Rapid test for leptospirosis

钩端螺旋体病快速检测

• 批准号: 8075076
• 负责人: Albert Icksang Ko
• 金额: $ 95.92万
• 依托单位: CHEMBIO DIAGNOSTIC SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8075076
• 关键词: Acute; Acute Kidney Failure; Address; Antibiotic Therapy; Antibodies; Biological Assay; Blood specimen; Brazil; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Clinical; Collection; Country; Dengue; Detection; Developing Countries; Development; Diagnosis; Diagnostic; Diagnostic tests; Disasters; Disease; Disease Outbreaks; Disease Progression; Early Diagnosis; Emerging Communicable Diseases; Ensure; Epidemic; Epidemiology; Evaluation; Event; Fever; Foundations; Health; Hemorrhage; Hospitals; Human; Illness Days; Immunoassay; Immunodominant Antigens; Immunoglobulins; Infection; Intervention; Laboratories; Leptospira; Leptospirosis; Life; Lung; Military Personnel; Morbidity - disease rate; Natural Disasters; Organ failure; Outpatients; Patients; Performance; Phase; Physicians; Population; Preparation; Prevention; Procedures; Production; Protein Fragment; Proteins; Protocols documentation; Public Health; Quality Control; Recombinants; Recreation; Reporting; Research; Research Infrastructure; Rural; Sampling; Serodiagnoses; Serological; Serum; Signal Transduction; Site; Slum; Specificity; Sports; System; Technology; Testing; Thailand; Therapeutic Intervention; Travel; United States National Institutes of Health; Universities; Urban Population; Validation; Viral Hemorrhagic Fevers; Whole Blood; Zoonotic Infection; antimicrobial; base; clinical practice; design; experience; farmer; global health; inner city; innovation; medical schools; mortality; neglect; novel diagnostics; performance tests; phase 1 study; phase 2 study; point of care; point-of-care diagnostics; prevent; prototype; research clinical testing; response

DESCRIPTION (provided by applicant): Leptospirosis is a life-threatening zoonotic infection that causes acute renal failure and pulmonary hemorrhage. In the US, human leptospirosis is an emerging disease due to outbreaks that have occurred during disasters and sporting events and the increase in travel and recreation-related exposures. Furthermore, leptospirosis is a "neglected" disease which imparts it largest burden in populations of urban slum dwellers and subsistence farmers. More than one million cases of leptospirosis are reported each year, mostly from developing countries. Mortality from severe clinical forms of the disease is >10%. In several regions leptospirosis has emerged as the major cause of hemorrhagic fever. The critical need in addressing leptospirosis is a rapid diagnostic test that can enable clinicians to make effective decisions on therapy and management. Antimicrobial therapy, when administered early in the illness, can prevent disease progression and mortality. Timely diagnosis requires a laboratory test since the clinical presentation of early-phase leptospirosis is non-specific and often confused as being dengue or other cases of an acute febrile illness. Yet currently available tests have inadequate sensitivity (<50%) in detecting early-phase leptospirosis. Our Phase I studies have demonstrated the feasibility of developing a high-performing rapid test for leptospirosis. We have identified novel diagnostic targets, Leptospira immunoglobulin-like (Lig) proteins, which are the immunodominant antigens recognized by antibodies during infection. We have applied recombinant Lig fragments to an innovative proprietary immunoassay format, the Dual Path Platform (DPP"), and found that a DPP prototype had an overall sensitivity of 85% and specificity of 90% in evaluations of samples from leptospirosis patients from Brazil and Thailand. Furthermore, the DPP prototype had a sensitivity of 78% in identifying leptospirosis in the first 7 days of illness, the "window-of- opportunity" during which initiation of antimicrobial therapy provides greatest benefit. In this Phase II application we propose to develop and evaluate a rapid diagnostic test for leptospirosis which will have required characteristics for general use worldwide. The specific aims are to: 1) develop and optimize assay design, 2) determine diagnostic test performance in a multicenter evaluation, and 3) validate test production protocols in preparation for regulatory approval. We expect that a developed and fully validated assay will have major beneficial consequences for clinical practices worldwide by allowing physicians to make a point-of-care diagnosis and initiate timely therapeutic interventions which are required to prevent the high mortality associated with leptospirosis. PUBLIC HEALTH RELEVANCE: There is no effective prevention for human leptospirosis, a life-threatening emerging zoonotic disease, whose global burden is estimated to be as high as 500,000 cases annually. Untreated leptospirosis often progresses to multi-organ failure and/or pulmonary hemorrhage, and prompt diagnosis and early initiation of antibiotic therapy are the key intervention to prevent the morbidity and mortality associated with these complications. The research proposed here aims to develop a rapid point-of-care diagnostic test for leptospirosis which would enable antibiotic therapy to be initiated during the acute phase of the infection, when it is most effective. As part of the proposed Phase II study, we will conduct clinical evaluations of the rapid diagnostic test in preparation for regulatory approval.

