epiglucan and Pneumonia--Pneumocystis

β-glucan is the most abundant polysaccharide in the cell wall of

Topics: beta-Glucans; Cell Wall; Glucans; Pneumocystis; Pneumonia, Pneumocystis

Pneumocystis jirovecii pneumonia (PJP) can be a life-threatening opportunistic infection in immunocompromised hosts. The diagnosis can be challenging, often requiring semi-invasive respiratory sampling. The serum 1,3-β-D-glucan (BDG) assay has been proposed as a minimally invasive test for the presumptive diagnosis of PJP.. We carried out a systematic review and meta-analysis using articles in the English language published between January 1960 and September 2019. We estimated the pooled sensitivity and specificity of BDG testing using a bivariate random effects approach and compared test performance in human immunodeficiency virus (HIV) and non-HIV subgroups with meta-regression. Data from the pooled sensitivity and specificity were transformed to generate pre- and post-test probability curves.. Twenty-three studies were included. The pooled sensitivity and specificity of serum BDG testing for PJP were 91% (95%CI 87-94%) and 79% (95%CI 72-84%) respectively. The sensitivity in patients with HIV was better than in patients without (94%, 95%CI 91-96%) versus 86% (95%CI 78-91%) (p 0.02), with comparable specificity (83%, 95%CI 69-92% versus 83%, 95%CI 72-90%) (p 0.10). A negative BDG was only associated with a low post-test probability of PJP (≤5%) when the pre-test probability was low to intermediate (≤20% in non-HIV and ≤50% in HIV).. Among patients with a higher likelihood of PJP, the pooled sensitivity of BDG is insufficient to exclude infection. Similarly, for most cases, the pooled specificity is inadequate to diagnose PJP. Understanding the performance of BDG in the population being investigated is therefore essential to optimal clinical decision-making.

Topics: beta-Glucans; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Sensitivity and Specificity; Serologic Tests

Early diagnosis and prompt initiation of appropriate antimicrobial therapy are crucial steps in the management of patients with invasive fungal infections. However, the diagnosis of invasive mycoses remains a major challenge in clinical practice, because presenting symptoms may be subtle and non-invasive diagnostic assays often lack sensitivity and specificity. Diagnosis is often expressed on a scale of probability (proven, probable and possible) based on a constellation of imaging findings, microbiological tools and histopathology, as there is no stand-alone assay for diagnosis. Recent data suggest that the carbohydrate biomarker (1→3)-β-d-glucan may be useful in both the diagnosis and therapeutic monitoring of invasive fungal infections due to some yeasts, molds, and dimorphic fungi. In this paper, we review recent advances in the use of (1→3)-β-d-glucan to monitor clinical response to antifungal therapy and explore how this assay may be used in the future.

Topics: Animals; Antifungal Agents; Aspergillosis; beta-Glucans; Bronchoalveolar Lavage Fluid; Candidiasis; Humans; Invasive Fungal Infections; Meningitis, Fungal; Pneumonia, Pneumocystis

Pneumocystis jirovecii is a ubiquitous fungus, which causes pneumonia in humans. Diagnosis was hampered by the inability to culture the organism, and based on microscopic examination of respiratory samples or clinical presentation. New assays can assist in the diagnosis and even aid with the emergence of resistant infections. Areas covered: This manuscript will provide background information on Pneumocystis pneumonia (PcP). Diagnosis, from radiological to non-microbiological (e.g. Lactate dehydrogenase) and microbiological investigations (Microscopy, PCR, β-D-Glucan) will be discussed. Recommendations on prophylactic and therapeutic management will be covered. Expert commentary: PcP diagnosis using microscopy is far from optimal and false negatives will occur. With an incidence of 1% or less, the pre-test probability of not having PcP is 99% and testing is suited to excluding disease. Microscopy provides a high degree of diagnostic confidence but it is not infallible, and its lower sensitivity limits its application. Newer diagnostics (PCR, β-D-Glucan) can aid management and improve performance when testing less invasive specimens, such as upper respiratory samples or blood, alleviating clinical pressure. Combination testing may allow PcP to be both diagnosed and excluded, and molecular testing can assist in the detection of emerging resistant PcP.

Topics: Antifungal Agents; beta-Glucans; Biomarkers; Dapsone; Disease Management; Humans; Incidence; L-Lactate Dehydrogenase; Microscopy; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Proteoglycans; Radiography, Thoracic; Trimethoprim, Sulfamethoxazole Drug Combination

Pneumocystis jirovecii is a prototypical opportunistic pathogen, causing an asymptomatic or mild infection in normal hosts and fulminating pneumonia (Pneumocystis pneumonia, PCP) in immunocompromised hosts. PCP is a leading cause of morbidity and mortality in immunocompromised patients such as AIDS patients. Microscopic detection of cysts and trophic forms of P. jirovecii in respiratory secretions is simple and useful but may underestimate the P. jirovecii infection. Conventional polymerase chain reaction (PCR) and nested PCR increase the sensitivity and specificity to identify PCP and provide an approach to discriminate PCP from pulmonary P. jirovecii colonization, but the targeted genes and cut-off value from quantitative real-time PCR remain to be determined. Serum (1-3)-β-D-glucan level and the specific serum antibody titer are ancillary indicators for PCP diagnosis. The successful cultivation of P. jirovecii in vitro is an important progress for PCP research. The diagnosis of PCP relies on the combination of these laboratory examinations as well as the clinical presentations.

Topics: Antibodies, Fungal; beta-Glucans; Biomarkers; DNA, Fungal; Humans; Immunocompromised Host; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Proteoglycans; Sensitivity and Specificity

Pneumocystis jirovecii is the only fungus of its kind to be pathogenic in humans. It is primarily responsible for pneumonia (PJP). The key to understanding immune defences has focused on T-cells, mainly because of the HIV infection epidemic. Patients presenting with PJP all have a CD4 count below 200/mm(3). The introduction of systematic primary prophylaxis and the use of new anti-retroviral drugs have significantly reduced the incidence of this disease in the HIV-infected population, mainly in developed countries. The increasingly frequent use of corticosteroids, chemotherapy, and other immunosuppressive drugs has led to an outbreak of PJP in patients not infected by HIV. These patients presenting with PJP have more rapid and severe symptoms, sometimes atypical, leading to delay the initiation of a specific anti-infective therapy, sometimes a cause of death. However, the contribution of new diagnostic tools and a better understanding of patients at risk should improve their survival.

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; beta-Glucans; Connective Tissue Diseases; Drug Therapy, Combination; Early Diagnosis; HIV Seronegativity; Humans; Immunocompromised Host; Immunologic Deficiency Syndromes; Immunologic Factors; Immunosuppressive Agents; Neoplasms; Organ Transplantation; Pneumocystis carinii; Pneumocystis Infections; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Postoperative Complications; Prognosis; Radiography; Trimethoprim, Sulfamethoxazole Drug Combination

Pneumocystis jirovecii pneumonia (PCP) can affect various types of immunocompromised patients. We sought to evaluate the diagnostic accuracy of (1→3)-β-D-glucan (BDG) for the diagnosis of PCP. We carried out a meta-analysis of relevant studies, identified through PubMed and Scopus. Eligible studies were those that reported BDG diagnostic data in cases with documented PCP and controls with other conditions. Cases of invasive fungal infections and healthy controls were excluded. We performed a bivariate meta-analysis of sensitivity and specificity and constructed a hierarchical summary receiver operating characteristics (HSROC) curve. Fourteen studies were included in the meta-analysis. BDG data were analysed for 357 PCP cases and 1723 controls. The average (95% confidence interval) sensitivity and specificity of BDG were 94.8% (90.8-97.1%) and 86.3% (81.7-89.9%), respectively. The positive and negative likelihood ratios were 6.9 (5.1-9.3) and 0.06 (0.03-0.11), respectively. The area under the HSROC curve was 0.965 (0.945-0.978). Serum BDG shows excellent sensitivity and very good specificity in the diagnosis of PCP. Still, in clinical practice the test results should be interpreted in the context of the underlying clinical characteristics of the individual patient.

Topics: AIDS-Related Opportunistic Infections; beta-Glucans; Biomarkers; Chi-Square Distribution; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Predictive Value of Tests; Proteoglycans; ROC Curve; Sensitivity and Specificity

Serum 1,3-β-d-glucan (BG) assay may be helpful as a marker for the diagnosis of Pneumocystis jiroveci pneumonia (PJP) and invasive fungal infection (IFI). We conducted a systematic review to assess the diagnostic accuracy of this assay. We searched MEDLINE, Web of Science, Cochrane Collaboration databases, Ichushi-Web, reference lists of retrieved studies, and review articles. Our search included studies of serum BG assay that used (i) positive cytological or direct microscopic examination of sputum or bronchoalveolar lavage fluid for PJP and (ii) European Organization for Research and Treatment of Cancer or similar criteria for IFI as a reference standard and provided data to calculate sensitivity and specificity. Only major fungal infections such as invasive candidiasis and invasive aspergillosis were included in the IFI group. Twelve studies for PJP and 31 studies for IFI were included from January 1966 to November 2010. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC-SROC) for PJP were 96% (95% confidence interval [95% CI], 92% to 98%), 84% (95% CI, 83% to 86%), 102.3 (95% CI, 59.2 to 176.6) and 0.96 (95% CI, 0.94 to 0.99), respectively. No heterogeneity was found. For IFI, the values were 80% (95% CI, 77% to 82%), 82% (95% CI, 81% to 83%), 25.7 (95% CI, 15.0 to 44.1), and 0.88 (95% CI, 0.82 to 0.93). Heterogeneity was significant. The diagnostic accuracy of the BG assay is high for PJP and moderate for IFI. Because the sensitivity for PJP is particularly high, the BG assay can be used as a screening tool for PJP.

Topics: Aspergillosis; beta-Glucans; Candidiasis, Invasive; Female; Humans; Male; Middle Aged; Pneumonia, Pneumocystis; Proteoglycans; ROC Curve; Sensitivity and Specificity; Serum

During the past 30 years, major advances have been made in our understanding of HIV/AIDS and Pneumocystis pneumonia (PCP), but significant gaps remain. Pneumocystis is classified as a fungus and is host-species specific, but an understanding of its reservoir, mode of transmission, and pathogenesis is incomplete. PCP remains a frequent AIDS-defining diagnosis and is a frequent opportunistic pneumonia in the United States and in Europe, but comparable epidemiologic data from other areas of the world that are burdened with HIV/AIDS are limited. Pneumocystis cannot be cultured, and bronchoscopy with bronchoalveolar lavage is the gold standard procedure to diagnose PCP, but noninvasive diagnostic tests and biomarkers show promise that must be validated. Trimethoprim-sulfamethoxazole is the recommended first-line treatment and prophylaxis regimen, but putative trimethoprim-sulfamethoxazole drug resistance is an emerging concern. The International HIV-associated Opportunistic Pneumonias (IHOP) study was established to address these knowledge gaps. This review describes recent advances in the pathogenesis, epidemiology, diagnosis, and management of HIV-associated PCP and ongoing areas of clinical and translational research that are part of the IHOP study and the Longitudinal Studies of HIV-associated Lung Infections and Complications (Lung HIV).

Topics: Adrenal Cortex Hormones; AIDS-Related Opportunistic Infections; Anti-Infective Agents; beta-Glucans; Biomarkers; Bronchoalveolar Lavage; Bronchoscopy; CD4 Lymphocyte Count; Dihydropteroate Synthase; Drug Resistance, Fungal; HIV Infections; Humans; Mutation; Pneumocystis carinii; Pneumonia, Pneumocystis; Pneumothorax; Polymerase Chain Reaction; Primary Prevention; Radiography, Thoracic; S-Adenosylmethionine; Secondary Prevention; Tetrahydrofolate Dehydrogenase; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination

Non-HIV-infected populations are increasingly identified as being at risk for developing Pneumocystis jirovecii pneumonia (PJP). These patients typically present with severe disease and poorly tolerate invasive diagnostic procedures. This review examines recently reported risks for PJP in non-HIV populations and summarizes new diagnostic techniques.. PJP is associated with immunomodulatory drug therapies, including monoclonal antibody therapies such as tumour necrosis factor α antagonists, and calcineurin inhibitors. Underlying disease states include solid-organ transplantation, connective tissue and rheumatologic disorders, inflammatory bowel disease, haematological malignancies, and solid tumours. Modern diagnostic techniques [conventional PCR, quantitative PCR, (1→3)-β-D-glucan assays, and PET] are reviewed with respect to predictive value and clinical utility. In particular, current literature regarding validation and specificity of molecular diagnostic techniques is summarized, including application to minimally invasive specimens.. HIV-negative populations at risk for PJP can be identified. Conventional PCR increases diagnostic sensitivity but may detect asymptomatic colonization. Quantitative PCR demonstrates potential for distinguishing colonization from infection, but clinical validation is required. Serum (1→3)-β-D-glucan may be elevated in PJP, although standardized cut-off values for clinical infection have not been determined. Further validation of serum markers and molecular diagnostic methods is necessary for early and accurate diagnosis in non-HIV populations.

Topics: beta-Glucans; HIV Seronegativity; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Positron-Emission Tomography; Risk Factors

Pneumocystis jirovecii has emerged as an important pulmonary pathogen. Historically associated with the immunocompromised, it is being increasingly observed in immunocompetent populations. (1→3)-ß-D-glucan (BG) is a major component of the cyst cell wall and plays an important role in the inflammatory response to the organism. Inflammatory synergy by co-stimulation with BG and Toll-like receptor ligands has been demonstrated in vitro and may be a factor in the pathophysiology of Pneumocystis pneumonia. Detection of highly elevated serum concentrations of BG in the serum of patients has been shown to be highly sensitive for the presence of pulmonary P. jirovecii.

Topics: beta-Glucans; Cell Wall; Female; Humans; Immunocompromised Host; Male; Pneumocystis carinii; Pneumonia, Pneumocystis; Toll-Like Receptors

The diagnosis of Pneumocystis jirovecii pneumonia (PCP) in patients presenting with severe pneumonia is challenging and delays in treatment were associated with worse prognosis. This study aimed to develop a rapid, easily available, noninvasive machine learning diagnostic model for PCP among patients with severe pneumonia.. A retrospective study was performed in West China Hospital among consecutive patients with severe pneumonia who had undergone bronchoalveolar lavage for etiological evaluation between October 2010 and April 2021. Factors associated with PCP were identified and four diagnostic models were established using machine learning algorithms including Logistic Regression, eXtreme Gradient Boosting, Random Forest (RF) and LightGBM. The performance of these models were evaluated by the area under the receiver operating characteristic curve (AUC).. Ultimately, 704 patients were enrolled and randomly divided into a training set (n = 564) and a testing set (n = 140). Four factors were ultimately selected to establish the model including neutrophil, globulin, β-D-glucan and ground glass opacity. The RF model exhibited the greatest diagnostic performance with an AUC of 0.907. The calibration curve and decision curve analysis also demonstrated its accuracy and applicability.. We constructed a PCP diagnostic model in patients with severe pneumonia using four easily available and noninvasive clinical indicators. With satisfying diagnostic performance and good clinical practicability, this model may help clinicians to make early diagnosis of PCP, reduce the delays of treatment and improve the prognosis among these patients.

