epiglucan and Mycoses

Understanding the host anti-fungal immunity induced by beta-glucan has been one of the most challenging conundrums in the field of biomedical research. During the last couple of decades, insights on the role of beta-glucan in fungal disease progression, susceptibility, and resistance have been greatly augmented through the utility of various beta-glucan cognate receptor-deficient mouse models. Analysis of dectin-1 knockout mice has clarified the downstream signaling pathways and adaptive effector responses triggered by beta-glucan in anti-fungal immunity. On the other hand, assessment of CR3-deficient mice has elucidated the compelling action of beta-glucans in neutrophil-mediated fungal clearance, and the investigation of EphA2-deficient mice has highlighted its novel involvement in host sensing and defense to oral mucosal fungal infection. Based on these accounts, this review focuses on the recent discoveries made by these gene-targeted mice in beta-glucan research with particular emphasis on the multifaceted aspects of fungal immunity.

Topics: Adaptive Immunity; Animals; beta-Glucans; Disease Models, Animal; Fungi; Gene Deletion; Humans; Immunity; Lectins, C-Type; Macrophage-1 Antigen; Mice; Mice, Knockout; Mycoses; Receptor, EphA2

Fungi are eukaryotic microorganisms that show complex life cycles, including both anamorph and teleomorph stages. Beta-1,3-1,6-glucans (BGs) are major cell wall components in fungi. BGs are also found in a soluble form and are secreted by fungal cells. Studies of fungal BGs extensively expanded from 1960 to 1990 due to their applications in cancer immunotherapy. However, progress in this field slowed down due to the low efficacy of such therapies. In the early 21st century, the discovery of C-type lectin receptors significantly enhanced the molecular understanding of innate immunity. Moreover, pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) were also discovered. Soon, dectin-1 was identified as the PRR of BGs, whereas BGs were established as PAMPs. Then, studies on fungal BGs focused on their participation in the development of deep-seated mycoses and on their role as a source of functional foods. Fungal BGs may have numerous and complex linkages, making it difficult to systematize them even at the primary structure level. Moreover, elucidating the structure of BGs is largely hindered by the multiplicity of genes involved in cell wall biosynthesis, including those for BGs, and by fungal diversity. The present review mainly focused on the characteristics of fungal BGs from the viewpoint of structure and immunological activities.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biomarkers; Cell Wall; Drug Discovery; Functional Food; Fungi; Glucans; Humans; Immunity, Innate; Immunotherapy; Lectins, C-Type; Mice; Mycoses; Pathogen-Associated Molecular Pattern Molecules; Receptors, Pattern Recognition; Structure-Activity Relationship

Echinocandins have been in use for over 15 years, starting with the first approval in 2001. Current trends, such as increasing resistance to fluconazole and shifts toward non-albicans spp. of Candida, suggest a growing role for echinocandins, as reflected by recent (2016) updates to guidelines that recommend echinocandins as first-line treatment for candidaemia. The efficacy, tolerability, and safety of echinocandins and their target site of action (1,3-β-d-glucan synthesis) have prompted research into potential new uses, such as for treatment of biofilm infections, MDR Candida auris and dermatophytes. Moreover, new mycobiome discoveries linking inflammatory bowel disease (IBD; for instance Crohn's disease) to fungi have led to preliminary but encouraging data regarding echinocandin therapy and treatment of IBD. In this article, we will review the available evidence and potential utility of echinocandins and 1,3-β-d-glucan synthesis inhibition in these areas of emerging interest.

Topics: Antifungal Agents; beta-Glucans; Biofilms; Biosynthetic Pathways; Candida; Echinocandins; Mycoses; Proteoglycans

With the high mortality rate associated with invasive fungal infections, methods for timely detection and diagnosis are necessary for appropriate and effective treatment. Testing for 1,3-β-D-glucan, a cell wall component of many medically important fungi, can be a useful adjunct in diagnosing such infections. The Fungitell assay (Associates of Cape Cod, East Falmouth, Massachusetts) is a US Food and Drug Administration-approved laboratory test that quantitatively measures 1,3-β-D-glucan levels and is widely available for clinical use as a relatively noninvasive method to aid in detecting the presence of invasive fungal infections. Numerous studies have evaluated its performance in clinical settings, and results have, overall, been favorable. It is not without its drawbacks, however, and the test must be interpreted and applied with care. Ordering practices are also widely variable among clinicians, and official guidelines have not been readily available. We present the details of this test and aim to propose evidence-based guidance for its use.

Topics: beta-Glucans; Humans; Microbiological Techniques; Mycoses; Sensitivity and Specificity

The serum (1 → 3)-β-D-glucan (BG) assay has been approved for diagnosing invasive fungal diseases (IFDs). However, the performance of (1 → 3)-β-D-glucan assay in bronchoalveolar lavage (BAL) fluid is various among studies. The present study aimed to assess the accuracy of (1 → 3)-β-D-glucan assay in bronchoalveolar lavage fluid for the diagnosis of invasive fungal diseases by means of meta-analysis and systematic review of relevant studies.. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (OR) and a summary receiver-operating characteristic curve of BAL-BG for diagnosing invasive fungal diseases were pooled using meta-analysis. We also performed meta-regression analysis.. A total of 838 patients (138 with proven or probable invasive fungal diseases), included in 6 studies, were analyzed. The pooled sensitivity, specificity, PLR, NLR and diagnostic odds ratio were 0.52 (95%CI, 0.38-0.53), 0.58 (95%CI, 0.55-0.61), 1.34 (95%CI, 1.08-1.66), 0.82 (95% CI, 0.63-1.07) and 1.71 (95%CI, 1.01-2.92) respectively. The area under the summary receiver operating characteristic curve, with 95% confidence intervals was 0.61 (95%CI, 0.67-0.55).. The accuracy of (1 → 3)-β-D-glucan test in bronchoalveolar lavage fluid is marginal, so that the results should not be interpreted alone but can be used as a part of full assessment with clinical features, image findings and other laboratory results for the diagnosis of invasive fungal diseases.

Topics: beta-Glucans; Bronchoalveolar Lavage Fluid; Humans; Invasive Fungal Infections; Mycoses; Predictive Value of Tests; Proteoglycans; Sensitivity and Specificity

The serum 1,3-beta-D-glucan (BDG) test is a pan-fungal serum marker considered to detect the majority of pathogenic fungi, including Aspergillus spp. and Candida spp. For this review we searched for publications dealing with serum BDG levels in patients undergoing renal replacement therapy (RRT). The influence of various different membrane materials used for RRTs in these publications on serum BDG has been reviewed. We found that unmodified cellulose containing membranes increased the serum BDG levels highly, whereas conflicting results have been observed for modified cellulose containing materials. Synthetic materials (e.g. polysuflone) had no influence on serum BDG levels in the majority of the reviewed publications.

Topics: Antigens, Fungal; beta-Glucans; Biomarkers; Cellulose; False Positive Reactions; Female; Humans; Male; Mycoses; Proteoglycans; Renal Dialysis; Reproducibility of Results

Innate recognition of fungi leads to strong adaptive immunity. Investigators are trying to exploit this observation in vaccine development by combining antigens with evolutionarily conserved fungal cell wall carbohydrates to induce protective responses. Best studied is β-1,3-glucan, a glycan that activates complement and is recognized by dectin-1. Administration of antigens in association with β-1,3-glucan, either by direct conjugation or complexed in glucan particles, results in robust humoral and cellular immune responses. While the host has a host of mannose receptors, responses to fungal mannoproteins generally are amplified if cells are cooperatively stimulated with an additional danger signal such as a toll-like receptor agonist. Chitosan, a polycationic homopolymer of glucosamine manufactured by the deacetylation of chitin, is being studied as an adjuvant in DNA and protein-based vaccines. It appears particularly promising in mucosal vaccines. Finally, universal and organism-specific fungal vaccines have been formulated by conjugating fungal cell wall glycans to carrier proteins. A major challenge will be to advance these experimental findings so that at risk patients can be protected.

Topics: Animals; Antigens, Fungal; beta-Glucans; Carbohydrates; Cell Wall; Chitin; Fungal Vaccines; Fungi; Humans; Immunoconjugates; Mannans; Mycoses

The serum 1,3-beta-D-glucan (BG) assay aids in the early diagnosis of invasive fungal diseases (IFDs) and has been approved for their diagnosis. However, reports on the screening performance of BG are scarce. We performed a meta-analysis of data extracted from only prospective cohort studies to evaluate the screening performance of the BG assay in the diagnosis of IFDs. We specifically searched 4 databases (the PubMed, Web of Science, Elsevier, and Cochrane Collaboration databases) according to EORTC-MSG criteria. A total of 1068 patients in 11 studies were analyzed. Deeks' funnel plot asymmetry test suggested a low likelihood of publication bias for the included studies (p = 0.055). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the summary receiver operating characteristic curve, with 95% confidence intervals, were 0.75(0.63,0.84), 0.87(0.81,0.92), 5.85(3.96,8.63), 0.30(0.20,0.45), 19.53(11.16,34.18), and 0.89(0.86,0.91), respectively. The findings of this meta-analysis suggest that the BG assay is a useful screening tool with high sensitivity and specificity for discriminating between patients with and without IFDs. In clinical practice, BG assay results should be evaluated together with clinical and microbiological findings.

Topics: beta-Glucans; Humans; Mycoses; Prospective Studies; Sensitivity and Specificity

Topics: Antigens, Fungal; beta-Glucans; Candidiasis, Invasive; Galactose; Humans; Mannans; Mycoses; Proteoglycans; Pulmonary Aspergillosis; Serologic Tests

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); β-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.

Topics: Antigens, Fungal; beta-Glucans; Biomarkers; Congresses as Topic; European Union; Galactose; Hematopoietic Stem Cell Transplantation; Leukemia; Mannans; Mycoses; Transplantation, Homologous

Despite the availability of newer antifungal drugs, outcomes for patients with invasive fungal infections (IFIs) continue to be poor, in large part due to delayed diagnosis and initiation of appropriate antifungal therapy. Standard histopathologic diagnostic techniques are often untenable in at-risk patients, and culture-based diagnostics typically are too insensitive or nonspecific, or provide results after too long a delay for optimal IFI management. Newer surrogate markers of IFIs with improved sensitivity and specificity are needed to enable earlier diagnosis and, ideally, to provide prognostic information and/or permit therapeutic monitoring. Surrogate assays should also be accessible and easy to implement in the hospital. Several nonculture-based assays of newer surrogates are making their way into the medical setting or are currently under investigation. These new or up-and-coming surrogates include antigens/antibodies (mannan and antimannan antibodies) or fungal metabolites (d-arabinitol) for detection of invasive candidiasis, the Aspergillus cell wall component galactomannan used to detect invasive aspergillosis, or the fungal cell wall component and panfungal marker β-glucan. In addition, progress continues with use of polymerase chain reaction- or other nucleic acid- or molecular-based assays for diagnosis of either specific or generic IFIs, although the various methods must be better standardized before any of these approaches can be more fully implemented into the medical setting. Investigators are also beginning to explore the possibility of combining newer surrogate markers with each other or with more standard diagnostic approaches to improve sensitivity, specificity, and capacity for earlier diagnosis, at a time when fungal burden is still relatively low and more responsive to antifungal therapy.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Agents; beta-Glucans; Biomarkers; Female; Fusariosis; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Meta-Analysis as Topic; Mycoses; Opportunistic Infections; Polymerase Chain Reaction

Invasive fungal infections (IFIs) are life-threatening complications in patients with hemato-oncological malignancies, and early diagnosis is crucial for outcome. The compound 1,3-β-D-glucan (BG), a cell wall component of most fungal species, can be detected in blood during IFI. Four commercial BG antigenemia assays are available (Fungitell, Fungitec-G, Wako, and Maruha). This meta-analysis from the Third European Conference on Infections in Leukemia (ECIL-3) assessed the performance of BG assays for the diagnosis of IFI in hemato-oncological patients.. Studies reporting the performance of BG antigenemia assays for the diagnosis of IFI (European Organization for Research and Treatment of Cancer and Mycoses Study Group criteria) in hemato-oncological patients were identified. The analysis was focused on high-quality cohort studies with exclusion of case-control studies. Meta-analysis was performed by conventional meta-analytical pooling and bivariate analysis.. Six cohort studies were included (1771 adult patients with 414 IFIs of which 215 were proven or probable). Similar performance was observed among the different BG assays. For the cutoff recommended by the manufacturer, the diagnostic performance of the BG assay in proven or probable IFI was better with 2 consecutive positive test results (diagnostic odds ratio for 2 consecutive vs one single positive results, 111.8 [95% confidence interval {CI}, 38.6-324.1] vs 16.3 [95% CI, 6.5-40.8], respectively; heterogeneity index for 2 consecutive vs one single positive results, 0% vs 72.6%, respectively). For 2 consecutive tests, sensitivity and specificity were 49.6% (95% CI, 34.0%-65.3%) and 98.9% (95% CI, 97.4%-99.5%), respectively. Estimated positive and negative predictive values for an IFI prevalence of 10% were 83.5% and 94.6%, respectively.. Different BG assays have similar accuracy for the diagnosis of IFI in hemato-oncological patients. Two consecutive positive antigenemia assays have very high specificity, positive predictive value, and negative predictive value. Because sensitivity is low, the test needs to be combined with clinical, radiological, and microbiological findings.

Topics: beta-Glucans; Hematologic Neoplasms; Humans; Mycoses; Reproducibility of Results; Sensitivity and Specificity

Topics: beta-Glucans; Biomarkers; Contact Tracing; Diagnosis, Differential; Japan; Mycoses; Recurrence; Serologic Tests; Travel

Invasive fungal infections are associated with high morbidity and mortality in critically ill patients due, in part, to diagnostic difficulties in the early stages. Nonculture-based techniques such as (1,3)-β-d-glucan, galactomannan, mannan and antimannan antibodies, Candida albicans germ tube-specific antibodies or fungal DNA are required for earlier diagnosis, prognostic information and monitoring outcome. A decision-tree algorithm based on the combination of nonculture-based techniques is suggested to optimize the diagnosis and evolution of critically ill patients at risk of invasive mycoses. The use of (1,3)-β-d-glucan and blood cultures twice a week is proposed; if positive, treatment initiation is recommended alongside the performance of the nonculture-based microbiological tool depending on suspected mycoses and the availability of techniques.

Topics: Antibodies, Fungal; Aspergillus; beta-Glucans; Candida; Decision Trees; DNA, Fungal; Galactose; Humans; Mannans; Mycoses; Proteoglycans; Serologic Tests

A growing population of immunosuppressed patients has resulted in increasingly frequent diagnoses of invasive fungal infections, including those caused by unusual yeasts. The incidence of non-albicans species of Candida is increasing compared with that of Candida albicans, and several species, such as Candida glabrata and Candida krusei, may be resistant to azole antifungal therapy. Trichosporon species are the second most common cause of fungaemia in patients with haematological malignant disease and are characterised by resistance to amphotericin and echinocandins and poor prognosis. Rhodotorula species belong to the family Cryptococcaceae, and are a cause of catheter-related fungaemia, sepsis, and invasive disease in severely immunosuppressed patients. An increasing number of sporadic cases of invasive fungal infections by non-neoformans cryptococci have been reported in immunocompromised hosts, especially for patients with advanced HIV infection or cancer who are undergoing transplant. Other uncommon yeasts that can cause invasive disease in severely immunosuppressed patients include Geotrichum, Hansenula, Malassezia, and Saccharomyces. Host immune status is a crucial determinant of the type of invasive fungal infection a patient is at risk for. Diagnosis can be challenging and relies heavily on traditional cultures of blood and other sterile sites, although serum (1,3)-β-D-glucan testing might have an adjunctive role. Although rare yeasts are emerging as opportunistic human pathogens, diagnosis remains challenging and treatment suboptimal.

Topics: beta-Glucans; Clinical Laboratory Techniques; Communicable Diseases, Emerging; Fungi; Humans; Immunocompromised Host; Incidence; Mycology; Mycoses; Opportunistic Infections; Proteoglycans

We aimed to assess the accuracy of measuring serum or plasma (1→3)-β-D-glucan (BDG) for the diagnosis of invasive fungal infections (IFIs) by means of a meta-analysis of relevant studies. We searched in bibliographic databases for relevant cohort or case-control studies. We primarily compared BDG between patients with proven or probable IFIs (excluding Pneumocystis jirovecii infections), according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group or similar criteria, and patients without IFIs (excluding healthy individuals as controls). A total of 2979 patients (594 with proven or probable IFIs), included in 16 studies, were analyzed. The pooled sensitivity of BDG was 76.8% (95% confidence interval [CI], 67.1%-84.3%), and the specificity was 85.3% (95% CI, 79.6%-89.7%). The area under the summary receiver operating characteristic curve was 0.89. Marked statistical heterogeneity was noted. BDG has good diagnostic accuracy for distinguishing proven or probable IFIs from no IFIs. It can be useful in clinical practice, if implemented in the proper setting and interpreted after consideration of its limitations.

Topics: beta-Glucans; Biomarkers; Clinical Laboratory Techniques; Humans; Mycoses; Plasma; Proteoglycans; ROC Curve; Sensitivity and Specificity; Serum

New classes of synthetic and semi-synthetic β-glucan inhibitors have recently emerged, providing analogs that, in some cases, have been proven to have a high degree of activity against fungi, offering the prospect of alternatives to the commercially available lipopeptide/echinocandin agents caspofungin, micafungin and anidulafungin.. This review covers applications disclosing compound classes that include synthetic pyridazinone analogs, bicyclic heteroaryl ring compounds, aniline derivates, and semi-synthetic echinocandin and enfumafungin derivatives. MK-3118 is an analog of the natural product enfumafungin that, in particular, shows promise as it has a spectrum of activity comparable with caspofungin but has the advantageous property of oral bioavailability.. The diversity of chemical classes in the present review, which have demonstrable activity against β-glucan and the prospect of oral bioavailability, offers hope that safe and effective antifungal drugs will emerge and be commercialized. Of particular note, the Merck compound MK-3118, with solid evidence of efficacy based on preclinical data, has moved into clinical trials.

Topics: Administration, Oral; Animals; Antifungal Agents; beta-Glucans; Biological Availability; Drug Design; Glycosides; Humans; Mycoses; Patents as Topic; Triterpenes

Dectin-1 is an innate immune pattern recognition receptor (PRR) that, through its ability to bind β-glucans, is involved in the recognition of several pathogenic fungi. Dectin-1 can stimulate a variety of cellular responses via the Syk/CARD9 signalling pathway, including phagocytosis, cytokine production and the respiratory burst. Several advances in our understanding of Dectin-1 immunobiology have been made in recent years, including characterisation of additional signalling pathways and demonstration of its ability to directly induce the development of adaptive immunity. However, the physiological role of many of the functions of this receptor is still unclear. This review aims to provide an update on Dectin-1 and its role within antifungal immune responses, focussing on progress made in the last two years.

Topics: Animals; Aspergillus fumigatus; beta-Glucans; Candida albicans; CARD Signaling Adaptor Proteins; Cytokines; Genotype; Host-Pathogen Interactions; Humans; Immunity, Innate; Intracellular Signaling Peptides and Proteins; Lectins, C-Type; Membrane Proteins; Mice; Mycoses; Nerve Tissue Proteins; Phagocytosis; Protein-Tyrosine Kinases; Reactive Oxygen Species; Signal Transduction; Syk Kinase; T-Lymphocyte Subsets; T-Lymphocytes

The (1→3)-β-D-Glucan (BG) assay has been approved for diagnosing invasive fungal disease (IFD). However, the test performance has been variable. We conducted a meta-analysis to determine the overall accuracy of BG assay for diagnosing IFD.. The sensitivity, specificity, and positive and negative likelihood ratios (PLR and NLR, respectively) of BG for diagnosing IFD were pooled using a bivariate meta-analysis. We also performed subgroup analyses.. Twelve reports, including 15 studies, were included for the analysis (proven and probable IFD vs possible or no IFD). The sensitivity, specificity, PLR and NLR were 0.76 (95% CI, 0.67-0.83), 0.85 (95% CI, 0.73-0.92), 5.05 (95% CI, 2.71-9.43), and 0.28 (95% CI, 0.20-0.39), respectively. Subgroup analyses showed that the BG assay had higher specificities for patients with hematological disorders and a positive BG result with two consecutive samples. The combination of galactomannan and BG increased the specificity value to 0.98 (95% CI, 0.95-0.99) for diagnosing invasive aspergillosis.. Serum BG determination is clinically useful for diagnosing IFD in at-risk patients, especially for hematology patients. The combination of galactomannan and BG was sufficient for diagnosing invasive aspergillosis. Since the BG assay is not absolutely sensitive and specific for IFD, the BG results should be interpreted in parallel with clinical findings.

Topics: Aspergillosis; beta-Glucans; Biomarkers; Candidiasis, Invasive; Galactose; Humans; Likelihood Functions; Linear Models; Mannans; Mycoses; Proteoglycans; ROC Curve; Sensitivity and Specificity

Fungal infections are of great relevance in surgical intensive care and Candida species represent the predominant part of fungal pathogens. Invasive aspergillosis is also relevant especially in patients with chronic pulmonary diseases. It is crucial for therapy success to begin adequate antifungal treatment at an early stage of the disease. Risk stratification of individual patient symptoms is essential for therapy timing. In case of suspected or proven candida infection, fluconazole is the agent of choice when the patient is clinically stable and no azoles have been administrated in advance and the local epidemiology makes azol resistance unlikely. For clinically instable patients with organ dysfunction the echinocandins serve as primary therapy because of their broad spectrum and reasonable safety profile. Due to a relevant proportion of azole resistant Candida species, susceptibility testing should be done routinely. Depending on the species detected de-escalating to an azole is feasible if organ dysfunctions have resolved. An invasive aspergillosis is primarily treated with voriconazole.

Topics: Adjuvants, Immunologic; Antifungal Agents; Azoles; beta-Glucans; Candidiasis; Critical Care; Cryptococcosis; Echinocandins; Galactose; Humans; Mannans; Mucus; Mycoses; Polyenes; Reverse Transcriptase Polymerase Chain Reaction; Risk Assessment; Tomography, X-Ray Computed

Chitin is an essential part of the carbohydrate skeleton of the fungal cell wall and is a molecule that is not represented in humans and other vertebrates. Complex regulatory mechanisms enable chitin to be positioned at specific sites throughout the cell cycle to maintain the overall strength of the wall and enable rapid, life-saving modifications to be made under cell wall stress conditions. Chitin has also recently emerged as a significant player in the activation and attenuation of immune responses to fungi and other chitin-containing parasites. This review summarises latest advances in the analysis of chitin synthesis regulation in the context of fungal pathogenesis.

Topics: Animals; Antifungal Agents; beta-Glucans; Cell Wall; Chitin; Drug Design; Fungi; Gene Expression Regulation, Fungal; Host-Pathogen Interactions; Humans; Mycoses

The increasing number of patient populations at high risk of opportunistic infections has highlighted the need for the improvement in antifungal treatments. Due to the limited number of currently available antifungal drugs and the concerns for possible prevalence of resistant strains, drugs with a new mechanism of action are most desirable.. Although the cell wall is considered to be one of the ideal targets for antifungal drugs, insufficient information on the enzymes involved in its construction has restricted the discovery of new inhibitors. This review introduces the recent discovery of the inhibitors of β-1,6-glucan, one of the essential components of the yeast cell wall.. The readers will gain the strategy to obtain the β-1,6-glucan synthesis inhibitors, their mechanisms of actions, and antifungal activities in vitro as well as in vivo.. The β-1,6-glucan inhibitors are considered to be promising candidates for new antifungal drugs which could give valuable options in a clinical setting, although their usage may be limited because of their fungistatic action and limited spectrum. Additionally, they can be useful tools in the study on β-1,6-glucan synthesis and the virulence of Candida species.

Topics: Antifungal Agents; beta-Glucans; Cell Wall; Fungi; Humans; Mycoses; Opportunistic Infections

In addition to their in vitro inhibitory and fungicidal effects, modern antifungal agents interact in vivo with host immune functions involved in defense against fungal pathogens. The nature of such interactions is diverse and depends on the drug, the immunological status of the host, and the fungal pathogen. Given the prominent role of the host's immune response in controlling invasive fungal infection, immunomodulation by antifungal drugs may prove to be clinically significant. Elucidation of the immunopharmacology of these drugs may aid in designing therapeutic regimens for specific clinical scenarios associated with defined immunological dysfunction.

Topics: Amphotericin B; Antifungal Agents; Antigens, Fungal; Azoles; beta-Glucans; Cytokines; Drug Combinations; Echinocandins; Humans; Immunity; Immunocompromised Host; Leukocytes; Mycoses; Phosphatidylcholines; Phosphatidylglycerols

The innate recognition of fungal pathogens is mediated by a variety of pattern recognition receptors (PRRs), although much interest has focussed on the Toll-like Receptors (TLR). More recently, however, there is growing appreciation that the non-TLRs have a major role in the control of infection with these organisms. One such molecule is Dectin-1, a C-type lectin-like receptor which induces numerous cellular responses upon recognition of fungal beta-glucans. Here we review our current understanding of the functions of Dectin-1 and the underlying molecular mechanisms, as well as explore the role of this receptor in antifungal immunity.

