Xpert MTB/RIF Ultra for Tuberculosis Testing in Children: A Mini-Review and Commentary

Tuberculosis (TB) remains a significant, yet under-recognized cause of death in the pediatric population, with a WHO estimate of 1 million new cases of childhood TB in 2016 resulting in 250,000 deaths. Diagnosis is notoriously difficult; manifestations are protean due to the high proportion of cases of extra-pulmonary TB in children, and logistical problems exist in obtaining suitable specimens. These issues are compounded by the paucibacillary nature of disease with the result that an estimated 96% of pediatric TB-associated mortality occurs prior to commencing anti-tuberculous treatment. Further development of sensitive, rapid diagnostic tests and their incorporation into diagnostic algorithms is vital in this population, and central to the WHO End-TB strategy. Initial gains were made with the expansion of nucleic acid amplification technology, particularly the introduction of the GeneXpert fully-automated PCR Xpert MTB/Rif assay in 2010, and more recently, the Xpert MTB/Rif Ultra (Ultra) assay in 2017. Ultra provides increased analytical sensitivity when compared with the initial Xpert assay in vitro; a finding now also supported by six clinical studies to date, two of which included pediatric samples. Here, we review the published evidence for the performance of Ultra in TB diagnosis in children, as well as studies in adults with paucibacillary disease providing results relevant to the pediatric population. Following on from this, we speculate upon future directions for Ultra, with focus on its potential use with alternative diagnostic specimens, which may be of particular utility in children

Cryptococcal Meningitis and Tuberculous Meningitis Co-infection in HIV-Infected Ugandan Adults.

We report 5 HIV-infected Ugandan adults with cryptococcal and tuberculous (TB) meningitis co-infection. All unmasked meningitis occurred within 5 weeks of starting HIV therapy. Xpert MTB/RIF Ultra facilitated prompt diagnosis; however, 60% in-hospital mortality occurred. TB meningitis coinfection prevalence was 0.8% (5/586) among cryptococcal meningitis, 2 during second cryptococcal episodes

Ophthalmic signs in Ugandan adults with HIV-associated cryptococcal meningitis: A nested analysis of the ASTRO-CM cohort.

Cryptococcal meningitis is a leading cause of morbidity and mortality among HIV-infected persons, accounting for 15% of AIDS-related deaths. Visual disturbance is commonly reported, and a wide range of ophthalmic signs may be present on examination. There is limited published literature to date describing the range and incidence of ophthalmic signs in HIV-associated cryptococcal meningitis. Nested within the Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis (ASTRO-CM) trial (ClinicalTrials.gov number: NCT01802385), we conducted an observational study of 696 Ugandan adults with HIV-associated cryptococcal meningitis. Patients were screened for visual disturbance and external ophthalmic signs at initial presentation and at follow-up appointments over 18 weeks. Assessment comprised simple clinical history and basic examination and required no specialist equipment. More than a quarter of our cohort demonstrated ocular signs or symptoms, which were observed throughout the study period.  A broad range of ocular signs were demonstrated: these included neurological signs (10.9%), localized ocular pathology (4.5%), and evidence of concurrent systemic disease (12.9%). The range of signs observed demonstrates the complexities of case management in patients with advanced HIV and cryptococcosis and also the importance of basic ocular examination in low resource settings. There remains an urgent need for studies conducting comprehensive ocular examination in patients with HIV-associated cryptococcal meningitis; these studies should include formal assessment of visual acuity, slit lamp examination and dilated indirect ophthalmoscopy. Prospective studies should investigate whether there is a correlation between reported visual disturbance and objective signs, in order to further clarify the underlying mechanisms and to guide effective diagnosis, follow-up and management

UK guideline for the use of HIV Post-Exposure Prophylaxis Following Sexual Exposure, 2015.

We present the updated British Association for Sexual Health and HIV guidelines for HIV post-exposure prophylaxis following sexual exposure (PEPSE). This document includes a review of the current data to support the use of PEPSE, considers how to calculate the risks of infection after a potential exposure, and provides recommendations on when PEPSE should and should not be considered. We also review which medications to use for PEPSE, provide a checklist for initial assessment, and make recommendations for monitoring individuals receiving PEPSE. Special scenarios, cost-effectiveness of PEPSE, and issues relating to service provision are also discussed. Throughout the document, the place of PEPSE within the broader context of other HIV prevention strategies is considered

Xpert MTB/RIF Ultra for Tuberculosis Testing in Children: A Mini-Review and Commentary.