Topics: beta-Glucans; Bronchoalveolar Lavage; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies

The current study evaluated the diagnostic performance of serum (1,3)-beta-D Glucan (BDG) in differentiating PJP from P. jirovecii-colonization in HIV-uninfected patients with P. jirovecii PCR-positive results.. This was a single-center retrospective study between 2019 and 2021. The diagnosis of PJP was based on the following criteria: detection of P. jirovecii in sputum or BAL specimen by qPCR or microscopy; Meet at least two of the three criteria: (1) have respiratory symptoms of cough and/or dyspnea, hypoxia; (2) typical radiological picture findings; (3) receiving a complete PJP treatment. After exclusion, the participants were divided into derivation and validation cohorts. The derivation cohort defined the cut-off value of serum BDG. Then, it was verified using the validation cohort.. Two hundred and thirteen HIV-uninfected patients were enrolled, with 159 PJP and 54 P. jirovecii-colonized patients. BDG had outstanding specificity, LR, and PPV for PJP in both the derivation (90.00%, 8.900, and 96.43%) and the validation (91.67%, 9.176, and 96.30%) cohorts at ≥ 117.7 pg/mL. However, it had lower sensitivity and NPV in the derivation cohort (89.01% and 72.97%), which was even lower in the validation cohort (76.47% and 57.89%). Of note, BDG ≥ 117.7 pg/mL has insufficient diagnostic efficacy for PJP in patients with lung cancer, interstitial lung disease (ILD) and nephrotic syndrome. And although lymphocytes, B cells, and CD4. Serum BDG ≥ 117.7 pg/mL could effectively distinguish P. jirovecii-colonization from infection in qPCR-positive HIV-uninfected patients with infectious diseases, solid tumors (excluding lung cancer), autoimmune or inflammatory disorders, and hematological malignancies. Of note, for patients with lung cancer, ILD, and nephrotic diseases, PJP should be cautiously excluded at BDG < 117.7 pg/mL.

Topics: beta-Glucans; Glucans; HIV Infections; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies

Both 1,3-beta-D-glucan (BDG) and galactomannan (GM) are polysaccharide components of the fungal cell wall. Although elevated levels of serum BDG and Aspergillus GM suggest invasive fungal infection or Pneumocystis pneumonia and aspergillosis, respectively, it is also necessary to consider the possibility of false-positives. We herein report a 68-year-old man with marked elevation in serum BDG and GM levels accompanied by Mendelson's syndrome after rice aspiration. With the improvement of Mendelson's syndrome, his serum BDG and GM levels decreased. The false-positive serum BDG and GM findings may have been due to his aspiration of food containing them. It is important to take a detailed history of aspiration in addition to making a conventional differential diagnosis in patients with pneumonia with elevated serum BDG and GM levels.

Topics: Aged; Aspergillus; beta-Glucans; Galactose; Glucans; Humans; Male; Mannans; Oryza; Pneumonia, Aspiration; Pneumonia, Pneumocystis; Sensitivity and Specificity

Pneumocystis species interaction with myeloid cells is well known, especially in macrophages; however, how the organism binds to lung epithelial cells is incompletely understood. Ephrin type-A receptor 2 (EphA2) has been previously identified as a lung epithelial pattern recognition receptor that binds to fungal β-glucans. Herein, we also report that EphA2 can also bind Pneumocystis β-glucans, both in isolated forms and also on exposed surfaces of the organism. Furthermore, binding of Pneumocystis β-glucans resulted in phosphorylation of the EphA2 receptor, which has been shown to be important for downstream proinflammatory response. Indeed, we also show that interleukin 6 cytokine is significantly increased when lung epithelial cells are exposed to Pneumocystis β-glucans, and that this response could be blocked by preincubation with a specific antibody to EphA2. Our study presents another Pneumocystis lung epithelial cell receptor with implications for initial colonization and possible therapeutic intervention.

Topics: beta-Glucans; Carrier Proteins; Epithelial Cells; Humans; Lung; Pneumocystis; Pneumonia, Pneumocystis; Receptor, EphA2

Non-human immunodeficiency virus (HIV) Pneumocystis pneumonia (PCP) is a fulminant disease with an increasing incidence. The serum beta-D-glucan (BDG) assay is used as an adjunct to the diagnosis of PCP; however, the cut-off value for this assay is not well-defined, especially in the non-HIV PCP population. Therefore, we aimed to identify the assay cut-off value for this population.. In this retrospective observational study, we reviewed the medical records of all patients (≥ 18 years old) with clinical suspicion of PCP who underwent evaluation of respiratory tract specimens between December 2008 and June 2014 at Kameda Medical Center. We created a receiver operating characteristic curve and calculated the area under the curve to determine the cut-off value for evaluating the inspection accuracy of the BDG assay.. A total of 173 patients were included in the study. Fifty patients showed positive results in specimen staining, loop-mediated isothermal amplification assay, and polymerase chain reaction test, while 123 patients showed negative results. The receiver operating characteristic analyses suggested that the BDG cut-off level was 8.5 pg/mL, with a sensitivity and specificity of 76% and 76%, respectively.. The Wako-BDG cut-off value for the diagnosis of non-HIV PCP is 8.5 pg/mL, which is lower than the classical cut-off value from previous studies. Clinicians should potentially consider this lower BDG cut-off value in the diagnosis and management of patients with non-HIV PCP..  The participants were retrospectively registered.

Topics: beta-Glucans; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Retrospective Studies; Sensitivity and Specificity

Early diagnosis of invasive fungal diseases (IFDs) remains a major challenge in routine clinical practice.. The aim of this retrospective cohort study was to evaluate the diagnostic performance of the fungal biomarker (1,3)-ß-d-glucan (BDG) using the β-Glucan test (GT) and the well-established Fungitell assay® (FA) in real-life clinical practice.. We included 109 patients with clinical suspicion of IFD who were treated at Jena University Hospital, Germany, between November 2018 and March 2019. The patients were classified according to the latest update of the EORTC/MSG consensus definitions of IFD. The first serum sample of every patient was analysed for BDG using the FA and the GT, respectively.. Fifty-six patients (51.4%) had at least one host factor for IFD. In patients with proven (n = 11) or probable IFDs (n = 20), median BDG concentrations were 145.0 pg/ml for the FA and 5.1 pg/ml for the GT, respectively. A positive test result of both BDG assays at manufacturer's cut-offs predicted 89.5%-98.3% of proven or probable IFD, but the sensitivity of both assays was limited: The FA identified 60.7% of IFDs (cut-off: 80 pg/ml). Reducing the GT cut-off value from 11.0 to 4.1 pg/ml increased the detection rate of IFDs from 35.5% to 54.8%.. A positive test result of both BDG assays at manufacturer's cut-off was highly predictive for IFD, but except for Pneumocystis jirovecii pneumonia sensitivities were limited. Adjustment of the GT cut-off value equalised sensitivities of GT and FA.

Topics: Aged; beta-Glucans; Biomarkers; Diagnostic Tests, Routine; Early Diagnosis; Female; Germany; Glucans; Humans; Invasive Fungal Infections; Male; Middle Aged; Pneumocystis; Pneumonia, Pneumocystis; Retrospective Studies; ROC Curve; Sensitivity and Specificity

In this retrospective study, (1->3)-β-d-glucan (B-glucan) was an unreliable marker for AIDS-related Pneumocystis jirovecii pneumonia (PCP) because a high percentage of participants with progressive disseminated histoplasmosis and respiratory symptoms had a positive B-glucan result. Where histoplasmosis is common, attributing B-glucan positivity to PCP without further testing risks misdiagnosis.

Topics: Acquired Immunodeficiency Syndrome; beta-Glucans; Glucans; Histoplasmosis; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies

Pneumocystis jirovecii pneumonia (PJP) is difficult to be diagnosed, so this study explored if PJP could be diagnosed by metagenomic next-generation sequencing (mNGS) and if mNGS could guide the therapy of PJP. mNGS was successfully diagnosed 13 out of 14 PJP recipients with 11 through peripheral blood samples, verified by PCR. Ten non-PJP recipients were enrolled as the control group. Blood tests revealed a high β-D-glucan (BDG) level in all recipients with PJP during the hospitalization. Four (28.6%) of 14 PJP patients were infected with cytomegalovirus simultaneously, while 8 (57.1%) suffered from a combined infection caused by Torque teno virus. Five (35.7%) of 14 cases died of PJP or the subsequent bacteremias/bacterial pneumonia with a longer interval between the onset and diagnosis of/the available therapy against PJP than survival cases. Univariate analysis of characteristics between PJP and non-PJP recipients revealed that BDG assays was higher at the admission in PJP group (P =0.011). This present study supports the value of mNGS detection of blood sample in diagnosing PJP, which could assist clinical decision for therapy against PJ and improve outcome of PJP. The study also highlights the sensitivity of BDG assays. Cytomegalovirus and Torque teno virus infections often occur at the same time of PJP, thus can be alerts of PJP.

Topics: Adult; beta-Glucans; Bronchoalveolar Lavage Fluid; Female; High-Throughput Nucleotide Sequencing; Humans; Immunocompromised Host; Kidney Transplantation; Male; Metagenomics; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies; Transplant Recipients; Young Adult

From clinical case records, we abstracted demographic and clinical information and categorised patients as having confirmed or probable PCP, or an alternative diagnosis. We calculated sensitivity, specificity and positive predictive value (PPV) of serum BDG concentrations >400 pg/mL and negative predictive value (NPV) of BDG <80 pg/mL.. 76 patients were included; 29 had laboratory-confirmed PCP, 17 had probable PCP and 30 had an alternative diagnosis. Serum BDG >400 pg/mL had a sensitivity of 83%, specificity of 97% and PPV 97% for diagnosis of PCP; BDG <80 pg/mL had 100% NPV for exclusion of PCP.. In PWH with suspected PCP, BDG <80 pg/mL excludes a diagnosis of PCP, whereas BDG concentrations >400 pg/mL effectively confirm the diagnosis. Values 80-400 pg/mL should prompt additional diagnostic tests.

Topics: Adult; beta-Glucans; HIV Infections; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Sensitivity and Specificity

Pneumocystis major surface glycoprotein (Msg) is a 120-kD surface protein complex on the organism with importance in adhesion and immune recognition. In this study, we show that Msg significantly impairs tumor necrosis factor (TNF)-α secretion by macrophages induced by Saccharomyces cerevisiae and Pneumocystis carinii (Pc) β-glucans.. Major surface glycoprotein was shown to greatly reduce β-glucan-induced Dectin-1 immunoreceptor tyrosine-based activating motif (ITAM) phosphorylation. Major surface glycoprotein also down regulated Dectin-1 receptor messenger ribonucleic acid (mRNA) expression in the macrophages. It is interesting that Msg incubation with macrophages resulted in significant mRNA upregulation of both C-type lectin receptors (CLR) Mincle and MCL in Msg protein presence alone but to even greater amounts in the presence of Pc β-glucan.. The silencing of MCL and Mincle resulted in TNF-α secretions similar to that of macrophages treated with Pneumocystis β-glucan alone, which is suggestive of an inhibitory role for these 2 CLRs in Msg-suppressive effects on host cell immune response.. Taken together, these data indicate that the Pneumocystis Msg surface protein complex can act to suppress host macrophage inflammatory responses to the proinflammatory β -glucan components of the organisms.

Topics: Animals; beta-Glucans; Fungal Proteins; Lectins, C-Type; Macrophages; Membrane Glycoproteins; Mice; Pneumocystis; Pneumocystis carinii; Pneumonia, Pneumocystis; RAW 264.7 Cells; RNA, Messenger; Saccharomyces cerevisiae; Tumor Necrosis Factor-alpha

Non-HIV immunocompromised patients with Pneumocystis jirovecii pneumonia (PCP) have lower fungal load than those with AIDS, potentially affecting the accuracy of diagnostic biomarkers. Therefore, we investigated the performance of serum (1,3)-Beta-d-Glucan (BDG) in conjunction with quantitative Pneumocystis jirovecii PCR (qPCR) in non-HIV cancer patients.. We reviewed records of non-HIV cancer patients and classified them as definite, probable, or possible PCP cases, according to clinicoradiological features, microscopy findings, and qPCR results in bronchoscopy specimens. We evaluated the diagnostic performance of serum BDG and its correlation with qPCR results.. We identified 101 PCP patients (73 definite/probable, 28 possible) and 74 controls. Correlation of BDG and qPCR was low among all 101 qPCR-positive patients (Spearman's = 0.38) and in definite/probable PCP cases (Spearman's = 0.18). Considering all qPCR-positive patients, BDG showed consistently low sensitivity at different cutoffs. Among definite/probable cases, the diagnostic accuracy of BDG remained poor, yet slightly improved with high qPCR thresholds (AUC = 0.86 at ≥2000 DNA copies/mL). BDG had a low PPV but excellent NPV across different qPCR and BDG cutoffs.. BDG and qPCR levels correlate poorly in non-HIV cancer patients with PCP. BDG diagnostic performance is suboptimal but a negative test may be useful to rule out PCP in this population.

Topics: beta-Glucans; Humans; Neoplasms; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Sensitivity and Specificity

The Fungitell assay (FA) and the Wako β-glucan test (GT) are employed to measure the serum/plasma 1,3-β-D-glucan (BDG), a well-known invasive fungal disease biomarker. Data to convincingly and/or sufficiently support the GT as a valuable alternative to the FA are yet limited. In this study, we evaluated the FA and the GT to diagnose invasive aspergillosis (IA), invasive candidiasis (IC), and Pneumocystis jirovecii pneumonia (PJP). The FA and GT performances were compared in sera of patients with IA (n = 40), IC (n = 78), and PJP (n = 17) with respect to sera of control patients (n = 187). Using the manufacturer's cutoff values of 80 pg/mL and 11 pg/mL, the sensitivity and specificity for IA diagnosis were 92.5% and 99.5% for the FA and 60.0% and 99.5% for the GT, respectively; for IC diagnosis were 100.0% and 97.3% for the FA and 91.0% and 99.5% for the GT, respectively; for PJP diagnosis were 100.0% and 97.3% for the FA and 88.2% and 99.5% for the GT, respectively. When an optimized cutoff value of 7.0 pg/mL for the GT was used, the sensitivity and specificity were 80.0% and 97.3% for IA diagnosis, 98.7% and 97.3% for IC diagnosis, and 94.1% and 97.3% for PJP diagnosis, respectively. At the 7.0-pg/mL GT cutoff, the agreement between the assays remained and/or became excellent for IA (95.1%), IC (97.3%), and PJP (96.5%), respectively. In conclusion, we show that the GT performed as well as the FA only with a lowered cutoff value for positivity. Further studies are expected to establish the equivalence of the two BDG assays.

