Persistently elevated intracranial pressure in cryptococcal meningitis- 76 therapeutic lumbar punctures.

Cryptococcal meningitis still remains the most common form of adult meningitis in sub-Saharan Africa, due to the burden of HIV/AIDS. Increased intracranial pressure (ICP) is a major complication of cryptococcosis and requires aggressive management with therapeutic lumbar punctures (LPs). In this report, we describe a patient with persistently elevated ICP who underwent 76 LPs over 46 days with good outcome. While unusual, this highlights the importance of serial therapeutic LPs. 2012 Elsevier Ltd. All rights reserved.

Outpatient Cryptococcal Antigen Screening Is Associated With Favorable Baseline Characteristics and Improved Survival in Persons With Cryptococcal Meningitis in Uganda.

BACKGROUND: It is unknown whether persons with symptomatic cryptococcal meningitis detected during routine blood cryptococcal antigen (CrAg) screening have better survival than persons presenting with overt meningitis. METHODS: We prospectively enrolled Ugandans with HIV and cryptocococcal meningitis from December 2018 to December 2021. Participants were treated with amphotericin-based combination therapy. We compared outcomes between persons who were CrAg screened then referred to hospital with those presenting directly to the hospital with symptomatic meningitis. RESULTS: Among 489 participants with cryptococcal meningitis, 40% (194/489) received blood CrAg screening and were referred to hospital (median time to referral 2 days; interquartile range [IQR], 1-6). CrAg-screened persons referred to hospital had lower 14-day mortality than non-CrAg-screened persons who presented directly to hospital with symptomatic meningitis (12% vs 21%; hazard ratio, .51; 95% confidence interval, .32-.83; P = .006). Fewer CrAg-screened participants had altered mental status versus non-CrAg-screened participants (29% vs 41%; P = .03). CrAg-screened persons had lower quantitative cerebrospinal fluid (CSF) culture burden (median [IQR], 4570 [11-100 000] vs 26 900 [182-324 000] CFU/mL; P = .01) and lower CSF opening pressures (median [IQR], 190 [120-270] vs 225 [140-340] mmH2O; P = .004) compared with non-CrAg-screened persons. CONCLUSIONS: Survival from cryptococcal meningitis was higher in persons with prior CrAg screening than those without CrAg screening. Altered mental status was the most potent predictor for mortality in a multivariate model. We suggest that CrAg screening detects cryptococcal meningitis at an earlier stage, as evidenced by a favorable baseline risk profile and notably fewer persons with altered mental status.

Utility of Cerebrospinal Fluid Protein Levels as a Potential Predictive Biomarker of Disease Severity in HIV-Associated Cryptococcal Meningitis.

Background: Cerebrospinal fluid (CSF) protein levels exhibit high variability in HIV-associated cryptococcal meningitis from being normal to markedly elevated. However, the clinical implications of CSF protein levels in cryptococcal meningitis remain unclear. Methods: We analysed data from 890 adults with HIV-associated cryptococcal meningitis randomized into two clinical trials in Uganda between 2015 and 2021. CSF protein was grouped into ≥100 mg/dL (n=249) and <100 mg/dL (n=641). We described baseline clinical variables and mortality by CSF protein levels. Results: Approximately one-third of individuals had a baseline CSF protein ≥100 mg/dL. Those with CSF protein ≥100 mg/dL were more likely to present with Glasgow coma scale scores <15 (P<0.01), self-reported seizures at baseline (P=0.02), higher CD4 T-cells (p<0.001), and higher CSF white cells (p<0.001). Moreover, those with a baseline CSF protein ≥100 mg/dL also had a lower baseline CSF fungal burden (p<0.001) and a higher percentage of sterile CSF cultures at day 14 (p=0.02). Individuals with CSF protein ≥100 mg/dL demonstrated a more pronounced immune response consisting of upregulation of immune effector molecules pro-inflammatory cytokines, type-1 T-helper cell cytokines, type-3 chemokines, and immune-exhaustion marker (p<0.05). 18-week mortality risk in individuals with a CSF protein <100 mg/dL was 34% higher, (unadjusted Hazard Ratio 1.34; 95% CI, 1.05 to 1.70; p=0.02) than those with ≥100 mg/dL. Conclusion: In cryptococcal meningitis, individuals with CSF protein ≥100 mg/dL more frequently presented with seizures, altered mental status, immune activation, and favourable fungal outcomes. Baseline CSF protein levels may serve as a surrogate marker of immune activation and prognosis.

