The current global situation for tuberculous meningitis : epidemiology, diagnostics, treatment and outcomes [version 1; peer review: 2 approved]

CITATION: Seddon, J., et al. 2019. The current global situation for tuberculous meningitis : epidemiology, diagnostics, treatment and outcomes [version 1; peer review: 2 approved]. Wellcome Open Research, 4:167, doi:10.12688/wellcomeopenres.15535.1.The original publication is available at https://wellcomeopenresearch.orgTuberculous meningitis (TBM) results from dissemination of M. tuberculosis to the cerebrospinal fluid (CSF) and meninges. Ischaemia, hydrocephalus and raised intracranial pressure frequently result, leading to extensive brain injury and neurodisability. The global burden of TBM is unclear and it is likely that many cases are undiagnosed, with many treated cases unreported. Untreated, TBM is uniformly fatal, and even if treated, mortality and morbidity are high. Young age and human immunodeficiency virus (HIV) infection are potent risk factors for TBM, while Bacillus Calmette–Guérin (BCG) vaccination is protective, particularly in young children. Diagnosis of TBM usually relies on characteristic clinical symptoms and signs, together with consistent neuroimaging and CSF parameters. The ability to confirm the TBM diagnosis via CSF isolation of M. tuberculosis depends on the type of diagnostic tests available. In most cases, the diagnosis remains unconfirmed. GeneXpert MTB/RIF and the next generation Xpert Ultra offer improved sensitivity and rapid turnaround times, and while roll-out has scaled up, availability remains limited. Many locations rely only on acid fast bacilli smear, which is insensitive. Treatment regimens for TBM are based on evidence for pulmonary tuberculosis treatment, with little consideration to CSF penetration or mode of drug action required. The World Health Organization recommends a 12-month treatment course, although data on which to base this duration is lacking. New treatment regimens and drug dosages are under evaluation, with much higher dosages of rifampicin and the inclusion of fluoroquinolones and linezolid identified as promising innovations. The inclusion of corticosteroids at the start of treatment has been demonstrated to reduce mortality in HIV-negative individuals but whether they are universally beneficial is unclear. Other host-directed therapies show promise but evidence for widespread use is lacking. Finally, the management of TBM within health systems is sub-optimal, with drop-offs at every stage in the care cascade.https://wellcomeopenresearch.org/articles/4-167Publisher's versio

Treatment Outcomes in Adult Tuberculous Meningitis: A Systematic Review and Meta-analysis.

BACKGROUND: There is substantial variation in the reported treatment outcomes for adult tuberculous meningitis (TBM). Data on survival and neurological disability by continent and HIV serostatus are scarce. METHODS: We performed a systematic review and meta-analysis to characterize treatment outcomes for adult TBM. Following a systematic literature search (MEDLINE and EMBASE), studies underwent duplicate screening by independent reviewers in 2 stages to assess eligibility for inclusion. Two independent reviewers extracted data from included studies. We employed a random effects model for all meta-analyses. We evaluated heterogeneity by the I 2 statistic. RESULTS: We assessed 2197 records for eligibility; 39 primary research articles met our inclusion criteria, reporting on treatment outcomes for 5752 adults with TBM. The commonest reported outcome measure was 6-month mortality. Pooled 6-month mortality was 24% and showed significant heterogeneity (I 2 > 95%; P 50%. CONCLUSIONS: Mortality in adult TBM is high and varies considerably by continent and HIV status. The highest mortality is among HIV-positive adults in Sub-Saharan Africa. Standardized reporting of treatment outcomes will be essential to improve future data quality and increase potential for data sharing, meta-analyses, and facilitating multicenter tuberculosis research to improve outcomes

Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation study.

