Cytokine Profiles in Cerebrospinal Fluid of Human Immunodeficiency Virus ‐Infected Patients with Cryptococcal Meningitis: No Leukocytosis despite High Interleukin‐8 Levels

Abstract 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 culture-positive 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 6 months. 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. Among patients, all treated with enhanced consolidation antifungal therapy and ART, residual cryptococcal culture positivity was not found to be associated with poor clinical outcomes.

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Relationship of Human Immunodeficiency Virus Viral Load in Cerebrospinal Fluid and Plasma in Patients Co-infected With Cryptococcal Meningitis

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx032 ◽

2017 ◽

Vol 4 (2) ◽

Cited By ~ 4

Author(s):

Christina C. Chang ◽

Richard Kangethe ◽

Saleha Omarjee ◽

Keshni Hiramen ◽

Bernadett Gosnell ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cerebrospinal Fluid ◽

Cryptococcal Meningitis ◽

Cd4 T Cell ◽

Hiv Rna ◽

Cell Percentage ◽

Immunodeficiency Virus ◽

A Prospective Study ◽

Relationship Of ◽

Inflammatory Syndrome

Abstract We measured human immunodeficiency virus (HIV) ribonucleic acid (RNA) in paired cerebrospinal fluid (CSF) and plasma samples in a prospective study of 91 HIV-infected, antiretroviral therapy-naive patients with cryptococcal meningitis. Cerebrospinal fluid HIV RNA was lower than in plasma (median 4.7 vs 5.2 log10 copies/mL, P < .0001) and positively correlated with plasma HIV RNA, peripheral CD4+ T-cell percentage, and CSF CXCL10. Plasma/CSF ratio of HIV RNA ranged widely from 0.2 to 265.5 with a median of 2.6. Cerebrospinal fluid quantitative cryptococcal culture positively correlated with CSF CCL2 and CCL3. CSF-plasma viral discordance was not associated with cryptococcal-associated immune reconstitution inflammatory syndrome.

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Unique Cerebrospinal Fluid Profiles of Patients With Human Immunodeficiency Virus- Associated Cryptococcal Meningitis With a Ventriculoperitoneal Shunt : A Retrospective Cohort Study

10.21203/rs.3.rs-819656/v1 ◽

2021 ◽

Author(s):

Ran Tao ◽

Lijun Xu ◽

Yongzheng Guo ◽

Xiaoke Xu ◽

Jiesheng Zheng ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cerebrospinal Fluid ◽

Cohort Study ◽

Cryptococcal Meningitis ◽

Retrospective Cohort ◽

Protein Levels ◽

Ventriculoperitoneal Shunting ◽

Immunodeficiency Virus ◽

Cerebrospinal Fluid Protein

Abstract Background: The long-term complications of ventriculoperitoneal shunting in patients with human immunodeficiency virus-associated cryptococcal meningitis remain unclear. We conducted a case-control study investigating the long-term effects of ventriculoperitoneal shunting in patients with human immunodeficiency virus-associated cryptococcal meningitis. Methods: Between January 2011 and December 2019, 112 patients with human immunodeficiency virus-associated cryptococcal meningitis from our hospital were enrolled in this retrospective cohort study. Of those, 30 (26.8%) patients underwent ventriculoperitoneal shunting (VPS group); the remaining (n = 82; 73.2%) were included in the non-VPS group. Survival was estimated using the Kaplan–Meier method. Univariate and multivariate Cox regression analyses were performed to identify factors associated with ventriculoperitoneal shunting. Results: The VPS group (n=21) had lower cerebrospinal fluid glucose (2.51±0.81 vs. 3.16±0.48 mmol/L; P=0.002) and higher cerebrospinal fluid protein levels (1.37 [0.83–1.49] vs. 0.49 [0.49–0.49] g/L; P=0.011) than did the non-VPS group (n=21). Intracranial pressure decreased from 400 (375–450) to 164 (145–172) mmH2O in the VPS group (log-rank, P<0.001). The 24-week cumulative survival rates in the VPS and non-VPS groups were 100.0% and 79.8%, respectively (P=0.035). The misdiagnosis rates of tuberculous meningitis were 28.6% and 0.0%, respectively (P=0.008). Conclusions: Ventriculoperitoneal shunting decreased the intracranial pressure and 24-week mortality in patients with human immunodeficiency virus-associated cryptococcal meningitis, but significantly increased cerebrospinal fluid protein levels, leading to a higher misdiagnosis rate of tuberculous meningitis. Physicians should be aware of these changes in the cerebrospinal fluid profiles of patients with human immunodeficiency virus-associated cryptococcal meningitis with a ventriculoperitoneal shunt.

