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Background: Vitamin D deficiency is a world-wide epidemic with recent estimates indicating that greater than 50 % of the global population is at risk. In Uganda, 80 % of healthy community children in a survey were found to be vitamin D insufficient. Protein-energy malnutrition is likely to be associated with vitamin D intake deficiency. The aim of this study was to determine the prevalence of vitamin D deficiency and the associated factors among children admitted with protein-energy malnutrition to the pediatrics wards of Mulago hospital in Kampala, Uganda. Methods: Consecutive sampling was done with 158 children, aged 6-24 months, enrolled in a cross sectional study. One hundred and seventeen malnourished and 41 non malnourished children were enrolled from the Acute Care unit, pediatrics in-patient wards, outpatient and immunization clinics, following informed consent obtained from the children's parents/guardians. Children with protein energy malnutrition were categorized based on anthropometric measurements of weight-for-height and weight for length compared with the recommended WHO reference Z-score. Serum 25-hydroxyvitamin D, calcium and phosphate were assayed. Results: One hundred seventeen malnourished and 41 non malnourished children were enrolled. The majority of study participants were male, 91 (57.6 %). The mean serum vitamin D levels among the malnourished was 32.5 mmol/L (±12.0 SD) and 32.2 mmol/L (10.9 SD) among the malnourished, p = 0.868. Fifteen (36.6 %) of the non malnourished children and 51 (43.6 %) of the malnourished had suboptimal levels, p = 0.689. Malnourished children admitted with meningitis and cerebral palsy had lower serum vitamin D levels than those with other infections. Conclusion: There was no statistically significant difference in vitamin D values between the malnourished and non malnourished children. Clinicians should actively screen for children for serum vitamin D levels regardless of nutritional status. [ABSTRACT FROM AUTHOR]

Background: Vitamin D deficiency is a world-wide epidemic with recent estimates indicating that greater than 50 % of the global population is at risk. In Uganda, 80 % of healthy community children in a survey were found to be vitamin D insufficient. Protein-energy malnutrition is likely to be associated with vitamin D intake deficiency. The aim of this study was to determine the prevalence of vitamin D deficiency and the associated factors among children admitted with protein-energy malnutrition to the pediatrics wards of Mulago hospital in Kampala, Uganda. Methods: Consecutive sampling was done with 158 children, aged 6–24 months, enrolled in a cross sectional study. One hundred and seventeen malnourished and 41 non malnourished children were enrolled from the Acute Care unit, pediatrics in-patient wards, outpatient and immunization clinics, following informed consent obtained from the children’s parents/guardians. Children with protein energy malnutrition were categorized based on anthropometric measurements of weight-for-height and weight for length compared with the recommended WHO reference Z-score. Serum 25-hydroxyvitamin D, calcium and phosphate were assayed. Results: One hundred seventeen malnourished and 41 non malnourished children were enrolled. The majority of study participants were male, 91 (57.6 %). The mean serum vitamin D levels among the malnourished was 32.5 mmol/L (±12.0 SD) and 32.2 mmol/L (10.9 SD) among the malnourished, p = 0.868. Fifteen (36.6 %) of the non malnourished children and 51 (43.6 %) of the malnourished had suboptimal levels, p = 0.689. Malnourished children admitted with meningitis and cerebral palsy had lower serum vitamin D levels than those with other infections. Conclusion: There was no statistically significant difference in vitamin D values between the malnourished and non malnourished children. Clinicians should actively screen for children for serum vitamin D levels regardless of nutritional status. [ABSTRACT FROM AUTHOR]