INTRODUCTION: Tuberculous meningitis accounts for 1-5% of tuberculosis cases. Diagnostic delay contributes to poor outcomes. We evaluated the performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis diagnosis. METHODS: In this prospective validation study, we tested the cerebrospinal fluid (CSF) of adults presenting with suspected meningitis (ie, headache or altered mental status with clinical signs of meningism) to the Mulago National Referral Hospital and Mbarara Regional Referral Hospital in Uganda. We centrifuged the CSF, resuspended the cell pellet in 2 mL CSF, and tested 0·5 mL aliquots with Xpert Ultra, Xpert MTB/RIF (Xpert), and mycobacterial growth indicator tube (MGIT) culture. We quantified diagnostic performance against the uniform case definition of probable or definite tuberculous meningitis and a composite microbiological reference standard. FINDINGS: From Nov 25, 2016, to Jan 24, 2019, we screened 466 adults with suspected meningitis and tested 204 for tuberculous meningitis. Uniform clinical case definition classified 51 participants as having probable or definite tuberculous meningitis. Against this uniform case definition, Xpert Ultra had 76·5% sensitivity (95% CI 62·5-87·2; 39 of 51 patients) and a negative predictive value of 92·7% (87·6-96·2; 153 of 165), compared with 55·6% sensitivity (44·0-70·4; 25 of 45; p=0·0010) and a negative predictive value of 85·8% (78·9-91·1; 121 of 141) for Xpert and 61·4% sensitivity (45·5-75·6; 27 of 44; p=0·020) and negative predictive value of 85·2% (77·4-91·1; 98 of 115) for MGIT culture. Against the composite microbiological reference standard, Xpert Ultra had sensitivity of 92·9% (80·5-98·5; 39 of 42), higher than Xpert at 65·8% (48·6-80·4; 25 of 38; p=0·0063) and MGIT culture at 72·2% (55·9-86·2; 27 of 37; p=0·092). Xpert Ultra detected nine tuberculous meningitis cases missed by Xpert and MGIT culture. INTERPRETATION: Xpert Ultra detected tuberculous meningitis with higher sensitivity than Xpert and MGIT culture in this HIV-positive population. However, with a negative predictive value of 93%, Xpert Ultra cannot be used as a rule-out test. Clinical judgment and novel highly sensitive point-of-care tests are still required. FUNDING: Wellcome Trust, National Institute of Health, National Institute of Neurologic Diseases and Stroke, Fogarty International Center, and National Institute of Allergy and Infectious Diseases

Standardized Urine-Based Tuberculosis (TB) Screening With TB-Lipoarabinomannan and Xpert MTB/RIF Ultra in Ugandan Adults With Advanced Human Immunodeficiency Virus Disease and Suspected Meningitis.

BACKGROUND: Diagnosis of extrapulmonary tuberculosis (TB) remains challenging. We sought to determine the prevalence of disseminated TB by testing urine with TB-lipoarabinomannan (TB-LAM) lateral flow assay and Xpert MTB/RIF Ultra (Ultra) in hospitalized adults. METHODS: We prospectively enrolled human immunodeficiency virus (HIV)-positive adults with suspected meningitis in Uganda during 2018-2020. Participants underwent standardized urine-based TB screening. Urine (60 mcL) was tested with TB-LAM (Alere), and remaining urine was centrifuged with the cell pellet resuspended in 2 mL of urine for Xpert Ultra testing. RESULTS: We enrolled 348 HIV-positive inpatients with median CD4 of 37 cells/mcL (interquartile range, 13-102 cells/mcL). Overall, 26% (90 of 348; 95% confidence interval [CI], 21%-30%) had evidence of disseminated TB by either urine assay. Of 243 participants with both urine TB-LAM and Ultra results, 20% (48 of 243) were TB-LAM-positive, 12% (29 of 243) were Ultra-positive, and 6% (14 of 243) were positive by both assays. In definite and probable TB meningitis, 37% (14 of 38) were TB-LAM-positive and 41% (15 of 37) were Ultra-positive. In cryptococcal meningitis, 22% (40 of 183) were TB-LAM-positive and 4.4% (6 of 135) were Ultra-positive. Mortality trended higher in those with evidence of disseminated TB by either assay (odds ratio = 1.44; 95% CI, 0.83-2.49; P = .19) and was 6-fold higher in those with definite TB meningitis who were urine Ultra-positive (odds ratio = 5.67; 95% CI, 1.13-28.5; P = .04). CONCLUSIONS: In hospitalized Ugandans with advanced HIV disease and suspected meningitis, systematic screening with urine TB-LAM and Ultra found a high prevalence of urine TB test positivity (26%). In those with TB meningitis, urine tests were positive in over one third. There was little concordance between Ultra and TB-LAM, which warrants further investigation

A pragmatic approach to managing antiretroviral therapy-experienced patients diagnosed with HIV-associated cryptococcal meningitis: impact of antiretroviral therapy adherence and duration

