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Background The World Health Organization recommends GeneXpert MTB/RIF Ultra (Xpert Ultra), a fully automated PCR assay, as the initial tuberculous meningitis (TBM) diagnostic test. The assay’s PCR cycle threshold (Ct) values represent the number of PCR cycles required for probe signal to be detected (low Ct value = high bacillary load) and may approximate TB bacillary load. We measured the relationship between cerebrospinal fluid (CSF) TB bacillary load with mortality. Methods We prospectively enrolled 102 HIV-positive Ugandans with probable or definite TBM from April 2015 to August 2019. Xpert Ultra Ct tertiles and semi-quantitative categories were separately analyzed as predictors of 2-week mortality. We investigated associations between CT and baseline clinical and CSF parameters. Results Subjects with Ct values in the low tertile (i.e. high bacillary load) had 57% 2-week mortality; worse than the intermediate (17%) and high (25%) Ct tertiles and Xpert Ultra-negative (30%) probable TBM cases (p=.01). In contrast, the reported semi-quantitative Xpert Ultra categorization was less precise; with medium to low category trending towards worse 2-week survival (42%) compared with very low (28%), trace (26%) and negative (30%) categories (p=.48). Ct tertile was significantly associated with baseline CSF lactate (p=.03). Conclusions High CSF TB bacillary load, as measured by Xpert Ultra Ct tertile, is associated with an almost 2-fold higher 2-week mortality in HIV-associated TBM and is a better predictor than the reported Xpert Ultra semi-quantitative category. Xpert Ultra Ct values could identify TBM patients at increased risk of death who may benefit from enhanced supportive care.

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.

Over the last decade excellent progress has been made globally in HIV management thanks to antiretroviral therapy (ART) rollout and international guidelines now recommending immediate initiation of ART in all HIV-positive people. Despite this, advanced HIV disease (CD4 less than 200 cells/mL) and opportunistic infections remain a persistent challenge and contribute significantly to HIV-associated mortality, which equates to 23,000 deaths in Uganda in 2018 alone. Our Meningitis Research Team based in Uganda is committed to conducting clinical trials to answer important questions regarding diagnostics and management of HIV-associated opportunistic infections, including tuberculosis and cryptococcal meningitis. However, clinical research is impossible without research participants and results are meaningless unless they are translated into benefits for those affected by the disease. Therefore, we held a series of community engagement events with the aims of giving clinical research participants a voice in sharing their experiences of clinical research and messages of hope around advanced HIV disease with the community, dispelling myths and stigma around HIV, raising awareness about the complications of advanced HIV disease and local ongoing clinical research and recent scientific advances. The purpose of this Open Letter is to describe our community engagement experience in Uganda, which we hope will lay the foundation for further clinical research public engagement activities, giving research participants a greater voice to share their experiences.

A 62-year-old man presented to the emergency department with 5 weeks of worsening lower abdominal pain associated with watery diarrhoea, vomiting and 10% loss of body weight. He had recently experienced night blindness.There was no history of foreign travel. His past medical history included hypertension, sickle cell trait and type 2 diabetes well controlled on metformin. He had not been prescribed any recent steroids and denied significant alcohol intake.On examination, he had a tachycardia at 110 bpm and was afebrile and normotensive. He was malnourished with pedal pitting oedema extending to both knees. His abdomen was soft but distended and diffusely tender.Blood tests showed a serum albumin of 12 g/L. Stool samples were negative. HIV testing was negative, and immunoglobulin levels were normal.CT of the abdomen showed thickened, hyperenhancing jejunal loops with diffuse mesenteric inflammatory fat stranding and enlarged mesenteric lymph nodes. Colonoscopy was unremarkable.Enteroscopy showed granular oedematous mucosa and extensive, deep ulcerations. Jejunal biopsies were obtained. Microscopy samples were negative for tuberculosis (TB) culture.Histology revealed inflamed and ulcerated small bowel mucosa with plump endothelial cells with the appearance below. There were no granulomata (figures 1 and 2). Figure 1Endoscopic examination of the jejunum. Figure 2Plump endothelial cells seen on microscopy.QuestionWhat is the differential diagnosis?