Evaluation of the MODS Culture Technique for the Diagnosis of Tuberculous Meningitis

Tuberculous meningitis (TBM) is a devastating condition. The rapid instigation of appropraite chemotherapy is vital to reduce morbidity and mortality. However rapid diagnosis remains elusive; smear microscopy has extremely low sensitivity on cerebrospinal fluid (CSF) in most laboratories and PCR requires expertise with advanced infrastructure and has sensitivity of only around 60% under optimal conditions. Neither technique allows for the microbiological isolation of M. tuberculosis and subsequent drug susceptibility testing. We evaluated the recently developed microscopic observation drug susceptibility (MODS) assay format for speed and accuracy in diagnosing TBM.Two hundred and thirty consecutive CSF samples collected from 156 patients clinically suspected of TBM on presentation at a tertiary referal hospital in Vietnam were enrolled into the study over a five month period and tested by Ziehl-Neelsen (ZN) smear, MODS, Mycobacterial growth Indicator tube (MGIT) and Lowenstein-Jensen (LJ) culture. Sixty-one samples were from patients already on TB therapy for >1day and 19 samples were excluded due to untraceable patient records. One hundred and fifty samples from 137 newly presenting patients remained. Forty-two percent (n = 57/137) of patients were deemed to have TBM by clinical diagnostic and microbiological criteria (excluding MODS). Sensitivity by patient against clinical gold standard for ZN smear, MODS MGIT and LJ were 52.6%, 64.9%, 70.2% and 70.2%, respectively. Specificity of all microbiological techniques was 100%. Positive and negative predictive values for MODS were 100% and 78.7%, respectively for HIV infected patients and 100% and 82.1% for HIV negative patients. The median time to positive was 6 days (interquartile range 5-7), significantly faster than MGIT at 15.5 days (interquartile range 12-24), and LJ at 24 days (interquartile range 18-35 days) (P<0.01).We have shown MODS to be a sensitive, rapid technique for the diagnosis of TBM with high sensitivity, ease of performance and low cost (0.53 USD/sample)

The Management of Staphylococcus aureus Bacteremia in the United Kingdom and Vietnam: A Multi-Centre Evaluation

Background Staphylococcus aureus bacteremia is a common and serious infection worldwide and although treatment guidelines exist, there is little consensus on optimal management. In this study we assessed the variation in management and adherence to treatment guidelines of S. aureus bacteremia. Methodology/Principal Findings We prospectively recorded baseline clinical characteristics, management, and in-hospital outcome of all adults with S. aureus bacteremia treated consecutively over one year in eight centres in the United Kingdom, three in Vietnam and one in Nepal. 630 adults were treated for S. aureus bacteremia: 549 in the UK (21% methicillin-resistant), 80 in Vietnam (19% methicillin-resistant) and 1 in Nepal. In the UK, 41% had a removable infection focus (50% intravenous catheter-related), compared to 12% in Vietnam. Significantly (p50% of treatment with oral antibiotics alone (25% versus 4%). UK centres varied significantly (p50% of treatment (range 12–40%), in those treated for longer than 28 days (range 13–54%), and in those given combination therapy (range 14–94%). 24% died during admission: older age, time in hospital before bacteremia, and an unidentified infection focus were independent predictors of in-hospital death (p<0.001). Conclusions/Significance The management of S. aureus bacteremia varies widely between the UK and Vietnam and between centres in the UK with little adherence to published guidelines. Controlled trials defining optimal therapy are urgently required

Reliability and Diagnostic Performance of CT Imaging Criteria in the Diagnosis of Tuberculous Meningitis

