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

Dynamic prediction of death in patients with tuberculous meningitis using time-updated Glasgow coma score and plasma sodium measurements.

BACKGROUND Pre-treatment predictors of death from tuberculous meningitis (TBM) are well-established, but whether outcome can be predicted more accurately after the start of treatment by updated clinical variables is unknown. Hence, we developed and validated models that dynamically predict mortality using time-updated Glasgow coma score (GCS) and plasma sodium measurements, together with patient baseline characteristics. METHODS We included 1048 adults from four TBM studies conducted in southern Vietnam from 2004-2016. We used a landmarking approach to predict death within 120 days after treatment initiation using time-updated data during the first 30 days of treatment. Separate models were built for patients with and without human immunodeficiency virus (HIV) infection. We used the area under the receiver operating characteristic curve (AUC) to evaluate performance of the models at day 10, 20 and 30 of treatment to predict mortality by 60, 90 and 120 days. Our internal validation was corrected for over-optimism using bootstrap. We provide a web-based application that computes mortality risk within 120 days. RESULTS Higher GCS indicated better prognosis in all patients. In HIV-infected patients, higher plasma sodium was uniformly associated with good prognosis, whereas in HIV-uninfected patients the association was heterogeneous over time. The bias-corrected AUC of the models ranged from 0.82-0.92 in HIV-uninfected, and 0.81-0.85 in HIV-infected individuals. The models outperformed the previously published baseline models. CONCLUSIONS Time-updated GCS and plasma sodium measurements improved predictions based solely on information obtained at diagnosis. Our models may be used in practice to define those with poor prognosis during treatment

Chapter Preface

This work contains updated and clinically relevant information about tuberculosis. It is aimed at providing a succinct overview of history and disease epidemiology, clinical presentation and the most recent scientific developments in the field of tuberculosis research, with an emphasis on diagnosis and treatment. It may serve as a practical resource for students, clinicians and researchers who work in the field of infectious diseases

Chapter References

This work contains updated and clinically relevant information about tuberculosis. It is aimed at providing a succinct overview of history and disease epidemiology, clinical presentation and the most recent scientific developments in the field of tuberculosis research, with an emphasis on diagnosis and treatment. It may serve as a practical resource for students, clinicians and researchers who work in the field of infectious diseases

Chapter 2 Pathogenesis

This work contains updated and clinically relevant information about tuberculosis. It is aimed at providing a succinct overview of history and disease epidemiology, clinical presentation and the most recent scientific developments in the field of tuberculosis research, with an emphasis on diagnosis and treatment. It may serve as a practical resource for students, clinicians and researchers who work in the field of infectious diseases

‘Power plays plus push’: experts’ insights into the development and implementation of active tuberculosis case-finding policies globally, a qualitative study

Objective: To explore experts’ views on factors influencing national and global active case-finding (ACF) policy development and implementation, and the use of evidence in these processes. Design: This is an exploratory study based on semistructured expert interviews. Framework analysis was applied. Participants: The study involved a purposive sample of 39 experts from international, non-governmental and non-profit organisations, funders, government institutions, international societies, think tanks, universities and research institutions worldwide. Results: This study highlighted the perceived need among experts for different types of evidence for ACF policy development and implementation, and for stakeholder engagement including researchers and policymakers to foster evidence use. Interviewees stressed the influence of government, donor and non-governmental stakeholders in ACF policy development. Such key stakeholders also influence ACF policy implementation, in addition to available systems and processes in a given health system, and implementers’ motivation and incentives. According to the interviewees, the World Health Organization (WHO) guidelines for systematic screening face the innate challenge of providing guidance to countries across the broad area of ACF in terms of target groups, settings and screening algorithms. The guidelines could be improved by focusing on what should be done rather than what can be done in ACF, and by providing howto examples. Leadership, integration into health systems and long-term financing are key for ACF to be sustainable. Conclusions: We provide new insights into ACF policy processes globally, particularly regarding facilitators for and barriers to ACF policy development, evidence need and use, and donor organisations’ influence. According to expert participants, national and global ACF policy development and implementation can be improved by broadening stakeholder engagement. Meanwhile, using diverse evidence to inform ACF policy development and implementation could mitigate the ‘power plays plus push’ that might otherwise disrupt and mislead these policy processes

Factors influencing active tuberculosis case-finding policy development and implementation: a scoping review

ABSTRACT Objective To explore antecedents, components and influencing factors on active case- finding (ACF) policy development and implementation. Design Scoping review, searching MEDLINE, Web of Science, the Cochrane Database of Systematic Reviews and the World Health Organization (WHO) Library from January 1968 to January 2018. We excluded studies focusing on latent tuberculosis (TB) infection, passive case- finding, childhood TB and studies about effectiveness, yield, accuracy and impact without descriptions of how this evidence has/could influence ACF policy or implementation. We included any type of study written in English, and conducted frequency and thematic analyses. Results Seventy- three articles fulfilled our eligibility criteria. Most (67%) were published after 2010. The studies were conducted in all WHO regions, but primarily in Africa (22%), Europe (23%) and the Western- Pacific region (12%). Forty- one percent of the studies were classified as quantitative, followed by reviews (22%) and qualitative studies (12%). Most articles focused on ACF for tuberculosis contacts (25%) or migrants (32%). Fourteen percent of the articles described community- based screening of high- risk populations. Fifty- nine percent of studies reported influencing factors for ACF implementation; mostly linked to the health system (eg, resources) and the community/individual (eg, social determinants of health). Only two articles highlighted factors influencing ACF policy development (eg, politics). Six articles described WHO’s ACF- related recommendations as important antecedent for ACF. Key components of successful ACF implementation include health system capacity, mechanisms for integration, education and collaboration for ACF. Conclusion We identified some main themes regarding the antecedents, components and influencing factors for ACF policy development and implementation. While we know much about facilitators and barriers for ACF policy implementation, we know less about how to strengthen those facilitators and how to overcome those barriers. A major knowledge gap remains when it comes to understanding which contextual factors influence ACF policy development. Research is required to understand, inform and improve ACF policy development and implementation