Severe H1N1 Influenza Infection During Pregnancy: Pathophysiologic Mechanisms

妊娠期严重 H1N1 流感感染：病理生理机制

• 批准号: 7912427
• 负责人: Mark Phillippe
• 金额: $ 22.75万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912427
• 关键词: Address; Americas; Animals; Asia; Blood Coagulation Disorders; C57BL/6 Mouse; Centers for Disease Control and Prevention (U.S.); Cessation of life; Country; Depressed mood; Disease Outbreaks; Dose; Europe; Event; Future; Goals; Hospitalization; Human; Hypoxia; Immune response; Infection; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Injury; Intensive Care; Lung; Maternal Mortality; Mediating; Metabolic; Mexico; Middle East; Morbidity - disease rate; Mus; Organ failure; Patients; Phase; Pregnancy; Pregnant Women; Publishing; Reporting; Research Personnel; Rest; Risk; Sepsis Syndrome; Septic Shock; Septicemia; Testing; Time; United States; Viral; Viral Load result; Virus; World Health Organization; adverse outcome; base; chemokine; clinical care; cytokine; experience; influenza outbreak; influenzavirus; lung injury; mortality; novel; pandemic disease; pandemic influenza; pregnant; public health relevance; response

DESCRIPTION (provided by applicant): In March/April of this year, an outbreak of an influenza-like illness (ILI) caused by a novel strain of H1N1 influenza began in Mexico, and then rapidly spread to and throughout the United States. During May and early June, this novel H1N1 infection spread to multiple other countries in the Americas, Europe, Asia, the Middle East, and the Pacific basin, resulting in the World Health Organization (WHO) increasing its influenza threat rating to 6, signifying a global influenza pandemic. Although the early phase of this new pandemic has been associated with mild morbidity and low mortality, a significant numbers of patients have died in the U.S. and world-wide. The second reported death in the U.S. was a pregnant woman; an event consistent with the clinically recognized increase in morbidity and mortality for pregnant women who become infected with influenza. In a recent report from the Centers for Disease Control and Prevention (CDC), 34 pregnant women with confirmed or probable cases of H1N1 infection were encountered during the first month of the outbreak in the U.S. Among these 34 pregnant women, 11 (32%) required hospitalization, three were admitted to intensive care and one died. This CDC report also noted that among 45 deaths in the U.S. between April and June 14th, 13% (6) occurred in pregnant women. During past influenza pandemics, pregnancy has been associated with a 2 to 3 fold higher mortality risk; however, the pathophysiologic mechanisms underlying this increased pregnancy-related morbidity and mortality are currently unknown. It has been speculated that the increased maternal mortality is the result of 1) a depressed immune response to infection during pregnancy, 2) an excessive innate immune response (cytokine storm) during pregnancy, and/or 3) the increased metabolic demands of pregnancy predisposing to hypoxia and septic shock. Although reasonable speculations, there is currently no experimental evidence supporting any of these pathophysiologic events during pregnancy. The goal of this new R21 application is to utilize pregnant C57BL/6 mice infected with a lethal doses of H1N1 influenza virus (mouse-adapted PR8 strain) to begin to test the novel hypothesis that the increased maternal mortality from severe influenza infection is caused by a dysfunctional immune response resulting in an inappropriate cytokine/chemokine response leading to increased lung injury, reduced ability to clear virus, and overwhelming viral septicemia culminating in the systemic inflammatory response syndrome (SIRS), multi-organ failure and death. Testing of this hypotheses will begin with the following two Specific Aims: Aim #1: Test the hypothesis that the increased maternal mortality is mediated by an excessive viral load associated with increased pulmonary injury, profound systemic hypoxia and evidence of the systemic inflammatory response syndrome (SIRS) characterized by coagulopathy and multi-organ failure. Aim #2: Test the hypothesis that the increased pulmonary and systemic manifestations of severe influenza infection during pregnancy occur in response to a dysfunctional inflammatory cytokine and chemokine response. These experimental animal studies will begin to provide the scientific basis for the clinical care of pregnant women with severe influenza infections, hopefully in time to address the needs of the current (and future) influenza pandemics. PUBLIC HEALTH RELEVANCE: In March/April of this year, an outbreak of an influenza-like illness (ILI) caused by a novel strain of H1N1 influenza began in Mexico, and then rapidly spread to the United States and the rest of the world leading the World Health Organization (WHO) to declare a global influenza pandemic on June 11th. During the current and past influenza pandemics, pregnancy has been associated with significantly higher adverse outcomes; however, the pathophysiologic mechanisms underlying this increased pregnancy-related morbidity and mortality are currently unknown. The goal of this new R21 application is to utilize pregnant C57BL/6 mice infected with a lethal doses of H1N1 influenza virus to 1) test the hypothesis that the increased maternal mortality is mediated by an excessive viral load associated with increased pulmonary injury, profound systemic hypoxia and evidence of the systemic inflammatory response syndrome (SIRS) characterized by coagulopathy and multi-organ failure, and 2) test the hypothesis that the increased pulmonary and systemic manifestations of severe influenza infection during pregnancy occur in response to a dysfunctional inflammatory cytokine/chemokine response.

