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

描述（由申请人提供）：急性肺损伤（ALI）是发病率、死亡率和医疗支出的主要原因。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。小鼠模型表明，亚临床CMV感染可在肺部产生显著的生物学效应，如炎症和纤维化。亚临床巨细胞病毒感染的每一种生物学效应要么先前已被证实（炎症、纤维化），要么在脓毒症相关ALI及其并发症中理论上可能是重要的（免疫抑制）。最近，CMV已被证明在免疫功能正常的脓毒症成人的血液和肺中通常会重新激活，并且与延长机械通气时间、增加ICU和住院时间独立相关。此外，在体外和体内均已证实巨细胞病毒感染可引发多种促炎和促纤维化介质，这些介质先前被假设在ALI及其并发症（包括多器官系统衰竭）的发病机制中很重要。因此，我们假设CMV血清阳性急性肺损伤患者的CMV再激活放大并延续了肺部和全身炎症，导致持续的肺功能障碍和多器官系统衰竭。我们建议在ALI免疫正常的患者中使用抗巨细胞病毒预防来阻断病毒诱导的炎症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，以检验巨细胞病毒感染和肺损伤的机制途径。临床方案是对脓毒症相关ALI患者进行更昔洛韦/缬更昔洛韦预防的II期双盲安慰剂对照多中心II期试验。该研究的主要终点是第14天的血清IL-6水平。辅助项目将确定潜伏性MCMV （MCMV）放大肺炎症反应损伤的机制，以及MCMV再激活促进肺损伤期间胶原沉积的机制。具体来说，我们将在小鼠模型中研究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，以及分离的ALI是否会导致MCMV再激活；MCMV再激活是否通过增加胶原沉积或减少降解来增加ALI期间的胶原积累；以及更昔洛韦是否会改变MCMV感染小鼠的急性肺损伤过程。相关性：本研究将探讨预防一种常见的病毒感染（称为巨细胞病毒感染）是否能减少肺部炎症，从而改善败血症或肺炎后急性肺损伤的免疫正常患者的预后。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)