Topics: Adult; Aged; Aspergillosis; Aspergillus; beta-Glucans; Candida albicans; Candidiasis, Invasive; Diagnostic Tests, Routine; Female; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; ROC Curve

Topics: beta-Glucans; CARD Signaling Adaptor Proteins; Humans; Immunity, Innate; Pneumocystis; Pneumocystis carinii; Pneumonia, Pneumocystis

INTRODUCTIONDespite the widespread use of prophylactic antibiotics in high-risk individuals,

Topics: beta-Glucans; Biomarkers; Female; Humans; Male; Pneumocystis carinii; Pneumonia, Pneumocystis

The aim of this study was to investigate the efficacy of combination therapy of caspofungin and TMP/SMZ (trimethoprim/sulfamethoxazole) in moderate to severe pneumocystis jirovecii pneumonia (PJP) in patients without human immunodeficiency virus infection (HIV) and the relationship between therapeutic effect and plasma (1, 3) Beta-d-Glucan (BDG) levels.. We retrospectively reviewed HIV-negative patients with PJP diagnosed in our department, who were treated with combination therapy of caspofungin and TMP/SMZ or monotherapy of TMP/SMZ during a six and a half year period.. A total of 126 moderate to severe PJP patients were enrolled in the study. In the multivariate analysis, low lymphocyte counts, high serum lactate dehydrogenase levels at the diagnosis of PJP and progression to shock were significant risk factors for death. In all patients, there was no significant difference in risk of death at 3 months. In the group of BDG≥800pg/m, patients receiving combination therapy was associated with a significantly decreased risk of death at 3 months, whereas in the group of BDG<800pg/ml, there were no statistically significant difference in survival rate between the two treatment regimens.. High initial plasma (1, 3) Beta-d-Glucan concentration may be a predictor of satisfactory caspofungin response to HIV-negative patients with PJP. Based on our findings, we suggest the choice of combination therapy with caspofungin and TMP/SMZ as the initial treatment when BDG≥800pg/ml in moderate to severe HIV-negative patients with PJP.

Topics: Adult; Antifungal Agents; beta-Glucans; Caspofungin; Drug Monitoring; Female; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination

Currently, the biological diagnosis of Pneumocystis jirovecii pneumonia (PjP infection) usually relies on microbiological investigations in bronchial-alveolar lavage fluid (BALF) by conventional staining methods and/or molecular biology. However, bronchial-alveolar lavage is sometimes complicated to manage, especially in weakened patients. Therefore, alternative clinical samples-easier to collect-are warranted in such specific contexts.. Over a four-year period, diagnostic performance of an original method based on combination of quantitative real-time polymerase chain reaction (qPCR) in nasopharyngeal aspirate (NPA) with measurement of β-(1, 3)-D-glucan antigen (BDG) in serum was prospectively assessed in a single centre.. Results were compared with those obtained in BALF through direct staining methods and qPCR. True positives were defined by an independent committee based on clinical, radiological and biological data. Overall, 48 individuals with a definitive diagnosis of PjP infection were included, and 48 controls were selected upon matching for age, sex and underlying disease(s).. qPCR results were strongly correlated between BALF and NPA (P < .0001). Altogether, greater diagnostic performance was achieved when establishing the positive cut-off of BDG antigen at 143 pg/mL. In such conditions, sensitivity of the testing based on either positive BDG measurement or positive qPCR in NPA was then calculated at 93.75%,. Further validation through multicentre studies is now required, especially for establishing clear cut-offs. However, one could already state that combination of qPCR in the NPA with BDG measurement in serum may be a valuable substitute for BALF examination.

Topics: Aged; beta-Glucans; Bronchoalveolar Lavage Fluid; Female; Humans; Male; Middle Aged; Nasopharynx; Pneumocystis carinii; Pneumonia, Pneumocystis; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity

1,3-β-D-glucan (BG), a cell-wall component of most fungi including Pneumocystis (PC), is recommended by international guidelines for screening for pneumocystis pneumonia (PCP) in hematologic patients. We retrospectively validated the BG test in our tertiary university hospital. Forty-five patients (median age 53 years, 33% female) tested for PC by polymerase chain reaction (PCR) and/or immunoflourescence (IF)-microscopy with a stored blood sample within ±5 days of the PC test were tested by the Fungitell (cutoff <60 and >80 pg/ml). Cases had symptoms and radiology compatible with PCP and positive IF-microscopy (proven PCP, n = 8) or positive PCR (probable PCP, n = 10). Controls had no compatible symptoms/radiology and negative tests for PC on conventional testing (no PCP, n = 24), or positive PCR/IF-microscopy (colonized, n = 3). Median BG-levels were 1108 pg/ml (proven PCP), 612 pg/ml (probable PCP), 29 pg/ml (colonized), and 48 pg/ml (controls, P < 0.001). Compared to the PCP case/control classification, the BG test showed sensitivities of 83-89% and specificities of 64-74%, positive likelihood ratio (LR) of 3.2 and negative LR of 0.23 at recommended cutoff and moderate agreement between tests. Optimal cutoff was ≥73 pg/ml. In PCR-positive cases, the agreement between the BG test and IF-microscopy was 78-89% with fair/moderate agreement. Elevated BG levels were seen in controls with probable invasive fungal infections (n = 4), hemodialysis, bacterial infections and/or betalactams. To conclude, 11% of patients with PCP would be missed if the BG test had been used for diagnosing PCP. Specificity was moderate. Among PCR-positive patients, the BG test identified more cases than IF-microscopy. BG testing is potentially helpful but sensitivity is insufficient to exclude PCP.

Topics: Adolescent; Adult; Aged; beta-Glucans; Bronchoalveolar Lavage Fluid; Child; Child, Preschool; Denmark; Female; Hospitals, University; Humans; Infant; Infant, Newborn; Invasive Fungal Infections; Male; Middle Aged; Pneumonia, Pneumocystis; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity; Tertiary Care Centers; Young Adult

Serum (1,3)-beta-D glucan (BDG) is increasingly used to guide the management of suspected Pneumocystis pneumonia (PCP). BDG lacks specificity for PCP, and its clinical performance in high-risk cancer patients has not been fully assessed. Polymerase chain reaction (PCR) for PCP detection is highly sensitive, but cannot differentiate between colonization and infection. We evaluated the diagnostic performance of serum BDG in conjunction with PCP PCR on respiratory samples in patients with cancer and unexplained lung infiltrates.. We performed a retrospective analysis of adult patients evaluated for PCP at our institution from 2012 to 2015, using serum BDG and PCP PCR. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the serum BDG at different thresholds were evaluated using PCP PCR alone or in conjunction with clinical presentation in PCP PCR-positive patients.. With PCP PCR alone as the reference method, BDG (≥80 pg/mL) had a sensitivity of 69.8%, specificity of 81.2%, PPV of 34.6%, and NPV of 95.2% for PCP. At ≥200 pg/mL in patients with a positive PCR and a compatible PCP clinical syndrome, BDG had a sensitivity of 70%, specificity of 100%, PPV of 100%, and NPV of 52.0% for PCP.. Patients negative by both BDG and PCR were unlikely to have PCP. In patients with a compatible clinical syndrome for PCP, higher BDG values (>200 pg/mL) were consistently associated with clinically-significant PCP infections among PCP PCR-positive oncology patients.

Topics: beta-Glucans; DNA, Fungal; Female; Humans; Male; Middle Aged; Neoplasms; Pneumocystis carinii; Pneumonia, Pneumocystis; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity

Topics: beta-Glucans; Humans; Neoplasms; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction

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

Fibrosing interstitial lung disease is the poor prognostic non-infectious lung disease by unknown etiology. Here, we present one case developing interstitial pneumonia with fibrosis after treatment of pneumocystis pneumonia (PCP) in newly diagnosed HIV-1 infected case.. A previously healthy 63-year old male was referred to our institute because of protracted dyspnea on effort in 2 weeks after pneumocystis pneumonia treatment. At referral, arterial blood oxygen pressure was within normal range (93.5 mmHg) at rest, but decreased rapidly 30 s after a slow walk (44.5 mmHg). Respiratory function tests showed severe restrictive ventilator impairment (vital capacity = 36.5%; forced expiratory volume in 1 s = 107.4%). Chest computed tomography showed severe fibrotic changes at bilateral basal parts and diffuse fibrotic changes in which PCP lesions were seen initially in previous images although β-D glucan was not elevated and P. jirovecii was not detected in saliva at referral. Other etiologies of fibrotic IP including infectious and/or autoimmune diseases were excluded by serology. Fibrotic lesion did not expand thereafter although it had not responded to the high-dose corticosteroid therapy.. We report the first case of fibrosing interstitial lung disease triggered by HIV-related PCP.

Topics: AIDS-Related Opportunistic Infections; beta-Glucans; Forced Expiratory Volume; HIV Infections; Humans; Immunocompromised Host; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination

For patients with non-human immunodeficiency virus (HIV) Pneumocystis pneumonia (PCP), data are limited on serial changes in serum biomarkers and the correlations with clinical outcomes.. This study evaluated serial change in serum biomarkers and clinical outcomes of non-HIV PCP.. We retrospectively reviewed data from 63 patients treated for non-HIV PCP at Toho University Omori Medical Center. The patients were classified as survivors and nonsurvivors on the basis of 60-day PCP mortality. The groups were compared for clinical course and levels of serum biomarkers (β-D glucan, Krebs von den Lungen-6 antigen [KL-6], and surfactant protein-D [SP-D]), which were measured at baseline, and 7 days and 14 days after starting treatment. In addition, serial changes in serum biomarkers were analyzed in survivors and nonsurvivors.. There were 14 PCP nonsurvivors and 49 survivors. Biomarker values were not different between groups at baseline. At 7 and 14 days after starting treatment, the proportions of patients with elevated β-D glucan and KL-6 did not significantly differ between groups; however, the proportion of patients with elevated SP-D was significantly lower among survivors than among nonsurvivors (57.1% vs. 100%, p = 0.009; 30% vs. 100%, p < 0.001; respectively). SP-D on day 14 was significantly lower than that at baseline among survivors (99.6 [61.0-190.3] vs. 156 [100.8-283.5]; p = 0.045) but significantly higher among nonsurvivors (974 [744.5-1565] vs. 317 [211-448]; p = 0.03).. Serum SP-D value continues to increase after failure of treatment for non-HIV PCP and may thus be associated with outcomes for non-HIV PCP patients.

Topics: Aged; Anti-Bacterial Agents; beta-Glucans; Biomarkers; Combined Modality Therapy; Female; Glucocorticoids; Humans; Immunocompromised Host; Male; Middle Aged; Mucin-1; Oxygen Inhalation Therapy; Pneumocystis carinii; Pneumonia, Pneumocystis; Pulmonary Surfactant-Associated Protein D; Retrospective Studies; Survivors; Treatment Failure; Trimethoprim, Sulfamethoxazole Drug Combination

Pneumocystis jirovecii pneumonia (PCP) is one of the most common HIV-related opportunistic infections. The diagnosis of PCP is based on analyses from respiratory tract specimens which may require the invasive procedure of a diagnostic bronchoscopy. The objective of this study was to evaluate the diagnostic potential of Pneumocystis jirovecii PCR in serum combined with the 1,3-β-D-glucan (betaglucan) test for the diagnosis of PCP in HIV-infected patients.. This was a retrospective case-control study including serum samples from 26 HIV-infected patients with PCP collected within 5 days prior to the start of PCP treatment, 21 HIV-infected control subjects matched by blood CD4. All patients with PCP had detectabe Pneumocystis jirovecii DNA in serum yielding a sensitivity for the Pneumocystis jirovecii PCR assay in serum of 100%. All blood donors had negative Pneumocystis PCR in serum. The specificity when testing HIV-infected patients was 71%, but with a PCR Cycle threshold (Ct) value of 34 as cut-off the specificity was 90%. At a putative pretest probaility of 20%, the negative and positive predictive value for the Pneumocystis PCR assay in serum was 0.99 and 0.71, respectively. Betaglucan with cut-off level 200 pg/ml combined with a positive Pneumocystis jirovecii PCR result had sensitivity and specificity of 92 and 90%, respectively. The concentration of Pneumocystis jirovecii DNA in serum samples, expressed by the PCR Ct values, correlated inversely to the betaglucan levels in serum.. In this case-control study including 70% of all HIV-infected patients with PCP treated at Sahlgrenska University Hospital during a time period of 13 years, Pneumocystis PCR analysis on serum samples had a very high sensitivity and negative predictive value for the diagnosis of PCP in HIV-infected patients. A serum-based diagnostic procedure either based on Pneumocystis jirovecii PCR alone or in combination with betaglucan analysis may thus be feasible and would facilitate the care of HIV-infected patients with suspected PCP.

Topics: Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; beta-Glucans; Blood Donors; Case-Control Studies; DNA, Fungal; Female; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Retrospective Studies; Sensitivity and Specificity

The Dynamiker® Fungus (1-3)-β-D-Glucan Assay (D-BDG) has recently become available in the Western Hemisphere for the diagnosis of invasive fungal disease (IFD). Evaluations of its performance for Pneumocystis pneumonia (PcP) are limited. A retrospective evaluation of D-BDG diagnosis of PcP was performed (23 PcP cases and 23 controls). Sensitivity and specificity were 87% and 70%, respectively, reducing the positivity threshold to 45 pg/ml increased sensitivity (96%), whereas a threshold of 300 pg/ml increased specificity (96%). The performance of D-BDG for the detection of PcP is comparable to other IFD, but sensitivity is below that required to confidently exclude PcP.

Topics: beta-Glucans; Diagnostic Tests, Routine; Fungal Polysaccharides; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies; Sensitivity and Specificity

Topics: beta-Glucans; Diagnostic Tests, Routine; Female; Fungal Polysaccharides; Germany; Humans; Immunocompromised Host; Immunoturbidimetry; Male; Middle Aged; Pneumocystis; Pneumonia, Pneumocystis; Real-Time Polymerase Chain Reaction; Retrospective Studies; Sensitivity and Specificity

Topics: Aged; Anti-Bacterial Agents; Arthritis, Rheumatoid; beta-Glucans; Connective Tissue Diseases; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Methotrexate; Middle Aged; Pneumonia, Pneumocystis; Tomography, X-Ray Computed; Treatment Outcome

Invasive fungal disease (IFD) can be caused by a range of pathogens. Conventional diagnosis has the capacity to detect most causes of IFD, but poor performance limits impact. The introduction of non-culture diagnostics, including the detection of (1-3)-β-D-Glucan (BDG), has shown promising performance for the detection of IFD in variety of clinical settings. Recently, the Dynamiker® Fungus (1-3)-β-D-Glucan assay (D-BDG) was released as an IFD diagnostic test. This article describes an evaluation of the D-BDG assay for the diagnosis of invasive aspergillosis (IA), invasive candidiasis (IC) and Pneumocystis pneumonia (PCP) across several high-risk patient cohorts and provides comparative data with the Associates of Cape Cod Fungitell® and BioRad Platelia™ Aspergillus Ag (GM) assays. There were 163 serum samples from 121 patients tested, from 21 probable IA cases, 28 proven IC cases, six probable PCP cases, one probable IFD case, 14 possible IFD cases and 64 control patients. For proven/probable IFD the mean BDG concentration was 209pg/ml, significantly greater than the control population (73pg/ml; P: <.0001). The sensitivity, specificity, and diagnostic odds ratio for proven/probable IFD was 81.4%, 78.1%, and 15.5, respectively. Significant BDG false positivity (9/13) was associated post abdominal surgery. D-BDG showed fair and good agreement with the Fungitell®, and GM assays, respectively. In conclusion, the D-BDG provides a useful adjunct test to aid the diagnosis of IFD, with technical flexibility that will assist laboratories processing low sample numbers. Further, large scale, prospective evaluation is required to confirm the clinical validity and determine clinical utility.

