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aspBIOmics

aspBIOmics

Invasive aspergillosis (IA) is the most common cause of infection-associated mortality in patients being treated for haematological malignancies and is an emerging disease in solid organ transplant recipients, critical care patients and in those receiving novel immunomodulatory therapies. Although, IA may be perceived to be an uncommon disease, with an incidence of 10,000 patients annually in Europe, there is increasing evidence that this devastating infection is affecting a broader range of patient groups. Due to the frequent need to treat suspected cases, IA is the most expensive opportunistic infection in immunosuppressed patients. The annual cost of treating fungal infections in Europe is >100 million Euro. In-hospital stays complicated by IA cause additional costs of 75,000 Euro per patient in comparison to uninfected patients, underlining the socio-economic relevance of IA.

A major problem in the management of IA is the poor diagnosis. A better and earlier diagnosis will lead to more cost-effective therapy due to an improved efficacy of the antifungal therapy, a reduced duration of treatment and a reduction in cost of antifungals which are often used prophylactically without true justification. Diagnosis of IA is based on clinical and serological criteria consensually agreed in the clinical community. However, based on these criteria most cases are only recognized as possible or probable. This is a clear indication that diagnosis must be improved; so far the verification of proven cases still requires the presence of the fungus in a biopsy or autopsy specimen. All serological diagnostic methods developed to date have been hampered by delayed, by false positive and false negative results.

Recently, it was shown that integrated strategies compiling the changes in multiple, pathogen and host parameters have emerged as new alternatives for diagnosis of bacterial and viral infections difficult to identify (e. g. cytomegalovirus and Epstein Barr virus).

With this consortium, we propose to develop and evaluate a battery of in vitro assays for a comprehensive multimodality analysis, combining the detection of Aspergillus elements (RNA, polysaccharides, proteins), host factors including cytokine profiles, together with the individual genetic susceptibility of the host.  Existing diagnostic parameters will be included in the analysis to validate the improvement of the methods under development over the existing ones.

The intended advance will be the availability of a panel of biomarkers incorporated into rapid and sensitive ex vivo assays. This is the first time that a combined multi-parameter diagnostic strategy is undertaken to target aspergillosis. In addition, this strategy has the potential to identify patients who are at highest risk of IA before the infection occurs so that tailored prophylaxis can be given, and in patients who have established IA to monitor the success of antifungal therapy and the outcome of the infection. The development of this new approach proposed herein would not have been possible in the past since we will benefit from the recent advances in the knowledge of Aspergillus genomics and their integrated system biology, resulting from the availability of comparative genomics, transcriptome and proteome tools. At the end of the project, the selection of the biomarkers (host and pathogen) most relevant for the characterization of IA will lead to the development of commercial reagents and kits.  Such a strategy will take us to a more cost-effective therapy due to an improved efficacy of the antifungal therapy, a reduced duration of treatment and reduced cost of antifungals, often used prophylactically or in combination without true justification.

The strategy of the project will demand a multidisciplinary approach that will involve collaboration between molecular biologists, immunologists, microbiologists, epidemiologists, and clinicians. Such an approach is only feasible on a European level to bring together top experts in each discipline across Europe.

All partners of the consortium have already collaborated in a highly synergistic and productive way which underlines the high quality of this consortium and its close collaboration. Members of this consortium have been selected on the basis of their excellent track record and on their experience in the research fields addressed in this proposal. A further criterion for the selection of the groups was the complementarity of technologies and research areas, each contributing a separate and crucial part of the overall project resources.

The University Hospital of Wuerzburg (H. Einsele, J. Loeffler) coordinates the project, which has excellent knowledge of the diagnosis and therapy of IA and all the background and expertise to analyze host responses to the fungus. H. Einsele has already successfully coordinated 1 EU consortium under FP6 (www.manasp.org), participated in 3 others European consortia (Allostem, EuroNet Leukaemia, Nano II) and has excellent contacts to official European bodies (EORTC, EBMT, European Leukemia Network, EAPCRI).