Tuberculous Meningitis In Children Research Articles

Rapid Accurate Identification of Tuberculous Meningitis Among South African Children Using a Novel Clinical Decision Tool.

Early diagnosis of tuberculous meningitis (TBM) is crucial to achieve optimum outcomes. There is no effective rapid diagnostic test for use in children. We aimed to develop a clinical decision tool to facilitate the early diagnosis of childhood TBM. Retrospective case-control study was performed across 7 hospitals in KwaZulu-Natal, South Africa (2010-2014). We identified the variables most predictive of microbiologically confirmed TBM in children (3 months to 15 years) by univariate analysis. These variables were modelled into a clinical decision tool and performance tested on an independent sample group. Of 865 children with suspected TBM, 3% (25) were identified with microbiologically confirmed TBM. Clinical information was retrieved for 22 microbiologically confirmed cases of TBM and compared with 66 controls matched for age, ethnicity, sex and geographical origin. The 9 most predictive variables among the confirmed cases were used to develop a clinical decision tool (CHILD TB LP): altered Consciousness; caregiver HIV infected; Illness length >7 days; Lethargy; focal neurologic Deficit; failure to Thrive; Blood/serum sodium <132 mmol/L; CSF >10 Lymphocytes ×10/L; CSF Protein >0.65 g/L. This tool successfully classified an independent sample of 7 cases and 21 controls with a sensitivity of 100% and specificity of 90%. The CHILD TB LP decision tool accurately classified microbiologically confirmed TBM. We propose that CHILD TB LP is prospectively evaluated as a novel rapid diagnostic tool for use in the initial evaluation of children with suspected neurologic infection presenting to hospitals in similar settings.

Secondary complications in tuberculous meningitis in children: A prospective cohort study from India

Background : There is a paucity of data on nature and frequency of complications during the course of management of Tuberculous Meningitis (TBM) in developing countries. Methods : This was a single center prospectivecohort of children less than 12 years of age diagnosed with TBM from January 2011 to Aug 2015. Results : Out of 281 children with TBM, hydrocephalous was present 245 children out of which 206 children needed neurosurgical intervention.24.3%, 35.5 % and 40.2% were in stage 1, stage 2 and 3(MRC) respectively. 164children underwent ventriculo-peritoneal shunt, 32 external ventricular drainage, and 10 underwent Omayya chamber drainage. Major complications were Shunt infection/Ventriculitis-16(7.7%) and Shunt Block 11(5.3%), Shunt Tract hemmorhage 12(5.8%). Other complications that were noted includedpersisting hydrocephalous after shunt, post shunt hygroma, shunt fracture, CSF ascites/ pseudocyst, skin Problems at shunt site, and intraventricular hemorrhage. 59.6%(n=148) had serum sodium <135meq/L and 37% (n=92) had a serum sodium <130 meq/L. Furthermore, 3.6%(n=9) had cerebral salt wasting, 5.2%(n=13) had SIADH and 1.25%(n=3) had central diabetes insipidus. While more than one of these entities was seen in 3 children. Suspected hospital acquired sepsis needing adding of second line antibiotics was seen in 24.26% of the children. Conclusion : In this cohort of children in resource constraint setting who present with advanced hydrocephalous and severe encephalopathy, the major shunt complication rates like infection and malfunction were remarkably low compared to available literature.

Tuberculous Meningitis in Children and Adults: New Insights for an Ancient Foe.

Tuberculous meningitis is the most devastating manifestation of infection with Mycobacterium tuberculosis and represents a medical emergency. Approximately one half of tuberculous meningitis patients die or suffer severe neurologic disability. The goal of this review will be to review the pathogenic, clinical, and radiologic features of tuberculous meningitis and to highlight recent advancements in translational and clinical science. Pharmacologic therapy includes combination anti-tuberculosis drug regimens and adjunctive corticosteroids. It is becoming clear that a successful treatment outcome depends on an immune response that is neither too weak nor overly robust, and genetic determinants of this immune response may identify which patients will benefit from adjunctive corticosteroids. Recent clinical trials of intensified anti-tuberculosis treatment regimens conducted in Indonesia and Vietnam, motivated by the pharmacologic challenges of treating M. tuberculosis infections of the central nervous system, have yielded conflicting results regarding the survival benefit of intensified treatment regimens. More consistent findings have been observed regarding the relationship between initial anti-tuberculosis drug resistance and mortality among tuberculous meningitis patients. Prompt initiation of anti-tuberculosis treatment for all suspected cases remains a key aspect of management. Priorities for research include the improvement of diagnostic testing strategies and the optimization of host-directed and anti-tuberculosis therapies.

