Central Nervous System Candidiasis Research Articles

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

BackgroundCentral 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.MethodsPatients 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.ResultsThirty-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.ConclusionCNSC 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.

AN UNUSUAL PRESENTATION OF CNS CANDIDIASIS

AN UNUSUAL PRESENTATION OF CNS CANDIDIASIS

Central nervous system candidiasis beyond neonates: Lessons from a nationwide study.

Candida is a yeast and is the most common cause of fungal infections worldwide. Candida central nervous system (CNS) infections are rare, severe, and poorly described. We report a retrospective study from January 2005 to December 2018 including patients aged≥28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included (14 men, median age 51 years). Seventeen patients had CNS localization secondary to disseminated candidiasis from blood to CNS (10 with hematologic malignancies [HM], the seven other patients had infective endocarditis [IE]). Seven patients had isolated CNS involvement related to neurosurgery (n=2), CARD9 deficiency (n=2), intravenous drug use (n=1), diabetes mellitus (n=1), or no identified risk factor (n=1).During Candida CNS infections, brain lesions were meningitis abscesses or vascular complications. Cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. Forty-two percent of patients died from infection: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection.

Candidiasis of the Central Nervous System in Neonates and Children with Primary Immunodeficiencies.

Candida infections of the central nervous system (CNS) are a life-threatening complication of invasive infections that most often affect vulnerable groups of patients, including neonates and children with primary immunodeficiency disorders (PID). Here, we review the currently known risk factors for CNS candidiasis, focusing predominantly on the PID caused by biallelic mutations in CARD9. How the CNS is protected itself against fungal invasion is poorly understood. CARD9 promotes neutrophil recruitment and function, and is the only molecule shown to be critical for protection against CNS candidiasis in humans thus far. Fundamental insights into the pathogenesis of CNS candidiasis gained from studying rare CARD9-deficient patients has significant implications for other patients at risk for this disease, such as CARD9-sufficient neonates. These findings will be important for the development of adjunctive immune-based therapies, which are urgently needed to tackle the global burden of invasive fungal diseases.

Candidemia from Genitourinary Tract Infection Complicated by Infection of Central Nervous System and Endophthalmitis in Patient with Newly Diagnosed Diabetes Mellitus Type 2

1. Abstract Infections due to Candida species have been major causes of morbidity and mortality in humans, responsible for a broad spectrum of clinical manifestations. The incidence of invasive candidiasis with deep organ infections increases steadily and is usually associated with immunosuppression and prolonged intensive care. We present a case of a patient with newly diagnosed diabetes type 2 complicated with multiple deep organ candidiasis with central nervous system involvement. 2. Keywords: Central nervous system candidiasis; CNS candidiasis; Diabetes mellitus type 2; Fungal endophthalmitis; Invasive candidiasis

High-Dose Micafungin for Preterm Neonates and Infants with Invasive and Central Nervous System Candidiasis.

High doses of micafungin are advocated in neonates with systemic candidiasis, but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, three of whom had meningitis, were treated for at least 14 days with 8 to 15 mg/kg of body weight/day of intravenous micafungin. Plasma micafungin concentrations (four measurements for each patient) were determined after the third dose, and the cerebrospinal fluid (CSF) micafungin concentrations in three patients were also obtained. Population PK analyses were used to identify the optimal model, and the model was further validated using external data (n = 5). The safety of micafungin was assessed by measurement of the levels of liver and kidney function biomarkers. The mean age and weight at the initiation of treatment were 2.33 months (standard deviation [SD], 1.98 months) and 3.24 kg (SD, 1.61 kg), respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase concentration ratio. The CSF of three patients was sampled, and the observed concentrations were between 0.80 and 1.80 mg/liter. The model-predicted mean micafungin area under the concentration-time curve over 24 h was 336 mg · h/liter (SD, 165 mg · h/liter) with the 10-mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection, but 5 had neurologic impairments. Among the transaminases, alkaline phosphatase measurements were significantly higher posttreatment, with a geometric mean ratio of 1.17 (90% confidence interval, 1.01, 1.37). Furthermore, marked elevations in the gamma-glutamyltransferase (GGT) level were observed in three patients treated with 10- to 15-mg/kg/day doses, and improvement of the GGT level was noted after a dose reduction. Higher weight-based doses of micafungin were generally well tolerated in neonates and infants and achieved pharmacokinetic profiles predictive of an effect.

