Management and outcome of intracranial fungal infections in children and adults in Africa: a scoping review.

INTRODUCTION: Intracranial fungal infections' (IcFIs) varying clinical manifestations lead to difficulties in diagnosis and treatment. African populations are disproportionately affected by the high burden of the disease. There is a lack of clarity as to the diagnostic and treatment modalities employed across the continent. In this review, we aim to detail the management, and outcome of IcFIs across Africa. METHODS: This scoping review was conducted using the Arksey and O'Malley framework. MEDLINE, EMBASE, Cochrane Library, African Index Medicus, and African Journals Online were searched for relevant articles from database inception to August 10th, 2021. The Preferred Reporting Items for Systematic Review and Meta-Analysis extension for Scoping Reviews guidelines were used to report the findings of the review. RESULTS: Of the 5,779 records identified, 131 articles were included. The mean age was 35.6 years, and the majority (56.4%) were males. The majority (n = 8,433/8,693, 97.0%) of IcFIs presented as a meningitis, the most common communicable predisposing factor of IcFIs was HIV/AIDS (n = 7,815/8,693, 89.9%), and the most common non-communicable risk factor was diabetes mellitus (n = 32/8,693, 0.4%). Cryptococcus species was the most common (n = 8,428/8,693, 97.0%) causative organism. The most commonly used diagnostic modality was cerebrospinal (CSF) cultures (n = 4,390/6,830, 64.3%) for diffuse IcFIs, and MRI imaging (n = 12/30, 40%) for focal IcFIs. The most common treatment modality was medical management with antifungals only (n = 4,481/8,693, 51.6%). The most commonly used antifungal agent in paediatric, and adult patients was amphotericin B and fluconazole dual therapy (51.5% vs 44.9%). The overall mortality rate was high (n = 3,475/7,493, 46.3%), and similar for both adult and paediatric patients (47.8% vs 42.1%). CONCLUSION: Most IcFIs occurred in immunosuppressed individuals, and despite the new diagnostic techniques, CSF culture was mostly used in Africa. Antifungals regimens used was similar between children and adults. The outcome of IcFIs in Africa was poor for both paediatric and adult patients.

Metagenomic next-generation sequencing could play a pivotal role in validating the diagnosis of invasive mold disease of the central nervous system.

Background: Invasive mold diseases of the central nervous (CNS IMD) system are exceedingly rare disorders, characterized by nonspecific clinical symptoms. This results in significant diagnostic challenges, often leading to delayed diagnosis and the risk of misdiagnosis for patients. Metagenomic Next-Generation Sequencing (mNGS) holds significant importance for the diagnosis of infectious diseases, especially in the rapid and accurate identification of rare and difficult-to-culture pathogens. Therefore, this study aims to explore the clinical characteristics of invasive mold disease of CNS IMD in children and assess the effectiveness of mNGS technology in diagnosing CNS IMD. Methods: Three pediatric patients diagnosed with Invasive mold disease brain abscess and treated in the Pediatric Intensive Care Unit (PICU) of the First Affiliated Hospital of Zhengzhou University from January 2020 to December 2023 were selected for this study. Results: Case 1, a 6-year-old girl, was admitted to the hospital with "acute liver failure." During her hospital stay, she developed fever, irritability, and seizures. CSF mNGS testing resulted in a negative outcome. Multiple brain abscesses were drained, and Aspergillus fumigatus was detected in pus culture and mNGS. The condition gradually improved after treatment with voriconazole combined with caspofungin. Case 2, a 3-year-old girl, was admitted with "acute B-lymphoblastic leukemia." During induction chemotherapy, she developed fever and seizures. Aspergillus fumigatus was detected in the intracranial abscess fluid by mNGS, and the condition gradually improved after treatment with voriconazole combined with caspofungin, followed by "right-sided brain abscess drainage surgery." Case 3, a 7-year-old girl, showed lethargy, fever, and right-sided limb weakness during the pending chemotherapy period for acute B-lymphoblastic leukemia. Rhizomucor miehei and Rhizomucor pusillus was detected in the cerebrospinal fluid by mNGS. The condition gradually improved after treatment with amphotericin B combined with posaconazole. After a six-month follow-up post-discharge, the three patients improved without residual neurological sequelae, and the primary diseases were in complete remission. Conclusion: The clinical manifestations of CNS IMD lack specificity. Early mNGS can assist in identifying the pathogen, providing a basis for definitive diagnosis. Combined surgical treatment when necessary can help improve prognosis.