The treatment of tuberculous meningitis in children with A combination of isoniazid, rifampicin and streptomycin (a preliminary report).

Twenty-two cases of tuberculous meningitis have been treated with isoniazid, streptomycin and rifampicin and 19 cases with isoniazid, P.A.S. and streptomycin. Both groups received corticosteroid at the beginning of the treatment. The 2 groups were compared on the clinical and neurological improvement, duration of necessary hospitalization, the presence of sequelae, and the death rate. Also the tolerability of both regimens was compared.

Role of cerebrospinal fluid adenosine deaminase activity in the diagnosis of tuberculous meningitis in children

Background: Early and correct treatment is essential for successful outcome in patients of tuberculous men-ingitis. Adenosine deaminase activity in the cerebrospinal fluid has been found to be a simple and useful investigation in the diagnosis of tuberculous meningitis in children.Methods: It is a cross sectional observational hospital based study conducted at the Department of Paediatrics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, India. Children aged 2 months to 12 years were included in the study during April 2016 to October 2016.Results: The mean value of adenosine deaminase activity in the cerebrospinal fluid of tuberculous meningitis cases was 13.3±14.49. The mean cerebrospinal fluid adenosine deaminase levels in tuberculous meningitis patients was significantly higher than non-tuberculous meningitis patients with P &lt;0.01.Conclusions: The mean cerebrospinal fluid adenosine deaminase level was significantly raised in tuberculous meningitis patients.

Clinical Profile and Factors Associated with a Poor Outcome in Childhood Tuberculous Meningitis in a Developing Country: A 10 Year Case Review

Clinical Profile and Factors Associated with a Poor Outcome in Childhood Tuberculous Meningitis in a Developing Country: A 10 Year Case Review

Проблемы диагностики туберкулезного менингита у детей и подростков в практике педиатраProblems of diagnosing tuberculous meningitis in children and adolescents in paediatric practice

Проблемы диагностики туберкулезного менингита у детей и подростков в практике педиатраProblems of diagnosing tuberculous meningitis in children and adolescents in paediatric practice

Gene-based neonatal immune priming potentiates a mucosal adenoviral vaccine encoding mycobacterial Ag85B

Tuberculosis remains a major public health hazard worldwide, with neonates and young infants potentially more susceptible to infection than adults. BCG, the only vaccine currently available, provides some protection against tuberculous meningitis in children but variable efficacy in adults, and is not safe to use in immune compromised individuals. A safe and effective vaccine that could be given early in life, and that could also potentiate subsequent booster immunization, would represent a significant advance. To test this proposition, we have generated gene-based vaccine vectors expressing Ag85B from Mycobacterium tuberculosis (Mtb) and designed experiments to test their immunogenicity and protective efficacy particularly when given in heterologous prime-boost combination, with the initial DNA vaccine component given soon after birth. Intradermal delivery of DNA vaccines elicited Th1-based immune responses against Ag85B in neonatal mice but did not protect them from subsequent aerosol challenge with virulent Mtb H37Rv. Recombinant adenovirus vectors encoding Ag85B, given via the intranasal route at six weeks of age, generated moderate immune responses and were poorly protective. However, neonatal DNA priming following by mucosal boosting with recombinant adenovirus generated strong immune responses, as evidenced by strong Ag85B-specific CD4+ and CD8+ T cell responses, both in the lung-associated lymph nodes and the spleen, by the quality of these responding cells (assessed by their capacity to secrete multiple antimicrobial factors), and by improved protection, as indicated by reduced bacterial burden in the lungs following pulmonary TB challenge. These results suggest that neonatal immunization with gene-based vaccines may create a favorable immunological environment that potentiates the pulmonary mucosal boosting effects of a subsequent heterologous vector vaccine encoding the same antigen. Our data indicate that immunization early in life with mycobacterial antigens in an appropriate vaccine setting can prime for protective immunity against Mtb.

IMCI indicators of childhood TBM at primary health care level in the Western Cape Province of South Africa.