Topics: Animals; beta-Glucans; Fungi; Humans; Immunity, Innate; Lectins, C-Type; Ligands; Membrane Proteins; Mycoses; Nerve Tissue Proteins; Signal Transduction

The incidence of deep fungal infections has increased in immunocompromised patients. Prompt and reliable diagnosis is crucial for improving the outcome of this life-threatening disease. Non-culture-based diagnostic methods, such as antigen (antibody) detection, are very often used. Detection of 1,3-Beta-D-glucan, a panfungal antigen from fungal cell walls, is one of the new commercially available diagnostic techniques that appear to be useful for patients with suspicion of fungal infection (aspergillosis, candidiasis and infection with rare species). This test can be used directly for early diagnosis of invasive fungal infection or as a tool to identify false positive results of other methods.

Topics: Antigens, Fungal; beta-Glucans; Humans; Immunocompromised Host; Mycoses; Proteoglycans; Sensitivity and Specificity; Serologic Tests

Topics: Antifungal Agents; Aspergillosis; beta-Glucans; Biomarkers; Candidiasis; Galactose; Hematologic Diseases; Humans; Immunocompromised Host; Lung Diseases, Fungal; Mannans; Molecular Diagnostic Techniques; Mycoses

Serologic markers such as fungal antigens and beta-D-glucan are becoming increasingly important for early diagnosis of invasive fungal infections (IFI). Fungal antigens detected with commercially available kits include mannan from Candida spp., galactomannan from Aspergillus spp., and galactoxylomannan from Cryptococcus spp. Measurement of (1,3)-beta-D-glucan in blood may be useful as a preliminary screening tool for IFI, despite the fact that beta-D-glucan can be detected in a number of other fungi. The clinical sensitivity and specificity of serologic assays for diagnosing IFI are somewhat variable. These variations are mainly related to the patient population examined, the test conditions and the frequency of the serologic survey. A large number of cases should be evaluated to clarify the characteristics of the assay kits.

Topics: Antigens, Fungal; beta-Glucans; Biomarkers; Diabetes Complications; Humans; Mannans; Mycoses; Reagent Kits, Diagnostic; Serologic Tests; Sugar Acids

In the last few years, major advances in the treatment of transplant recipients, with hemato-oncological diseases or admitted to the intensive care unit, has been accompanied by an increase in classical fungal infections and by the emergence of uncommon fungal infections. Despite the development of new diagnostic techniques such as galactomannan detection and the availability of new antifungal agents, these opportunistic infections continue to pose a diagnostic challenge, prolong length of hospital stay, and increase costs. In addition, mortality from these infections is high. The present chapter provides a brief review of the epidemiology of these infections, diagnostic advances, and the new antifungal agents that have been developed in the last few years.

Topics: Anidulafungin; Antifungal Agents; Aspergillosis; beta-Glucans; Candidiasis; Clinical Trials as Topic; Critical Care; Diabetes Complications; Disease Susceptibility; Echinocandins; Fungemia; Galactose; Hematologic Diseases; Humans; Immunocompromised Host; Mannans; Meta-Analysis as Topic; Mycoses; Neoplasms; Opportunistic Infections

Management of invasive mold infections in patients with prolonged neutropenia and hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) has been hampered by the difficulty in diagnosing these infections. Definite diagnosis invariably centers on histologic identification of hyphae in tissue or on culture from a sterile body site. Therefore, most practitioners have relied on prophylaxis and empiric therapy. Currently, emphasis is shifting from routine prophylaxis and empiric therapy to screening of patients with neutropenia at high risk so that clinicians can administer appropriate antifungal therapy early, when it can potentially improve patient outcome. Non-culture-based microbiologic tools are at the forefront of this paradigm shift. Commercially available methods to detect fungal antigens and sophisticated techniques to detect fungal DNA may be used as screening tools during the highest risk period. Together with assessment of clinical signs, cultures, and especially CT scanning, these methods are useful for starting antifungal therapy preemptively. While awaiting further evaluation of these tools during the postengraftment period of allogeneic HSCT, mold-active prophylaxis targeting the subgroup of patients with severe acute or chronic GVHD may be justified. However, some critical issues have not yet been adequately addressed, including the generalizability of study results, impact of mucositis and gastrointestinal GVHD on drug bioavailability, need for therapeutic drug monitoring, impact of prophylaxis on the performance of diagnostic assays, and optimal treatment of breakthrough invasive fungal infections.

Topics: Antifungal Agents; Antigens, Fungal; Aspergillosis; beta-Glucans; Enzyme-Linked Immunosorbent Assay; Humans; Immunocompromised Host; Mycoses; Neoplasms; Neutropenia; Proteoglycans; Risk Assessment; Tomography, X-Ray Computed; Triazoles

Measurement of (1-->3)-beta-D-glucan for invasive fungal infection is used practically in Japan. The problem of false positive results due to the frequent occurrence of non-specific reaction in alkaline treatment, chromogenic automated kinetic assay to measure (1-->3)-beta-D-glucan had been recognized in Japan. But this important problem was resolved in July 2005 by improvement made in the pretreatment reagent in a (1-->3)-beta-D-glucan measurement kit. In this manuscript, we describe the process of improvement of this kit and its clinical usefulness.

Topics: beta-Glucans; Biomarkers; Clinical Chemistry Tests; False Positive Reactions; Humans; Mycoses; Predictive Value of Tests; Reagent Kits, Diagnostic; Sensitivity and Specificity

Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandin drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking beta-1,3-d-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two "hot-spot" regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by 1000-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom.

Topics: Amino Acid Substitution; Antifungal Agents; beta-Glucans; Candida albicans; Candidiasis; Drug Resistance, Fungal; Echinocandins; Glucosyltransferases; Humans; Membrane Proteins; Microbial Sensitivity Tests; Mutation; Mycoses; Saccharomyces cerevisiae Proteins

Early diagnosis of fungal infections and the implementation of appropriate treatment represent major issues for clinicians, nowadays. Histopathological demonstration of microorganisms in tissue specimens or growth of fungal agents in culture media is still considered the "gold standard", but obtaining such specimens may be difficult. Several groups have investigated serological assays for cell wall elements unique to fungal organisms in serum or other body fluids to improve diagnostics in patients with haematological malignancies or undergoing haematopoietic stem-cell transplantation. In this review we have concentrated on the currently available assays allowing for detection of highly immunogenic components of fungal cell wall: galactomannan, mannan, and also (1-->3)-beta-D-glucan. Rapid serological tests appear to be useful for screening high-risk haematological patients, since they allow for the early diagnosis of invasive fungal infections, including infections with the most common pathogens such as Aspergillus and Candida. Based on current literature, factors increasing the probability of obtaining false-positive or false-negative results detected by each test were also analysed and tabulated.

Topics: Antigens, Fungal; beta-Glucans; Body Fluids; Galactose; Humans; Mannans; Mycoses; Proteoglycans; Serologic Tests

In the last years, the main advances in the serological diagnosis of mycoses caused by yeasts have occurred in the area of antibody and (1-3)-beta-D-glucan detection. Commercialization of the Candida albicans IFA IgG test and detection of antibodies against recombinant antigens Hwp1 and enolase are the most important contributions to the first area. Detection of (1-3)-beta-D-glucan confirms its usefulness as a good marker for the diagnosis of invasive candidiasis. The most recent studies suggest that combination of two tests to detect antígen, antibodies, (1-3)-beta-D-glucan and DNA will be needed to optimize the diagnosis of systemic yeast infections.

Topics: Antibodies, Fungal; Antigens, Fungal; beta-Glucans; Biomarkers; Candida albicans; Candidiasis; DNA, Fungal; Early Diagnosis; Fungemia; Humans; Mycoses; Proteoglycans; Yeasts

The echinocandins are a new and unique class of antifungal agents that act on the fungal cell wall by way of noncompetitive inhibition of the synthesis of 1,3-beta-glucans. All agents of this class are of parenteral formulation, with no oral preparations available. Caspofungin (Cancidas) was the first approved echinocandin, followed recently by micafungin (Mycamine) and anidulafungin (Eraxis). The precise role of the echinocandins in the antifungal armamentarium is still unfolding. Caspofungin is approved for the treatment of candidal esophagitis and candidemia, salvage therapy of Aspergillus infections and for empirical therapy of febrile neutropenia. Micafungin is likewise approved for candidal esophagitis, in addition to antifungal prophylaxis for hematopoietic stem cell transplant recipients. Anidulafungin is also approved for treatment of candidal esophagitis, as well as therapy of candidemia. There has been anecdotal use of these agents to treat less common fungal pathogens, as well as limited use as a component of combination antifungal therapy. The echinocandins are an important addition to the antifungal armamentarium in the treatment of fungal infections in both immunocompromised patients and those with normal immunity.

Topics: Anidulafungin; Animals; Antifungal Agents; beta-Glucans; Caspofungin; Echinocandins; Fungal Proteins; Humans; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic

Early treatment of invasive mold infections improves the outcome. Therapy is often delayed, however, because available diagnostic tools such as culture, microscopy and conventional radiology lack sensitivity; consequently, empirical initiation of antifungal therapy has been advocated, particularly for patients with prolonged unexplained neutropenic fever.. Much recent progress has been made in the development and evaluation of nonculture-based assays, including the detection of the fungal antigens galactomannan and beta-D-glucan and the detection of fungal DNA by polymerase chain reaction techniques. These new tools should aid the rapid, early diagnosis of invasive fungal disease, especially when used as screening tools in conjunction with sensitive imaging techniques.. The review will consider these recent developments with the purpose of introducing the concept of preemptive antifungal therapy.

Topics: Antifungal Agents; Antigens, Fungal; beta-Glucans; Diagnostic Imaging; DNA, Fungal; Galactose; Humans; Mannans; Mycoses; Proteoglycans

Micafungin is a new drug in the echinocandin class and is currently being investigated in Phase III clinical trials. Like other echinocandins, it inhibits 1,3-beta-D-glucan synthesis, thus achieving fungicidal activity against virtually all Candida spp., including those resistant to fluconazole, and fungistatic activity against Aspergillus spp. Micafungin sodium is available for intravenous administration only. It has a favorable safety and drug-drug interaction profile. Micafungin has been approved by the US FDA for treatment of esophageal candidiasis and for antifungal prophylaxis during the pre-engraftment phase in patients undergoing hematopoietic stem cell transplantation. Considering the competitive pricing as well as the good tolerability and efficacy, at present micafungin seems to be another choice for both of these indications. Current research has proven micafungin sodium to add a rational and effective option to the antifungal armamentarium, especially in esophageal candidiasis refractory to fluconazole treatment, in those intolerant to triazoles or in patients needing concomitant therapy interacting with triazoles. In addition to the current indications, recent uncontrolled clinical trials have demonstrated a marked success in the treatment of candidemia and invasive candidiasis. Results from in vitro studies, animal models, small clinical trials, as well as the obvious comparison with the more established caspofungin, hint at possible future indications such as invasive aspergillosis and empirical antifungal therapy. However, preclinical data on micafungin is inconsistent and published well-designed clinical studies are scarce. More controlled and sufficiently scaled trials are imperative in order to establish micafungin as a reliable and safe option in clinical practice.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus; beta-Glucans; Candida; Candidiasis; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic; Proteoglycans

The recognition of conserved microbial structures is a key aspect of metazoan immunity, and beta-glucans are emerging as a major target for the recognition of fungal pathogens. A number of receptors for these carbohydrates have been identified, which upon recognition, trigger a variety of immune responses. In contrast to many other systems, there is little apparent conservation in these mechanisms between vertebrates and invertebrates. In this review, we will highlight all the known receptors for beta-glucans and will discuss the various immune responses they can initiate, with reference to fungal infection, in both vertebrates and invertebrates.

Topics: Animals; beta-Glucans; Fungi; Hemolymph; Humans; Immunity; Invertebrates; Mycoses; Receptors, Cell Surface; Vertebrates

Topics: beta-Glucans; Biomarkers; Cellulose; Deferoxamine; Glucans; Humans; Membranes, Artificial; Mycoses; Peritoneal Dialysis, Continuous Ambulatory; Reagent Kits, Diagnostic

Topics: Amphotericin B; Antifungal Agents; beta-Glucans; Biomarkers; Disease Progression; Fatal Outcome; Fluconazole; Glucans; Humans; Immunocompromised Host; Male; Middle Aged; Mycoses; Otorhinolaryngologic Diseases; Risk Factors

Early diagnosis and treatment for an immunocompromised patient with a deep-seated mycosis are very important for the prognosis of the patient. Several methods of serodiagnosis for deep-seated mycosis have been developed and are clinically available. Detection of (1,3)-beta-D-glucan from serum samples of a patient can be evaluated with high sensitivity and specificity. Antigens detection test for fungi is another useful method for this serodiagnosis. A novel sandwich ELISA to detect galactomannan has higher sensitivity than the latex agglutination test. The cryptococcus capsular antigen detection technique is also very useful for patients with cryptococcosis. Thus, serodiagnosis for deep-seated mycosis appears to be a useful tool for treatment of immunocompromised patients.

Topics: Antigens, Fungal; beta-Glucans; Biomarkers; Glucans; Humans; Immunocompromised Host; Mycoses; Sensitivity and Specificity; Serologic Tests

The dramatic increase in nosocomial invasive mycoses over the past two decades has led to increased interest in the area of antifungal development. Unfortunately, the infusion of new diagnostic technology into the clinical mycology laboratory has lagged behind. Although newer, automated, continuous-monitoring blood culture systems are as sensitive as the older, manual "gold standard" system, the recovery of fungi from blood, as well as other clinical specimens, remains an insensitive marker for invasive fungal infection. Antigen assays for the rapid diagnosis of invasive fungal infections are in development, and galactomannan and glucan are two such promising antigens. Glucan may be present in the blood of patients with infection secondary to a wide variety of fungal pathogens, including Candida, Aspergillus, Fusarium, Saccharomyces, Trichosporon and Acremonium species. Early data suggest galactomannan may be present in the blood in detectable levels very early in the course of invasive aspergillosis. The galactomannan assay currently undergoing evaluations may actually be positive prior to the clinical suspicion for infection and may be useful in monitoring therapeutic response as well; however, the etiology of false-positive results following cytotoxic chemotherapy still has to be elucidated. PCR assays are also being developed in the research laboratory, however, the PCR assays will require a significant amount of adaptation and validation before they are ready for clinical care. Well-planned studies to evaluate the performance characteristics as well as appropriate clinical and cost-effective application of these new tests are needed.

Topics: Antigens, Fungal; Aspergillosis; beta-Glucans; Biotechnology; Candidiasis; Centrifugation; Culture Media; Enzyme-Linked Immunosorbent Assay; Fungemia; Glucans; Humans; Immunocompromised Host; Mannans; Medical Laboratory Science; Membrane Glycoproteins; Mycoses; Polymerase Chain Reaction

Liver transplantation is one of the transplant fields where invasive mycosis is frequently encountered. The diagnosis of fungal infection in this population is often very difficult due to the fact that the liver itself is a key organ for immune defence for infection and due to immunosuppressive state of the patient. Although the majority of fungal infection is caused by Candida, Aspergillus infection is gradually increasing and mortality following invasive infection, often multifactorial, reaches to 70%. A characteristic feature of the infection in liver transplant recipients is the high incidence of preceding occult infection, often from the pretransplant period. Although the specificity is not satisfactory, peritransplant screening culture for fungi is a good prognostic parameter. Plasma beta-D-glucan is also very useful in the decision for preemptive treatment, although its plasma level is potentially affected by the reticuloendothelial system of the grafted liver. Referring to these parameters, avoidance of excessive antibiotics and/or immunosuppressants, maintenance of graft function, and a high index of suspicion are always necessary.

Topics: beta-Glucans; Biomarkers; Fungi; Glucans; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Transplantation; Mycoses

Invasive deep mycoses following bone marrow and solid-organ transplantation remain a major cause of morbidity and mortality. Species of Candida and Aspergillus account for more than 80% of these mycoses. Because these infections are often difficult to diagnose and treat successfully, antifungal prophylaxis is recommended in high-risk patients. Fluconazole is useful in patients who are at risk of invasive candidiasis, including bone marrow transplants, liver and pancreatic transplants. Although invasive aspergillosis is frequent in patients with bone marrow, lung and heart transplantation, no established methods have been available for its prophylaxis. Recently, efforts to improve the efficiency of diagnostic tests have been directed toward the detection of fungal components or metabolites. The requirements for clinical use (monitoring) are as follows: capability of early diagnosis, quantitative measurement, and easy sampling and simple assay procedure. The detection of plasma (1-3)-beta-D-glucan (BDG), a characteristic cell wall component of almost all fungi, is widely used in Japan. Twenty-seven episodes of fungemia were observed in our hematology ward and all were positive with BDG. Positive results were observed before the documentation of fungemia in 14 patients (51.9%). Although the positive rate of BDG also was 100% in 17 patients with invasive aspergillosis, it rose slightly at an early stage of the disease in 13 patients (76.5%). The determination of plasma BDG appears useful in the monitoring of deep fungal infection, but its usefulness for early diagnosis remains to be determined. The utility of detection of Aspergillus galactomannan by ELISA and fungal DNA by polymerase chain reaction are also discussed.

Topics: Animals; Antifungal Agents; Antigens, Fungal; beta-Glucans; Biomarkers; Galactose; Glucans; Humans; Mannans; Monitoring, Physiologic; Mycoses; Organ Transplantation; Polymerase Chain Reaction; Postoperative Complications

Candidemia is still a major source of high morbidity and mortality in severely disease patients. However, the etiology and risk factor is still unknown.. To evaluate the risk factor of fungal infection in intensive care patients.. 505 patients who stayed in the intensive care unit of the Critical Care Center, Kyorin University more than 10 days between May 1, 1997 to June 31, 1998 were studied. They were divided into 7 groups: 1) trauma (injury severity score<10), 2) burn (burn index<10), 3) cerebro-vascular disease (unconsciousness15), were in a coma, and had severe injury of lung parenchyme with chest AIS 3 or higher. In these serious patients, it is necessary to make a rapid diagnosis and treatment based on the surveillance culture and serological examination of sputum and urine for occult fungal infection.

Topics: Antifungal Agents; beta-Glucans; Biomarkers; Fungi; Glucans; Humans; Immunocompromised Host; Intensive Care Units; Length of Stay; Mycoses; Respiration, Artificial; Risk; Severity of Illness Index

Plasma (1-->3)-beta-D-glucan determination has been developed for the diagnosis of fungemia and deep mycosis to make up for the low yield of blood culture. This method uses Factor G, a coagulation enzyme of the horseshoe crab that is highly sensitive to this glucan. Since (1 -->3)-beta-D-glucan is a characteristic fungal cell-wall constituent which is common to virtually all fungi, the method aims to screen fungal infections as a whole. This is advantageous today when new fungi are appearing one after another as a causative agent of opportunistic deep fungal infections. Plasma (1-->3)-beta-D-glucan concentrations in 60 normal individuals were less than 10pg/ml. With a cutoff value at 20pg/ml, the sensitivity of the test was 90%, and the specificity was 100%. No cases of fungal colonization showed values above the cutoff level. In addition to invasive candidiasis, aspergillosis, and cryptococcosis, trichosporonosis was also found positive with the test. Glucanemia was not associated with primary cryptococcosis, probably because the growth of the organism is checked by the competent immunity in these afebrile patients. Levels of plasma (1-->3)-beta-D-glucan were variable in aspergilloma, indicating that the disease is essentially a colonization, but that (1-->3)-beta-D-glucan may appear in the blood when cavitary walls are invaded, depending on the integrity of local or systemic immunity. In addition to being useful for diagnosis, the test is also helpful in initiating early treatment of deep mycosis with improved survival.

Topics: beta-Glucans; Clinical Trials as Topic; Glucans; Humans; Multicenter Studies as Topic; Mycoses; Sensitivity and Specificity

Fungal infections are increasingly common and, in certain vulnerable patients, can be serious and even life threatening. The fungal cell wall, a structure with no mammalian counterpart, presents an attractive therapeutic target. Inhibitors of the synthesis of one cell-wall component, beta-(1,3)-glucan, are currently under development as antifungal and antipneumocystis agents.

Topics: Antifungal Agents; beta-Glucans; Carbohydrate Sequence; Cell Wall; Chitin; Chitin Synthase; Glucans; Glucosyltransferases; Molecular Sequence Data; Mycoses

The purpose of this study was to evaluate a preemptive approach with serum 1,3-beta-d-glucan (BDG) as a marker for treatment stratification of systemic antifungal (AF) therapy in patients with clinical suspected invasive fungal infections (IFI) at intensive care units (ICU), and the impact of surgical procedures. A total of 66 ICU patients with clinical suspected IFI were included in this retrospective analysis. Serum BDG testing was performed prior to initiation of AF treatment and in addition to routine diagnostic measures. Based on the BDG results the initial clinical decision whether or not to start systemic AF therapy was re-evaluated. Impact of surgical procedures on clinical utility of serum BDG was evaluated in a sub-group of 25 patients who had undergone surgical procedures prior to BDG evaluation. BDG test results led to discontinuation of AF therapy in 13 patients, and initiation of AF therapy in seven patients. In 46 patients the clinical decision was confirmed by BDG. The majority of suspected, probable and proven IFI cases (10/13, 77%) was predicted by the test. BDG testing turned out positive in 9/25 (36%) of patients that had undergone recent surgery and levels correlated with clinical findings. Serum BDG evaluation seems to be a promising tool to guide AF therapy in ICU patients even after recent surgical procedures.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Aspergillus; beta-Glucans; Candida; Female; Humans; Intensive Care Units; Male; Middle Aged; Mycoses; Retrospective Studies; Young Adult

Invasive fungal infection (IFI) related to surgery in elderly patients is often associated with high morbidity and mortality. The aim of the present study was to determine 1,3-β-D-glucan (βDG) levels after gastric cancer surgery in elderly patients and to prospectively evaluate the efficacy of pre-emptive antifungal therapy using βDG as an aid for the early diagnosis of IFI.. In all, 81 patients aged ≥70 years who had undergone gastric cancer surgery between 2009 and 2011 were prospectively enrolled in the study. Patients with plasma βDG levels >11 pg/mL (the cut-off value) were randomly assigned to either receive antifungal treatment or not (n=13 in each group). Postoperative outcomes were assessed using various clinical parameters.. After gastric cancer surgery, plasma βDG levels were ≥11 pg/mL in 26 of 81 elderly patients (32.1%). Of the βDG-positive patients, significantly more had stages III and IV rather than stages I and II disease (44.1% vs 23.4%, respectively; P=0.049). Fever on postoperative day 8 was significantly reduced in the pre-emptive antifungal-treated group than in the control group (36.8°C vs 37.2°C, respectively; P=0.045). However, there were no significant differences in mortality, morbidity, βDG levels, white blood cell count, and C-reactive protein levels between the two groups.. Pre-emptive antifungal treatment based on βDG after gastric surgery in elderly patients may help reduce the incidence of postoperative fever and suppress IFI. However, this needs to be confirmed in a larger prospective randomized, controlled trial.

Topics: Aged; Aged, 80 and over; Antifungal Agents; beta-Glucans; Biomarkers; Early Diagnosis; Female; Gastrectomy; Humans; Male; Mycoses; Neoplasm Staging; Perioperative Care; Postoperative Complications; Prospective Studies; Proteoglycans; Stomach Neoplasms; Treatment Outcome

This study was conducted as a prospective, multicenter trial to evaluate the efficacy and safety of micafungin as an empirical therapy for suspected invasive fungal infections (IFIs), including febrile neutropenia (FN), and to evaluate the usefulness of β-D: -glucan (BG) and Aspergillus galactomannan (GM) antigen in patients with hematologic diseases. A total of 121 patients were enrolled and assessed for safety, and 119 were examined for clinical efficacy. The main underlying diseases were acute myeloid leukemia (38.0%), acute lymphoblastic leukemia (18.2%), and malignant lymphoma (18.2%). The median initial daily dose and duration of micafungin treatment were 150 mg/day and 13 days, respectively. The overall response rate for suspected IFIs (n = 119), based on four composite endpoints, including baseline IFI, breakthrough IFIs (proven and probable), survival, and premature discontinuation, was 79.0%. In addition, the response rate for FN (n = 81), based on these four endpoints as well as defervescence during neutropenia, was 39.5%. Breakthrough IFIs (proven, probable, and possible) occurred in five patients during micafungin treatment. All of these patients were positive for either BG or GM before the breakthrough IFIs. The incidence of adverse events (AEs) associated with micafungin was 10.7% and most were mild. The majority of AEs were liver dysfunction. These results indicate the effectiveness and safety of micafungin as an empirical therapy for suspected IFIs, including FN, and the usefulness of monitoring both BG and GM to detect breakthrough IFIs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Antigens, Bacterial; Aspergillosis; beta-Glucans; Candidiasis, Invasive; Chemical and Drug Induced Liver Injury; Early Diagnosis; Echinocandins; Female; Galactose; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Lymphoma; Male; Mannans; Micafungin; Middle Aged; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult

The limited number of available effective agents necessitates the development of new antifungals. We report that jervine, a jerveratrum-type steroidal alkaloid isolated from Veratrum californicum, has antifungal activity. Phenotypic comparisons of cell wall mutants, K1 killer toxin susceptibility testing, and quantification of cell wall components revealed that β-1,6-glucan biosynthesis was significantly inhibited by jervine. Temperature-sensitive mutants defective in essential genes involved in β-1,6-glucan biosynthesis, including

Topics: Alkaloids; Antifungal Agents; beta-Glucans; Candida; Cell Wall; Fungi; Humans; Mycoses; Plant Extracts; Veratrum

Fungal infection in the lungs can cause fungal infectious diseases. This disease develops rapidly and involves a wide range. Pathogenic fungi are also more serious types of pathogenic bacteria. If it invades deep organs and tissues, it will endanger life, so it needs timely diagnosis.. To investigate the diagnostic value of serum soluble myeloid cell triggering receptor-1 (sTREM-1), procalcitonin (PCT), and 1,3-. In this study, a case-control study was conducted. 50 patients with immune-related pulmonary disease complicated with fungal infection (infection group) diagnosed by sputum culture in our hospital from January 2017 to December 2021 were selected as the control group, and 50 patients with immune-related pulmonary disease without fungal infection were selected as the control group. The levels of sTREM-1, PCT, and 1,3-. The levels of sTREM-1, PCT, and 1,3-. The detection of sTREM-1, PCT, and 1,3-

Topics: beta-Glucans; Biomarkers; C-Reactive Protein; Case-Control Studies; Humans; Immune System Diseases; Lung; Lung Diseases; Mycoses; Myeloid Cells; Procalcitonin; Prospective Studies; Triggering Receptor Expressed on Myeloid Cells-1

Early, accurate diagnosis of invasive fungal disease (IFD) improves clinical outcomes. 1,3-beta-d-glucan (BDG) (Fungitell, Associates of Cape Cod, Inc., Falmouth, MA, USA) detection can improve IFD diagnosis but has been unavailable in Australia.. To assess performance of serum BDG for IFD diagnosis in a high-risk Australian haematology population.. We compared the diagnostic value of weekly screening of serum BDG with screening by Aspergillus polymerase chain reaction and Aspergillus galactomannan in 57 at-risk episodes for the diagnosis of IFD (proven, probable, possible IFD).. IFD episodes were: proven (n = 4); probable (n = 4); possible (n = 18); and no IFD (n = 31). Using two consecutive BDG results of ≥80 pg/mL to call a result 'positive', the sensitivity, specificity, positive predictive value and negative predictive value was 37.5%, 64.5%, 23.1% and 80.7% respectively. For invasive aspergillosis, test performance increased to 50%, 90.3%, 57.1% and 87.5% respectively if any two of serum BDG/Aspergillus polymerase chain reaction/galactomannan yielded a 'positive' result. In proven/probable IFD, five of eight episodes returned a positive BDG result earlier (mean 6.6 days) than other diagnostic tests. False-negative BDG results occurred in three of eight episodes of proven/probable IFD, and false positive in 10 of 31 patients with no IFD. Erratic patterns of BDG values predicted false positive results (P = 0.03). Using serum BDG results, possible IFD were reassigned to either 'no' or 'probable' IFD in 44% cases. Empiric anti-fungal therapy use may have been optimised by BDG monitoring in 38.5% of courses.. The BDG assay can add diagnostic speed and value but was hampered by low sensitivity and positive predictive value in Australian haematology patients.