Tuberculosis (TB) remains a significant, yet under-recognized cause of death in the pediatric population, with a WHO estimate of 1 million new cases of childhood TB in 2016 resulting in 250,000 deaths. Diagnosis is notoriously difficult; manifestations are protean due to the high proportion of cases of extra-pulmonary TB in children, and logistical problems exist in obtaining suitable specimens. These issues are compounded by the paucibacillary nature of disease with the result that an estimated 96% of pediatric TB-associated mortality occurs prior to commencing anti-tuberculous treatment. Further development of sensitive, rapid diagnostic tests and their incorporation into diagnostic algorithms is vital in this population, and central to the WHO End-TB strategy. Initial gains were made with the expansion of nucleic acid amplification technology, particularly the introduction of the GeneXpert fully-automated PCR Xpert MTB/Rif assay in 2010, and more recently, the Xpert MTB/Rif Ultra (Ultra) assay in 2017. Ultra provides increased analytical sensitivity when compared with the initial Xpert assay in vitro; a finding now also supported by six clinical studies to date, two of which included pediatric samples. Here, we review the published evidence for the performance of Ultra in TB diagnosis in children, as well as studies in adults with paucibacillary disease providing results relevant to the pediatric population. Following on from this, we speculate upon future directions for Ultra, with focus on its potential use with alternative diagnostic specimens, which may be of particular utility in children

Do UK sheep farmers use orf vaccine correctly and could their vaccination strategy affect vaccine efficacy?

© British Veterinary Association 2019. No commercial re-use. See rights and permissions. Published by BMJ. Orf, a parapoxvirus, is a zoonosis causing a contagious pustular dermatitis, and has a high morbidity in sheep worldwide. Despite a vaccine being available, orf prevalence in England is estimated to be 2 per cent in ewes and 20 per cent in lambsa €a €. There is concern that farmers are not complying with the vaccination guidelines and therefore the objective of this study was to investigate if orf vaccine is used correctly on sheep farms in the UK and to identify barriers and motivators of sheep farmers to use the vaccine. The survey was completed by 570 respondents. The results show several areas of concern; only 27 per cent of respondents used the correct site (axilla), 37 per cent of respondents would use orf vaccine up to a week after opening a vial (shelf life is eight hours), 33 per cent of respondents would vaccinate their ewes too close to lambing and 73 per cent of respondents did not separate vaccinated and non-vaccinated animals (both leading to infection risk for non-vaccinated animals). When vaccinating, only 53 per cent of respondents were wearing gloves and 31 per cent washed their hands just before and immediately after vaccination. Results demonstrate that orf vaccination is not carried out correctly on all UK sheep farms, which is likely to affect vaccine efficacy. A concern around vaccine efficacy, the a € hassle' of the scratch administration, the a € risk of making it worse' and the zoonotic risk when vaccinating were the most common barriers for using orf vaccine, highlighting the importance of veterinary advice when prescribing orf vaccine

Performance of Lipoarabinomannan Assay using Cerebrospinal fluid for the diagnosis of Tuberculous meningitis among HIV patients.

Background: The diagnostic utility of the Mycobacteria tuberculosis lipoarabinomannan (TB-LAM) antigen lateral flow assay on cerebrospinal fluid (CSF) for the diagnosis of tuberculous meningitis (TBM) has not been extensively studied and the few published studies have conflicting results. Methods: Lumbar CSF from 59 HIV-positive patients with suspected TBM was tested with TB-LAM and Xpert MTB/Rif Ultra. The diagnostic performance of CSF TB-LAM was compared to positive CSF Xpert MTB/Rif Ultra (definite TBM) and a composite reference of probable or definite TBM according to the uniform case definition.  Results: Of 59 subjects, 12 (20%) had definite TBM and five (9%) had probable TBM. With reference to definite TBM, CSF TB-LAM assay had a diagnostic sensitivity of 33% and specificity of 96%. When compared to a composite reference of definite or probable TBM, the sensitivity was 24% and specificity was 95%. There were two false positive tests with TB-LAM (3+ grade). In-hospital mortality in CSF TB-LAM positive patients was 17% compared to 0% in those with definite TBM by Xpert MTB/Rif Ultra but negative LAM. Conclusions: Lumbar CSF TB-LAM has a poor performance in diagnosing TBM. Both urine TB-LAM and Xpert Ultra should be further investigated in the diagnosis of TBM

The role of optic nerve sheath diameter ultrasound in brain infection.

Brain infections cause significant morbidity and mortality worldwide, especially in resource-limited settings with high HIV co-infection rates. Raised intracranial pressure [ICP] may complicate brain infection and worsen neurological injury, yet invasive ICP monitoring is often unavailable. Optic nerve sheath diameter [ONSD] ultrasound may allow detection of raised ICP at the bedside; however, pathology in brain infection is different to traumatic brain injury, in which most studies have been performed. The use of ONSD ultrasound has been described in tuberculous meningitis, cryptococcal meningitis and cerebral malaria; however correlation with invasive ICP measurement has not been performed. Normal optic nerve sheath values are not yet established for most populations, and thresholds for clinical intervention cannot be assumed to match those used in non-infective brain pathology. ONSD ultrasound may be suitable for use in resource-limited settings by clinicians with limited ultrasound training. Standardisation of scanning technique, consensus on normal ONSD values, and action on abnormal results, are areas for future research. This scoping review examines the role of ONSD ultrasound in brain infection. We discuss pathophysiology, and describe the rationale, practicalities, and challenges of utilising ONSD ultrasound for brain infection monitoring and management. We discuss the existing evidence base for this technique, and identify knowledge gaps and future research priorities