AIDS-associated Talaromyces marneffei central nervous system infection in patients of southwestern China.

BACKGROUND: The clinical and laboratory characteristics of AIDS-associated Talaromyces marneffei infection, a rare but a fatal mycosis disease of the central nervous system, remain unclear. CASE PRESENTATION: Herein, we conducted a retrospective study of ten AIDS patients with cerebrospinal fluid culture-confirmed central nervous system infection caused by Talaromyces marneffei. All 10 patients were promptly treated with antifungal treatment for a prolonged duration and early antiviral therapy (ART). Among them, seven patients were farmers. Nine patients were discharged after full recovery, while one patient died during hospitalization, resulting in a mortality rate of 10%. All patients initially presented symptoms and signs of an increase in intracranial pressure, mainly manifesting as headache, dizziness, vomiting, fever, decreased muscle strength, diplopia or even altered consciousness with seizures in severe patients. Nine patients (90%) showed lateral ventricle dilatation or intracranial infectious lesions on brain CT. Cerebrospinal fluid findings included elevated intracranial pressure, increased leukocyte count, low glucose, low chloride and high cerebrospinal fluid protein. The median CD4+ T count of patients was 104 cells/µL (IQR, 36-224 cells/µL) at the onset of the disease. The CD4+ T cell counts of three patients who eventually died were significantly lower (W = 6.00, p = 0.020) than those of the patients who survived. CONCLUSIONS: The common clinical symptoms of T. marneffei central nervous system infection are associated with high intracranial pressure and intracranial infectious lesions. Earlier recognition and diagnosis and a prolonged course of amphotericin B treatment followed by itraconazole combined with early ART might reduce the mortality rate.

Infectious causes and outcomes in patients presenting with cerebral spinal fluid pleocytosis.

To evaluate the infectious etiologies, clinical features, and outcomes of patients with CNS infections at a tertiary care center. Patients that present with a pleocytosis in the cerebral spinal fluid (CSF), defined as a CSF WBC count > 5 cells/mm3, from July 2015 to June 2016 at a tertiary care hospital were analyzed for this report. Data from patients with confirmed (n = 43) and presumed (n = 51) CNS infections were analyzed. CNS infection was the leading known cause of CSF pleocytosis (n = 43, 18% of all patients with a pleocytosis in the CSF), and HSV-2 was identified as the leading causative pathogen (n = 10) followed by varicella zoster virus (n = 5). Fifty-three percent of patients with a pleocytosis in the CSF did not receive a diagnosis. In the patients that did not receive a diagnosis, CNS infection was presumed to be the cause in 51 patients (21% of patients with CSF pleocytosis). The mean time to diagnosis for patients with confirmed CNS infection was 16 days, but time to diagnosis was highly variable depending on the causative pathogen. There was a significant overlap in CSF parameters and peripheral white blood cell counts in patients diagnosed with a viral, bacterial, or fungal infection. Neuroimaging changes were present in only 44% of CNS infections. The overall mortality was 7% for CNS infections, and 17% of patients with a CNS infection had a severe neurologic deficit at presentation while only 3% had a severe deficit at the last neurologic assessment. This study provides new insights into the infectious causes of disease in a cohort of patients with pleocytosis in the CSF. The study provides new insights into the time to diagnosis and outcomes in patients that present with pleocytosis in the CSF.

Evaluation of a Commercial Multiplex Molecular Panel for Diagnosis of Infectious Meningitis and Encephalitis.

Rapid and accurate laboratory tests are important for the timely diagnosis and treatment of central nervous system infections. The FilmArray meningitis/encephalitis (ME) panel (BioFire Diagnostics, Salt Lake City, UT) is an FDA-cleared, multiplex molecular panel that allows the detection of 14 pathogens (bacterial [n = 6], viral [n = 7], and fungal [n = 1] pathogens) from cerebrospinal fluid (CSF). In this study, we evaluated the performance characteristics of the FilmArray ME panel using clinical, residual CSF samples (n = 291) that tested positive by a routine method(s) (e.g., bacterial culture, individual real-time PCR assay) for a pathogen represented on the ME panel. Of note, a subset (n = 76) of the CSF specimens was collected during the prevaccine era and had been characterized as positive for a bacterial pathogen. The FilmArray ME panel demonstrated an overall percent positive agreement (PPA) of 97.5% (78/80) for bacterial pathogens, 90.1% (145/161) for viruses, and 52% (26/50) for Cryptococcusneoformans/C. gattii Despite the low overall agreement (52%) between the ME panel and antigen testing for detection of C. neoformans/C. gattii, the percent positive agreement of the FilmArray assay for C. neoformans/C. gattii was 92.3% (12/13) when the results were compared directly to the results of routine fungal smear or culture. The FilmArray ME panel offers a rapid (∼60-min), syndrome-based approach for the detection of select meningitis and encephalitis pathogens.

