Aspergillus Galactomannan Antigenemia Research Articles

Pharmacodynamics of Posaconazole in Experimental Invasive Pulmonary Aspergillosis: Utility of Serum Galactomannan as a Dynamic Endpoint of Antifungal Efficacy.

Aspergillus galactomannan antigenemia is an accepted tool for the diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients. Little is known, however, about the utility of this biomarker to assess the efficacy of antifungal therapies. The pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole in treatment and prophylaxis were investigated in the persistently neutropenic rabbit model of Aspergillus fumigatus IPA at doses between 2 and 20 mg/kg per day. Sparse plasma sampling was used to obtain PK data at steady state, and the serum galactomannan index (GMI), as a dynamic endpoint of antifungal response, was obtained every other day, in addition to conventional outcome parameters including survival and fungal tissue burden. Nonparametric PK/PD model building was performed using the Pmetrics package in R. A one-compartment model with linear elimination best described the PK of posaconazole. The PD effect of posaconazole exposure in plasma on the GMI in serum was best described by dynamic Hill functions reflecting growth and killing of the fungus. Through calculations of the area under the concentration-time curve from 0 to 24 h (AUC0-24) at steady state, the exposure-response relationship between posaconazole and the GMI for treatment followed a sigmoidal function with an asymptote forming above an AUC0-24 of 30 mg · h/liter. All prophylactic doses were able to control the fungal burden. A nonparametric population PK/PD model adequately described the effect of posaconazole in prophylaxis and treatment of experimental IPA. An AUC0-24 greater than 30 mg · h/liter was associated with adequate resolution of the GMI, which well supports previously suggested exposure-response relationships in humans.

The interaction between piperacillin–tazobactam and Aspergillus galactomannan antigenemia assay: is the story over?

The interaction between piperacillin–tazobactam and Aspergillus galactomannan antigenemia assay: is the story over?

Viral Respiratory Infections After Allogeneic Hemaotpoietic Stem Cell Transplantation: Outcome and Prognosis