Topics: Aspergillosis; beta-Glucans; Candidiasis, Invasive; Diagnostic Tests, Routine; Female; Fungal Polysaccharides; Humans; Male; Middle Aged; Pneumonia, Pneumocystis; Sensitivity and Specificity

Pneumocystis jirovecii pneumonia (PCP) is a major cause of disease in immunocompromised individuals. Diagnosis is typically obtained by microscopy and/or PCR. For ambiguous PCR results, we evaluated the new biomarker 1,3-Beta-D-Glucan (BDG).. BDG serum levels were assessed and correlated to PCR results in immunosuppressed patients with ARDS.. 11 (22%) out of 50 patients had suspected PCP. APACHE II (26 vs. 24; p < 0.002), SOFA score (16 vs. 14; p < 0.010) and mortality rate (34 vs. 69% p < 0.004; 34 vs. 80% p < 0.003) were significantly altered in patients with positive (pPCR) and slightly positive (spPCR) PCJ PCR as compared to patients with no-PCP (nPCP). BDG levels were significantly lower in patients with nPCP (86; 30-315 pg/ml) than in patients with pPCR (589; 356-1000 pg/ml; p < 0.001) and spPCP (398; 297-516 pg/ml; p < 0.004) referring to the cutoff in this study for PCP of 275 pg/ml. An overall sensitivity (S) of 92% (95% CI 86-96%) and specificity (SP) of 84% (95% CI 79-85%) for PCP were found for the BDG Fungitell assay. In detail, S of 98% (95% CI 94-100%) and SP of 86% (95% CI 82-92%) for pPCP and S of 98% (95% CI 96-100%) and SP of 88% (95% CI 86-96%) for spPCO were found.. Serum BDG levels were strongly elevated in PCP, and the negative predictive value is high. BDG could be used as a preliminary test for patients with suspected PCP, especially in patients with slightly positive PCR results.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta-Glucans; Critical Illness; Female; Humans; Male; Microscopy; Middle Aged; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Predictive Value of Tests; Proteoglycans; Respiration, Artificial; Respiratory Distress Syndrome; Sensitivity and Specificity; Young Adult

The life cycle of the opportunistic fungal pathogen

Topics: Animals; Antigen Presentation; beta-Glucans; CD4-Positive T-Lymphocytes; Dendritic Cells; Gene Expression Regulation; Histocompatibility Antigens Class II; Lymphocyte Activation; Mice; Pathogen-Associated Molecular Pattern Molecules; Pneumocystis; Pneumonia, Pneumocystis; Transcription Factors

Diagnosis of pneumocystis pneumonia (PCP) relies on microscopic visualization of P. jirovecii, or detection of Pneumocystis DNA in respiratory specimens, which involves invasive procedures such as bronchoalveolar lavage. The (1-3)-β-D-glucan (BG) assay has been proposed as a less invasive and less expensive diagnostic test to rule out PCP. We therefore compared blood levels of BG in patients with PCP with those of patients with candidemia, chronic disseminated candidiasis (CDC), invasive aspergillosis, mucormycosis, and tuberculosis and those of healthy volunteers.. Adult patients who were diagnosed with PCP, candidemia, CDC, invasive aspergillosis, mucormycosis, and tuberculosis whose blood samples were available, and healthy volunteers were enrolled in a tertiary hospital in Seoul, South Korea, during a 21-month period. The blood samples were assayed with the Goldstream Fungus (1-3)-β-D-glucan test (Gold Mountain River Tech Development, Beijing, China).. A total of 136 individuals including 50 patients P. jirovecii,15 candidemia, 6 CDC, 15 invasive aspergillosis, 10 mucormycosis, and 40 controls (20 TB and 20 healthy volunteers) were included. The mean±SD of the concentration of 1-3-β-D-glucan in the patients with PCP (290.08 pg/mL±199.98) were similar to those of patients with candidemia (314.14 pg/mL±205.60, p = 0.90 at an α = 0.005) and CDC (129.74 pg/mL±182.79, p = 0.03 at an α = 0.005), but higher than those of patients with invasive aspergillosis (131.62 pg/mL±161.67, p = 0.002 at an α = 0.005), mucormycosis (95.08 pg/mL±146.80, p<0.001 at an α = 0.005), and tuberculosis (103.31 pg/mL±140.81, p<0.001 at an α = 0.005) as well as healthy volunteers (101.18 pg/mL±197.52, p<0.001 at an α = 0.005). At a cut-off value > 31.25 pg/mL, which is highly sensitive for PCP versus tuberculosis plus healthy volunteers at the expense of specificity, the BG assay had a sensitivity of 92% (95% CI 81%-98%) and a specificity of 55% (95% CI 39%-71%).. The BG assay appears to be a useful adjunct test for PCP.

Topics: Adult; Aged; Aspergillosis; beta-Glucans; Candidiasis; Case-Control Studies; Diagnosis, Differential; Female; Healthy Volunteers; Humans; Male; Middle Aged; Mucormycosis; Pneumocystis carinii; Pneumonia, Pneumocystis; Republic of Korea; Tuberculosis, Pulmonary

β-glucans, which can activate innate immune responses, are a major component in the cell wall of the cyst form of Pneumocystis In the current study, we examined whether β-1,3-glucans are masked by surface proteins in Pneumocystis and what role β-glucans play in Pneumocystis-associated inflammation. For 3 species, including Pneumocystis jirovecii, which causes Pneumocystis pneumonia in humans, Pneumocystis carinii, and Pneumocystis murina, β-1,3-glucans were masked in most organisms, as demonstrated by increased exposure following trypsin treatment. Using quantitative polymerase chain reaction and microarray techniques, we demonstrated in a mouse model of Pneumocystis pneumonia that treatment with caspofungin, an inhibitor of β-1,3-glucan synthesis, for 21 days decreased expression of a broad panel of inflammatory markers, including interferon γ, tumor necrosis factor α, interleukin 1β, interleukin 6, and multiple chemokines/chemokine ligands. Thus, β-glucans in Pneumocystis cysts are largely masked, which likely decreases innate immune activation; this mechanism presumably was developed for interactions with immunocompetent hosts, in whom organism loads are substantially lower. In immunosuppressed hosts with a high organism burden, organism death and release of glucans appears to be an important contributor to deleterious host inflammatory responses.

Topics: Animals; Antifungal Agents; beta-Glucans; Caspofungin; Cytokines; Disease Models, Animal; Echinocandins; Lipopeptides; Mice, Knockout; Microarray Analysis; Pneumocystis; Pneumonia; Pneumonia, Pneumocystis; Real-Time Polymerase Chain Reaction

Recent data demonstrate the usefulness of (1,3) ß-d-glucan (BG) detection in serum samples to distinguish patients developing Pneumocystis pneumonia and patients who are colonized by the fungus. In contrast, data of BG detection in bronchoalveolar lavage (BAL) samples from these patient populations are still rare.. In this context, we determined BG levels in BAL samples from 11 Pneumocystis pneumonia (PCP) patients, 10 colonized patients, and 24 Pneumocystis-uninfected patients.. BG levels were determined on each BAL sample using the Fungitell(®) kit (Associates of Cape Cod, Inc., Cape Cod, MA, USA) according to the manufacturer's instructions applied to serum sample examination.. The BG levels in BAL samples from the PCP patient group (mean value 20 588 pg/mL) were significantly higher than those in the colonized patient group (mean value 105 pg/mL) (P=0.0001, Mann-Whitney test) and than those in the Pneumocystis-uninfected patient group (mean value 74 pg/mL) (P<0.0001, Mann-Whitney test). The BG levels in BAL samples from the colonized patient group did not differ significantly from those in the Pneumocystis-uninfected patients group (P=0.21).. The results suggest that measurements of BAL BG levels may facilitate the differential diagnosis of PCP and pulmonary colonization with Pneumocystis.

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; Bronchoalveolar Lavage Fluid; Diagnosis, Differential; Female; Humans; Lung; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Predictive Value of Tests; Young Adult

The diagnosis of Pneumocystis pneumonia (PCP) relies on microscopic visualization of Pneumocystis jirovecii organisms or DNA detection in pulmonary specimens. This study aimed to assess the usefulness of (1-3)-β-d-glucan (BG), Krebs von den Lungen-6 antigen (KL-6), lactate dehydrogenase (LDH) and S-adenosyl methionine (SAM) as serologic biomarkers in the diagnosis of PCP. Serum levels of BG, KL-6, LDH and SAM were investigated in 145 Portuguese patients, 50 patients from the Netherlands, 25 Spanish patients and 40 Portuguese blood donors. Data on clinical presentation, chest imaging and gasometry tests were available. PCP cases were confirmed by microscopy and PCR techniques. A cost-effectiveness analysis was performed. BG was found to be the most reliable serologic biomarker for PCP diagnosis, followed by KL-6, LDH and SAM. The BG/KL-6 combination test was the most accurate serologic approach for PCP diagnosis, with 94.3% sensitivity and 89.6% specificity. Although less sensitive/specific than the reference standard classic methods based on bronchoalveolar lavage followed by microscopic or molecular detection of P. jirovecii organisms, the BG/KL-6 test may provide a less onerous procedure for PCP diagnosis, as it uses a minimally invasive and inexpensive specimen (blood), which may be also a major benefit for the patient's care. The BG/KL-6 combination test should be interpreted within the clinical context, and it may be used as a preliminary screening test in patients with primary suspicion of PCP, or as an alternative diagnostic procedure in patients with respiratory failure or in children, avoiding the associated risk of complications by the use of bronchoscopy.

Topics: Adolescent; Adult; Aged; beta-Glucans; Biomarkers; Child; Child, Preschool; Cost-Benefit Analysis; Female; Humans; L-Lactate Dehydrogenase; Male; Microscopy; Middle Aged; Mucin-1; Netherlands; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Portugal; Proteoglycans; Radiography, Thoracic; S-Adenosylmethionine; Sensitivity and Specificity; Serologic Tests; Spain; Young Adult

Although acquired bone marrow failure (BMF) is considered a T cell-mediated autoimmune disease, few studies have considered contributing roles of innate immune deviations following otherwise innocuous infections as a cause underlying the immune defects that lead to BMF. Type I IFN signaling plays an important role in protecting hematopoiesis during systemic stress responses to the opportunistic fungal pathogen Pneumocystis. During Pneumocystis lung infection, mice deficient in both lymphocytes and type I IFN receptor (IFrag(-/-)) develop rapidly progressing BMF associated with accelerated hematopoietic cell apoptosis. However, the communication pathway eliciting the induction of BMF in response to this strictly pulmonary infection has been unclear. We developed a conditional-null allele of Ifnar1 and used tissue-specific induction of the IFrag(-/-) state and found that, following Pneumocystis lung infection, type I IFNs act not only in the lung to prevent systemic immune deviations, but also within the progenitor compartment of the bone marrow to protect hematopoiesis. In addition, transfer of sterile-filtered serum from Pneumocystis-infected mice as well as i.p. injection of Pneumocystis into uninfected IFrag(-/-) mice induced BMF. Although specific cytokine deviations contribute to induction of BMF, immune-suppressive treatment of infected IFrag(-/-) mice ameliorated its progression but did not prevent loss of hematopoietic progenitor functions. This suggested that additional, noncytokine factors also target and impair progenitor functions; and interestingly, fungal β-glucans were also detected in serum. In conclusion, our data demonstrate that type 1 IFN signaling protects hematopoiesis within the bone marrow compartment from the damaging effects of proinflammatory cytokines elicited by Pneumocystis in the lung and possibly at extrapulmonary sites via circulating fungal components.

Topics: Anemia, Aplastic; Animals; Apoptosis; beta-Glucans; Bone Marrow Diseases; Bone Marrow Failure Disorders; Hematopoiesis; Hematopoietic Stem Cells; Hemoglobinuria, Paroxysmal; Homeodomain Proteins; Interferon Type I; Interferon-gamma; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, SCID; Pneumocystis; Pneumonia, Pneumocystis; Receptor, Interferon alpha-beta; Signal Transduction

(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

Pneumocystis polymerase chain reaction (PCR) and blood (1→3)-β-D-glucan assays are known to be useful for the diagnosis of Pneumocystis pneumonia (PCP). However, their impact on the outcome of clinically suspected PCP patients has not yet been elucidated. Between January 2008 and July 2011, we prospectively observed 190 immunocompromised patients who had ground-glass opacity on chest computed tomography scans and were suspected to have PCP. The blood β-D-glucan levels of these patients were measured, and PCR was used to detect Pneumocystis jirovecii in the respiratory samples. The 30-day mortality rates and related factors were assessed. The 30-day mortality rate of all included patients was 21.6%. Both β-D-glucan-positive (10.1%) and PCR-positive patients (15.0%) had significantly lower mortality rates than β-D-glucan-negative (28.1%) or PCR-negative patients (30.1%). All of the 13 definite PCP patients had positive PCR and β-D-glucan results, received anti-PCP treatments, and survived. Among the 72 patients who were negative for microscopic detection of P. jirovecii but received anti-PCP treatments, positive PCR results (odds ratio [OR], 0.14; 95% confidence interval [CI], 0.02-0.74), a high Sequential Organ Failure Assessment score (OR, 1.42; CI, 1.08-1.88), and positive β-D-glucan levels (OR 0.25, CI 0.06-1.02) were associated with mortality rates using stepwise logistic regression analyses. A positive Pneumocystis PCR or β-D-glucan test was a candidate predictor of survival in patients who were suspected of having PCP, even though negative for visual detection by microscopy.

Topics: Aged; Analysis of Variance; beta-Glucans; DNA, Fungal; Female; Humans; Immunocompromised Host; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Prospective Studies

Pneumocystis pneumonia (PcP) is a major HIV-related illness caused by Pneumocystis jirovecii. Definitive diagnosis of PcP requires microscopic detection of P. jirovecii in pulmonary specimens. The objective of this study was to evaluate the usefulness of two serum markers in the diagnosis of PcP. Serum levels of (1-3)-beta-d-glucan (BG) and lactate dehydrogenase (LDH) were investigated in 100 HIV-positive adult patients and 50 healthy blood donors. PcP cases were confirmed using indirect immunofluorescence with monoclonal anti-Pneumocystis antibodies and nested-PCR to amplify the large subunit mitochondrial rRNA gene of P. jirovecii in pulmonary specimens. BG and LDH levels in serum were measured using quantitative microplate-based assays. BG and LDH positive sera were statistically associated with PcP cases (P ≤ 0.001). Sensitivity, specificity, positive/negative predictive values (PPV/NPV), and positive/negative likelihood ratios (PLR/NLR) were 91.3 %, 61.3 %, 85.1 %, 79.2 %, 2.359, and 0.142, respectively, for the BG kit assay, and 91.3 %, 35.5 %, 75.9 %, 64.7 %, 1.415 and 0.245, respectively, for the LDH test. Serologic markers levels combined with the clinical diagnostic criteria for PcP were evaluated for their usefulness in diagnosis of PcP. The most promising cutoff levels for diagnosis of PcP were determined to be 400 pg/ml of BG and 350 U/l of LDH, which combined with clinical data presented 92.8 % sensitivity, 83.9 % specificity, 92.8 % PPV, 83.9 % NPV, 5.764 PLR and 0.086 NLR (P < 0.001). This study confirmed that BG is a reliable indicator for detecting P. jirovecii infection. The combination between BG/LDH levels and clinical data is a promising alternative approach for PcP diagnosis.

