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.
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.
|Limaye, Ajit P; Stapleton, Renee D; Peng, Lili et al. (2017) Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness: A Randomized Clinical Trial. JAMA 318:731-740|
|Lopez Roa, Paula; Hill, Joshua A; Kirby, Katharine A et al. (2015) Coreactivation of Human Herpesvirus 6 and Cytomegalovirus Is Associated With Worse Clinical Outcome in Critically Ill Adults. Crit Care Med 43:1415-22|
|Horne, David J; Narita, Masahiro; Spitters, Christopher L et al. (2013) Challenging issues in tuberculosis in solid organ transplantation. Clin Infect Dis 57:1473-82|
|Mikkelsen, Mark E; Shah, Chirag V; Meyer, Nuala J et al. (2013) The epidemiology of acute respiratory distress syndrome in patients presenting to the emergency department with severe sepsis. Shock 40:375-81|
|Limaye, Ajit P; Santo Hayes, Tracy K; Huang, Meei-Li et al. (2013) Quantitation of cytomegalovirus DNA load in dried blood spots correlates well with plasma viral load. J Clin Microbiol 51:2360-4|
|Boeckh, Michael; Geballe, Adam P (2011) Cytomegalovirus: pathogen, paradigm, and puzzle. J Clin Invest 121:1673-80|
|Marty, Francisco M; Boeckh, Michael (2011) Maribavir and human cytomegalovirus-what happened in the clinical trials and why might the drug have failed? Curr Opin Virol 1:555-62|
|Limaye, Ajit P; Boeckh, Michael (2010) CMV in critically ill patients: pathogen or bystander? Rev Med Virol 20:372-9|