A Randomzied Phase II Trial of CMV Prevention in Acute Lung Injury

描述(申请人提供)：急性肺损伤(ALI)是导致发病率、死亡率和医疗费用的主要原因。巨细胞病毒(CMV)是一种人类疱疹病毒，已知感染50%-70%的美国成年人。小鼠模型已经表明，亚临床CMV感染可以在肺部产生显著的生物学效应，如炎症和纤维化。CMV亚临床感染的这些生物学效应中的每一种都已被证实(炎症、纤维化)，或者在理论上可能在脓毒症相关的ALI及其并发症中起重要作用(免疫抑制)。最近，巨细胞病毒被证明在免疫功能正常的成人脓毒症患者的血液和肺中通常重新激活，并与延长机械通气时间、增加ICU和住院时间独立相关。此外，CMV感染在体外和体内都被证明可以诱导多种促炎和促纤维化介质，这些介质以前被认为在ALI及其并发症(包括多器官系统衰竭)的发病机制中起重要作用。因此，我们假设在CMV血清阳性的急性肺损伤患者中，CMV的重新激活既放大并持续肺和全身炎症，导致持续性肺功能障碍和多器官系统衰竭。我们建议在免疫功能正常的ALI受试者中使用抗CMV预防来阻断病毒诱导的炎性细胞因子介导的肺损伤的级联放大。我们还建议在小鼠模型中进行机制研究，以检查CMV感染和肺损伤的机制途径。临床方案是在败血症相关性ALI患者中进行更昔洛韦/伐更昔洛韦预防的II期双盲、安慰剂对照的多中心II期试验。研究的主要终点是第14天血清中IL-6的水平。辅助项目将确定潜伏的MCMV(MCMV)放大肺炎性反应损伤的机制，以及MCMV重新激活促进肺损伤期间胶原沉积的机制。具体地说，我们将在小鼠模型中检查急性肺损伤的初始炎症反应是否受到小鼠巨细胞病毒(MCMV)感染的影响，以及单独的ALI是否导致MCMV重新激活；MCMV重新激活是否通过增加胶原沉积或减少降解来增加ALI期间胶原的积累；以及更昔洛韦是否改变了MCMV感染小鼠的急性肺损伤过程。相关性：这项研究将检验对一种称为巨细胞病毒感染的常见病毒感染的预防是否可以减少肺部炎症，从而改善免疫功能良好的脓毒症或肺炎后急性肺损伤患者的预后。如果成功，这种疗法有可能改变急性肺损伤患者的护理标准，并改善整体预后。(摘要结束)

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a major cause of morbidity, mortality and health care expenditure. Cytomegalovirus (CMV) is a human herpesvirus known to infect 50-70% of US adults. Mouse models have shown that subclinical CMV infection can produce significant biologic effects in the lung, such as inflammation and fibrosis. Each of these biologic effects of subclinical CMV infection have either previously been demonstrated (inflammation, fibrosis) or could theoretically be important (immunosuppression) in sepsis associated ALI and its complications. Recently, CMV has been demonstrated to commonly reactivate in the blood and lung of immunocompetent adults with sepsis, and to be independently associated with prolonged mechanical ventilation and increased ICU and hospital length of stay. Furthermore, CMV infection has been demonstrated both in vitro and in vivo to elicit multiple pro-inflammatory and pro-fibrosis mediators that have previously been hypothesized to be important in the pathogenesis of ALI and its complications, including multi-organ system failure. Thus, we hypothesize that CMV reactivation in CMV seropositive patients with acute lung injury both amplifies and perpetuates pulmonary and systemic inflammation, resulting in persistent lung dysfunction and multi-organ system failure. We propose to use anti-CMV prophylaxis in immunocompetent subjects with ALI to interrupt the cascade of virus-induced magnification of inflammatory cytokine-mediated lung damage. We also propose mechanistic studies in a mouse model to examine the mechanistic pathway of CMV infection and lung injury. The Clinical Protocol is to conduct a phase II double-blind placebo-controlled multicenter phase II trial of ganciclovir/valganciclovir prophylaxis in patients with sepsis -associated ALI. The primary endpoint of the study is IL-6 levels in serum at day 14. The Ancillary Project will determine the mechanisms by which latent MCMV (MCMV) amplifies lung inflammatory responses injury and the mechanisms by which MCMV reactivation promotes collagen deposition during lung injury. Specifically, we will examine in the mouse model whether the initial inflammatory response to acute lung injury is affected by murine CMV (MCMV) infection and whether isolated ALI results in MCMV reactivation; whether MCMV reactivation increases collagen accumulation during ALI by increased collagen deposition or by decreased degradation; and whether ganciclovir alters the course of acute lung injury in mice with MCMV infection. RELEVANCE: This study will examine whether prophylaxis against a common viral infection, called cytomegalovirus infection, reduces inflammation in the lung and thereby improves outcome in immune competent patients with acute lung injury following sepsis or pneumonia. If successful, this therapy has the potential to change the standard of care for patients with acute lung injury and to improve overall prognosis. (End of Abstract)