Topics: Australia; beta-Glucans; Hematology; Humans; Mycoses; Sensitivity and Specificity

Because Japanese cedar pollen (JCP) contains beta-1,3-d-glucan (BG), there is concern that its lingering presence in the atmosphere, especially during its scattering period, may cause false positives in the factor-G-based Limulus amebocyte lysate (LAL) assay used to test for deep mycosis (i.e., G-test). Hence, we examined whether the LAL assay would react positively with substances contained in JCP by using the G-test to measure JCP particles and extracts. BG was purified from the JCP extract on a BG-specific affinity column, and the percentage extractability was measured using three different BG-specific quantitative methods. The G-test detected 0.4 pg BG in a single JCP particle and 10 fg from a single particle in the extract. The percentage extractability of JCP-derived BG was not significantly different among the three quantitative methods. As the JCP particles should technically have been removed during serum separation, they should be less likely to be a direct false-positive factor. However, given that the LAL-assay-positive substances in the JCP extract were not distinguishable by the three BG-specific quantitative methods, we conclude that they may cause the background to rise. Therefore, in Japan false positives arising from JCP contamination should be considered when testing patients for deep mycosis.

Topics: beta-Glucans; Cryptomeria; False Positive Reactions; Hydrogen-Ion Concentration; Lectins, C-Type; Mycoses; Pollen

The prevalence of fungal infection (FI) in developing countries is high, but the diagnosis of FI is still challenging to determine, so it is needed evaluation of biomarkers other than microbiological culture, because the culture has low sensitivity, high cost, not available in every laboratory and needs a long time. The detection of human galactomannan Aspergillus antigen (GAL) and 1,3-beta-D-glucan (BDG) on the fungal cell wall could be the promising biomarkers for fungal infection. Neutropenia, lymphopenia and CD4T cells in the immunocompromised patients are essential factors, but these cell associations with BDG and GAL levels have not been evaluated yet. The study aimed to evaluate GAL and BDG for detecting fungal infection and their association with total leucocyte count, neutrophil, monocyte, lymphocyte and CD4T cells.. A cross-sectional study was conducted among 86 patient with suspected FI. Fungal infection established using EORTC/MSG criteria. Serology test performed using ELISA. Leucocyte cells were measured using a haematology autoanalyser, and CD4T cells were analysed using BD FACSPresto. Statistical analysis obtained using Spearman's correlation coefficient, ROC curve analysis and 2 × 2 contingency table.. Serum Galactomannan and BDG had a significant correlation with CD4T cells and total lymphocyte count (p < 0.05). The cut-off OD GAL >0.3 had sensitivity 54.6%, specificity 87.5% and AUC 0.71; meanwhile, the BDG cut-off >115.78 pg/ mL had sensitivity 71.2%, specificity 52.4% and AUC 0.63 for detecting fungal infection.. The immunocompromised patients can undergo GAL for determining the diagnose of FI. The lower the CD4T cells and total lymphocyte count, the higher the GAL and BDG serum levels.

Topics: Adolescent; Adult; Aged; Antigens, Fungal; Aspergillus; beta-Glucans; Cross-Sectional Studies; Female; Follow-Up Studies; Galactose; Humans; Immunocompromised Host; Male; Mannans; Middle Aged; Mycoses; Prognosis; Young Adult

To overcome the limitations of the

Topics: Aspergillus; beta-Glucans; Biosensing Techniques; Candida; Endotoxins; Humans; Mycoses; Single Molecule Imaging

The presence of (1 → 3)-β-D-glucan in human plasma is a marker for fungal infections. Currently, the Limulus amebocyte lysate (LAL)-based assay is widely used for the quantification of plasma (1 → 3)-β-D-glucan. However, it has limitations in clinical use, such as an unstable supply of natural resources, complicated manufacturing process, and low-throughput of the reagents. Alternative assays exploiting specific antibodies against (1 → 3)-β-D-glucan have been developed to overcome these challenges. However, these methods are associated with low sensitivity and poorly correlate with the data obtained by the LAL-based assay. The aim of this study is to develop a novel enzyme immunoassay that is as sensitive and accurate in determining plasma (1 → 3)-β-D-glucan levels as compared to that obtained with the LAL-based assay. We generated specific monoclonal antibodies against (1 → 3)-β-D-glucan that recognizes four-unit glucose oligomers with (1 → 3)-β-D-linkages, and constructed a sandwich enzyme-linked immunosorbent assay (ELISA) using these antibodies. The newly developed ELISA showed proportional increase in absorbance with the volume of (1 → 3)-β-D-glucan added. The limit of detection of the assay was 4 pg/ml of plasma (1 → 3)-β-D-glucan that was equivalent to the LAL-based assay and the working range was 4-500 pg/ml. The intra-assay coefficient of variation was 2.2-5.4% using three different concentrations of plasma samples. We observed strong correlation (R = 0.941, slope = 0.986) between the measurements obtained by our ELISA and Fungitec G test ES Nissui, a commonly used LAL-based assay, using 26 types of plasma samples. This could be attributed to the epitopes of the antibodies. Both antibodies could inhibit the LAL-based assay, suggesting that the antibodies recognize the identical regions in β-D-glucan, thereby inactivating factor G, an initiation zymogen for coagulation cascade, in the LAL-based assay. Thus, the ELISA developed in this study can detect fungal infections in clinical settings with similar efficiency as the LAL-based assay. This assay is characterized by good performance, stable supply of materials, and simple manufacturing process and is more suitable for the high-throughput diagnosis of fungal infections.

Topics: Antibodies, Monoclonal; Antibody Affinity; Antibody Specificity; beta-Glucans; Biomarkers; Enzyme-Linked Immunosorbent Assay; Epitopes; Humans; Limulus Test; Mycoses; Predictive Value of Tests; Reproducibility of Results

Topics: Aspergillosis; beta-Glucans; Candidiasis; Humans; Mycoses; Plasma; Pneumonia, Pneumocystis; Reagent Kits, Diagnostic; Sensitivity and Specificity; Serologic Tests; Serum

β-(1,3)-d-glucan (BDG) is used to rule out invasive fungal disease (IFD) but its usefulness in cystic fibrosis (CF) has not been evaluated. We measured serum BDG in CF patients with no clinical suspicion of IFD. Samples from 46 adult CF patients during a stable period and during pulmonary exacerbation were tested. The association of BDG with clinical variables was analyzed. Three hundred and three non-CF patients with suspected IFD were used as comparators. Both samples were negative in 52% of CF patients, whereas 67% of comparators had only negative results (P=0.08). CF patients with pancreatic insufficiency and CF-related diabetes had fewer negative results (P<0.05 for both). Negative results were more common in older CF patients (P<0.05). Use of antibiotics, presence of fungi in sputum and CF liver disease did not impact BDG levels. In conclusion, patients with CF experience significant BDG antigenaemia in the absence of IFD.

Topics: Adult; Aged; beta-Glucans; Cystic Fibrosis; Female; Humans; Male; Middle Aged; Mycoses; Serum; Young Adult

This study attempts to describe the immunostimulatory effects of three fungal glucans on innate immunity responses in an in vitro assays using Pacific red snapper leukocytes. First, the yield glucans obtained was higher in Aspergillus niger, follow by Aspergillus ochraceus and Alternaria botrytis (40, 20 and 10%, respectively). Structural characterization of these fungal glucans by proton nuclear magnetic resonance (NMR) indicated structures containing (1-6)-branched (1-3)-β-D-glucan. The immunostimulatory activity of fungal glucans were assessed in head-kidney leukocytes at 24 h using colorimetric assays and molecular gene expression. In addition, the response against bacterial infection using Aeromonas hydrophila was evaluated by flow cytometry with annexin V/propidium iodide. Leukocytes responded positively to fungal glucans where the viability was higher than 80%. Interestingly, A. niger β-glucans enhanced the phagocytic ability and capacity in head-kidney leukocytes. Immunological assays reveled an increased in nitric oxide production, myeloperoxidase, superoxide dismutase and catalase activities, in fish stimulated with A. niger β-glucans. Induction of cytokines (IL-1β, TNF-α, IL-6, IL-8 and IL-12) were more pronounced in A. niger β-glucans leukocytes stimulated compared to other group. Finally, flow cytometry assay showed that A. botrytis and A. niger β-glucans were able to inhibit apoptosis caused by Aeromonas hydrophila in the Pacific red snapper leukocytes indicating an immunostimulant potent response by fungi derived-glucans. These results strongly support the idea that fungal β-glucans can stimulate the immune mechanism in head-kidney leukocytes and that Aspergillus niger β-glucan possess immunostimulatory properties cell increasing viability, and reducing necrotic cell death caused by Aeromonas hydrophila.

Topics: Aeromonas hydrophila; Alternaria; Animals; Apoptosis; Aspergillus niger; Aspergillus ochraceus; beta-Glucans; Cells, Cultured; Cytokines; Fish Diseases; Gram-Negative Bacterial Infections; Head Kidney; Immunity, Innate; Immunization; Inflammation Mediators; Leukocytes; Lymphocyte Activation; Mycoses; Nitric Oxide; Perciformes

Acid nucleic aptamers are RNA or DNA oligonucleotides capable of binding to a target molecule with high affinity and selectivity. These molecules are promising tools in nuclear medicine. Many aptamers have been used as targeting molecule of radiopharmaceuticals in preclinical studies. (1→3)-β-D-glucans are the main structural cell wall components of fungi and some bacteria. In the present study two radiolabeled (1→3)-β-D-glucan aptamers (seq6 and seq30) were evaluated to identity infectious foci caused by fungal or bacterial cells.. Aptamer labeling with. Seq6 and seq30 aptamers proved to be inefficient for diagnosis of C. albicans infection. Nevertheless, their applicability for diagnosis of S. aureus and other bacterial infections by scintigraphy should be further explored.

Topics: Animals; Aptamers, Nucleotide; beta-Glucans; Candida albicans; Disease Models, Animal; Drug Stability; Isotope Labeling; Mice; Mycoses; Proteoglycans; Staphylococcal Infections; Staphylococcus aureus; Technetium; Tissue Distribution

Various fungi have the ability to colonize surfaces and to form biofilms. Fungal biofilm-associated infections are frequently refractory to targeted treatment because of resistance to antifungal drugs. One fungus that frequently colonises the respiratory tract of cystic fibrosis (CF) patients is the opportunistic black yeast-like fungus Exophiala dermatitidis. We investigated the biofilm-forming ability of E. dermatitidis and its susceptibility to various antiinfective agents and natural compounds. We tested 58 E. dermatitidis isolates with a biofilm assay based on crystal violet staining. In addition, we used three isolates to examine the antibiofilm activity of voriconazole, micafungin, colistin, farnesol, and the plant derivatives 1,2,3,4,6-penta-O-galloyl-b-D-glucopyranose (PGG) and epigallocatechin-3-gallate (EGCG) with an XTT reduction assay. We analysed the effect of the agents on cell to surface adhesion, biofilm formation, and the mature biofilm. The biofilms were also investigated by confocal laser scan microscopy. We found that E. dermatitidis builds biofilm in a strain-specific manner. Invasive E. dermatitidis isolates form most biomass in biofilm. The antiinfective agents and the natural compounds exhibited poor antibiofilm activity. The greatest impact of the compounds was detected when they were added prior cell adhesion. These findings suggest that prevention may be more effective than treatment of biofilm-associated E. dermatitidis infections.

Topics: Antifungal Agents; Bacterial Adhesion; beta-Glucans; Biofilms; Catechin; Colistin; Cystic Fibrosis; Echinocandins; Exophiala; Farnesol; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mycoses; Voriconazole

1,3-ß-D-glucan (BDG) is increasingly used to diagnose invasive fungal infections (IFI), although false positive results are a concern. To evaluate the potential interaction of blood products with the BDG assay, human albumin (HA), fresh frozen plasma (FFP), undiluted platelet transfusion (UPT) and packed red blood cells (PRBC) were tested for their BDG content using two different b-D-glucan tests. UPTs tested negative, FFP, PBRC and HA tested positive for BDG. In serial dilution, BDG concentration correlated with blood product concentration. To investigate the clinical impact of blood product transfusions, we measured BDG levels before and after the transfusion in three patients (2 PRBC, 1 HA). In the patients receiving PRBC transfusions, BDG values increased from 13 and 17 pg ml(-1) to 183 and 361 pg ml(-1), the HA transfusion increased the serum level from 42 to 58 pg ml(-1). BDG concentrations measured in blood products can be used to predict false positive BDG results.

Topics: beta-Glucans; Blood Component Transfusion; Blood Platelets; Erythrocytes; False Positive Reactions; Humans; Mycoses; Plasma; Serum Albumin

We herein report a case of Penicillium marneffei infection (PMI) in a Japanese man who was infected with human immunodeficiency virus-1 (HIV-1), who was diagnosed on the basis of a bone marrow culture and who was effectively treated with itraconazole. Our review of the PMI cases reported in Japan suggests that increased serum (1→3)-β-D-glucan levels are a useful diagnostic tool in cases of suspected PMI.

Topics: Aged; AIDS-Related Opportunistic Infections; Antifungal Agents; beta-Glucans; Humans; Itraconazole; Japan; Male; Mycoses; Penicillium

Cerebral spinal fluid from a patient affected by a brain abscess caused by Nocardia abscessus gave a positive result for (1-3)-β-d-glucan (BG) assay, in absence of any fungal infection. This study aimed to assess whether Nocardia spp. show cross-reactivity with BG assay. All Nocardia spp. analyzed provided positive reactions.

Topics: Aged; beta-Glucans; Brain Abscess; Cross Reactions; Diagnosis, Differential; Female; Humans; Mycoses; Nocardia; Nocardia Infections; Proteoglycans

Detection of the fungal cell wall component beta-glucan (BG) in serum is increasingly used to diagnose invasive fungal infections (IFI), but its optimal use in hematology patients with high risk of IFI is not well defined. We retrospectively analyzed the diagnostic accuracy, optimal cut-off level, and potential confounding factors of BG reactivity. The inclusion criteria were: adult patients with hematologic disease who were admitted to the hematology ward during the 2-year study period and who had two or more consecutive BG assays performed. In total, 127 patients were enrolled. Thirteen patients with proven or probable IFI, as defined by the 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria, were identified. Receiver operating characteristic (ROC) curve analysis showed a high overall diagnostic performance (area under the ROC curve = 0.98) and suggested an optimal cut-off level of 158 pg/ml, with a sensitivity and a specificity of 92 % and 96 %, respectively. Multiway analysis of variance indicated that treatment with pegylated asparaginase (p < 0.001), admission to the intensive care unit (ICU; p = 0.0007), and treatment with albumin, plasma, or coagulation factors (p = 0.01) are potential confounding factors of BG reactivity. We propose that a higher cut-off level than that recommended by the manufacturer should be used to monitor adult hematology patients at high risk for IFI. Our results also suggest that elevated BG levels in patients treated with pegylated asparaginase, albumin, plasma, or coagulation factors, or those admitted to the ICU should be interpreted with caution.

Topics: Adolescent; Adult; Aged; beta-Glucans; Data Interpretation, Statistical; Diagnostic Tests, Routine; False Positive Reactions; Female; Hematologic Diseases; Humans; Male; Middle Aged; Mycoses; Retrospective Studies; ROC Curve; Sensitivity and Specificity; Serum; Young Adult

Disseminated Scedosporium prolificans infection occurs mainly in immunocompromised patients. The mortality rate is high, as the fungus is resistant to most antifungal agents. Here, we present the case of a 66-year-old female with acute myeloid leukemia who developed infective endocarditis caused by S. prolificans infection during induction chemotherapy. Her 1,3-β-D-glucan levels were elevated and computed tomography revealed bilateral sinusitis and disseminated small nodular masses within the lungs and spleen; it nonetheless took 6 days to identify S. prolificans by blood culture. The patient died of multi-organ failure despite the combined use of voriconazole and terbinafine. Autopsy revealed numerous mycotic emboli within multiple organs (caused by mitral valve vegetation) and endocarditis (caused by S. prolificans). The geographic distribution of this infection is limited to Australia, the United States, and southern Europe, particularly Spain. The first Japanese case was reported in 2011, and four cases have been reported to date, including this one. Recently, the incidence of S. prolificans-disseminated infection in immunocompromised patients has increased in Japan. Therefore, clinicians should consider S. prolificans infection as a differential diagnosis when immunocompromised patients suffer disseminated infections with elevated 1,3-β-D-glucan levels.

Topics: Aged; Antifungal Agents; beta-Glucans; Endocarditis; Female; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Multiple Organ Failure; Mycoses; Naphthalenes; Proteoglycans; Scedosporium; Terbinafine; Voriconazole

In real life and somewhat contrary to biostatistical textbook knowledge, sensitivity and specificity (and not only predictive values) of diagnostic tests can vary with the underlying prevalence of disease. In meta-analysis of diagnostic studies, accounting for this fact naturally leads to a trivariate expansion of the traditional bivariate logistic regression model with random study effects. In this paper, a new model is proposed using trivariate copulas and beta-binomial marginal distributions for sensitivity, specificity, and prevalence as an expansion of the bivariate model. Two different copulas are used, the trivariate Gaussian copula and a trivariate vine copula based on the bivariate Plackett copula. This model has a closed-form likelihood, so standard software (e.g., SAS PROC NLMIXED) can be used. The results of a simulation study have shown that the copula models perform at least as good but frequently better than the standard model. The methods are illustrated by two examples.

Topics: Algorithms; beta-Glucans; Bias; Binomial Distribution; Computer Simulation; Glucose Tolerance Test; Humans; Meta-Analysis as Topic; Models, Statistical; Mycoses; Prevalence; Proteoglycans; Research Design; Sensitivity and Specificity; Software

Topics: beta-Glucans; Humans; Mycoses

Fungal peritonitis is an uncommon but serious complication of peritoneal dialysis (PD) due to the fact that routine culture to recovered the etiologic agents are time consuming and KOH staining has very low sensitivity. Peritoneal (1→3)-β-D-glucan (BG) or galactomannan (GM), both fungal cell wall components, are candidate biomarkers of fungal peritonitis. Hence, a comparative cross-sectional analysis of peritoneal dialysis fluid (PDF) BG (Fungitell, Cape Cod, MA, USA) and GM (Platelia Aspergillus Ag kits, Bio-rad, France) from all PD patients with and without fungal peritonitis (13 cases, identified by culture), over a 1 year period, was performed. PDF of the fungal peritonitis group showed very high BG (494 ± 19 pg/ml) and high GM (3.41 ± 1.24) similar results were noted in specimens from cases of peritonitis with other causes, especially gram negative bacterial peritonitis. A BG cut-off value at 240 pg/ml and GM at 0.5 showed sensitivity/ specificity at 100%/ 83% and 77%/ 58%, respectively. A concomitantly positive GM reduced the false positive rate of BG from nonfungal peritonitis. In conclusion, BG and GM in peritoneal fluid with provisional cut-off values were applicable as surrogate biomarkers for the diagnosis of fungal peritonitis in PD patients.

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; Biomarkers; Cross-Sectional Studies; Dialysis Solutions; Female; Galactose; Humans; Male; Mannans; Middle Aged; Mycoses; Peritoneal Dialysis; Peritonitis; Pilot Projects; Proteoglycans; Sensitivity and Specificity

The diagnosis of neonatal invasive fungal disease (IFD) is difficult and often delayed. The platelet parameters and (1, 3)-β-D-Glucan (BG) may be useful for diagnosing IFD, but their diagnostic performance are not well characterized in neonates. We studied 63 preterm infants with IFD, 160 preterm infants without sepsis (preterm control), and 41 preterm infants with bacterial sepsis. Platelet parameters at the first day of onset of IFD and at the fourteenth day after antifungal treatment were evaluated. Serum BG was measured. Platelet count (PC), plateletcrit (PCT), and platelet distribution width (PDW) values were significantly lower, and mean platelet volume (MPV) values significantly higher in the IFD versus preterm control infants. PC and PCT values were much lower in infants with IFD versus bacterial sepsis, and there were significant differences in BG value between the two groups. After 14 days of antifungal treatment, significant elevations in PC, PCT, PDW and reductions in MPV levels in IFD group were observed. Receiver operating characteristic (ROC) curves showed that PC and PCT were strong predictors of IFD. The PC and PCT cut-offs for predicting IFD were 119.5 (sensitivity 78%, specificity 95%) and 0.21 (sensitivity 83%, specificity 85%), respectively. There were significant differences in PC and PCT levels between deceased and survived patients. The PC and PCT cut-offs for predicting deceased IFD were 39 (sensitivity 62%, specificity 86%) and 0.04 (sensitivity 50%, specificity 95%), respectively. The sensitivity in diagnosing IFD by a BG cutoff of ≥10 pg/ml was 68.3% and specificity was 75.6%. PC and PCT levels in the BG ≥400 pg/ml group were significantly lower compared to the BG<400 pg/ml group. Platelet parameters and BG could be useful biomarkers for the diagnosis and prognosis of neonatal IFD.

Topics: beta-Glucans; Biomarkers; Blood Platelets; Case-Control Studies; Female; Fluconazole; Humans; Infant, Newborn; Infant, Premature; Male; Mean Platelet Volume; Mycoses; Platelet Count; Prognosis; ROC Curve; Sensitivity and Specificity; Sepsis

While the assessment of β-D-glucan (BDG) levels in adults improves the early diagnosis of invasive fungal disease (IFD), data on BDG levels in children are limited. We therefore assessed in a prospective cohort study the value of serial BDG screening for early detection of IFD in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT). IFD was defined according to the revised European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria, with the necessary modification that BDG was not included as a microbiological criterion. For the analysis, a total of 702 serum samples were obtained in 34 pediatric HSCT recipients. Proven IFD occurred in two patients (fusariosis and Candida sepsis, respectively), and probable invasive aspergillosis was diagnosed in four patients. Analyses including different cutoff values for BDG levels and different definitions of the onset of IFD demonstrated that the BDG assay has a relatively high sensitivity and good negative predictive value, whereas the positive predictive value has major limitations (<30%). Receiver operating characteristic analyses suggested an optimal cutoff between 60 and 70 pg/ml for different definitions of the onset of IFD. Our data show that BDG screening in pediatric HSCT recipients has a low positive predictive value and is therefore of limited usefulness.