The diagnosis of tuberculous meningitis (TBM) in children is often delayed, with disastrous consequences. The Integrated Management of Childhood Illness (IMCI) strategy aims to ensure the accurate assessment of ill children using simple yet reliable clinical signs. We conducted a retrospective observational study of 30 consecutive children aged 3 months to 5 years diagnosed with TBM at Tygerberg Hospital, Cape Town, South Africa. Clinical records were reviewed to assess diagnostic delay and identify IMCI indicators that were present at the time of initial presentation. Six patients (20%) presented with stage I, 6 (20%) with stage II and 18 (60%) with stage III TBM. Recent contact with an adult TB source case was recorded in 21 (70%) cases. The median number of health care visits before hospital admission was 4.0 (range 1-6). At the first health care visit, 21 (70%) had potential TB features and recent contact with an adult household TB source case. Adequate implementation of IMCI clinical indicators is essential to ensure earlier diagnosis and prompt treatment initiation in children with TBM, as the majority of cases present with advanced disease. Recent contact with an adult TB source case is an important consideration.

Outcome of tuberculous meningitis in children: the first comprehensive retrospective cohort study in Indonesia.

Tuberculous meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis. To assess hearing, visual, motor function, neurological and mental development outcomes in paediatric TBM. A retrospective cohort study was conducted among 139 children with TBM registered and treated at the Department of Child Health, Dr Hasan Sadikin Hospital, Bandung, Indonesia, from January 2007 to December 2010. Hearing and visual function, appearance of optic disc, motor function, and neurological and mental development were evaluated. Of a final 128 patients (10 died during hospitalisation, 1 was excluded), 34 (26.5%) died after hospital discharge, the addresses of 58 patients could not be found and 7 parents refused to participate. The remaining 29 patients (16 males, 13 females) were available for evaluation; the mean age was 44 months (range 7-162). Hearing loss and visual impairment were identified in respectively 11/28 and 10/25 patients. Most patients had motor disorders. Delayed neurological and mental development was observed in nearly three quarters of patients, 11 of whom had normal or borderline intelligence quotient. TBM causes high mortality and sequelae involving hearing and visual impairment, and neurological and mental development.

Diagnostic accuracy of a uniform research case definition for TBM in children: a prospective study.

Bacteriological confirmation of tuberculous meningitis (TBM) is problematic, and rarely guides initial clinical management. A uniform TBM case definition has been proposed for research purposes. We prospectively enrolled patients aged 3 months to 13 years with meningitis confirmed using cerebrospinal fluid analysis at Tygerberg Hospital, Cape Town, South Africa. Criteria that differentiated TBM from other causes were explored and the accuracy of a probable TBM score assessed by comparing bacteriologically confirmed cases to 'non-TBM' controls. Of 139 meningitis patients, 79 were diagnosed with TBM (35 bacteriologically confirmed), 10 with bacterial meningitis and 50 with viral meningitis. Among those with bacteriologically confirmed TBM, 15 were Mycobacterium tuberculosis culture-positive and 20 were culture-negative but positive on GenoType(®) MTBDRplus or Xpert(®) MTB/RIF; 18 were positive on only a single commercial nucleic acid amplification test. A probable TBM score provided a sensitivity of 74% (95%CI 57-88) and a specificity of 97% (95%CI 86-99) compared to bacteriologically confirmed TBM. A probable TBM score demonstrated excellent specificity compared to bacteriological confirmation. However, 26% of children with TBM would be missed due to the limited accuracy of the case definition. Further prospective testing of an algorithm-based approach to TBM is advisable before recommendation for general clinical practice.

Tubercular meningitis in children: Clinical, pathological, and radiological profile and factors associated with mortality.

Context:Childhood tuberculosis is a major public health problem in developing countries with tubercular meningitis being a serious complication with high mortality and morbidity.Aim:To study the clinicopathological as well as radiological profile of childhood tuberculous meningitis (TBM) cases.Settings and Design:Prospective, observational study including children <14 years of age with TBM admitted in a tertiary care hospital from Western India.Subjects and Methods:TBM was diagnosed based on predefined criteria. Glassgow coma scale (GCS) and intracranial pressure (ICP) was recorded. Staging was done as per British Medical Council Staging System. Mantoux test, chest X-ray, cerebrospinal fluid (CSF) examination, neuroimaging, and other investigations were done to confirm TB.Statistical Analysis Used:STATA software (version 9.0) was used for data analysis. Various risk factors were determined using Chi-square tests, and a P< 0.05 was considered significant.Results:Forty-seven children were included, of which 11 (24.3%) died. Fever was the most common presenting symptom, and meningismus was the most common sign. Twenty-nine (62%) children presented with Stage III disease. Stage III disease, low GCS, and raised ICP were predictors of mortality. Findings on neuroimaging or CSF examination did not predict mortality.Conclusions:Childhood TBM presents with nonspecific clinical features. Stage III disease, low GCS, lack of Bacillus Calmette–Guérin vaccination at birth and raised ICP seem to the most important adverse prognostic factors.

