galactomannan and Candidiasis

Invasive fungal diseases are important clinical problems that are often complicated by severe illness and therefore the inability to use invasive measures to definitively diagnose the disease. Tests for a range of fungal biomarkers that do not require an invasive sample-collection procedure have been incorporated into adult clinical practice, but pediatric data and pediatric-specific recommendations for some of these diagnostic tools are lacking. In this review, we summarize the published literature and contemporary strategies for using the biomarkers galactomannan, (1→3)-β-d-glucan, Candida mannan antigen and anti-mannan antibody, and fungal polymerase chain reaction for diagnosing invasive fungal disease in children. Data on biomarker use in neonates and children with cancer, history of hematopoietic stem cell transplant, or primary immunodeficiency are included. Fungal biomarker tests performed on blood, other body fluids, or tissue specimens represent promising adjuncts to the diagnostic armamentarium in populations with a high prevalence of invasive fungal disease, but substantial gaps exist in the correct use and interpretation of these diagnostic tools in pediatric patients.

Topics: Antibodies, Fungal; Antigens, Fungal; Aspergillosis; Aspergillus; beta-Glucans; Biomarkers; Candida; Candidiasis; Child; DNA, Fungal; Galactose; Humans; Immunoassay; Invasive Fungal Infections; Mannans; Polymerase Chain Reaction

The biomarkers galactomannan and 1,3-β-d-glucan have been well studied over the past years and are gaining a role in the diagnosis of invasive fungal infections. Although not as well studied until recently, molecular methods for the diagnosis of invasive fungal infection are also being evaluated. Outcomes data for molecular testing are expanding, but have not yet provided enough evidence for inclusion of molecular diagnostics in formal clinical guidelines. Lack of standardization and validation of the various molecular assays and platforms has hindered their widespread acceptance in the evaluation of invasive fungal infections, although the future is promising.

Topics: Aspergillosis; beta-Glucans; Biomarkers; Bronchoalveolar Lavage Fluid; Candidiasis; False Positive Reactions; Galactose; Humans; Mannans; Pathology, Molecular; Polymerase Chain Reaction; Predictive Value of Tests; Sugar Alcohols

Invasive fungal infections (IFIs) are difficult to diagnose, especially early in the course of infection when antifungal therapy is most effective. There are two commercially available biomarker assays useful for detection of the IFIs most commonly seen in patients with hematologic malignancies, the galactomannan and beta glucan assays. The former is specific for aspergillosis, the latter positive for not only Aspergillus and Candida species, but several other clinically relevant fungal pathogens as well. Both have good assay performance characteristics, provide rapid test results, are widely available, can be assayed non-invasively, and are positive early in the course of infection, often before onset of signs and symptoms of infection. Adoption of these assays into clinical practice has led to reduced need to perform invasive procedures to obtain deep tissue to establish the diagnosis of invasive fungal infections. Improved survival rates from aspergillosis are, in part, due to earlier detection of infection and earlier therapy.

Topics: Acute Disease; Aspergillosis; Aspergillus; beta-Glucans; Biomarkers; Candida; Candidiasis; Galactose; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Mannans; Transplantation, Homologous

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

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

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

Recognition and treatment of invasive fungal infections in acute leukemia and hematopoietic stem cell transplant patients are important clinical challenges. New diagnostic tools, such as fungal serologic assays and high-resolution CT scans, offer the hope for earlier initiation of antifungal therapy and improved treatment results. New antifungal agents offer choices that in some cases are less toxic than older drugs and in other cases are more efficacious. Combining the new diagnostic tools with new drugs, novel strategies are being evaluated to change our approaches to these deadly infections.

