Fungal Encephalitis Research Articles

Autopsy Diagnosis of Invasive Pulmonary Aspergillosis and Fungal Encephalitis Due to Disseminated Pulmonary Mucormycosis in a Pediatric Patient.

Autopsy Diagnosis of Invasive Pulmonary Aspergillosis and Fungal Encephalitis Due to Disseminated Pulmonary Mucormycosis in a Pediatric Patient.

Next generation sequencing for diagnosis of central nervous system aspergillosis in liver transplant recipients.

BackgroundFungal encephalitis is uncommon and sometimes fatal in liver transplant (LT) recipients. Early diagnosis of central nervous system (CNS) fungal infections, especially aspergillosis, is difficult based on routine tests of cerebrospinal fluid (CSF) alone. Next-generation sequencing (NGS) as a new tool may help in this respect.MethodsShotgun metagenomics was used to detect pathogens in CSF of patients, who were clinically suspected of CNS infection. Sequencing was performed at BGIseq-50 platform (BGI, Shenzhen).ResultsNGS technique identified Aspergillus in CSF of 5 patients, who were suspected of CNS infection, although clinical symptoms of these patients varied dramatically. The resulting sequence reads corresponding to Aspergillus species ranged from 2 to 25, with genomic coverage ranging from 0.0003% to 0.0036%. Rapid identification of Aspergillus enabled early appropriate antifungal therapy, although 4 patients eventually died of severe infection.ConclusionsThis is the first study to highlight the utility of NGS in early diagnosis of CNS aspergillosis in LT recipients. This new tool may be helpful in improving the diagnosis of CNS aspergillosis.

Disseminated phaeohyphomycosis in a dog with seizures and suspected hyperadrenocorticism in the United Kingdom

A twelve-year-old female entire Lurcher-cross dog presented for investigation of an acute onset of cluster seizures and elevation of the liver enzymes. Physical examination was unremarkable; neurological examination was suggestive...

Blastomyces helicus, a New Dimorphic Fungus Causing Fatal Pulmonary and Systemic Disease in Humans and Animals in Western Canada and the United States

Blastomyces helicus (formerly Emmonsia helica) is a dimorphic fungus first isolated from a man with fungal encephalitis in Alberta, Canada. The geographic range, epidemiology, and clinical features of disease are unknown. We reviewed human and veterinary isolates of B. helicus identified among Blastomyces and Emmonsia isolates at the University of Alberta Microfungus Collection and Herbarium, University of Texas Health San Antonio's Fungus Testing Laboratory, and Associated Regional and University Pathologists Laboratories. Isolates were selected based on low Blastomyces dermatitidis DNA probe values and/or atypical morphology. Species identification was confirmed for most isolates by DNA sequence analysis of the internal transcribed spacer with or without D1/D2 ribosomal RNA regions. Epidemiological and clinical data were analyzed. We identified isolates from 10 human and 5 veterinary cases of B. helicus infection; all were referred from western regions of Canada and the United States. Isolates remained sterile in culture, producing neither conidia nor sexual spores in the mycelial phase, but often producing coiled hyphae. Isolates were most frequently cultured from blood and bronchoalveolar lavage in humans and lungs in animals. Most infected persons were immunocompromised. Histopathological findings included pleomorphic, small or variably sized yeast-like cells, with single or multiple budding, sometimes proliferating to form short, branching, hyphal-like elements. Disease carried a high case-fatality rate. Blastomyces helicus causes fatal pulmonary and systemic disease in humans and companion animals. It differs from B. dermatitidis in morphological presentation in culture and in histopathology, by primarily affecting immunocompromised persons, and in a geographic range that includes western regions of North America.

Updated results of single-agent ibrutinib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL).