Clinicopathological and diagnostic imaging findings in a dog with neurocandidiasis.

Neurocandidiasis is systemic candidiasis with central nervous system involvement. This case report describes the clinical presentation, diagnostic test results, and histopathology of a dog with neurocandidiasis. A 3-year-old German shepherd dog was presented for a 3-day history of abnormal mentation, neck pain, and ataxia. Magnetic resonance imaging (MRI) scan of the brain revealed multifocal, small, round, intra-axial lesions within the forebrain. Examination of the cerebrospinal fluid revealed severe neutrophilic inflammation. Extensive testing for infectious diseases was negative. The dog was administered immunosuppressive doses of corticosteroids. The dog's clinical signs improved transiently but got worse 12 days after starting the treatment. Repeat MRI scan revealed multiple, intra-axial, target-like nodular lesions scattered throughout the brain parenchyma. In the temporal muscles, nodules were seen. Cytology of the fine needle aspirates of the nodules in the temporal muscles revealed a neutrophilic inflammation with hyalohyphomycosis. Postmortem examination was compatible with a severe systemic fungal infection. Candida albicans was isolated from the brain, kidney, and heart.

Fusarium species central nervous system infection.

PURPOSE OF REVIEW: Fusarium species are an increasingly important cause of meningitis and invasive disease in immunocompromised patients as well as in otherwise healthy patients as observed in two recent healthcare-associated outbreaks. This review summarizes recently published information on treatment and diagnosis of this infection. RECENT FINDINGS: Incidence of Fusarium species meningitis and invasive fusariosis are increasing. Molecular techniques are improving the speed of diagnosis. New antifungal agents in development show good in vitro activity against some Fusarium species. New technologies, including cerebrospinal fluid (CSF) filtration, may play a role in treatment of central nervous system (CNS) disease. Due to the continued prime importance of the host immune system in recovery, immunomodulatory treatments may play a role in treatment. SUMMARY: The overall incidence of CNS fusariosis is increasing with a continued poor prognosis, but new diagnostic and treatment modalities are in development which may offer improvements.

Clinical characteristics, diagnosis, and treatment of central nervous system sporotrichosis: Systematic review and meta-analysis.

BACKGROUND: The clinical features of central nervous system (CNS) sporotrichosis are derived from case reports and a limited series of cases. Our objective was to carry out a systematic review and meta-analysis of CNS sporotrichosis. METHODS: We searched PubMed/MEDLINE, Embase, Scopus, and LILACS on 9 September 2023. Our inclusion criteria were documentation of Sporothrix and demonstrated CNS involvement. A metaproportion or metamean analysis was performed to estimate a summary proportion with 95% confidence intervals. RESULTS: We included 52 cases of CNS sporotrichosis published from 1966 to 2023. Forty-six patients were male (88%, 95% CI: 77-95), and the mean age was 39 years (95% CI: 36-43). Close contact with cats was reported in 55% of cases (95% CI: 37-72). Thirty-two (61.5%) patients were from Brazil, 18 patients from the United State of America (34.6%). Only two Sporothrix species were reported: S. schenckii (26/41, 63%), and S. brasiliensis (15/41, 37%). The most common neurological symptom was headache. Meningitis was chronic in approximately 80% of cases. A significant majority of the patients were immunocompromised. HIV infection was the primary cause of immunosuppression (85%, 95% CI: 61-95). Overall mortality was 56% (22/39). The comparison of Kaplan-Meier survival curve showed a higher mortality with a statistically significant difference in immunosuppressed patients (p = .019). CONCLUSION: CNS sporotrichosis represents a notable cause of chronic meningitis, especially in individuals living in the Americas with HIV infection and concurrent skin lesions.