Topics: Adult; Aged; beta-Glucans; Biomarkers; Female; HIV Infections; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Pneumonia, Pneumocystis; Predictive Value of Tests; Proteoglycans; Sensitivity and Specificity; Serum; Young Adult

Pneumocystis jirovecii pneumoniae (PJP) may be difficult to diagnose. Since pneumocystis cannot be cultured, the diagnosis of PJP requires microscopic examination to identify pneumocystis from induced sputum or bronchoalveolar lavage (BAL) fluid. In order to evaluate the usefulness of (1→3) beta-D-glucan (BDG) levels in the early diagnosis of PJP, we describe the case of PJP in a 25-year-old male with acute lymphoblastic leukaemia (ALL) admitted to hospital with progressive dyspnea and fever with chills. The patient was not infected with human immunodeficiency virus (HIV). Sputum, blood, and urine cultures were negative; smears for acid-fast bacilli and tests for viral antibodies were both negative. The microbiology study of the BAL with Giemsa and immunofluorescence staining, seven days after admission showed the existence of P. jiroveci in the lungs. Further, one day and five days after admission, (1→3) beta-D-glucan (BDG) levels were very high. The high serum level of BDG considerably decreased after treatment with trimethoprim-sulfamethoxazole (TMP-SMX) and the clinical condition of the patient increasingly improved.

Topics: beta-Glucans; Early Diagnosis; Humans; Male; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Young Adult

To investigate the utility of beta-D-glucan (BDG) testing in bronchoalveolar lavage (BAL) fluid for the diagnosis of invasive fungal infection (IFI), as compared to BAL galactomannan (GM).. We retrospectively reviewed medical records of 132 consecutive patients at the National Institutes of Health (NIH) in whom BAL BDG testing was performed for diagnosis of pneumonia. Using the European Organization for Research and Treatment of Cancer/Mycoses Study Group guidelines, we determined which patients had proven or probable IFI, and assessed the diagnostic performance of BAL BDG testing, relative to BAL GM. We also determined the reproducibility of the BDG assay in BAL via repeat testing of patient samples.. Ten patients had Pneumocystis pneumonia, and 34 patients had proven/probable IFI, including 14 with invasive aspergillosis (IA). BAL BDG was 100% sensitive for Pneumocystis. Although BAL BDG had similar sensitivity to BAL GM for the diagnosis of IA and IFI, it exhibited inferior specificity. Repeat testing demonstrated poor reproducibility of the BDG assay in BAL but not in serum.. BDG testing exhibits poor specificity and reproducibility in BAL. Identification of the BAL-specific factors that may interfere with the performance of the assay could improve the clinical usefulness of BAL BDG testing.

Topics: beta-Glucans; Bronchoalveolar Lavage Fluid; Female; Fusariosis; Galactose; Humans; Invasive Pulmonary Aspergillosis; Lung Diseases, Fungal; Male; Mannans; Mucormycosis; Paecilomyces; Pneumonia, Pneumocystis; Reproducibility of Results; Retrospective Studies; Scopulariopsis; Sensitivity and Specificity

Polymerase chain reaction (PCR) technique is being increasingly used for the microbiological diagnosis of Pneumocystis pneumonia (PCP). As PCR is highly sensitive, it can be positive even in a patient with Pneumocystis colonization. In this study, we evaluated whether the β-d-glucan assay could be used to differentiate between PCP and Pneumocystis jirovecii colonization in immunocompromised patients with pulmonary infiltrates. We retrospectively evaluated data from 166 consecutive patients who underwent bronchoalveolar lavage for the diagnosis of PCP. Serum levels of β-d-glucan in the negative, colonization, probable PCP, and definite PCP groups were 20.2 ± 6.3, 48.8 ± 15.9, 89.9 ± 20.2, 224.9 ± 25.9 pg/mL, respectively. The β-D-glucan levels in the definite PCP group were significantly higher than those in the other 3 groups (p < 0.001). Serum β-d-glucan levels in patients with either definite or probable PCP (173.1 ± 18.8 pg/mL) were significantly greater than those in patients with colonization who had positive PCR results but improved without anti-PCP treatment (p < 0.002). The cut-off level for discrimination was estimated to be 33.5 pg/mL, with which the positive predictive value was 0.925. These results indicate that β-D-glucan is a useful marker to differentiate between PCP and Pneumocystis colonization. A positive β-D-glucan assay result might be a good indication to begin anti-PCP treatment.

Topics: Aged; beta-Glucans; Biomarkers; Bronchoalveolar Lavage Fluid; Carrier State; Diagnosis, Differential; DNA, Fungal; Female; Humans; Immunocompromised Host; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Predictive Value of Tests; Proteoglycans; Retrospective Studies

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

The diagnosis of patients with pulmonary infiltrates and human immunodeficiency virus (HIV) infection remains a challenge. In current clinical practice the gold standard for Pneumocystis jirovecii pneumonia (PCP) diagnosis remains the identification of the organism in bronco alveolar lavage (BAL) using microscopy (e.g., silver stain). (1->3)-β -d-glucan (BG) is a polysaccharide that is present within the cell wall of Pneumocystis and other fungi.. We analyzed serum and BAL lavage fluid from a cohort of 119 patients that did have HIV, a diagnosis of pneumonia and underwent bronchoscopy (FOB) for diagnosis of PCP.. The discriminative power of serum BG for the diagnosis of PCP in this group of patients was very high. Using a cutoff of 300 pg/mL, the sensitivity, specificity, positive predictive value(PPV) and negative predictive value (NPV) were 91%, 92%, 89% and 93% respectively. A model for ROC with just serum BG (N = 108) had an AUC of 0.95. Serum procalcitonin (PCT) and BAL BG were not as accurate for the diagnosis of PCP. For BAL BG using a cutoff of 783 pg/mL, the sensitivity,specificity, positive predictive value (PPV) and negative predictive value (NPV) were 72%, 79%,72% and 79% respectively. The differences between the medians for serum PCT between the group with a without PCP did not reach statistical significance (p = 0.6137).. The measurement of serum BG should be incorporated in the diagnostic work up of HIV positive patients with dyspnea and infiltrates on chest X X-ray. Our study confirms the diagnostic value of serum BG previously reported by others but we add a cutoff value that we believe is more accurate for patients with AIDS and suspicion of PCP.

Topics: Adult; AIDS-Related Opportunistic Infections; beta-Glucans; Biomarkers; Bronchoalveolar Lavage Fluid; CD4 Lymphocyte Count; Female; Humans; Male; Middle Aged; Pneumonia, Pneumocystis; Predictive Value of Tests; Sensitivity and Specificity

Topics: beta-Glucans; Female; Humans; Male; Pneumonia, Pneumocystis; S-Adenosylmethionine

The objective of this study was to define the test characteristics of plasma beta-glucan for diagnosis of Pneumocystis jirovecii pneumonia (PCP) in AIDS patients with respiratory symptoms.. Analysis of baseline blood samples in a randomized strategy study of patients with acute opportunistic infections, limited to participants with respiratory symptoms.. Participants in the 282-person ACTG A5164 trial had baseline plasma samples assayed for beta-glucan testing. As part of A5164 trial, two study investigators independently adjudicated the diagnosis of PCP. Respiratory symptoms were identified by investigators from a list of all signs and symptoms with an onset or resolution in the 21 days prior to or 14 days following study entry. Beta-glucan was defined as positive if at least 80 pg/ml and negative if less than 80 pg/ml.. Of 252 study participants with a beta-glucan result, 159 had at least one respiratory symptom, 139 of whom had a diagnosis of PCP. The sensitivity of beta-glucan for PCP in participants with respiratory symptoms was 92.8% [95% confidence interval (CI) 87.2-96.5], and specificity 75.0% (95% CI 50.9-91.3). Among 134 individuals with positive beta-glucan and respiratory symptoms, 129 had PCP, for a positive predictive value of 96.3% (95% CI 91.5-98.8). Fifteen of 25 patients with a normal beta-glucan did not have PCP, for a negative predictive value of 60% (95% CI 38.7-78.9).. Elevated plasma beta-glucan has a high predictive value for diagnosis of PCP in AIDS patients with respiratory symptoms. We propose an algorithm for the use of beta-glucan as a diagnostic tool on the basis of the pretest probability of PCP in such patients.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; beta-Glucans; Biomarkers; Humans; Plasma; Pneumocystis carinii; Pneumonia, Pneumocystis; Predictive Value of Tests; Randomized Controlled Trials as Topic

The opportunistic pathogen Pneumocystis jirovecii is a significant cause of disease in HIV-infected patients and others with immunosuppressive conditions. Pneumocystis can also cause complications in treatment following antiretroviral therapy or reversal of immunosuppressive therapy, as the newly reconstituted immune system can develop a pathological inflammatory response to remaining antigens or a previously undetected infection. To target β-(1,3)-glucan, a structural component of the Pneumocystis cell wall with immune-stimulating properties, we have developed immunoadhesins consisting of the carbohydrate binding domain of Dectin-1 fused to the Fc regions of the 4 subtypes of murine IgG (mIgG). These immunoadhesins bind β-glucan with high affinity, and precoating the surface of zymosan with Dectin-1:Fc can reduce cytokine production by macrophages in an in vitro stimulation assay. All Dectin-1:Fc variants showed specificity of binding to the asci of Pneumocystis murina, but effector activity of the fusion molecules varied depending on Fc subtype. Dectin-1:mIgG2a Fc was able to reduce the viability of P. murina in culture through a complement-dependent mechanism, whereas previous studies have shown the mIgG1 Fc fusion to increase macrophage-dependent killing. In an in vivo challenge model, systemic expression of Dectin-1:mIgG1 Fc significantly reduced ascus burden in the lung. When administered postinfection in a model of immune reconstitution inflammatory syndrome (IRIS), both Dectin-1:mIgG1 and Dectin-1:mIgG2a Fc reduced hypoxemia despite minimal effects on fungal burden in the lung. Taken together, these data indicate that molecules targeting β-glucan may provide a mechanism for treatment of fungal infection and for modulation of the inflammatory response to Pneumocystis and other pathogens.

Topics: Animals; Antibodies, Monoclonal; B-Lymphocytes; beta-Glucans; Cell Wall; Cytokines; Immune Reconstitution Inflammatory Syndrome; Immunoglobulin G; Inflammation; Lectins, C-Type; Lung; Macrophages; Mice; Mice, Inbred C57BL; Pneumonia, Pneumocystis; T-Lymphocytes; Zymosan

This study assessed a quantitative PCR (qPCR) assay for Pneumocystis jirovecii quantification in bronchoalveolar lavage (BAL) fluid samples combined with serum (1→3)-β-d-glucan (BG) level detection to distinguish Pneumocystis pneumonia (PCP) from pulmonary colonization with P. jirovecii. Forty-six patients for whom P. jirovecii was initially detected in BAL fluid samples were retrospectively enrolled. Based on clinical data and results of P. jirovecii detection, 17 and 29 patients were diagnosed with PCP and colonization, respectively. BAL fluid samples were reassayed using a qPCR assay targeting the mitochondrial large subunit rRNA gene. qPCR results and serum BG levels (from a Fungitell kit) were analyzed conjointly. P. jirovecii DNA copy numbers were significantly higher in the PCP group than in the colonization group (1.3 × 10(7) versus 3.4 × 10(3) copies/μl, P < 0.05). A lower cutoff value (1.6 × 10(3) copies/μl) achieving 100% sensitivity for PCP diagnosis and an upper cutoff value (2 × 10(4) copies/μl) achieving 100% specificity were determined. Applying these two values, 13/17 PCP patients and 19/29 colonized patients were correctly assigned to their patient groups. For the remaining 14 patients with P. jirovecii DNA copy numbers between the cutoff values, PCP and colonization could not be distinguished on the basis of qPCR results. Four of these patients who were initially assigned to the PCP group presented BG levels of ≥100 pg/ml. The other 10 patients, who were initially assigned to the colonization group, presented BG levels of <100 pg/ml. These results suggest that the combination of the qPCR assay, applying cutoff values of 1.6 × 10(3) and 2 × 10(4) copies/μl, and serum BG detection, applying a 100 pg/ml threshold, can differentiate PCP and colonization diagnoses.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta-Glucans; Bronchoalveolar Lavage Fluid; Carrier State; Child; Diagnosis, Differential; DNA, Fungal; Female; Humans; Lung; Male; Middle Aged; Molecular Diagnostic Techniques; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity; Serum; Young Adult

Topics: beta-Glucans; Diagnosis, Differential; HIV Infections; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Sensitivity and Specificity

Pneumocystis jirovecii causes pneumonia in premature, newborn or malnourished children, as well as in immunocompromised subjects such as chemotherapy receiving, transplant and AIDS patients. Since the mortality and morbidity rates of Pneumocystis pneumonia (PCP) in these patients were high, rapid and accurate diagnosis is important. The aim of this study was to evaluate the diagnostic value of Giemsa staining (GS), direct fluorescent antibody (DFA) assay, (1→3)-β-D-Glucan (BDG) test and real-time polymerase chain reaction (PCR) for the detection of P.jirovecii in clinical specimens. A total of 100 PCP-suspected patients with underlying diseases who were followed-up in outpatient and inpatient clinics of our hospital between December 2008-July 2010 were included in the study. All the patients (66 male, 34 female; mean age: 42.04 years) were under long-term immunosuppressive drug therapy due to their hematological malignancies, kidney transplantation, neutropenia or chronic diseases. Respiratory samples [86 bronchoalveolar lavage (BAL), 8 endotracheal aspirate, 1 nasotracheal aspirate, 3 pleural, 2 lung biopsy samples] obtained from the patients have been studied with GS (Merck, Germany), DFA (Pneumo Cel, Cellabs, Australia) and PCR (primers targeting MSG gene, LightCycler, Roche, USA), while serum samples (n= 100) with BDG (Fungitell, ACC Inc, USA) and PCR methods. In BAL samples two were found positive by GS, DFA and PCR, and six were positive only by PCR, yielding a total positivity in 8 (8%) samples. All of the sera were negative with PCR, however 29 of them were positive (> 80 pg/ml), five were equivocal (61-79 pg/ml) and 66 were negative (< 60 pg/ml) with BDG test. Eight patients with positive results in BAL-PCR were also positive with BDG test. Although the agreement between GS and DFA was high (κ= 1), it was observed as low between PCR and DFA (κ= 0.38), DFA and BDG (κ= 0.07), BAL-PCR and BDG (κ= 0.28). DFA taken as the gold standard, the sensitivity and specificity values of GS, PCR and BDG methods were calculated as 100% and 100%; 100% and 93%; 100% and 67%, respectively. In the ROC analysis performed for BDG test, with DFA and BAL-PCR taken as the gold standards, the sensitivity, specificity and cut-off values of BDG were estimated as 100%, 93.9% and 494 pg/ml, and 100%, 72.8% and 62 pg/ml, respectively. Our data indicated that, overall specificity was high (100%) when using GS and DFA tests together, while the sensitivity has been elevated to 93

Topics: Adult; Azure Stains; beta-Glucans; Bronchoalveolar Lavage; Coloring Agents; Female; Fluorescent Antibody Technique, Direct; Humans; Immunocompromised Host; Male; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Real-Time Polymerase Chain Reaction; Respiratory System; ROC Curve; Sensitivity and Specificity

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; beta-Glucans; Biomarkers; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis

We evaluated whether quantitative PCR (qPCR) and (1 → 3)-β-d-glucan assays could be used to differentiate Pneumocystis pneumonia (PCP) from Pneumocystis jirovecii colonization in immunocompromised patients with pulmonary infiltrates. A total of 40 bronchoalveolar lavage samples and 107 induced sputum samples from 147 patients who were suspected of having PCP were obtained for PCR detection of P. jirovecii. Diagnoses of definite PCP, probable PCP, pneumonia with P. jirovecii colonization (colonization) and pneumonia without colonization (non-colonization) were made in 11, 42, 15 and 60 patients, respectively. A PCP diagnosis was undetermined in 19 patients. The copy numbers, determined using qPCR, were significantly higher in definite PCP and probable PCP patients than in colonized patients. The area under the receiver-operating characteristic curve (AUC), sensitivity and specificity for discriminating definite PCP from colonization were 0.96, 100.0% and 80.0%, respectively, at a cut-off value of 1300 copies/mL. The values for discriminating probable PCP from colonization were 0.71, 66.7% and 73.3%, respectively, at a cut-off value of 340 copies/mL. β-d-glucan levels were significantly higher in patients with both definite PCP and probable PCP than in colonized patients. The AUC, sensitivity and specificity for discriminating definite PCP were 0.91, 100.0% and 80.0%, respectively, at a cut-off value of 15.6 pg/mL. The values for discriminating probable PCP were 0.78, 76.2% and 73.3%, respectively, at a cut-off value of 6.0 pg/mL. Both qPCR and the β-d-glucan assay displayed high accuracy for discriminating colonization from definite PCP and displayed moderate accuracy for discriminating colonization from probable PCP.

