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: 10248886
• 负责人: H. Clifford Lane
• 金额: $ 24.04万
• 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/10248886
• 关键词: 1 year old; Acute; Admission activity; Adult; Africa; Age; Amodiaquine; Anthrax Attack; Anthrax disease; Antibody titer measurement; Antimalarials; Antiviral Agents; Area; Argentina; Biological; Biological Assay; Blood specimen; COVID-19; Capital; Categories; Cessation of life; Characteristics; Chikungunya virus; Child; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical Trials Data Monitoring Committees; Conduct Clinical Trials; Conflict (Psychology); Constitutional; Control Groups; Creatinine; Democratic Republic of the Congo; Dengue Virus; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Outbreaks; Double-Blind Method; Ebola Hemorrhagic Fever; Ebola virus; Emerging Communicable Diseases; Enrollment; Epidemiology; Equilibrium; Ethics; Etiology; Evaluation; Event; Fever; Genitourinary system; Government; Hemagglutination; Heterogeneity; Hospitalization; Hospitals; Hour; Immune; Immune Plasma; Immunoglobulins; Individual; Indonesia; Infection; Influenza; Influenza A virus; Influenza B Virus; Infusion procedures; Inhalation; Intravenous Immunoglobulins; Investigational Therapies; Laboratories; Longterm Follow-up; Meta-Analysis; Microbiology; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Multi-Institutional Clinical Trial; Names; Neuraxis; Observational Study; Onset of illness; Oseltamivir; Outcome; Outpatients; Participant; Pathogenesis; Patients; Placebos; Plasma; Polymerase Chain Reaction; Population; Prevention; Randomized; Randomized Controlled Trials; Research; Resolution; Respiratory Tract Infections; Rickettsia; Risk; Risk Factors; Role; Safety; Saline; Salmonella; Seoul virus; Serological; Serum; Severe Acute Respiratory Syndrome; Severities; Site; Skin Tissue; Societies; Specimen; Statistical Models; Subgroup; Survivors; Swab; Symptoms; Teaching Hospitals; Testing; Thailand; Therapeutic; Therapeutic Studies; Time; Transaminases; Treatment Efficacy; United States; Vaccines; Viral Load result; Virus; Virus Diseases; Virus Shedding; Whole Blood; accurate diagnosis; anti-influenza; arm; base; clinical efficacy; cohort; eligible participant; follow-up; gastrointestinal; improved; influenzavirus; intravenous administration; mortality; novel strategies; novel therapeutics; pandemic disease; pandemic influenza; prevent; primary endpoint; prospective; reduce symptoms; remdesivir; respiratory; soft tissue; standard care; standard of care; volunteer; 1 year old; Acute; Admission activity; Adult; Africa; Age; Amodiaquine; Anthrax Attack; Anthrax disease; Antibody titer measurement; Antimalarials; Antiviral Agents; Area; Argentina; Biological; Biological Assay; Blood specimen; COVID-19; Capital; Categories; Cessation of life; Characteristics; Chikungunya virus; Child; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical Trials Data Monitoring Committees; Conduct Clinical Trials; Conflict (Psychology); Constitutional; Control Groups; Creatinine; Democratic Republic of the Congo; Dengue Virus; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Outbreaks; Double-Blind Method; Ebola Hemorrhagic Fever; Ebola virus; Emerging Communicable Diseases; Enrollment; Epidemiology; Equilibrium; Ethics; Etiology; Evaluation; Event; Fever; Genitourinary system; Government; Hemagglutination; Heterogeneity; Hospitalization; Hospitals; Hour; Immune; Immune Plasma; Immunoglobulins; Individual; Indonesia; Infection; Influenza; Influenza A virus; Influenza B Virus; Infusion procedures; Inhalation; Intravenous Immunoglobulins; Investigational