Impact of Infection Status and Cyclosporine on Voriconazole Pharmacokinetics in an Experimental Model of Cerebral Scedosporiosis.

Cerebral Scedosporium infections usually occur in lung transplant recipients as well as in immunocompetent patients in the context of near drowning. Voriconazole is the first-line treatment. The diffusion of voriconazole through the blood-brain barrier in the context of cerebral infection and cyclosporine administration is crucial and remains a matter of debate. To address this issue, the pharmacokinetics of voriconazole was assessed in the plasma, cerebrospinal fluid (CSF), and brain in an experimental model of cerebral scedosporiosis in rats receiving or not receiving cyclosporine. A single dose of voriconazole (30 mg/kg, i.v.) was administered to six groups of rats randomized according to the infection status and the cyclosporine dosing regimen (no cyclosporine, a single dose, or three doses; 15 mg/kg each). Voriconazole concentrations in plasma, CSF, and brain samples were quantified using ultra-performance liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography UV methods and were documented up to 48 hours after administration. Pharmacokinetic parameters were estimated using a noncompartmental approach. Voriconazole pharmacokinetic profiles were similar for plasma, CSF, and brain in all groups studied. The voriconazole Cmax and area under the curve (AUC) (AUC0 ≥ 48 hours) values were significantly higher in plasma than in CSF [CSF/plasma ratio, median (range) = 0.5 (0.39-0.55) for AUC0 ≥ 48 hours and 0.47 (0.35 and 0.75) for Cmax]. Cyclosporine administration was significantly associated with an increase in voriconazole exposure in the plasma, CSF, and brain. In the plasma, but not in the brain, an interaction between the infection and cyclosporine administration reduced the positive impact of cyclosporine on voriconazole exposure. Together, these results emphasize the impact of cyclosporine on brain voriconazole exposure.

Fungal infection in cerebrospinal fluid from some patients with multiple sclerosis.

Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system and spinal cord, leading to axonal demyelination of neurons. Recently, we have found a correlation between fungal infection and MS in peripheral blood of patients. The present work provides evidence of fungal infection in the cerebrospinal fluid (CSF) of some MS patients. Thus, fungal antigens can be demonstrated in CSF, as well as antibodies reacting against several Candida species. Comparison was made between CSF and blood serum for the presence of fungal antigens (proteins) and antibodies against different Candida spp. Analyses of both CSF and serum are complementary and serve to better evaluate for the presence of disseminated fungal infection. In addition, PCR analyses indicate the presence of DNA from different fungal species in CSF, depending on the patient analyzed. Overall, these findings support the notion that fungal infection can be demonstrated in CSF from some MS patients. This may constitute a risk factor in this disease and could also help in understanding the pathogenesis of MS.

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.

Characteristic Cytokine and Chemokine Profiles in Encephalitis of Infectious, Immune-Mediated, and Unknown Aetiology.

BACKGROUND: Encephalitis is parenchymal brain inflammation due to infectious or immune-mediated processes. However, in 15-60% the cause remains unknown. This study aimed to determine if the cytokine/chemokine-mediated host response can distinguish infectious from immune-mediated cases, and whether this may give a clue to aetiology in those of unknown cause. METHODS: We measured 38 mediators in serum and cerebrospinal fluid (CSF) of patients from the Health Protection Agency Encephalitis Study. Of serum from 78 patients, 38 had infectious, 20 immune-mediated, and 20 unknown aetiology. Of CSF from 37 patients, 20 had infectious, nine immune-mediated and eight unknown aetiology. RESULTS: Heat-map analysis of CSF mediator interactions was different for infectious and immune-mediated cases, and that of the unknown aetiology group was similar to the infectious pattern. Higher myeloperoxidase (MPO) concentrations were found in infectious than immune-mediated cases, in serum and CSF (p = 0.01 and p = 0.006). Serum MPO was also higher in unknown than immune-mediated cases (p = 0.03). Multivariate analysis selected serum MPO; classifying 31 (91%) as infectious (p = 0.008) and 17 (85%) as unknown (p = 0.009) as opposed to immune-mediated. CSF data also selected MPO classifying 11 (85%) as infectious as opposed to immune-mediated (p = 0.036). CSF neutrophils were detected in eight (62%) infective and one (14%) immune-mediated cases (p = 0.004); CSF MPO correlated with neutrophils (p<0.0001). CONCLUSIONS: Mediator profiles of infectious aetiology differed from immune-mediated encephalitis; and those of unknown cause were similar to infectious cases, raising the hypothesis of a possible undiagnosed infectious cause. Particularly, neutrophils and MPO merit further investigation.

