highest quartile of UV-B exposure was 78% (95% CI 57–88%, p<0.001) lower than that in countries in the lowest quartile, taking into account other vitamin D-proxies and covariates. Of the explained global variation in tuberculosis incidence, 6.3% could be attributed to variations in annual UV-B exposure. Exposure to UV-B had a similar, but weaker association with tuberculosis notification rates in the multilevel analysis with sub-national level data for large countries (highest versus lowest quartile 29% lower incidence; p=0.057). The potential preventive applications of vitamin D supplementation in high-risk groups for tuberculosis merits further investigation. Variation in UV-B exposure may partly clarify previously unexplained global differences in TB incidence http://ow.ly/lrrl30aZiHN