Topics: Adolescent; beta-Glucans; Child; Child, Preschool; Diagnostic Tests, Routine; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Mass Screening; Mycoses; Predictive Value of Tests; Prospective Studies; Proteoglycans; ROC Curve; Sensitivity and Specificity; Serum; Transplantation, Homologous

Using 415 residual blood samples subjected to (1→3) -β-D-glucan assay, we studied the correlation of measurement results between Fungitec G Test MKII "Nissui" (Nissui Pharmaceutical Co., Ltd., Tokyo) and its predecessor, Fungitec G Test MK (Seikagaku Corporation, Tokyo), which is now out of production. Their major difference is that MK II uses reagents derived from blood cells of Limulus polyphemus, the American horseshoe crab, whereas MK used those of Tachypleus tridentatus, an Asian horseshoe crab. Passing-Bablok analysis showed a linear regression with nearly one-to-one correspondence (slope=1.065, intercept=-0.287) between the two test kits over the regular range of measurements (4.0 pg/ml -500 pg/ml ). This was also true when data were subdivided and analyzed in the low to medium (≦150 pg/ml ) and in the low range (≦50 pg/ml ). There were several cases, however, that showed a wide discrepancy between the pair of measurements. This discrepancy is believed to be due in part to the difference between Limulus and Tachypleus in their reactivity to β-glucans with diverse side chains. Despite of this, the even distribution on either side of the regression line of those samples that are associated with deep fungal infection and the abrupt disappearance of such samples below 20 pg/ml attest that MK II "Nissui" is an acceptable successor of MK.

Topics: Animals; beta-Glucans; Biomarkers; Horseshoe Crabs; Humans; Japan; Microbiological Techniques; Mycoses; Reagent Kits, Diagnostic; Sensitivity and Specificity; Serologic Tests

To explore the diagnostic value of plasma ( 1, 3 )-β-D-glucan test ( G test ) in diagnosis of invasive fungal infections ( IFI ) and the influence of albumin on G test.. A prospective observational study was conducted. 267 patients admitted to medical intensive care unit ( MICU ) of Dalian Municipal Central Hospital from January 21st, 2012 to October 31st, 2014 were enrolled. According to IFI guideline, the patients were divided into without IFI group ( n = 35 ), possible IFI group ( n = 70 ), hypotheticle IFI group ( n = 145 ) and proven IFI group ( n = 17 ). G test was examined routinely using microbiology kinetic rapid reader MB-80.The different threshold values were calculated on G test. The difference among G tests, fungal culture and clinical diagnosis were compared. The results of G test ahead of and post albumin administration in each group were compared, and the value of G test for diagnosis of IFI during albumin infusion was evaluated.. When the cut-off value was 20 ng/L for IFI diagnosis, higher sensitivity ( 79.8% ), specificity ( 87.9% ), and Youden index ( 67.7% ) were found. The positive rates of G test, fungal culture and clinical diagnosis of IFI were 57.7% ( 154/267 ), 60.7% ( 162/267 ) and 54.3% ( 145/267 ) respectively, without showing significant differences ( all P > 0.05 ). The result of G test ( ng/L ) was not obviously changed after albumin administration compared with that before in without IFI, possible IFI, hypotheticle IFI, and proven IFI groups ( without IFI group: 11.25±2.33 vs. 10.99±1.07, t = -1.723, P = 0.085; possible IFI group: 53.14±5.53 vs. 49.22±8.11, t = -0.395, P = 0.693; hypotheticle IFI group: 90.30±9.38 vs. 85.41±10.11, t = 710.500, P = 0.860; proven IFI group: 100.98±19.24 vs. 103.21±17.66, t = 653.000, P = 0.449 ). Prior to the administration of albumin, sensitivity, specificity, positive predictive value ( PPV ), negative predictive value ( NPV ) and Youden index were 79.8%, 87.9%, 45.6%, 96.7%, 67.7%, respectively. However, after the administration of albumin, they were 81.5%, 85.7%, 44.8%, 96.5%, and 67.2%, respectively, without significant difference.. G test is method for early diagnosis of IFI. The sensitivity and specificity are higher with 20 ng/L as the critical value. The result of G test is not interfered by albumin administration.

Topics: Albumins; beta-Glucans; Early Diagnosis; Humans; Intensive Care Units; Invasive Fungal Infections; Mycoses; Prospective Studies; Proteoglycans; Sensitivity and Specificity

The fungus Saprochaete capitata causes opportunistic human infections, mainly in immunocompromised patients with hematological malignancies. The best therapy for this severe infection is still unknown. We evaluated the in vitro killing activity and the in vivo efficacy of posaconazole at 5, 10, or 20 mg/kg twice a day (BID) in a murine neutropenic model of systemic infection with S. capitata by testing a set of six clinical isolates. Posaconazole showed fungistatic activity against all of the isolates tested. The different doses of the drug, especially the highest one, showed good efficacy, measured by prolonged survival, reduction of (1-3)-β-D-glucan levels in serum, tissue burden reduction, and histopathology.

Topics: Animals; Antifungal Agents; Basidiomycota; beta-Glucans; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Immunocompromised Host; Kidney; Male; Mice, Inbred Strains; Microbial Sensitivity Tests; Mycoses; Neutropenia; Proteoglycans; Triazoles

Recently, a cluster of patients with an intractable allergic fungal cough who were characterized by sensitization to Bjerkandera adusta was reported. In the present study, the role of Toll-like receptors and myeloid differentiation factor 88 (MyD88) in B. adusta-induced lung inflammation was investigated.. Wild-type (WT), TLR2-/-,TLR4-/-, and MyD88-/- BALB/c mice were intratracheally challenged with B. adusta 4 times at 2-week intervals. Lung pathology, bronchoalveolar lavage fluid (BALF) cytological profiles, and inflammatory mediators in BALF were investigated. Bone marrow-derived macrophages (BMDM) from TLR2-/-,TLR4-/-, TLR2/4-/-, TLR7/9-/-,MyD88-/-, and WT C57BL/6J mice were stimulated with B. adusta for 12 h, and inflammatory mediators in the culture medium were measured.. B. adusta caused lung inflammation along with Th2 cytokine [interleukin (IL)-5 and IL-13] and eosinophil-related chemokine [eotaxin and monocyte chemotactic protein (MCP-3)] production, an increase in eosinophils in BALF, and eosinophil infiltration in the airways in WT and TLR4-/- mice. However, Th2 and eosinophil-related responses in TLR2-/- and MyD88-/- mice were low or undetectable. The induction of neutrophils and IL-6, IL-12, IL-17A, and MCP-1 in the BALF of MyD88-/- mice was attenuated compared to that in WT mice. The induction of IL-6, TNF-α, MCP-1, and macrophage inflammatory protein-1α was reduced or undetectable in B. adusta-stimulated BMDM from TLR7/9-/- and MyD88-/- mice compared to WT mice.. These results suggest that TLR2 and the adapter protein MyD88 may play an important role in the induction of eosinophils by B. adusta. However, TLR7/9-MyD88 might be important in the induction of neutrophils and the relevant inflammatory mediators, especially IL-17A.

Topics: Animals; beta-Glucans; Bone Marrow Cells; Bronchoalveolar Lavage Fluid; Cell Count; Cells, Cultured; Coriolaceae; Cytokines; Lipopolysaccharides; Lung; Macrophages; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mycoses; Myeloid Differentiation Factor 88; Pneumonia; Toll-Like Receptors

(1->3)-β-D-glucan (BDG) is a constituent of the fungal cell wall and its blood level is known as a marker of fungal infection including pneumocystis pneumonia (PCP). Meanwhile, peripheral blood neutrophil CD64 expression (CD64) is upregulated in various infections. We analyzed patients with positive BDG (cut off 11.0 pg/mL) and those whose CD64 was measured simultaneously. In patients who visited our hospital from 2005 to 2011, BDG was measured in 3,960 samples. The number of positive samples were 441 obtained from 185 patients. In patients with positive BDG, the initial BDG was 24.3 [16.4-70.5] pg/mL (median [interquartile range]). Positive BDG samples were derived mainly from the department of Rheumatology or that of Allergy and Respirology. Common primary diseases were rheumatoid arthritis (RA) or other connective tissue diseases, followed by malignancy, none (only abnormal chest X-ray) and bronchial asthma. The rates of afebrile patients, patients on immunosuppressive therapy and those with a normal range of white blood cell count were 63.7%, 50.9% and 40.8%, respectively. The main causes of positive BDG were PCP (n = 38, 20.5%) and non-PCP mycosis (n = 48, 25.9%, including 26 cases of aspergillosis). Others (99 patients, 53.6%) had positive BDG of unknown origin and 53 of them ameliorated spontaneously, most of whom could have been examples of pseudo-positive BDG. The number of deceased patients was 57 (30.8%) consisting of 9 PCP, 16 non-PCP mycosis and others. The median initial positive BDG levels in patients with PCP, non-PCP mycosis and others were 49.9, 28.9 and 19.7pg/mL, respectively. The positive rate of CD64 (cut off 2,000 molecules/cell) measured simultaneously with initial positive BDG was 77.8%. In RA patients with PCP, 94.7% of them had positive CD64 and the levels of CD64 were significantly higher than those in RA patients with bacterial pneumonia (median 9,386 vs 4,399 molecules/cell) in that same period. The positive rate of CD64 was lower in patients with positive BDG of unknown origin than those with PCP or non-PCP mycosis, which implies positive CD64 can exclude pseudo-positive BDG. Immunosuppressed patients often exhibit positive BDG. Simultaneous measurement of BDG and CD64, a quick pan-infection marker, assists the decision whether the positive BDG is true or false-positive.

Topics: Adult; Aged; beta-Glucans; Biomarkers; Female; Humans; Male; Middle Aged; Mycoses; Neutrophils; Pneumonia, Pneumocystis; Receptors, IgG

Alzheimer's disease (AD) is characterized by the presence in the brain of amyloid plaques and neurofibrillary tangles that provoke neuronal cell death, vascular dysfunction and inflammatory processes. In the present work, we have analyzed the existence of fungal infection in AD patients. A number of tests have been carried out in blood serum, including the detection of antibodies against several yeast species and fungal proteins, and also the presence of fungal (1,3)-β-glucan. Results from this analysis indicate that there is disseminated fungal infection in the majority of AD patients tested. Of interest, several AD patients contain high levels of fungal polysaccharides in peripheral blood, reflecting that disseminated fungal infection occurs in these patients. Together, these results suggest the presence of disseminated mycoses in blood serum from AD patients. To our knowledge these findings represent the first evidence that fungal infection is detectable in blood samples in AD patients. The possibility that this may represent a risk factor or may contribute to the etiological cause of AD is discussed.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antibodies, Fungal; beta-Glucans; Female; Humans; Male; Mycoses; Prevalence; Proteoglycans

Acremonium is an emerging fungal pathogen causing severe infections. We evaluated the virulence of three clinically relevant species within the genus, i.e., Acremonium kiliense (currently Sarocladium kiliense), Acremonium sclerotigenum-A. egyptiacum complex and Acremonium implicatum in a murine model of disseminated infection. Both immunocompetent and immunosuppresssed mice were infected with two inocula concentrations (2 × 10(6) and 2 × 10(8) conidia/animal) of two strains of each species. Tissue burden, mortality rate, histopathology and levels of (1→3)-β-D-glucan were used as virulence markers. None of the species of Acremonium tested was able to cause infection in immunocompetent mice. Conversely, severe infections were produced in immunocompromised mice, the spleen being the most affected organ. In general, the virulence of the Acremonium species tested was low, S. kiliense being the most virulent species.

Topics: Acremonium; Animal Structures; Animals; beta-Glucans; Colony Count, Microbial; Communicable Diseases, Emerging; Disease Models, Animal; Histocytochemistry; Humans; Male; Mice; Microscopy; Mycoses; Opportunistic Infections; Proteoglycans; Survival Analysis; Virulence

Dectin-1 recognizes β-glucan and plays important roles for the antifungal immunity through the activation of spleen tyrosine kinase (Syk) in dendritic cells or macrophages. Recently, expression of Dectin-1 was also identified in human and mouse mast cells, although its physiological roles were largely unknown. In this report, rat mast cell line RBL-2H3 was analyzed to investigate the molecular mechanism of Dectin-1-mediated activation and responses of mast cells. Treatment of cells with Dectin-1-specific agonist curdlan induced tyrosine phosphorylation of cellular proteins and the interaction of Dectin-1 with the Src homology 2 domain of Syk. These responses depended on tyrosine phosphorylation of the hemi-immunoreceptor tyrosine-based activation motif in the cytoplasmic tail of Dectin-1, whereas they were independent of the γ-subunit of high-affinity IgE receptor. DNA microarray and real-time PCR analyses showed that Dectin-1-mediated signaling stimulated gene expression of transcription factor Nfkbiz and inflammatory cytokines, such as monocyte chemoattractant protein-1, IL-3, IL-4, IL-13, and tumor necrosis factor (TNF)-α. The response was abrogated by pretreatment with Syk inhibitor R406. These results suggest that Syk is critical for Dectin-1-mediated activation of mast cells, although the signaling differs from that triggered by FcϵRI activation. In addition, these gene expressions induced by curdlan stimulation were specifically observed in mast cells, suggesting that Dectin-1-mediated signaling of mast cells offers new insight into the antifungal immunity.

Topics: Animals; Antifungal Agents; beta-Glucans; Cell Line, Tumor; Cytokines; Dendritic Cells; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Immunity, Innate; Intracellular Signaling Peptides and Proteins; Lectins, C-Type; Macrophages; Mast Cells; Mice; Mycoses; Phosphorylation; Protein-Tyrosine Kinases; Rats; Signal Transduction; Syk Kinase; Tyrosine

Dectin-1 functions as a pattern recognition receptor for sensing fungal infection. It has been well-established that Dectin-1 induces innate immune responses through caspase recruitment domain-containing protein 9 (CARD9)-mediated NF-κB activation. In this study, we find that CARD9 is dispensable for NF-κB activation induced by Dectin-1 ligands, such as curdlan or Candida albicans yeast. In contrast, we find that CARD9 regulates H-Ras activation by linking Ras-GRF1 to H-Ras, which mediates Dectin-1-induced extracellular signal-regulated protein kinase (ERK) activation and proinflammatory responses when stimulated by their ligands. Mechanistically, Dectin-1 engagement initiates spleen tyrosine kinase (Syk)-dependent Ras-GRF1 phosphorylation, and the phosphorylated Ras-GRF1 recruits and activates H-Ras through forming a complex with CARD9, which leads to activation of ERK downstream. Finally, we show that inhibiting ERK activation significantly accelerates the death of C. albicans-infected mice, and this inhibitory effect is dependent on CARD9. Together, our studies reveal a molecular mechanism by which Dectin-1 induces H-Ras activation that leads to ERK activation for host innate immune responses against fungal infection.

Topics: Animals; beta-Glucans; Candida albicans; Candidiasis; CARD Signaling Adaptor Proteins; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Fungi; Humans; Immunity, Innate; Lectins, C-Type; Mice; Mice, Knockout; Multiprotein Complexes; Mycoses; NF-kappa B; Protein Binding; ras Proteins; ras-GRF1; Signal Transduction

Concurrent infection may be found in Pneumocystis jirovecii pneumonia (PJP) of non-acquired immunodeficiency syndrome (AIDS) patients, however, its impact on immune dysregulation of PJP in non-AIDS patients remains unknown.. We measured pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-17, monocyte chemoattractant protein-1 (MCP-1) and anti-inflammatory cytokines including IL-10 and transforming growth factor (TGF)-β1 and IL-1 receptor antagonist (IL-1RA) and inflammatory markers including high mobility group box 1, Krebs von den Lungen-6, receptor for advanced glycation end product, advanced glycation end product, surfactant protein D in bronchoalveolar lavage fluid (BALF) and blood in 47 pure PcP and 18 mixed PJP and other pulmonary infections (mixed PJP) in non-AIDS immunocompromised patients and explored their clinical relevance. The burden of Pneumocystis jirovecii in the lung was determined by counting number of clusters of Pneumocystis jirovecii per slide and the concentration of β-D-glucan in BALF. PJP severity was determined by arterial oxygen tension/fraction of inspired oxygen concentration ratio, the need of mechanical ventilation and death.. Compared with pure PJP group, mixed PJP group had significantly higher BALF levels of IL-1β, TNF-α and IL-8 and significantly higher blood levels of IL-8. The BALF ratios of TNF-α/IL-10, IL-8/IL-10, IL-1β/IL-10, TNF-α/TGF-β1, IL-8/TGF-β1, IL-1β/TGF-β1 and IL-1β/IL-1RA were significantly higher in mixed than in pure PJP patients. There was no significant difference in clinical features and outcome between pure and mixed PJP groups, including inflammatory biomarkers and the fungal burden. In pure PJP patients, significantly higher BALF levels of IL-8 and the ratios of IL-8/IL-10, IL-1β/TGF-β1, MCP-1/TGF-β1, MCP-1/IL1RA and IL-8/TGF-β1 were found in the patients requiring mechanical ventilation and in non-survivors.. In summary, concurrent pulmonary infection might enhance immune dysregulation of PJP in non-AIDS immunocompromised patients, but did not affect the outcome as evidenced by morbidity and mortality. Because of limited number of cases studied, further studies with larger populations are needed to verify these issues.

Topics: Adult; Aged; beta-Glucans; Biomarkers; Bronchoalveolar Lavage Fluid; Coinfection; Cytokines; Female; Humans; Immunocompromised Host; Male; Middle Aged; Mycoses; Oxygen; Partial Pressure; Pneumocystis carinii; Pneumonia, Pneumocystis; Respiration, Artificial

Currently, it is important to identify a good biomarker to predict treatment-related complications in patients with transplantation. This study aimed to evaluate the significance of serum hepcidin-25 in predicting invasive fungal disease (IFD) after transplantation.. A total of 57 patients who underwent transplantation were included in this study, and their serum samples were obtained and stored at -80°C for analysis. The serum hepcidin-25 were assayed using enzyme-liked immunosorbent assay (ELISA), and hypersensitive C reactive protein (hsCRP) and 1,3-beta-D glucan were measured using standard laboratory techniques. These indices were monitored weekly, from one week before transplantation to four weeks after transplantation.. The median pretransplant serum hepcidin-25 level was 37.00 ng/mL which was higher than that of healthy volunteers (p < 0.001). Because the higher hepcidin-25 level of the third tertile among the patients was 39.855 ng/mL, we set a cutoff level of 40 ng/mL to divide them into low- and high-hepcidin-25 groups (n = 38 and 19, respectively). The prevalences of the documented infection in the two groups were 2.6% and 26%, respectively (p = 0.019). The high-hepcidin-25 group was monitored after transplantation. The hepcidin-25 level peaked one week after transplantation, followed by gradual decrease. The plasma (1-3)-beta-D-glucan reached the summit two week. The proven of IFD was delayed 10 days on average after hepcidin-25 had arrived summit and 5 days after (1-3)-beta-D-glucan peaked..  The pretransplant serum hepcidin-25 level would be a useful indicator for predicting the risk of infection after transplantation; and the dynamic changes of hepcidin-25 in patients with high-hepcidin-25 group would help to predict IFD after transplantation.

Topics: Adult; Aged; Antimicrobial Cationic Peptides; beta-Glucans; Biomarkers; C-Reactive Protein; Female; Hepcidins; Humans; Male; Middle Aged; Mycoses; Organ Transplantation; Postoperative Complications; Predictive Value of Tests; Young Adult

Invasive fungal infections (IFIs) frequently occur and are associated with high morbidity and mortality in patients with hematologic malignancies (HMs) and hematopoietic stem cell transplant (HSCT) recipients. Early diagnosis of IFI in these patients facilitates prompt institution of therapy and leads to improved clinical outcomes. This article reviews widely used methodologies for diagnosing IFIs in patients with HM and HSCT recipients. Advantages and limitations of radiologic studies; microbiologic and histopathologic techniques; fungal biomarker assays, including those for galactomannan antigen and β-(1-3)-D-glucan; and molecular assays that are available to establish an early diagnosis of clinically relevant invasive fungal infections are discussed. Recommendations are provided regarding effective use of these methodologies in clinical practice.

Topics: beta-Glucans; Biomarkers; Diagnostic Imaging; Galactose; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Mannans; Mycological Typing Techniques; Mycoses; Proteoglycans

The incidence of invasive fungal infections (IFI) has increased in recent years, especially among immunocompromised hosts (ICH). In 2003, the Fungitell(®) assay received FDA clearance for the presumptive diagnosis of IFI using serum and detects (1-3)-β-D-glucan, which is a major cell wall component of certain fungi (e.g., Candida, Aspergillus, and Pneumocystis). The goal of the current study was to assess the performance of the assay on bronchoalveolar lavage (BAL) fluid and serum to identify IFI in ICH. Patients were classified as having proven, probable, possible, or no IFI according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) guidelines. Among 109 patients for whom the results of Fungitell were compared to the EORTC/MSG criteria, Fungitell showed a low positive predictive value for the identification of IFI from both BAL (20.0%) and serum (26.7%). However, the negative predictive value of Fungitell was significantly higher for both sample types (BAL, 83.0%; serum, 84.8%). Interestingly, the results of Fungitell were positive in BAL and serum in 7/8 (87.5%) patients diagnosed with Pneumocystis pneumonia (PcP) by real-time, non-nested PCR. These data indicate that the Fungitell assay has a low positive predictive value for the diagnosis of IFI in ICH, regardless of the specimen type that is tested. However, testing of serum samples by Fungitell may permit a rapid and noninvasive initial screening approach in patients with presumed PcP.

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; Bronchoalveolar Lavage Fluid; Female; Humans; Immunocompromised Host; Male; Microbiological Techniques; Middle Aged; Mycoses; Predictive Value of Tests; Proteoglycans; Serum; Young Adult

Fungal wound infection is a leading cause of burn wound infections, and diagnosis is often delayed as it conventionally requires culture and histopathology. Fungal screening assays have sped diagnosis of invasive fungal infections in other populations. Few studies have evaluated the performance of fungal screening assays outside of the hematologic malignancy and hematopoietic stem cell transplant populations.. We performed a three year retrospective analysis of all fungal screening assays in burn patients in the ICU between 2008 and 2011. The primary goal was to evaluate the correlation between the two available fungal screening assays, (1→3)-β-d-glucan (BG) and galactomannan (GM) assay, and fungal wound colonization (FWC) and infection (FWI). We also evaluated previously hypothesized causes of false positives and their associations with false positives in the burn population.. We identified 53 patients [median 29% total body surface area burned (TBSA), IQR 17-51] with BG or GM serological tests available, of which 15 had a FWI or FWC. FWC/FWI was associated with higher TBSA (p=0.02). BG and GM correlated with TBSA (BG 0.57, p<0.01; GM 0.35, p=0.02), but neither assay was associated with FWI/FWC or species of fungus involved when FWI/FWC was diagnosed.. Positive BG and GM fungal screening assays are not associated with FWI/FWC, or with species of fungus when FWC/FWI is present. BG false positives are common and associated with higher TBSA burns.

Topics: Adult; Antigens, Fungal; beta-Glucans; Biomarkers; Burns; Female; Galactose; Humans; Male; Mannans; Middle Aged; Mycoses; Retrospective Studies; Wound Infection

Topics: beta-Glucans; False Positive Reactions; Humans; Mycoses; Proteoglycans; Serum

Diagnosis of invasive fungal disease (IFD) in patients under intensive care is challenging. Circulating biomarkers, (1,3)-β-D-glucan (BG) and galactomannan (GM), were prospectively assessed in 98 critically ill patients at risk of IFD. There were 11 cases of invasive aspergillosis (IA; 4 proven and 7 probable), 9 cases of proven invasive candidiasis (IC), 1 case of mixed proven IC and probable IA, 1 case of proven zygomycosis, and 1 case of mixed mycelial proven IFD. In all IA cases there was no significant difference when the area under the receiver operating characteristic curve (AUC) of GM (0.873 [95%CI, 0.75-0.99]) and BG (0.856 [95% CI, 0.71-0.99]) were compared (p = 0.871). The AUC for BG in IC and for the rest of the IFD cases was 0.605 (95% CI, 0.39-0.82) and 0.768 (95% CI, 0.63-0.90) respectively. Positive BG (40%) predated blood culture (n = 3) and abdominal pus (n = 1) a mean of 3.25 days before Candida was grown. In patients with IFD caused by molds, BG appeared a mean of 5.65 days before culture results. For the diagnosis of patients at risk of IC, BG has shown a high NPV (94.5%), with positive results also predating blood cultures in 30% of patients. In conclusion, early BG results permit a timely initiation of antifungal therapy in patients at risk of IFD.

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; Critical Illness; Female; Galactose; Humans; Male; Mannans; Middle Aged; Mycoses; Prospective Studies; Proteoglycans; ROC Curve; Sepsis

The purpose of this study was to investigate the interaction between intravenous ampicillin-sulbactam treatment and (1,3)-beta-D-glucan (BDG) assay. Fifteen patients with a median age of 60 (16-81) without known risk factors for invasive fungal infections who received a daily dose of 3×2g ampicillin-sulbactam monotherapy from different batches were included in the study. Thirteen patients had soft tissue infections. The 5 of 13 patients who went under surgery had surgical dressings. Serum samples were obtained both before and after antibiotic infusion on the first, third, seventh and tenth days of an ampicillin-sulbactam treatment course. BDG was assayed using the Fungitell kit (Associates of Cape Cod, East Falmouth, MA, USA) according to manufacturers' specifications. All serum samples were also tested for galactomannan (GM) antigenemia by Platelia Aspergillus ELISA (Bio-Rad Laboratories, Marnes-la-Coquette, France). A total of 37 of 117 serum samples were positive for BDG at a threshold of 80pg ml(-1) . Seven of 37 BDG positive serum samples had a GM index ≥0.5. When a cutoff value of ≥0.5 was used for GM positivity, 16 (13.3%) serum samples were positive. For a cutoff value of ≥0.7, eight (6.6%) serum samples were positive. There were no statistically significant differences in the median BDG levels (P=0.47) or median GM indices (P =0.28) of the various sampling times. None of the SAM vials tested positive for BDG or GM. After ruling out fungal infections and all known potential causes of false BDG positivity, environmental contamination remained possible cause of BDG reactivity. We did not observe any significant association of ampicillin-sulbactam administration and positive assays for BDG or GM.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ampicillin; Anti-Infective Agents; Antigens, Fungal; beta-Glucans; False Positive Reactions; Female; Humans; Male; Middle Aged; Mycoses; Proteoglycans; Sulbactam; Young Adult

We assessed the performance of galactomannan and (1→3)-β-d-glucan in 29 serum samples from patients with multiple myeloma and Waldenstrom's macroglobulinemia without invasive fungal disease to address issues of false positivity and uninterpretable results previously reported among patients with these conditions. Galactomannan and (1→3)-β-d-glucan assays were not falsely elevated in any patient. (1→3)-β-d-glucan assay results were uninterpretable in 24% of patients. Patients with IgG levels of >2,000 mg/dl had higher odds of uninterpretable (1→3)-β-d-glucan results.

