Invasive Aspergillosis Diagnosis by Antigen Capture with Lateral-Flow Technology

通过侧流技术捕获抗原来诊断侵袭性曲霉病

基本信息

批准号：
7779333
负责人：
Christopher Rowland Thornton
金额：
$ 17.94万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-17 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7779333
关键词：
Adverse effects Affect Affinity Chromatography Amino Acid Sequence Animal Model Animals Antifungal Agents Antifungal Therapy Antigen Targeting Antigens Aspergillosis Aspergillus Aspergillus fumigatus Biochemical Biological Biological Assay Biological Markers Carbohydrates Cavia Chromatography Clinical Clinical Trials Computers Data Detection Development Devices Diagnosis Diagnostic Diagnostic Sensitivity Disease Drug Interactions Early Diagnosis Ensure Enzyme-Linked Immunosorbent Assay Fractionation Glycoproteins Goals Growth Hematologic Neoplasms Hematopoietic Stem Cell Transplantation Histopathology Human Immunocompromised Host Immunoglobulin G Immunoglobulin M Immunosuppressive Agents In Vitro Incidence Infection Laboratories Lateral Lectin Link Liquid substance Lung Measures Modeling Molds Monoclonal Antibodies Morbidity - disease rate Mycoses Opportunistic Infections Organ Transplantation Outcome Pathogenesis Patients Peptide Sequence Determination Pharmaceutical Preparations Principal Investigator Property Prophylactic treatment Proteins Reporting Resolution Sampling Screening procedure Sensitivity and Specificity Serum Simulate Site Solid Specificity Surrogate Markers Technology Test Result Testing Therapeutic Time Tissues Transplant Recipients Treatment outcome United States National Institutes of Health Urine Voriconazole antimicrobial base clinical Diagnosis clinically relevant comparative diagnostic accuracy extracellular galactomannan genome database high risk improved in vivo indexing mortality partial response point of care point-of-care diagnostics polyglucosan programs protein aminoacid sequence response tomography tool

项目摘要

DESCRIPTION (provided by applicant): Invasive aspergillosis is a leading cause of morbidity and mortality in immunocompromised patients. Patients at high-risk for this opportunistic fungal infection include those with hematologic malignancies, patients undergoing hematopoietic stem cell transplantation, and solid organ transplant recipients. Despite the increased availability of newer antifungal agents response rates to treatment are suboptimal with only 50% of patients having a complete or partial response to voriconazole, the drug of choice for the primary treatment of this invasive disease. Prophylaxis with antifungal agents has been shown to reduce the incidence of invasive fungal disease in heavily immunocompromised patients and improve patient outcomes. However, this strategy is costly and exposes patients to significant adverse effects and clinically relevant drug-drug interactions associated with extended antifungal exposure. Early diagnosis and initiation of appropriate therapy based on radiographic assessment and serial screening of diagnostic biomarkers, such as galactomannan and (1->3)-?- D-glucan, has also been shown to improve outcomes and reduce the unnecessary use of antifungal therapy. However, this approach of pre-emptive treatment has not yet been confirmed in larger clinical trials. Furthermore, the sensitivity of these diagnostic biomarkers may be reduced in patients with antifungal exposure, and it is unknown how well they correlate with response to antifungal therapy. Thus, the development of new surrogate markers for the early diagnosis of invasive aspergillosis and for measuring response to antifungal therapy is needed to improve treatment outcomes in patients with this highly invasive disease. Our objective is to assess a new candidate biomarker of invasive aspergillosis, an extracellular glycoprotein antigen secreted during invasive disease caused by Aspergillus, in relation to disease development and time of diagnosis. Furthermore, we will determine the utility of incorporating monoclonal antibodies against this biomarker into lateral-flow devices in order to allow for point-of-care diagnosis of this opportunistic infection. We will also develop enzyme-linked immunosorbent assays (ELISA) for quantitative analysis as a means of establishing a threshold above which patients are classified as being positive for invasive disease. The ELISA assays will also serve as a confirmatory test to the lateral-flow devices to ensure the accuracy of the diagnosis. The sensitivity and specificity of these assays will be determined in an established animal model of invasive pulmonary aspergillosis as well as in samples collected from patients with proven or probable disease. We will also determine the utility of these assays in following therapeutic response to antifungal agents.

描述（由申请人提供）：侵袭性曲霉病是免疫功能低下患者发病和死亡的主要原因。这种机会性真菌感染的高危患者包括患有血液系统恶性肿瘤的患者、接受造血干细胞移植的患者以及实体器官移植受者。尽管新型抗真菌药物的可用性不断增加，但治疗反应率仍不理想，只有 50% 的患者对伏立康唑（这种侵袭性疾病主要治疗的首选药物）有完全或部分反应。抗真菌药物预防已被证明可以降低免疫功能严重低下患者侵袭性真菌病的发生率并改善患者的预后。然而，这种策略成本高昂，并使患者面临与延长抗真菌药物暴露相关的显着副作用和临床相关药物间相互作用。基于放射学评估和诊断生物标志物（例如半乳甘露聚糖和 (1->3)-?-D-葡聚糖）的系列筛查的早期诊断和开始适当的治疗也被证明可以改善结果并减少不必要的抗真菌治疗。然而，这种先发制人的治疗方法尚未在更大规模的临床试验中得到证实。此外，在接触抗真菌药物的患者中，这些诊断生物标志物的敏感性可能会降低，并且尚不清楚它们与抗真菌治疗反应的相关性如何。因此，需要开发新的替代标志物来早期诊断侵袭性曲霉病和测量抗真菌治疗的反应，以改善患有这种高度侵袭性疾病的患者的治疗结果。我们的目标是评估侵袭性曲霉病的新候选生物标志物，这是一种由曲霉引起的侵袭性疾病期间分泌的细胞外糖蛋白抗原，与疾病发展和诊断时间相关。此外，我们将确定将针对这种生物标志物的单克隆抗体纳入侧流装置中的效用，以便对这种机会性感染进行即时诊断。我们还将开发用于定量分析的酶联免疫吸附测定（ELISA），作为建立阈值的一种手段，高于该阈值的患者将被归类为侵袭性疾病阳性。 ELISA检测还将作为侧流装置的验证性测试，以确保诊断的准确性。这些测定的敏感性和特异性将在已建立的侵袭性肺曲霉病动物模型以及从已证实或可能患有疾病的患者收集的样本中确定。我们还将确定这些测定在抗真菌药物治疗反应中的效用。