CSF lactate in diseases of the CNS.

The usefulness of the CSF lactate concentration in the diagnosis of bacterial meningitis was studied in 109 adults and children with a variety of infectious and neurologic diseases. A positive correlation was found between elevated lactate levels and the presence of leukocytes in the CSF. Elevations of the CSF lactate concentration with concomitantly negative Gram's stains and cultures were found in patients with infections at anatomic sites other than the CNS, accidental or neurosurgical head trauma, subarachnoid hemorrhage, and seizures due to alcoholism. When performed routinely on CSF, the positive predictive value was 31%, indicating that a diagnosis other than bacterial meningitis is more likely. We conclude that the CSF lactate concentration does not contribute to the diagnosis in children or adults with suspected meningitis.

Fungal and yeast infections of the central nervous system. A clinical review.

In the past 20 years, there has been a marked increase in the number of reported cases of meningitis and brain abscess due to fungi and yeasts. This increase is due in part to better diagnostic techniques and greater awareness of the possibility of fungal invasion of the nervous system; but the increase can also be attributed to a growing pool of severely compromised hosts, many of whom are undergoing treatment with adrenal glucocorticoids or immunosuppressive agents. The diagnosis and treatment of aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, infections caused by dematiaceous fungi, histoplasmosis, paracoccidioidomycosis, petriellidosis, and sporotrichosis, as well as relatively rare infections of the central nervous system caused by other fungi, are discussed. The efficacy of amphotericin B and 5-fluorocytosine in the treatment of CNS fungal and yeast infections is also evaluated.

Detection of fungi in cerebrospinal fluid.

With the exception of Cryptococcus neoformans, fungi are rarely detected in cerebrospinal fluid obtained from patients having or suspected of having fungal meningitis. A review of the literature reveals that several fungi have been either isolated, observed, or both in cerebrospinal fluid specimens. These fungi include Acremonium species, Aspergillus amstelodami, A. flavus, A. fumigatus, A. oryzae, A. terreus, Blastomyces dermatitidis, Candida albicans, C. tropicalis, C. viswanathii, Coccidioides immitis, Cryptococcus albidus, C. neoformans, Histoplasma capsulatum, Paecilomyces variotii, Paracoccidioides brasiliensis, Pseudallescheria boydii, Schizophyllum species, and Sporothrix schenckii. Laboratory findings for cerebrospinal fluid specimens obtained from such patients and clinical presentations are summarized.

The role of lumbar puncture in the evaluation of dementia: the Durham Veterans Administration/Duke University Study.

The use of lumbar puncture (LP) and cerebrospinal fluid (CSF) analysis in the routine, initial evaluation of patients with dementia continues to be questioned. This is especially true in the investigation of infectious causes of dementia. To explore this question further, the authors performed a retrospective analysis of 672 hospitalized patients specifically evaluated for dementia. LP and CSF analysis were performed on 402 patients (60 per cent); routine bacteriologic, acid-fast, and fungal cultures were also obtained for 333 of these patients. Most patients were white (64 per cent) and male (63 per cent), their mean age being 66 +/- 11 years. Four patients were diagnosed as having meningitis--two with Cryptococcus neoformans, one with apparent Mycobacterium tuberculosis, and one with coagulase-positive Staphylococcus aureus. These patients were characterized by a subacute change in mental status, fever or meningismus, and CSF pleocytosis with abnormal CSF chemistries. None of the patients were found to have newly diagnosed neurosyphilis. The authors conclude that LP and CSF analysis should not be part of the routine evaluation of patients with dementia and should be performed only in the presence of such indications as a subacute duration of dementia, fever, and signs of meningeal irritation.

