Simultaneous Diagnosis of Dengue and Prognosis of Severe Dengue with a Single Point-of-Care Test

通过单点护理测试同时诊断登革热和严重登革热的预后

• 批准号: 10475305
• 负责人: Michael F Marusich
• 金额: $ 29.99万
• 依托单位: MABDX, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-25 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475305
• 关键词: Affect; Antibodies; Antibody-Dependent Enhancement; Antigens; Biological Assay; Biological Markers; Caring; Clinical; Cross Infection; Data; Decision Making; Dengue; Dengue Fever; Dengue Infection; Dengue Virus; Detection; Development; Diagnosis; Disease; Drops; Economic Burden; Economics; Epitopes; Fatality rate; Health Care Costs; Hospitals; Hour; Human; Immunity; Individual; Infection; Life; Ligands; Monoclonal Antibodies; Morbidity - disease rate; Neutralization Tests; Nucleic Acid Amplification Tests; Patient Triage; Patients; Performance; Phase; Primary Infection; Prognosis; Proteins; Publishing; Reagent; Reporter; Resource-limited setting; Resources; Risk; Risk Factors; Serotyping; Serum; Specificity; Supportive care; Symptoms; Testing; Time; Virus Diseases; Visual; antibody detection; antigen detection; base; care outcomes; clinical care; clinical practice; cross reactivity; detection limit; innovation; lateral flow assay; mortality; mosquito-borne; neutralizing antibody; point of care; point of care testing; prognostic; prognostic assays; response; secondary infection; severe dengue

Dengue is the most common mosquito-borne viral disease and the cause of tremendous morbidity, mortality and economic burden. Yearly, there are an estimated 390 million (M) Dengue virus (DENV) infections, 96M symptomatic cases of Dengue Fever, and 0.5M cases of Severe Dengue. Untreated Severe Dengue has a fatality rate of 20-40%, but the fatality rate drops to less than 1% with timely in-hospital care. Unfortunately, Severe Dengue is now detected only by skillful observation of clinical warning signs, and progression to severe disease can occur within hours, making effective care difficult. Therefore, there is an urgent need for prognostic tests that can identify patients most likely to progress to Severe Dengue. There are four serotypes of DENV and infection with any one serotype generates strong, potentially life-long immunity to reinfection by that same serotype, due to development of neutralizing antibodies against serotype-specific epitopes. However, most antibodies induced by first infections are cross-reactive and non-neutralizing, and paradoxically can increase the risk of Severe Dengue in patients who suffer a later infection with a different serotype, due to a phenomenon termed Antibody-Dependent Enhancement (ADE). Heterotypic secondary infection is the major accepted risk factor for Severe Dengue but heterotypic secondary infections cannot now be identified within the time available for decision making to impact clinical care and outcome. We propose to create a simple, inexpensive, Point-of-Care (POC) test with visual plus/minus readout that will not only diagnose DENV infections early, but also be prognostic for Severe Dengue by quickly identifying patients who have secondary heterotypic infections. Phase I will create key biomarker detection reagents and incorporate them into two sets of serotype-specific Lateral Flow Assays (LFAs): 1) antigen LFAs to diagnose and serotype current infections (by detecting DENV- NS1 made during active infections), and 2) antibody LFAs to diagnose and serotype past infections (by detecting anti-DENV-antibodies made by patients in response to previous infections). Phase II will combine the individual assays in a single dual reporter LFA and then generate analytical and clinical performance data to support applications for CE Mark and FDA 510(k) clearance as a POC IVD. Innovation: The proposal creatively combines a well-established clinical observation (heterotypic secondary infection is the major risk factor for Severe Dengue), with two significant technical advances:1) rapid serotyping of current infections, and 2) rapid serotyping of past infections. With this combination we will develop a first-in- class POC test for DENV diagnosis and Severe Dengue prognosis that will change clinical practice. Impact: A simple, inexpensive POC test that provides timely prognostic results even in resource-limited settings would enable dramatic reductions in Dengue morbidity and mortality while reducing health care costs by allowing clinicians to focus resources effectively and efficiently on patients who may need them most.

登革热是最常见的蚊子传播病毒疾病，是巨大发病率，死亡率的原因 和经济负担。估计有3.9亿（M）登革热病毒（DENV）感染，9600万 登革热的有症状病例和0.5亿例严重登革热病例。未经处理的严重登革热有 死亡率为20-40％，但由于及时的住院护理，死亡率下降到不到1％。很遗憾， 现在，仅通过熟练观察临床警告信号才能检测到严重的登革热 疾病可能会在几个小时内发生，从而使有效的护理变得困难。因此，迫切需要 预后测试可以鉴定出最有可能发展为严重登革热的患者。有四个血清型 DENV和任何一种血清型感染都会产生强大的，潜在的终身免疫力，以通过 由于开发了针对血清型特异性表位的中和抗体，该血清型。 但是，大多数首次感染诱导的抗体是交叉反应和非中和化的，并且自相矛盾 可能会增加因以后感染不同血清型的患者的严重登革热风险 一种称为抗体依赖性增强（ADE）的现象。异型的继发感染是 严重登革热的主要接受危险因素，但现在无法识别出异型的继发性感染 在可影响临床护理和结果的决策的时间内。 我们建议使用Visual Plus/减读数创建一个简单，廉价的护理（POC）测试 这不仅会尽早诊断DENV感染，而且还可以迅速对严重登革热进行预后 识别患有继发性异型感染的患者。 第一阶段将创建关键的生物标志物检测试剂，并将其纳入两组血清型特异性 横向流量测定（LFA）：1）抗原LFA诊断和血清型电流感染（通过检测DENV- NS1在活性感染过程中产生的）和2）抗体LFA诊断和血清型过去感染的抗体（通过 检测患者响应先前感染而产生的抗DenV抗体）。第二阶段将结合 单个双重记者LFA中的个体测定，然后产生分析和临床性能数据 支持CE Mark和FDA 510（k）清除率作为POC IVD的应用。 创新：该提案创造性地结合了一个完善的临床观察（异性型次要 感染是严重登革热的主要危险因素），有两个重大的技术进步：1）快速血清型 当前感染和2）过去感染的快速血清分型。通过这种组合，我们将开发 用于DENV诊断和严重登革热预后的类POC测试将改变临床实践。 影响：一个简单，廉价的POC测试，即使在资源有限的 设置将使登革热发病率和死亡率大大减少，同时降低医疗保健成本 通过允许临床医生有效，有效地将资源集中在可能最需要的患者上。