The original publication is available at http:// www.plosone.orgPublication of this article was funded by the Stellenbosch University Open Access Fund.Introduction: Abnormalities on CT imaging may contribute to the diagnosis of tuberculous meningitis (TBM). Recently, an expert consensus case definition (CCD) and set of imaging criteria for diagnosing basal meningeal enhancement (BME) have been proposed. This study aimed to evaluate the sensitivity, specificity and reliability of these in a prospective cohort of adult meningitis patients. Methods: Initial diagnoses were based on the CCD, classifying patients into: ‘Definite TBM’ (microbiological confirmation), ‘Probable TBM’ (diagnostic score $10), ‘Possible TBM’ (diagnostic score 6–9), ‘Not TBM’ (confirmation of an alternative diagnosis) or ‘Uncertain’ (diagnostic score of ,6). CT images were evaluated independently on two occasions by four experienced reviewers. Intra-rater and inter-rater agreement were calculated using the kappa statistic. Sensitivities and specificities were calculated using both ‘Definite TBM’ and either ‘Definite TBM’ or ‘Probable TBM’ as gold standards. Results: CT scan criteria for BME had good intra-rater agreement (k range 0.35–0.78) and fair to moderate inter-rater agreement (k range 0.20–0.52). Intra- and inter-rater agreement on the CCD components were good to fair (k = ranges 0.47–0.81 and 0.21–0.63). Using ‘Definite TBM’ as a gold standard, the criteria for BME were very specific (61.5%–100%), but insensitive (5.9%–29.4%). Similarly, the imaging components of the CCD were highly specific (69.2–100%) but lacked sensitivity (0–56.7%). Similar values were found when using ‘Definite TBM’ or ‘Probable TBM’ as a gold standard. Discussion: The fair to moderate inter-rater agreement and poor sensitivities of the criteria for BME suggest that little reliance should be placed in these features in isolation. While the presence of the CCD criteria of acute infarction or tuberculoma(s) appears useful as rule-in criteria, their absence is of little help in excluding TBM. The CCD and criteria for BME, as well as any new criteria, need to be standardized and validated in prospective cohort studies.Funding: KB received funding from the Discovery Foundation (Academic Fellowship Award; http://www.discovery.co.za/portal/loggedout-individual/discoverycommunity- about), College of Neurology of South Africa (K.M. Browse Award; http://www.collegemedsa.ac.za/Default.aspx ) and the University of Stellenbosch. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Publisher's versio

Projected costs associated with school-based screening to inform deployment of Dengvaxia: Vietnam as a case study

Background: After new analysis, Sanofi Pasteur now recommends their dengue vaccine (Dengvaxia) should only be given to individuals previously infected with dengue and the World Health Organization's recommendations regarding its use are currently being revised. As a result, the potential costs of performing large-scale individual dengue screening and/or dengue serosurveys have become an important consideration for decision making by policymakers in dengue-endemic areas. Methods: We used an ingredients-based approach to estimate the financial costs for conducting both a school-based dengue serosurvey and school-based individual dengue screening within a typical province in Vietnam, using an existing commercial indirect immunoglobulin G enzyme-linked immunosorbent assay kit. This costing is hypothetical and based on estimates regarding the resources that would be required to perform such activities. Results: We estimated that performing a school-based individual screening of 9-year-olds would cost US$9.25 per child tested or US$197,827 in total for a typical province. We also estimated that a school-based serosurvey would cost US$10,074, assuming one class from each of the grades that include 8- to 11-year-olds are sampled at each of the 12 selected schools across the province. Conclusions: The study indicates that using this vaccine safely on a large-scale will incur noteworthy operational costs. It is crucial that these be considered in future cost-effectiveness analyses informing how and where the vaccine is deployed

Knowledge gaps and research priorities in tuberculous meningitis.

Tuberculous meningitis (TBM) is the most severe and disabling form of tuberculosis (TB), accounting for around 1-5% of the global TB caseload, with mortality of approximately 20% in children and up to 60% in persons co-infected with human immunodeficiency virus even in those treated. Relatively few centres of excellence in TBM research exist and the field would therefore benefit from greater co-ordination, advocacy, collaboration and early data sharing. To this end, in 2009, 2015 and 2019 we convened the TBM International Research Consortium, bringing together approximately 50 researchers from five continents. The most recent meeting took place on 1 st and 2 nd March 2019 in Lucknow, India. During the meeting, researchers and clinicians presented updates in their areas of expertise, and additionally presented on the knowledge gaps and research priorities in that field. Discussion during the meeting was followed by the development, by a core writing group, of a synthesis of knowledge gaps and research priorities within seven domains, namely epidemiology, pathogenesis, diagnosis, antimicrobial therapy, host-directed therapy, critical care and implementation science. These were circulated to the whole consortium for written input and feedback. Further cycles of discussion between the writing group took place to arrive at a consensus series of priorities. This article summarises the consensus reached by the consortium concerning the unmet needs and priorities for future research for this neglected and often fatal disease

Personalised randomised controlled trial designs—a new paradigm to define optimal treatments for carbapenem-resistant infections