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; Diagnostic Errors; Female; Galactose; Humans; Male; Mannans; Middle Aged; Multiple Myeloma; Mycoses; Proteoglycans; Serum; Waldenstrom Macroglobulinemia

Topics: Antifungal Agents; beta-Glucans; Biomarkers; Delayed Diagnosis; Drug Resistance, Fungal; Humans; Immune Reconstitution Inflammatory Syndrome; Liver; Microbial Sensitivity Tests; Mycoses

The aim of this multicenter prospective study was to evaluate the incidence of invasive fungal infections (IFIs) in adult and pediatric patients with hematologic malignancies, involving nine nosocomial facilities in Southern Italy over a period of 18 months. Furthermore, results of an environmental microbial surveillance routinely carried out in some of the enrolled hospitals are reported. A total of 589 onco-hematological patients were enrolled and 27 IFIs were documented. The main infections were caused by yeasts, more than filamentous fungi (overall incidence of 2.7% and 1.9%, respectively). The yeasts were mainly represented by Candida spp. (87.5%), all isolated by blood cultures; C. parapsilosis was the most common species. Among mould infections, the most frequent site was the lung, with regard to aspergillosis (81.8%). In six of the 10 patients with suspected aspergillosis, the diagnosis was made by the detection of galactomannan and (1,3)-β-d-glucan antigens. The microbiological surveillance carried out on 156 air, 312 water and 312 surface samples revealed low environmental contamination: Alternaria alternata was the only fungus isolated from two surface samples. Our data, especially the low occurrence of filamentous fungi, suggest a particular local epidemiology. Further studies are needed to confirm this microbiological trend in onco-hematological patients in Southern Italy, the results of which might be helpful to improve the management of these patients.

Topics: Adolescent; Adult; Aged; Alternaria; Antineoplastic Agents; beta-Glucans; Bone Marrow Transplantation; Candida; Child; Child, Preschool; Female; Galactose; Hematologic Neoplasms; Humans; Incidence; Male; Mannans; Middle Aged; Mycoses; Prospective Studies; Proteoglycans; Young Adult

Translocation of gastrointestinal bacteria in HIV-infected individuals is associated with systemic inflammation, HIV progression, mortality, and comorbidities. HIV-infected individuals are also susceptible to fungal infection and colonization, but whether fungal translocation occurs and influences HIV progression or comorbidities is unknown.. Serum (1→3)-β-D-glucan (BG) was measured by a Limulus Amebocyte Lysate assay (Fungitell) in 132 HIV-infected outpatients. Selected plasma cytokines and markers of peripheral T-cell activation were measured. Pulmonary function testing and Doppler echocardiography were performed. Relationship of high (≥40 pg/mL) and low (<40 pg/mL) levels of BG with HIV-associated variables, inflammation markers, and pulmonary function and pulmonary hypertension measures were determined.. Forty-eight percent of patients had detectable BG, and 16.7% had high levels. Individuals with high BG were more likely to have CD4 counts less than 200 cells/μL (31.8% vs. 8.4%, P = 0.002), had higher log10 HIV viral levels (2.85 vs. 2.13 log copies/mL, P = 0.004), and were less likely to use antiretroviral therapy (68.2% vs. 90.0%, P = 0.006). Plasma IL-8 (P = 0.033), TNF-α (P = 0.029), and CD8CD38 (P = 0.046) and CD8HLA-DR (P = 0.029) were also increased with high levels. Abnormalities in diffusing capacity (P = 0.041) and in pulmonary artery pressures (P = 0.006 for pulmonary artery systolic pressure and 0.013 for tricuspid regurgitant velocity) were more common in those with high BG.. We found evidence of peripheral fungal cell wall polysaccharides in an HIV-infected cohort. We also demonstrated an association between high serum BG, HIV-associated immunosuppression, inflammation, and cardiopulmonary comorbidity. These results implicate a new class of pathogen in HIV-associated microbial translocation and suggest a role in HIV progression and comorbidities.

Topics: Adult; beta-Glucans; Cytokines; Echocardiography; Female; HIV Infections; Humans; Hypertension, Pulmonary; Immune Tolerance; Inflammation; Limulus Test; Male; Middle Aged; Mycoses; Outpatients; Proteoglycans; Respiratory Function Tests; Serum; T-Lymphocytes

Early identification and treatment of fungal infections is essential for recipients of liver transplants, but the sensitivity of surveillance culture is insufficient. Measurement of the serum level of β-D-glucan is a rapid diagnostic strategy for invasive fungal infection. We aimed to evaluate the significance of serum β-D-glucan levels in transplant recipients after living donor liver transplantation (LDLT).. We retrospectively analyzed the clinical and laboratory data of 100 consecutive adult transplant recipients after LDLT performed between August 1997 and August 2009.. Seventy-one had high serum β-D-glucan levels (>20 pg/ml) after LDLT. Nearly half (47.2%) of the episodes of increase occurred within the first 5 days after surgery. The mortality rate of the recipients with high serum β-D-glucan levels was similar to that of the recipients without high levels. However, in terms of the time line of increase, the recipients with high serum β-D-glucan levels from 15 days onward after surgery showed a significantly higher mortality rate than those with high levels before 15 days after surgery (33.3 and 4.3%, respectively; p < 0.001).. High serum levels of β-D-glucan at late time points after LDLT indicate established fungal infection and higher mortality.

Topics: Adolescent; Adult; Aged; beta-Glucans; Biomarkers; Female; Follow-Up Studies; Graft Rejection; Humans; Liver Transplantation; Living Donors; Male; Middle Aged; Mycoses; Predictive Value of Tests; Retrospective Studies; Young Adult

A highly sensitive (1→3)-β-d-glucan (β-glucan)-specific sandwich ELISA was developed using a fragment of recombinant horseshoe crab factor G protein. The factor G fragment, which was expressed in Escherichia coli, contains a QQWS motif, two β-glucan-binding domains, and an additional N-terminal cysteine residue. The sensitivity of our ELISA was comparable to a conventional (1→3)-β-d-glucan detection method using a horseshoe crab-clotting reaction such as an amebocyte lysate-based assay. In addition, the β-glucan levels measured by our sandwich ELISA in plasma samples showed a good correlation with those measured by the amebocyte lysate-based assay. In the case of our sandwich ELISA, it is not necessary to pre-inactivate interfering substances in plasma samples that is essential for the conventional amebocyte lysate-based assay. Moreover, the assay time of the ELISA method is much shorter than that of the amebocyte lysate-based assay. Because of these advantages, the ELISA system will be more suitable for high-throughput analysis in clinical laboratories using general clinical auto-analyzers. β-glucan is a typical biomarker for fungal infections and the measurements of β-glucan levels by our ELISA could be useful for the diagnosis of fungal infections.

Topics: Amino Acid Sequence; Animals; Base Sequence; beta-Glucans; Blood Chemical Analysis; Blood Coagulation Factors; Carrier Proteins; DNA Primers; Enzyme-Linked Immunosorbent Assay; Horseshoe Crabs; Humans; Lectins; Limulus Test; Molecular Sequence Data; Mycoses; Protein Binding; Proteoglycans; Recombinant Proteins; Sensitivity and Specificity; Sequence Homology, Amino Acid

Fungitell, a (1→3)-β-D: -glucan (β-D: -glucan) measurement kit, was approved in the United States in 2004. Three other kits for measurement of β-D: -glucan, Fungitec G test MK (G-MK), β-Glucan test Wako (Wako), and β-Glucan test Maruha (Maruha), are commonly used for diagnosis of invasive fungal diseases in Japan. We evaluated the clinical viability of the Fungitell kit and compared it with the 3 kits generally used in Japan. The plasma β-D: -glucan values measured with each kit showed some differences, possibly because different β-D: -glucan standards, blood pretreatment methods, and kinds of horseshoe crab (a raw material for the main reagent) are used in each kit. Measures of diagnostic efficiency, for example the sensitivity, specificity, and positive and negative predictive values, varied among the kits. Although the areas under the receiver operating characteristic curves of the kits were not significantly different, the sensitivity of the Fungitell kit was the highest, followed by that of the G-MK kit. The sensitivity of the Wako and Maruha kits was low, but the specificity of these tests was higher than that of the G-MK or Fungitell kits. These inconsistent β-D: -glucan measurements could interfere with diagnosis of invasive fungal infection. Early establishment of an international standard method for measurement of β-D: -glucan is required.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta-Glucans; Biomarkers; Female; Humans; Japan; Male; Middle Aged; Mycology; Mycoses; Reagent Kits, Diagnostic; ROC Curve; Sensitivity and Specificity

There is an increasing interest in the development of therapeutic antibodies (Ab) to improve the control of fungal pathogens, but none of these reagents is available for clinical use. We previously described a murine monoclonal antibody (mAb 2G8) targeting β-glucan, a cell wall polysaccharide common to most pathogenic fungi, which conferred significant protection against Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans in animal models. Transfer of this wide-spectrum, antifungal mAb into the clinical setting would allow the control of most frequent fungal infections in many different categories of patients. To this aim, two chimeric mouse-human Ab derivatives from mAb 2G8, in the format of complete IgG or scFv-Fc, were generated, transiently expressed in Nicotiana benthamiana plants and purified from leaves with high yields (approximately 50 mg Ab/kg of plant tissues). Both recombinant Abs fully retained the β-glucan-binding specificity and the antifungal activities of the cognate murine mAb against C. albicans. In fact, they recognized preferentially β1,3-linked glucan molecules present at the fungal cell surface and directly inhibited the growth of C. albicans and its adhesion to human epithelial cells in vitro. In addition, both the IgG and the scFv-Fc promoted C. albicans killing by isolated, human polymorphonuclear neutrophils in ex vivo assays and conferred significant antifungal protection in animal models of systemic or vulvovaginal C. albicans infection. These recombinant Abs represent valuable molecules for developing novel, plant-derived immunotherapeutics against candidiasis and, possibly, other fungal diseases.

Topics: Animals; Antibodies, Fungal; Antibodies, Monoclonal; Antigens, Fungal; Aspergillus fumigatus; beta-Glucans; Candida albicans; Candidiasis; Cell Adhesion; Cell Line; Cell Wall; Cryptococcus neoformans; Female; Humans; Immunoglobulin Fc Fragments; Immunoglobulin G; Immunotherapy; Mice; Models, Animal; Mycoses; Nicotiana; Plant Leaves; Plantibodies; Rats; Recombinant Fusion Proteins; Single-Chain Antibodies

To evaluate the diagnostic value of serum galactomannan antigen (GM) and (1→3)-β-D-glucan antigen (BG) assay in invasive fungal infections (IFI) in the patients with hematologic malignancies and the role in monitoring therapeutic response.. Fifty one patients with hematological malignancies met the criteria for inclusion: (1) body temperature above 38°C for 48 hours, (2) failure to respond to broad-spectrum antibiotic treatment, or (3) temperature rose again after the responded drop. Blood samples were collected twice at the first week, then once a week in at least four weeks. The double antibody sandwich enzyme-linked immunosorbent assay (ELISA) and colorimetric assay were used for detecting GM and BG. The positive GM test is defined as two consecutive tests at different time GM value > 0.5 or > 0.8 and the positive G test is defined as BG value > 80 pg/ml. The patients were assigned into four groups as proven, probable, possible, and non-fungal infection respectively, and 21 normal volunteers were as controls.. Two hundred and forty serum samples were collected from 51 patients including 2 of proven IFI, 26 probable IFI, 17 possible IFI and 6 non-fungal infection. The true-positive group including the proven and probable groups, and true negative group was the non-fungal infection group. GM tests were positive in 21 of 28 cases in true positive group, and only one of 6 cases in non-fungal infection. The sensitivity, specificity, positive predictive value and negative predictive value were 75%, 83.3%, 95.5% and 41.7%, respectively. G tests were positive in all 28 cases of the true positive group, and 4 in 6 non-fungal infection cases. The sensitivity, specificity, positive predictive value and negative predictive value were 100%, 33.3%, 87.5% and 100%, respectively. G test is more sensitive than GM test (P = 0.015), but there was no significant difference in specificity of the two tests (P = 0.242). In 19 of 21 patients with GM test positive, anti-fungal treatment was effective, and GM value gradually decreased to negative, two invalid patients were persistent with GM test positive. After two weeks treatment, the average GM value was significantly lower in the effective group than in the ineffective group (P < 0.05). BG values in the responded patients showed a gradual decline similar to that of GM values, but not to negative. The changes of BG value in ineffective group varied with a trend upward. The changes in BG value had no relation with treatment effectiveness.. Serum GM and BG antigens detection provides strong evidence for early diagnosis of IFI. Combination of GM and G tests can improve the diagnostic specificity and reduce the false positive GM test seems superior to G test for monitoring GM and BG values during treatment.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Fungal; beta-Glucans; Female; Galactose; Hematologic Neoplasms; Humans; Male; Mannans; Middle Aged; Mycoses; Young Adult

β-D-(1,3)-glucan (BG) is a component of the cell walls of many fungal organisms. Our aims were to investigate the feasibility of the BG assay and its contribution to early diagnosis of different types of invasive fungal infections (IFI) commonly diagnosed in a tertiary care centre. The BG serum levels of 28 patients diagnosed with six IFI [13 probable invasive aspergillosis (IA), 2 proven IA, 2 zygomycosis, 3 fusariosis, 3 cryptococcosis, 3 candidaemia and 2 pneumocystosis] were retrospectively evaluated. The kinetic variations in BG serum levels from the 15 patients diagnosed with IA were compared with those of the galactomannan antigen (GM). In 5/15 cases of IA, BG was positive earlier than GM (time lapse from 4 to 30 days), in 8/15 cases, BG was positive at the same time as GM and, in 2/15 cases, BG was positive after GM. For the five other fungal diseases, BG was highly positive at the period of diagnosis except for the two cases of zygomycosis and one of the three cases of fusariosis. This study, which reflects the common activity of a tertiary care centre, confirms that BG detection could be of interest for IFI screening in patients with haematological malignancies.

Topics: Aspergillosis; beta-Glucans; France; Galactose; Hematologic Neoplasms; Humans; Immunocompromised Host; Mannans; Mycoses; Predictive Value of Tests; Proteoglycans; Retrospective Studies; Time Factors

Beta-glucan is a major component of fungal cell walls and shows various immunopharmacological activities including antitumor activity. Previously, we detected anti-beta-glucan antibody in human sera. Anti-beta-glucan antibody participates in the immune response to fungal cell wall beta-glucan. Patients on dialysis are at high risk of infection including fungal infections. We examined the plasma beta-glucan level and the titer of anti-beta-glucan antibody in dialysis patients. We measured plasma beta-1,3-glucan concentrations with the limulus G test and anti-beta-glucan antibody titers by ELISA with Candida beta-glucan-coated plates. We also examined the influence of the period of dialysis and the kind of dialysis membrane. The patients were positive for beta-1,3-glucan in their plasma. The anti-beta-glucan antibody titer was lower in the dialysis patients than in healthy volunteers. Long-term dialysis patients showed lower anti-beta-glucan antibody titers than short-term dialysis patients. No significant difference was found between the kinds of dialysis membrane. The titer of anti-beta-glucan antibody as recognition molecule of beta-glucan was low in dialysis patients compared with healthy volunteers. This is likely to be one factor explaining the sensitivity to infection of the dialysis patients. An appropriate application of culinary-medicinal mushroom such as Agaricus brasiliensis has potential for the prevention of fungal infection in dialysis patients.

Topics: Agaricus; Aged; Antibodies, Fungal; Aspergillus niger; beta-Glucans; Candida; Candida albicans; Cell Wall; Female; Humans; Kidney Failure, Chronic; Limulus Test; Male; Middle Aged; Mycoses; Renal Dialysis

A laminarin-diphtheria toxoid (CRM197) conjugate vaccine conferred protection against fungal infections in mice. We have now generated novel beta-glucan-CRM197 vaccines, with either natural (Curd-CRM197) or synthetic linear (15mer-CRM197), or beta-(1,6)-branched (17mer-CRM197) beta-(1,3)-oligosaccharides, formulated with the human-acceptable adjuvant MF59. Curd-CRM197 and 15mer-CRM197 conjugates, which induced high titers of anti-beta-(1,3)-glucan IgG, but no antibodies against beta-(1,6)-glucan, conferred protection to mice lethally challenged with C. albicans. In contrast, the 17mer-CRM197 conjugate, which induced anti-beta-(1,6)-glucan antibodies in addition to the anti-beta-(1,3)-glucan IgG, was non-protective. These data provide some insights on beta-glucan epitope(s) mediating antifungal protection and open the way to develop a synthetic oligosaccharide vaccine against fungal diseases.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Fungal; Bacterial Proteins; beta-Glucans; Female; Fungal Vaccines; Humans; Immunoglobulin G; Mice; Mycoses; Survival Analysis; Vaccines, Conjugate

The aim of the study was to assess the antifungal prophylactic efficacy, safety, and tolerability of micafungin, 150 mg daily, and to evaluate the usefulness of monitoring 1,3-beta-d-glucan (BG) in neutropenic patients undergoing chemotherapy for hematological malignancies. This investigation was a retrospective, non-randomized study. A group of patients who did not receive systemic antifungal prophylaxis was compared to another group of patients who received micafungin 150 mg daily. All patients admitted with hematological malignancy and undergoing chemotherapy or stem cell transplant were included. The plasma BG level was measured once weekly. The clinical endpoint was the diagnosis of invasive fungal infection (IFI). Antifungal prophylaxis led to a significant decrease in the occurrence of IFI (from 12.3% to 1.5%, p = 0.001). Few severe adverse effects clearly attributable to micafungin were seen. Sensitivity, specificity, positive predictive value, negative predictive value, and efficiency of BG values >8.9 pg/mL for diagnosis of IFI were 0.90, 0.99, 0.82, 0.99, and 0.99, respectively. Micafungin, 150 mg daily, is an effective and safe drug for antifungal prophylaxis, and monitoring of BG antigenemia is a useful tool for diagnosis of IFI in neutropenic patients with hematological malignancies.

Topics: Adult; Aged; Aged, 80 and over; Antibiotic Prophylaxis; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; beta-Glucans; Echinocandins; Female; Follow-Up Studies; Hematologic Neoplasms; Humans; Lipopeptides; Male; Maximum Tolerated Dose; Micafungin; Middle Aged; Mycoses; Neutropenia; Prognosis; Proteoglycans; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Young Adult

To evaluate the performance of the galactomannan enzyme immunoassay (GM test) and (1,3)beta-D-glucan assay (G test) for the diagnosis of invasive fungal infection (IFI).. A retrospective study was performed in 115 hospitalized patients at Peking University First Hospital who were at risk of IFI. Patients were diagnosed as IFI according to revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated at different cutoff values for two assays respectively. Two tests were combined to evaluate the changes of sensitivity, specificity, PPV and NPV.. The best sensitivity (54.5%, 63.6%) and specificity (77.9%, 69.2%) were obtained with the cutoff values of 0.5 and 20 x 10(3) pg/L in GM test and G test respectively. The PPV were 20.7% and 17.9%, and the NPV were 94.2% and 94.7% respectively. The sensitivity increased to 90.9% and the specificity was 52.9% after a combined utility of two tests.. The GM test and G tests are both useful in diagnosis of IFI with the cutoff values of 0.5 and 20 x 10(3) pg/L. A better sensitivity is acquired if there is a combined utility of two tests.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta-Glucans; Child; Female; Galactose; Humans; Immunoenzyme Techniques; Male; Mannans; Middle Aged; Mycoses; Plasma; Predictive Value of Tests; Retrospective Studies; Sensitivity and Specificity; Serum; Young Adult

Early diagnosis of fungal infection plays an important role in increasing antifungal therapeutic response, but meaningful tests such as microbiological cultures and histopathological diagnosis are usually insensitive and time-consuming. A sensitive amperometric biosensor for beta-glucans was fabricated by immobilizing Dectin-1 onto Nafion-thionine-gold nanoparticle-chitosan multilayer films to trap its corresponding ligand from sample solution. On formation of ligand-receptor complex, detection of beta-glucans was accomplished by monitoring the decrease of the electrochemical signal of the modified electrode due to the inhibition of the transmission of electrons. Dectin-1 was constructed by cloning the extracellular carbohydrate recognition domain of the mouse Dectin gene into the pET28a(+) prokaryotic expression vector. Optimal conditions and analytical performances of the described biosensor were investigated. Under the optimal conditions, the biosensor response for beta-glucans presented good accuracy, stability, and reproducibility. The proposed biosensor not only could be used for rapid analysis of serum beta-glucans but also provided a screening procedure for the determination of fungal infections.

Topics: Animals; beta-Glucans; Biosensing Techniques; Chitosan; Electrochemical Techniques; Electrodes; Fluorocarbon Polymers; Gold; Lectins, C-Type; Membrane Proteins; Metal Nanoparticles; Mice; Mycoses; Nerve Tissue Proteins; Phenothiazines

Patients taking immunosuppressive drugs, like cyclosporine A (CsA), that inhibit calcineurin are highly susceptible to disseminated fungal infections, although it is unclear how these drugs suppress resistance to these opportunistic pathogens. We show that in a mouse model of disseminated Candida albicans infection, CsA-induced susceptibility to fungal infection maps to the innate immune system. To further define the cell types targeted by CsA, we generated mice with a conditional deletion of calcineurin B (CnB) in neutrophils. These mice displayed markedly decreased resistance to infection with C. albicans, and both CnB-deficient and CsA-treated neutrophils showed a defect in the ex vivo killing of C. albicans. In response to the fungal-derived pathogen-associated molecular pattern zymosan, neutrophils lacking CnB displayed impaired up-regulation of genes (IL-10, Cox2, Egr1, and Egr2) regulated by nuclear factor of activated T cells, the best characterized CnB substrate. This activity was Myd88 independent and was reproduced by stimulation with the beta(1,3) glucan curdlan, indicating that dectin-1, rather than toll-like receptors, is the upstream activator of calcineurin. Our results suggest that disseminated fungal infections seen in CsA-treated patients are not just a general consequence of systemic suppression of adaptive immunity but are, rather, a result of the specific blockade of evolutionarily conserved innate pathways for fungal resistance.

Topics: Animals; Antifungal Agents; beta-Glucans; Calcineurin; Candida albicans; Candidiasis; Cyclosporine; Disease Susceptibility; Homeostasis; Humans; Immunity, Innate; Immunosuppressive Agents; Mice; Mycoses; Neutrophils; Polysaccharides, Bacterial; Zymosan

beta-Glucan is a major component of the cell walls and pathogen-associated microbial patterns of fungi. We previously reported the presence of an antibody which reacts to beta-glucan, anti-beta-glucan (BG) antibody, in human sera. In livestock and domestic pets, the antibody's response to fungal cell wall beta-glucan is little understood. In this study, we examined the existence and reactivity of anti-BG antibody in various animal species. We demonstrated the presence of the anti-BG antibody in each animal's serum. Individual differences in the titer existed. The antibody was highly reactive to Candida solubilized cell wall beta-glucan (CSBG) while reacting little to grifolan (GRN) from Grifola frondosa. This suggested that the anti-BG antibody interacted with fungal cell wall beta-glucan and participated in the immune-response to pathogenic fungi.

Topics: Animals; Antibodies, Fungal; Antibody Specificity; beta-Glucans; Cattle; Cell Wall; Chickens; Dogs; Enzyme-Linked Immunosorbent Assay; Fungi; Goats; Guinea Pigs; Haplorhini; Horses; Immunity, Humoral; Mycoses; Rabbits; Swine; Turkey

We have evaluated the contribution of the 1,3-beta-d-glucan (BG) assay for the screening of invasive fungal infections (IFIs) in patients with haematological malignancies. Serum samples from patients at risk of IFI were collected twice a week and retrospectively tested using the BG assay. BG screening was performed on 1143 samples from 91 patients during 104 anticancer treatment cycles. Proven and probable cases of IFI occurred in 9 (8.7 %) treatment cycles. Depending on the criterion of positivity used (1x >60 pg ml(-1), 1x >80 pg ml(-1), 2x >60 pg ml(-1) or 2x >80 pg ml(-1)) the sensitivity and specificity were 89, 89, 67 and 44 %, and 20, 48, 33 and 56 %, respectively. Although the test was marked as positive in 82, 68, 54 and 45 % of all the treatment cycles, in the majority of cases, these positivities were probably false. The major limit of the BG test was an extremely low positive predictive value (10 to 12 %). We have analysed mucositis, candida colonization, bacteraemia, use of antimicrobials, erythrocyte and thrombocyte filtered blood products, collecting tubes or sampling via venous catheters. Even though no factor is a major source of BG, it could at least partially influence BG assay performance. Thus, BG detection has a limited usefulness as a screening method for IFIs in patients with haematological malignancies.