Post covid cerebral phaeohyphomycosis by Rhinocladiella mackenziei: An unusual association.

Cerebral phaeohyphomycosis (CP) is a rare but a highly morbid fungal infection of the central nervous system caused by the fungi belonging to the order Chaetothyriales, which includes Cladophialophora bantiana, Exophiala dermatitidis, Rhinocladiella mackenziei (RM) etc. This disease is associated with poor clinical outcomes, with reported mortality of over 80%. We present the case of a 65-year gentleman who developed CP secondary to RM infection following COVID-19 and the associated challenges in his medical and surgical management.

First case of Rhinocladiella mackenziei brain abscess in Turkey: Case report and review of the literature.

Rhinocladiella mackenziei is a highly neurotropic fungus, mainly reported from the Middle East. However, in recent years, there have been some cases from outside this region. We described an additional fatal case of R. mackenziei cerebral infection for the first time from Turkey and made a literature review of all previously reported cases. During 34 years (1988-2022), there have been 42 R. mackenziei brain abscess cases. Most patients have been reported from Saudi Arabia (n = 14, 33.3%). It is noteworthy that 40.5% of patients, including our case, were immunocompetent at initial diagnosis and mostly presented with a single lesion (n = 10, 23.8%). The most frequent comorbidities were solid organ transplant (n = 9, 21.4%), diabetes mellitus (n = 6, 14.3%), malignancy (n = 6, 14.3%) and prior surgery (n = 3, 7.1%). The most commonly used initial antifungal regimen were amphotericin B together with itraconazole (n = 9, 21.4%), combinations of lipid preparations of amphotericin B, voriconazole and/or posaconazole (n = 9, 21.4%) and amphotericin B alone (n = 8, 19%). Although both surgical procedures and antifungal medication in the majority of patients were performed, mortality rates remained high (90.4%). The area at risk of R. mackenziei cerebral abscess cases extends to other countries. Clinicians should be aware of this emerging disease and take a detailed travel history in patients with atypical and undocumented brain abscesses. Our case confirms the hypothesis that this fungus might spread more widely than previously predicted regions.

Clinical characteristics of central nervous system candidiasis due to Candida albicans in children: a single-center experience.

BACKGROUND: Central nervous system candidiasis due to Candida albicans (CNSC) in children is easily misdiagnosed and is associated with poor outcomes and a high mortality rate. There is no big data research or systematic review of CNSC. METHODS: Patients diagnosed as CNSC with positive culture results of Candida albicans in Beijing Children's Hospital affiliated to Capital Medical University from March 2010 to March 2019 were included. Patients receiving immunosuppressive therapy or transplantation, or with malignant tumours were excluded. We analysed the clinical characteristics, follow-up results, drug susceptibility tests and whole-exome sequencing (WES) results. RESULTS: Thirty-three definitive patients were enrolled, including 22 males and 11 females. Twenty-five patients suffered from CNSC when they were less than 1 year old, and a total of 29 patients had high-risk factors. The main clinical manifestations were fever, convulsions, and positive neurological signs. Twenty-two patients had CNS infections alone, and 11 patients had CNS infections combined with invasive infections involving multiple sites. Twenty-seven cases had a positive CSF and/or blood culture at our hospital. All strains were susceptible to fluconazole, and 2 strains had intermediate susceptibility to voriconazole. As for amphotericin B, all the strains were wild type (WT). WES of 16 patients revealed 2 cases with CARD9 mutations, who suffered from recurrent onychomycosis or thrush before. CONCLUSION: CNSC mostly existed in children younger than 1 year old, who all had underlying risk factors. CNSC patients with onset at an older age or with recurrent superficial fungal infections might have primary immunodeficiency.