Abstract 491▪FN2▪This icon denotes a clinically relevant abstract Rational:Influenza (FLU, parainfluenza (PIF), respiratory syncitial (RSV) virus, Adenovirus (ADV) and less frequently Epstein Barr virus (EBV), Herpes Simplex (HSV) and Cytomegalovirus (CMV) are responsible for VRI leading to a mortality rate of 5 to 30% after HSCT. New VRI have been recently described with paradoxical conclusions concerning their pathogenicity after HSCT: rhinovirus (RV), metapneumovirus (MPV), coronarovirus (CV), Human Herpes Virus 6 (HHV6) and poliomavirus KI (KI). Methods:This study aims to describe VRI infections, outcomes and risk factors for 100-day mortality in patients who received a first HSCT in our center from 01/2007 to 10/2010. Diagnosis of VRI was performed on nasopharyngeal secretion (by nasopharyngeal aspiration (NPA)) or broncho-alveolar lavage (BAL). Viruses were detected by a multiplex PCR assay (RespiFinder19) that detects FLU, PIF, RSV, ADV, RV, MPV, CV (OC43, 229E, NL63), (and C. pneumoniae, M. pneumoniae, L. pneumophila, B. pertussis) prospectively from 09/2009 and retrospectively before this date. Real time quantitative PCR for ADV, HSV, CMV, HHV6, KI and EBV were also performed from 01/2007. Other bacterial and fungal infections were documented by usual method (sputum, BAL, aspergillus galactomannan antigenemia, radiological findings, L. pneumophila antigen and S. pneumonia urinary antigens). Factors associated with 100-day mortality were estimated using Cox proportional cause-specific Hazard models. Results:127 patients with at least one episode of VRI were studied. Median age was 41 years (range: 8 to 66) with 38% women. The majority of patients was transplanted for hematological malignancy (87%), after a reduced intensity conditioning regimen (66%) with peripheral blood stem cells (63%) [Bone marrow 22%, cord blood 15%]. VRI was essentially diagnosed by NPA (90%) and was associated with a documented bacterial or fungal co-infection in 12% of patients. At VRI diagnosis, 143 viruses were identified in the 127 patients (concomitant viruses in some patients). The distribution of virus was: RV (32%), CV (17%), PIF (17%), ADV (11%), RSV (9%), MPV (7%), HHV6 (5%), FLU (4%), CMV (3%), PM (3%), EBV (2%), HSV (1%). After excluding patients with several virus or another co-pathogen, distribution of virus was RV (28%), CV (12%), PIF (10%), ADV (7%), RSV (6%), MPV (5%), HHV6 (2%), FLU (2%), CMV (1%), PM (2%), EBV (1%), HSV (1%). Thirty-two patients had nosocomial VRI and 36 were hospitalized during VRI evolution. At diagnosis, lower respiratory tract was involved in 52% of patients and 14% required oxygenotherapy. Four patients were transferred into intensive care unit. Seven patients died within 30 days and 14 within 3 months leading to a 3-month survival at 89%. None of them had an isolated VRI as sole cause of death: VRI was associated with active GVHD in 3 patients, active GVHD and co-infection in 3 patients, progressive malignancy in 3 patients, engraftment failure and co-infection in 2 patients, acute non-respiratory organ failure in 3 patients. Virus distribution in the 14 patients who died within 3 months was: CV (n=3), HHV6 (n=3), PIF (n=2), RV, RSV, MPV, FLU, KI, ADV (1 patient for each). Risk factors in univariate analysis for death at 3 months identified ongoing steroid therapy ≥ 1 mg/kg (HR: 4.65, P=0.004), lymphocytes count < 0.5 G/L (HR: 12.4, P=0.04), lower tract involvement (HR: 3.69, P=0.045), presence of a co-infection (HR: 3.38, P=0.043) and oxygenotherapy (HR: 4.57, P=0.008). The delay between transplantation and VRI has no evident effect on outcome. Multivariate analysis showed that lymphocyte count and steroid dose at VRI onset were associated with the 3-month survival. More precisely, patients with lymphocyte count > 0.5 G/L had the best prognosis, while those with lymphopenia had a proportionally increasing risk of death according to the steroid dose (P=0.0002), with HR at 5.75 (95%CI 2.31 to 14.3) if they received less than 1 mg/kg and 33.0 (95%CI 5.32 to 204.9) if they received 1 mg/kg or more. Importantly, the prognostic value of these factors remained true during follow-up (Figure 1). [Display omitted] Conclusion:RV, MPV, CV (OC43, 229E, NL63) are frequently isolated in cases of respiratory symptoms. Early mortality attributable to all VRI is relatively low and occurred only in patients with comorbidity. Prognosis of VRI may be related to the underlying immune defect induced by GVHD and its treatment, especially on lymphocyte counts. Disclosures:Peffault de Latour:Alexion: Consultancy, Research Funding.

Contribution de la biologie moléculaire et de l’antigénémie galactomannane aspergillaire au diagnostic de l’histoplasmose

We report a case of a pulmonary histoplasmosis in an HIV-positive patient usually living in Cambodia, with a positive Aspergillus galactomannan antigenemia resulting from a cross-reaction, that decreased after antifungal therapy. We discuss the potential interest of the detection of fungal DNA by PCR and Aspergillus galactomannan antigenemia for the diagnosis of histoplasmosis, especially in countries where Histoplasma capsulatum antigen testing is not available.

Sodium Gluconate Containing Parenteral Nutrition Solution as a Cause of False Positive Aspergillus Galactomannan Assay in Paediatric Patients with Hematological Malignancies.

