Diagnosis of central nervous system invasive aspergillosis in a liver transplant recipient using microbial cell-free next generation DNA sequencing.

Invasive aspergillosis (IA) is an important opportunistic infection among patients with liver disease and liver transplants. Diagnosis of IA may be challenging, especially among patients with central nervous system infection. Herein, we demonstrate the utility of next-generation sequencing of microbial cell-free DNA in the diagnosis of fungal brain abscess in a liver transplant recipient.

Lung aspergilloma with pituitary invasive aspergillosis presenting as headache and hyponatraemia.

Fungal infections involving the pituitary gland are rare and can be life threatening. A 75-year-old man with hypertension and diabetes mellitus presented with headache and hyponatraemia. Imaging study showed right upper lung mass, and mass resection showed aspergilloma without tissue invasion on histology. The patient developed visual impairment a few weeks later, and MRI of the brain revealed bilateral sphenoid sinusitis and pituitary invasion. The trans-sphenoidal biopsy confirmed invasive Aspergillus infection. His sphenoidal sinuses were endoscopically debrided, and he was treated with oral voriconazole. Pituitary aspergillosis should be considered in the differential diagnosis in patients with lung aspergilloma with headache and sinusitis. Prompt biopsy and antifungal treatment are important due to the high mortality rate of the infection.

Central nervous system aspergillosis in immunocompetent patients: Case series and literature review.

The aim of this study was to investigate the clinical characteristics of central nervous system (CNS) aspergillosis in immunocompetent patients.This study enrolled six immunocompetent patients diagnosed with CNS aspergillosis. Additionally, we reviewed the clinical profiles for 28 cases reported in the literature. The age, gender, etiology of Aspergillus infection, clinical manifestations, location of the lesion, treatment, and prognosis were analyzed.There were 19 men (average age, 54.6 ±â€Š14.3 years) and 15 women (average age, 47.0 ±â€Š19.4 years). The clinical manifestations included headache (55.9%; n = 19), visual impairment (32.4%; n = 11), diplopia (32.4%; n = 11), hemiplegia (20.6%; n = 7), fever (17.6%; n = 6), and epilepsy (8.8%; n = 3). According to the radiological features, CNS aspergillosis lesions were divided into two subtypes: parenchymal lesions in the cerebral lobes (n = 11), and meningeal lesions in the meninges (n = 23). The patients with meningeal lesions are easy to be complicated with more serious cerebrovascular diseases, such as subarachnoid hemorrhage and massive infarction. Most of the lesions in brain parenchyma were abscess formation, and magnetic resonance imaging showed ring enhancement. The clinical diagnosis of Aspergillus infection was mainly based on brain biopsy (n = 14), autopsy (n = 8), pathological examination of adjacent brain tissues (n = 7), cerebrospinal fluid (CSF) or tissue culture (n = 3), and second-generation sequencing analysis of the CSF (n = 3). Clinical improvement was achieved in 23 cases, and 11 patients succumbed to the disease. Voriconazole treatment was effective in 24 (70.6%) cases.Immunocompetent subjects are also at risk for Aspergillus infections. Concomitant cerebrovascular diseases are common in patients with CNS aspergillosis, especially in patients with meningeal aspergillosis. Parenchymal aspergillosis lesions are usually localized and manifest as brain abscesses with annular enhancement on magnetic resonance imaging. Biopsy, CSF culture, and next-generation sequencing are mainstream diagnostic modalities. Voriconazole is an effective treatment for Aspergillus infection, and early diagnosis and treatment should be highlighted.

Cerebral and pulmonary aspergillosis, treatment and diagnostic challenges of mixed breakthrough invasive fungal infections: case report study.