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.

BACKGROUND: HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. METHODS: The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. FINDINGS: The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95% CI 1314-1424) in the AmBisome group and $1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to $80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to $121 in Uganda. INTERPRETATION: The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. FUNDING: European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. TRANSLATIONS: For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.

Distal jejunal obstruction due to Cryptococcus neoformans and rifampicin-resistant Mycobacterium tuberculosis co-infection: A case report.

Jejunal obstruction secondary to Cryptococcus neoformans and rifampicin-resistant Mycobacterium tuberculosis co-infection in HIV is not previously reported. This is a case of a 30-year-old HIV-positive male with severe headaches, a positive cerebrospinal fluid cryptococcal antigen assay, and elevated intracranial pressure requiring serial lumbar punctures and opioids. He developed constipation and abdominal distension, had partial jejunectomy and histopathology revealed Cryptococcus yeasts and caseous granulomas with Mycobacterium tuberculosis (TB). Post-operatively, rifampicin-resistant TB was detected in urine.

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

Background: Sodium abnormalities are frequent in central nervous system infections and may be caused by cerebral salt wasting, syndrome of inappropriate antidiuretic hormone secretion, or medication adverse events. In cryptococcal meningitis (CM), the prevalence of baseline hyponatremia and whether hyponatremia adversely impacts survival is unknown. Methods: We conducted a secondary analysis of data from 2 randomized trials of human immunodeficiency virus-infected adult Ugandans with CM. We grouped serum sodium into 3 categories: <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 CM, 741 (91%) had a baseline sodium measurement available: 121 (16%) had grade 3-4 hyponatremia (<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 (<125 mmol/L) was associated with higher initial cerebrospinal fluid (CSF) quantitative culture burden (P < .001), higher initial CSF opening pressure (P < .01), lower baseline Glasgow Coma Scale score (P < .01), and a higher percentage of baseline seizures (P = .03). Serum sodium <125 mmol/L was associated with increased 2-week mortality in unadjusted and adjusted survival analyses (adjusted hazard ratio, 1.87 [95% confidence interval, 1.26-2.79]; P < .01) compared to those with sodium 130-145 mmol/L. Conclusions: Hyponatremia is common in CM and is associated with excess mortality. A standardized management approach to correctly diagnose and correct hyponatremia in CM needs to be developed and tested.

Early empiric anti-Mycobacterium tuberculosis therapy for sepsis in sub-Saharan Africa: a protocol of a randomised clinical trial.

INTRODUCTION: Sub-Saharan Africa shoulders the highest burden of global sepsis and associated mortality. In high HIV and tuberculosis (TB) prevalent settings such as sub-Saharan Africa, TB is the leading cause of sepsis. However, anti-TB therapy is often delayed and may not achieve adequate blood concentrations in patients with sepsis. Accordingly, this multisite randomised clinical trial aims to determine whether immediate and/or increased dose anti-TB therapy improves 28-day mortality for participants with HIV and sepsis in Tanzania or Uganda. METHODS AND ANALYSIS: This is a phase 3, multisite, open-label, randomised controlled clinical 2×2 factorial superiority trial of (1) immediate initiation of anti-TB therapy and (2) sepsis-specific dose anti-TB therapy in addition to standard of care antibacterials for adults with HIV and sepsis admitted to hospital in Tanzania or Uganda. The primary endpoint is 28-day mortality. A sample size of 436 participants will provide 80% power for testing each of the main effects of timing and dose on 28-day mortality with a two-sided significance level of 5%. The expected main effect for absolute risk reduction is 13% and the expected OR for risk reduction is 1.58. ETHICS AND DISSEMINATION: This clinical trial will determine the optimal content, dosing and timing of antimicrobial therapy for sepsis in high HIV and TB prevalent settings. The study is funded by the National Institutes of Health in the US. Institutional review board approval was conferred by the University of Virginia, the Tanzania National Institute for Medical Research, and the Uganda National Council for Science and Technology. Study results will be published in peer-reviewed journals and in the popular press of Tanzania and Uganda. We will also present our findings to the Community Advisory Boards that we convened during study preparation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT04618198).

Diagnostic and Prognostic Value of Cerebrospinal Fluid Lactate and Glucose in HIV-Associated Tuberculosis Meningitis.