The role of lumbar puncture in the evaluation of dementia: the University of Pittsburgh Study.

In a retrospective study of 80 patients over 55 years old, the efficacy of lumbar puncture in evaluating elderly demented patients was examined. Despite a cost of $381 per procedure, in addition to cerebrospinal fluid (CSF) evaluation, no diagnosis was made on the basis of the information obtained in any of the patients (53 per cent) who underwent lumbar puncture. The only abnormalities found were 11 cases of nonspecific elevations in CSF protein and one case of abnormal cellularity not related to bacterial infection. An additional 422 cases of dementia from other series were reviewed, and only four patients were found whose diagnosis could have been made by lumbar puncture--one patient had neurosyphilis, and the other three were postencephalitic. In addition, the literature on complications of lumbar puncture was reviewed. There were no serious complications of lumbar puncture in the present study. The authors concluded that although it is low-risk, lumbar puncture cannot currently be recommended for routine use in the evaluation of elderly demented patients, but should be used in evaluating demented patients under 55 years of age, patients with rapid onset or progression of dementia, patients with syphilis serology in suspected cases of viral encephalitis, and patients with signs and symptoms of fungal meningitis.

Cerebrospinal fluid broth culture isolates: their significance for antibiotic treatment.

Enriched broth medium is routinely used as a supplement for agar plate culture of cerebrospinal fluid (CSF). To assess the clinical utility of broth cultures, 151 consecutive CSF bacterial and fungal isolates obtained from 91 patients were retrospectively reviewed for the effect of results on treatment. Treatment decisions associated with individual CSF specimens for which isolates were recovered from thioglycollate broth only were compared with the treatment decisions associated with CSF specimens for which isolates were recovered by agar plate culture. Treatment was defined as initiation of or change in antimicrobial therapy based on the reporting of CSF culture isolates. Thirty-six (24%) of the 151 isolates were recovered in broth only. Three (8%) of these 36 isolates (from 34 patients) resulted in treatment with antimicrobial agents; however, 2 of the 3 treated isolates (Candida tropicalis, Proteus mirabilis) were recovered from a second CSF specimen in agar plate culture within 24 hours. Thus, only a single isolate (3%; Staphylococcus epidermidis) was treated based solely on a positive broth culture result. In contrast, 60 (52%) of the 115 isolates recovered in agar plate culture from 23 (40%) of 57 patients were treated (staphylococci, 28; gram-negative bacilli, 14; Cryptococcus neoformans, 10; Streptococcus pneumoniae, 3; Streptococcus sanguis, 1; other, 4). We conclude that treatment with antimicrobial agents based on isolates recovered from CSF specimens in broth culture alone is infrequent and infer from the data that the use of CSF broth cultures contributes little to treatment decisions.

Use of cerebrospinal fluid lactic acid concentration in the diagnosis of fungal meningitis.

A patient with a several year history of normal pressure hydrocephalus was found to have an infection owing to Cryptococcus neoformans. Cryptococcal infection was not suspected until typical cells were observed in a Wright's stained smear of cerebrospinal fluid (CSF). A review of past medical findings in this patient showed elevated CSF values for lactic acid and protein. This case prompted us to review the use of lactic acid as an indicator of fungal meningitis and compare it to other more commonly used nonspecific indicators of fungal meningitis, notably the concentrations of glucose and protein, and the number of leukocytes in CSF. In our institution, all 10 culturally proven cases of fungal meningitis, for which the lactic acid concentration in the CSF was available, were found to have an elevated lactic acid concentration (range 3.2 to 13.3 mmol per L vs normal range 0.8 to 2.8 mmol per L). No other nonspecific indicator was elevated in all 10 patients. In view of the poor sensitivity of stained smear or wet preparations and cultures, when less than five ml of CSF are used for culture, an elevated lactic acid value in a patient with or without signs of meningitis should raise the suspicion of fungal infection.

Laboratory diagnosis of parasitic and fungal diseases of the central nervous system.

This review is presented to bring attention to those fungal and parasitic organisms that have been associated with central nervous system (CNS) infection and to offer an approach for handling their laboratory diagnosis. Treatment of the cerebrospinal fluid (CSF) to yeild best results on direct smear examination and culture are discussed. Culture procedures and staining methods to be done are given in chart form. Those immunologic tests useful in supporting the diagnosis of fungal or parasitic CNS infections are also included.