BACKGROUND: Breakthrough invasive fungal infections (bIFIs) are an area of concern in the scarcity of new antifungals. The mixed form of bIFIs is a rare phenomenon but could be potentially a troublesome challenge when caused by azole-resistant strains or non-Aspergillus fumigatus. To raise awareness and emphasize diagnostic challenges, we present a case of mixed bIFIs in a child with acute lymphoblastic leukemia. CASE PRESENTATION: A newly diagnosed 18-month-old boy with acute lymphoblastic leukemia was complicated with prolonged severe neutropenia after induction chemotherapy. He experienced repeated episodes of fever due to extended-spectrum beta-lactamase-producing Escherichia coli bloodstream infection and pulmonary invasive fungal infection with Aspergillus fumigatus (early-type bIFIs) while receiving antifungal prophylaxis. Shortly after pulmonary involvement, his condition aggravated by abnormal focal movement, loss of consciousness and seizure. Cerebral aspergillosis with Aspergillus niger diagnosed after brain tissue biopsy. The patient finally died despite 108-day antifungal therapy. CONCLUSIONS: Mixed bIFIs is a rare condition with high morbidity and mortality in the patients receiving immunosuppressants for hematological malignancies. This case highlights the clinical importance of Aspergillus identification at the species level in invasive fungal infections with multiple site involvement in the patients on antifungal prophylaxis.

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.

Special scenarios in the management of central nervous system aspergillosis: a case series and review of literature.

Aspergillus is a rare but important opportunistic pathogen to invade the central nervous system (CNS). It is a significant pathogen of not only immunocompromised but also immunocompetent patients. Its manifestations are pleiotropic, reflecting multiple mechanisms of pathogenesis and host interactions. Despite significant advances in diagnostic methods and therapeutic options, the mortality remains high. Several advances have been made in medications and surgical management, yet, current treatment practices lack uniformity. Patient woes are further heightened by the high costs of treatment and prolonged duration of therapy. In view of the challenging aspects of this disease, we present a short review of four challenging cases touching on the varied aspects of management of CNS aspergillosis covering pathogenesis, diagnostic pitfalls, surgical and medical options and evidence-based guidelines for the management of the same.

Aspergillus mural endocarditis presenting with multiple cerebral abscesses.

BACKGROUND: Fungal endocarditis is a rare and lethal cardiac infection which most commonly presents in immunocompromised patients or patients with other predisposing conditions. In a small subset of these patients, lesions present as mural masses and do not have any involvement with native valves or implanted devices. Here we present one such case which was diagnosed in the antemortem period in time to be managed with surgical resection. CASE PRESENTATION: A 70 year-old female patient who presented with multiple cerebral abscesses and was found on echocardiography to have a mass along the inferior wall of the left ventricle. She underwent surgical resection which revealed an Aspergillus vegetation along the left ventricle wall without any involvement of the cardiac valves. An intraoperative photograph was obtained and is presented in this case. The patient was started on antifungal therapy and expired on day 30 of treatment. CONCLUSIONS: Fungal endocarditis is a rare yet lethal disease. It can be difficult to detect and workup should be initiated immediately if there is any clinical suspicion. This is especially true in any patient with predisposing conditions or any patient who presents with undiagnosed, culture-negative fevers or evidence of embolic foci. Once diagnosis is made, early initiation of antifungal therapy coupled with aggressive surgical debridement is required for any significant chance of survival.

Acute Stroke as First Manifestation of Cerebral Aspergillosis.

OBJECTIVES: To describe the neurological manifestations of invasive aspergillosis presenting with a focal neurological deficit compatible with an acute stroke. MATERIALS AND METHODS: Retrospective analysis of a clinical series of patients between 2011 and 2017 with invasive aspergillosis and neurological symptoms compatible with an acute brain stroke. Clinical and epidemiological data, microbiological results, radiological findings, treatment, and course were recorded. RESULTS: Five patients were selected with a mean age of 55.4years. All patients were immunosuppressed. In 4, systemic infection was unknown. In every case, neurology on call was alerted because of acute focal neurological symptoms. None of the patients received revascularization procedures. Galactomannan antigen was positive in all of the patients and culture was positive in 3. Mortality was 100% despite specific antifungal treatment. CONCLUSIONS: Acute stroke can be the first manifestation of disseminated aspergillosis. This form of presentation was frequent in our series and should be suspected in immunocompromised patients with acute neurological deficits.

Chronic Meningitis Investigated via Metagenomic Next-Generation Sequencing.