Cryptococcal meningitis accounts for 15% of all HIV-related deaths [1]. The overall number of cryptococcal meningitis cases has remained relatively stable in many low-to-middle income countries (LMICs) despite increasing roll-out of antiretroviral therapy (ART). Increasing numbers of patients are at risk of developing cryptococcal meningitis following ART failure or discontinuation, offsetting declines in those presenting for the first time with advanced HIV [2–4]. Over half of patients diagnosed with cryptococcal meningitis in recent studies in sub-Saharan Africa are ART-experienced (i.e. currently receiving or previously received ART) [5,6]. Although there is robust evidence from prospective randomized trials that ART initiation should be delayed until 4–6 weeks after starting antifungal therapy in ART-naïve cryptococcal meningitis patients [7,8], the approach to ART management among ART-experienced cryptococcal meningitis patients lacks adequate evidence, with a paucity of published data

Cryptococcal Antigenemia in Human Immunodeficiency Virus Antiretroviral Therapy-Experienced Ugandans With Virologic Failure.

BACKGROUND: Detectable serum or plasma cryptococcal antigen (CrAg) precedes symptomatic cryptococcal meningitis. The World Health Organization recommends CrAg screening for human immunodeficiency virus-positive persons with CD4 count <100 cells/μL initiating antiretroviral therapy (ART). However, an increasing proportion of patients with cryptococcosis are now ART experienced. Whether CrAg screening is cost-effective in those with virologic failure is unknown. METHODS: We retrospectively performed nationwide plasma CrAg testing among ART-experienced Ugandan adults with virologic failure (≥1000 copies/mL) using leftover plasma after viral load testing during September 2017-January 2018. For those who were CrAg positive, we obtained ART history, meningitis occurrence, and 6-month survival via medical records review. RESULTS: Among 1186 subjects with virologic failure, 35 (3.0%) were CrAg positive with median ART duration of 41 months (interquartile range, 10-84 months). Among 25 subjects with 6-month outcomes, 16 (64%) survived, 7 (28%) died, and 2 (8%) were lost. One survivor had suffered cryptococcal meningitis 2 years prior. Two others developed cryptococcal meningitis and survived. Five survivors were known to have received fluconazole. Thus, meningitis-free survival at 6 months was 61% (14/23). Overall, 91% (32/35) of CrAg-positive persons had viral load ≥5000 copies/mL compared with 64% (735/1151) of CrAg-negative persons (odds ratio, 6.0 [95% confidence interval, 1.8-19.8]; P = .001). CrAg prevalence was 4.2% (32/768) among those with viral loads ≥5000 copies/mL and 0.7% (3/419) among those with viral loads <5000 copies/mL. CONCLUSIONS: In addition to the CD4 threshold of <100 cells/μL, reflexive CrAg screening should be considered in persons failing ART in Uganda with viral loads ≥5000 copies/mL

Tuberculosis in HIV-Associated Cryptococcal Meningitis is Associated with an Increased Risk of Death.

Tuberculosis (TB) and cryptococcal meningitis are leading causes of morbidity and mortality in advanced HIV disease. Data are limited on TB co-infection among individuals with cryptococcal meningitis. We performed a retrospective analysis of HIV-infected participants with cryptococcal meningitis from 2010-2017. Baseline demographics were compared between three groups: 'prevalent TB' if TB treated >14 days prior to cryptococcal meningitis diagnosis, 'concurrent TB' if TB treated ± 14 days from diagnosis, or 'No TB at baseline'. We used time-updated proportional-hazards regression models to assess TB diagnosis as a risk for death. Of 870 participants with cryptococcal meningitis, 50 (6%) had prevalent TB, 67 (8%) had concurrent TB, and 753 (86%) had no baseline TB. Among participants without baseline TB, 67 (9%) were diagnosed with incident TB (after >14 days), with a median time to TB incidence of 41 days (IQR, 22-69). The 18-week mortality was 50% (25/50) in prevalent TB, 46% (31/67) in concurrent TB, and 45% (341/753) in the no TB group (p = 0.81). However, TB co-infection was associated with an increased hazard of death (HR = 1.75; 95% CI, 1.33-2.32; p < 0.001) in a time-updated model. TB is commonly diagnosed in cryptococcal meningitis, and the increased mortality associated with co-infection is a public health concern

Baseline Cytomegalovirus Viremia at Cryptococcal Meningitis Diagnosis Is Associated With Long-term Increased Incident TB Disease and Mortality in a Prospective Cohort of Ugandan Adults With HIV.

