NeuroEbola

神经埃博拉病毒

• 批准号: 10673017
• 负责人: JEAN-CLAUDE MWANZA
• 金额: $ 52.91万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673017
• 关键词: Acute; Address; Aftercare; Age; Antibody Response; Attention; Auditory; Biological Assay; Biological Markers; Biomedical Research; Brain; Case Fatality Rates; Cells; Cessation of life; Cicatrix; Color Visions; Congo; Contrast Sensitivity; Corneal Diseases; Country; Democratic Republic of the Congo; Disease; Disease Outbreaks; Disease Progression; Ebola; Ebola Hemorrhagic Fever; Ebola virus; Enzyme-Linked Immunosorbent Assay; Evaluation; Eye; Genetic; Goals; Health; Human; Human Milk; Immune; Immune System Diseases; Immunoglobulin G; Immunologics; Individual; Infection; Inflammatory; Knowledge; Life; Measures; Mediating; Mental Depression; Mental Tests; Mission; Molecular Biology; Monoclonal Antibodies; National Institute of Allergy and Infectious Disease; National Institute of Neurological Disorders and Stroke; Neurocognition; Neurocognitive; Onset of illness; Optical Coherence Tomography; Organ; Outcome; Participant; Performance; Plasma; Proteins; Psychophysics; RNA chemical synthesis; Recovery; Recurrence; Reporting; Research; Retina; Reverse Transcriptase Polymerase Chain Reaction; Seminal fluid; Survival Rate; Survivors; Symptoms; System; Testing; Time; Uncertainty; United States National Institutes of Health; Uveitis; Viral Load result; Virus Diseases; Virus Inhibitors; Virus Replication; Vision; Visual; Visual Acuity; Visual Fields; Visual Pathways; Woman; Work; clinically relevant; cognitive skill; computerized; cytokine; disorder prevention; experience; follow-up; global health; immune activation; improved; inflammatory marker; instrument; man; men; mortality; non-verbal; pathogen; remdesivir; research and development; response

SUMMARY Ebolaviruses (EBOV) are among the deadliest pathogens known to man, with a case fatality rate of 25–90% depending on the outbreak. For the first time, monoclonal antibodies Zmapp, Mab114, REGN-EB3 and Remdesivir (inhibitor of viral RNA synthesis) were used, improving survival rates in Ebola treatment units (ETU) during the ongoing outbreak of Ebola virus disease (EVD) in Congo-Kinshasa. Despite treatments, 34% of EVD survivors experienced eye complications. In addition, they had lower [mean (SD)] minimental test examination (MMSE) scores i.e. [25 (5.5)] relative to controls [29.9 (0.6)] (p < 0.01); and women perform poorly [24.8 (5.90] relative to men [28.4 (3.2)](p < 0.01). The odds of depression were higher in EVD survivors [OR: 14.9 (95%CI: 4.4 – 50.1)], mostly in women [OR: 4.4. (95%CI: 2.1 – 9.6)] and, intriguingly, MMSE deficit in women was associated with higher initial EBOV viral load [OR: 0.84 (95%CI: 0.73 – 0.98, p = 0.03, for one-unit increase in ctXptNP; lower ctXpt = higher viral load] after adjustment for age and depression status. EBOV persisted in breastmilk, wet preps, and semen for several months after acute EVD. We propose to test the hypothesis that occurrence of neuroophthalmologic sequalae is dictated by initial and/or persistence of EBOV viral load with discernable IgG responses, and/or a persistent inflammatory state driven by elevated cytokines and immune cell activation; by addressing the following specific aims: Aim 1. To contrast neuro- ophthalmologic deficits (spectrum & extent) found in confirmed EVD survivors to relevant profiles seen in their IgG+ but EVD-free close contacts, and IgG- controls (N = 90 per group). In Aim 1A, study participants will have longitudinal (0, 6, 12, 24, 36, and 48 month-time-points) assessments of neurocognition using the computerized Test of Variables of Attention (auditory and visual), the Test of Attentional Performance, and CogState for nonverbal cognitive skills. In Aim 1B, they will undergo psychophysical tests for visual acuity, contrast sensitivity, color vision, and visual field; as well as spectral domain-optical coherence tomography to elucidate structural biomarkers of disease within visual pathways. Aim differences levels overabundance 2 will determine whether group- on neuroophthalmologic outcomes found in Aim 1 are mediated by EBOV viral load or persistence, of anti-EBOV IgG, alterations in levels or activation status of circulating immune cells, and/or of proinflammatory cytokines. Aim 3 will enhance capacity in neurocognitive assessments, ophthalmologic evaluations and EVD immunoprofiling and molecular biology (RT-PCR). Gaps of knowledge to be filled include lack of understanding of (1) EBOV persistence, (2) long-lasting immune dysregulation, (3) IgG positivity with no overt EVD symptoms, all in contexts of post-EVD treatment. The overall goal of the proposed work aligns with the global health mission of the NIH while integrating the institute-specific missions of FIC, NEI, NIAID, NINDS, and the Office of Disease Prevention.