A putative urinary biosignature for diagnosis and follow-up of tuberculous meningitis in children: outcome of a metabolomics study disclosing host–pathogen responses

Tuberculous meningitis (TBM) is a severe manifestation of tuberculosis, presenting with high morbidity and mortality in children. Existing diagnostic methods for TBM are invasive and time-consuming and the need for highly sensitive and selective diagnosis remains high on the TBM agenda. Our aim was to exploit metabolomics as an approach to identify metabolites as potential diagnostic predictors for children with TBM through a non-invasive means. Urine samples selected for this study were from three paediatric groups: patients with confirmed TBM (n = 12), patients clinically suspected with TBM but later confirmed to be negative (n = 19) and age-matched controls (n = 29). Metabolomics data were generated through gas chromatography–mass spectrometry analysis and important metabolites were identified according to standard statistical procedures used for metabolomics data. A global metabolite profile that characterized TBM was developed from the data, reflecting the host and microbial responses. Nine different logistic regression models were fitted to selected metabolites for the best combination as predictors for TBM. Four metabolites—methylcitric, 2-ketoglutaric, quinolinic and 4-hydroxyhippuric acids—showed excellent diagnostic ability and provided prognostic insight into our TBM patients. This study is the first to illustrate holistically the metabolic complexity of TBM and provided proof-of-concept that a biosignature of urinary metabolites can be defined for non-invasive diagnosis and prognosis of paediatric TBM patients. The biosignature should be developed and validated through future prospective studies to generate a medical algorithm for diagnosis in the initial stages of the disease and for monitoring of treatment strategies.

Linezolid is Associated with Improved Early Outcomes of Childhood Tuberculous Meningitis.

Linezolid serves as an important component for the treatment of drug-resistant tuberculosis although there is little published data about linezolid use in children, especially in childhood tuberculous meningitis (TBM). In this study, we retrospectively reviewed records of childhood TBM patients who started treatment between January 2012 and August 2014. A total of 86 childhood TBM patients younger than 15 years old were enrolled. Out of 86 children, 36 (41.9%) received the regimen containing linezolid. Thirty-two (88.9%) of 36 linezolid-treated cases had favorable outcomes, and 35 (70.0%) cases were successfully treated in the control group. The frequency of favorable outcome of linezolid group was significantly higher than that of control group (P = 0.037). In addition, compared with cases with fever clearance time of <1 week, the control group had more cases with fever clearance time of 1-4 weeks (P = 0.010) and >4 weeks (P = 0.000) than linezolid group. Furthermore, there was no significant difference in the frequency of adverse events between the two regimens (P = 0.896). In addition, the patients with adverse events were more likely to have treatment failure, the P value of which was 0.008. Our data demonstrate that linezolid improves early outcome of childhood TBM. The low frequency of linezolid-associated adverse effects highlights the promising prospects of its use for treatment of childhood TBM.

Impeded Immunity? Reduced Tuberculosis Vaccine Response with Exposure to Environmental Chemicals.