Topics: Antineoplastic Agents; beta-Glucans; Female; Hematologic Neoplasms; Humans; Immunoassay; Immunocompromised Host; Male; Mycoses; Opportunistic Infections; Predictive Value of Tests; Sensitivity and Specificity

The Fungitell assay for (1,3)β-D-glucan (BG) detection in serum has been evaluated in patients with invasive fungal infections (IFIs) and healthy controls and for the early diagnosis of IFI in cancer patients. We evaluated the BG assay for the detection of IFI in lung transplant recipients. Serial serum samples were prospectively collected from patients undergoing lung transplants at Duke Hospital. Fungal infections were classified according to revised European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. A receiver operator characteristic (ROC) curve was generated; possible causes for false-positive and false-negative tests were investigated by linear regression analysis. Seven hundred fifty-six serum specimens from 59 subjects without IFI and 41 specimens from 14 patients with proven or probable IFI were tested. The area under the ROC curve was 0.69. Based on a 60-pg/ml positive cutoff, per-patient sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 64%, 9%, 14%, and 50%, respectively; per-test estimates were 71%, 59%, 9%, and 97%, respectively. The majority (92%) of patients not diagnosed with an IFI had at least one BG level of ≥60 pg/ml, and 90% had at least one BG level of ≥80 pg/ml. Respiratory colonization with mold and hemodialysis significantly affected mean BG levels. In conclusion, the accuracy of the BG test is marginal and its utility as a tool for the early diagnosis of IFI is questionable in the lung transplant population. Although the NPV of the BG test is high, the low PPV limits its utility as a screening tool for early diagnosis of IFI.

Topics: Adult; beta-Glucans; Early Diagnosis; Female; Humans; Immunocompromised Host; Lung Transplantation; Male; Middle Aged; Mycology; Mycoses; Predictive Value of Tests; Prospective Studies; Proteoglycans; Sensitivity and Specificity; Serum

Interleukin-17 (IL-17) producing T helper cells (T(H)-17) comprise a newly recognized T cell subset with an emerging role in adaptive immunity to a variety of fungi. Whether different airborne fungi trigger a common signaling pathway for T(H)-17 induction, and whether this ability is related to the inherent pathogenic behavior of each fungus is currently unknown. Here we show that, as opposed to primary pathogenic fungi (Histoplasma capsulatum), opportunistic fungal pathogens (Aspergillus and Rhizopus) trigger a common innate sensing pathway in human dendritic cells (DCs) that results in robust production of IL-23 and drives T(H)-17 responses. This response requires activation of dectin-1 by the fungal cell wall polysaccharide b-glucan that is selectively exposed during the invasive growth of opportunistic fungi. Notably, unmasking of b-glucan in the cell wall of a mutant of Histoplasma not only abrogates the pathogenicity of this fungus, but also triggers the induction of IL-23 producing DCs. Thus, b-glucan exposure in the fungal cell wall is essential for the induction of IL-23/T(H)-17 axis and may represent a key factor that regulates protective immunity to opportunistic but not pathogenic fungi.

Topics: Air Microbiology; beta-Glucans; Cells, Cultured; Dendritic Cells; Fungi; Humans; Interleukin-23; Lectins, C-Type; Leukocytes, Mononuclear; Membrane Proteins; Mycoses; Nerve Tissue Proteins; Th17 Cells

Topics: Antigens, Fungal; beta-Glucans; Biomarkers; Colorimetry; Humans; Immunity, Cellular; Immunocompromised Host; Mycoses; Nephelometry and Turbidimetry; Opportunistic Infections; Reference Values; Specimen Handling; Sugar Alcohols

To evaluate the value of plasma 1, 3-β-D-glucan (G), serum mannan, galactomannan (GM) and cryptococcus capsular antigen assays for diagnosis of invasive fungal infections (IFI) in non-neutropenic adult patients.. This was a prospective case control study. Plasma and serum samples from 25 patients with IFI (candidiasis, aspergillosis, cryptococcosis, zygomycosis, pneumocystis carinii pneumonia), 27 patients with bacterial infections, and 25 healthy adults were collected from February 2007 to February 2009 in Beijing Hospital. The serum antigenic assays were performed and their sensitivity and specificity were analyzed. Optimal cut-off level of G test and mannan was established with receiver operating characteristic curve (ROC).. The concentration of G test in plasma of patients with IFI [89.4 (25.8, 336.9) ng/L] was significantly higher than that of patients with bacterial infection [8.1 (5.0, 34.9) ng/L, U = 120.5, P < 0.001] and healthy adults [3.8 (3.8, 26.0) ng/L, U = 76.5, P < 0.001]. The area under curve (AUC) was 0.858, and the optimal cut-off value was 71.7 ng/L. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 65.0% (13/20), 92.3% (48/52), 76.5% (13/17) and 87.2% (48/55) respectively. The concentration of mannan in serum from patients with candidiasis [1.13 (0.44, 1.22) µg/L] was significantly higher than that from patients with non-candidiasis IFI [0.21 (0.14, 0.27) µg/L, U = 19, P < 0.05], bacterial infection [0.26 (0.22, 0.32) µg/L, U = 36.5, P < 0.001] and healthy adults [0.25 (0.22, 0.30) µg/L, U = 29.5, P < 0.001]. The AUC was 0.894, and the optimal cut-off value was 0.41 µg/L. The sensitivity, specificity, PPV and NPV were 83.3% (10/12), 90.4% (47/52), 66.7% (10/15) and 96.0% (47/49) respectively. The sensitivity, specificity, PPV and NPV of GM antigen to diagnose aspergillosis were 25.0% (1/4), 96.1% (50/52), 33.3% (1/3) and 92.6% (50/54) respectively. The sensitivity, specificity, PPV and NPV of cryptococcus capsular antigen to diagnose cryptococcosis were all 100%.. 1,3-β-D-glucan, mannan and cryptococcus capsular antigen were useful for diagnosis of IFI in non-neutropenic adult patients. GM antigen did not show a good sensitivity for diagnosis of aspergillosis in non-neutropenic adult patients.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Fungal; Bacterial Infections; beta-Glucans; Case-Control Studies; Female; Galactose; Humans; Male; Mannans; Middle Aged; Mycoses; Predictive Value of Tests; Prospective Studies; Proteoglycans; Sensitivity and Specificity

Previous studies have reported that galactomannan (GM) enzyme immunoassay and 1,3 beta-glucan (BG) assay may be useful diagnostic tools, but their sensitivities are variable. We compared the performances of both tests. Between October 2002 and May 2005, 82 patients were prospectively monitored for 12 weeks. A total of 414 samples were tested by GM assay and 409 samples were tested by BG assay for the following four groups of patients: those with invasive aspergillosis (IA), those with other mold infections (Fusarium, scedosporium, zygomycosis, etc.), those with candidemia, and control patients. Blood samples were obtained twice on week 1 and once every other week for a total of 12 weeks. Patients in the invasive fungal infection groups had comparable risk factors. The sensitivity of the GM test was significantly higher for patients with IA due to non-fumigatus Aspergillus species than for patients with IA due to Aspergillus fumigatus (49% versus 13%; P < 0.0001) or with other mold infections (49% versus 6%; P < 0.0001). However, the sensitivity range (47% to 64%) and specificity (88%) of the BG assay were comparable among all patients tested, regardless of the infecting pathogen. The performance of GM-based diagnosis appears to be better for detecting non-fumigatus Aspergillus species. The diagnostic marker BG was shown to have a higher sensitivity than that of GM in detecting IA and other mold infections in hematologic malignancy patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta-Glucans; Child; Female; Galactose; Hematologic Neoplasms; Humans; Immunoenzyme Techniques; Male; Mannans; Middle Aged; Mycoses; Proteoglycans; Sensitivity and Specificity

Invasive fungal infections are associated with high morbidity and increased mortality. This study was performed to assess the epidemiology of fungal infections and to determine (1,3)-beta-D-glucan serum concentrations in patients admitted to intensive care units (ICUs).. Overall 197 patients were admitted to nine medical and surgical intensive care units (ICUs) at a 2200-bed university hospital during a 3-month period. Retrospectively, the patients were split into three groups: group A comprised 24 patients with proven invasive fungal infections admitted for a median of 40 days. Group B comprised 58 patients who were admitted to the ICU for 30 days but without fungal infection. One hundred and fifteen post-operative patients served as controls (group C). The levels of (1,3)-beta-D-glucan were monitored in all patients twice weekly during their ICU admittance.. Average (1,3)-beta-D-glucan concentrations were significantly higher in the patients with fungal infections compared to group B and group C (median 44 vs. 22 and 12.9 pg/ml, respectively; p<0.001). For a serum (1,3)-beta-D-glucan level of 40 pg/ml, the sensitivity, the specificity, the positive predictive value, the negative predictive value, the area under the curve of the receiver operating characteristics (AUC ROC) curve, the likelihood ratio (LR)+ and LR- were 52.2, 75.9, 46.2, 80, 0.7, 2.16, and 0.63, respectively, on day 7. Patients in group A had bacterial infections significantly more often than patients in group B (p=0.003). The hospitalization before ICU admittance for group A was significantly longer than for groups B and C (median 19 (group A) vs. 6 (group B) vs. 10 (group C) days; p<0.05).. Longer hospitalization and multiple bacterial infections were found to be the main risk factors for invasive fungal infections. Long-term ICU patients have elevated (1,3)-beta-D-glucan levels, not only due to invasive fungal infections, but also due to the serious underlying diseases and conditions, inter-current complications, and intensive care measures. Yet, persistently high serum levels of (1,3)-beta-D-glucan in ICU patients may be indicative of invasive fungal infections and warrant additional diagnostic efforts.

Topics: Aspergillosis; Aspergillus; beta-Glucans; Candida; Candidiasis; Female; Humans; Incidence; Intensive Care Units; Length of Stay; Male; Mycoses; Predictive Value of Tests; Proteoglycans

This single-center observational prospective study evaluated the performance of (1-->3)-beta-D-glucan as an adjunct diagnostic tool in 12 patients with proven invasive fungal disease with different risk factors. The infections were due to either uncommon fungal pathogens such as dematiaceous molds (Scedosporium apiospermum, Alternaria infectoria, and Cladosporium macrocarpum) and hyaline septate molds (Fusarium solani and Blastoschizomyces capitatus) or Aspergillus spp. with unusual clinical presentations.

Topics: Aged; Alternaria; Aspergillus; beta-Glucans; Child, Preschool; Cladosporium; Dipodascus; Female; Fusarium; Humans; Male; Middle Aged; Mycoses; Prospective Studies; Proteoglycans; Scedosporium

Deep mycosis (aspergillus pneumonia (AsP)) and carinii pneumonitis (PCP) are complications of immunosuppressive treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The objective was to clarify the clinical significance of plasma titer of antibody against beta-glucans (anti-BG antibody) as a predictor of complications such as AsP or PCP and the prognosis of patients. Enzyme-linked immunosorbent assay was used to measure the plasma titer of antibodies against beta-glucans (BG) from Candida albicans in 22 healthy subjects and 52 patients with various stages of AAV. The mean plasma titer of the anti-BG antibody was 2,677 +/- 1,686 U in healthy subjects, 691 +/- 522 U in patients with untreated active vasculitis (n = 14), and 547 +/- 416 U in patients soon after immunosuppressive treatment (n = 24). Healthy subjects had significantly higher antibody titers than the other two groups (P < 0.05). Repeated measurements over the clinical course of AAV revealed an increase during remission to 1,180 +/- 130 U (n = 11), while there was a significant rapid decrease to 369 +/- 441 U (P < 0.01) concomitantly with elevation in plasma C-reactive protein and BG levels in patients with AAV that had AsP or PCP infection. Antifungal therapy resulted in a rapid rise of anti-BG antibody titer. Experiments in mice suggested that the anti-BG antibody neutralizes BG. Rapid decrease of the anti-BG antibody titer may be a useful indicator for diagnosis of the presence of AsP or PCP and for estimating the prognosis of patients with these opportunistic infections during immunosuppressive treatment of AAV.

Topics: Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Antifungal Agents; Aspergillus; beta-Glucans; Candida albicans; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycoses; Pneumonia; Remission Induction; Reproducibility of Results; Vasculitis

1,3-beta-D glucan (BG) -- the antigen of fungal cell wall can be detected by a commercially available test for early detection of invasive fungal infections (IFI). The main advantage of this test is its broad coverage of fungal species. The aim of our study was to evaluate usefulness of BG detection for screening of IFI and for confirmation of galactomannan (GM) positive blood samples. Combination of the results of both tests could lead to correct and early diagnosis of invasive aspergillosis (IA).. Between January 2005 and July 2007 blood samples were collected in patients from intermediate to high risk of IFI. Moreover, between February and October 2007 all patients that had consecutive positive results of GM had their positive symplex tested also for BG.. In BG screening study, 1154 of blood samples from 104 treatment cycles were tested for BG. The incidence of IFI was 17.3 % (n = 18) and probable or proven IFI was detected in 9 cases (8.6%). The highest sensitivity, specificity, PPV and NPV (88.9 %, 40.7 %, 13.6 % and 97.2 %) were obtained when as criteria for positivity cut off 80 pg/ml and one positive result were used. When consecutive positivity of the test was applied as criterium, cut off 60 pg/ml was found more useful (sensitivity 66.7 %, specificity 47.7 %, PPV 11.8 % and NPV 93.2 %). Low PPV, caused by frequent false positive results, was identified as main limitation of this assay. 65 treatment cycles were positive if 1 sample above 80 pg/ml was used as a cut of for positivity. If consecutive positivity with cut off 60 pg/ml was used, 58 treatment cycles were positive. But in 51 (78.4 %) and 45 (77.5 %) cases, respectively, the positivity was not associated with IFI (false positivity). We did not find any correlation between positive BG assay result and frequency of empirical antifungal treatment, mucositis, yeast colonization, administration of selected antibiotics or infusion solutions or bacteriaemia. In our confirmation study, 40 GM positive episodes in 39 patients were identified. In 31 (78 %) GM positivity was false and was not associated with clinical signs and symptoms of IA. Sensitivity of GM detection in IA was 100 % but PPV only 18 %. Confirmation of consecutive GM positive samples (using cut off index positivity 0,5) by consecutive positivity of BG (with cut off 60 pg/ml) was found very useful for diagnosis of IA -- most of GM false positive results were eliminated and PPV increased to 88 %.. Our analysis focused on routine use of BG test for panfungal screening of IFI in patients with hematological malignancy and confirmed limited usefulness of this test in such setting. Low sensitivity together with low PPV are major limits of this test. On the other hand, BG testing seems to be a promising tool for confirmation of consecutive GM positive result in serum in patients with IA. Positivity of both tests could increase their PPV of tests and eliminate false positive results.

Topics: Antigens, Fungal; beta-Glucans; Female; Galactose; Hematologic Neoplasms; Humans; Male; Mannans; Mycoses; Opportunistic Infections; Predictive Value of Tests; Proteoglycans; Sensitivity and Specificity

Invasive fungal infections (IFIs) remain a major cause of infectious morality in neutropenic patients receiving chemotherapy or hematopoietic stem cell transplantation (HSCT). Micafungin exhibits broad antifungal activity against both Aspergillus and Candida species. We performed a retrospective study to determine the efficacy and safety of prophylactic micafungin against IFI in pediatric neutropenic patients during chemotherapy or HSCT.. Forty patients were given micafungin (3 mg/kg/day) intravenously for neutropenia: 131 patient-cycles (39 patients) after chemotherapy and 15 patient-cycles (14 patients) after HSCT. Median duration of neutropenia and micafungin prophylaxis was 13 and 23 days after chemotherapy and HSCT, respectively.. Treatment success rate, defined as absence of proven, probable, possible, or suspected IFIs, was 93.9% (121/131) and 80.0% (12/15) for chemotherapy and HSCT, respectively. Proven or probable IFI was documented in only one patient after HSCT. No adverse events were observed that could be related to micafungin prophylaxis.. These results suggest that prophylactic micafungin is well tolerated and may prevent IFIs in pediatric patients with neutropenia receiving chemotherapy or HSCT.

Topics: Adolescent; Antifungal Agents; Antineoplastic Agents; beta-Glucans; Child; Child, Preschool; Echinocandins; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lipopeptides; Micafungin; Mycoses; Neoplasms; Neutropenia; Retrospective Studies

The invasive fungal infections (IFI) in immunocompromised patients are associated with a high mortality rate and diagnostic difficulty. Serological methods such as aspergillus galactomannan assay (GM test) and (1, 3)-beta-D glucan (BG) assay (G test) can be used as an adjunctive method for IFI diagnosis based on their characteristics of easy-operating, rapidness and high sensitivity. Compared with GM test, G test can be more widely used except for the diagnosis of aspergillosis. The purpose of this study was to investigate the value of G test in the diagnosis of IFI in patients with hematological disorders. The plasma was collected from 162 suspected IFI patients with hematological disorders in Beijing Daopei Hospital, including 85 patients after chemotherapy and 77 patients after stem cell transplantation from May 2007 to May 2008, BG level was measured with MB-80 Microbiology Kinetic Rapid Reader and the measured results together with the clinical characteristics were retrospectively analyzed. According to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria, there were 2 patients diagnosed as proven IFI, 18 as probable IFI, 75 as possible IFI and 67 as no IFI. The results showed that at a cutoff of 20 pg/ml, the sensitivity and specificity of G test were 75% and 91% respectively, with a positive predictive value (PPV) of 71.4% and a negative predictive value (NPV) of 92.4%. 51 out of the 75 possible IFI patients with elevated BG level were responsive to antifungal treatment but non responsive to broad-spectrum antibiotics, retrospectively were diagnosed as IFI, suggesting that G test improved the IFI diagnostic rate by 31.4%. In conclusion, G test is a rapid and simple method for early diagnosis of IFI in patients with hematological disorders.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta-Glucans; Child; Female; Hematologic Diseases; Humans; Male; Middle Aged; Mycoses; Plasma; Young Adult

Diagnosis of invasive fungal disease (IFD) is challenging, and it remains a significant cause of morbidity and mortality in immunocompromised patients. The (1-->3)-beta-D-glucan (BG) assay may be a useful adjunct, but its diagnostic performance is not well characterized.. We retrospectively assessed the diagnostic indices of the BG assay in patients at risk of IFD who had a compatible clinical syndrome for the diagnosis of IFD a week after initial BG testing and at the end of the hospitalization associated with the first BG value. Patients with IFD were classified according to current European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria, independent of BG results.. A total of 1308 BG assays were performed for 871 patients. One hundred twelve proven or probable IFD cases were diagnosed within 1 week after initial testing, and 116 cases were diagnosed by the end of hospitalization. Sensitivity of an initial BG level 80 pg/mL for IFD at 1 week was 0.64 (95% confidence interval [CI], 0.55-0.73), specificity was 0.84 (95% CI, 0.81-0.86), the positive likelihood ratio was 3.93 (95% CI, 2.94-5.26), and the negative likelihood ratio was 0.43 (95% CI, 0.31-0.59). Albumin, intravenous immunoglobulin, and hemodialysis were associated with elevated BG levels in patients without IFD (odds ratio, 4.78; 95% CI, 2.59-8.80). After excluding patients with these factors, specificity and the positive likelihood ratio of an initial BG level 80 pg/mL increased slightly. Empirical systemic antifungal treatment did not reduce overall BG sensitivity. Sensitivity was slightly lower among patients with hematologic malignancy or stem cell transplantation. Consideration of BG results would have increased the diagnostic certainty to probable in 54% of possible IFD cases.. BG level appears to be a fair diagnostic adjunct for IFD in patients with appropriate pretest probability and a suggestive clinical syndrome, especially when checked serially in patients not receiving factors associated with an elevated BG level in the absence of IFD.

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; Female; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mycoses; Proteoglycans; Retrospective Studies; Sensitivity and Specificity; Young Adult

The incidence of invasive fungal infection (IFI) has risen dramatically along with the prolongation of immunocompromised individuals' lifespan. This study aimed to investigate the incidence of IFI among high risk pediatric patients and to evaluate the diagnostic value of circulating (1,3)-beta-D-glucan (BG) in IFI.. High risk pediatric inpatients from hemato-oncology department and ICU were enrolled from November 2007 to June 2008. All the patients had persistent fever for 4 to 7 days or longer. Circulating BG levels were detected once or twice weekly until the signs and symptoms improved, or IFI was excluded, or death. Circulating BG levels were determined by the GKT-5M Set Kinetic Fungus Detection Kit. Detection of plasma BG was judged positive when the level was > or = 10 pg/mL.. A total of 130 patients were enrolled. Two patients with candidemia were classified as proven IFI, 20 as probale IFI,7 as possible IFI, and 101 without IFI. The patients with proven or probable IFI had a longer length of hospital stay (P< 0.05) and an increased mortality rate (P< 0.05). The patients with IFI demonstrated a higher plasma level of BG than those without IFI (P< 0.01). The sensitivity, specificity, positive and negative predictive values for plasma BG detction were 81.8%, 82.4%, 48.6% and 95.7% respectively. Positive BG results occurred before the abnormal results on computed tomography scan or fungal culture or simultaneously in 72.2% of the cases.. IFI is not rare among pediatric high-risk patients. Circulating BG detection is accurate to a certain extent in the diagnosis of IFI. It is a useful adjunct means for IFI screening in high-risk patients.

Topics: Adolescent; beta-Glucans; Child; Child, Preschool; Early Diagnosis; Female; Humans; Infant; Male; Mycoses; ROC Curve

Topics: Bacteremia; beta-Glucans; Cross Reactions; Diagnosis, Differential; False Positive Reactions; Humans; Mycoses; Proteoglycans; Pseudomonas aeruginosa; Pseudomonas Infections

Dectin-1 is the archetypal signaling, non-Toll-like pattern recognition receptor that plays a protective role in immune defense to Candida albicans as the major leukocyte receptor for beta-glucans. Dectin-1-deficiency is associated with impaired recruitment of inflammatory leukocytes and inflammatory mediator production at the site of infection. In this study, we have used mice to define the mechanisms that regulate the dectin-1-mediated inflammatory responses. Myeloid cell activation by dectin-1 is controlled by inherent cellular programming, with distinct macrophage and dendritic cell populations responding differentially to the engagement of this receptor. The inflammatory response is further modulated by the progression of the phagocytosis, with "frustrated phagocytosis" resulting in dramatically augmented inflammatory responses. These studies demonstrate that dectin-1 in isolation is sufficient to drive a potent inflammatory response in a context-dependent manner. This has implications for the mechanism by which myeloid cells are activated during fungal infections and the processes involved in the therapeutic manipulation of the immune system via exogenous dectin-1 stimulation or blockade.

Topics: Animals; beta-Glucans; Candida albicans; Dendritic Cells; Inflammation; Lectins, C-Type; Macrophages; Membrane Proteins; Mice; Mice, Knockout; Mycoses; Myeloid Cells; Nerve Tissue Proteins; Phagocytosis

To evaluate the significance of a serum 1,3-beta-D-glucan (BG) assay for early diagnosis of invasive fungal infection (IFI) and determine its cutoff value in Chinese post-hematopoietic stem cell transplant (HSCT) recipients.. Serum BG levels were measured twice weekly by Glucatell kit (G-Test) in 36 post-HSCT patients with suspected IFI. The sensitivities and specificities of the assay for clinical proven IFI and non-IFI patients were calculated retrospectively according to different G-Test positive criteria and determined its cutoff.. The sensitivity, specificity, positive and negative predictive values were 81.0%, 81.8%, 89.5% and 69.2% (P=0.002) respectively, as the cutoff value was set at more than 80 ng/L once or 60 ng/L consecutively twice.. The cutoff value of G test in Chinese post HSCT patients basically is the same as specified in the instruction of the kit, and it is a quick and reliable method for early diagnosis of IFI.

Topics: beta-Glucans; Early Diagnosis; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Mycoses; Postoperative Complications; Predictive Value of Tests; Proteoglycans; Sensitivity and Specificity

A sensitive and highly specific nested PCR (nPCR) protocol was developed for the specific detection of Fusarium oxysporum DNA in clinical specimens. The diagnostic value of F. oxysporum-specific DNA and (1-->3)-beta-D-glucan (BDG) detection was subsequently evaluated in serum and bronchoalveolar lavage (BAL) specimens of mice infected intravenously with F. oxysporum conidia. Mice were sacrificed in groups of six daily up to day 8 and then on days 11 and 14. The F. oxysporum-specific DNA and BDG in serum and BAL specimens were detected using nPCR and a Fungitell kit, respectively. Cultures of lung homogenate of all of the infected animals yielded F. oxysporum and the fungus was also observed in KOH/Calcofluor mounts of 67 % of the tissues. The BDG (cut-off value 80 pg ml(-1)) and nPCR sensitivity in BAL and serum specimens was 15 and 98 %, and 92 and 75 %, respectively. Combined detection of F. oxysporum DNA and BDG in serum enhanced the sensitivity to 98 %. However, the kinetics of the two markers were slightly different. Whilst BDG positivity in serum remained high throughout the infection period, nPCR positivity declined slowly. The data obtained in this study suggest that combined detection of BDG and DNA in serum offers a sensitive and specific diagnostic approach for invasive Fusarium infection.

