Challenging diagnosis of chronic cerebral fungal infection: Value of (1→3)-ß-D-glucan and mannan antigen testing in cerebrospinal fluid and of cerebral ventricle puncture.

Primary fungal infection of the central nervous system (CNS) is rare but often associated with severe prognosis. Diagnosis is complicated since cerebrospinal fluid (CSF) samples obtained from lumbar puncture usually remain sterile. Testing for fungal antigens in CSF could be a complementary diagnostic tool. We conducted such measurements in CSF from patients with CNS fungal infection and now discuss the usefulness of ventricular puncture. Mannan and (1→3)ß-D-glucan (BDG) testing were retrospectively performed in CSF samples from three patients with proven chronic CNS fungal infection (excluding Cryptococcus), and subsequently compared to 16 controls. Results from lumbar punctures and those from cerebral ventricles were confronted. BDG detection was positive in all the CSF samples (from lumbar and/or ventricular puncture) from the three confirmed cases. In case of Candida infection, mannan antigen measurement was positive in 75% of the CSF samples. In the control group, all antigen detections were negative (n = 15), except for one false positive. Faced with suspected chronic CNS fungal infection, measurement of BDG levels appears to be a complementary diagnostic tool to circumvent the limitations of mycological cultures from lumbar punctures. In the event of negative results, more invasive procedures should be considered, such as ventricular puncture.

Plasma (1 → 3)-ß-D-glucan and suPAR levels correlate with neurocognitive performance in people living with HIV on antiretroviral therapy: a CHARTER analysis.

Despite antiretroviral therapy (ART), people living with HIV (PLWH) have higher rates of non-AIDS disorders, such as neurocognitive (NC) impairment (NCI) than the general population. (1-3)-ß-D-Glucan (BDG) is a fungal cell wall component which serves as a biomarker for gut barrier integrity failure and microbial and fungal translocation. The primary objective of this study was to determine whether higher plasma and cerebrospinal fluid (CSF) levels of BDG and suPAR were associated with NCI in PLWH. Paired blood and CSF samples were collected cross-sectionally from 61 male adult PLWH on ART (95% virally suppressed) who underwent a detailed NC assessment as part of the prospective CHARTER study between 2005 and 2015. BDG and soluble urokinase plasminogen activator receptor (suPAR) were measured in frozen blood and CSF samples while soluble CD14 (sCD14), intestinal fatty acid binding protein (IFABP), and CD4/CD8 ratio were measured in blood only. Spearman's rho correlation analysis assessed associations between BDG, other biomarkers, and NC performance. Median BDG levels were 18 pg/mL in plasma (range 2-60 pg/mL) and 20 pg/mL in CSF (range 0-830 pg/mL). Higher levels of plasma BDG were associated with worse NC performance (Spearman's rho = - 0.32; p = 0.013) and with the presence of NCI (p = 0.027). A plasma BDG cutoff of > 30 pg/mL was 30% sensitive and 100% specific for NCI. After adjusting for age, higher plasma suPAR levels were also associated with worse NC performance (p < 0.01). No significant associations were observed between the remaining biomarkers and the NC variables. Plasma levels of BDG and age-adjusted suPAR may be new biomarkers for the detection of NCI in PLWH on suppressive ART.

Detection of (1,3)-ß-d-Glucan in Cerebrospinal Fluid in Histoplasma Meningitis.

The diagnosis of central nervous system (CNS) histoplasmosis is often difficult. Although cerebrospinal fluid (CSF) (1,3)-ß-d-glucan (BDG) is available as a biological marker for the diagnosis of fungal meningitis, there are limited data on its use for the diagnosis of Histoplasma meningitis. We evaluated CSF BDG detection, using the Fungitell assay, in patients with CNS histoplasmosis and controls. A total of 47 cases and 153 controls were identified. The control group included 13 patients with a CNS fungal infection other than histoplasmosis. Forty-nine percent of patients with CNS histoplasmosis and 43.8% of controls were immunocompromised. The median CSF BDG level was 85 pg/ml for cases, compared to <31 pg/ml for all controls (P < 0.05) and 82 pg/ml for controls with other causes of fungal meningitis (P = 0.27). The sensitivity for detection of BDG in CSF was 53.2%, whereas the specificity was 86.9% versus all controls and 46% versus other CNS fungal infections. CSF BDG levels of ≥80 pg/ml are neither sensitive nor specific to support a diagnosis of Histoplasma meningitis.