Antimicrobial resistance is impacting treatment decisions for, and patient outcomes from, bacterial infections worldwide, with particular threats from infections with carbapenem-resistant Enterobacteriaceae, Acinetobacter baumanii, or Pseudomonas aeruginosa. Numerous areas of clinical uncertainty surround the treatment of these highly resistant infections, yet substantial obstacles exist to the design and conduct of treatment trials for carbapenem-resistant bacterial infections. These include the lack of a widely acceptable optimised standard of care and control regimens, varying antimicrobial susceptibilities and clinical contraindications making specific intervention regimens infeasible, and diagnostic and recruitment challenges. The current single comparator trials are not designed to answer the urgent public health question, identified as a high priority by WHO, of what are the best regimens out of the available options that will significantly reduce morbidity, costs, and mortality. This scenario has an analogy in network meta-analysis, which compares multiple treatments in an evidence synthesis to rank the best of a set of available treatments. To address these obstacles, we propose extending the network meta-analysis approach to individual randomisation of patients. We refer to this approach as a Personalised RAndomised Controlled Trial (PRACTical) design that compares multiple treatments in an evidence synthesis, to identify, overall, which is the best treatment out of a set of available treatments to recommend, or how these different treatments rank against each other. In this Personal View, we summarise the design principles of personalised randomised controlled trial designs. Specifically, of a network of different potential regimens for life-threatening carbapenem-resistant infections, each patient would be randomly assigned only to regimens considered clinically reasonable for that patient at that time, incorporating antimicrobial susceptibility, toxicity profile, pharmacometric properties, availability, and physician assessment. Analysis can use both direct and indirect comparisons across the network, analogous to network meta-analysis. This new trial design will maximise the relevance of the findings to each individual patient, and enable the top-ranked regimens from any personalised randomisation list to be identified, in terms of both efficacy and safety

The estimates of the health and economic burden of dengue in Vietnam

Dengue has been estimated to cause a substantial health and economic burden in Vietnam. The most recent studies have estimated that it is responsible for 39884 disability-adjusted life years (DALYs) annually, representing an economic burden of US$94.87 million per year (in 2016 prices). However, there are alternative burden estimates that are notably lower. This variation is predominantly due to differences in how the number of symptomatic dengue cases is estimated. Understanding the methodology of these burden calculations is vital when interpreting health economic analyses of dengue. This review aims to provide an overview of the health and economic burden estimates of dengue in Vietnam. We also highlight important research gaps for future studies

Valuing the unpaid contribution of community health volunteers to mass drug administration programs

Community health volunteers (CHVs) are being used within a growing number of healthcare interventions, and they have become a cornerstone for the delivery of mass drug administration within many neglected tropical disease control programs. However, a greater understanding of the methods used to value the unpaid time CHVs contribute to healthcare programs is needed. We outline the two main approaches used to value CHVs' unpaid time (the opportunity cost and the replacement cost approaches). We found that for mass drug administration programs the estimates of the economic costs relating to the CHVs' unpaid time can be significant, with the averages of the different studies varying between US$0.05-0.16 per treatment. We estimated that the time donated by CHVs' to the African Programme for Onchocerciasis Control alone would be valued between US$60-90 million. There is a need for greater transparency and consistency in the methods used to value CHVs' unpaid time

Pre-treatment cerebrospinal fluid bacterial load correlates with inflammatory response and predicts neurological events during tuberculous meningitis treatment.

Background Mycobacterium tuberculosis (Mtb) bacillary load in the brain of those with tuberculous meningitis (TBM) may reflect the host ability to control the pathogen and determine disease severity and treatment outcomes. Methods We measured pre-treatment cerebrospinal fluid (CSF) Mtb bacterial load by GeneXpert in 692 adults with TBM. We sought to understand the relationship between CSF bacterial load and inflammation, and their respective impact on disease severity and treatment outcomes. Results Ten-fold higher Mtb load was associated with increased disease severity (Odds Ratio=1.59, p=0.001 for grade 1 versus grade 3), and increased CSF neutrophils (r=0.364, p<0.0001) and cytokine concentrations (r=0.438, p<0.0001). High Mtb load predicted new neurological events after starting treatment (Multinomial logistic regression, p=0.005), but not death. Death was previously associated with attenuated inflammatory response at the start of treatment, with reduced cytokine concentrations compared to survivors. In contrast, patients with high pre-treatment CSF bacterial loads, cytokines, and neutrophils were more likely to subsequently suffer neurological events. Conclusions Pre-treatment GeneXpert-derived Mtb load may be a useful predictor of neurological complications occurring during TBM treatment. Therapeutic strategies aimed at reducing neurological complications and deaths from TBM may need reassessment, given the evidence for their divergent pathogenesis