Background: The detection of Aspergillus galactomannan antigenemia (GM-Ag) is a contributive method in the diagnosis of invasive aspergillosis (IA). Herein, we report 3 cases of false positive GM-Ag in paediatric patients (pts) receiving NP2 Enfants AP-HP® parenteral nutrition (Fresenius, France), and none of them had or developed IA.Methods: In December 2006, the sera of these 3 pts (1 allogeneic transplant recipient and 2 neutropenic acute leukaemia pts) taken before, during, and after cessation of NP2 solution were tested for the presence of GM-Ag using the Platelia® Aspergillus kit. This solution, its 30 components and 8 other commercially available solutions for parenteral nutrition were tested for the presence of GM.Results: GM became detectable within 1 day after IV administration of NP2 with indices up to 9.25, remained positive throughout treatment, and became negative (≤0.5) within 48 hours in 2/3 pts. The NP2 solution and a single one of its components, sodium gluconate (SG), tested positive with GM estimated at 55.4ng/ml. No Aspergillus DNA was detected by real-time PCR. Three NP2 and 6 SG batches from different origins yielded similar results. On the other hand, 6 different batches of calcium gluconate and 8 other commercially available SG-free parenteral nutrition solutions tested negative.Conclusions: These results suggest a strong cross reactivity of Platelia® kit with SG-containing NP2, as recently described with Plasma-Lyte® (Baxter Distribution Centre Europe). We estimate that clinicians and biologists should become aware of this problem which might lead to inappropriate invasive investigations and/or treatments.

Rapid diagnosis of invasive aspergillosis by antigen detection.

Aspergillosis is a serious and often fatal infection in the bone marrow or organ transplant patient, for which improved methods of diagnosis are desperately needed. Currently, the diagnosis is most often made based on clinical findings and radiographic findings, which are nonspecific, and toxic therapies are initiated empirically, often without ever establishing the diagnosis. Without a definitive diagnosis, physicians often withhold or reduce the doses of the antifungal agent when toxicity develops or the patient improves, permitting progression of disease in those with invasive aspergillosis. The Platelia Aspergillus galactomannan antigenemia assay may assist physicians in making these decisions. With a sensitivity of 81% and a specificity of 89% in the studies leading to its FDA clearance, physicians still must be aware of the potential for false-positive and false-negative results; the test does not replace careful microbiological and clinical evaluation. This report will review the relevant literature and provide guidelines for use of the test in patient management.

Surveillance of Aspergillus galactomannan antigenemia for invasive aspergillosis by enzyme-linked immunosorbent assay in neutropenic patients treated for hematological malignancies.

The incidence of invasive fungal infections is increasing in patients with hematological malignancies. Invasive aspergillosis is one of the most frequently encountered infections with a high mortality rate. New diagnostic tests for invasive aspergillosis such as the detection of Aspergillus galactomannan antigen by a sandwich enzyme-linked immunosorbent assay (ELISA) have recently been described. The objective of this study was to evaluate this assay as a potential surrogate for invasive procedures used to diagnose IA. We analyzed the performance of a commercially available ELISA test which we routinely use for the surveillance of galactomannan antigenemia in patients with hematological malignancies experiencing chemotherapy-induced prolonged neutropenia (ANC < 500/mm(3) for more than 7 days). Serum samples were collected on a weekly basis. Test positivity was defined in accordance with the manufacturer's recommendations. Over the 2 year study period, we analyzed 507 samples obtained during 193 neutropenic episodes from 135 patients. Ten, six and two patients were considered to have proven, probable or possible invasive aspergillosis, respectively, based on clinical, radiological or microbiological data. Forty-four positive (Index>1.5) and 26 'undetermined' (1.5 > Index > 1.0) test results were observed in 17 and ten patients respectively. All invasive aspergillosis cases had at least a positive or an undetermined test result. Only one positive and one undetermined result were found in two patients before the onset of clinical or radiological signs suggesting invasive aspergillosis. Sensitivity was 69% and specificity 96% if only positive results are considered; when 'undetermined' test results were combined with positive results, sensitivity attained 100% and specificity 92% suggesting that the cutoff value for positivity can be lowered from 1.5 to 1.0. Although the ELISA test did not appear to play a role in the early diagnosis of invasive aspergillosis and in the anticipation of antifungal therapy in our experience, it clarifies the diagnosis of infection in probable or possible invasive aspergillosis especially when the cutoff value is lowered and is useful for monitoring patients receiving specific therapy.