Performance of serum biomarkers for the early detection of invasive aspergillosis in febrile, neutropenic patients: a multi-state model

International audienceBACKGROUND: The performance of serum biomarkers for the early detection of invasive aspergillosis expectedly depends on the timing of test results relative to the empirical administration of antifungal therapy during neutropenia, although a dynamic evaluation framework is lacking.METHODS: We developed a multi-state model describing simultaneously the likelihood of empirical antifungal therapy and the risk of invasive aspergillosis during neutropenia. We evaluated whether the first positive test result with a biomarker is an independent predictor of invasive aspergillosis when both diagnostic information used to treat and risk factors of developing invasive aspergillosis are taken into account over time. We applied the multi-state model to a homogeneous cohort of 185 high-risk patients with acute myeloid leukemia. Patients were prospectively screened for galactomannan antigenemia twice a week for immediate treatment decision; 2,214 serum samples were collected on the same days and blindly assessed for (1->3)- β-D-glucan antigenemia and a quantitative PCR assay targeting a mitochondrial locus.RESULTS: The usual evaluation framework of biomarker performance was unable to distinguish clinical benefits of β-glucan or PCR assays. The multi-state model evidenced that the risk of invasive aspergillosis is a complex time function of neutropenia duration and risk management. The quantitative PCR assay accelerated the early detection of invasive aspergillosis (P = .010), independently of other diagnostic information used to treat, while β-glucan assay did not (P = .53). CONCLUSIONS: The performance of serum biomarkers for the early detection of invasive aspergillosis is better apprehended by the evaluation of time-varying predictors in a multi-state model. Our results provide strong rationale for prospective studies testing a preemptive antifungal therapy, guided by clinical, radiological, and bi-weekly blood screening with galactomannan antigenemia and a standardized quantitative PCR assay

An economic evaluation of irbesartan in the treatment of patients with type 2 diabetes, hypertension and nephropathy: cost-effectiveness of Irbesartan in Diabetic Nephropathy Trial (IDNT) in the Belgian and French settings

Background. In the Irbesartan in Diabetic Nephropathy Trial (IDNT), treatment with irbesartan demonstrated 23 and 20% reductions in the combined endpoint of doubling of serum creatinine (DSC), end-stage renal disease (ESRD) or death in patients with hypertension, type 2 diabetes and overt nephropathy compared with amlodipine and control, respectively. A simulation model was developed to project long-term cost consequences of the IDNT in Belgium and France. Methods. A Markov model simulated progression from nephropathy to DSC, ESRD and death in patients with hypertension, type 2 diabetes and overt nephropathy. Treatment-specific probabilities were derived from IDNT. Country-specific ESRD-related data were retrieved from published sources. Delay in onset of ESRD, life expectancy and mean lifetime costs were calculated for patients with a baseline age of 59 years. Future costs were discounted at 3% per annum (p.a.), and clinical benefits were discounted at 0 and 3% p.a.. Extensive sensitivity analyses were performed. Results. Onset of ESRD was delayed with irbesartan by 1.41 and 1.35 years vs amlodipine and control, respectively. When a 10-year time horizon was considered, delay in ESRD onset led to anticipated improvements in life expectancy of 0.13 years vs amlodipine and 0.26 years vs control. Irbesartan was associated with cost savings of €14 949 and €9205/patient in Belgium, and €20 128 and €13 337 in France, vs amlodipine and control, respectively. The results were robust under a wide range of plausible assumptions. Conclusions. Treating patients with hypertension, type 2 diabetes and overt nephropathy using irbesartan was both cost- and life-saving compared with amlodipine and contro

Cost-effectiveness of irbesartan in diabetic nephropathy: a systematic review of published studies

Background. To review published studies on the cost-effectiveness of the use of irbesartan for treatment of advance overt nephropathy in patients with type 2 diabetes and hypertension. Methods. Articles were identified based on a search of the PubMed databases using the keywords ‘irbesartan', ‘ESRD', ‘cost-effectiveness', ‘nephropathy' and ‘costs', and by personal communication with the authors. Only studies published in the last 10 years were included. All costs data from the cost-effectiveness studies were inflated to 2003 Euros using published governmental conversion tables. Results. Seven published studies were identified, spanning the following country settings: the US, Belgium and France, Germany, Hungary, Italy, Spain, and the UK. In each, the same pharmacoeconomic model was adapted using country-specific data to project and evaluate the clinical and cost outcomes of the treatment arms of the Irbesartan in Diabetic Nephropathy Trial (IDNT) (irbesartan, amlodipine or standard blood pressure control). Mean time to onset of ESRD was 8.23 years for irbesartan, 6.82 years for amlodipine and 6.88 years for the control (values were the same for Belgium, France, Germany, Hungary, Italy and Spain as transition probabilities for progression to ESRD were all derived from the IDNT). Mean cumulative incidence of ESRD was 36% with irbesartan, 49% with amlodipine and 45% with control treatment. Treatment with irbesartan was projected to improve life expectancy compared to both amlodipine and control in all seven published studies. Analysis of total lifetime costs showed that irbesartan treatment was cost saving compared to the other two treatment regimens, due to the associated reduction in ESRD cases. Cost savings with irbesartan became evident very early; after 2-3 years of treatment in most settings. Conclusions. Modelling studies based on the IDNT published to date suggest that irbesartan treatment in patients with type 2 diabetes, hypertension and advanced nephropathy is both life- and cost-saving compared to amlodipine or contro