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In Vitro and In Vivo Efficacies of the New Triazole Albaconazole against Cryptococcus neoformans

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.2.384-387.2004 ◽

2004 ◽

Vol 48 (2) ◽

pp. 384-387 ◽

Cited By ~ 29

Author(s):

J. L. Miller ◽

W. A. Schell ◽

E. A. Wills ◽

D. L. Toffaletti ◽

M. Boyce ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cerebrospinal Fluid ◽

Cryptococcus Neoformans ◽

Cryptococcal Meningitis ◽

Rabbit Model ◽

Weight Basis ◽

Csf Penetration ◽

Immunodeficiency Virus

ABSTRACT The activity of albaconazole (UR-9825; J. Uriach & Cía. S.A., Barcelona, Spain) was compared to that of fluconazole against 12 isolates of Cryptococcus neoformans in vitro and against 1 isolate in vivo in a rabbit model of cryptococcal meningitis. Albaconazole was 100-fold more potent in vitro than fluconazole on a per-weight basis and was fungicidal at potentially relevant concentrations for two isolates. MICs ranged from ≤0.0012 to 1.25 μg/ml, with the MICs for most isolates being between 0.039 and 0.156 μg/ml. Isolates were from human immunodeficiency virus (HIV)-infected and non-HIV-infected patients and were of serotypes A, B, and C; and the fluconazole MICs for some of the isolates were elevated. Infected rabbits were treated with either fluconazole or albaconazole at dosages ranging from 5 to 80 mg/kg of body weight/day. The peak concentrations of albaconazole in serum and cerebrospinal fluid (CSF) averaged 4.14 and 0.62 μg/ml, respectively, in animals receiving 80 mg/kg/day. Comparison of the concentrations in serum and CSF suggested a level of CSF penetration of approximately 15%. Despite limited penetration into the subarachnoid space, at all three doses tested albaconazole was as effective as fluconazole for the treatment of cryptococcal meningitis in rabbits.

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Cryptococcal Antigen in Serum and Cerebrospinal Fluid for Detecting Cryptococcal Meningitis in Adults Living With Human Immunodeficiency Virus: Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1243 ◽

2020 ◽

Cited By ~ 1

Author(s):

Elvis Temfack ◽

Jean Joel Bigna Rim ◽

Rene Spijker ◽

Angela Loyse ◽

Tom Chiller ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cerebrospinal Fluid ◽

Sensitivity And Specificity ◽

Antifungal Therapy ◽

Cryptococcal Meningitis ◽

Meta Analysis ◽

Test Accuracy ◽

Fungal Culture ◽

Cryptococcal Antigen ◽

Immunodeficiency Virus

Abstract Cryptococcal antigen (CrAg) detection could direct the timely initiation of antifungal therapy. We searched MEDLINE and Embase for studies where CrAg detection in serum/cerebrospinal fluid (CSF) and CSF fungal culture were done on adults living with human immunodeficiency virus (HIV) who had suspected cryptococcal meningitis (CM). With Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), we evaluated the risk of bias in 11 included studies with 3600 participants, and used a random-effects meta-analysis to obtain summary sensitivity and specificity of serum and CSF CrAg, as well as agreement between CSF CrAg and CSF culture. Summary sensitivity and specificity of serum CrAg were 99.7% (97.4–100) and 94.1% (88.3–98.1), respectively, and summary sensitivity and specificity of CSF CrAg were 98.8% (96.2–99.6) and 99.3% (96.7–99.9), respectively. Agreement between CSF CrAg and CSF culture was 98% (97–99). In adults living with HIV who have CM symptoms, serum CrAg negativity may rule out CM, while positivity should prompt induction antifungal therapy if lumbar puncture is not feasible. In a first episode of CM, CSF CrAg positivity is diagnostic.

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Seizures in Human Immunodeficiency Virus-Associated Cryptococcal Meningitis: Predictors and Outcomes

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz478 ◽

2019 ◽

Vol 6 (11) ◽

Cited By ~ 2

Author(s):

Katelyn A Pastick ◽

Ananta S Bangdiwala ◽

Mahsa Abassi ◽

Andrew G Flynn ◽

Bozena M Morawski ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cerebrospinal Fluid ◽

