DESCRIPTION (provided by applicant): The CDC reports that between 5-20% of all Americans are infected with the influenza virus every year and an average of 226,000 of these patients require hospitalization. Considerable focus has been placed on vaccination programs and on the development of antiviral therapies. These strategies, however, are challenged by rapidly emerging influenza strains and increasing resistance to existing antiviral agents. In addition, they do not target the host inflammatory response to the infection which contributes to illness severity, organ damage, and death. The class of medications referred to as "statins" have been effective in reducing cholesterol levels and have secondary anti-inflammatory and immune-modulating effects. Multiple studies have suggested an association between use of statin drugs and a reduction in morbidity and mortality in other types of infection. As there is currently no medicinal therapy (apart from antivirals) aimed at the treatment of influenza or progression of disease severity once contracted, my goal in the current proposal is to investigate the potential and promising therapeutic benefit of statin therapy in patients with acute influenza infection. I have worked previously on multiple projects including clinical trials or patients with influenza, as wel as interventional trials for statin therapy in patients with infecton. I propose that the anti-inflammatory effects of statin drugs will attenuate severity of the influena infection once contracted. My primary hypothesis for this trial is that the administration of stati medication will attenuate the inflammatory response in patients with acute influenza, resulting in 1.) Decreased levels of circulating markers of inflammation and 2.) A reduction in the severity of illness and time to clinical resolution of influenza symptoms. Data to support this hypothesis includes: 1.) laboratory and clinical data implicating the host inflammatory response in both illness severity and outcomes in influenza; 2.) strong observational data demonstrating a morbidity and mortality benefit conferred by statin drugs to patients with influenza infection; 3.) prospective pilot human data and controlled animal studies demonstrating a reduction in the level of inflammatory biomarkers in patients with septic shock treated with a statin. In order to test our hypothesis, we will perform a randomized trial in which patients with acute influenza will receive either statin therapy or placebo. We and others have shown that short-term statin therapy for patients with critical illness is both safe and feasible. We further hypothesize that influenza infection will cause a range of metabolic derangements in the host which will allow for elucidation of an influenza metabolomic profile and the potential identification of other anti-influenza therapeutic targets. Receipt of this award will allow me to continue my career in clinical investigations, to further develop as a physician-investigator and to test important hypotheses with potentially significant therapeutic benefits for patients with influenza.

PUBLIC HEALTH RELEVANCE: Influenza (the 'flu') is a common virus infecting approximately 5-20% of the population in the United States and causing as many as 500,000 deaths worldwide each year. Currently, there are only a few treatments for influenza infection and none of these target inflammation that can be caused by the virus. This study will test whether the anti-inflammatory effects of statins, a class of drugs most often used to treat high cholesterol, will decrease the severity of illness in patients who are infected with influenza by testing markers of inflammation in the blood and recording resolution of influenza illness.