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

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. We sought to comprehensively characterize sCNSc and to dissect the mechanisms by which a hypomorphic CARD9 mutation causes susceptibility to Candida species. 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. 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. 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.

Efficacy of Caspofungin in a Juvenile Mouse Model of Central Nervous System Candidiasis

Neonatal candidiasis is an increasingly common occurrence causing significant morbidity and mortality and a higher risk of dissemination to the central nervous system (CNS) than that seen with older patients. The current understanding of optimal antifungal therapy in this setting is limited. We have developed a model of disseminated candidiasis with CNS involvement in juvenile mice to assess the efficacy of the echinocandin caspofungin relative to amphotericin B (AmB). Juvenile mice were inoculated intravenously with 5.64 × 10(4) CFU of Candida albicans MY1055. Treatment with caspofungin at 1, 2, 4, and 8 mg/kg of body weight/day, AmB at 1 mg/kg/day, or a vehicle control (VC) was initiated 30 h after infection and continued for 7 days. Pharmacokinetic parameters for caspofungin were also determined. Culture and histology showed evidence of disseminated candidiasis with multifocal encephalitis at the start of antifungal therapy. Survival was 100% in all treated groups, while mortality was 100% in the VC by day 11 after infection. By day 5, all mice in the caspofungin treatment (four doses) groups showed reductions in kidney and brain burden relative to the VC, while AmB treatment reduced kidney burden but gave no reduction of brain fungal burden. Systemic levels of caspofungin were similar in infected and uninfected mice, while brain levels were higher in infected animals. In this juvenile mouse model, caspofungin demonstrated dose-dependent activity, equivalent to or better than that of AmB at 1 mg/kg, against disseminated candidiasis with CNS involvement.

Central nervous system candidiasis in the high-risk neonate

Central nervous system involvement in neonatal candidiasis is not rare, although possibly less frequent than in previous decades. In addition to increasing the potential for neurodevelopmental morbidity, this infection poses major challenges in establishing diagnosis and assuring adequate treatment. In the setting of candidemia or other severe invasive candida disease, suggestive imaging studies or inflammatory changes in cerebrospinal fluid should prompt careful consideration of central nervous system candidiasis even if culture of the fluid is negative. Although delivery of amphotericin to cerebrospinal fluid appears much better in premature infants than in older individuals, the availability of other agents with superior delivery to the central nervous system suggests that strong consideration be given to their use as alternative or adjunct therapy if central nervous system involvement appears likely. Careful surveillance for neurodevelopmental sequelae may permit early detection, timely rehabilitative intervention, and potentially better long-term functional outcomes.

Central nervous system candidiasis in preterm infants: Limited value of biochemical markers for diagnosis

Two rare cases of isolated central nervous system (CNS) candidiasis in preterm infants have been diagnosed in a tertiary neonatal centre over the past 6 years. Despite the life-threatening nature of the disease, biochemical infection markers were not useful for the early identification of localized fungal infection. Because the infection was likely to have been blood borne, we postulated that the initial fungal load was probably low and that the organisms were rapidly eliminated from the circulation after a few had been deposited in the CNS. Hence, the absence of fungaemia or systemic involvement precluded the activation of cytokines and cellular markers. Clinicians should be aware of the limitation of biochemical infection markers so that diagnosis and treatment of fungal infection will not be delayed.

Central nervous system candidiasis in very low-birth-weight premature neonates and infants: US characteristics and histopathologic and MR imaging correlates in five patients.