Cryptococcal Meningitis ◽

Proportional Hazards ◽

Neurocognitive Function ◽

Cox Proportional Hazards ◽

Neurocognitive Performance ◽

Cox Proportional Hazards Models ◽

Immunodeficiency Virus ◽

Z Scores

Abstract Background Seizures commonly occur in patients with cryptococcal meningitis, yet risk factors and outcomes related to seizures are not well described. Methods We performed post hoc analyses on participants prospectively enrolled in 3 separate human immunodeficiency virus (HIV)-associated cryptococcal meningitis clinical trials during 2010–2017. Documentation of seizures at presentation or during hospitalization and antiseizure medication receipt identified participants with seizures. We summarized participant characteristics by seizure status via Kruskal-Wallis and χ 2 tests. Cox proportional hazards models analyzed the relationship between seizures and mortality. We compared mean quantitative neurocognitive performance Z (QNPZ-8) scores, and individual domain z-scores, at 3-months using independent t tests. Results Among 821 HIV-infected cryptococcal meningitis participants, 28% (231 of 821) experienced seizures: 15.5% (127 of 821) experienced seizures at presentation, and 12.7% (104 of 821) experienced incident seizures. Participants with seizures at presentation had a significantly lower Glasgow coma scale ([GCS] <15; P < .001), CD4 count (<50 cells/mcL; P = .02), and higher cerebrospinal fluid (CSF) opening pressure (>25 cm H2O; P = .004) when compared with participants who never experienced seizures. Cerebrospinal fluid fungal burden was higher among those with seizures at presentation (125 000 Cryptococcus colony-forming units [CFU]/mL CSF) and with seizures during follow-up (92 000 CFU/mL) compared with those who never experienced seizures (36 000 CFU/mL, P < .001). Seizures were associated with increased 10-week mortality (adjusted hazard ratio = 1.45; 95% confidence interval, 1.11–1.89). Participants with seizures had lower neurocognitive function at 3 months (QNPZ-8 = −1.87) compared with those without seizures (QNPZ-8 = −1.36; P < .001). Conclusions Seizures were common in this HIV-associated cryptococcal meningitis cohort and were associated with decreased survival and neurocognitive function.

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Differences in human immunodeficiency virus-1C viral load and drug resistance mutation between plasma and cerebrospinal fluid in patients with human immunodeficiency virus-associated cryptococcal meningitis in Botswana

Medicine ◽

10.1097/md.0000000000022606 ◽

2020 ◽

Vol 99 (41) ◽

pp. e22606

Author(s):

Nametso Kelentse ◽

Sikhulile Moyo ◽

Mompati Mogwele ◽

Kwana Lechiile ◽

Natasha O. Moraka ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Drug Resistance ◽

Cerebrospinal Fluid ◽

Viral Load ◽

Cryptococcal Meningitis ◽

Resistance Mutation ◽

Drug Resistance Mutation ◽

Immunodeficiency Virus

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Genome-Wide Association Study Identifies Novel Colony Stimulating Factor 1 Locus Conferring Susceptibility to Cryptococcosis in Human Immunodeficiency Virus-Infected South Africans

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa489 ◽

2020 ◽

Vol 7 (11) ◽

Author(s):

Shichina Kannambath ◽

Joseph N Jarvis ◽

Rachel M Wake ◽

Nicky Longley ◽

Angela Loyse ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Association Study ◽

Cryptococcal Meningitis ◽

Genome Wide Association Study ◽

Ex Vivo ◽

Genome Wide Association ◽

Colony Stimulating Factor ◽

Genome Wide ◽

Immunodeficiency Virus ◽

Stimulating Factor

Abstract Background Cryptococcus is the most common cause of meningitis in human immunodeficiency virus (HIV)-infected Africans. Despite universal exposure, only 5%–10% of patients with HIV/acquired immune deficiency syndrome and profound CD4+ T-cell depletion develop disseminated cryptococcosis: host genetic factors may play a role. Prior targeted immunogenetic studies in cryptococcosis have comprised few Africans. Methods We analyzed genome-wide single-nucleotide polymorphism (SNP) genotype data from 524 patients of African descent: 243 cases (advanced HIV with cryptococcal antigenemia and/or cryptococcal meningitis) and 281 controls (advanced HIV, no history of cryptococcosis, negative serum cryptococcal antigen). Results Six loci upstream of the colony-stimulating factor 1 (CSF1) gene, encoding macrophage colony-stimulating factor (M-CSF) were associated with susceptibility to cryptococcosis at P < 10–6 and remained significantly associated in a second South African cohort (83 cases; 128 controls). Meta-analysis of the genotyped CSF1 SNP rs1999713 showed an odds ratio for cryptococcosis susceptibility of 0.53 (95% confidence interval, 0.42–0.66; P = 5.96 × 10−8). Ex vivo functional validation and transcriptomic studies confirmed the importance of macrophage activation by M-CSF in host defence against Cryptococcus in HIV-infected patients and healthy, ethnically matched controls. Conclusions This first genome-wide association study of susceptibility to cryptococcosis has identified novel and immunologically relevant susceptibility loci, which may help define novel strategies for prevention or immunotherapy of HIV-associated cryptococcal meningitis.

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