There is some evidence that early-life exposures to polychlorinated biphenyls (PCBs) and other persistent environmental chemicals can alter the developing immune system and may be associated with diminished effectiveness for certain vaccines. 1 , 2 This could have serious implications for parts of the world where diseases that are preventable with vaccines remain a major public health threat. 3 In this issue of EHP, researchers present new evidence that two persistent organic pollutants are associated with a lower antibody response to the tuberculosis vaccine, which could potentially lower resistance to infection. 4 “Our findings show that environmental chemicals may be playing a role in immune disruption—in this case the suppression of immune response to a vaccine,” says lead author Todd Jusko, an epidemiologist at the University of Rochester in New York. BCG, the most widely used vaccine in the world, is routinely given to babies in areas with high rates of tuberculosis. Although not routinely administered in the United States, the tuberculosis vaccine, called bacille Calmette-Guerin (BCG), is the most widely given vaccine in the world. 5 BCG is administered shortly after birth, and in young children it has substantially reduced the risk of severe forms of tuberculosis in which the disease spreads beyond the lungs. 6 But for unknown reasons the vaccine confers poor protection against pulmonary tuberculosis in older children and adults. 7 Early-life environmental exposures may be an overlooked factor in the maintenance of immune protection over time, write the study authors. 4 The researchers analyzed the blood of approximately 500 mother–infant pairs in eastern Slovakia for PCB-153 and for p,p´-DDE-DDE (a metabolite of the insecticide DDT). Their goal was to determine whether prenatal and early postnatal exposures to these chemicals were associated with reduced infant response to BCG at age 6 months. Both are considered chemicals of concern by the U.S. Environmental Protection Agency for their ability to persist in the environment and accumulate in the human body over time. 8 The researchers found that infants with the highest blood levels of PCB-153 had an average 37% lower level of BCG-specific immunoglobin (Ig) G and A than infants with the lowest PCB exposures. Associations with the highest blood levels of p,p´-DDE were very similar to those for PCB-153. They also found that infants with the highest levels of both PCB-153 and p,p´-DDE had an average 85% lower level of IgA and 94% lower level of IgG, compared with infants with the lowest levels of both chemicals. Levels of PCB-153 and p,p´-DDE in maternal and cord blood samples collected at birth were not associated with infant antibody levels, suggesting that early infancy may be a critical period for environmental exposures to disrupt the developing immune system. 4 While the study showed lower antibody levels in highly exposed children, indicating a weakened response, it’s unclear what these findings mean for the efficacy of the BCG vaccine. Experts aren’t sure at what level the vaccine stops protecting people from tuberculosis. It’s also unclear whether PCB-153 and p,p´-DDE actually caused the antibody reductions. p,p´-DDE isn’t known to be particularly immunotoxic, points out Philippe Grandjean, an epidemiologist at the Harvard School of Public Health. Perhaps p,p´-DDE and PCB-153 are not the causative agents but rather markers for other chemicals in the same environment that are more immunotoxic, says Grandjean, who was not involved in the study. The mechanisms by which environmental chemicals may suppress the immune system and diminish vaccine response are poorly understood. In a previous study with the Slovakian cohort, Jusko and colleagues found that infants with higher PCB exposures had a lower thymus volume. 9 The thymus is an organ in the chest where specialized immune system cells called T-cells mature. “Antibody production almost always is T-cell dependent,” says David Sherr, an immunotoxicologist at Boston University, who was not involved in the study. “The immune system is a complex and adaptive system. [Findings such as these] may just be scratching the surface.” Jusko says more research is needed to address the pathways through which chemicals such as PCBs may suppress antibody response. “The immune system is a mediator of so many health outcomes,” says Jusko, “yet immune disruption by environmental chemicals is a pretty under-researched area of child development.”

Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis.

BackgroundAmong the various forms of TB, tuberculous meningitis (TBM) is the most severe, with about 30 % mortality and 50 % of survivors left with neurological sequelae. Children suffer more frequently from TBM than adults and outcomes are often poor due to difficulties in making the diagnosis and uncertainty regarding the best anti-tuberculosis drug regimen. The aim of this prospective study was to describe the pharmacokinetics of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of children with tuberculous meningitis treated with the standard TBM regimen.MethodsWe performed a prospective observational study of 100 consecutively treated children (≤15 years of age) with tuberculous meningitis in Ho Chi Minh City, Vietnam. Children were treated according to the 2006 WHO recommended pediatric treatment regimen consisting of isoniazid (5 mg/kg), rifampicin (10 mg/kg) and ethambutol (15 mg/kg) for 8 months, with the addition of pyrazinamide (25 mg/kg) for the first 3 months and streptomycin (15 mg/kg) for the first 2 months. Pyrazinamide, isoniazid and rifampicin concentrations were measured in plasma at day 14 and in cerebrospinal fluid (CSF) at 1 month by HPLC-UV. A naïve-pooled non-compartmental data analysis was used to describe the pharmacokinetic properties of drugs in the two-age groups of children ≤ 4 years or > 4 years of age.ResultsYounger children, when compared to older children, presented a higher body weight-normalized clearance and volume of distribution, and lower median total plasma exposures for the three studied drugs with −14 %, −22 % and −16 % for Pyrazinamide, Isoniazid and Rifampicin, respectively. In CSF, individual concentrations of isoniazid and pyrazinamide were comparable to that in plasma in both age groups; but rifampicin concentrations were lower than the minimum inhibitory concentration of susceptible bacteria in all but two children.ConclusionsThere is an age-dependent variation in the plasma and cerebrospinal fluid pharmacokinetics of rifampicin, isoniazid and pyrazinamide. The safety and efficacy of higher doses of rifampicin should be investigated for the treatment of childhood tuberculous meningitis.