Intraocular pressure measurement by tonometry and optic nerve sheath diameter measurement by ultrasound have imprecise but statistical correlation with intracranial pressure. Neither technique is an effective surrogate measure of intracranial pressure in cryptococcal meningitis; manometry should be used.Background. Cryptococcal meningitis is associated with increased intracranial pressure (ICP). Therapeutic lumbar puncture (LP) is recommended when the initial ICP is >250 mm H2O, yet the availability of manometers in Africa is limited and not always used where available. We assessed whether intraocular pressure could be a noninvasive surrogate predictor to determine when additional therapeutic LPs are necessary.Methods. Ninety-eight human immunodeficiency virus-infected Ugandans with suspected meningitis (81% Cryptococcus) had intraocular pressure measured using a handheld tonometer (n = 78) or optic nerve sheath diameter (ONSD) measured by ultrasound (n = 81). We determined the diagnostic performance of these methods for predicting ICP vs a standard manometer.Results. The median ICP was 225 mm H2O (interquartile range [IQR], 135–405 mm H2O). The median intraocular pressure was 28 mm Hg (IQR, 22–37 mm Hg), and median ultrasound ONSD was 5.4 mm (IQR, 4.95–6.1 mm). ICP moderately correlated with intraocular pressure (ρ = 0.45, P < .001) and with ultrasound ONSD (ρ = 0.44, P < .001). There were not discrete threshold cutoff values for either tonometry or ultrasound ONSD that provided a suitable cutoff diagnostic value to predict elevated ICP (>200 mm H2O). However, risk of elevated ICP >200 mm H2O was increased with an average intraocular pressure >28 mm Hg (relative risk [RR] = 3.03; 95% confidence interval [CI], 1.55–5.92; P < .001) or an average of ONSD >5 mm (RR = 2.39; 95% CI, 1.42–4.03; P = .003). As either intraocular pressure or ONSD increased, probability of elevated ICP increased (ie, positive predictive value increased).Conclusions. Noninvasive intraocular pressure measurements by tonometry or ultrasound correlate with cerebrospinal fluid opening pressure, but both are a suboptimal replacement for actual ICP measurement with a manometer. [ABSTRACT FROM PUBLISHER]

Background: Cryptococcal meningitis (CM) is a major cause of death in HIV-infected patients in sub-Saharan Africa. Many CM patients experience cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), which is often fatal. We sought to identify transcriptomic biomarker pathways in peripheral blood that are associated with or predict the development of death or fatal C-IRIS among patients with CM who were enrolled in the Cryptococcal Optimal ART Timing Trial. Methods: We assessed peripheral blood gene expression using next-generation RNA sequencing in 4 groups of patients with CM: (1) no C-IRIS or Death; (2) C-IRIS survivors; (3) fatal C-IRIS; (4) Death without C-IRIS. Gene expression was assessed at the time of ART initiation, at 1, 4, and 8 weeks on ART, and at the time of C-IRIS events. Results: We identified 12 inflammatory and stress response pathways, including interferon type 1 signaling, that were upregulated at the time of ART initiation in patients with future fatal C-IRIS, as compared with survivors. The upregulation of transcripts involved in innate immunity (inflammasome, Toll-like receptor signaling), was observed at the time of fatal or nonfatal C-IRIS events. At the time of fatal C-IRIS events, numerous transcripts within fMLP, Rho family GTPases, HMGB1, and other acute phase response signaling pathways were upregulated, which reflects the severity of inflammation and systemic oxidative stress. Patients who died without recognized C-IRIS also had increased expression of pathways associated with oxidative stress and tissue damage. Conclusions: Our results showed that overactivated innate immunity, involving Toll-like receptor/inflammasome pathways, and inflammation-induced oxidative stress, are associated with fatal outcomes. The results of this study provide insight into the molecular drivers of death and fatal C-IRIS to inform future diagnostic test development or guide targeted treatments. [ABSTRACT FROM AUTHOR]

Background. Though peripheral blood is a crucial sample to study immunology, it is unclear whether the immune environment in the peripheral vasculature correlates with that at the end-organ site of infection. Using cryptococcal meningitis as a model, we investigated the correlation between serum and cerebrospinal fluid biomarkers over time. Methods. We analyzed the cerebrospinal fluid and serum of 160 subjects presenting with first episode cryptococcal meningitis for soluble cytokines and chemokines measured by Luminex assay. Specimens were collected at meningitis diagnosis, 1-week, and 2-week post cryptococcal diagnosis. We compared paired samples by Spearman's correlation and the p value was set at <0.01. Results. Of the 21 analytes tested at baseline, there was no correlation detected between nearly all analytes. A weak negative correlation was found between serum and cerebrospinal fluid levels of interferon-gamma (Rho = − 0.214 ; p =.007) and interleukin-4 (Rho = − 0.232 ; p =.003). There was no correlation at 1-week post cryptococcal diagnosis. However, at 2-week post cryptococcal diagnosis, there was a weak positive correlation of granulocyte-macrophage colony-stimulating factor levels (Rho = 0.25 ; p =.007) in serum and cerebrospinal fluid. No cytokine or chemokine showed consistent correlation overtime. Conclusion. Based on our analysis of 21 biomarkers, serum and cerebrospinal fluid immune responses do not correlate. There appears to be a distinct immune environment in terms of soluble biomarkers in the vasculature versus end-organ site of infection. While this is a model of HIV-related cryptococcal meningitis, we postulate that assuming the blood compartment is representative of the immune function at the end-organ site of infection may not be appropriate. [ABSTRACT FROM AUTHOR]

Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. Methods We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010–2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. Results Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40–0.59 (n = 182), 39% for 0.30–0.39 (n = 112), 35% for 0.20–0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P  = .002). The lowest EFA group had lower median CD4 T-cell counts (P  < .01) and lower proportion of patients with CSF pleocytosis (P  < .001). Conclusions EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint. [ABSTRACT FROM AUTHOR]

Background Cryptococcal meningitis and tuberculosis are both important causes of death in persons with advanced human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Cytomegalovirus (CMV) viremia may be associated with increased mortality in persons living with HIV who have tuberculosis. It is unknown whether concurrent CMV viremia is associated with mortality in other AIDS-related opportunistic infections. Methods We prospectively enrolled Ugandans living with HIV who had cryptococcal meningitis from 2010–2012. Subsequently, we analyzed stored baseline plasma samples from 111 subjects for CMV DNA. We compared 10-week survival rates among those with and without CMV viremia. Results Of 111 participants, 52% (58/111) had detectable CMV DNA (median plasma viral load 498 IU/mL, interquartile range [IQR] 259–2390). All samples tested were positive on immunoglobin G serology. The median CD4+ T cell count was 19 cells/µL (IQR 9–70) and did not differ by the presence of CMV viremia (P =.47). The 10-week mortality rates were 40% (23/58) in those with CMV viremia and 21% (11/53) in those without CMV viremia (hazard ratio 2.19, 95% confidence interval [CI] 1.07–4.49; P =.03), which remained significant after a multivariate adjustment for known risk factors of mortality (adjusted hazard ratio 3.25, 95% CI 1.49–7.10; P =.003). Serum and cerebrospinal fluid cytokine levels were generally similar and cryptococcal antigen-specific immune stimulation responses did not differ between groups. Conclusions Half of persons with advanced AIDS and cryptococcal meningitis had detectable CMV viremia. CMV viremia was associated with an over 2-fold higher mortality rate. It remains unclear whether CMV viremia in severely immunocompromised persons with cryptococcal meningitis contributes directly to this mortality or may reflect an underlying immune dysfunction (ie, cause vs effect). Clinical Trials Registration NCT01075152. [ABSTRACT FROM AUTHOR]

Altered mental status in cryptococcal meningitis results in poorer survival, but underlying causes of altered mentation are poorly understood. Within two clinical trials, we assessed risk factors for altered mental status (GCS score<15) considering baseline clinical characteristics, CSF cytokines/chemokines, and antiretroviral therapy. Among 326 enrolled participants, 97 (30%) had GCS<15 and these patients had lower median CSF cryptococcal antigen titers (P = .042) and CCL2 (P = .005) but higher opening pressures (320 vs. 269 mm H2O; P = .016), IL-10 (P = .044), and CCL3 (P = .008) compared with persons with GCS=15. Altered mental status may be associated with host immune response rather than Cryptococcus burden. [ABSTRACT FROM AUTHOR]

Background: Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus.Methods: In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with ClinicalTrials.gov, number NCT01802385.Findings: Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any sertraline dose averaged a CSF clearance rate of -0·37 colony forming units per mL per day (95% CI -0·41 to -0·33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration-approved dosing of 100-200 mg/day and higher doses of 300-400 mg/day (hazard ratio 1·27, 95% CI 0·69-2·32; p=0·45).Interpretation: Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy.Funding: National Institutes of Health, Grand Challenges Canada. [ABSTRACT FROM AUTHOR]

The effect of tenofovir and amphotericin coadministration on kidney function is poorly characterized. We measured creatinine during induction therapy and at 4 weeks after diagnosis in Ugandans undergoing cryptococcal meningitis therapy and classified as not receiving antiretroviral therapy (ART), receiving nontenofovir ART or receiving tenofovir-based ART. Longitudinal creatinine changes and grade 2-4 creatinine adverse events were evaluated across groups. Creatinine concentrations were similar across ART groups. At 4 weeks after diagnosis, creatinine was 0.25 mg/dL higher than at diagnosis, but similar across groups. Adverse event incidence was also similar across ART groups. Tenofovir and amphotericin coadministration did not increase the risk of kidney dysfunction. [ABSTRACT FROM AUTHOR]

