Treating influenza with statins and other immunomodulatory agents

• Most of the world’s people have no access to influenza vaccines and antiviral drugs.
• Immunomodulatory agents such as statins help to reverse a dysregulated host response to influenza.
• These agents might reduce influenza mortality in all countries with basic health care.
• These agents are produced as inexpensive generic drugs in developing countries.
• Research should discover new ways to manage influenza patients, not simply explain disease.

Statins not only reduce levels of LDL-cholesterol, they counteract the inflammatory changes associated with acute coronary syndrome and improve survival. Similarly, in patients hospitalized with laboratory-confirmed seasonal influenza, statin treatment is associated with a 41% reduction in 30-day mortality.Most patients of any age who are at increased risk of influenza mortality have chronic low-grade inflammation characteristic of metabolic syndrome. Moreover, differences in the immune responses of children and adults seem responsible for the low mortality in children and high mortality in adults seen in the 1918 influenza pandemic and in other acute infectious and non-infectious conditions. These differences probably reflect human evolutionary development. Thus the host response to influenza seems to be the major determinant of outcome.Outpatient statins are associated with reductions in hospitalizations and deaths due to sepsis and pneumonia. Inpatient statins are also associated with reductions in short-term pneumonia mortality. Other immunomodulatory agents – ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), PPARγ and PPARα agonists (glitazones and fibrates) and AMPK agonists (metformin) – also reduce mortality in patients with pneumonia (ACEIs, ARBs) or in mouse models of influenza (PPAR and AMPK agonists). In experimental studies, treatment has not increased virus replication. Thus effective management of influenza may not always require targeting the virus with vaccines or antiviral agents.Clinical investigators, not systems biologists, have been the first to suggest that immunomodulatory agents might be used to treat influenza patients, but randomized controlled trials will be needed to provide convincing evidence that they work. To guide the choice of which agent(s) to study, we need new types of laboratory research in animal models and clinical and epidemiological research in patients with critical illness. These studies will have crucial implications for global public health. During the 2009 H1N1 influenza pandemic, timely and affordable supplies of vaccines and antiviral agents were unavailable to more than 90% of the world’s people. In contrast, statins and other immunomodulatory agents are currently produced as inexpensive generics, global supplies are huge, and they would be available to treat patients in any country with a basic health care system on the first pandemic day. Treatment with statins and other immunomodulatory agents represents a new approach to reducing mortality caused by seasonal and pandemic influenza. This article forms part of a symposium in Antiviral Research on “Treatment of influenza: targeting the virus or the host”.