描述（由申请人提供）：今年3月/ 4月，由新型H1N1流感病毒株引起的流感样疾病（ILI）在墨西哥爆发，然后迅速蔓延到整个美国。在5月和6月初，这种新型H1N1感染传播到美洲、欧洲、亚洲、中东和太平洋盆地的其他多个国家，导致世界卫生组织（WHO）将其流感威胁等级提高到6级，这意味着全球流感大流行。尽管这种新大流行的早期阶段与轻度发病率和低死亡率有关，但在美国和世界范围内，仍有大量患者死亡。美国报告的第二例死亡病例是一名孕妇；这一事件与临床公认的感染流感的孕妇发病率和死亡率增加相一致。在美国疾病控制与预防中心（CDC）最近的一份报告中，34名确诊或可能感染甲型H1N1流感的孕妇在疫情爆发的第一个月内被发现。在这34名孕妇中，11人（32%）需要住院治疗，3人被送入重症监护室，1人死亡。美国疾病控制与预防中心的这份报告还指出，在4月至6月14日期间，美国有45人死亡，其中13%(6)是孕妇。在过去的流感大流行期间，怀孕与死亡风险高出2至3倍有关；然而，这种妊娠相关发病率和死亡率增加的病理生理机制目前尚不清楚。据推测，产妇死亡率的增加是1)怀孕期间对感染的免疫反应下降，2)怀孕期间过度的先天免疫反应（细胞因子风暴），和/或3)怀孕期间代谢需求增加易导致缺氧和感染性休克。虽然合理的推测，目前没有实验证据支持任何这些病理生理事件在怀孕期间。这项新的R21应用的目标是利用感染了致死剂量H1N1流感病毒（小鼠适应PR8株）的妊娠C57BL/6小鼠开始测试新的假设，即严重流感感染导致的孕产妇死亡率增加是由免疫反应功能失调引起的，导致细胞因子/趋化因子反应不适当，导致肺损伤增加，清除病毒的能力降低，以及压倒性的病毒性败血症，最终导致全身性炎症反应综合征（SIRS）、多器官衰竭和死亡。对这一假设的检验将从以下两个具体目标开始：目的1：检验产妇死亡率增加是由与肺损伤增加、深度全身性缺氧和以凝血功能障碍和多器官衰竭为特征的全身性炎症反应综合征（SIRS）相关的过量病毒载量介导的假设。目的2：验证以下假设：妊娠期严重流感感染的肺部和全身表现增加是对炎性细胞因子和趋化因子反应功能失调的反应。这些实验性动物研究将开始为严重流感感染孕妇的临床护理提供科学依据，希望能及时满足当前（和未来）流感大流行的需求。