Importance: Identifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. Objective: To present a case series of patients with diagnostically challenging subacute or chronic meningitis using metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) supported by a statistical framework generated from mNGS of control samples from the environment and from patients who were noninfectious. Design, Setting, and Participants: In this case series, mNGS data obtained from the CSF of 94 patients with noninfectious neuroinflammatory disorders and from 24 water and reagent control samples were used to develop and implement a weighted scoring metric based on z scores at the species and genus levels for both nucleotide and protein alignments to prioritize and rank the mNGS results. Total RNA was extracted for mNGS from the CSF of 7 participants with subacute or chronic meningitis who were recruited between September 2013 and March 2017 as part of a multicenter study of mNGS pathogen discovery among patients with suspected neuroinflammatory conditions. The neurologic infections identified by mNGS in these 7 participants represented a diverse array of pathogens. The patients were referred from the University of California, San Francisco Medical Center (n = 2), Zuckerberg San Francisco General Hospital and Trauma Center (n = 2), Cleveland Clinic (n = 1), University of Washington (n = 1), and Kaiser Permanente (n = 1). A weighted z score was used to filter out environmental contaminants and facilitate efficient data triage and analysis. Main Outcomes and Measures: Pathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results. Results: The 7 participants ranged in age from 10 to 55 years, and 3 (43%) were female. A parasitic worm (Taenia solium, in 2 participants), a virus (HIV-1), and 4 fungi (Cryptococcus neoformans, Aspergillus oryzae, Histoplasma capsulatum, and Candida dubliniensis) were identified among the 7 participants by using mNGS. Evaluating mNGS data with a weighted z score-based scoring algorithm reduced the reported microbial taxa by a mean of 87% (range, 41%-99%) when taxa with a combined score of 0 or less were removed, effectively separating bona fide pathogen sequences from spurious environmental sequences so that, in each case, the causative pathogen was found within the top 2 scoring microbes identified using the algorithm. Conclusions and Relevance: Diverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for 1 year, the first reported case of CNS vasculitis caused by Aspergillus oryzae, and the fourth reported case of C dubliniensis meningitis. Prioritizing metagenomic data with a scoring algorithm greatly clarified data interpretation and highlighted the problem of attributing biological significance to organisms present in control samples used for metagenomic sequencing studies.

Aspergilosis cerebral como causa de lesión cerebral focal asociada SIDA: a propósito de un caso y revisión de la literatura / Focal brain lesion due to cerebral aspergillosis in a patient with AIDS: case report and literature review

Resumen La aspergilosis cerebral es una patología infrecuente, pero de elevada mortalidad en pacientes con SIDA. Es importante considerarla entre los diagnósticos diferenciales ante una lesión expansiva cerebral. Se requiere un alto grado de sospecha para poder realizar un diagnóstico precoz. Se presenta el caso de un paciente con infección por VIH con un cuadro neurológico rápidamente progresivo por Aspergillus sección flavi. Se realiza una revisión de 40 casos publicados de aspergilosis cerebral en pacientes con SIDA.

Cerebral aspergillosis is a rare disease with high mortality rates in AIDS patients. It is important to take this into account in the differential diagnosis of a brain expansive lesion. A high level of suspicion is required to make an early diagnosis. We present a case of an HIV-infected patient with progresive neurological disease caused by Aspergillus flavi. We review 40 previously published cases of central nervous system aspergillosis in patients with AIDS.

Intracranial Aspergillosis in an Immunocompetent Young Woman.

Intracranial aspergillosis (ICA) is very rare in the immunocompetent individuals, usually misdiagnosed as a tumor or an abscess. A high index of clinical suspicion is required in patients who present with focal neurological deficits, headache, or seizures. We report the case of a 25-year-old immunocompetent female, who presented with a 15-month history of headache, seizures, left-sided proptosis and ophthalmoplegia, and right hemiparesis. Recovery from the symptoms and decrease in the lesion size seen on the radiological assessment were achieved through two decompressive craniotomies followed by prolonged combined systemic antifungal therapies. Although the initial neuroimaging suggested a mitotic pathology, the surgical sample confirmed ICA. Now the patient is on single antifungal therapy (Tab. voriconazole, 200 mg twice daily) and doing her daily activities, but with a reduced intelligent quotient. We report a challenging case of ICA where multiple courses of combined antifungal therapies and repeat surgeries paved the way for a good prognosis.