7515 Background: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Ibrutinib has shown promising clinical response in Mantle cell lymphoma, CLL, Marginal Zone, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. Methods: Eligible patients had r/r PCNSL or SCNSL, age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. Results: Twenty-five patients were enrolled (3 at 560 mg; 22 at 840 mg). Median age was 68 (range 21-85); 15 were women. Median ECOG was 1 (0: 2, 1: 15, 2: 8). 64% had PCNSL and 36% SCNSL; 68% had recurrent disease. Seventeen had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 5 both. Seven grade 4 adverse events were observed in 7 patients neutropenia (in 3 patients), lymphopenia (2), sepsis (1), and ALT elevation (1). Fourteen patients developed 20 grade 3 toxicities, including lymphopenia in 5 patients, hyperglycemia in 3, ALT elevation in 2, thrombocytopenia in 2, lung infection in 2, AST elevation in 1, neutropenia in 1, urinary tract infection in 1, colitis in 1, febrile neutropenia in 1 and fungal encephalitis in 1. The most common toxicities at any grade were hyperglycemia, thrombocytopenia and anemia of which most were grade 1/2. No grade 5 events have been observed. After a median follow-up of 414 days (range 289-674), 22/25 patients were evaluated for response (3 did not complete at least 15 days of drug treatment). Over all response was 68% (17/22; 77% (17/22) in patient that completed at least 15 days of drug treatment) with 10 CR, 7 PR, 2 SD and 3 PD as best response. The median PFS is 4.6 months (5.4 months in patients that completed at least 15 days of drug treatment; longest: 15.3 months). The median overall survival has not been reached. Conclusions: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Clinical response was seen in 68% of CNS lymphoma patients. Clinical trial information: NCT02315326.

Single-Agent Ibrutinib in Recurrent/Refractory Central Nervous System Lymphoma

BACKGROUNDPrimary Central Nervous System Lymphoma (PCNSL) is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Response rates (ORR) range between 30-60% with a PFS of 2-5 months. Ibrutinib has shown promising clinical response in Mantel cell lymphoma, CLL, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. METHODSEligible patients had r/r PCNSL or Secondary CNS Lymphoma (SCNSL), age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. RESULTSTwenty patients were enrolled (3 at 560 mg; 17 at 840 mg). Median age was 69 (range 21-85); 12 were women. Median ECOG was 1 (0: 2, 1: 12, 2: 6). 65% had PCNSL and 35% SCNSL; 70% had recurrent disease. Eleven had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 6 both. Five grade 4 adverse events were observed in 4 patients (lymphopenia (2), sepsis (1), neutropenia (2)). Ten patients developed grade 3 toxicities, including lymphopenia in 3 patients, thrombocytopenia in 2, hyperglycemia in 2, lung infection in 2, neutropenia in 1, urinary tract infection in 1, colitis in 1, and fungal encephalitis in 1. The most common toxicities were hyperglycemia, anemia, and thrombocytopenia. After a median follow-up of 193 days, 19/20 patients were evaluated for response: 8 CR, 7 PR, 1 SD and 3 PD; 75% (15/20) ORR. The median PFS is 7.29 months (95% CI: 3.80-15.43 months (longest: 15.3 months)). The mean Ibrutinib concentration in the CSF 2h post administration at day 1 and 29 is 1.75 ng/mL (3.97 nM) and 2.51 ng/mL (5.6 nM) which is above the IC50 (1nM) required in vitro to reduce growth of lymphoma cells.An additional treatment arm has been added to the trial which will evaluate adverse events of the combination of ibrutinib and high-dose methotrexate chemotherapy. Enrollment into the combination arm is ongoing and updates will be presented at the meeting. CONCLUSIONPatients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Drug concentrations in CSF are higher at steady state (day 29) and meaningful CSF concentrations are reached. Clinical response was seen in 75% of CNS lymphoma patients. A combination arm will assess the adverse events of ibrutinib in combination with high-dose methotrexate chemotherapy. DisclosuresNo relevant conflicts of interest to declare.

Aspergillus flavus-Induced Brain Abscess in an Immunocompetent Child: Case report.