BACKGROUND: Adults with HIV-associated cryptococcal meningitis have overlapping burdens of cytomegalovirus (CMV) and tuberculosis (TB) coinfections. CMV infection/reactivation is strongly associated with CMV-specific memory T-cell activation and upregulation of type 1 interferons, which may lead to increased risk of TB disease and poor outcomes. METHODS: We conducted a cohort study of 2-week survivors of cryptococcal meningitis during 2010-2021 to determine TB incidence and all-cause mortality over time stratified by baseline CMV status. RESULTS: We followed 497 Ugandans with HIV-associated cryptococcal meningitis for a median (interquartile range) of 4.6 (2.6-53.9) months. Overall, 42% (210/497) developed incident TB disease or died. One-fifth (98/497, 19.7%) developed incident TB disease, and 29% (142/497) of participants died during follow-up. Of 259 participants with CMV viral load measured at baseline, 37% (96/259) had concurrent CMV viremia (defined as anyone with detectable CMV DNA in plasma/serum by qualitative polymerase chain reaction [PCR] detection). Of 59 with measured CMV immunoglobulin G (IgG), 100% had positive CMV IgG antibody serology (≥10 enzyme-linked immunosorbent assay units/mL). CMV viremia was positively associated with higher HIV viral load (196 667 vs 73 295 copies/mL; P = .002) and higher cerebrospinal fluid fungal burden (68 500 vs 14 000 cfu/mL; P = .002) compared with those without. Participants with high-level CMV viremia (defined as CMV viral load ≥1000 IU/mL) had twice the risk of incident TB (subdistribution adjusted hazard ratio [aHR], 2.18; 95% CI, 1.11-4.27) and death (aHR, 1.99; 95% CI, 1.14-3.49) compared with participants with no or low-level CMV viremia. There was no association between the CMV IgG index and the incidence of TB/death (P = .75). CONCLUSIONS: CMV viremia >1000 IU/mL at meningitis diagnosis was associated with increased incident TB disease and mortality during long-term follow-up. Future studies to determine the causal relationship and potential for therapeutic intervention are warranted

High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults: A Phase II Open-Label Randomized Controlled Trial.

BACKGROUND: High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. METHODS: In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration, and grade 3-5 adverse events. RESULTS: We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/µL (interquartile range [IQR] 46-56). On day 2, geometric mean plasma AUC0-24hr was 42.9·h mg/L with standard-of-care 10 mg/kg dosing, 249·h mg/L for IV-20 and 327·h mg/L for PO-35 (P < .001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2-2.5) for IV-20 and 2.17 mg/L (1.6-2.9) for PO-35 regimens (P < .001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (P = .34). CONCLUSIONS: Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures ~6- and ~8-fold higher than standard of care, and CSF levels above the MIC

Association of Hyponatremia on Mortality in Cryptococcal Meningitis: A Prospective Cohort.

BACKGROUND: Sodium abnormalities are frequent in CNS infections and may be caused by cerebral salt wasting, syndrome of inappropriate antidiuretic hormone secretion (SIADH), or medication adverse events. In cryptococcal meningitis, the prevalence of baseline hyponatremia and whether hyponatremia adversely impacts survival is unknown. METHODS: We conducted a secondary analysis of data from two randomized trials of HIV-infected adult Ugandans with cryptococcal meningitis. We grouped serum sodium into 3 categories: &amp;lt;125, 125-129, and 130-145 mmol/L. We assessed whether baseline sodium abnormalities were associated with clinical characteristics and survival. RESULTS: Of 816 participants with cryptococcal meningitis, 741 (91%) had a baseline sodium measurement available: 121 (16%) had Grade 3-4 hyponatremia (&amp;lt;125 mmol/L), 194 (26%) had Grade 2 hyponatremia (125-129 mmol/L), and 426 (57%) had a baseline sodium of 130-145 mmol/L. Hyponatremia (&amp;lt;125 mmol/L) was associated with higher initial CSF quantitative culture burden (P &amp;lt; .001), higher initial CSF opening pressure (P &amp;lt; 0.01), lower baseline Glasgow Coma Score (P &amp;lt; 0.01), and a higher percentage of baseline seizures (P = .03). Serum sodium &amp;lt;125 mmol/L was associated with increased 2-week mortality in unadjusted and adjusted survival analyses; adjusted hazard ratio of 1.87 (95%CI, 1.26 to 2.79; p &amp;lt; 0.01) compared to those with sodium 130-145 mmol/L. CONCLUSIONS: yponatremia is common in cryptococcal meningitis and is associated with excess mortality. A standardized management approach to correctly diagnose and correct hyponatremia in cryptococcal meningitis needs to be developed and tested