Pathogenesis, Treatment and Prevention of Emerging Infectious Diseases

新发传染病的发病机制、治疗和预防

• 批准号: 9552533
• 负责人: H. Clifford Lane
• 金额: $ 20.9万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9552533
• 关键词: Adult; Adult Respiratory Distress Syndrome; Africa; Age; Air; Anthrax Attack; Anthrax disease; Antibody titer measurement; Antiviral Agents; Area; Blood Coagulation Disorders; Blood Pressure; Case Study; Characteristics; Child; Childhood; Clinical; Clinical Trials; Cohort Studies; Complement; Development; Diagnostic; Diarrhea; Disease; Disease Outbreaks; Drops; Ebola Hemorrhagic Fever; Ebola Vaccines; Ebola virus; Eligibility Determination; Emerging Communicable Diseases; Enrollment; Evaluation; Event; Exanthema; Fever; Government; Health Personnel; Hemagglutination; Hepatitis; Hospitalized Child; Hospitals; Hypoxia; Infection; Influenza; Influenza A virus; Influenza B Virus; International; Intravenous Immunoglobulins; Kidney Failure; Life; Longitudinal Studies; Measures; Mechanical ventilation; Mechanics; Medical center; Meningoencephalitis; Monoclonal Antibodies; Morbidity - disease rate; Myocardial dysfunction; Oxygen; Participant; Pathogenesis; Patients; Phase II Clinical Trials; Plasma; Pregnant Women; Prevention; Prevention approach; Protocols documentation; Randomized; Reporting; Research; Respiratory Failure; Respiratory Tract Diseases; Respiratory Tract Infections; Safety; Series; Serious Adverse Event; Severe Acute Respiratory Syndrome; Stroke; Supportive care; Survivors; Symptoms; Testing; Time; United States National Institutes of Health; Uveitis; Vaccines; Virus Diseases; anti-influenza; arm; biodefense; chemotherapeutic agent; cohort; experience; follow-up; mortality; neuromuscular; novel strategies; novel therapeutics; open label; pandemic disease; programs; protocol development; research study; respiratory; response; standard care; therapy development; volunteer

Research in this project is currently focused on four areas. These are characterization of the survivors of the anthrax attacks of 2001; characterization of emerging respiratory infections including SARS and influenza; development of novel therapies for influenza; and evaluation of experimental vaccines and treatments for Ebola virus as well as characterizing the long-term sequelae of Ebola virus infection. The anthrax study has enrolled a cohort of volunteers who are currently undergoing an extensive diagnostic evaluation. To be ready to deal with emerging infectious diseases of the respiratory tract, an international protocol in in place to systematically study patients presenting with an influenza-like illness. This protocol has been complemented by the development of treatment protocols that study either hyperimmune plasma, intravenous immunoglobulin or a combination of antiviral chemotherapeutic agents. As part of the US government response to the 2014 Ebola outbreak in West Africa, a series of protocols have been initiated at the NIH Clinical Center and in West Africa to study the pathogenesis, treatment, long-term sequelae and prevention of Ebola virus disease. These include studies of the monoclonal antibody cocktail ZMapp, the candidate rVSV and ChAd3 platform Ebola vaccines and an observational cohort study of survivors of Ebola virus disease. Influenza causes substantial morbidity and mortality despite available treatments. Anecdotal reports have suggested that plasma with high antibody titers to influenza might be of benefit in the treatment of severe influenza but this hypothesis has never been rigorously tested. We conducted a randomized, open-label, multicenter, phase 2 trial to assess the safety and efficacy of anti-influenza plasma with hemagglutination inhibition antibody titers of 1:80 or more to the infecting strain. Hospitalized children and adults (including pregnant women) with severe influenza A or B (defined as the presence of hypoxia or tachypnea) were randomly assigned to receive either two units (or pediatric equivalent) of anti-influenza plasma plus standard care, versus standard care alone, and were followed up for 28 days. The primary endpoint was time to normalization of patients' respiratory status (respiratory rate of 20 breaths per min for adults or age-defined thresholds of 20-38 breaths per min for children) and a room air oxygen saturation of 93% or more. 113 participants were screened for eligibility and 98 were randomized to one of the two treatment arms. Of the 87 participants with confirmed influenza (by PCR), 28 (67%) of 42 in the plasma plus standard care group normalized their respiratory status by day 28 compared with 24 (53%) of 45 participants on standard care alone (p=0069). Six participants died, one (2%) in the plasma plus standard care group and five (10%) in the standard care alone group (HR 019 95% CI 002-165, p=0093). Participants in the plasma plus standard care group had non-statistically significant reductions in days in hospital (median 6 days IQR 4-16 vs 11 days 5-25, p=013) and days on mechanical ventilation (median 0 days IQR 0-6 vs 3 days 0-14, p=014). Fewer plasma plus standard care participants had serious adverse events compared with standard care alone recipients (nine 20% of 46 vs 20 38% of 52, p=0041). The most frequent serious adverse events were acute respiratory distress syndrome (one 2% vs two 4% patients) and stroke (one 2% vs two 4% patients). A health care worker from West Africa was evacuated to the National Institutes of Health Clinical Center on day 7 of documented Ebola virus disease. On arrival, he had symptoms of early Ebola virus disease including neuromuscular weakness, fever, hepatitis and coagulopathy. Over the next two weeks this evolved to diarrhea, skin rash, renal insufficiency and respiratory failure requiring mechanical ventilatory support. The was followed by meningoencephalitis and, as the patient began to recover from these manifestations of disease, the development of myocardial dysfunction and uveitis. This case study precisely depicts the course of a patient with Ebola virus disease who, despite never demonstrating a drop in blood pressure experienced a series of potentially life-threatening complications of infection that, with the use of standard supportive measures, began to resolve spontaneously. This highlights the fact that the high mortality figures previously reported for Ebola virus infection are likely due in large part to the lack of the type of supportive care available in tertiary medical centers.