Topics: Antibiotic Prophylaxis; Antifungal Agents; Aspergillosis; Candidiasis; Clinical Trials as Topic; Galactose; Glucans; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Mannans

We assessed the success rate of empirical antifungal therapy with itraconazole and evaluated risk factors for predicting the failure of empirical antifungal therapy. A multicenter, prospective, observational study was performed in patients with hematological malignancies who had neutropenic fever and received empirical antifungal therapy with itraconazole at 22 centers. A total of 391 patients who had abnormal findings on chest imaging tests (31.0%) or a positive result of enzyme immunoassay for serum galactomannan (17.6%) showed a 56.5% overall success rate. Positive galactomannan tests before the initiation of the empirical antifungal therapy (P=0.026, hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.10-4.69) and abnormal findings on the chest imaging tests before initiation of the empirical antifungal therapy (P=0.022, HR, 2.03; 95% CI, 1.11-3.71) were significantly associated with poor outcomes for the empirical antifungal therapy. Eight patients (2.0%) had premature discontinuation of itraconazole therapy due to toxicity. It is suggested that positive galactomannan tests and abnormal findings on the chest imaging tests at the time of initiation of the empirical antifungal therapy are risk factors for predicting the failure of the empirical antifungal therapy with itraconazole. (Clinical Trial Registration on National Cancer Institute website, NCT01060462).

Topics: 14-alpha Demethylase Inhibitors; Adolescent; Adult; Aged; Antifungal Agents; Aspergillosis; Candidiasis; Coccidioidomycosis; Febrile Neutropenia; Female; Galactose; Hematologic Neoplasms; Humans; Itraconazole; Male; Mannans; Middle Aged; Prospective Studies; Treatment Outcome; Young Adult

(1-->3)-beta-D-Glucan is one of the major structural components of fungi, and it seems that it can be detected by the fractionated (1-->3)-beta-D-glucan-sensitive component from a Limulus lysate, factor G. We evaluated the concentration of (1-->3)-beta-D-glucan by using factor G and other fungal antigens in 24 patients with clinical evidence of mycosis and 36 healthy subjects. The mean concentration of (1-->3)-beta-D-glucan in the plasma of the healthy subjects was found to be 2.7 +/- 1.9 pg/ml (range, < 6.9 pg/ml), and it was found to be substantially higher in all 11 patients with candidemia (mean, 2,207.4 pg/ml; range, 325.4 to 8,449.0 pg/ml). Eight of those 11 patients with candidemia (73%) were positive for the Cand-Tec heat-labile candida antigen and only 3 patients (27%) were positive for mannan antigen. Three patients with invasive pulmonary aspergillosis were positive for galactomannan and had, in addition, high concentrations of (1-->3)-beta-D-glucan (mean, 323.3 pg/ml; range, 27.0 to 894.0 pg/ml). All 10 patients with cryptococcosis (including 2 patients with probable cryptococcosis) were positive for cryptococcal antigen by the Eiken latex test; however, (1-->3)-beta-D-glucan levels were not elevated in these patients (mean, 7.0 pg/ml; range, < 16.5 pg/ml). Our results indicated that (1-->3)-beta-D-glucan levels are elevated in patients with candidiasis and aspergillosis but not in those with cryptococcosis.

Topics: Adult; Antigens, Fungal; Aspergillosis; beta-Glucans; Candidiasis; Cryptococcosis; Female; Fungemia; Galactose; Glucans; Humans; Limulus Test; Male; Mannans; Middle Aged; Serologic Tests

The incidence of Aspergillus and Candida CNS infection, which are characterised by high mortality rates, is underestimated. This underdiagnosis presumably results from the limitations of available diagnostic tools and the need for invasive sampling. Little is known about the role of serologic biomarkers in the setting of CNS aspergillosis and candidiasis.. Serum and cerebrospinal fluid (CSF; 10) samples of 19 patients, whose CNS specimens yielded growth of Aspergillus or Candida, were analysed for different biomarkers for fungal infection, that is galactomannan (GM), galactomannoprotein (GP), mannan, anti-mannan-antibodies and β-1,3-D-glucan (BDG). Serum and CSF specimens of time-matched patients (two each for every case of fungal CNS infection) were included as controls.. Galactomannan, GP and BDG seropositivity was found in one, two and three of five cases of CNS aspergillosis. BDG and mannan/anti-mannan-antibody sensitivity in proven CNS candidiasis was 40% and 20%, respectively. Applying the serum cut-off, sensitivity in CSF testing was 100% for GM and BDG and 50% for mannans. While serum specificity for all assays ranged from 89 to 97%, specificity for CSF BDG was only 70%. No false-positive GM results from CSF were obtained.. Sensitivity for diagnosing CNS aspergillosis and CNS candidiasis from serum is mediocre for all serological biomarkers. GM testing in CSF proved excellent performance. With a sensitivity of 100% but a specificity of only 70%, CSF BDG might be most useful when used in patients with a high pre-test probability.

