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流感菌株引起的流感样疾病（ILI）的爆发始于墨西哥，然后迅速传播到美国和整个美国。在5月和6月初，这种新颖的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）将其流感威胁评级提高到6，象征6个全球流感流行病。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，但在美国和全球范围内，大量患者死亡。第二个报道在美国死亡是孕妇。这一事件与感染流感的孕妇的发病率和死亡率的增加一致。在疾病控制与预防中心（CDC）的最新报告中，在美国疫情爆发的第一个月中，遇到了34名患有或可能的H1N1感染病例的孕妇，在这34名孕妇中，有11名（32％）所需的住院治疗，3名被接受了强化护理，其中1例死亡。该疾病预防控制中心的报告还指出，在4月至6月14日在美国的45例死亡中，孕妇发生了13％（6）。在过去的流感大流行中，怀孕与死亡率更高2至3倍有关；但是，目前尚不清楚这种与妊娠有关的发病率和死亡率增加的病理生理机制。据推测，增加的孕产妇死亡率是1）怀孕期间对感染的免疫反应抑制作用降低，2）怀孕期间过量的先天免疫反应（细胞因子风暴）和/或3）孕妇的代谢需求增加了易感性低氧和败血性休克。尽管有合理的猜测，但目前尚无实验证据支持怀孕期间这些病理生理事件中的任何一个。 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病毒和压倒性的病毒败血症最终导致全身性炎症综合征（SIRS），多器官衰竭和死亡。该假设的测试将从以下两个具体目的开始：目标＃1：测试假设，即孕产妇死亡率增加是由与肺部损伤增加，严重的全身性缺氧和全身性炎症反应综合征（SIR）（SIR）相关的过多病毒载荷介导的，这些综合症（SIR）表现为凝血症和多轨衰竭。 AIM＃2：检验以下假设：妊娠期间严重流感感染的肺和全身表现增加，这是由于功能障碍的炎性细胞因子和趋化因子反应而发生的。这些实验性动物研究将开始为患有严重流感感染的孕妇的临床护理提供科学基础，希望能够及时满足当前（和未来）流感流感的需求。 公共卫生相关性：今年3月/4月，由新颖的H1N1流感菌株引起的流感样疾病（ILI）爆发，然后在墨西哥开始，然后迅速传播到美国和世界其他地区，领导世界卫生组织（WHO）宣布全球流行性的流感pandemic在6月11日。在当前和过去的流感大流感学中，妊娠与不良后果的明显相关。但是，目前尚不清楚这种与妊娠有关的发病率和死亡率增加的病理生理机制。这种新的R21应用的目的是利用怀孕的C57BL/6小鼠感染了致死剂量的H1N1流感病毒，以进行1）测试以下假设：孕产妇死亡率的增加是由与肺部炎症的严重缺氧和次数炎症反应的强化（SIR）的特征性（SIR）的特征性（SIR）的特征性（SIR）特征性（SIR）特征性的，并通过增加的病毒负荷介导检验以下假设，即怀孕期间严重流感感染的肺部和全身表现增加，这是由于功能障碍炎症性细胞因子/趋化因子反应而发生的。