Topics: Animals; beta-Glucans; Bronchoalveolar Lavage Fluid; DNA, Fungal; Fusarium; Mice; Mycoses; Polymerase Chain Reaction; Proteoglycans; Serum

Diagnosis of invasive fungal infection (IFI) remains a challenge. A retrospective study was performed on 279 patients at three French university hospitals to evaluate the performance of the (1-->3)-beta-D-glucan assay (BG assay; Fungitell; Associates of Cape Cod, Inc.) for the diagnosis of IFI. The results of one serum per subject were analyzed for 117 patients who had probable or proven IFI according to the European Organization for Research and Treatment of Cancer criteria (70 invasive pulmonary aspergilloses [IPA], 27 fungal bloodstream infections, and 20 Pneumocystis jiroveci pneumonias), 40 blood donors, and 122 patients who were hospitalized in hematology wards or intensive care units and were at risk for IFI but in whom IFI had not been diagnosed. For the overall IFI diagnosis, the BG assay had 77.8% sensitivity and specificities of 92.5 and 70.5% for blood donors and patients at risk, respectively. The assay was positive in 48 patients with IPA (68%), in 23 with bloodstream infections (85.2%), and in all who had P. jiroveci pneumonias (100%), and the false-positive rate varied depending on the controls used. It allowed a higher rate of detection among IPA patients compared to the galactomannan enzyme-linked immunosorbent assay (ELISA) (48 versus 39 patients, respectively) and among candidemia patients compared to the mannan ELISA (20 versus 11 patients, respectively). This assay therefore appears to be useful in the diagnosis of IFI, particularly for serum analysis of pneumocystosis pneumonia patients, but further studies are needed to evaluate false-positive rates and its future role in IFI diagnosis.

Topics: Aspergillosis; beta-Glucans; Blood Donors; Candidiasis; False Positive Reactions; France; Fungemia; Hospitals, University; Humans; Lung Diseases, Fungal; Mycoses; Pneumonia, Pneumocystis; Proteoglycans; Reagent Kits, Diagnostic; Sensitivity and Specificity

Invasive fungal infections (IFIs) are life-threatening complications in neutropenic patients with hematological malignancies. Because early diagnosis of IFI is difficult, new noninvasive, culture-independent diagnostic tools are needed to improve clinical management. Recent studies have reported that detection of 1,3-beta-D-glucan (BG) antigenemia may be useful for diagnosis of IFI. The aim of the present prospective study was to evaluate the usefulness of monitoring BG in patients undergoing chemotherapy for acute leukemia.. BG antigenemia was measured by a colorimetric assay twice weekly in the absence of fever and daily in the presence of fever. IFIs were classified according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group.. During 190 consecutive neutropenic episodes (median duration, 22 days; range, 7-113 days) in 95 patients, 30 proven or probable IFIs (13 aspergillosis, 15 candidiasis, and 2 mixed IFIs) were diagnosed. Sensitivity, specificity, positive predictive value, negative predictive value, and efficiency of 2 consecutive BG values > or =7 pg/mL for diagnosis of proven or probable IFI was 0.63 (95% confidence interval, 0.44-0.79), 0.96 (95% confidence interval, 0.89-0.98), 0.79 (95% confidence interval, 0.57-0.92), 0.91 (95% confidence interval, 0.84-0.95), and 0.89, respectively. The time interval between onset of fever as first sign of IFI and BG antigenemia was significantly shorter than the time to diagnosis of IFI by clinical, microbiological, radiological, and/or histopathological criteria (P < .001). BG values >50 pg/mL were observed in only 2 patients, both of whom experienced failure of antifungal therapy.. Monitoring of BG antigenemia is a useful noninvasive method for early diagnosis of IFI in patients with acute leukemia.

Topics: Adult; Aged; Antigens, Fungal; Aspergillosis; beta-Glucans; Candidiasis; Female; Fungemia; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycoses; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Predictive Value of Tests; Proteoglycans; Sensitivity and Specificity

The performance of the Fungitell assay was investigated in 100 patients with haematological malignancy undergoing chemotherapy who developed antibiotic-unresponsive neutropenic fever (AUNF). Serum beta-D-glucan (BG) concentrations were significantly elevated on the first day of AUNF and all subsequent alternate days to day 10 in 38 patients who developed an invasive fungal infection (IFI) compared to 42 patients remaining free of such infections. The mean and median values of BG were 171.9+/-29.6 and 95.8 pg ml(-1), respectively, for patients with IFI and 64.4+/-17.1 and 32.9 pg ml(-1) for patients with only AUNF (P<0.0001). The differences remained significant over the 10 days despite antifungal therapy. The occurrence of > or =2 sequential concentrations of > or =80 pg ml(-1) ('positive' test) was found to give the best overall option for diagnosis, with an accuracy of 81.3%, sensitivity of 86.8%, positive predictive value of 76.7% and negative predictive value of 86.5%. Of the patients with an IFI, 78% developed a positive test at or before the clinical diagnosis was made -- this occurred at a mean (range) of 1.25 (-14 to +14) days prior to the IFI diagnosis. By starting sampling of blood from the first day of neutropenia rather than from the first day of AUNF, 50% of the patients with subsequent IFI would have been identified 5 days earlier. Increasing sampling to daily from alternate-day frequency did not further improve this earlier timing of an IFI diagnosis. A greater proportion of patients with persistent high levels of BG without overt IFI had severe enterocyte damage or mucositis than those with lower levels of BG without IFI (P=0.002). If the results of the initial BG test had been acted on to change antifungal therapy, discontinuation would have been inappropriate in 30% of patients and would have delayed definitive antifungal therapy. Although the findings for the cohort of patients studied are very useful, there is inter-patient variability in the test's performance. An holistic diagnostic approach is therefore necessary to interpret the test results optimally. Future studies should address this in further detail as well as the impact of empirical antifungal drug use and patient outcome.

Topics: Adolescent; Adult; Antifungal Agents; Antigens, Fungal; beta-Glucans; Female; Fever; Fungemia; Hematologic Neoplasms; Humans; Male; Middle Aged; Mycoses; Neutropenia; Predictive Value of Tests; Sensitivity and Specificity

Microglia are the resident mononuclear phagocytic cells that are critical for innate and adaptive responses within the CNS. Like other immune cells, microglia recognize and are activated by various pathogen-associated molecular patterns. beta-glucans are pathogen-associated molecular patterns present within fungal cell walls that are known to trigger protective responses in a number of immune cells. In an effort to better understand microglial responses to beta-glucans and the underlying response pathways, we sought to determine whether Dectin-1, a major beta-glucan receptor recently identified in leukocytes, plays a similar role in beta-glucan-induced activation in microglia. In this study, we report that Dectin-1 is indeed expressed on the surface of murine primary microglia, and engagement of the receptor with particulate beta-glucan resulted in an increase in tyrosine phosphorylation of spleen tyrosine kinase, a hallmark feature of the Dectin-1 signaling pathway. Moreover, phagocytosis of beta-glucan particles and subsequent intracellular production of reactive oxygen species were also mediated by Dectin-1. However, unlike in macrophages and dendritic cells, beta-glucan-mediated microglial activation did not result in significant production of cytokines or chemokines; thus, the interaction of microglial Dectin-1 with glucan elicits a unique response. Our results suggest that the Dectin-1 pathway may play an important role in antifungal immunity in the CNS.

Topics: Animals; beta-Glucans; Cell Membrane; Cells, Cultured; Chemokines; Cytokines; Intracellular Signaling Peptides and Proteins; Lectins, C-Type; Membrane Proteins; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Microglia; Mycoses; Nerve Tissue Proteins; Phagocytosis; Phosphorylation; Protein-Tyrosine Kinases; Reactive Oxygen Species; Signal Transduction; Solubility; Syk Kinase; Toll-Like Receptor 2; Zymosan

Topics: beta-Glucans; Child; Child, Preschool; Female; Humans; Infant; Male; Mycoses; Nephrotic Syndrome

The prevalence of invasive fungal infection is increasing. An effective diagnostic test is required to identify and treat them successfully.. All autopsy records at our hospital for the period from January 2000 through December 2005 [corrected] were reviewed for cases of invasive fungal infection. The diagnostic efficacy of a serum (1-->3)-beta-D-glucan (beta-glucan) assay was examined using only those cases in which patients had been tested for fungal infection within 2 weeks before death.. Of 456 autopsies, 54 (11.8%) involved cases of invasive fungal infection. Leukemias were the most frequent underlying disease (in 52% of cases of invasive fungal infection), and Aspergillus species was the most frequent pathogen detected (in 70%). Of the 54 patients with invasive fungal infection, 41 had beta-glucan testing performed within 2 weeks before death, as did 63 patients without invasive fungal infection; 48 of 54 patients with invasive fungal infection had a blood culture performed. The sensitivity and specificity of the beta-glucan test for the detection of invasive fungal infection were 95.1% and 85.7%, respectively, with a cutoff value of 30 pg/mL; 85.4% and 95.2%, respectively, with a cutoff value of 60 pg/mL; and 78.0% and 98.4%, respectively, with a cutoff value of 80 pg/mL. The sensitivity of blood culture testing was 8.3%. With a prevalence of 11.8%, the positive and negative predictive values for the beta-glucan test were 47.1% and 99.2%, respectively, with a cutoff of 30 pg/mL; 70.4% and 98.0%, respectively, with a cutoff of 60 pg/mL; and 86.7% and 97.1%, respectively, with a cutoff of 80 pg/mL. During the 6-year period studied, of 21 patients with fungus-positive blood cultures that were preceded or followed by a beta-glucan test within 2 weeks, 4 had negative beta-glucan test results (beta-glucan level, <30 pg/mL), and 17 had positive results (beta-glucan level, >60 pg/mL); the concordance between culture results and beta-glucan test results was 81.0%. Contrary to the general belief, 5 of 6 cases of cryptococcemia were associated with high serum beta-glucan levels.. The beta-glucan test is an effective diagnostic tool for invasive fungal infection.

Topics: Autopsy; beta-Glucans; Blood; Fungemia; Fungi; Humans; Mycoses; Predictive Value of Tests; Proteoglycans; Sensitivity and Specificity; Statistics as Topic

Invasive fungal infection (IFI) is a leading cause of infection-related mortality among patients with cancer and prolonged neutropenia and among allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease. Invasive candidiasis was the principal IFI in the period predating fluconazole prophylaxis, whereas today, invasive aspergillosis and other mold infections cause the majority of deaths from fungal infection in this patient population. The changing epidemiology of IFI, in addition to advances made in antifungal therapeutics and early diagnosis of IFI, warrant a reevaluation of earlier strategies aimed at prevention and early treatment of IFI that were developed several years ago. Here, we propose that persistent neutropenic fever is nonspecific for an IFI and should not be used as the sole criterion for empirical modification in the antifungal regimen in a patient receiving mold-active prophylaxis. We explore the potential benefits and gaps in knowledge associated with employing chest CT scans and laboratory markers as diagnostic adjuncts for IFI. Finally, we discuss the implications of newer antifungal agents and diagnostic adjuncts in the design of future clinical trials to evaluate prophylaxis and early prevention strategies.

Topics: Antifungal Agents; beta-Glucans; Biomarkers; Evaluation Studies as Topic; Fever; Fungi; Galactose; Hematopoietic Stem Cell Transplantation; Humans; Mannans; Mycoses; Neoplasms; Neutropenia; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Tomography, X-Ray Computed; Yeasts

To evaluate the diagnostic value of the detection of plasma 1, 3-beta-D-glucan for invasive fungal infections (IFI).. Plasma of patients with IFI, bacterial pneumonia, and oral pharyngeal fungal colonization, and healthy controls were collected from January 2005 to February 2006 in Nanjing General Hospital of Nanjing Military Command of PLA. G-test was used to measure the concentration of 1, 3-beta-D-glucan in the plasma.. The concentration of 1, 3-beta-D-glucan in plasma of patients with IFI [(29.5+/-11.5) ng/L] was significantly higher than that of patients with bacterial pneumonia [(13.1+/-5.2) ng/L], fungal colonization [(12.7+/-5.1) ng/L], and healthy controls [(11.7+/-3.5) ng/L], P<0.01. The concentration of 1, 3-beta-D-glucan in patients with bacterial pneumonia was not different as compared to that of patients with fungal colonization, and healthy controls, P>0.05. The concentration of 1, 3-beta-D-glucan in plasma of patients with invasive aspergillosis and invasive candidiasis were (24.7+/-5.8) ng/L and (33.3+/-11.4) ng/L, respectively, the difference being not significant, P>0.05. The concentration of 1, 3-beta-D-glucan in plasma of a patients with invasive pulmonary Cryptococcus neoformans infection and a patient with histoplasmosis were 13.6 ng/L and 25.7 ng/L, respectively. If 20 ng/L was taken as the cut-off value, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 1, 3-beta-D-glucan were 84%, 91%, 84% and 91% respectively.. The concentration of 1, 3-beta-D-glucan in plasma of patients with IFI increases markedly, which indicates that the detection of 1, 3-beta-D-glucan in plasma is a useful method to diagnose IFI, but can not be used to differentiate aspergillosis from yeast fungus infection. If Fungitec-G kit is used to detect 1, 3-beta-D-glucan and 20 ng/L is used as the cut-off value, the sensitivity and specificity for IFI are high.

Topics: Adult; Aged; beta-Glucans; Case-Control Studies; Female; Humans; Lung Diseases, Fungal; Male; Middle Aged; Mycoses; Proteoglycans; Sensitivity and Specificity; Young Adult

Invasive fungal infection remains a major challenge in liver transplantation and the mortality rate is high. Early diagnosis and treatment are required for better results.. We prospectively measured plasma (1 --> 3)beta-D-glucan (BDG) levels in 180 living donor liver transplant recipients for 1 year after surgery. Fungal infection was defined as proposed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group. Preemptive treatment (intravenous fluconazole and trimethoprim-sulfamethoxazole) was started when the BDG level was greater than 40 pg/ml.. Twenty-four patients (13%) were diagnosed with invasive fungal infection. The responsible pathogens included Candida spp. in 14 cases, Aspergillus fumigatus in 5, Cryptococcus neoformans in 3, and Pneumocystis jiroveci in 2. Preemptive treatment was performed in 22% of patients (n = 40). Renal impairment and mild gastrointestinal intolerance due to the drugs were observed in 28% (11/40) of patients during treatment. Among them 14 patients were diagnosed with fungal infection including seven candidiasis, five aspergillosis, and two Pneumocystis jiroveci pneumonia. The sensitivity and specificity of BDG for overall fungal infection was 58% and 83%, respectively, with a positive predictive value of 35% and a negative predictive value of 93%, and a positive likelihood ratio of 3.41 and a negative likelihood ratio of 1.98. The overall mortality for fungal infection in our series was 0.6%.. Although the sensitivity and positive predictive value were low, the low mortality rate after fungal infection and the mild side effects of the preemptive treatment might justify our therapeutic strategy. Based on the effectiveness, this strategy warrants further investigation.

Topics: Antifungal Agents; beta-Glucans; Female; Humans; Liver Transplantation; Male; Middle Aged; Mycoses; Predictive Value of Tests; Prospective Studies; Proteoglycans; Sensitivity and Specificity

Topics: Animals; beta-Glucans; Humans; Immunologic Factors; Mycoses

The strong microbicidal effects of an engineered synthetic killer peptide (KP), which functionally mimics a fungal killer toxin, have been demonstrated extensively. Beta-glucan has been identified as a receptor for KP on fungal cell walls. Although the direct microbicidal and related therapeutic effects have been studied in depth, no information currently exists about the interaction of KP with immune cells. In this study, we exploited the possibility of KP binding to different murine immune cell populations. The results demonstrate that KP binds selectively to dendritic cells (DC) and to a lesser extent, to macrophages but not to lymphocytes and neutrophils; KP binding possibly occurs through major histocompatibility complex (MHC) class II, CD16/32, and cellular molecules recognized by anti-specific intercellular adhesion molecule-grabbing nonintegrin R1 antibodies; and KP modulates the expression of costimulatory and MHC molecules on DC and improves their capacity to induce lymphocyte proliferation. These findings provide evidence that this synthetic KP interacts selectively with DC and modulating their multiple functions, might also serve to improve the immune antimicrobial response.

Topics: Animals; Antifungal Agents; beta-Glucans; Cell Proliferation; Cells, Cultured; Dendritic Cells; Histocompatibility Antigens Class II; Immunity, Cellular; Leukocytes; Mice; Mice, Inbred BALB C; Mycoses; Oligopeptides; Receptors, IgG

Topics: beta-Glucans; Humans; Mycoses; Predictive Value of Tests; Proteoglycans; Sensitivity and Specificity

Invasive fungal infection is a fatal complication in liver transplantation and it is very difficult to diagnose at the early stage. The aim of this study was to review our experience with invasive fungal infections in living donor liver transplantation (LDLT) and to analyze the risk factors and the impact of beta-D glucan. From 1991 to 2005, 96 LDLTs were performed in our institution and we measured the serum level of beta-D glucan in order to clarify the diagnosis. Invasive fungal infection was diagnosed based on clinical symptoms, culture, radiological evidence and beta-D glucan. Active fungal infection was treated with fluconazole, amphotericin B, flucytosine and micafungin. Risk factors both pre- and post- LDLT were analyzed. Candida albicans was the most frequently isolated species (70%). The risk factors identified by univariate analysis include the following four conditions: acute blood purification (plasma exchange with or without continuous hemodiafiltration), hepatic vein complications, renal failure and respiratory failure. By logistic regression analysis, hepatic vein complications and respiratory failure were identified as independent risk factors. The risk factors for invasive fungal infection of LDLT in Japan have not been well analyzed and this report will provide valuable information for the prevention of the fungal infection.

Topics: Adolescent; Adult; beta-Glucans; Biomarkers; Child; Child, Preschool; Female; Hepatic Veins; Humans; Infant; Liver Diseases; Liver Transplantation; Living Donors; Male; Middle Aged; Mycoses; Renal Insufficiency; Respiratory Insufficiency; Retrospective Studies; Risk Factors; Sensitivity and Specificity

Topics: beta-Glucans; Biological Assay; Candidiasis; Humans; Mycoses

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; beta-Glucans; Cross Reactions; False Positive Reactions; Humans; Injections, Intravenous; Mycoses; Proteoglycans

Forty-four intravenous antimicrobials were tested for the presence of (1-->3)-beta-d-glucan (BG). Colistin, ertapenem, cefazolin, trimethoprim-sulfamethoxazole, cefotaxime, cefepime, and ampicillin-sulbactam tested positive for BG at reconstituted-vial concentrations but not when diluted to usual maximum plasma concentrations. False-positive BG assays may occur when some antimicrobials are administered; however, this needs to be confirmed.

Topics: Anti-Bacterial Agents; beta-Glucans; False Positive Reactions; Humans; Injections, Intravenous; Mycoses; Proteoglycans; Reagent Kits, Diagnostic

We had reported that the rate of non-specific reaction in measurement of (1-->3)-beta-D-glucan was decreased by improvement of the alkaline pretreatment reagent of Fungitec G-test MK (MK assay). To compare the clinical usefulness between conventional MK assay and new MK assay using improved alkaline pretreatment reagent, 121 plasma samples were tested. The sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV) in conventional MK assay were 91.7%, 85.3%, 44.0% and 98.8%, respectively. Those in new MK assay were 75.0%, 91.6%, 52.9% and 96.7%, respectively. On the other hand, area under the curve (AUC) of receiver operating characteristic (ROC) analysis in conventional and new MK assay was 0.9175 and 0.9123 without a significant difference. It has been recognized that the sensitivity in conventional MK assay is higher than those in other beta-glucan assays. Then, the specificity of new MK assay was improved by using improved alkaline pretreatment reagent, without decreasing the sensitivity. Thus, the present findings indicate that the new MK assay is clinically quite useful.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alkalies; beta-Glucans; Female; Humans; Male; Middle Aged; Mycoses; Sensitivity and Specificity

Measurement of (1-->3)-beta-D-Glucan (BG) has emerged as an adjunct diagnostic strategy for invasive fungal infections (IFI).. Subjects at 6 clinical sites in the United States were enrolled as either fungal infection-negative subjects (n = 170) or subjects with proven or probable IFI according to European Organization for the Research and Treatment of Cancer/Mycoses Study Group criteria (n = 163). A central laboratory and 4 sites performed assays. A single sample was obtained per patient and was evaluated using an assay to detect serum BG derived from fungal cell walls (range, 0 to > 7000 pg/mL).. At a cutoff of 60 pg/mL, the sensitivity and specificity of the assay were 69.9% and 87.1%, respectively, with a positive predictive value (PPV) of 83.8% and a negative predictive value (NPV) of 75.1%. At a cutoff value of 80 pg/mL, the sensitivity and specificity were 64.4% and 92.4%, respectively, with a PPV of 89% and an NPV of 73%. Of the 107 patients with proven candidiasis, 81.3% had positive results at a cutoff value of 60 pg/mL, and 77.6% had positive results at a cutoff value of 80 pg/mL. Of the 10 patients with aspergillosis, 80% had positive results at cutoff values of 60 and 80 pg/mL. The 3 subjects diagnosed with Fusarium species had positive results at a cutoff value of 60 pg/mL. Patients infected with Mucor or Rhizopus species (both of which lack BG) had negative results at both cutoff values, and of the 12 patients with Cryptococcus infection, 3 had positive results at a cutoff value of 60 pg/mL, and 2 had positive results at a cutoff value of 80 pg/mL. Of the subjects with proven positive results who were receiving antifungal therapy (n = 118), 72.9% had results positive for BG at a cutoff value of 60 pg/mL, and 69.5% had results positive for BG at a cutoff value of 80 pg/mL. The interlaboratory sample test r2 was 0.93.. Reproducible assay results with high specificity and high PPV in a multicenter setting demonstrate that use of an assay to detect serum BG derived from fungal cell walls is a useful diagnostic adjunct for IFI.

Topics: Adult; Aged; beta-Glucans; Female; Humans; Male; Middle Aged; Mycoses; Proteoglycans; Reproducibility of Results; Sensitivity and Specificity

Measurement of blood (1-->3)-beta-D-glucan is useful for early diagnosis and follow-up of the therapeutic process of deep seated mycoses. The Fungitec G test MK (Seikagaku Corp., Tokyo) kit using alkaline-pretreatment followed by chromogenic kinetic assay has been widely used in Japan because of its high sensitivity and easy handling of a large number of samples. Discrepancy in the levels of (1-->3)-beta-D-glucan and/or in the quantitative judgement, however, has been pointed out between this kit and other commercial kits. One of the reasons for this discrepancy has been reported to be non-specific reactions caused by substances other than beta-glucan. In this study, we have improved the alkaline pretreatment reagent by changing the concentration of KOH and salts, resulting in a marked reduction of the non-specific reaction. Recovery of standard beta-glucan added to plasma or serum after the improved pretreatment was 80 to 120%, and no amidolytic activity was detected either in plasma or in serum. By the improved pretreatment, the incidence of non-specific reactions, i.e., those that exceed the quantitation limit (3.9 pg/mL), were markedly decreased from 139 to 16 out of 200 plasma samples and from 106 to 22 out of 170 serum samples. The incidence of strong non-specific reactions, i.e., those that exceed the cut-off level (20 pg/mL), were also decreased from seven to one with plasma and seven to zero with serum samples. Correlation between corrected beta-glucan measurements by the current pretreatment and non-corrected ones by the improved pretreatment was quite good. The improved method is thus expected to decrease the frequency of non-specific false-positive reactions, with the high sensitivity of Fungitec G test MK.

Topics: Adult; beta-Glucans; Blood Chemical Analysis; False Positive Reactions; Female; Humans; Male; Mycoses; Reagent Kits, Diagnostic; Sensitivity and Specificity

Blood (1 --> 3)-beta-D-glucan (betaG) measurement is widely used as an effective sero-diagnostic method for deep-seated mycosis. Antitumor betaG (lentinan, schizophyllan) administration is known as one of the false-positive factors of blood betaG measurement. To understand the influence of administered betaG preparation to betaG measurement in blood, we compared the interfering effect of betaG administration in different betaG measuring methods.. betaG concentration in plasma was measured by three different methods.. betaG concentration was measured in plasma of 18 samples of 7 cases with betaG administration and 86 samples without betaG administration. The period after last betaG administration was three days to three years.. In the cases for which betaG was administered, blood betaG level drastically increased using the method which employs alkaline pretreatment. Even in the cases for which betaG was administered three years previously; betaG value measured by alkaline pretreatment was significantly high. Thus, interference of betaG administration in blood betaG measurement continued for years after the last administration.. Disparity in betaG values measured by different methods for betaG administered cases is due to differences among sample pretreatment methods. Conformation of administered betaG seemed to be transformed into a sensitive form to factor G by alkaline pretreatment. Especially in the case of the alkaline pretreatment method, betaG administration disturbance was much stronger than for dilution-heating pretreatment. Therefore, in suspected cases, it is important to pay attention to betaG administration during the previous few years.

Topics: Aged; beta-Glucans; Colorimetry; Female; Glucans; Humans; Male; Middle Aged; Mycoses; Nephelometry and Turbidimetry; Reagent Kits, Diagnostic; Time Factors

We investigated the detection of non-specific reactions in the measurement of plasma (1-->3)-beta-D-glucan (beta-glucan) and countermeasures against them using alkaline treatment, chromogenic automated kinetic assay (alkaline-kinetic assay). In this study, we reexamined the values of beta-glucan using the alkaline-kinetic assay with and without laminaran oligosaccharides (LO) as a kind of beta-glucan that blocks the Limulus reaction. The materials for this study were 584 plasma samples in which beta-glucan had been measured. These were taken from 232 patients in Kawasaki Medical School Hospital between January 2002 and March 2002. Non-specific reactions were judged by a calculated value under a LO additive condition. Determination as to whether or not the each time course of the Limulus reaction was influenced by a non-specific reaction was also studied by applying a non-specific reaction index set up independently. Non-specific reactions were recognized in 51.9% of the samples (81/156). The amount of non-specific reaction was 9.9 pg/ml or less in major samples. On the other hand, when the cut off value of the index for detection of non-specific reactions was set at 0.5, the sensitivity was 88.9% and specificity was 73.7%. The positive and negative predictive values were 93.5% and 60.9% respectively. Non-specific reactions can be approximately distinguished by applying the non-specific reaction index. By so doing, unnecessary initiation of anti fugal therapy in response to non-specific reactions can be avoided. Further prospective and radical studies of non-specific reactions in the alkaline-kinetic assay are necessary.