Topics: Aspergillosis; Aspergillus; beta-Glucans; Biomarkers; Candida; Candidiasis; Central Nervous System; Galactose; Humans; Mannans; Sensitivity and Specificity

Topics: Adult; Aged; Aged, 80 and over; Antigens, Fungal; Aspergillosis; Candidiasis; Disaccharides; Europe; Female; Galactose; Humans; Intersectoral Collaboration; Invasive Fungal Infections; Male; Mannans; Mass Spectrometry; Middle Aged; Mucormycosis; Sensitivity and Specificity; Young Adult

Here, we report a patient developing a postoperative peritoneal infection by Aspergillus fumigatus. While galactomannan serum levels were negative throughout the time course, galactomannan levels in peritoneal fluids yielded high results. Serological testing of peritoneal fluids for fungal antigens might be a useful and easily applicable tool to support diagnosis of intraabdominal aspergillosis, which represents a rare type of invasive fungal infection.

Topics: Aged; Antigens, Fungal; Ascitic Fluid; Aspergillosis; Aspergillus fumigatus; Candida glabrata; Candidiasis; Galactose; Germany; Humans; Male; Mannans; Peritoneal Cavity; Peritonitis; Postoperative Complications; Thoracic Surgical Procedures

Candida lusitaniae is usually susceptible to echinocandins. Beta-1,3-glucan synthase encoded by FKS genes is the target of echinocandins. A few missense mutations in the C. lusitaniae FKS1 hot spot 1 (HS1) have been reported. We report here the rapid emergence of antifungal resistance in C. lusitaniae isolated during therapy with amphotericin B (AMB), caspofungin (CAS), and azoles for treatment of persistent candidemia in an immunocompromised child with severe enterocolitis and visceral adenoviral disease. As documented from restriction fragment length polymorphism (RFLP) and random amplified polymorphic DNA (RAPD) analysis, the five C. lusitaniae isolates examined were related to each other. From antifungal susceptibility and molecular analyses, 5 different profiles (P) were obtained. These profiles included the following: profile 1 (P1) (CAS MIC [μg/ml], 0.5; fluconazole [FLC] MIC, 0.25), determined while the patient was being treated with liposomal AMB for 3 months; P2 (FLC MIC [μg/ml], 0.25; CAS MIC, 4), while the patient was being treated with CAS for 2 weeks; P3 (CAS MIC [μg/ml], 0.5; FLC MIC, 32), while the patient was being treated with azoles and CAS initially followed by azoles alone for a week; P4 (CAS MIC [μg/ml], 8; FLC MIC, 8), while the patient was being treated with both drugs for 3 weeks; and P5 (AMB MIC [μg/ml], 0.125; CAS MIC, 8), while the patient was being treated with AMB and FLC for 2 weeks. CAS resistance was associated with resistance not only to micafungin and anidulafungin but also to AMB. Analysis of CAS resistance revealed 3 novel FKS1 mutations in CAS-resistant isolates (S638Y in P2; S631Y in P4; S638P in P5). While S638Y and -P are within HS1, S631Y is in close proximity to this domain but was confirmed to confer candin resistance using a site-directed mutagenesis approach. FLC resistance could be linked with overexpression of major facilitator gene 7 (MFS7) in C. lusitaniae P2 and P4 and was associated with resistance to 5-flurocytosine. This clinical report describes resistance of C. lusitaniae to all common antifungals. While candins or azole resistance followed monotherapy, multidrug antifungal resistance emerged during combined therapy.