The role of cerebrospinal fluid (CSF) lactate in tuberculosis meningitis (TBM) diagnosis and prognosis is unclear. The aim of this study was to evaluate the performance of CSF lactate alone and in combination with CSF glucose in predicting a diagnosis of TBM and 14-day survival. HIV-positive Ugandan adults were investigated for suspected meningitis. The baseline CSF tests included smear microscopy; Gram stain; cell count; protein; and point-of-care glucose, lactate, and cryptococcal antigen (CrAg) assays. Where CrAg was negative or there was suspicion of TBM, a CSF Xpert MTB/RIF Ultra (Xpert Ultra) test was performed. We recorded baseline demographic and clinical data and 2-week outcomes. Of 667 patients, 25% (n = 166) had TBM, and of these, 49 had definite, 47 probable, and 70 possible TBM. CSF lactate was higher in patients with definite TBM (8.0 mmol/L; interquartile ratio [IQR], 6.1 to 9.8 mmol/L) than in those with probable TBM (3.4 [IQR, 2.5 to 7.0] mmol/L), possible TBM (2.6 [IQR 2.1 to 3.8] mmol/L), and non-TBM disease (3.5 [IQR 2.5 to 5.0] mmol/L). A 2-fold increase in CSF lactate was associated with 8-fold increased odds of definite TBM (odds ratio, 8.3; 95% confidence interval [CI], 3.6 to 19.1; P < 0.01) and 2-fold increased odds of definite/probable TBM (odds ratio, 2.3; 95% CI, 1.4 to 3.7; P < 0.001). At a cut point of >5.5 mmol/L, CSF lactate could be used to diagnose definite TBM with a sensitivity of 87.7%, specificity of 80.7%, and a negative predictive value of 98.8%. CSF lactate was not predictive of 2-week mortality. IMPORTANCE Tuberculosis meningitis (TBM) is the most severe form of tuberculosis, and its fatality is largely due to delays in diagnosis. The role of CSF lactate has not been evaluated in patients with HIV presenting with signs and symptoms of meningitis. In this study, using a point-of-care handheld lactate machine in patients with HIV-associated meningitis, we showed that high baseline CSF lactate (>5.5 mmol) may be used to rapidly identify patients with TBM and shorten the time to initiate treatment with a similar performance to the Xpert Ultra assay for definite TBM. Elevated CSF lactate levels, however, were not associated with increased 2-week mortality in patients with HIV-associated TBM. Due to moderate specificity, other etiologies of meningitis should be investigated.

Determinants of cryptococcal antigen (CrAg) screening uptake in Kampala, Uganda: An assessment of health center characteristics.

Cryptococcal antigen (CrAg) screening and pre-emptive antifungal therapy for people with CD4 cell counts <100 cells/µl are recommended by the World Health Organization and several national HIV guidelines. We sought to evaluate CrAg screening program implementation across Uganda, in relation to health center level and distance from the capital. We conducted a cross-sectional study of 22 health centers across southern Uganda from April to June 2019. We reviewed laboratory records regarding number of CD4 cell count tests performed, proportion of outpatients with CD4 counts <200 cells/µl, and number of CrAg screening tests performed. We administered surveys to health center staff to understand barriers to advanced HIV care. We observed no significant difference in health center level and performance of CrAg screening; with each subsequent health center level, there was 1.17-fold (95% CI: 0.92-1.41) higher odds of CrAg screening performed per level. CrAg screening uptake was not associated with distance from the capital city (odds ratio = 0.96, 95% CI: 0.89-1.04). Qualitative data from surveys indicated that limitations to uptake of CrAg screening were secondary to dysfunctional CD4 machines, lack of provider awareness of CrAg screening guidelines, and inadequate/intermittent supply of CrAg tests. There were no significant associations between CrAg screening uptake and level of health center or distance of health center from the capital city. We identified systemic barriers to CrAg screening related to inadequate CD4 testing, insufficient knowledge regarding national screening guidelines, and irregular laboratory testing supplies. LAY SUMMARY: The objective of this study was to evaluate cryptococcal antigen (CrAg) screening program implementation in Uganda, by type of healthcare center and by distance from the capital city. CrAg screening uptake was not associated with distance from the capital city, or the type of healthcare center.

Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

BACKGROUND: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known. METHODS: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin. RESULTS: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%). CONCLUSIONS: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).

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.