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 Fungal Infection-Related Stroke: A Descriptive Study of Mold and Yeast-Associated Ischemic Stroke.

OBJECTIVE: Central nervous system (CNS) ischemic events caused by fungal infections are rare, and clinical characteristics of these ischemic events are largely unknown. The objective of this manuscript is to highlight characteristics of fungal-related strokes and describe possible mechanistic differences between CNS mold and yeast infection-related strokes. METHODS: We report a single-center retrospective case series of all adult patients who presented with concurrent CNS fungal infection and stroke between 2010 and 2018. Patients believed to have a stroke etiology due to cardioembolic, atheroembolic, or strokes nontemporally associated with a CNS fungal infection and those with incomplete stroke workups were excluded from analysis. RESULTS: Fourteen patients were identified with ischemic stroke and concurrent CNS fungal infection without other known ischemic stroke etiology. Eight patients had a CNS yeast infection, and 6 had a CNS mold infection. All patients presented with recurrent or progressive stroke symptoms. Six patients were immune-compromised. Four patients admitted to intravenous drug use. All yeast infections were identified by cerebrospinal fluid culture or immunologic studies while all but one of the mold infections required identification by tissue biopsy. Leptomeningeal enhancement was only associated with CNS yeast infections, while basal ganglia stroke was only associated with CNS mold infections. CONCLUSION: Ischemic stroke secondary to CNS fungal infections should be considered in patients with recurrent or progressive cryptogenic stroke, regardless of immune status and cerebrospinal fluid profile. CNS yeast and mold infections have slightly different stroke and laboratory characteristics and should have a distinct diagnostic method. Depending on clinical suspicion, a thorough diagnostic approach including spinal fluid analysis and biopsy should be considered.

Role of microglia in fungal infections of the central nervous system.

Most fungi are capable of disseminating into the central nervous system (CNS) commonly being observed in immunocompromised hosts. Microglia play a critical role in responding to these infections regulating inflammatory processes proficient at controlling CNS colonization by these eukaryotic microorganisms. Nonetheless, it is this inflammatory state that paradoxically yields cerebral mycotic meningoencephalitis and abscess formation. As peripheral macrophages and fungi have been investigated aiding our understanding of peripheral disease, ascertaining the key interactions between fungi and microglia may uncover greater abilities to treat invasive fungal infections of the brain. Here, we present the current knowledge of microglial physiology. Due to the existing literature, we have described to greater extent the opportunistic mycotic interactions with these surveillance cells of the CNS, highlighting the need for greater efforts to study other cerebral fungal infections such as those caused by geographically restricted dimorphic and rare fungi.

Immunomodulation over the course of experimental Arthrographis kalrae infection in mice.

Arthrographis kalrae is occasionally described as an opportunistic human pathogen. This study investigated the immune response to A. kalrae during murine experimental infection (7, 14, 28 and 56 days post infection). The fungal load was higher in the early phase and mice presented with neurological syndrome over the course of the infection. There was a gradual increase in the level of anti-A. kalrae IgG and increased levels of DTH at 14 days. There was decreased IFN-γ (14-56 days) and an increase in IL-4 (7 and 56 days). Decreased levels of cytokines (IFN-γ, IL-4, IL-10 and IL-17) were observed in the brain at 56 days p.i. The results suggest that the immune response during murine A. kalrae infection modulates to the pattern of Th2 response. This study shows for the first time the cytokines and cellular immunomodulation that occur in response to an experimental infection with A. kalrae in mice.

[Dementia in Patients with Central Nervous System Mycosis].

Central nervous system (CNS) mycosis is a potentially life-threatening but treatable neurological emergency. CNS mycoses progress slowly and are sometimes difficult to distinguish from dementia. Though most patients with CNS mycosis have an underlying disease, such as human immunodeficiency virus (HIV) infection, cancer, diabetes mellitus, and/or use of immunosuppressants, cryptococcosis can occur in non-immunosuppressed persons. One of the major difficulties in accurate diagnosis is to detect the pathogen in patients' cerebrospinal fluid (CSF) cultures. Thus, the clinical diagnosis is often made by combining circumstantial evidence, including mononuclear cell-dominant pleocytosis with low glucose and protein elevation in the CSF, as well as positive results from an antigen-based assay and a (1-3)-beta-D-glucan assay using plasma and/or CSF. Polymerase chain reaction (PCR)-based diagnostics, which are not performed as routine examinations and are mostly performed as part of academic research in Japan, are sensitive tools for the early diagnosis of CNS mycosis. Mognetic resonance imaging (MRI) is useful to assess the complications of fungal meningitis, such as abscess, infarction, and hydrocephalus. Clinicians should realize the advantages and disadvantages of these diagnostic tools. Early and accurate diagnosis, including identification of the particular fungal species, enables optimal antifungal treatment that produces good outcomes in patients with CNS mycosis.

Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians.

BACKGROUND: Caspase recruitment domain-containing protein 9 (CARD9) deficiency is an autosomal recessive primary immunodeficiency conferring human susceptibility to invasive fungal disease, including spontaneous central nervous system candidiasis (sCNSc). However, clinical characterization of sCNSc is variable, hindering its recognition. Furthermore, an in-depth understanding of the bases for this susceptibility has remained elusive. OBJECTIVES: We sought to comprehensively characterize sCNSc and to dissect the mechanisms by which a hypomorphic CARD9 mutation causes susceptibility to Candida species. METHODS: We describe the clinical and radiologic findings of sCNSc caused by CARD9 deficiency in a French-Canadian cohort. We performed genetic, cellular, and molecular analyses to further decipher its pathophysiology. RESULTS: In our French-Canadian series (n = 4) sCNSc had onset in adulthood (median, 38 years) and was often misinterpreted radiologically as brain malignancies; 1 patient had additional novel features (eg, endophthalmitis and osteomyelitis). CARD9 deficiency resulted from a hypomorphic p.Y91H mutation and allelic imbalance established in this population through founder effects. We demonstrate a consistent cellular phenotype of impaired GM-CSF responses. The ability of CARD9 to complex with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is intact in our series, arguing against its involvement in susceptibility to fungi. Instead, we show that the p.Y91H mutation impairs the ability of CARD9 to complex with Ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1), leading to impaired activation of nuclear factor κB and extracellular signal-regulated kinase (ERK) in monocytes and subsequent GM-CSF responses. Successful treatment of a second patient with adjunctive GM-CSF bolsters the clinical relevance of these findings. CONCLUSIONS: Hypomorphic CARD9 deficiency caused by p.Y91H results in adult-onset disease with variable penetrance and expressivity. Our findings establish the CARD9/RASGRF1/ERK/GM-CSF axis as critical to the pathophysiology of sCNSc.

Multiple Brain Abscesses Due to Phialemonium in a Renal Transplant Recipient: First Case Report in the Literature.

Fungal brain abscesses are a rare but serious complication in transplant recipients. Phialemonium organisms are rare causes of invasive mold infections. Here, we present the first case of a renal transplant recipient with multiple brain abscesses caused by Phialemonium infection A. A 51-year-old female kidney transplant recipient was admitted with pneumonia of an unknown cause and treated with empiric intravenous antibiotics. Her treatment was uneventful, and she was discharged 1010 days later. After 5 days, she was readmitted with fever, cerebral palsy, and speech disorder. The patient had undergone living-donor renal transplant 7 months earlier. A cranial computed tomography and magnetic resonance imaging were performed for a possible cerebrovascular pathology. The magnetic resonance imaging scan showed multiple brain abscesses located at the left parietal, frontal and occipital lobes; right parietal and occipital lobes; right basal ganglia; and left cerebellum. The patient received meropenem, linezolid, sulfamethoxazole and trimethoprim, and AmBisome for probable pathogenic infection, and immunosuppressive agents dosage was reduced increasingly immunosuppressed. We identified Phialemonium in cerebrospinal fluid culture. The patient received voriconazole 200 mg twice daily. Lesions could not be drained due to lack of capsula formation. The patient died on the 30th day of antifungal therapy. Phialemonium organisms, although a rare cause of fungal infections, are associated with a high mortality rate in immunocompromised patients. To our knowledge, this is the first case report in the literature describing multiple brain abscesses due to Phialemonium in a transplant recipient. Clinicians recipient should be alert about these rare opportunistic fungi in the differential diagnosis of brain abscess, and bronchoscopy and bronchoalveolar lavage are recommended for transplant patients when they are admitted with pneumonia exclude fungal infections.

A zebrafish larval model reveals early tissue-specific innate immune responses to Mucor circinelloides.

