Severe H1N1 Influenza Infection During Pregnancy: Pathophysiologic Mechanisms

描述(申请人提供)：今年3/4月，由一种新的H1N1流感毒株引起的流感样疾病(ILI)在墨西哥爆发，然后迅速蔓延到美国和整个美国。在5月和6月初，这种新型H1N1感染蔓延到美洲、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级，标志着一场全球流感大流行。虽然这种新的大流行的早期阶段与轻微的发病率和低死亡率有关，但在美国和世界范围内已经有相当数量的患者死亡。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孕妇感染流感的发病率和死亡率上升一致。在美国疾病控制和预防中心(CDC)最近的一份报告中，在美国甲型H1N1疫情爆发的第一个月里，遇到了34名确诊或可能感染H1N1病例的孕妇。在这34名孕妇中，有11名(32%)需要住院，3名被送往重症监护病房，1名死亡。CDC的这份报告还指出，在4月至6月14日期间美国的45例死亡病例中，13%(6例)发生在孕妇身上。在过去的流感大流行期间，怀孕与死亡风险增加2至3倍有关；然而，导致与怀孕有关的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，孕产妇死亡率增加的原因是：1)妊娠期间对感染的免疫反应低下，2)妊娠期间过度的先天免疫反应(细胞因子风暴)，和/或3)妊娠代谢需求增加，易于缺氧和感染性休克。尽管有合理的推测，但目前没有实验证据支持怀孕期间的任何这些病理生理事件。这一新的R21应用程序的目标是利用感染致命剂量H1N1流感病毒(小鼠适应的PR8株)的怀孕C57BL/6小鼠开始测试这一新假设，即严重流感感染导致的孕产妇死亡率增加是由免疫反应障碍引起的，该免疫反应导致不适当的细胞因子/趋化因子反应，导致肺损伤增加，清除病毒的能力降低，以及压倒性的病毒败血症，最终导致全身炎症反应综合征(SIRS)、多器官衰竭和死亡。对这一假说的检验将从以下两个具体目标开始：目的1：检验这一假说，即产妇死亡率的增加是由过度病毒负荷导致的肺损伤增加、严重的全身缺氧以及以凝血障碍和多器官衰竭为特征的全身炎症反应综合征(SIRS)的证据所致。目的#2：检验一种假设，即妊娠期间严重流感感染的肺部和全身症状的增加是对功能失调的炎性细胞因子和趋化因子反应的反应。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，有望及时满足当前(和未来)流感大流行的需要。 与公共卫生相关：今年3/4月，由一种新型H1N1流感毒株引起的流感样疾病(ILI)在墨西哥爆发，然后迅速蔓延到美国和世界其他地区，导致世界卫生组织(WHO)于6月11日宣布全球流感大流行。在当前和过去的流感大流行期间，怀孕与显著更高的不良后果有关；然而，导致与怀孕相关的发病率和死亡率增加的病理生理机制目前尚不清楚。这一新的R21应用程序的目标是利用感染致命剂量H1N1流感病毒的怀孕C57BL/6小鼠1)检验以下假设：孕产妇死亡率增加是由过度病毒负荷与肺损伤增加、严重全身缺氧和以凝血反应和多器官衰竭为特征的全身炎症反应综合征(SIRS)的证据有关的假说；2)测试妊娠期间严重流感感染的肺部和全身症状增加是对功能失调的炎性细胞因子/趋化因子反应的反应的假说。

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.