Background. Amphotericin-based combination antifungal therapy reduces mortality from human immunodeficiency virus (HIV)-associated cryptococcal meningitis. However, 40%-50% of individuals have positive cerebrospinal fluid (CSF) fungal cultures at completion of 2 weeks of amphotericin induction therapy. Residual CSF culture positivity has historically been associated with poor clinical outcomes. We investigated whether persistent CSF fungemia was associated with detrimental clinical outcomes in a contemporary African cohort. Methods. Human immunodeficiency virus-infected individuals with cryptococcal meningitis in Uganda and South Africa received amphotericin (0.7-1.0 mg/kg per day) plus fluconazole (800 mg/day) for 2 weeks, followed by "enhanced consolidation" therapy with fluconazole 800 mg/day for at least 3 weeks or until cultures were sterile, and then 400 mg/day for 8 weeks. Participants were randomized to receive antiretroviral therapy (ART) either 1-2 or 5 weeks after diagnosis and observed for 6 months. Survivors were classified as having sterile or nonsterile CSF based on 2-week CSF cultures. Mortality, immune reconstitution inflammatory syndrome (IRIS), and culturepositive relapse were compared in those with sterile or nonsterile CSF using Cox regression. Results. Of 132 participants surviving 2 weeks, 57% had sterile CSF at 2 weeks, 23 died within 5 weeks, and 40 died within 6months. Culture positivity was not significantly associated with mortality (adjusted 6-month hazard ratio, 1.2; 95% confidence interval, 0.6-2.3; P = .28). Incidence of IRIS or relapse was also not significantly related to culture positivity. Conclusions. Amongpatients, all treated with enhanced consolidation antifungal therapyandART, residual cryptococcal culture positivity was not found to be associated with poor clinical outcomes. [ABSTRACT FROM AUTHOR]

Intracranial pressure management with repeat lumbar puncture (LP) was investigated in patients with cryptococcal meningitis in sub-Saharan Africa. Conducting at least 1 additional LP soon after cryptococcal diagnosis was related to decreased risk of acute mortality regardless of initial pressure.Introduction. Cryptococcal meningitis is the most common cause of adult meningitis in sub-Saharan Africa. Raised intracranial pressure (ICP) is common in cryptococcosis. Prior studies suggest elevated ICP is associated with mortality, and guidelines recommend frequent lumbar punctures (LPs) to control ICP. However, the magnitude of the impact of LPs on cryptococcal-related mortality is unknown.Methods. In sum, 248 individuals with human immunodeficiency virus (HIV)-associated cryptococcal meningitis, screened for the Cryptococcal Optimal ART Timing (COAT) trial in Uganda and South Africa, were observed. Individuals received an LP to diagnose meningitis, and subsequent therapeutic LPs were recommended for elevated ICP (>250 mmH2O) or new symptoms. We compared survival, through 11 days, between individuals receiving at least 1 therapeutic LP with individuals not receiving therapeutic LPs. The COAT trial randomized subjects at 7–11 days; thus, follow-up stopped at time of death, randomization, or 11 days.Results. Seventy-five (30%) individuals had at least 1 therapeutic LP. Individuals receiving therapeutic LPs had higher cerebrospinal fluid (CSF) opening pressures, higher CSF fungal burdens, and were more likely to have altered mental status at baseline than those with no therapeutic LPs. Thirty-one deaths (18%) occurred among 173 individuals without a therapeutic LP and 5 deaths (7%) among 75 with at least 1 therapeutic LP. The adjusted relative risk of mortality was 0.31 (95% confidence interval: .12–.82). The association was observed regardless of opening pressure at baseline.Conclusions. Therapeutic LPs were associated with a 69% relative improvement in survival, regardless of initial intracranial pressure. The role of therapeutic LPs should be reevaluated. [ABSTRACT FROM AUTHOR]

The article discusses a research study which investigated the timing of antiretroviral therapy (ART) after diagnosis of cryptococcal meningitis. Study results are presented including the mortality rate with earlier ART initiation and with deferred ART initiation, the hazard ratio for death, confidence interval, and the incidence rate of recognized cryptococcal immune reconstitution inflammatory syndrome between the earlier-ART and deferred ART patient groups.