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; Chromogenic Compounds; Clinical Chemistry Tests; Female; Glucans; Humans; Limulus Test; Male; Middle Aged; Mycoses; Predictive Value of Tests; Reagent Kits, Diagnostic; Sensitivity and Specificity

Topics: beta-Glucans; Chromogenic Compounds; Evaluation Studies as Topic; Female; Glucans; Humans; Limulus Test; Male; Middle Aged; Mycoses; Reagent Kits, Diagnostic

The Glucatell (1-->3)- beta-D-glucan (BG) detection assay (Associates of Cape Cod) was studied as a diagnostic adjunct for invasive fungal infections (IFIs). On the basis of findings from a preliminary study of 30 candidemic subjects and 30 healthy adults, a serum BG level of >or=60 pg/mL was chosen as the cutoff. Testing was performed with serial serum samples obtained from 283 subjects with acute myeloid leukemia or myelodysplastic syndrome who were receiving antifungal prophylaxis. At least 1 serum sample was positive for BG at a median of 10 days before the clinical diagnosis in 100% of subjects with a proven or probable IFI. IFIs included candidiasis, fusariosis, trichosporonosis, and aspergillosis. Absence of a positive BG finding had a 100% negative predictive value, and the specificity of the test was 90% for a single positive test result and >or=96% for >or=2 sequential positive results. The Glucatell serum BG detection assay is highly sensitive and specific as a diagnostic adjunct for IFI.

Topics: Adult; beta-Glucans; Candidiasis; Fungemia; Humans; Leukemia, Myeloid, Acute; Limulus Test; Mycoses; Myelodysplastic Syndromes; Neutropenia; Polysaccharides; Predictive Value of Tests; Proteoglycans; Reagent Kits, Diagnostic; Sensitivity and Specificity

Clinical applications and in vitro studies show that all antimycotics are most effective against infection when applied as early as possible. An early diagnosis is, therefore, essential. At this time for aspergillosis and particularly candidosis, a statement is only possible by combining several diagnostic methods. Inflammatory parameters like procalcitonin, C-reactive protein and proinflammatory cytokines are most important evidence of infection. Antigen tests are more significant by higher sensitivity. Attention should be focused on the detection of mannan by ELISA test, beta-glucan and D-arabinitol. Given the present research level in the field of proteomics, the diagnostic importance of transmembranal receptor proteins or other regulatory proteins seems promising.

Topics: Antifungal Agents; Antigens, Fungal; beta-Glucans; C-Reactive Protein; Calcitonin; Cytokines; Early Diagnosis; Mannans; Mycoses; Protein Precursors; Sugar Alcohols

beta-Glucan Test MARUHA for high sensitive diagnosis of deep mycosis which was developed recently detects (1-->3)-beta-D-glucan, a component of the cell wall. The performance of beta-Glucan Test MARUHA is evaluated in this report. Although existing methods to detect (1-->3)-beta-D-glucan have trouble with sulfa drugs, hemolysis, and immunoglobulin G (IgG), these problems were overcome by the beta-Glucan Test MARUHA: No effect was observed for beta-Glucan Test MARUHA at lower than 200 micrograms/ml, 500 mg/dl, and 6,000 mg/dl of sulfa drugs, hemoglobin, and IgG, respectively. The effect of drugs administrated on the measurement value of beta-glucan Test MARUHA was checked at several concentrations. However, almost no effect of drugs, such as, 5 kinds of antifungals, 8 kinds of antibiotics, a kind of antibacterial, 2 kinds of infusions, and a kind of contrast media was observed at the practical concentrations.

Topics: beta-Glucans; Biomarkers; Evaluation Studies as Topic; Glucans; Humans; Mycoses; Reagent Kits, Diagnostic; Sensitivity and Specificity

Using Amebocyte lysate of horseshoe crab to measure (1-->3)-beta-D-glucan specifically, a component of the cell wall, several kinds of diagnostic methods for deep mycosis are in practical use in Japan. However, the most important problem is that the judgment of positive or negative is method dependent. To elucidate the cause of the problem, each measurement value of the identical sample by four methods, beta-Glucan Test Maruha (MARUHA), beta-Glucan Test Wako (WAKO). FUNGITEC G Test (FUNGITEC-G) and FUNGITEC G Test MK (FUNGITEC-MK) was compared with the clinical data using 119 cases and 289 tests. Each case was divided into three groups; proven fungal infection, probable fungal infection and non-fungal infection. The negative cases for all the methods tested in the groups of proven fungal infection and probable fungal infection were allergic bronchopulmonary aspergillosis and cryptococcosis, and that for all the methods tested except FUNGITEC-MK method in the group was pulmonary aspergilloma. It seems that these cases cannot be detected correctly by only measuring (1-->3)-beta-D-glucan. On the other hand, the ratio of false positive, positive for non-fungal infection group was high in the case of FUNGITEC-MK. About 23% against the total case was positive for FUNGITEC-MK method, but negative for MARUHA, WAKO, and FUNGITEC-G methods. Although the difference of the sensitivity among four methods was not observed, the specificity, the diagnostic efficiency, and the positive predictive value of FUNGITEC-MK method were remarkably lower than those of the other methods due to false positive measurement. In conclusion, MARUHA, WAKO and FUNGITEC-G except FUNGITEC-MK is not method dependent. It is suggested that FUNGITEC-MK detects non-specific reaction resulted in false positive.

Topics: beta-Glucans; Glucans; Humans; Mycoses; Reagent Kits, Diagnostic; Sensitivity and Specificity

The level of (1-->3)-beta-D-glucan in blood is a diagnostic index of fungal infection because it is released from the fungal cell wall. However, high levels of plasma (1-->3)-beta-D-glucan in patients administered blood components may give false positive results. High levels of (1-->3)-beta-D-glucan have been detected in blood components. We suspected that (1-->3)-beta-D-glucan from cellulose filters had been eluted into blood components by filtration in the manufacturing process. To investigate the contamination of blood components by (1-->3)-beta-D-glucan from cellulose filters, in vitro experiments were performed by using six cellulose filters and a nylon filter. Human serum albumin (HSA) solution (100 ml) was flowed through each filter after rinsing with 100 ml of distilled water, and (1-->3)-beta-D-glucan in each fraction was determined by Fungitec G test MK. The concentration of (1-->3)-beta-D-glucan eluted from cellulose filters in 100-ml distilled water fractions ranged from 6 to 207 pg/ml, and that of HSA fractions ranged from 33 to 20,784 pg/ml. These data showed that remarkably higher (1-->3)-beta-D-glucan levels were detected in HSA fractions flowed through cellulose filters in spite of advance rinsing with 100 ml of distilled water. In the case of a nylon filter, (1-->3)-beta-D-glucan was not eluted in either fraction. These results indicate that (1-->3)-beta-D-glucan contamination in blood components is caused by filtration with cellulose filters in the manufacturing process.

Topics: beta-Glucans; Blood Chemical Analysis; Cellulose; False Positive Reactions; Filtration; Glucans; Humans; In Vitro Techniques; Manufactured Materials; Membranes, Artificial; Mycoses

The false-positive elevation of plasma (1-->3)-beta-D-glucan level, a serodiagnostic test for deep-seated mycosis, is suspected in patients administered with blood components.. (1-->3)-beta-D-Glucan and endotoxin levels in blood components consisting of 12 albumins, 8 immunoglobulins, and 3 blood coagulation factors were measured by fungal infection tests (Fungitec G-test, Seikagaku Co.; the Wako WB003 test, Wako Pure Chemical Industries; and the Endospec ES test, Seikagaku Co.). In vitro release of (1-->3)-beta-D-glucan from the depth-type filters made by cellulose membrane to process blood components was analyzed through an in vitro filtration process as a source of (1-->3)-beta-D-glucan in blood components.. The amounts of (1-->3)-beta-D-glucan in blood components ranged from 0 to 7510 pg per mL in the Fungitec G-test, with wide variations among brands. The positive rates over 20 pg per mL were 75 percent in albumin solutions, 40 percent in blood coagulation factors, and 63 percent in immunoglobulin solutions. (1-->3)-beta-D-Glucan levels released from the five depth filters ranged from 5 to 2516 pg per mL. The (1-->3)-beta-D-glucan level in filtration fluid was decreased by rinsing with distilled water, but rebounded again during the albumin filtration process.. Depth filters are considered the source of (1-->3)-beta-D-glucan content in some blood components.

Topics: Artifacts; Bacterial Proteins; beta-Glucans; Biomarkers; Blood Coagulation Factors; Blood Component Transfusion; Blood Proteins; Cell Wall; Cellulose; Endotoxins; False Positive Reactions; Filtration; Fungi; Glucans; Glycoside Hydrolases; Humans; Immunoglobulins; Membranes, Artificial; Mycoses; Reagent Kits, Diagnostic; Serum Albumin; Solubility; Solutions

Determination of the blood (1-->3)-beta-D-glucan (beta-DG) concentration is a sensitive marker to detect the presence of deep mycosis and fungal infections. Although cellulose material is known to contain beta-DG, the influence of a cellulose dialyzer membrane on the blood beta-DG level remains to be elucidated. In this study, we determined the plasma beta-DG levels in dialysis outpatients using either a modified regenerated cellulose (MRC) or a synthetic polysulfone (PS) membrane for more than 3 months. Plasma beta-DG levels were extremely high in patients using the MRC (2,778 +/- 549 pg/ml, n = 9) but not the PS membrane (18.8 +/- 3.7 pg/ml, n = 8) compared to normal ranges (<20 pg/ml). A single dialysis session using the MRC membrane further increased blood beta-DG values to 5,561 +/- 722 pg/ml (p < 0.01). After changing the membranes from MRC to PS, the blood beta-DG levels gradually decreased and reached 29.6 +/- 6.0 pg/ml at 6 months. In contrast, the PS membrane did not affect plasma beta-DG levels after a single dialysis session (16.0 +/- 3.9 pg/ml) or 4 months later (24.0 +/- 4.9 pg/ml). These findings suggested that a cellulose membrane could influence the measurement of blood beta-DG concentrations in the long-term. Careful assessment is required to diagnose the presence of fungal infection in HD patients using a cellulose membrane.

Topics: Aged; beta-Glucans; Biocompatible Materials; Cellulose; False Positive Reactions; Glucans; Humans; Kidney Failure, Chronic; Membranes, Artificial; Middle Aged; Mycoses; Polymers; Renal Dialysis; Sulfones

The measurement of serum (1-3)-beta-D-glucan (beta-glucan) in cases with deep seated mycosis is a useful diagnostic method. Beta-glucan has usually been measured using two different methods: by an alkali treatment, chromogenic automated kinetic assay (chromogenic assay), and by detergent dilution and heating methods, kinetic turbidimetric assay (turbidimetric assay). However, there are often large discrepancies in the beta-glucan values measured by these two methods. In this study, we reexamined the values of beta-glucan obtained by the two techniques, using 343 serum samples from 146 patients who had been treated in Kawasaki Medical School between January 1999 and May 1999, and then analyzed the reasons for the differences. Serum beta-glucan results measured were evaluated by segregating them into three clinical categories: cases with proven deep mycosis, cases with probable deep mycosis and cases without deep mycosis. In addition, the beta-glucan in the samples was suppressed by carboxy-methylated curdlan (CM-curdlan), and then was remeasured to find a non-specific reaction. Although a certain correlation was found between the serum beta-glucan results measured by the two methods, the values measured by the chromogenic assay were, in general, higher than those measured by the turbidimetric assay. There were also many samples in the cases without deep mycosis that showed positive values with the chromogenic assay, but not with the turbidimetric assay. With the turbidimetric assay, the addition of CM-curdlan suppressed the values of beta-glucan in all samples; however, when measured by the chromogenic assay the values in many samples remained high. These results suggest that a non-specific reaction which did not include beta-glucan was detected by the chromogenic assay. Further studies are needed to evaluate the characteristics and comparable usefulness of the two assays.

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; Biomarkers; Colorimetry; Female; Glucans; Humans; Male; Middle Aged; Mycoses; Nephelometry and Turbidimetry; Reagent Kits, Diagnostic; Sensitivity and Specificity

The clinical features of invasive deep mycosis in the critical care center was studied and the usefulness for determinations of plasma (1-->3)-beta-D-glucan, one of the major structural components of fungi, in making the diagnosis of deep mycosis was evaluated in comparison with that of blood culture and candida antigen titer using CAND-tec kit. A total of 92 febrile patients (mean age = 54.5 yr., M/F = 70/22) in our critical care center were enrolled in this study. Seventeen out of the 92 febrile patients (18.5%) were those with deep mycosis. In the deep mycosis group, there were 10 patients with fungal panperitonitis, 5 with fungaemia, one with candidal pneumonia and one with candidal empyema. A total of 52 blood samples were obtained from 17 patients with deep mycosis. Forty five out of the 52 blood samples (86.5%) were positive for serum (1-->3)-beta-D-glucan while only 10 were culture-positive. In contrast, six (15.0%) out of the 40 blood samples were obtained from 17 patients with deep mycosis were positive for candida antigen by CAND-tec kit. In the critical care center, deep mycosis is a common infection and determination of serum concentration of (1-->3)-beta-D-glucan is found to be a very useful examination in screening of deep mycosis with high sensitivity and specificity.

Topics: Antigens, Fungal; beta-Glucans; Candida; Emergency Medical Services; Female; Glucans; Humans; Male; Middle Aged; Mycoses; Sensitivity and Specificity

The present multicentre clinical study was conducted to assess the clinical utility of a new diagnostic method for deep mycosis in which (1-->3)-beta-D-glucan, a fungal cell wall component existing in plasma, was quantitatively measured by the kinetic turbidimetric Limulus test (WB003). Plasma (1-->3)-beta-D-glucan concentrations were 0.57 +/- 0.10 microgram/l in 92 healthy subjects and 0.62 +/- 0.32 microgram/l in 26 patients with non-mycotic diseases (disease control group). In comparison with these healthy subjects and patients with non-mycotic diseases, patients with mycosis had significantly higher plasma (1-->3)-beta-D-glucan concentrations: 19.63 +/- 73.28 micrograms/l in 12 patients with candidaemia, 11.28 +/- 21.42 micrograms/l in 7 patients with urinary Candida infection, 4.84 +/- 12.71 micrograms/l in 5 patients with pulmonary candidiasis, and 12.21 +/- 31.31 micrograms/l in 4 patients with invasive pulmonary aspergillosis. On the statistical analysis of these data, a cut-off value was set at 1.0 microgram/l. Using this cut-off value, 3 patients with pulmonary cryptococcosis and 4 patients (4/6) with pulmonary aspergilloma were all negative with low plasma (1-->3-beta-D-glucan levels. The test WB003 provided equivalent or higher efficiency of diagnosis of candidiasis and aspergillosis, in comparison with commercially available antigen detection kits, demonstrating its utility as a diagnostic reagent. It may also be useful in assessing therapeutic effectiveness when used periodically after treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aspergillosis; beta-Glucans; Candidiasis; Cryptococcosis; Diagnostic Errors; Evaluation Studies as Topic; Female; Fungemia; Glucans; Humans; Kinetics; Limulus Test; Lung Diseases, Fungal; Male; Middle Aged; Mycoses; Nephelometry and Turbidimetry; Time Factors; Urinary Tract Infections

The Measurement of serum (1-->3)-beta-D-glucan (beta-glucan) has been considered to be useful in the early diagnosis of deep mycosis. In this study, we investigated the clinical significance of beta-glucan in pleural effusion or liquor from patients with various conditions. beta-glucan was measured in 29 samples of pleural effusion from 27 patients (male: 17, female: 10 median age: 62.1). Two patients undergoing hemodialysis treatment were excluded from the study of normal range of beta-glucan in these samples. beta-glucan was also measured in 39 samples of liquor from 23 inpatients (male: 15, female: 8 median age: 48.4) with certain neurological disorders. In these cases, only two patients had deep mycosis. beta-glucan in the pleural effusion from a patient with Aspergillus pyothorax showed an extremely high value of more than 1100 pg/ml. Slight elevation of beta-glucan was observed in the spinal fluid from a patient with cryptococal, meningitis. In the other cases with no mycotic infection or any factor influencing the value of beta-glucan, beta-glucan in pleural effusion and spinal fluid were generally lower than the normal range of serum samples. However, there is false positive elevation of beta-glucan in pleural effusion. The above results indicated that measurement of beta-glucan in pleural effusion or spinal fluid may be useful for the diagnosis of mycotic infection as the cause of pleuritis or meningitis.

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; Biomarkers; Female; Glucans; Humans; Male; Middle Aged; Mycoses; Pleural Effusion

(1-->3)-beta-D-glucan is a characteristic fungal cell-wall constituent. To assess the clinical usefulness of this glucan in screening for invasive fungal infection or fungal febrile episodes, we measured the plasma concentration at the time of routine blood culture in 202 febrile episodes by means of factor G, a horseshoe-crab coagulation enzyme that is extremely sensitive to this polysaccharide. With a plasma cut-off value of 20 pg/mL, 37 of 41 episodes of definite fungal infections (confirmed at necropsy or by microbiology) had positive results (sensitivity 90%). All of 59 episodes of non-fungal infections, tumour fever, or collagen diseases had concentrations below the cut-off value (specificity 100%). Of 102 episodes of fever of unknown origin, 26 had plasma glucan concentrations of more than 20 pg/mL. With those 102 cases taken as non-fungal infections, the positive predictive value of the test was estimated as 59% (37/63), the negative predictive value as 97% (135/139), and the efficiency as 85% (172/202). The positive predictive value should improve if there were a sensitive gold standard that could discriminate fungal from non-fungal infections. Causative fungi included candida, aspergillus, cryptococcus, and trichosporon. Determination of plasma (1-->3)-beta-D-glucan with factor G is a highly sensitive and specific test for invasive deep mycosis and fungal febrile episodes, and will substantially benefit immunocompromised patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aspergillosis; beta-Glucans; Blood Coagulation Factors; Candidiasis; Child; Child, Preschool; Female; Fever; Fungemia; Glucans; Humans; Male; Middle Aged; Mycoses; Sensitivity and Specificity; Serine Endopeptidases

Efficacy of fluconazole (FLCZ), an anti-fungal agent of triazole derivatives, was evaluated in patients with systemic mycoses and suspected mycoses associated with hematologic malignancies including leukemia, myelodysplastic syndrome and malignant lymphoma. Plasma beta-D-glycan levels, the differences between the levels determined toxicolor test and in endospecy test, were also investigated. Fourteen patients with systemic mycoses and 31 patients with suspected mycotic infections were treated with intravenous administration of FLCZ at a daily dose of 400 mg. Excellent to good responses were observed in 4 of the 14 patients (28.6%) with definitive diagnosis of mycosis, and in 18 of the 31 patients (58.1%) with suspected fungal infections, with an overall efficacy rate of 48.9% (22/45). Levels of plasma beta-D-glycan correlated well with efficacies of FLCZ in 19 of 30 patients. In several cases, however, plasma beta-D-glucan levels were low during the entire course of treatment. Even in 10 cases of definite mycosis, 4 cases showed low levels of plasma beta-D-glucan (below 15 pg/ml by repeated determinations). The results indicate that FLCZ is an effective agent for the treatment of severe systemic fungal infections in patients with hematologic disorders. Deep seated mycosis cannot be ruled out even when its plasma levels of beta-D-glucan are low.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta-Glucans; Biomarkers; Drug Evaluation; Female; Fluconazole; Glucans; Humans; Leukemia; Lymphoma; Male; Middle Aged; Mycoses

An assessment has been made regarding usefulness of measuring beta-D-glucan (beta-glucan) as fungal serodiagnosis in 50 cases of fungal infection with hematological diseases. Further, an assessment has been made regarding relation between hematological findings and therapeutic effect by administering miconazole, an antifungal agent (MCZ: Florid, clinically to the subjects. Positivity of beta-glucan (beta-glucan > or = 10 pg/ml) was observed in 54.5% (24/44), and the effective rate of MCZ in the positive cases was 75.0% (18/24). In the cases in whom fungus was detected, beta-glucan-positive rate was 50.0% (8/16), and MCZ-effective rate in beta-glucan-positive cases was 62.5% (5/8). The total effective rate of MCZ was 80% (40/50). Side effects were observed in 3 cases, but continual administration of MCZ was possible in all of the 3 cases. By the assessment regarding the relation between hematological findings and therapeutic effect of MCZ, it was found that the effective rates in the cases who underwent a transition with neutrophil and lymphocyte counts less than 500/microliters during the period of MCZ administration were 64.7% (11/17) and 50% (5/10), respectively, and large effects were observed in the cases who underwent a transition with the neutrophil and lymphocyte counts more than 500/microliters was 86.7% (19/22) and 91.7% (22/24), respectively. These results suggested that lymphocytes rather than neutrophils had an important role in the morbidity of fungal infection. It was noteworthy that MCZ was effective for the treatment of deep seated mycosis and significant effective rate was obtained in the group of patients who had neutrophils and lymphocytes less than 500/microliters.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta-Glucans; Child; Female; Glucans; Hematologic Diseases; Humans; Male; Miconazole; Middle Aged; Mycoses; Serologic Tests

The number of deep mycosis has been increasing because of increases in immunocompromised hosts and in fungal colonization associated with increasing use of broad-spectrum antibacterial antibiotics. Based on these phenomenon, a simple test method for an early diagnosis of deep mycosis is urgently desired. We therefore investigated the usefulness of assaying a fungal cell component, (1-->3)-beta-D-glucan (beta-glucan). The amount of beta-glucan was obtained from the difference between the amounts determined using Toxicolor and Endospecy, and the serum levels of more than 10 pg/ml were considered positive signs for beta-glucan. The following results were obtained: We found that beta-glucan was positive in 75% of the patients who had been definitely diagnosed to have mycosis, and in 58.3% of the patients strongly suspected of mycosis. The numbers of beta-glucan positive patients' in these 2 groups of patients were significantly different from that in those without mycosis (14.7%, P < 0.05). Thus a usefulness of beta-glucan measurement for the diagnosis of mycosis was demonstrated. However, beta-glucan was sometimes negative even in patients with fungemia at an early phase of the disease and turned positive several days later. Even in a patient with definite lung mycosis, who had a latent circumscribed lesion (afebrile and CRP-negative), beta-glucan was also negative. From these findings, one should be aware that the beta-glucan test produces false negatives even in patients with definite mycosis and that the test should be repeated during the course of the disease.

Topics: Aged; beta-Glucans; Female; Glucans; Hematologic Diseases; Humans; Immunocompromised Host; Limulus Test; Male; Middle Aged; Mycoses

We present additional evidence that plasma from patients with deep-seated mycoses contains (1-->3)-beta-D-glucan. Digestion of such samples with endo-(1-->3)-beta-D-glucanase completely abolished the ability of the plasma to activate factor-G, a horseshoe crab coagulation enzyme that is extremely sensitive to this polysaccharide. Measurement of plasma (1-->3)-beta-D-glucan is a promising method for the diagnosis of deep-seated mycoses and for monitoring the response of these infections to antifungal therapy.

Topics: Amino Acid Sequence; beta-Glucans; Biomarkers; Glucan Endo-1,3-beta-D-Glucosidase; Glucans; Humans; Male; Middle Aged; Molecular Sequence Data; Mycoses

Topics: Antifungal Agents; Antigens, Fungal; beta-Glucans; Candida; Catheterization, Central Venous; Fluorescein Angiography; Fungi; Glucans; Humans; Latex Fixation Tests; Mycoses; Risk Factors

In order to correctly diagnose and treat severe postoperative infections, it may be critical to detect and differentiate between endotoxin derived from Gram-negative bacteria and/or beta-glucan derived from fungi. In addition to the chromogenic assay, the turbidimetric kinetic assay has been performed for the quantification of endotoxin in plasma using Limulus amebocyte lysate as previously reported. However, it is also known that beta-glucan triggers the coagulation of Limulus amebocyte lysate. In the present study, the differentiation of beta-glucan from endotoxin and its clinical application were studied. Endotoxin was able to be inactivated in plasma using one-tenth dilution by 10 per cent ethanol or distilled water, followed by heating at 100 degrees C for 120 min, without affecting the activity of coexisting beta-glucan. The treated sample was then subjected to the turbidimetric kinetic assay using Toxinometer ET-201. Using this method, as little as 30 pg/ml of beta-glucan in the plasma may be assayed separately, with the amount of circulating beta-glucan in the plasma of normal subjects being less than 50 pg/ml. On the other hand, in patients with a fungal infection, the amount of beta-glucan in their plasma was elevated significantly. Clinically, beta-glucanemia may often occur in severe postoperative infection even if fungi are not detected.

Topics: beta-Glucans; Candidiasis; Endotoxins; Escherichia coli Infections; Glucans; Humans; Mycoses; Pseudomonas aeruginosa; Pseudomonas Infections; Reference Values; Salmonella Infections; Surgical Wound Infection