Clinical and radiological prognostic indicators in childhood tuberculous meningitis

Tuberculous meningitis (TBM), the severest form of tuberculosis, continues to affect children in India. The disease has a high rate of mortality and disabling consequences. Scarce literature exists on prognostic indicators in children and none on radiological prognostic features. Our aim is to delineate clinical, laboratory and radiological prognostic indicators in childhood TBM. Children with TBM diagnosed according to pre-decided criteria and admitted to a teaching hospital in Northern India were enrolled for study. Demographic, clinical, laboratory and radiologic features at admission were charted. Patients were followed up to 3 months from discharge or until death. Features at admission were compared between those with good and bad outcome by univariate and logistic regression analysis. A total of 53 of 68 enrolled children were followed for 3 months. Significant factors on univariate analysis were age, headache, Glasgow coma score (GCS), muscle tone, extensor plantar response, decerebrate posturing, clinical stage of disease and infarcts on computerized tomography scan head. On logistic regression, only age ≤ 3 yr, GCS < 10 and increased muscle tone were significantly associated with bad outcome. Younger age, lower GCS and increased muscle tone at initial diagnosis are significant independent predictors of bad outcome in TBM in children.

The diagnostic value of cerebrospinal fluid chemistry results in childhood tuberculous meningitis.

Cerebrospinal fluid (CSF) hypoglycorrhachia and elevated protein is well-described in bacterial meningitis, but evidence for its differential diagnostic value in tuberculous meningitis (TBM) is lacking. We aimed to assess the diagnostic utility of CSF glucose, CSF to serum glucose ratio and CSF protein in children with suspected TBM. We describe CSF glucose and protein values as well as CSF to serum glucose ratios in a prospective evaluation of TBM suspects seen at Tygerberg Children's Hospital, Cape Town, South Africa, from January 1985 to January 2014. Of 615 TBM suspects, 88 (14%) had microbiologically confirmed TBM, 381 (62%) 'probable' TBM and 146 (24%) 'non-TBM'. Mean absolute CSF glucose concentration was significantly lower in the microbiologically confirmed (1.87 ± 1.15 mmol/L) and 'probable' TBM (1.82 ± 1.19 mmol/L) groups compared to non-TBM (3.66 ± 0.88 mmol/L). A CSF glucose concentration of <2.2 mmol/L diagnosed TBM with sensitivity 0.68 and specificity 0.96. Sensitivity using a CSF to serum glucose ratio of <0.5 was 0.90. Mean CSF protein was significantly elevated in the microbiologically confirmed TBM (1.91 ± 1.44 g/L) and 'probable' TBM (2.01 ± 1.49 g/L) groups compared to the non-TBM (0.31 ± 0.31 g/L). A CSF protein >1 g/L diagnosed TBM with sensitivity 0.78 and specificity 0.94. Absolute CSF glucose values of <2.2 mmol/L and protein values of >1 g/L differentiated between TBM and non-bacterial meningitis with good specificity, although sensitivity was poor. A CSF to serum glucose ratio is more informative than the absolute value.

Impact of the BCG vaccination policy on tuberculous meningitis in children under 6 years in metropolitan France between 2000 and 2011.

In France, Bacillus Calmette–Guérin (BCG) vaccination by multipuncture device was withdrawn in 2006. In 2007, universal mandatory BCG vaccination was replaced by vaccination of high-risk children. To evaluate the impact of these changes on tuberculous meningitis (TBM) epidemiology, data on culture-positive and culture-negative (or unknown microbiological result) TBM in ≤5 years olds were collected from 2000–2011. Ten culture-positive and 17 culture-negative TBM cases were identified, with an annual incidence rate ranging from 0.16 to 0.66 cases per 10 million inhabitants. The average annual numbers of TBM cases were 2.7 and 1.8 from 2000–2005 and 2006–2011, respectively. In Ile-de-France where all children are considered at risk, the overall incidence rates were 1.14 and 0.29 per million for the two periods. In other regions where only at-risk children are vaccinated since 2007, rates were 0.30 and 0.47, respectively. None of these differences were significant. Annual incidence rates for each one year age group cohort were comparable before and after changes. Childhood TBM remains rare in France. No increase in incidence was observed after changes in BCG vaccination strategy. Ongoing surveillance should be maintained, as a slight increase in TBM in the coming years remains possible, in the context of suboptimal vaccination coverage of high-risk children.

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

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. 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. 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. 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.