The cytopathology of cerebrospinal fluid. I. Nonneoplastic conditions, lymphoma and leukemia.

In this review, the historical background of cerebrospinal fluid (CSF) cytopathology is presented, with particular emphasis on the technical and cytopreparatory advances that have increased the sensitivity and accuracy of this technique. Normal cells, contaminants and nonneoplastic processes, including a broad spectrum of inflammatory conditions, are discussed. The role of central nervous system (CNS) cytopathology in the management of patients with leukemia and lymphoma is presented. This discussion includes the natural history, cytologic presentation and diagnostic pitfalls that are associated with these hematologic diseases.

Cerebrospinal fluid.

A quick and accurate diagnosis of maladies affecting the central nervous system (CNS) is imperative. Procurement and analysis of cerebrospinal fluid (CSF) are paramount in helping the clinician determine a patient's clinical condition. Various staining methods, measurement of white blood cell counts, glucose and protein levels, recognition of xanthochromia, and microbiologic studies are CSF parameters that are collectively important in the ultimate determination by a clinician of the presence or absence of a catastrophic CNS condition. Many of these CNS parameters have significant limitations that should be recognized to minimize under treating patients with catastrophic illness.

[Clinical evaluation of fluconazole].

Clinical evaluation of fluconazole was performed on 12 cases of mycotic infections (7 cases of Candida esophagitis; one each case of cryptococcal meningitis with AIDS, Candida tropicalis fungemia and disseminated cryptococcosis in kidney transplant patient; 2 cases of Candida pneumonia). Satisfactory responses were obtained except 1 case of Candida pneumonia in which clinical efficacy could not be evaluated. Hiccup was noted in 1 case during the fluconazole treatment. No other adverse reaction was observed. When 150 mg and 200 mg of fluconazole were administered orally to a patient with hemodialysis (HD) after HD on separate occasions, concentrations of the drug in serum at 20 hours after ingestion were 5.9 micrograms/ml and 11.6 micrograms/ml, respectively, and in cerebrospinal fluid (CSF) were 3.5 micrograms/ml and 9.2 micrograms/ml, respectively. Two clinical benefits were obtained in our studies. First, it was possible to treat the AIDS-patient as an outpatient with Candida esophagitis using orally administered fluconazole. Second, it was possible to treat the case of cryptococcal meningitis, in which relapse often occurs, to complete the therapy when the cryptococcal antigen in serum and CSF diminished to an undetectable level and to maintain the therapy preventing relapse without severe adverse effects. Ongoing and future clinical trials will define the specific roles of fluconazole more clearly in the treatment of systemic mycosis.

Evaluation of human body fluids for the diagnosis of fungal infections.

Invasive fungal infections are a major cause of morbidity and mortality in immunocompromised patients. Because the etiologic agents of these infections are abundant in nature, their isolation from biopsy material or sterile body fluids is needed to document infection. This review evaluates and discusses different human body fluids used to diagnose fungal infections.

ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients.

As culture-based methods for the diagnosis of invasive fungal diseases (IFD) in leukemia and hematopoietic SCT patients have limited performance, non-culture methods are increasingly being used. The third European Conference on Infections in Leukemia (ECIL-3) meeting aimed at establishing evidence-based recommendations for the use of biological tests in adult patients, based on the grading system of the Infectious Diseases Society of America. The following biomarkers were investigated as screening tests: galactomannan (GM) for invasive aspergillosis (IA); ß-glucan (BG) for invasive candidiasis (IC) and IA; Cryptococcus Ag for cryptococcosis; mannan (Mn) Ag/anti-mannan (A-Mn) Ab for IC, and PCR for IA. Testing for GM, Cryptococcus Ag and BG are included in the revised EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) consensus definitions for IFD. Strong evidence supports the use of GM in serum (A II), and Cryptococcus Ag in serum and cerebrospinal fluid (CSF) (A II). Evidence is moderate for BG detection in serum (B II), and the combined Mn/A-Mn testing in serum for hepatosplenic candidiasis (B III) and candidemia (C II). No recommendations were formulated for the use of PCR owing to a lack of standardization and clinical validation. Clinical utility of these markers for the early management of IFD should be further assessed in prospective randomized interventional studies.