Therapies; Laboratories; Longterm Follow-up; Meta-Analysis; Microbiology; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Multi-Institutional Clinical Trial; Names; Neuraxis; Observational Study; Onset of illness; Oseltamivir; Outcome; Outpatients; Participant; Pathogenesis; Patients; Placebos; Plasma; Polymerase Chain Reaction; Population; Prevention; Randomized; Randomized Controlled Trials; Research; Resolution; Respiratory Tract Infections; Rickettsia; Risk; Risk Factors; Role; Safety; Saline; Salmonella; Seoul virus; Serological; Serum; Severe Acute Respiratory Syndrome; Severities; Site; Skin Tissue; Societies; Specimen; Statistical Models; Subgroup; Survivors; Swab; Symptoms; Teaching Hospitals; Testing; Thailand; Therapeutic; Therapeutic Studies; Time; Transaminases; Treatment Efficacy; United States; Vaccines; Viral Load result; Virus; Virus Diseases; Virus Shedding; Whole Blood; accurate diagnosis; anti-influenza; arm; base; clinical efficacy; cohort; eligible participant; follow-up; gastrointestinal; improved; influenzavirus; intravenous administration; mortality; novel strategies; novel therapeutics; pandemic disease; pandemic influenza; prevent; primary endpoint; prospective; reduce symptoms; remdesivir; respiratory; soft tissue; standard care; standard of care; volunteer

Research in this project is currently focused on seven areas. These are: characterization of the survivors of the anthrax attacks of 2001; evaluation of the etiology of febrile illness in Indonesia; characterization of emerging respiratory infections including SARS, COVID-19, and influenza; development of novel therapies for influenza; evaluation of experimental vaccines and treatments for Ebola virus; characterizing the long-term sequelae of Ebola virus infection; and evaluating experimental therapeutics for COVID-19. The anthrax study has enrolled a cohort of volunteers who are currently undergoing an extensive diagnostic evaluation. The epidemiology of acute febrile illness, a common cause of hospitalization in Indonesia, was studied in a prospective observational study that enrolled 1486 febrile patients aged 1 year from July 2013 until June 2016 at eight government referral teaching hospitals in seven provincial capitals in Indonesia. Patients were managed according to the hospital standard-of-care, and blood samples were drawn for molecular and serological assays. Clinical data, laboratory results, and specimens for additional tests were collected at enrollment, days 14-28, and at three months. Patients presented with multi-organ (52%), gastrointestinal (33%), respiratory (8%), constitutional (4%), skin and soft-tissue (2%), central nervous system (1%), or genitourinary (0.3%) manifestations. Microbiological diagnoses were found in 68% of participants, of which 35% were not diagnosed during hospitalization using local standard of care diagnostic tests. Missed diagnoses included all cases caused by Rickettsia spp., chikungunya, influenza, and Seoul virus. The most common etiologic agents identified were dengue virus (47%), Salmonella spp. (10%), and Rickettsia spp. (10%). The overall mortality was 5.9% some of which could have been prevented with accurate diagnosis and treatment. Infection with influenza virus causes substantial morbidity and mortality globally. While there are several licensed therapies, they have only minimal impact on clinical outcomes. In an attempt to develop better therapies for influenza three therapeutic studies were undertaken to examine: 1) the role of immune plasma in hospitalized patients; 2) the role of immune immunoglobulin in hospitalized patients and; 3) the role of oseltamivir in