Translational Development and Application of (1→3)-ß-d-Glucan for Diagnosis and Therapeutic Monitoring of Invasive Mycoses.

Early diagnosis and prompt initiation of appropriate antimicrobial therapy are crucial steps in the management of patients with invasive fungal infections. However, the diagnosis of invasive mycoses remains a major challenge in clinical practice, because presenting symptoms may be subtle and non-invasive diagnostic assays often lack sensitivity and specificity. Diagnosis is often expressed on a scale of probability (proven, probable and possible) based on a constellation of imaging findings, microbiological tools and histopathology, as there is no stand-alone assay for diagnosis. Recent data suggest that the carbohydrate biomarker (1→3)-ß-d-glucan may be useful in both the diagnosis and therapeutic monitoring of invasive fungal infections due to some yeasts, molds, and dimorphic fungi. In this paper, we review recent advances in the use of (1→3)-ß-d-glucan to monitor clinical response to antifungal therapy and explore how this assay may be used in the future.

Successful treatment of Aspergillus ventriculitis through voriconazole adaptive pharmacotherapy, immunomodulation, and therapeutic monitoring of cerebrospinal fluid (1→3)-ß-D-glucan.

Aspergillus ventriculitis is an uncommon but often fatal form of invasive aspergillosis of the central nervous system (CNS). As little is known about the diagnosis, treatment, and outcome of this potentially lethal infection, we report the strategies used to successfully treat Aspergillus ventriculitis complicating a pineal and pituitary germinoma with emphasis on the critical role of adaptive pharmacotherapy of voriconazole and serial monitoring of (1→3)-ß-D-glucan in cerebrospinal fluid. We describe several rationally based therapeutic modalities, including adaptive pharmacotherapy, combination therapy, sargramostim-based immunomodulation, and biomarker-based therapeutic monitoring of the CNS compartment. Through these strategies, our patient remains in remission from both his germinoma and Aspergillus ventriculitis making him one of the few survivors of Aspergillus ventriculitis.

Candida meningitis in an immunocompetent patient detected through (1→3)-beta-d-glucan.

A 44-year-old female presented with a 3-month history of headache, dizziness, nausea, and vomiting. Her past medical history was significant for long-standing intravenous drug abuse. Shortly after admission, the patient became hypertensive and febrile, with fever as high as 38.8°C. The lumbar puncture profile supported an infectious process; however multiple cultures of blood and cerebrospinal fluid (CSF) did not initially show growth of organisms. Finally after 9 days of incubation, a CSF culture showed evidence of a few colonies of Candida albicans. To confirm the diagnosis, preserved CSF from that sample was tested for (1→3)-ß-d-glucan, showing levels >500pg/ml. This report illustrates a rare complication of intravenous drug use in an immunocompetent patient and demonstrates the utility of (1→3)-ß-d-glucan testing in possible Candida meningitis.

Voriconazole treatment of Candida tropicalis meningitis: persistence of (1,3)-ß-D-glucan in the cerebrospinal fluid is a marker of clinical and microbiological failure: A case report.

INTRODUCTION: Infections are still the most common complications of cerebral shunt procedures. Even though fungal etiologies are considered to be rare, they are associated with significant morbidity and mortality. Due to their uncommonness, diagnostic procedures and optimal therapy are poorly defined. We report a case of Candida tropicalis infection of ventriculo-peritoneal cerebrospinal fluid (CSF) shunt in a 49-year-old immune competent male treated with voriconazole (VOR). METHODS: Microbiological and CSF markers (1,3-b-D-glucan-BDG) of fungal infection, biofilm production capacity, sensitivity of serial isolates of the pathogen, and the concentration of the antifungal drug have been monitored and related to the clinical course of this infection. RESULTS: Despite appropriate treatment with VOR, in terms of adequate achieved CSF drug concentrations and initial effective therapeutic response, loss of VOR susceptibility of the C tropicalis and treatment failure were observed. CONCLUSION: Biofilm production of the C. tropicalis isolate might have had a significant role in treatment failure. Of interest, clinical and microbiological unfavorable outcome was anticipated by persistence of BDG in CSF. Rising titers of this marker were associated with relapse of fungal infection.