Topics: Adult; Aged; beta-Glucans; Bronchoalveolar Lavage Fluid; Clinical Laboratory Techniques; DNA, Fungal; Female; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity; Sputum

Pneumocystis species are opportunistic fungal organisms that cause severe pneumonia in immune-compromised hosts, with resultant high morbidity and mortality. Recent work indicates that IL-17 responses are important components of host defense against fungal pathogens. In the present study, we demonstrate that cell-surface β-glucan components of Pneumocystis (PCBG) stimulate human dendritic cells (DCs) to secrete IL-23 and IL-6. These cytokines are well established to stimulate a T helper-17 (Th17) phenotype. Accordingly, we further observe that PCBG-stimulated human DCs interact with lymphocytes to drive the secretion of IL-17 and IL-22, both Th17-produced cytokines. The activation of DCs was shown to involve the dectin-1 receptor with a downstream activation of the Syk kinase and subsequent translocation of both the canonical and noncanonical components of the NF-κB transcription factor family. Finally, we demonstrate that glycosphingolipid-rich microdomains of the plasma membrane participate in the activation of DCs by PCBG through the accumulation of lactosylceramide at the cell surface during stimulation with PCBG. These data strongly support the idea that the β-glucan surface components of Pneumocystis drive the activation of the IL-23/IL-17 axis during this infection, through a glycosphingolipid-initiated mechanism.

Topics: beta-Glucans; Cell Wall; Cells, Cultured; Dendritic Cells; Glycosphingolipids; Humans; Interleukin-17; Interleukin-22; Interleukin-23; Interleukin-6; Interleukins; Intracellular Signaling Peptides and Proteins; Lectins, C-Type; Membrane Microdomains; NF-kappa B; Pneumocystis; Pneumonia, Pneumocystis; Protein-Tyrosine Kinases; Signal Transduction; Syk Kinase; Th1 Cells; Th17 Cells

The kinetics of serum (1 → 3)-β-d-glucan (BG) following the diagnosis of invasive fungal disease and administration of antifungal therapy are poorly characterized. It is unknown whether early BG changes have prognostic implications. We assessed the post-diagnostic kinetics of BG in patients with an initial serum BG ≥80 pg/mL and at least one additional post-diagnostic BG value in the setting of invasive aspergillosis (IA, n=69), invasive candidiasis (IC, n=40), or Pneumocystis jirovecii pneumonia (PCP, n = 18), treated with antifungal therapy. Clinical failure of antifungal therapy and mortality were assessed at 6 and 12 weeks, and Cox modelling was used to assess the hazard of initial BG and change in BG at 1 or 2 weeks for these outcomes. In patients with at least two BG values, median initial BG was >500 pg/mL (interquartile range (IQR) 168 to >500; range 80 to >500) in IA, 136 pg/mL (IQR 88 to >500; range 31 to >500) in IC and >500 pg/mL (IQR 235 to >500; range 86 to >500) in PCP. In patients with at least two BG values through to 1 week after diagnosis, overall 1-week decline in BG was 0 pg/mL (IQR 0-53) in IA, 0 (IQR - 65 to 12) in IC and 17 (IQR 0-82) in PCP. Most patients with BG values through 6 and 12 weeks had persistent levels >80 pg/mL. Initial BG and the early trajectory of BG were not predictive of 6-week or 12-week clinical failure or mortality. Whereas BG eventually declines in patients with IA, IC and PCP, it lacks prognostic value within a clinically meaningful time frame.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Antigens, Fungal; Aspergillosis; Aspergillus; beta-Glucans; Candida; Candidiasis, Invasive; Cause of Death; Female; Humans; Kinetics; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Prognosis; Proteoglycans; Treatment Failure; Young Adult

Circulating Pneumocystis jirovecii DNA and (1→3)-β-d-glucan determined in 70 serum samples from immunocompromised patients were compared to fungal load in bronchoalveolar lavage fluids assessed using quantitative polymerase chain reaction. Both serum biomarkers are influenced by pulmonary fungal load, which should be taken into account when diagnosing Pneumocystis infection.

Topics: beta-Glucans; Biomarkers; Bronchoalveolar Lavage Fluid; Cohort Studies; Colony Count, Microbial; DNA, Fungal; Humans; Immunocompromised Host; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Retrospective Studies

Topics: Aged; Antifungal Agents; beta-Glucans; Cryptococcosis; Diagnostic Errors; Echinocandins; Fatal Outcome; Female; Humans; Immunocompromised Host; Lipopeptides; Micafungin; Pneumonia, Pneumocystis; Purpura Fulminans; Tomography, X-Ray Computed

Pneumocystis jirovecii (carinii) pneumonia (PJP) is a major cause of disease in immunocompromised individuals. However, until recently no reliable and specific serological parameters for the diagnosis of PJP have been available. (1 → 3)-β-D-Glucan (BG) is a cell wall component of P. jirovecii and of various other fungi. Data from the past few years have pointed to serum measurement of BG as a promising new tool for the diagnosis of PJP. We therefore conducted a retrospective study on 50 patients with PJP and 50 immunocompromised control patients to evaluate the diagnostic performance of serum BG measurement. Our results show an excellent diagnostic performance with a sensitivity of 98.0% and a specificity of 94%. While the positive predictive value was only 64.7%, the negative predictive value was 99.8% and therefore a negative BG result almost rules out PJP. BG levels were already strongly elevated in an average of 5 days and up to 21 days before microbiological diagnosis demonstrating that the diagnosis could have been confirmed earlier. BG levels at diagnosis and maximum BG levels during follow-up did not correlate with the outcome of patients or with the P. jirovecii burden in the lung as detected by Real-Time PCR. Therefore, absolute BG levels seem to be of no prognostic value. Altogether, BG is a reliable parameter for the diagnosis of PJP and could be used as a preliminary test for patients at risk before a bronchoalveolar lavage is performed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta-Glucans; Biomarkers; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Pneumonia, Pneumocystis; Predictive Value of Tests; Prognosis; Proteoglycans; Retrospective Studies; Sensitivity and Specificity; Serum; Time Factors; Young Adult

To prospectively assess the diagnostic utility of S-adenosylmethionine (AdoMet) and (1→3)-β-D-glucan (β-D-glucan) serum markers for Pneumocystis pneumonia (PCP) in HIV-negative patients.. HIV-negative, immunocompromised patients suspected of PCP based on clinical presentation and chest imaging were included. PCP was confirmed or rejected by results of direct microscopy and/or real-time PCR on broncho-alveolar lavage (BAL) fluid. Measurement of serum β-D-glucan and AdoMet was performed on serum samples collected at enrollment and during follow-up. Both serum β-D-glucan and AdoMet were assessed for diagnostic accuracy and correlation with clinical and laboratory parameters.. In 31 patients enrolled (21 PCP-positive, 10 PCP-negative), AdoMet levels did not discriminate between patients with and without PCP. Elevated serum β-D-glucan was a reliable indicator for PCP with a sensitivity of 0.90 and specificity of 0.89 at the 60 pg/ml cut-off. In PCP-positive patients β-D-glucan serum levels decreased during treatment and inversely correlated with Pneumocystis PCR cycle threshold values in BAL fluid.. The level of β-D-glucan--but not AdoMet--was diagnostic for PCP within the clinical context and may serve as marker for pulmonary fungal load and treatment monitoring.

Topics: Aged; beta-Glucans; Biomarkers; Female; HIV Seronegativity; Humans; Immunocompromised Host; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Prospective Studies; Proteoglycans; S-Adenosylmethionine; Sensitivity and Specificity

The number of patients with non-HIV Pneumocystis pneumonia (PCP) is increasing with widespread immunosuppressive treatment. We investigated the clinical characteristics of non-HIV PCP and its association with microbiological genotypes.. Between January 2005 and March 2010, all patients in 2 university hospitals who had been diagnosed with PCP by PCR were enrolled in this study. Retrospective chart review of patients, microbiological genotypes, and association with 30-day mortality were examined.. Of the 82 adult patients investigated, 50 patients (61%) had inflammatory diseases, 17 (21%) had solid malignancies, 12 (15%) had hematological malignancies, and 6 (7%) had received transplantations. All patients received immunosuppressive agents or antitumor chemotherapeutic drugs. Plasma (1→3) β-D-glucan levels were elevated in 80% of patients, and were significantly reduced after treatment in both survivors and non-survivors. However, β-D-glucan increased in 18% of survivors and was normal in only 33% after treatment. Concomitant invasive pulmonary aspergillosis was detected in 5 patients. Fifty-six respiratory samples were stored for genotyping. A dihydropteroate synthase mutation associated with trimethoprim-sulfamethoxazole resistance was found in only 1 of the 53 patients. The most prevalent genotype of mitochondrial large-subunit rRNA was genotype 1, followed by genotype 4. The most prevalent genotype of internal transcribed spacers of the nuclear rRNA operon was Eb, followed by Eg and Bi. Thirty-day mortality was 24%, in which logistic regression analysis revealed association with serum albumin and mechanical ventilation, but no association with genotypes.. In non-HIV PCP, poorer general and respiratory conditions at diagnosis were independent predictors of mortality. β-D-glucan may not be useful for monitoring the response to treatment, and genotypes were not associated with mortality.

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; DNA, Bacterial; DNA, Mitochondrial; Female; Genotype; HIV Infections; Humans; Japan; Male; Middle Aged; Opportunistic Infections; Pneumocystis carinii; Pneumonia, Pneumocystis; Prognosis; Retrospective Studies; Young Adult

Serum (1→3)-β-D-Glucan (BG) is a biomarker for Pneumocystis jirovecii pneumonia (PJP). However, information concerning its usefulness for monitoring the clinical course is lacking. We conducted a retrospective study to investigate whether consecutive BG-measurements can be used to assess treatment response in PJP. Analysis of sera from 18 patients during PJP therapy shows that decreasing BG-levels strongly correlate with a favourable clinical course. In contrast, increasing BG-levels were associated with treatment failure or fatal outcome is only 44% of patients. As a consequence, BG-kinetics might be used to confirm treatment success but seem to be of limited value for the identification of treatment failure.

Topics: beta-Glucans; Biomarkers; Drug Monitoring; Humans; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Retrospective Studies; Treatment Outcome

Topics: beta-Glucans; Child; Humans; Immunocompromised Host; Pneumocystis carinii; Pneumonia, Pneumocystis

Topics: beta-Glucans; Diagnostic Tests, Routine; HIV Infections; Humans; Plasma; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Serologic Tests

(See the editorial commentary by Morris and Masur, on pages 203-204.). Improved noninvasive diagnostic tests for Pneumocystis jirovecii pneumonia (PCP) are needed. We evaluated the test characteristics of plasma (1 → 3)-β-D-glucan (β-glucan) for HIV-related PCP among a large group of patients presenting with diverse opportunistic infections (OIs).. The study population included all 282 participants in AIDS Clinical Trials Group A5164, a study of early versus deferred antiretroviral therapy in conjunction with initial therapy of acute OIs. Baseline plasma samples were assayed for β-glucan, with standard assay reference values defining ≥ 80 pg/mL as positive. Before this analysis, diagnosis of PCP was independently adjudicated by 2 study investigators after reviewing reports from study sites.. A total of 252 persons had a β-glucan result that could be analyzed, 173 (69%) of whom had received a diagnosis of PCP. Median β-glucan with PCP was 408 pg/mL (interquartile range [IQR], 209-500 pg/mL), compared with 37 pg/mL (IQR, 31-235 pg/mL) without PCP (P < .001). The sensitivity of β-glucan dichotomized at 80 pg/mL for the diagnosis of PCP was 92% (95% confidence interval [CI], 87%-96%), and the specificity was 65% (95% CI, 53%-75%); positive and negative predictive values were 85% (95% CI, 79%-90%) and 80% (95% CI, 68%-89%) respectively, based on the study prevalence of 69% of patients with PCP. Rates of abnormal lactate dehyrogenase levels did not differ significantly between those with and without PCP.. Blood (1 → 3)-β-D-glucan is strongly correlated with HIV-related PCP. In some clinical centers, this may be a more sensitive test than the induced sputum examination and could reduce the need for both bronchoscopy and empirical therapy of PCP.

Topics: Adult; beta-Glucans; Diagnostic Tests, Routine; Female; HIV Infections; Humans; Male; Plasma; Pneumocystis carinii; Pneumonia, Pneumocystis; Predictive Value of Tests; Proteoglycans; Sensitivity and Specificity

Serum β-D-glucan has been demonstrated as a reliable, adjunct diagnostic marker for PCP, but its kinetics after PCP treatment are poorly understood. To evaluate the correlation between the levels of β-D-glucan and the clinical response, we investigated the individual transition of serum β-D-glucan levels after the initiation of PCP treatment.. Retrospective study. Seventeen PCP patients with AIDS who were admitted to our hospital were analyzed.. All subjects showed the serum β-D-glucan levels above the cut-off value, and the median level was 224 pg/mL [IQR: 78-597] at the time of PCP diagnosis. There were no correlations between serum β-D-glucan levels and CRP, LDH, or AaDO(2) at room air. Although there was a downward trend in serum β-D-glucan level as PCP treatment was initiated, a significant number of subjects showed a marked increase in the serum β-D-glucan levels despite their evident clinical improvement.. The serum β-D-glucan level does not reflect the severity and prognosis of PCP infection, and thus it may not be suitable for monitoring the response to treatment.