概括 埃博拉病毒 (EBOV) 是人类已知的最致命的病原体之一，病死率为 25-90% 根据疫情情况，首次使用单克隆抗体 Zmapp、Mab114、REGN-EB3 和 使用瑞德西韦（病毒 RNA 合成抑制剂），提高了埃博拉治疗单位的生存率 (ETU) 在刚果-金沙萨持续爆发埃博拉病毒病 (EVD) 期间，尽管进行了治疗，仍有 34% 的患者死亡。 的埃博拉病毒病幸存者出现了眼部并发症，此外，他们的简易智力测试结果也较低。 考试 (MMSE) 分数，即 [25 (5.5)] 相对于对照组 [29.9 (0.6)] (p < 0.01)；并且女性表现不佳 [24.8 (5.90] 相对于男性 [28.4 (3.2)](p < 0.01)。EVD 幸存者患抑郁症的几率更高[或： 14.9 (95% CI: 4.4 – 50.1)]，主要是女性 [OR: 4.4 (95% CI: 2.1 – 9.6)]，并且有趣的是，MMSE 存在缺陷。 女性与较高的初始 EBOV 病毒载量相关 [OR：0.84（95%CI：0.73 – 0.98，p = 0.03，对于一个单位 调整年龄和抑郁状态后，ctXptNP 增加；较低的 ctXpt = 较高的病毒载量。 急性埃博拉病毒病后，母乳、湿制剂和精液中持续存在几个月。 假设神经眼科后遗症的发生是由埃博拉病毒的初始和/或持续存在决定的 病毒载量具有可辨别的 IgG 反应，和/或由细胞因子升高驱动的持续炎症状态 和免疫细胞激活；通过解决以下具体目标： 目标 1. 对比神经细胞 在确诊的埃博拉病毒病幸存者中发现的眼科缺陷（范围和程度）与他们的相关资料一致 IgG+ 但无 EVD 的密切接触者和 IgG- 对照（每组 N = 90），研究参与者将。 使用以下方法对神经认知进行纵向（0、6、12、24、36 和 48 个月时间点）评估 计算机化的注意力变量测试（听觉和视觉）、注意力表现测试以及 CogState 用于非语言认知技能 在目标 1B 中，他们将接受视敏度的心理物理测试， 对比敏感度、色觉和视野；以及谱域光学相干断层扫描 阐明视觉通路内疾病的结构生物标志物。 差异 级别 过剩 2 将确定是否组- 目标 1 中发现的神经眼科结果是由 EBOV 病毒载量或持续性介导的， 抗埃博拉病毒 IgG 的变化、循环免疫细胞水平或激活状态的改变，和/或 目标 3 将增强神经认知评估的能力， 眼科评估以及 EVD 免疫分析和分子生物学 (RT-PCR) 的知识差距。 需要填补的问题包括缺乏对 (1) EBOV 持久性、(2) 长期免疫失调、(3) IgG 的了解 阳性且没有明显的埃博拉病毒病症状，所有这些都是在埃博拉病毒病后治疗的背景下进行的。 工作与 NIH 的全球卫生使命相一致，同时整合了 FIC 的机构特定使命， NEI、NIAID、NINDS 和疾病预防办公室。

项目成果

Cost-effectiveness of incorporating Ebola prediction score tools and rapid diagnostic tests into a screening algorithm: A decision analytic model.

将埃博拉预测评分工具和快速诊断测试纳入筛查算法的成本效益：决策分析模型。

• 发表时间: 2023
• 影响因子: 3.7
• 作者: Tshomba, Antoine Oloma;Mukadi;De Weggheleire, Anja;Tshiani, Olivier M;Kayembe, Charles T;Mbala;Muyembe;Ahuka;Chenge, Faustin M;Jacobs, Bart Karl M;Mumba, Dieudonné N;Tshala
• 通讯作者: Tshala

Development of Ebola virus disease prediction scores: Screening tools for Ebola suspects at the triage-point during an outbreak.

埃博拉病毒疾病预测评分的开发：在疫情爆发期间的分诊点筛选埃博拉疑似病例的工具。

• 发表时间: 2022
• 影响因子: 3.7
• 作者: Tshomba, Antoine Oloma;Mukadi-Bamuleka, Daniel-Ricky;De Weggheleire, Anja;Tshiani, Olivier M.;Kitenge, Richard O.;Kayembe, Charles T.;Jacobs, Bart K. M.;Lynen, Lutgarde;Mbala-Kingebeni, Placide;Muyembe-Tamfum, Jean-Jacques;Ahuka-Mundeke, Steve;Mumba, Dieudonne N.;Tshala-Katumbay, Desire D.;Mulangu, Sabue
• 通讯作者: Mulangu, Sabue