IDEAS TO TREAT FLU IN A PINCH
29 June 2007 - University of Chicago

University of Chicago lung researchers believe doctors put in that difficult position could turn to experimental therapies designed to prevent an infection from destroying the lungs. Rather than fight the virus itself, the drugs would dampen the immune system's aggressive, and ultimately self-destructive, response to such viruses.

The approach would address what the U. of C. team sees as potential weaknesses in the Bush administration's proposal to buy billions of dollars' worth of flu vaccines and anti-flu medications such as Tamiflu. Those supplies will not be in place for several years, and the drugs may have limitations.

Last week, researchers from Vietnam reported that two bird flu patients had developed rapid resistance to Tamiflu and died.

The development underscored the need for other options in case anti-flu drugs like Tamiflu and Relenza don't work or the drugs are in short supply, said Dr. Steven Dudek, a pulmonary researcher at the U. of C.

'The drugs in our armament may not be as effective as people are hoping,' Dudek said. 'It would be nice to have some other way of treating people who get sick.'

Bird flu cannot spread among humans. But scientists fear it could mutate to acquire that ability and spiral into a worldwide pandemic. If that happened, lung experts say they could be at ground zero of a massive explosion of patients, with no reliable way of treating the deadly disease.

One solution may be drugs already being studied to treat other conditions that result in massive lung injury. Experts estimate that 80,000 people die each year from ailments that injure the lungs, most often infections with pneumonia, staph and other types of bacteria and viruses.

Stopping such lung injury in its tracks could reduce the pressing health threat posed by ordinary infections, in addition to addressing the still-theoretical risk of a flu pandemic, said Dr. Skip Garcia, chairman of the department of medicine at the U. of C.

'Right now all we can do for most of these patients is give them supportive care,' Garcia said. 'We're not stopping what's causing the injury.'

As with bird flu, infections with pneumonia and other bugs often kill patients indirectly, by unleashing an immune response that winds up tearing into the patient's own tissue.

The immune response is especially strong for the Asian bird flu strain called H5N1, because most humans have never been exposed to that virus. Studies suggest the immune system's attempt to fend off the virus causes a 'cytokine storm' that brings about massive inflammation and blood vessel leakage in the lungs.

'These people end up drowning in their own fluid,' Dudek said.

Having a healthy immune system is no defense against such damage. In fact, some experts speculate that younger people with active immune systems may be even more at risk from auto-immune injury. In Thailand, the death rate from bird flu has been 89 percent for victims younger than 15, according to a September report in the New England Journal of Medicine.

The U. of C. team led by Garcia and Dudek is investigating drugs that may help stop the blood vessel leaks that crop up once the lungs become swollen.

Researchers still do not fully understand the immune reactions that harm avian flu patients, noted Dr. Steven Wolinsky, director of the infectious diseases department at Northwestern University. But he said it makes sense to explore whether doctors could save the lungs from damage by the immune system.

'With any patient one would want to go to antiviral drugs first, because you want to fight the infection at its source,' Wolinsky said. In addition to that, however, 'if the immune effect really is a storm of cytokines, anything that could possibly deter or lessen their effect would be worthwhile to try.'

One drug already available to treat respiratory distress is Xigris, which can reduce inflammation. But the drug is expensive, about $8,000 for a four-day course, and does not directly address the blood vessel leakage problem.

To do that, Dudek and Garcia are studying two drugs not yet approved by the U.S. Food and Drug Administration. Both medications are based on compounds the body produces in response to injury. Those compounds cause cells in the walls of blood vessels to move closer together, preventing fluid from leaking out.

In addition to protecting the lungs, such treatment could help prevent multi-organ failure, which is a common result of massive infections. In many cases leakage from the blood vessels causes the organs to swell up and cease to function.

To study the experimental medications, Dudek's group places a substance found in bacterial cell walls down the airways of laboratory rodents and dogs. The bacterial material triggers an aggressive immune response, causing the animals' lungs to fill with fluid.

The animal studies suggest that the experimental compounds reduced blood vessel leakage, Dudek said. The results were encouraging because one of the experimental drugs, called FTY720, is in advanced human clinical trials for use in transplant patients. If the FDA approves that drug, Dudek said, his team plans on looking into studying it for human patients suffering from lung injury.

No one knows what treatments might be available if or when a flu pandemic strikes. But Garcia and Dudek said that if their options were limited, and antiviral drugs such as Tamiflu were in short supply, they would consider using their experimental options.

'Especially if I were in Asia or Africa, or someplace where I had no other opportunities, and there was an outbreak, I'd pull out the stops for sure,' Garcia said.

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