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Alum promotes chronic disease meds against inflammatory response

Yale Medicine Magazine, 2013 - Spring


Statins. Metformin. Glitazones. Fibrates. Familiar drugs to clinicians who treat patients with cardiovascular diseases and diabetes. They tamp down inflammatory overreaction to the disease. Could they also work in acute illnesses, even infections? David Fedson, M.D. ’65, believes they could be useful against severe influenza, sepsis, trauma, and severe burn injury conditions that can also provoke a deadly inflammatory response. He believes this question is worth investigating and is waging a campaign to persuade researchers to do so.

Fedson, who is retired and lives in France near Geneva, Switzerland, where his wife works for the World Health Organization, is no stranger to public health. During medical school, he studied an experimental smallpox drug, but it turned out to be ineffective. In 1968, as a resident at Johns Hopkins, he participated in a research project in Kolkata (Calcutta) with investigators who were instrumental in developing oral rehydration therapy (ORT) to treat cholera. Later, he studied influenza vaccination at the NIH; and in 1976, while on the faculty of the University of Chicago, he organized the university’s swine flu vaccination program. Six years later he published a recommendation that is now national policy: routinely offering influenza and pneumococcal vaccination to patients being discharged from the hospital. After 13 years on the faculty of the University of Virginia, where he was head of the Division of General Medicine, he moved to France in 1995 to become director of medical affairs at Sanofi Pasteur MSD, a vaccine company. There he continued his work on the epidemiology and cost-effectiveness of influenza and pneumococcal vaccination.

In the early 2000s, when H5N1 avian influenza emerged as a global public health threat, Fedson recognized that vaccination alone would not save many lives—it would be difficult to produce and distribute in a short period of time. Like many researchers, he also wondered why the 1918 influenza pandemic had spared children but killed young adults. Clinicians and epidemiologists, he said, have noticed similar mortality differences in patients with other infectious diseases, in trauma victims, and in those with acute lung injury due to malaria and sickle cell disease. Children fare better than adults because their immune systems tend not to launch a damaging and sometimes fatal inflammatory response. No one knows why, but Fedson believes it makes evolutionary sense. “Children may be programmed to devote their energy to growth, not immune defense. Once they reach an age where they can reproduce, energy metabolism is redirected to immune defense,” he said.

Fedson recalled a study in which adult mice reacted more severely to liver injury than juveniles. When researchers treated adult mice with the diabetes drug rosiglitazone, the adults had less severe inflammation and better survival. In effect, he said, the researchers “rolled back the host response of the young adult to that of a child.” Similar effects on acute inflammation have been seen in studies of statins for heart attack victims and in studies of other immunomodulatory drugs in animal models of sepsis and influenza. In each instance, these drugs act to restore homeostasis. Equally important, they are produced as inexpensive generics and are available in any country with a basic health care system.

But much work needs to be done to determine whether these inexpensive drugs could be used routinely to treat patients with severe acute illness, including avian influenza. Unfortunately, said Fedson, research on the muted host response to disease in children, as well as on strategies to mimic this response in adults, has been neglected—especially by influenza scientists and immunologists.

Fedson has lectured at conferences, published in medical journals and the lay press, and contacted dozens of prominent researchers, journalists, and policymakers. Responses to what he calls his “cry in the wilderness” have been few and mostly noncommittal. He blames narrow specialization and a driving desire among biomedical scientists to explain mechanisms of disease rather than seek practical ways to manage it.

It doesn’t help, he adds, that most experts are not M.D.s, but Ph.D.s, who have a better understanding of the virus than the host response it can produce.

ORT for cholera, Fedson pointed out, was introduced at a time when researchers were trying and failing to develop an effective cholera vaccine. ORT treated the host response—the diarrhea and subsequent dehydration—without attacking the infectious organism. The strategy has saved tens of millions of lives worldwide. Might a physiologic treatment of the host response to pandemic influenza do the same?

“Let’s see if we can use what we’ve already got,” Fedson said. “We don’t know whether these agents will work, but we can’t afford not to do the research to find out.”