Topics: Amino Acid Sequence; Antifungal Agents; beta-Glucans; Candida; Candidiasis; DNA, Fungal; Drug Monitoring; Drug Resistance, Multiple, Fungal; Female; Galactose; Humans; Immunocompromised Host; Infant; Leukemia, Myeloid, Acute; Mannans; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Polymorphism, Restriction Fragment Length

Invasive aspergillosis (IA) is associated with high mortality. Successful outcome with treatment is linked to early diagnosis. The utility of classic diagnostic methods, however, is limited.. To aid in the diagnosis of IA, we retrospectively assessed our diagnostic service, using real-time polymerase chain reaction (PCR) and galactomannan sandwich enzyme-linked immunosorbent assay (ELISA).. A total of 203 patients at risk of invasive fungal infection were screened by PCR, and 116 of the patients were also tested by ELISA. The patient group comprised 176 patients with hematological malignancy and 28 control patients with evidence of invasive candidal infection. Consensus European Organisation for Research and Treatment of Cancer and Mycoses Study Group criteria were used to classify fungal infection, which, by definition, excluded the PCR result. The PCR method was sensitive (up to 92.3% sensitivity) and specific (up to 94.6% specificity) and had good agreement with the galactomannan ELISA (76.7%) and high-resolution computed tomography scan results.. A negative PCR result can be used to rule out IA and to limit the need for empirical antifungal therapy; thus, it has a role in diagnosing IA infections, especially in combination with antigen testing. PCR-positive cases classified as "false positives" regularly reflect the limitations of classic microbiological procedures or restricted use of consensus clinical methods employed to classify infection.

Topics: Adolescent; Adult; Antifungal Agents; Antineoplastic Agents; Aspergillosis; Aspergillus; Blood; Candidiasis; Child; DNA, Fungal; Enzyme-Linked Immunosorbent Assay; Galactose; Hematologic Neoplasms; Humans; Mannans; Middle Aged; Opportunistic Infections; Polymerase Chain Reaction; Retrospective Studies; RNA, Fungal; Sensitivity and Specificity; Stem Cell Transplantation; Tomography, X-Ray Computed

Topics: Adolescent; Adult; Aged; Aspergillosis; Candidiasis; Enzyme-Linked Immunosorbent Assay; Galactose; Humans; Mannans; Middle Aged; Prospective Studies; Sensitivity and Specificity; Single-Blind Method

Mouse models of systemic and gastrointestinal infection with the yeast Candida albicans were used to investigate the ability of a commercial mannan antigen enzyme immunoassay and a commercial (1-->3) beta-D-glucan limulus assay to detect systemic infection and to differentiate between colonization and infection. Both assays were positive in all i.v. infected mice and negative in all uninfected control mice. In gastrointestinal infection both tests were positive whenever organ cultures were positive. In colonized mice with no detectable dissemination, there were mostly negative results with the glucan assay whereas the mannan assay was positive or intermediate in all colonized mice. Therefore, in the mouse model used, glucan detection appeared to be superior for differentiation between colonization and dissemination.

Topics: Animals; Candida albicans; Candidiasis; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Fungemia; Galactose; Gastrointestinal Diseases; Glucans; Linear Models; Mannans; Mice; Mice, Inbred BALB C; Probability; Sensitivity and Specificity