Topics: Acquired Immunodeficiency Syndrome; Adult; beta-Glucans; Biomarkers; Female; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies; Treatment Outcome

Topics: beta-Glucans; Diagnostic Tests, Routine; Female; HIV Infections; Humans; Male; Pneumocystis carinii; Pneumonia, Pneumocystis

Topics: beta-Glucans; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Sensitivity and Specificity

While tumor necrosis factor (TNF) inhibitors have dramatically improved the clinical outcomes of rheumatoid arthritis (RA) in recent years, infectious complications are a serious concern. Adalimumab (ADA) is a newly-developed human monoclonal antibody against TNF-alpha. Here we report 2 cases of pneumocystis pneumonia (PCP) which developed in RA patients during ADA therapy. One patient is a 66-year-old woman who had a history of RA for 6 months. The patient was given ADA at 40 mg biweekly for her active arthritis which had been refractory to 6 mg/week of methotrexate (MTX), and 5 mg/day of prednisolone (PSL). One hundred and six days later, she was admitted to our hospital because of fever, cough, and dyspnea. Another patient is a 62-year-old man who had a history of RA for 3 years. Since his arthritis was so active even under the treatment with MTX (8 mg/week) and PSL (15 mg/day), the patient started to be given ADA at 40 mg biweekly. After 28 days, the patient was admitted to the hospital because of dyspnea. Chest roentgenogram and computed tomography revealed interstitial pneumonia in both patients. Beta-D-glucan levels were so high in their serum suggesting the diagnosis of PCP, which was confirmed by the detection of Pneumocystis jirovecii DNA in the sputa by polymerase chain reaction. The patients were immediately treated with sulfamethoxazole/trimethoprim and high-dose prednisolone, which successfully improved pneumonia, and they were discharged from the hospital on the 8(th) and 16(th) day, respectively. PCR and β-D-glucan were useful for the early diagnosis of PCP and lead to the timely induction of adequate treatment and the rescue of these patients.

Topics: Adalimumab; Aged; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; beta-Glucans; Biomarkers; DNA, Fungal; Early Diagnosis; Female; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Prednisolone; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Tumor Necrosis Factor-alpha

Topics: beta-Glucans; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Serum

Topics: beta-Glucans; HIV Infections; Humans; Pneumonia, Pneumocystis; Proteoglycans; Serum

Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express beta -1,3-D-glucan synthetase and contain abundant beta -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of beta -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased beta -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens.

Topics: Animals; beta-Glucans; Disease Models, Animal; Echinocandins; Fluorescent Dyes; Lung; Mice; Pneumonia, Pneumocystis; Proteoglycans; Rats

Host defense against opportunistic fungi requires coordination between innate and adaptive immunity for resolution of infection. Antibodies generated in mice vaccinated with the fungus Pneumocystis prevent growth of Pneumocystis organisms within the lungs, but the mechanisms whereby antibodies enhance antifungal host defense are poorly defined. Nearly all species of fungi contain the conserved carbohydrates β-glucan and chitin within their cell walls, which may be targets of innate and adaptive immunity. In this study, we show that natural IgM antibodies targeting these fungal cell wall carbohydrates are conserved across many species, including fish and mammals. Natural antibodies bind fungal organisms and enhance host defense against Pneumocystis in early stages of infection. IgM antibodies influence recognition of fungal antigen by dendritic cells, increasing their migration to draining pulmonary lymph nodes. IgM antibodies are required for adaptive T helper type 2 (Th2) and Th17 cell differentiation and guide B cell isotype class-switch recombination during host defense against Pneumocystis. These experiments suggest a novel role for the IgM isotype in shaping the earliest steps in recognition and clearance of this fungus. We outline a mechanism whereby serum IgM, containing ancient specificities against conserved fungal antigens, bridges innate and adaptive immunity against fungal organisms.

Topics: Adaptive Immunity; Animals; Antibodies, Bacterial; beta-Glucans; Cell Wall; Immune Sera; Immunity, Innate; Immunoglobulin Heavy Chains; Immunoglobulin M; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, SCID; Molecular Sequence Data; Phylogeny; Pneumocystis; Pneumocystis carinii; Pneumonia, Pneumocystis; Protein Binding; Species Specificity; Th17 Cells; Th2 Cells

Pneumocystis pneumonia (PcP) is the most common opportunistic disease in immunocompromised patients. Alveolar macrophages are responsible for the clearance of Pneumocystis organisms; however, they undergo a high rate of apoptosis during PcP due to increased intracellular polyamine levels. In this study, the sources of polyamines and mechanisms of polyamine increase and polyamine-induced apoptosis were investigated. The level of ornithine decarboxylase (ODC) was elevated in alveolar macrophages, and the number of alveolar macrophages that took up exogenous polyamines was increased 20-fold during PcP. Monocytes, B lymphocytes, and CD8+ T lymphocytes that were recruited into the lung during PcP expressed high levels of ornithine decarboxylase, suggesting that these cells are sources of polyamines. Both protein and mRNA levels of antizyme inhibitor (AZI) were increased in alveolar macrophages during PcP. This AZI overexpression correlated with increased polyamine uptake by alveolar macrophages, because AZI expression knockdown decreased the polyamine uptake ability of these cells. AZI expression knockdown also decreased the apoptosis rate of alveolar macrophages. Pneumocystis organisms and zymosan A were found to induce AZI overexpression in alveolar macrophages, suggesting that beta-glucan, which is the major component of the Pneumocystis cell wall, induces AZI overexpression. The levels of mRNA, protein, and activity of polyamine oxidase were increased in alveolar macrophages during PcP, indicating that the H(2)O(2) generated during polyamine catabolism caused alveolar macrophages to undergo apoptosis. Taken together, results of this study indicate that Pneumocystis organisms induce AZI overexpression in alveolar macrophages, leading to increased polyamine synthesis and uptake and apoptosis rate of these cells.

Topics: Animals; Apoptosis; B-Lymphocytes; beta-Glucans; Carrier Proteins; CD8-Positive T-Lymphocytes; Cell Wall; Gene Expression Regulation; Humans; Hydrogen Peroxide; Macrophages, Alveolar; Male; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Pneumocystis carinii; Pneumonia, Pneumocystis; Polyamines; Rats; Rats, Sprague-Dawley

New serum markers (1-->3) beta-D-glucan (beta-D-glucan) and KL-6 are reported to be useful for the clinical diagnosis of Pneumocystis jirovecii pneumonia (PCP). However, the utility of these markers in PCP with HIV infection (HIV PCP) and without HIV (non-HIV PCP) is unknown. This study was aimed to evaluate the utility of beta-D-glucan and KL-6 for the diagnosis of PCP in patients with HIV infection (HIV PCP) and non-HIV PCP.. Retrospective study.. We reviewed the medical records of consecutive 35 patients. The serum levels of beta-D-glucan and KL-6 in HIV PCP and non-HIV PCP were comparatively evaluated. We evaluated these markers in survivors and non survivors.. The detection rates of serum beta-D-glucan and KL-6 levels in non-HIV PCP were lower than those in HIV PCP (88% vs. 100%, 66% vs. 88%, respectively). The false positive rates of these markers in both groups were similar (12%, 37%, respectively). Oxygenation index, serum albumin, and mechanical ventilation were the variables which were significantly associated with poor outcome in the univariate analysis.. In conclusion, beta-D-glucan was a reliable diagnostic marker for PCP. However, the detection rate of beta-D-glucan and KL-6 in non-HIV PCP was lower than in HIV PCP. Neither beta-D-glucan nor KL-6 was associated with the outcome of PCP.

Topics: Adult; Aged; AIDS-Related Opportunistic Infections; beta-Glucans; Biomarkers; Bronchoalveolar Lavage Fluid; Case-Control Studies; False Positive Reactions; Female; Humans; Male; Middle Aged; Mucin-1; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Retrospective Studies

In patients with chronic respiratory disease, Pneumocystis jirovecii (P. jirovecii) colonization is observed, and may influence disease progression and systemic inflammation. Pneumocystis pneumonia causes interstitial changes, so making a diagnosis of PCP in patients who have interstitial pneumonia (IP) with P. jirovecii colonization is sometimes difficult based on radiography.. This study investigated the prevalence of P. jirovecii colonization in IP patients and assessed pulmonary injury due to P. jirovecii colonization by measurement of serum markers (KL-6, SP-A, SP-D, and (1-->3) beta-D-glucan (beta-D-glucan)) and the peripheral lymphocyte counts, prospectively. A total of 75 patients with idiopathic pulmonary fibrosis (n = 29), collagen vascular-related interstitial pneumonia (n = 19), chronic bronchitis or pneumonia (n = 20), and Pneumocystis pneumonia (n = 7) were enrolled in this prospective study. P. jirovecii DNA was detected in sputum samples, while serum markers and the lymphocyte count were measured in the peripheral blood.. IP patients (idiopathic pulmonary fibrosis and collagen vascular-related IP) who received oral corticosteroids had a high prevalence of P. jirovecii colonization (23.3%). In IP patients, oral corticosteroid therapy was a significant risk factor for P. jirovecii colonization (P < 0.05). Serum markers did not show differences between IP patients with and without P. jirovecii colonization. The beta-D-glucan level and lymphocyte count differed between patients with Pneumocystis pneumonia or P. jirovecii colonization.. Serum levels of KL-6, SP-A, SP-D, and beta-D-glucan were not useful for detecting P. jirovecii colonization in IP patients. However, the serum beta-D-glucan level and lymphocyte count were useful for distinguishing P. jirovecii colonization from pneumocystis pneumonia in IP patients.

Topics: Adrenal Cortex Hormones; Aged; beta-Glucans; Biomarkers; Female; Humans; Idiopathic Pulmonary Fibrosis; Lymphocyte Count; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Prevalence; Prospective Studies; Risk Factors

(1,3)-beta-d-Glucan (BG) is a component of the Pneumocystis jiroveci cell wall. Thirty-one immunocompromised patients with pneumonia (16 with presumptive pneumocystis pneumonia [PCP] and 15 with non-PCP) were evaluated for serum BG levels. Serum from all 16 presumptive PCP patients and from 2/15 patients with non-PCP was positive for BG. Results indicate that BG is a reliable marker for diagnosing PCP.

Topics: beta-Glucans; Biomarkers; Case-Control Studies; Cell Wall; Humans; Immunocompromised Host; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans

High serum (1-->3) beta-D-glucan levels are described in patients with Pneumocystis pneumonia (PCP). We evaluated the diagnostic value of beta-D-glucan in 111 patients with AIDS who had PCP and confirmed its usefulness. However, it does not correlate with disease severity and is not suitable for monitoring response to treatment.

Topics: Adult; beta-Glucans; Biomarkers; Female; HIV Infections; Humans; Male; Middle Aged; Pneumonia, Pneumocystis; Predictive Value of Tests; Proteoglycans

Invasive aspergillosis is a major cause of morbidity and mortality in immunocompromised patients receiving intensive care. The double-sandwich ELISA for galactomannan is reported to have a high sensitivity (96.5%) for the detection of invasive aspergillosis when a cut-off value of 0.8 ng/ml is used. However, we have experienced a case of lethal disseminated aspergillosis in a patient that presented with a negative galactomannan (GM) test and persistent elevation of beta-D glucan (BG) levels. A 63-year-old female was admitted to our Intensive Care Unit (ICU) in acute respiratory failure and elevated BG. She had been receiving medication for Good-pasture syndrome based on anti-glomerular basement membrane antibodies and myeloperoxidase-antineutrophil cytoplasmic antibodies for 9 months and was receiving long-term prednisolone therapy (20 mg/day). On admission, her trachea was immediately intubated, and a PCR analysis of the bronchoalveolar lavage sample revealed Pneumocystis jiroveci. Trimethoprimsulfamethoxazole therapy was started for Pneumocystis pneumonia. The levels of BG remained elevated (> 100 pg/ml) during the treatment period despite the clinical resolution of Pneumocystis pneumonia, raising concerns of another complicated invasive fungal disease; consequently, fosfluconazole was administered empirically. The serum BG levels, however, did not decrease. Blood cultures did not detect a fungal infection. Serum GM levels measured by a double-sandwich ELISA on the 6th, 11th, and 24th days in the ICU were negative (< 0.2 ng/ml). The patient ultimately died of multiple organ failure on the 45th ICU day. Postmortem examination revealed a disseminated fungal infection with aggressive vascular invasion of the lungs, heart, and brain. In situ hybridization with a 568-bp probe of the alkaline proteinase sequence of Aspergillus fumigatus showed specific positive staining within the fungus present in the infected lung tissue, revealing that this patient may have had a systemic infection by A. fumigatus or A. flavus. This is a case of serum GM-negative disseminated aspergillosis pathologically proven by autopsy. Persistent elevated BG levels (> 100 pg/ml) refractory to trimethoprim-sulfamethoxazole and fosfluconazole may suggest possible Aspergillus infection and should prompt the initiation of empiric anti-aspergillosis therapies in patients at risk for fungal infection.

Topics: Antifungal Agents; Aspergillosis; Aspergillus; beta-Glucans; Brain; Fatal Outcome; Female; Galactose; Heart; Humans; Immunosuppressive Agents; Intensive Care Units; Lung; Mannans; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Prednisolone; Trimethoprim, Sulfamethoxazole Drug Combination

(1-3)-Beta-D-Glucan (BG) reactivity was tested in serum samples from 28 patients with human immunodeficiency virus infection or a hematological malignancy and Pneumocystis jirovecii pneumonia (PCP) and 28 control patients. The sensitivity and specificity of BG detection with the Fungitell assay for PCP were 100 and 96.4%, respectively, using a cutoff value of 100 pg/ml. Serum BG testing looks promising for the noninvasive diagnosis of PCP. Our data suggest that a higher cutoff value for the diagnosis of PCP than for the diagnosis of invasive aspergillosis or candidiasis could be used safely and will improve the specificity of the test.

Topics: Adult; AIDS-Related Opportunistic Infections; beta-Glucans; Female; Hematologic Neoplasms; HIV Infections; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Sensitivity and Specificity; Young Adult

A 78-year-old man administered prednisolone and cyclosporin A for bullous pemphigoid and found in computed tomography (CT) to have a left-lung nodule was suspected of having a fungal infection due to elevated blood (1-->3)-beta-D-glucan. Despite empirical antifungal therapy, however, the nodule grew, followed by new nodules in both lungs. Disseminated nocardiosis was eventually diagnosed based on sputum, blood, and skin cultures growing Nocardia sp. Antinocardial treatment with imipenem/cilastatin and amikacin was started. The patient then developed pneumocystis pneumonia for which pentamidine was added. He had recovered completely when antimicrobial therapy was completed. A wide variety of microorganisms may infect patients with impaired cellular immunity, simultaneously involving multiple organisms in some cases. Definitive microbiological diagnosis with culture or biopsy specimens is therefore crucial for appropriate management.