Disseminated Rhinocladiella mackenziei infection in a kidney transplant recipient: A case report and literature review.

Rhinocladiella mackenziei is a rare fungal pathogen which belongs to a large group of pigmented fungi causing phaeohyphomycosis. R. mackenziei primarily infects the brain and leads to high fatality rates among both immunocompetent and immunocompromised individuals. Among solid organ transplant recipients, the infection may disseminate to extra-neuronal sites, necessitating comprehensive radiologic imaging. Here we describe a new case of R. mackenziei infection in a renal transplant patient involving the brain and renal allograft. She received liposomal amphotericin B and voriconazole but no surgical intervention. Ultimately, the patient died after two months of hospital stay. A review of all reported cases of transplant patients infected with R. mackenziei is also presented.

An unexpected intracerebral lesion - case report of a superinfected aspergillosis mimicking a brain metastasis.

BACKGROUND: Invasive aspergillosis of the central nervous system is a rare but increasingly prevalent disease. We present the unusual case of an immunosuppressed patient suffering from unexpected superinfected invasive aspergillosis with cerebral, pulmonal, and adrenal manifestations, mimicking a metastasized bronchial carcinoma. This report reveals the importance of including aspergillosis in the differential diagnosis of a cerebral mass lesion in the light of unspecific clinical findings. CASE PRESENTATION: A 58-year-old immunocompromised female presented to our emergency department with a single tonic-clonic seizure. Imaging showed a ring enhancing cerebral mass with perifocal edema and evidence of two smaller additional hemorrhagic cerebral lesions. In the setting of a mass lesion in the lung, and additional nodular lesions in the left adrenal gland the diagnosis of a metastasized bronchus carcinoma was suspected and the cerebral mass resected. However, histology did not reveal any evidence for a neoplastic lesion but septate hyphae consistent with aspergillus instead and microbiological cultures confirmed concomitant staphylococcal infection. CONCLUSIONS: A high index of suspicion for aspergillus infection should be maintained in the setting of immunosuppression. Clinical and radiological findings are often unspecific and even misleading. Definite confirmation usually relies on tissue diagnosis with histochemical stains. Surgical resection is crucial for establishing the diagnosis and guiding therapy with targeted antifungal medications.

Central nervous system blastomycosis clinical characteristics and outcomes.

Blastomycosis is a local or systemic infection, caused by Blastomyces dermatitidis (B. dermatitidis) or B. gilchristii. Blastomycosis has been described as "the great pretender," alluding to the fact that it manifests in a wide range of symptoms and disease severity. Central nervous system (CNS) involvement, although rare, carries significant mortality. Due to the limited published reports of CNS blastomycosis, we present an updated cohort with eight cases of proven or probable CNS blastomycosis describing presentation, diagnosis, treatment and outcomes. Headache was the most common presenting symptom. Magnetic resonance imaging (MRI) proved to be the superior imaging study. All patients in our cohort were diagnosed by histopathological staining or cultures of tissue or fluid obtained from CNS or extra-CNS lesions. All patients that received treatment with Liposomal amphrotericin B for at least 10 days followed by a prolonged azole therapy did not have relapse. Two patients with late diagnoses died during hospitalization. Our findings confirm the importance of timely diagnosis and treatment of CNS blastomycosis to improve outcomes especially with an azole that have a high CNS penetration and a good intrinsic activity for B. dermatitidis such as voriconazole.

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.

Isolated cerebral mucormycosis associated with intravenous drug use.

We present an uncommon case of isolated basal ganglia mucormycosis in a patient without any known cause of immunosuppression, but with a history of drug injection. The patient presented a good clinical and radiological response to antifungal treatment without aggressive surgical debridement (liposomal amphotericin B combined with isavuconazole for 4 weeks followed by isavuconazole as maintenance therapy for 10 months).