(1→3)-ß-D-Glucan Levels Correlate With Neurocognitive Functioning in HIV-Infected Persons on Suppressive Antiretroviral Therapy: A Cohort Study.

Microbial translocation from the gut is associated with immune dysfunction, persistent inflammation, and likely plays a role in the pathogenesis of neurocognitive dysfunction during HIV infection. (1→3)-ß-D-Glucan (BDG) is a component of most fungal cell walls and might be a useful indicator of gut mucosal barrier impairment. The objective of this study was to evaluate whether higher blood BDG levels correlate with impaired neurocognitive functioning in a cohort of HIV-infected adults with suppressed levels of HIV RNA in blood plasma. In this cross-sectional cohort study, we measured levels of BDG in blood plasma and cerebrospinal fluid (CSF) supernatant samples in a cohort of adults with acute/early HIV infection, who initiated antiretroviral therapy (ART) during the earliest phase of infection and achieved suppressed levels of HIV RNA in blood plasma (<50 copies/mL) thereafter. We compared BDG with established biomarkers of microbial translocation, immune activation, and cognitive dysfunction (evaluated by global deficit score). We found that higher blood BDG levels were significantly related to higher global deficit scores, reflecting worse neurocognitive performance (Spearman r = 0.47; P = 0.042) among HIV-infected adults with suppressed viral loads who initiated ART early in infection. Two CSF samples presented elevated BDG levels. Interestingly, these 2 samples originated from the 2 subjects with the highest global deficit scores of the cohort. BDG may be a promising independent biomarker associated with neurocognitive functioning in virologically suppressed HIV-infected individuals.

(1→3)-ß-d-Glucan in Cerebrospinal Fluid as a Biomarker for Candida and Aspergillus Infections of the Central Nervous System in Pediatric Patients.

BACKGROUND: Fungal infections of the central nervous system (FICNS) are important causes of morbidity and mortality among immunocompromised pediatric patients. Standard diagnostic modalities lack the sensitivity for detecting and therapeutically monitoring these life-threatening diseases. Current molecular methods remain investigational. (1→3)-ß-d-glucan (BDG) is a cell wall component found in several fungal pathogens, including Candida and Aspergillus spp. Detecting BDG in cerebrospinal fluid (CSF) may be an important approach for detecting and therapeutically monitoring FICNS. To date, there has been no study that has investigated the effectiveness of CSF BDG as a diagnostic and therapeutic marker of FICNS in children. METHODS: Serial BDG levels were measured in serum and CSF samples obtained from pediatric patients (aged 0-18 years) with a diagnosis of probable or proven Candida or Aspergillus CNS infection. RESULTS: Nine cases of FICNS were identified in patients aged 1 month to 18 years. Two patients were infected with an Aspergillus species, and 7 patients were infected with a Candida species. All the patients at baseline had detectable BDG in their CSF. Among 7 patients who completed therapy for an FICNS, all elevated CSF BDG levels decreased to <31 pg/mL. At the time of this writing, 1 patient was still receiving therapy and continued to have elevated BDG levels. One patient died from overwhelming disseminated candidiasis. The lengths of therapy for these 9 children ranged from 2 weeks to 28 months. CONCLUSION: The BDG assay is useful in diagnosing and therapeutically monitoring Candida and Aspergillus CNS infections in pediatric patients.

Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole.

Invasive aspergillosis (IA) is a severe disseminated fungal disease that occurs mostly in immunocompromised patients. However, central nervous system IA, combining meningitis and skull base involvement, does not occur only in groups with classic risk factors for IA; patients with chronic renal failure and diabetes mellitus are also at risk for more chronic forms. In both of our proven IA cases, voriconazole monotherapy was effective without surgery, and cerebrospinal fluid and serum 1,3-ß-d-glucan test results were initially positive, in contrast to galactomannan antigen results.