Pathogenesis, Treatment and Prevention of Emerging Infectious Diseases

新发传染病的发病机制、治疗和预防

基本信息

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
项目类别：
财政年份：
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

项目摘要

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.

该项目的研究目前集中在四个领域。这些是 2001 年炭疽袭击幸存者的特征；新出现的呼吸道感染（包括 SARS 和流感）的特征；开发流感新疗法；埃博拉病毒实验疫苗和治疗的评估以及埃博拉病毒感染的长期后遗症的特征。炭疽研究招募了一批志愿者，目前正在进行广泛的诊断评估。为了做好应对新出现的呼吸道传染病的准备，制定了一项国际协议来系统地研究患有流感样疾病的患者。研究超免疫血浆、静脉注射免疫球蛋白或抗病毒化疗药物组合的治疗方案的开发补充了该方案。作为美国政府应对 2014 年西非埃博拉疫情的一部分，NIH 临床中心和西非启动了一系列方案，研究埃博拉病毒病的发病机制、治疗、长期后遗症和预防。其中包括单克隆抗体鸡尾酒 ZMapp、候选 rVSV 和 ChAd3 平台埃博拉疫苗的研究以及埃博拉病毒病幸存者的观察性队列研究。尽管有可用的治疗方法，流感仍会导致严重的发病率和死亡率。坊间报道表明，具有高流感抗体滴度的血浆可能有助于治疗严重流感，但这一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、2 期试验，以评估血凝抑制抗体滴度为 1:80 或更高的抗流感血浆对感染菌株的安全性和有效性。患有严重甲型或乙型流感（定义为存在缺氧或呼吸急促）的住院儿童和成人（包括孕妇）被随机分配接受两个单位（或儿科同等量）的抗流感血浆加标准护理，与标准护理相比单独治疗，并随访 28 天。主要终点是患者呼吸状态正常化的时间（成人的呼吸频率为每分钟 20 次呼吸，儿童的年龄定义阈值为每分钟 20-38 次呼吸）和室内空气氧饱和度为 93% 或更高。 113 名参与者接受了资格筛查，98 名参与者被随机分配到两个治疗组之一。在 87 名确诊流感（通过 PCR）的参与者中，血浆加标准护理组的 42 名参与者中有 28 名（67%）在第 28 天时呼吸状态恢复正常，而仅接受标准护理的 45 名参与者中有 24 名（53%）呼吸状态正常化（p= 0069）。 6 名参与者死亡，其中 1 名（2%）在血浆加标准护理组中死亡，5 名（10%）在单独标准护理组中死亡（HR 019 95% CI 002-165，p=0093）。血浆加标准护理组的参与者的住院天数（中位 6 天 IQR 4-16 对比 11 天 5-25，p=013）和机械通气天数（中位 0 天 IQR 0-6）显着减少。与 3 天 0-14，p=014）。与仅接受标准护理的接受者相比，血浆加标准护理的参与者较少出现严重不良事件（46 人中的 9 人占 20%，52 人中的 20 人占 38%，p=0041）。最常见的严重不良事件是急性呼吸窘迫综合征（一名 2% 的患者对两名 4% 的患者）和中风（一名 2% 的患者对两名 4% 的患者）。一名来自西非的医护人员在埃博拉病毒病记录的第 7 天被疏散到美国国立卫生研究院临床中心。抵达后，他出现了早期埃博拉病毒病症状，包括神经肌肉无力、发烧、肝炎和凝血障碍。在接下来的两周内，病情发展为腹泻、皮疹、肾功能不全和呼吸衰竭，需要机械通气支持。随后出现脑膜脑炎，当患者开始从这些疾病表现中恢复时，出现心肌功能障碍和葡萄膜炎。该案例研究准确地描述了一名埃博拉病毒病患者的病程，尽管从未表现出血压下降，但他经历了一系列可能危及生命的感染并发症，通过使用标准支持措施，这些并发症开始自行缓解。这凸显了一个事实，即先前报道的埃博拉病毒感染高死亡率可能在很大程度上是由于三级医疗中心缺乏支持性护理。