描述（由申请方提供）：钩端螺旋体病是一种危及生命的人畜共患病感染，可引起急性肾衰竭和肺出血。在美国，人类钩端螺旋体病是一种新出现的疾病，由于在灾害和体育赛事期间爆发，以及旅行和娱乐相关暴露的增加。此外，钩端螺旋体病是一种“被忽视”的疾病，给城市贫民窟居民和自给农民带来最大负担。每年报告的钩端螺旋体病病例超过100万例，大部分来自发展中国家。严重临床形式的死亡率> 10%。在一些地区，钩端螺旋体病已成为出血热的主要病因。解决钩端螺旋体病的关键需要是一种快速诊断测试，可以使临床医生做出有效的治疗和管理决策。在疾病早期给予抗菌药物治疗，可以防止疾病进展和死亡。及时诊断需要实验室检查，因为早期钩端螺旋体病的临床表现是非特异性的，经常与登革热或其他急性发热性疾病混淆。然而，目前可用的测试在检测早期钩端螺旋体病方面的灵敏度不足（<50%）。我们的第一阶段研究已经证明了开发一种高效的钩端螺旋体病快速检测方法的可行性。我们已经确定了新的诊断目标，钩端螺旋体免疫球蛋白样（Lig）蛋白，这是免疫显性抗原的抗体在感染过程中识别。我们已经将重组Lig片段应用于创新的专有免疫测定形式，双路径平台（DPP”），并且发现DPP原型在来自巴西和泰国的钩端螺旋体病患者的样品的评估中具有85%的总体灵敏度和90%的特异性。此外，DPP原型在疾病的前7天内识别钩端螺旋体病的灵敏度为78%，在此期间开始抗菌治疗提供了最大的益处。在本II期申请中，我们建议开发和评估一种钩端螺旋体病快速诊断检测试剂，该试剂将具有全球通用的所需特性。具体目标是：1）开发和优化检测设计，2）在多中心评估中确定诊断检测性能，3）验证检测生产方案，为监管批准做准备。我们预计，一个开发和充分验证的检测方法将有重大的有益后果的临床实践在全球范围内，使医生作出床旁诊断，并启动及时的治疗干预，需要防止与钩端螺旋体病相关的高死亡率。公共卫生相关性：人类钩端螺旋体病是一种威胁生命的新出现的人畜共患疾病，目前尚无有效的预防措施，估计其全球负担每年高达50万例。未经治疗的钩端螺旋体病往往进展为多器官衰竭和/或肺出血，及时诊断和早期开始抗生素治疗是预防这些并发症相关发病率和死亡率的关键干预措施。本文提出的研究旨在开发一种用于钩端螺旋体病的快速即时诊断测试，这将使抗生素治疗能够在感染的急性期开始，此时最有效。作为拟议的II期研究的一部分，我们将对快速诊断测试进行临床评估，为监管部门的批准做准备。