Micafungin (FK463) is an echinocandin that demonstrates potent in vitro antifungal activities against Candida and Aspergillus species. However, little is known about its comparative antifungal activities in persistently neutropenic hosts. We therefore investigated the plasma micafungin pharmacokinetics and antifungal activities of micafungin against experimental disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. The groups with disseminated candidiasis studied consisted of untreated controls (UCs); rabbits treated with desoxycholate amphotericin B (DAMB) at 1 mg/kg of body weight/day; or rabbits treated with micafungin at 0.25, 0.5, 1, and 2 mg/kg/day intravenously. Compared with the UCs, rabbits treated with micafungin or DAMB showed significant dosage-dependent clearance of Candida albicans from the liver, spleen, kidney, brain, eye, lung, and vena cava. These in vivo findings correlated with the results of in vitro time-kill assays that demonstrated that micafungin has concentration-dependent fungicidal activity. The groups with invasive pulmonary aspergillosis studied consisted of UCs; rabbits treated with DAMB; rabbits treated with liposomal amphotericin B (LAMB) at 5 mg/kg/day; and rabbits treated with micafungin at 0.5, 1, and 2 mg/kg/day. In comparison to the significant micafungin dosage-dependent reduction of the residual burden (in log CFU per gram) of C. albicans in tissue, micafungin-treated rabbits with invasive pulmonary aspergillosis had no reduction in the concentration of Aspergillus fumigatus in tissue. DAMB and LAMB significantly reduced the burdens of C. albicans and A. fumigatus in tissues (P < 0.01). Persistent galactomannan antigenemia in micafungin-treated rabbits correlated with the presence of an elevated burden of A. fumigatus in pulmonary tissue. By comparison, DAMB- and LAMB-treated animals had significantly reduced circulating galactomannan antigen levels. Despite a lack of clearance of A. fumigatus from the lungs, there was a significant improvement in the rate of survival (P < 0.001) and a reduction in the level of pulmonary infarction (P < 0.05) in micafungin-treated rabbits. In summary, micafungin demonstrated concentration-dependent and dosage-dependent clearance of C. albicans from persistently neutropenic rabbits with disseminated candidiasis but not of A. fumigatus from persistently neutropenic rabbits with invasive pulmonary aspergillosis.

Topics: Animals; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Candidiasis; Echinocandins; Galactose; Lipopeptides; Lipoproteins; Lung; Mannans; Micafungin; Neutropenia; Organ Size; Peptides, Cyclic; Rabbits

To improve the immunohistopathological diagnosis of systemic bovine mycoses, we have evaluated the utility of antifungal polyclonal and monoclonal antibodies, and peroxidase and alkaline phosphatase staining techniques. A rabbit polyclonal antibody to mannan from Candida albicans was specific for candidosis. The diagnosis of aspergillosis was accomplished using a rat monoclonal antibody to the galactofuran side chains of Aspergillus galactomannan. A murine monoclonal antibody reacting with weakly Con-A binding 41 and 46 kDa somatic antigens from Absidia corymbifera was used for immunostaining of zygomycetic hyphae. Peroxidase antiperoxidase (PAP) and alkaline phosphatase antialkaline phosphatase (APAAP) complexes were visualized using aminoethylcarbazole and fast red substrates. A green staining of PAP reactions with dioctyl sulfosuccinate sodium and 3,3',5,5'-tetramethylbenzidine (DONS/TMB) was effective for the demonstration of fungi in dual and triple infections. Tissue sections of experimentally infected mice were used to determine the sensitivity and specificity of the antibodies. Tissues obtained from 161 bovine mycotic lesions previously studied by indirect immunofluorescence staining were further evaluated using the three antibodies. In all of 45 lesions solely affected by aspergillosis and in three solely affected by candidosis the diagnoses were confirmed by the new evaluation. In 85 of 96 cases of single infections with zygomycetes the diagnosis was confirmed, while none of the antibodies reacted with fungal elements in the remaining 11 lesions. Aspergillus hyphae were detected in all three lesions with dual aspergillosis and zygomycosis, whereas zygomycetic material was confirmed in only two of these cases. A mixed infection of candidosis and zygomycosis in a lymph node was confirmed too. In 13 cases in which a diagnosis had not hitherto been obtained, aspergillosis and zygomycosis were recorded each in three cases.

Topics: Animals; Antibodies; Antibodies, Monoclonal; Antigens, Fungal; Aspergillosis; Aspergillus; Candidiasis; Cattle; Cattle Diseases; Female; Galactose; Immunoenzyme Techniques; Mannans; Mice; Mice, Inbred BALB C; Mycoses; Omasum; Placenta; Pregnancy; Rabbits