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Quantitative cerebrospinal fluid (CSF) cultures provide a measure of disease severity in cryptococcal meningitis. The fungal clearance rate by quantitative cultures has become a primary endpoint for phase II clinical trials. This study determined the inter-assay accuracy of three different quantitative culture methodologies. Among 91 participants with meningitis symptoms in Kampala, Uganda, during August-November 2013, 305 CSF samples were prospectively collected from patients at multiple time points during treatment. Samples were simultaneously cultured by three methods: (1) St. George's 100 mcl input volume of CSF with five 1:10 serial dilutions, (2) AIDS Clinical Trials Group (ACTG) method using 1000, 100, 10 mcl input volumes, and two 1:100 dilutions with 100 and 10 mcl input volume per dilution on seven agar plates; and (3) 10 mcl calibrated loop of undiluted and 1:100 diluted CSF (loop). Quantitative culture values did not statistically differ between St. George-ACTG methods (P= .09) but did for St. George-10 mcl loop (P< .001). Repeated measures pairwise correlation between any of the methods was high (r≥0.88). For detecting sterility, the ACTG-method had the highest negative predictive value of 97% (91% St. George, 60% loop), but the ACTG-method had occasional (∼10%) difficulties in quantification due to colony clumping. For CSF clearance rate, St. George-ACTG methods did not differ overall (mean -0.05 ± 0.07 log10CFU/ml/day;P= .14) on a group level; however, individual-level clearance varied. The St. George and ACTG quantitative CSF culture methods produced comparable but not identical results. Quantitative cultures can inform treatment management strategies., (© The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 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]

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]

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]