Restauration de la flore des prés salés continentaux : expérimentation sur le marais de Saint-Beauzire (Puy-de-Dôme, 63)

This article presents a case study of recolonization by flora constituting a continental salt meadow type vegetation after the removal of an embankment on a continental salt marsh in the Limagne plain (Puy-de-Dôme, France). Salt marshes indicator plants was monitored in presence/absence in a network of 104 meshes of 10 m². We were able to show the rapid and lasting colonization of Puccinellia distans and Juncus gerardi, but also the slower and variable installation of Spergula media and Plantago maritima. We mapped spatial and temporal evolutions of this colonization for 6 different species. Among the halotolerant species, one should note the increase in the population of endangered species such as Inula britannica. The monitoring protocol allows us to conclude on the interest of this type of embankment removal operation to restore the abiotic parameters and the flora of the «continental salt meadow» vegetation.Cet article présente une étude de cas de recolonisation par la végétation de type pré salé continental après des travaux de suppression d’un remblai sur un marais salé continental dans la plaine de la Limagne (Puy-de-Dôme, France). Les plantes indicatrices des prés salés ont été suivies en présence/absence dans un réseau de 104 mailles de 10 m². Nous avons pu montrer la colonisation rapide et durable de Puccinellia distans et Juncus gerardi, mais aussi l’installation plus lente et variable de Spergula media et de Plantago maritima. Nous avons cartographié les évolutions spatiales et temporelles de cette colonisation pour 6 espèces différentes. Parmi les espèces halotolérantes, on notera l’augmentation de la population d’espèces menacées comme celle d’Inula britannica. Les résultats permettent de conclure sur l’intérêt de ce type d’opération de suppression de remblais pour restaurer les paramètres abiotiques et de la capacité de la flore de se réinstaller même après vingt-cinq ans pour reconstituer une communauté végétale caractéristique des « prés salés continentaux »

La végétation des sources thermominérales salées d’Auvergne

The authors accomplish a phytosociological study of the salt thermomineral spring vegetation in Auvergne. They follow a ‘braun-blanqueto-tüxenian’ approach of the association. Despite a large number of relevés carried out on the salty sites of Auvergne, the communities stay unknown as it seems necessary to synthesize them and clarify their phytosociological status.The authors carry out an analysis and a synthesis of 176 phytosociological relevés illustrating the communities of the twenty salty localities known in Auvergne. From 16 sites, 69 relevés were specifically produced as part of this study.Nine communities are presented on the floristical and synecological plan : three new associations and six new sub-associations are described.Les auteurs réalisent une étude phytosociologique de la végétation des sources thermominérales salées d’Auvergne, en s’inscrivant dans une approche «braun-blanqueto-tüxenienne» de l’association. Malgré un grand nombre de relevés réalisés sur les sites salés d’Auvergne, les groupements restent méconnus et il semblait nécessaire d’en réaliser la synthèse pour en préciser le statut phytosociologique.Après une rapide présentation du contexte physiographique des localités étudiées et un bref rappel des travaux phytosociologiques antérieurs, les auteurs réalisent une analyse et une synthèse de 176 relevés phytosociologiques illustrant les communautés de la vingtaine de localités salifères connues en Auvergne. Provenant de 16 sites, 69 relevés ont été spécifiquement réalisés dans le cadre de cette étude.Neuf groupements de rang association sont présentés sur le plan floristique et synécologique : trois associations et six sous-associations nouvelles sont décrites

Phagocytosis of Aspergillus fumigatus conidia by primary nasal epithelial cells in vitro

<p>Abstract</p> <p>Background</p> <p>Invasive aspergillosis, which is mainly caused by the fungus <it>Aspergillus fumigatus</it>, is an increasing problem in immunocompromised patients. Infection occurs by inhalation of airborne conidia, which are first encountered by airway epithelial cells. Internalization of these conidia into the epithelial cells could serve as a portal of entry for this pathogenic fungus.</p> <p>Results</p> <p>We used an <it>in vitro </it>model of primary cultures of human nasal epithelial cells (HNEC) at an air-liquid interface. <it>A. fumigatus </it>conidia were compared to <it>Penicillium chrysogenum </it>conidia, a mould that is rarely responsible for invasive disease. Confocal microscopy, transmission electron microscopy, and anti-LAMP1 antibody labeling studies showed that conidia of both species were phagocytosed and trafficked into a late endosomal-lysosomal compartment as early as 4 h post-infection. In double immunolabeling experiments, the mean percentage of <it>A. fumigatus </it>conidia undergoing phagocytosis 4 h post-infection was 21.8 ± 4.5%. Using combined staining with a fluorescence brightener and propidium iodide, the mean rate of phagocytosis was 18.7 ± 9.3% and the killing rate 16.7 ± 7.5% for <it>A. fumigatus </it>after 8 h. The phagocytosis rate did not differ between the two fungal species for a given primary culture. No germination of the conidia was observed until 20 h of observation.</p> <p>Conclusion</p> <p>HNEC can phagocytose fungal conidia but killing of phagocytosed conidia is low, although the spores do not germinate. This phagocytosis does not seem to be specific to <it>A. fumigatus</it>. Other immune cells or mechanisms are required to kill <it>A. fumigatus </it>conidia and to avoid further invasion.</p