outpatients. Since the 1918 influenza pandemic, non-randomized studies and small clinical trials have suggested that convalescent plasma or anti-influenza hyperimmune intravenous immunoglobulin (hIVIG) might have clinical benefit. Two randomized, double-blinded, controlled trials were conducted to test these hypotheses. In the first, a randomized, double-blinded, controlled trial was conducted to evaluate the clinical efficacy of high-titer (hemagglutination inhibition antibody titer 1:80) immune plasma compared to low-titer (1:10) plasma. Children and adults with PCR-confirmed influenza A infection and symptoms of influenza, and onset of illness within 6 days before randomization were eligible. Patients were randomly assigned (2:1) to receive high-titer plasma or low-titer plasma and were followed up for 28 days The primary endpoint was clinical status on day 7. 140 subjects were randomized to the high-titer group (n=92) or to the control low-titer group (n=48). The study was terminated in July 2018, when an independent efficacy analysis showed low conditional power to detect an effect of high-titer plasma. The proportional OR for improved clinical status on day 7 was 122 (95% CI 065229, p=054). Thus, high-titer anti-influenza plasma conferred no significant benefit over non-immune plasma. In the second, 313 patients with laboratory-confirmed influenza A or B and infection and clinical illness for 7 days or fewer were randomly assigned (1:1) to receive standard care plus either a single 500-mL infusion of high-titer hIVIG or saline placebo. The primary endpoint was a six-category ordinal outcome of clinical status at day 7, ranging in severity from death to resumption of normal activities after discharge. Based on the proportional odds model, the overall OR on day 7 was 125 (95% CI 079197; p=033). In subgroup analyses, the OR in patients with influenza A was 094 (055159) and was 319 (121842) for those with influenza B (interaction p=0023). Thus, for the cohort of patients with influenza A or B hIVIG was not superior to placebo while a substantial therapeutic . The striking finding of improved benefit for influenza B is the subject of additional study. The third study in influenza was a randomized, double-blinded multicenter clinical trial of the influenza antiviral oseltamivir was conducted in 501 adults with influenza A or B, without risk factors for complications of influenza, at 42 sites in Thailand, the United States, and Argentina. Eligible participants were randomized to receive oseltamivir 75 mg or placebo twice daily for 5 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at day 3. Ninety-nine (45.0%) of 220 participants in the oseltamivir arm had virus detected at day 3 compared with 131 (57.2%) of 229 participants in the placebo arm, P =; .010. The median time to alleviation of symptoms was 79.0 hours for the oseltamivir arm and 84.0 hours for the placebo arm (P =; .34). Thus, while oseltamivir decreased viral shedding in this low-risk population, it did not significantly decrease the time to resolution of clinical symptoms. The safety and efficacy of the 4 most promising therapies for Ebola virus disease were evaluated in the context of a randomized, controlled trial in the Democratic Republic of Congo in the context of their 2018-2020 outbreak. Patients of any age who were diagnosed with Ebola virus infection were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The primary end point was death at 28 days. A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial given that an interim analysis showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 51% in the ZMapp group; compared to 35% in the MAb114 group (P=0.007); 34% in the REGN-EB3 group (P=0.002); and 53% in the remdesivir group (P=NS). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. This trial, taking place in a conflict area in the DRC and yielding a highly significant result was named the top clinical trial of 2019 by the Society for Clinical Trials. Conclusive evidence from clinical studies about treatment efficacy requires an appropriate control group, usually requiring randomization to balance out factors. During fatal disease outbreaks, randomization may be difficult to conduct due to ethical concerns and challenging field conditions. To examine this issue, we performed a meta-analysis of six clinical studies conducted during the 2013-2016 West Africa Ebola virus disease outbreak. These studies evaluated the anti-viral favipiravir, the biologic ZMapp, the antimalarial drug amodiaquine, and convalescent plasma or whole blood. The non-randomized control groups of these six studies comprised 1147 individuals infected with Ebola virus. The analysis revealed heterogeneity not corrected by statistical modeling.

目前，该项目的研究集中在七个领域。 这些是：2001年炭疽袭击的幸存者的表征；评估印度尼西亚高热疾病的病因；包括SARS，COVID-19和流感的新兴呼吸道感染的表征；发展流感的新疗法；评估埃博拉病毒的实验疫苗和治疗方法；表征埃博拉病毒感染的长期后遗症；并评估COVID-19的实验疗法。 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。 一项前瞻性观察性研究中对急性发热疾病的流行病学研究是印度尼西亚住院的常见原因，该研究从2013年7月至2016年6月在印度尼西亚七个省级首都的八家政府转诊教学医院招募了1486名高级盛会患者。根据医院护理标准对患者进行管理，并抽取血液样本进行分子和血清学测定。在入学时，第14-28天和三个月收集了用于其他测试的临床数据，实验室结果和标本。出现了多器官（52％），胃肠道（33％），呼吸道（8％），宪法（4％），皮肤和软组织（2％），中枢神经系统（1％）或生殖（0.3％）表现的患者。在68％的参与者中发现了微生物诊断，其中35％在住院期间使用当地标准的护理诊断测试被诊断出来。错过的诊断包括立克属，基孔肯雅，流感和首尔病毒引起的所有病例。确定的最常见病因是登革热病毒（47％），沙门氏菌属。 （10％）和立克属。 （10％）。总体死亡率为5.9％，其中一些可以通过准确的诊断和治疗来预防。 流感病毒感染在全球引起大量的发病率和死亡率。 尽管有几种许可疗法，但它们对临床结果的影响最小。 为了开发更多的流感疗法，进行了三项治疗研究以检查：1）免疫血浆在住院患者中的作用； 2）免疫免疫球蛋白在住院患者中的作用； 3）奥司他韦在门诊患者中的作用。 自1918年流感大流行以来，非随机研究和小型临床试验表明，营政血浆或抗激素杀伤性高免疫静脉内免疫球蛋白（HIVIG）可能具有临床益处。 进行了两项随机，双盲对照试验，以检验这些假设。 首先，进行了一项随机，双盲，对照试验，以评估与低滴度（1:10）血浆相比，高滴度（血凝抑制抗体滴度1:80）免疫等离子体的临床疗效。 患有PCR确认的流感的儿童和成年人感染了流感和症状，并且在随机分组前的6天内发病是符合条件的。将患者随机分配（2：1）接收高位血浆或低位血浆血浆，然后进行28天的跟踪。主要终点是第7天的临床状态。140受试者被随机分配给高敏机组（n = 92）或对照低端组组（n = 48）。这项研究于2018年7月终止，当时独立的功效分析显示出低条件能力以检测高点等离子体的影响。 第7天的比例或改善临床状况为122（95％CI 065229，p = 054）。因此，高敏机抗炎性血浆比非免疫等离子体没有明显的好处。 在第二次，随机分配了313例实验室确认的流感A或B患者7天或更少的感染和临床疾病（1：1）接受标准护理，再加上单个500 mL高效率HIVIG或盐碱安慰剂。 主要终点是第7天临床状况的六类序列结果，从死亡到出院后正常活动的严重程度。基于比例赔率模型，总或第7天为125（95％CI 079197； p = 033）。在亚组分析中，流感A的患者的OR为094（055159），患有流感B的患者为319（121842）（相互作用P = 0023）。 因此，对于流感或B HIVIG的患者队列而言，同时进行了大量的治疗方法。 对流感B的提高益处的惊人发现是额外研究的主题。 第三项流感研究是一项随机，双盲的多中心临床试验，对抗病毒oseltamivir进行了流感抗病毒oseltamivir，是在501名流感A或B的成年人中进行的，没有流感并发症的风险因素，在美国泰国，美国泰国，美国和阿根廷的42个地点。 符合条件的参与者被随机分配，每天两次接受奥塞达米维尔75毫克或安慰剂，持续5天。主要终点是第3天通过聚合酶链反应在鼻咽拭子中可检测的病毒参与者的百分比。在Oseltamivir ARM中220名参与者中的220名参与者中有99名（45.0％）在第3天都检测到了病毒，与131（57.2％）的参与者相比，在229名参与者中，占地229名（57.2％）。 .010。缓解症状的中位时间为奥塞达米维尔臂79.0小时，安慰剂组为84.0小时（p =; .34）。 因此，虽然奥塞达米维尔（Oseltamivir）在这种低风险人群中降低了病毒脱落，但它并没有显着减少临床症状解决的时间。 在刚果民主共和国的一项随机对照试验的背景下，评估了埃博拉病毒疾病的四种最有前途的疗法的安全性和功效。 Patients of any age who were diagnosed with Ebola virus infection were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3.主要终点是28天的死亡。从2018年11月20日至2019年8月9日，总共招募了681名患者，此时，数据和安全监测委员会建议仅将患者分配给MAB114和REGN-EB3组在剩余的试验中，鉴于这些组的临时分析显示了这些组对ZMAPP和REMDESIVIR的优越性。 ZMAPP组的51％发生了28天的死亡。相比之下，MAB114组为35％（p = 0.007）； REGN-EB3组中的34％（p = 0.002）; Remdesivir组（P = NS）和53％。 入院前的症状持续时间较短，病毒负荷和血清肌酐和氨基转移酶水平的基线值较低，每个症状都与提高的生存率相关。 该试验发生在刚果民主共和国的冲突区域，并产生极为重要的结果，被临床试验协会评为2019年的最佳临床试验。 关于治疗疗效的临床研究的结论性证据需要适当的对照组，通常需要随机分组才能平衡因素。 在致命疾病暴发期间，由于道德问题和挑战性的现场状况，可能难以进行随机分组。 为了研究这个问题，我们对2013 - 2016年西非埃博拉病毒疾病暴发期间进行的六项临床研究进行了荟萃分析。 这些研究评估了抗病毒favipiravir，生物学ZMAPP，抗疟药氨二喹和疗养血浆或全血。 这六项研究的非随机对照组包括1147名感染了埃博拉病毒的人。 分析表明，未通过统计建模纠正异质性。