Candidate sepsis drug could prevent flu deaths

In some severe cases in the H1N1 influenza pandemic in 2009 the virus was resistant against all antiviral compounds, leaving doctors without drugs. The 1918 Spanish flu killed up to 40 million people. The swine flu pandemic in 2009 killed an estimated 284,000. Now, scientists have discovered a substance that could help doctors save lives during future influenza pandemics. Eritoran, a compound under investigation as a sepsis drug, dramatically reduces deaths from influenza in mice. “This could potentially open up a whole new class of anti-influenza drugs,” says Michael Osterholm, a flu expert at the Center for Infectious Disease Research and Policy at the University of Minnesota, Twin Cities, who was not involved in the work. At the moment, doctors have only one class of compounds available to combat influenza. The drugs, Tamiflu and Relenza, block neuraminidase, a surface protein that influenza viruses need to leave the cell after reproduction. The drugs, taken orally, have to be given soon after infection to be effective, however, and some flu strains have developed resistance against them. A few scientists have also questioned the safety and efficacy of the compounds, which many countries stockpiled during the 2009 H1N1 pandemic. “Basically, if you see the armamentarium we have today, it is limited and could be blown away overnight,” says Albert Osterhaus, a virologist at Erasmus MC in Rotterdam, the Netherlands.

Instead of targeting the virus, immunologist Stefanie Vogel at the University of Maryland, Baltimore, tried to interfere with the host immune system. Scientists have long speculated that some severe influenza cases are not the direct result of the virus wreaking havoc, but due to a so-called cytokine storm, a catastrophic overactivation of the immune system that leads to numerous inflammatory substances being released in the whole body, which can result in multiple organ failure. For instance, immune cells and fluid can accumulate in the lungs, blocking the airways. In 2008, a study in Cell suggested that the cascade was triggered by the activation of a molecule called Toll-like receptor 4 (TLR4), which normally alerts the immune system to the presence of certain bacteria in the body. If these pathogens overwhelm the body, TLR4 is thought to also trigger the whole-body inflammation known as sepsis. For that reason, blocking TLR4 has been looked at as a potential treatment in patients suffering from sepsis. Vogel and her colleagues investigated eritoran, a compound that blocks TLR4 and is now in clinical trials as a sepsis drug. They infected mice with a lab strain of influenza called PR8 and gave half of them eritoran injections for 5 days, starting 2 days after infection. Ninety percent of untreated mice died, compared with only 10% of those given the drug. If treatment was started 6 days after infection, 33% of the animals survived. The compound also reduced lung damage in cotton rats, a species that does not die from the influenza strain used for the study, the authors report online today in Nature.

“It’s an elegant study based on a rather bold hypothesis,” Osterhaus says. But the disease mechanism in mice could be different from that in humans, he says. “That does not disqualify the results, but it means we have to be cautious.” Vogel says that she has already submitted a grant to test the compound in ferrets, the animals most widely used for influenza studies. “Since eritoran has a very good safety record in people, we would hope that our preclinical studies will ultimately support clinical trials in humans for influenza and possibly other diseases that elicit pathology by a similar mechanism,” she writes in an e-mail to ScienceNOW. To Osterholm, the paper adds to the evidence that influenza causes illness by several different mechanisms. Some influenza strains, like the one that caused the Spanish flu in 1918, or the swine flu in 2009, are more likely to cause death by activating the immune system, leading to more deaths in younger age groups, he argues. “This is where this will have an application.” But Osterholm also cautions that many promising drug candidates fail at later stages. “We won’t know if this works until we put it in people.”

May 14, 2013

Original web page at ScienceNow