Verruculogen associated with Aspergillus fumigatus hyphae and conidia modifies the electrophysiological properties of human nasal epithelial cells

BACKGROUND: The role of Aspergillus fumigatus mycotoxins in the colonization of the respiratory tract by conidia has not been studied extensively, even though patients at risk from invasive aspergillosis frequently exhibit respiratory epithelium damage. In a previous study, we found that filtrates of A. fumigatus cultures can specifically alter the electrophysiological properties of human nasal epithelial cells (HNEC) compared to those of non pathogenic moulds. RESULTS: We fractionated the organic phase of filtrate from 3-day old A. fumigatus cultures using high-performance liquid chromatography. The different fractions were tested for their ability to modify the electrophysiological properties of HNEC in an in vitro primary culture model. The fraction collected between 20 and 30 min mimicked the effects of the whole filtrate, i.e. decrease of transepithelial resistance and increase of potential differences, and contained secondary metabolites such as helvolic acid, fumagillin, and verruculogen. Only verruculogen (10(-8 )M) had effects similar to the whole filtrate. We verified that verruculogen was produced by a collection of 67 human, animal, plant and environmental A. fumigatus isolates. Using MS-MS analysis, we found that verruculogen was associated with both mycelium and conidia extracts. CONCLUSION: Verruculogen is a secondary metabolite that modifies the electrophysiological properties of HNEC. The role of these modifications in the colonization and invasion of the respiratory epithelium by A. fumigatus on first contact with the epithelium remains to be determined

Verruculogen associated with Aspergillus fumigatus hyphae and conidia modifies the electrophysiological properties of human nasal epithelial cells

BACKGROUND: The role of Aspergillus fumigatus mycotoxins in the colonization of the respiratory tract by conidia has not been studied extensively, even though patients at risk from invasive aspergillosis frequently exhibit respiratory epithelium damage. In a previous study, we found that filtrates of A. fumigatus cultures can specifically alter the electrophysiological properties of human nasal epithelial cells (HNEC) compared to those of non pathogenic moulds. RESULTS: We fractionated the organic phase of filtrate from 3-day old A. fumigatus cultures using high-performance liquid chromatography. The different fractions were tested for their ability to modify the electrophysiological properties of HNEC in an in vitro primary culture model. The fraction collected between 20 and 30 min mimicked the effects of the whole filtrate, i.e. decrease of transepithelial resistance and increase of potential differences, and contained secondary metabolites such as helvolic acid, fumagillin, and verruculogen. Only verruculogen (10(-8 )M) had effects similar to the whole filtrate. We verified that verruculogen was produced by a collection of 67 human, animal, plant and environmental A. fumigatus isolates. Using MS-MS analysis, we found that verruculogen was associated with both mycelium and conidia extracts. CONCLUSION: Verruculogen is a secondary metabolite that modifies the electrophysiological properties of HNEC. The role of these modifications in the colonization and invasion of the respiratory epithelium by A. fumigatus on first contact with the epithelium remains to be determined

Heterogeneity of water physico-chemical characteristics in artificially pumped waterholes: do African herbivores drink at the same locations and does it lead to interference competition?

International audienc

Molecular Demonstration of a Pneumocystis Outbreak in Stem Cell Transplant Patients: Evidence for Transmission in the Daycare Center

Pneumocystis jirovecii pneumonia (PCP) is a life-threatening infection in hematology. Although occasionally reported, the role of interhuman transmission of P. jirovecii in PCP, compared to that of reactivation, remains an unresolved question; the recommendation to isolate PCP patients in the hematology ward are not well evidence-based. Following an unexpected increase in the number of febrile pneumonia patients with P. jirovecii DNA detected in respiratory samples in our hematology ward, we explored 12 consecutive patients from November 2015 to May 2016. Genotyping of P jirovecii was performed using microsatellite markers. The frequency of simultaneous occupancy of these 12 patients in the same unit on the same day from 4 months prior to the first diagnosis was recorded. In three patients, the P. jirovecii genotype could not be determined because DNA was insufficient. One rare single genotype (Gt2) was found in four of the other nine, all allogeneic stem cell transplant recipients. The transmission map showed that these 4 patients had multiple opportunities to meet on the same day (median, 6.5; range, 4–10) at the daycare center. It was much less among the eight non-Gt2 patients (median, 1; range, 0–9; P = 0.048). This study, based on modern molecular technics, strongly suggests that interhuman transmission of P. jirovecii between allogeneic stem cell transplant recipients is possible. P. jirovecii DNA detected in respiratory specimens supports that isolation and respiratory precautions be recommended in such cases in the hematology ward