Antifungal drugs: An updated review of central nervous system pharmacokinetics.

Invasive fungal infections (IFIs) in the central nervous system (CNS) are particularly hard to treat and are associated with high morbidity and mortality rates. Four chemical classes of systemic antifungal agents are used for the treatment of IFIs (eg meningitis), including polyenes, triazoles, pyrimidine analogues and echinocandins. This review will address all of these classes and discuss their penetration and accumulation in the CNS. Treatment of fungal meningitis is based on the antifungal that shows good penetration and accumulation in the CNS. Pharmacokinetic data concerning the entry of antifungal agents into the intracranial compartments are faulty. This review will provide an overview of the ability of systemic antifungals to penetrate the CNS, based on previously published drug physicochemical properties and pharmacokinetic data, for evaluation of the most promising antifungal drugs for the treatment of fungal CNS infections. The studies selected and discussed in this review are from 1990 to 2019.

Invasive rhino-orbital-cerebral aspergillosis in an immunocompetent patient.

INTRODUCTION: Rhino-orbital-aspergillosis (ROA) is a rare but serious disease in immunocompetent patients. Diagnosis is often delayed due to the absence of specific clinical symptoms. We describe the case of a patient who presented initially with ROA which spread progressively to the right ethmoid-sphenoid sinuses and then to the brain. OBSERVATION: A 61-year-old patient with a history of well-controlled diabetes presented with a sudden severe decrease in right visual acuity. Cerebral MRI showed the presence of an infiltrate in the right orbital apex extending to the homolateral cavernous sinus without any cerebral involvement. A diagnosis of right orbital myositis was made and corticosteroid therapy was started. His symptoms worsened progressively leading to quasi-blindness. A new MRI showed the development of right sphenoid-ethmoid osteolytic lesions. A fungal aetiology was suspected and tests for fungal biomarkers found a ß-(1-3)-D-glucan level of 99pg/ml but negative galactomannan. An ethmoid biopsy was performed for histological and mycological investigations, including the detection of Aspergillus DNA by qPCR. qPCR was positive and culture resulted in the isolation of multi-sensitive Aspergillus fumigatus. Treatment was initiated with voriconazole. Due to persistence of blindness and the appearance of a lesion extending to the right frontal lobe, surgical excision was performed followed by antifungal treatment for a total duration of 1year. The patient is currently stable, but has persistence of blindness in the right eye. CONCLUSION: Invasive ROA is a rare but serious disease in immunocompetent patients which should be evoked in the differential diagnosis of a tumour or vasculitis. Early diagnosis is essential for optimal management.

Intrathecal Antibacterial and Antifungal Therapies.

Intrathecal administration of anti-infectives is indicated in central nervous system infections by multiresistant pathogens when drugs that can reach adequate cerebrospinal fluid (CSF) concentrations by systemic therapy are not available. Antibiotics that readily pass the blood-brain and blood-CSF barriers and/or that have low toxicity allowing an increase in the daily dosage should not be used for intrathecal therapy. Intrathecal therapy is accompanied by systemic treatment. Antibacterials indispensable for intrathecal therapy include aminoglycosides, colistin, daptomycin, tigecycline, and vancomycin. Limited experience suggests the utility of the antifungals amphotericin B and caspofungin. Intraventricular administration ensures distribution throughout the CSF compartment, whereas intralumbar dosing often fails to attain adequate antibiotic concentrations in the ventricles. The individual dose is determined by the estimated size of the CSF space and by the estimated clearance from CSF. For moderately lipophilic anti-infectives with a molecular weight above approximately 1,000 g/mol, as well as for hydrophilic drugs with a molecular weight above approximately 400 g/mol, one daily dose is normally adequate. The ventricular drain should be clamped for 15 to 120 min to facilitate the distribution of the anti-infective in the CSF space. Therapeutic drug monitoring of the trough levels is necessary only in cases of therapeutic failure.