[Focal brain lesion due to cerebral aspergillosis in a patient with AIDS. Case report and literature review]. / Aspergilosis cerebral como causa de lesión cerebral focal asociada SIDA. A propósito de un caso y revisión de la literatura.

Cerebral aspergillosis is a rare disease with high mortality rates in AIDS patients. It is important to take this into account in the differential diagnosis of a brain expansive lesion. A high level of suspicion is required to make an early diagnosis. We present a case of an HIV-infected patient with progresive neurological disease caused by Aspergillus flavi. We review 40 previously published cases of central nervous system aspergillosis in patients with AIDS.

Molecular diagnosis of invasive mycoses of the central nervous system.

INTRODUCTION: In September 2012, the Centers for Disease Control and Prevention (CDC) began investigating an outbreak of fungal meningitis among patients who had received contaminated preservative-free methyl prednisolone acetate injections from the New England Compounding Center in Framingham, Massachusetts. Thousands of patients were potentially exposed to tainted corticosteroids, but establishing the diagnosis of fungal meningitis during the nationwide outbreak was difficult because little was known about the natural history of the disease. Areas covered: The challenges associated with this outbreak highlighted the need for rapid and reliable methodologies to assist in the diagnosis of invasive mycoses of the central nervous system (IMCNS), which may be devastating and difficult to treat. In this paper, we review the causative agents of these potentially-lethal infections, which include cryptococcal meningitis, cerebral aspergillosis, and hematogenous Candida meningoencephalitis. Expert commentary: While microscopy, culture, and histopathologic identification of fungal pathogens remain the gold standard for diagnosis, new platforms and species-specific assays have recently emerged, including lateral flow immunoassays (LFA), matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and multiplex PCR in conjunction with magnetic resonance (MR) to potentially aid in the diagnosis of IMCNS.

Magnetic Resonance Imaging of Cerebral Aspergillosis: Imaging and Pathological Correlations.

Cerebral aspergillosis is associated with a significant morbidity and mortality rate. The imaging data present different patterns and no full consensus exists on typical imaging characteristics of the cerebral lesions. We reviewed MRI findings in 21 patients with cerebral aspergillosis and correlated them to the immune status of the patients and to neuropathological findings when tissue was available. The lesions were characterized by their number, topography, and MRI signal. Dissemination to the brain resulted from direct spread from paranasal sinuses in 8 patients, 6 of them being immunocompetent. Hematogenous dissemination was observed in 13 patients, all were immunosuppressed. In this later group we identified a total of 329 parenchymal abscesses involving the whole brain with a predilection for the corticomedullary junction. More than half the patients had a corpus callosum lesion. Hemorrhagic lesions accounted for 13% and contrast enhancement was observed in 61% of the lesions. Patients with hematogenous dissemination were younger (p = 0.003), had more intracranial lesions (p = 0.0004) and had a higher 12-week mortality rate (p = 0.046) than patients with direct spread from paranasal sinuses. Analysis of 12 aneurysms allowed us to highlight two distinct situations. In case of direct spread from the paranasal sinuses, aneurysms are saccular and located on the proximal artery portions, while the hematogenous dissemination in immunocompromised patients is more frequently associated with distal and fusiform aneurysms. MRI is the exam of choice for cerebral aspergillosis. Number and type of lesions are different according to the mode of dissemination of the infection.

Malignant fungal infection of the cavernous sinus: case report.

Intracranial spread of fungal infection is a life-threatening condition that usually affects immunocompromised patients. Here the authors present a case of biopsy-proven Aspergillus fumigatus infection of the paranasal sinuses in an immunocompetent patient with documented spread to the orbit, cavernous sinus, and petrous apex despite medical antifungal treatment. As a life-saving treatment, cavernous sinus resection with external carotid artery-middle cerebral artery bypass was performed. The authors discuss the literature regarding the intracranial spread of paranasal sinus fungal infections in immunocompetent patients and management strategies.