Mucormycosis is an emerging fungal infection that is clinically difficult to manage, with increasing incidence and extremely high mortality rates. Individuals with diabetes, suppressed immunity or traumatic injury are at increased risk of developing disease. These individuals often present with defects in phagocytic effector cell function. Research using mammalian models and phagocytic effector cell lines has attempted to decipher the importance of the innate immune system in host defence against mucormycosis. However, these model systems have not been satisfactory for direct analysis of the interaction between innate immune effector cells and infectious sporangiospores in vivo. Here, we report the first real-time in vivo analysis of the early innate immune response to mucormycete infection using a whole-animal zebrafish larval model system. We identified differential host susceptibility, dependent on the site of infection (hindbrain ventricle and swim bladder), as well as differential functions of the two major phagocyte effector cell types in response to viable and non-viable spores. Larval susceptibility to mucormycete spore infection was increased upon immunosuppressant treatment. We showed for the first time that macrophages and neutrophils were readily recruited in vivo to the site of infection in an intact host and that spore phagocytosis can be observed in real-time in vivo. While exploring innate immune effector recruitment dynamics, we discovered the formation of phagocyte clusters in response to fungal spores that potentially play a role in fungal spore dissemination. Spores failed to activate pro-inflammatory gene expression by 6 h post-infection in both infection models. After 24 h, induction of a pro-inflammatory response was observed only in hindbrain ventricle infections. Only a weak pro-inflammatory response was initiated after spore injection into the swim bladder during the same time frame. In the future, the zebrafish larva as a live whole-animal model system will contribute greatly to the study of molecular mechanisms involved in the interaction of the host innate immune system with fungal spores during mucormycosis.

Fungal central nervous system infections: prevalence and diagnosis.

Fungal infections of the central nervous system (CNS) are rare but they pose a significant challenge. Their prevalence spans a wide array of hosts including immunosuppressed and immunocompetent individuals, patients undergoing neurosurgical procedures and those carrying implantable CNS devices. Cryptococcus neoformans and Aspergillus spp. remain the most common pathogens. Magnetic resonance imaging can help localize the lesions, but diagnosis is challenging since invasive procedures may be needed for the retrieval of tissue, especially in cases of fungal abscesses. Antigen and antibody tests are available and approved for use in the cerebrospinal fluid (CSF). PCR-based techniques are promising but they are not validated for use in the CSF. This review provides an overview on the differential diagnosis of the fungal CNS disease based on the host and the clinical syndrome and suggests the optimal use of diagnostic techniques. It also summarizes the emergence of Cryptococcus gatti and an unanticipated outbreak caused by Exserohilum rostratum.

[Fungal infections of the central nervous system in the immunocompetent host]. / Pilzinfektionen des Zentralnervensystems bei immunkompetentem Wirt.

The majority of mycoses which lead to mycotic tumors in patients without any predisposing underlying disease are either caused by Cryptococcus gattii and C. neoformans or by dematiaceous fungi which include Cladophialophora bantiana, Ramichloridium mackenziei, Exophiala and Fonsecaea species. The detection of hyphae in granuloma in the brain should lead to screening for pigmented fungi, which are recognized best in hematoxylin eosin (HE) or sometimes also in periodic acid-Schiff (PAS) stained sections. In patients who survive a near drowning accident and those who develop brain abscesses, scedosporiosis should always be considered as a possible infection.

Traffic of leukocytes and cytokine up-regulation in the central nervous system in a murine model of neuroparacoccidioidomycosis.

BACKGROUND: Paracoccidioidomycosis is the most important systemic mycosis in South America. In the last decades, it was observed that central nervous system involvement is frequent, occurring in 12.5 % of the cases. The aim of this study was to report the early inflammatory changes associated with an experimental model of neuroparacoccidioidomycosis (NPCM). METHODS: C57BL/6 mice were infected by intracranial route with 10(6) yeast cells of PB18 strain of Paracoccidioides brasiliensis. Leukocyte-endothelium interactions were assessed by intravital microscopy 1, 2, 4, and 8 weeks post-infection (p.i.). Chemokine/cytokine levels in the brain and histopathological changes were assessed 4 and 8 weeks p.i.. RESULTS: Intravital microscopy analysis revealed a progressive increase in leukocyte recruitment in the vessels of pia mater with a peak 4 weeks p.i. The chemokine CXCL9 was increased at 4 and 8 weeks p.i., while CCL2, CCL3, and CCL5 were increased at 8 weeks p.i. Histopathological analysis revealed the infiltration of inflammatory cells and the development of progressive granulomatous meningoencephalitis. CCL3 levels correlated with clinical manifestations of disease, as measured by the SHIRPA battery. CONCLUSIONS: The experimental model of NPCM showed increased leukocyte recruitment associated with increased expression of chemokines and nervous tissue inflammation which correlated with clinical manifestations of disease.