Evaluation of a micro/nanofluidic chip platform for diagnosis of central nervous system infections: a multi-center prospective study.

Central nervous system infection (CNSI) is a significant type of infection that plagues the fields of neurology and neurosurgical science. Prompt and accurate diagnosis of CNSI is a major challenge in clinical and laboratory assessments; however, developing new methods may help improve diagnostic protocols. This study evaluated the second-generation micro/nanofluidic chip platform (MNCP-II), which overcomes the difficulties of diagnosing bacterial and fungal infections in the CNS. The MNCP-II is simple to operate, and can identify 44 genus or species targets and 35 genetic resistance determinants in 50 minutes. To evaluate the diagnostic accuracy of the second-generation micro/nanofluidic chip platform for CNSI in a multicenter study. The limit of detection (LOD) using the second-generation micro/nanofluidic chip platform was first determined using six different microbial standards. A total of 180 bacterium/fungi-containing cerebrospinal fluid (CSF) cultures and 26 CSF samples collected from CNSI patients with negative microbial cultures were evaluated using the MNCP-II platform for the identification of microorganism and determinants of genetic resistance. The results were compared to those obtained with conventional identification and antimicrobial susceptibility testing methods. The LOD of the various microbes tested with the MNCP-II was found to be in the range of 250-500 copies of DNA. For the 180 CSF microbe-positive cultures, the concordance rate between the platform and the conventional identification method was 90.00%; eight species attained 100% consistency. In the detection of 9 kinds of antibiotic resistance genes, including carbapenemases, ESBLs, aminoglycoside, vancomycin-related genes, and mecA, concordance rates with the conventional antimicrobial susceptibility testing methods exceeded 80.00%. For carbapenemases and ESBLs-related genes, both the sensitivity and positive predictive values of the platform tests were high (>90.0%) and could fully meet the requirements of clinical diagnosis. MNCP-II is a very effective molecular detection platform that can assist in the diagnosis of CNSI and can significantly improve diagnostic efficiency.

A Retrospective Analysis of Invasive Fungal Diseases (IFD) of the Central Nervous System in Children With Lymphoid Malignancies.

BACKGROUND: Outcomes of childhood hematolymphoid malignancies have improved several fold because of immunosuppressive chemotherapy and broad-spectrum antibiotics for managing febrile neutropenia. An apparent trade-off has been an increase in invasive fungal disease (IFD), affecting multiple organs. We report the diagnostic and therapeutic challenges in 8 children with lymphoid cancers who developed intracranial (IC) fungal abscesses between 2010 and 2017. METHODS: Children below 15 years of age undergoing treatment for leukemia/lymphoma with clinicoradiologic and microbiologic evidence of IC fungal abscess were included. Demographic details, clinical profile, and management were retrospectively audited. Treatment was guided by European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definitions for IFD with therapeutic drug monitoring (TDM)-directed azole dosing, and surgical intervention. RESULTS: Eight patients (4 B-cell acute lymphoblastic leukemia, 2 relapsed B-cell acute lymphoblastic leukemia, and 2 non-Hodgkin lymphoma) were eligible for analysis. Proven, probable, and possible IFDs were seen in 2 (25%), 4 (50%), and 2 (25%) patients, respectively. Proven IFDs were invasive mucormycosis with remaining having mold infections. Cerebrospinal fluid galactomannan was positive in all 4 patients in whom it was tested. TDM was possible in 5/8 (63%) patients. Antifungal therapy was given for a median period of 4.2 months with 5 (63%) patients having complete resolution. Three (37%) patients expired, of which 2 were attributable to IFDs. CONCLUSIONS: IC fungal abscesses in children can cause significant morbidity and mortality in children with hematolymphoid cancers. Evaluation of cerebrospinal fluid galactomannan may help in early diagnosis and therapy. Prolonged antifungal therapy steered by TDM can help achieve resolution in some cases.