Intracranial aspergillosis is an extremely rare manifestation of invasive aspergillosis in immunocompetent children and is associated with high morbidity and mortality. We report a 12-year-old immunocompetent male child who was referred to the King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, in May 2010 after a sudden-onset headache and loss of consciousness. Brain imaging revealed a large right space-occupying occipital lesion and the patient underwent a craniotomy and resection. Histopathology of the lesion revealed necrotising granulomatous fungal encephalitis with many hyphae engulfed by multinucleated giant histiocytes. Two days later, a computed tomography scan showed debulking of the fungal mass and the patient was discharged on oral voriconazole. However, imaging at a six-week follow-up showed progression of the abnormality. A residual or persistent fungal brain lesion was suspected. Further neurosurgical resection of the lesion was performed and cultures showed growth of Aspergillus flavus. The patient was treated successfully with antifungal therapy over the following two years.

Detection of GB virus C genomic sequence in the cerebrospinal fluid of a HIV-infected patient in China: a case report and literature review

Hepatitis G virus or GB virus C (GBV-C) is a human virus of the Flaviviridae family that is structurally and epidemiologically closest to hepatitis C virus, but replicates primarily in lymphocytes. Co-infection with GBV-C has been reported to confer beneficial outcomes in some HIV-positive patients. Up to now, however, studies on GBV-C infection in the central nervous system (CNS) of HIV-infected patient have rarely been reported. Herein, we report on a 32-year-old HIV-1-infected patient with cerebral toxoplasmosis and fungal encephalitis. GBV-C viral loads were detected in CSF by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR), and the results showed that GBV-C viral load was 6·5 log copies/ml. We amplified and sequenced the E2 and 5'-untranslated regions from the purified viral RNA from CSF by RT-PCR. Both sequences belong to genotype 3 and there were some minor nucleotide divergence among the E2 sequences from the CSF of the patient. These data suggest that GBV-C may be able to penetrate the blood-brain barrier and colonize the CNS of HIV-infected patients. However, the exact mechanisms and potential effect of the infected GBV-C in CNS on HIV-associated neuropathy needs to be further explored.

Fungal encephalitis in human autopsy cases is associated with extensive neuronal damage but only minimal repair

The present study aimed at examining neuronal injury and repair in post mortem brain sections of humans who died from fungal central nervous system infections. Histological and immunohistochemical abnormalities in 15 autopsy cases with fungal central nervous system infections from 1990 to 2008 were compared with findings in 10 age- und sex-matched control cases that died from acute non-neurological causes. The fungal pathogens were identified by culture or polymerase chain reaction and morphology in post mortem tissue. Seven patients with fungal encephalitis had either an organ transplantation or a malignant haematological disorder; five out of 15 did not have a classical predisposing illness but suffered from severe septic infections as the principal cause of immunosuppression, and three from alcoholism. Fungal organisms detected were Aspergillus spp. and other moulds, Candida spp. and black yeast-like fungi including Cladosporium spp. Histological analyses identified microglial activation, astrocytosis and axonal injury in the white matter without additional demyelination as characteristic features of this infectious disease. An increased rate of hippocampal neuronal apoptosis was detected in fungal encephalitis, while the number of recently generated TUC-4 and calretinin-expressing neurones in the dentate gyrus did not differ between patients and controls. Unlike in other infectious diseases of the nervous system where a coexistence of damage and repair was observed, fungal encephalitis is characterized by strong damage and minimal neuronal regeneration.

Fungal encephalitis following bone marrow transplantation

Central nervous system fungal infections (FI) are important complications and a cause of mortality in patients who receive hematopoietic stem cell transplantation (HSCT). To study the clinical aspects of fungal encephalitis (FE). The study was carried out at the HSCT Center of the Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil. Clinical records and autopsy reports from patients submitted to HSCT with a diagnosis of FE. Twelve patients were diagnosed with FE presenting with lowered level of consciousness, hemiparesis and seizures. We were able to identify two subgroups regarding susceptibility to FE: (1) patients with early onset FI and severe leucopenia, and (2) patients with later onset FI with graft-versus-host disease using immunosuppressive drugs. Eleven of the patients died directly due to the neurological complication, all had post-mortem confirmation of the diagnosis of FI. These clinical, paraclinical and temporal patterns may provide the opportunity for earlier diagnosis and interventions.