To analyze the high-resolution (i.e., 5.0- or 7.5-MHz) ultrasonographic (US) imaging characteristics of central nervous system (CNS) candidiasis and their histopathologic and magnetic resonance (MR) imaging correlates in very low-birth-weight (VLBW) premature neonates and infants with systemic candidiasis. The US images obtained in one VLBW neonate (age, 24 days; weight, 846 g) and four VLBW infants (age range, 36-161 days; weight range, 800-1, 360 g) with proved CNS candidiasis complicating systemic candidiasis and the clinical (n = 5), histopathologic (n = 3), and MR imaging (n = 2) correlates were retrospectively reviewed. The cranial US findings consisted of parenchymal abnormalities in four and ventricular lesions in three patients. The most common findings were multiple echogenic, rim-like microabscesses (four patients) scattered in the subcortical, periventricular, and basal ganglial areas. Confluent macroabscess formation, seen as echogenic mass-like lesions with hypoechoic centers in the periventricular regions and/or thalami, was noted on the US images obtained in two patients. The ventricles showed dilatation in two, increased ependymal echogenicity in three, the presence of intraventricular echogenic septa in two, and a lumpy choroid plexus or the presence of debris in two patients. US findings correlated well with MR imaging and autopsy findings. The histopathologic changes in the posterior fossa were well demonstrated on MR images but not demonstrated on 5.0- or 7.5-MHz US images. CNS candidiasis in VLBW neonates and infants has characteristic US features that may help in the early diagnosis of CNS involvement in systemic candidiasis.

CENTRAL NERVOUS SYSTEM CANDIDIASIS IN AN INTENSIVE CARE NURSERY (ICN)

Intravenous Amphotericin B (IV AmB) is standard therapy for systemic candidiasis, but penetrates the central nervous system (CNS) poorly. From 1971-83, 22 infants in this ICN developed systemic candidiasis, defined by clinical signs of sepsis, blood and/or CSF cultures (19) or deep tissue histologic specimens positive for Candida (3), and failure to improve without antifungal therapy. Seven infants (31%) died of this infection. Fourteen of these 22 infants (64%) had culture or autopsy-proven evidence of Candida CNS infection - 10 had positive CSF cultures; 4 had cerebral or intramedullary cord abscesses at autopsy. Six of these 14 infants (43%) with CNS infection died - none of these 6 had received systemic antifungal therapy (culture results unavailable before death in 2 cases, isolate wrongly considered transient or contaminant in 3 cases, negative blood and CSF cultures in 1 case). Among the 8 treated survivors of CNS candidiasis, CSF was sterilized with IV AmB alone in only 2 cases. Four others required the addition of flucytosine (FC) which penetrates the CNS well, after 5,7,11 and 13 days respectively of IV AmB failed to sterilize CSF; one required intraventricular instillation of AmB after an unsuccessful 21 day course of IV AmB; one required FC only for CSF sterilization. These observations suggest that: 1) systemic candidiasis in ICN infants often involves the CNS; 2) blood/CSF cultures positive for Candida should be considered significant, until proven otherwise; 3) IV AmB alone is often inadequate to sterilize infected CSF and changes in medication or route of administration may be necessary.

Candidal infection in the central nervous system

Candida has become the most prevalent cerebral mycosis at autopsy, indicating a significant incidence coupled with inadequate eradication. Of 29 patients with systemic candidiasis, 48 percent (14 of 29) also had central nervous system involvement. Of these patients, however, only 21 percent (three of 14) had antemortem diagnosis, and only one of these three patients remains alive; the two patients with antemortem diagnosis who died had a meningeal form that, although easier to document on the basis of cerebrospinal fluid examination, is now distinctly rarer than other forms of the disease in adults. The lone surviving patient was treated with amphotericin B for endocarditis and mycotic aneurysms of the cerebral vessels. One clue to central nervous system candidal infection was the striking correlation between cardiac and cerebral involvement; 80 percent of patients with myocardial or valve infection also had central nervous system candidiasis. Most forms of immunosuppression represent a risk factor for both the systemic and cerebral mycoses. Neuropathologically, there is a spectrum of disease entities associated with Candida, including two previously unrecognized lesions reported herein: fungus balls of both white and gray matter and mycotic aneurysms secondary to Candida parapsilosis. Other parenchymal presentations include thrombosis, vasculitis, abscess, hemorrhage, and demyelination. For drug therapy such as amphotericin B to be more effective, earlier diagnosis of these parenchymal infections must be sought.

Predisposing factors in systemic and central nervous system candidiasis: Histopathological and cultural observations in the rat

Predisposing factors in systemic and central nervous system candidiasis: Histopathological and cultural observations in the rat

Candida Endocarditis of the Tricuspid Valve

A case of Candida tricuspid endocarditis occurred with widespread systemic involvement, including central nervous system candidiasis. In our patient the development of Candida tricuspid endocarditis appeared to be related to prior damage to the valve and antibiotic therapy.