目前，该项目的研究集中在四个领域。 这些是2001年炭疽袭击的幸存者的表征；包括SARS和流感在内的新兴呼吸道感染的表征；发展流感的新疗法；以及评估埃博拉病毒的实验疫苗和治疗方法，并表征了埃博拉病毒感染的长期后遗症。炭疽研究已经招募了一群志愿者，他们目前正在接受广泛的诊断评估。 准备应对呼吸道新兴的传染病，这是一种国际方案，可以系统地研究出现类似流感的疾病的患者。 该方案与研究过度免疫性血浆，静脉免疫球蛋白或抗病毒化学治疗剂组合的治疗方案的制定相辅相成。 作为美国政府对2014年西非埃博拉病毒爆发的反应的一部分，已在NIH临床中心和西非启动了一系列方案，以研究发病机理，治疗，长期后遗症和预防埃博拉病毒病。 其中包括对单克隆抗体鸡尾酒ZMAPP，候选RVSV和CHAD3平台埃博拉疫苗的研究，以及对埃博拉病毒疾病幸存者的观察队列研究。 尽管有可用的治疗，但流感仍会引起大量的发病率和死亡率。轶事报告表明，具有高抗体滴度的流感血浆可能在治疗严重的流感方面有益，但这种假设从未经过严格检验。 我们进行了一项随机，开放标签，多中心，第2阶段试验，以评估抗炎性血浆的安全性和功效，其血凝抑制抗体滴度对感染菌株为1:80或更多。随机分配住院的儿童和成人（包括孕妇）患有严重的流感A或B（定义为缺氧或tachypnea的存在），以接收两个抗炎性血浆的单位（或儿科等效）的抗炎症血浆，仅标准护理，仅对标准护理，并且进行了28天。主要终点是时间对患者呼吸状况进行标准化（成人每分钟呼吸率为20呼吸或儿童年龄定义的阈值20-38呼吸）和93％或更高的房间空气氧饱和度。 将113名参与者筛选为资格，并将98个随机分配到两个治疗臂之一。在87名确认流感的参与者中，血浆中的42名42名参与者在第28天之前将其呼吸状态标准化，而仅在标准护理中为45名参与者中的24名（53％）（p = 0069）。 6名参与者死亡，等离子和标准护理组中有1名（2％），仅标准护理组中有五名（10％）（HR 019 95％CI 002-165，p = 0093）。血浆加标准护理组的参与者在医院的天数（6天IQR 4-16 vs 11天5-25，p = 013）和机械通气的天数（中位数为6天4-16 vs）和机械通气（中位数为0天IQR 0-6 vs 3天0-14，p = 014）。与单独的标准护理接受者相比，血浆加标准护理参与者较少发生严重的不良事件（46个与20 38％的52，p = 0041的20％）。 最常见的严重不良事件是急性呼吸窘迫综合征（一名2％vs 2％的患者）和中风（一个2％vs 2％vs 2％4％的患者）。 来自西非的一名医疗保健工作者在埃博拉病毒疾病的第7天被撤离到美国国立卫生研究院临床中心。到达后，他患有早期埃博拉病毒疾病的症状，包括神经肌肉无力，发烧，肝炎和凝血病。 在接下来的两周中，这将演变为腹泻，皮疹，肾功能不全和呼吸衰竭，需要机械通气支持。 其次是脑膜脑炎，随着患者开始从这些疾病的表现中恢复，心肌功能障碍和葡萄膜炎的发展。 该案例研究精确地描述了埃博拉病毒疾病的患者的病程，尽管从未证明血压降低，但经历了一系列潜在的威胁生命的感染并发症，通过使用标准支持措施，这些并发症开始自发地解决。 这强调了以下事实：先前报道的埃博拉病毒感染的高死亡率数字很大程度上可能是由于缺乏高等教育中心可用的支持护理类型的原因。