[The immunologic factors in cerebrospinal liquor under bacterial, fungous or parasitic neuro-infections: a literature review].

The prognosis of course and outcome of inflectional inflammatory diseases of central nervous system, indicators of inflammatory reaction and immune response in cerebrospinal liquor in patients has been investigated.

Importancia de las imágenes y el diagnóstico etiológico en el paciente inmunocomprometido con afección del sistema nervioso central: Tercera parte / Importance of images and etiological diagnosis in immunocompromised patients with central nervous system involvement: Third part

A twenty four year-old male patient with a history of morbid obesity and acute lymphocytic leukemia diagnosed in 2003, underwent an autologous bone marrow transplantation the same year. He had two relapses of leukemia on 2003 and 2007. On January 2009, he underwent a double cord bone marrow transplantation with myeloablative conditioning and craneospinal radiotherapy. The patient received prophylaxis with aciclovir, cotrimoxazole and fluconazole. The latter was changed afterwards to posaconazole. On day 16 post-transplantation, fever and menin-geal signs appeared. The cerebrospinal fluid exam revealed pleocytosis with polymorphonuclear predominance. Empirical therapy was started with meropenem. Due to neurological impairment, at day 33, a brain magnetic resonance imaging (MRI) was performed, showing multiple hypodense supra and infratentorial nodules with peripheral edema. Biopsy, universal PCR for fungi and a new cerebrospinal fluid analysis were performed and amphotericin B was added showing a favorable response. He was discharged with itraconazole, as the universal PCR of brain tissue revealed Penicillium spp. This is the third report presented in this journal that stresses the importance of early neuroimaging, especially MRI to certify the involvement of the central nervous system in immunocompromised patients.

Paciente de 24 años, sexo masculino, con antecedente de obesidad mórbida que debutó con una leucemia linfática aguda (LLA) en el año 2003. Se le efectuó trasplante (Tx) de precursores hematopoyéticos, autólogo, recayendo el mismo año. En el año 2007 presentó una segunda recaída por lo que se le sometió a Tx doble de cordón como rescate en enero de 2009, con acondicionamiento mieloablativo y radioterapia cráneo-espinal recibiendo profilaxis con aciclovir, cotrimoxazol y fluconazol, el que fuera cambiado posteriormente a posaconazol. El día 16 post trasplante presentó fiebre y signos meníngeos, con LCR que revelaba una pleocitosis de predominio polimorfonuclear. Se inició terapia empírica con meropenem. Debido al deterioro neurológico, en el día 33, se le efectuó una resonancia magnética cerebral (RM) donde se evidenciaron múltiples nódulos hipodensos supra e infratentoriales con edema periférico. Se le realizó biopsia cerebral, cultivos, reacción de polimerasa en cadena (RPC) para hongos, nuevo estudio de LCR completo y se agregó anfotericina B deoxicolato presentando una respuesta favorable. Finalizada la terapia con anfotericina B se dio de alta con itraconazol ya que la RPC de tejido cerebral reveló Penicillium sp. Este es el tercer caso presentado en esta revista en los que enfatizamos la importancia de las neuroimágenes, en especial la RM, realizadas en forma precoz para certificar el compromiso del SNC en pacientes inmunocomprometidos.

Phylogeny and immune evasion: a putative correlation for cerebral Pseudallescheria/Scedosporium infections.

Representatives of the genus Pseudallescheria (anamorph: Scedosporium) are saprobes and the aetiologic agent of invasive mycosis in humans. After dissemination, the central nervous system (CNS) is one of the most affected organs. Prerequisites for the survival of Pseudallescheria/Scedosporium in the host are the ability to acquire nutrients and to evade the immune attack. The cleavage of complement compounds via the secretion of fungal proteases might meet both challenges since proteolytic degradation of proteins can provide nutrients and destroy the complement factors, a fast and effective immune weapon in the CNS. Therefore, we studied the capacity of different Pseudallescheria/Scedosporium species to degrade key elements of the complement cascade in the cerebrospinal fluid and investigated a correlation with the phylogenetic background. The majority of the Pseudallescheria apiosperma isolates tested were demonstrated to efficiently eliminate proteins like complement factors C3 and C1q, thus affecting two main components of a functional complement cascade, presumably by proteolytic degradation, and using them as nutrient source. In contrast, the tested strains of Pseudallescheria boydii have no or only weak capacity to eliminate these complement proteins. We hypothesise that the ability of Pseudallescheria/Scedosporium strains to acquire nutrients and to undermine the complement attack is at least partly phylogenetically determined.