Topics: Aged; beta-Glucans; Cyclosporine; Humans; Male; Nocardia Infections; Opportunistic Infections; Pemphigoid, Bullous; Pneumonia, Pneumocystis; Prednisolone

Topics: Adult; Antifungal Agents; beta-Glucans; Bronchoalveolar Lavage Fluid; HIV Infections; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans; Radiography, Thoracic; Sputum

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

To elucidate the clinical and radiological features of Pneumocystis pneumonia (PCP) in patients with rheumatoid arthritis (RA), compared with methotrexate (MTX) pneumonitis in RA and Pneumocystis pneumonia in acquired immunodeficiency syndrome (AIDS).. Retrospective analysis of 14 PCP cases in RA (RA-PCP), 10 MTX pneumonitis cases in RA (MTX-P) and 11 PCP cases in AIDS (AIDS-PCP) from 9 centers in the Kanto area in the last 6 years.. Compared with AIDS-PCP, both RA-PCP and MTX-P developed more rapidly, showing higher serum CRP and lower plasma beta-D-glucan levels, and more severe oxygenation impairment. In most of the RA-PCP cases, a high dose of corticosteroid was administered as adjunctive therapy, resulting in a favorable outcome. The mortality was 14% in RA-PCP, 0% in AIDS-PCP and 0% in MTX-P cases. In RA-PCP patients the CD4 cell count showed only mild suppression, not reaching the predisposing level for PCP in HIV infection, suggesting that there are risk factors for RA-PCP other than immunosuppression. Radiologic analysis revealed some characteristic patterns of each disease. In MTX-P, diffuse homogeneous ground glass opacity (GGO) with sharp demarcation by interlobular septa (type A GGO) was found in 70%, while in AIDS-PCP diffuse, homogeneous or nonhomogeneous GGO without interlobular septal boundaries (type B GGO) was predominant (91%). In RA-PCP, type A GGO was found in 6 cases and type B GGO in 5 cases, showing the complex nature of this disease.. RA-PCP differed considerably from AIDS-PCP clinically and radiologically. Clinically it occurred without severe immunosuppression, and showed characteristic aspects, with more intense inflammation and less parasite burden. Radiologically it mimicked MTX-P in some cases sharing the conspicuous CT features of MTX-P, rendering the distinction of these two disorders difficult.

Topics: Adult; Aged; Aged, 80 and over; AIDS-Related Opportunistic Infections; Arthritis, Rheumatoid; beta-Glucans; C-Reactive Protein; Diagnosis, Differential; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Pneumocystis carinii; Pneumonia; Pneumonia, Pneumocystis; Retrospective Studies; Tomography, X-Ray Computed

Pneumocystis pneumonia (PCP) remains the most common opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). Familiarity with the clinical features of PCP is crucial for prompt diagnosis, even if the patient is unaware of their HIV serostatus. We describe herein the clinical features of 34 episodes in 32 patients with AIDS-associated PCP and review the existing literature. As for symptoms, the frequency of fever, cough, and dyspnea was 74%, 74%, and 65%, respectively, and the complete triad was present in only 14 of the 34 episodes on first examination. Median duration from onset of symptoms until diagnosis was 3 weeks, and AIDS-associated PCP tended to take an insidious clinical course. Although laboratory findings were generally nonspecific, measurement of beta-D-glucan levels in the serum or plasma was highly useful in the diagnosis of PCP. All but 1 of the patients showed beta-D-glucan levels higher than the cutoff value (median, 147 pg/ml; range, 5-6920 pg/ml). Typical radiographic features of PCP are bilateral, symmetrical ground-glass opacities, but a wide variety of radiographic findings were observed. In our patients, high-resolution computed tomography (HRCT) of the lung showed ground-glass opacities sparing the lung periphery (41% of episodes) or displaying a mosaic pattern (29%), or being nearly homogeneous (24%), ground-glass opacities associated with air-space consolidation (21%), associated with cystic formation (21%), associated with linear-reticular opacities (18%), patchily and irregularly distributed (15%), associated with solitary or multiple nodules (9%), and associated with parenchymal cavity lesions (6%).

Topics: Adult; AIDS-Related Opportunistic Infections; beta-Glucans; CD4 Lymphocyte Count; Female; Humans; Male; Middle Aged; Pneumonia, Pneumocystis; Proteoglycans; Retrospective Studies; Tomography, X-Ray Computed; Viral Load

Pneumocystis carinii (PC) pneumonia is a leading opportunistic infection found among HIV-infected individuals worldwide. Although CD4(+) T cell deficiency clearly correlates with susceptibility to PC pneumonia, murine models of disease indicate that PC-directed Abs may prevent infection and/or inhibit growth of existing PC within the lungs. Recognition of PC by alveolar macrophages involves the beta-glucan receptor Dectin-1 and macrophage effector function against PC is enhanced by Abs derived from PC-vaccinated hosts. We developed a fusion protein consisting of the extracellular domain of Dectin-1 linked to the Fc portion of murine IgG1, which we hypothesized would enhance host recognition and opsonic phagocytosis of PC. The recombinant protein, Dectin-Fc, is dimeric and the Ag recognition site identifies beta-1,3 glucan linkages specifically and with high affinity (K(D) = 2.03 x 10(-7) M). Dectin-Fc enhances RAW264.7 macrophage recognition of the beta-glucan containing particulate zymosan in an FcgammaRII- and FcgammaRIII-dependent manner and preopsonization of PC organisms with Dectin-Fc increased alveolar and peritoneal macrophage-dependent killing of PC. SCID mice treated with a replication incompetent adenoviral vector expressing Dectin-Fc had attenuated growth of PC within the lungs, overall decreased PC lung burden, and diminished correlates of PC-related lung damage relative to SCID mice receiving a control vector. These findings demonstrate that targeting PC beta-glucan with Dectin-Fc enhances host recognition and clearance of PC in the absence of B and T cells, and suggest that FcgammaR-based targeting of PC, via cell wall carbohydrate recognition, may promote resistance against PC pneumonia in the immunodeficient host.

Topics: Adenoviridae; AIDS-Related Opportunistic Infections; Animals; Antibody-Dependent Cell Cytotoxicity; beta-Glucans; Disease Models, Animal; Humans; Immunocompromised Host; Immunoglobulin Constant Regions; Lectins, C-Type; Lung; Macrophages, Alveolar; Male; Membrane Proteins; Mice; Mice, SCID; Nerve Tissue Proteins; Pneumocystis carinii; Pneumonia, Pneumocystis; Receptors, IgG; Recombinant Fusion Proteins

The diagnosis of pneumocystis pneumonia (PCP) is difficult because it requires microscopic examination to identify pneumocystis from induced sputum or BAL fluid.. To evaluate the usefulness of four serum markers-lactate dehydrogenase (LDH), (1-->3) beta-D-glucan (beta-D-glucan), KL-6, and C-reactive protein (CRP)-in the diagnosis of PCP.. Case-control retrospective study.. We reviewed the medical records of 295 consecutive patients who underwent BAL for the diagnosis of PCP. Differential cell counts in BAL fluid and serum levels of LDH, beta-D-glucan, KL-6, and CRP were examined. Oxygenation index was determined using arterial oxygen tension and inspiratory oxygen concentration.. Based on the microscopic examination of BAL fluid, 57 patients were PCP positive and 238 patients were PCP negative. There were no significant differences in cell count or differentials in BAL fluid between the positive and negative cases. Serum levels of LDH, beta-D-glucan, and KL-6 were significantly higher in PCP-positive patients (p < 0.01). Receiver operating characteristic curves suggest that beta-D-glucan was the most reliable indicator. The cut-off level of beta-D-glucan was estimated to be 31.1 pg/mL, with which the positive and negative predictive values were 0.610 and 0.980, respectively. In PCP-positive patients, the oxygenation index was decreased and correlated with LDH. Both LDH and beta-D-glucan levels were correlated with the proportion of neutrophils in BAL fluid.. Serum beta-D-glucan is a reliable marker for the diagnosis of PCP. Since BAL procedure is invasive, measuring beta-D-glucan should be considered as a primary modality for a diagnosis of PCP, especially for patients with severe respiratory failure.

Topics: Adult; Aged; Antigens, Neoplasm; beta-Glucans; Biomarkers; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Immunoassay; Lactate Dehydrogenases; Leukocyte Count; Male; Middle Aged; Mucin-1; Mucins; Nephelometry and Turbidimetry; Neutrophils; Pneumonia, Pneumocystis; Prognosis; Proteoglycans; Retrospective Studies; Severity of Illness Index

Pneumocystis carinii pneumonia (PCP) is one of the fatal complications encountered after liver transplantation. The diagnosis of PCP is sometimes very difficult, because detection of the bacteria itself is not easy under some conditions, and the serum level of the chemical mediator is not yet considered to be a definitive diagnostic marker. We report a case of PCP that occurred 3 months after transplantation in a living-donor liver-transplant recipient; the disease developed during the course of outpatient follow-up when the patient's condition was stable. The patient was maintained with the usual level of immunosuppressants, using tacrolimus, steroid, and mycophenolate mofetil. The patient had a dry cough with mild fever, and a chest computed tomography (CT) scan showed a reticular shadow in the left lung field. The plasma level of beta-D: glucan was high (135 pg/ml). We suspected an invasive fungal infection, but no pathogen was detected by routine fungal culture and cytology. Finally, P. carinii was detected by polymerase chain reaction (PCR), and we started treatment with trimethoprim-sulfamethoxazole (TMP/SMX) combined with an antifungal agent. During this period, the level of beta-D: glucan correlated with the patient's clinical symptoms; this marker was very useful for monitoring the treatment of PCP in this living-donor liver-transplant recipient.

Topics: Antifungal Agents; beta-Glucans; Diagnosis, Differential; DNA, Fungal; Humans; Liver Failure, Acute; Liver Transplantation; Living Donors; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Postoperative Complications; Tomography, X-Ray Computed

Topics: Adult; Aged; Aged, 80 and over; beta-Glucans; Female; Humans; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Proteoglycans

Exuberant inflammatory responses are associated with respiratory failure during Pneumocystis pneumonia. Alveolar epithelial cells (AECs) promote Pneumocystis attachment and proliferation, but also contribute prominently to host cytokine-mediated inflammation during pneumonia. Recent investigations indicate that AECs produce macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-alpha (TNF-alpha) following challenge with Pneumocystis carinii. Nuclear factor-kappaB (NF-kappaB) is a ubiquitous transcription factor critical for regulation of proinflammatory cytokine expression. Herein, we assess rat AEC NF-kappaB responses to challenge with a P. carinii beta-glucan cell wall component (PCBG). Prominent nuclear translocation of p65 NF-kappaB was demonstrated following PCBG challenge. NF-kappaB activation was in part mediated through Protein Kinase C (PKC) signaling pathways. PCBG challenge of AECs was also shown to induce MIP-2 and TNF-alpha mRNA production, a response that was ameliorated by NF-kappaB inhibition. MIP-2 protein expression was also dramatically increased by PCBG challenge, in a manner that was significantly attenuated by both PKC and NF-kappaB inhibition. The data further demonstrate that AEC chemokine responses were not mediated by the recently described dectin-1 receptor, but instead involved participation of cell surface lactosylceramide. These data support a significant role for AECs in host responses during Pneumocystis pneumonia, and further indicate that beta-glucan induces inflammatory cytokine production through NF-kappaB-dependent mechanisms.

Topics: Animals; Antigens, CD; beta-Glucans; Chemokine CXCL2; Chemokines; Gene Expression; In Vitro Techniques; Lactosylceramides; Lectins, C-Type; Membrane Proteins; Monokines; Nerve Tissue Proteins; NF-kappa B; Pneumocystis carinii; Pneumonia, Pneumocystis; Protein Kinase C; Pulmonary Alveoli; Rats; Respiratory Mucosa; Tumor Necrosis Factor-alpha

Topics: Anti-Infective Agents; beta-Glucans; Female; Glucans; Humans; Immunocompromised Host; Middle Aged; Pneumonia, Pneumocystis; Trimethoprim, Sulfamethoxazole Drug Combination

A 40-year-old man was admitted to our hospital with acute respiratory failure. The patient was given a diagnosis of Pneumocystis carinii pneumonia (PCP) associated with acquired immunodeficiency syndrome (AIDS). After treatment with trimethoprim-sulfamethoxazole and corticosteroid, the respiratory failure was improved and the abnormal shadows disappeared. The serum beta-D-glucan level, significantly elevated (76.0 pg/ml) on admission, returned to the normal range within two weeks. Serum KL-6 (max. 7580 U/ml) and surfactant protein-D (SP-D) (max. 235 ng/ml), which are produced by type II pneumocytes, increased after elevation of the beta-D-glucan level and decreased gradually following successful treatment. These findings suggest that beta-D-glucan may be a serological marker for PCP infection and KL-6 may be a serological marker for lung injury in PCP with AIDS.

Topics: Adult; AIDS-Related Opportunistic Infections; Antigens; Antigens, Neoplasm; beta-Glucans; Biomarkers; Glucans; Glycoproteins; Humans; Male; Mucin-1; Mucins; Peptide Fragments; Pneumonia, Pneumocystis; Procollagen; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactants

We report a case of Pneumocystis carinii pneumonia in a patient with acquired immunodeficiency syndrome diagnosed and monitored with polymerase chain reaction (PCR) for Pneumocystis carinii on sputum and measurement of plasma (1-->3)-beta-D-glucan (G-test). Results of both studies paralleled the clinical and radiographic improvement. However, the plasma (1-->3)-beta-D-glucan level remained higher than normal when PCR for Pneumocystis carinii became negative in sputum. Both PCR for Pneumocystis carinii on sputum and measurement of plasma (1-->3)-beta-D-glucan are useful for noninvasive diagnosis and monitoring of Pneumocystis carinii, although further investigation is necessary to quantify their relationship.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-Infective Agents; beta-Glucans; Glucans; Glucocorticoids; Humans; Male; Methylprednisolone; Pneumocystis; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Radiography, Thoracic; Sputum; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination

We detected (1 --> 3) beta-D-glucan (beta-glucan), which is one of the major components of the cyst wall of Pneumocystis carinii, in sera obtained from patients with P. carinii pneumonia (PCP). We confirmed that beta-glucan was detectable by a beta-glucan detection kit (G test; Seikagaku Corporation) in bronchoalveolar lavage fluids (BALFs). The mean concentration of beta-glucan in BALFs obtained from specific-pathogen-free nude mice infected with P. carinii (n = 7; mean, 2,631 [range, 1,031 to 9,095] pg/ml) was significantly higher (P < 0.001) than that in uninfected, specific-pathogen-free mice (n = 7; 6.5 [range, 4.0 to 8.3] pg/ml). The mean level of beta-glucan in BALFs from PCP patients was significantly higher (P < 0.05) than that in BALFs from patients with other lung diseases (7,268 [range, 1,355 to 15,500] pg/ml [n = 4] versus 242.5 [17 to 615] pg/ml [n = 4]). In sera from six of seven patients with PCP, significant levels of beta-glucan (494.1 [8.5 to 1,135] pg/ml) were detected, while it was undetectable in patients with other lung diseases and in a control group. In five patients at follow-up, the level of beta-glucan decreased with clinical improvement. These results suggest that beta-glucan is detectable in sera from patients with PCP and it is a practical serological marker for monitoring of the disease during treatment.

Topics: Animals; beta-Glucans; Biomarkers; Bronchoalveolar Lavage Fluid; Female; Glucans; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Pneumonia, Pneumocystis

A new beta-1,3-D-glucan synthesis inhibitor, L-687,781 is produced by the cultivation of Dictyochaeta simplex ATCC 20960. L-687,781 exhibits potent in vitro antifungal activity as well as anti-Pneumocystis activity in a rat model.

Topics: Animals; Antifungal Agents; beta-Glucans; Candida; Candidiasis; Cryptococcus neoformans; Disease Models, Animal; Fermentation; Fungi; Glucans; Male; Mice; Mitosporic Fungi; Pneumonia, Pneumocystis; Pyrans; Rats; Rats, Inbred Strains