Study sheds light on lethality of 1918 flu virus

Jan 17, 2007 (CIDRAP News) – A virus recovered from victims of the 1918 influenza pandemic kills by replicating so rapidly that it revs the immune system into overdrive, turning the body against itself, a team of scientists report in today's issue of the journal Nature.

The finding, from a small study done in cynomolgus macaque monkeys, appears to confirm historical accounts of the 1918 pandemic that describe victims drowning from within as their lungs filled with blood and fluid.

And it may offer a starting place for interventions against future pandemics, because avian influenza H5N1, the viral strain currently considered the most substantial pandemic threat, causes a similar intense immune reaction in human victims.

H5N1 "appears to do this in a way that is quite similar to the 1918 virus, " Darwyn Kobasa of the Public Health Agency of Canada's National Microbiological Laboratory, the paper's first author, said in a media briefing before the paper's release. "So we think a greater understanding of the viruses that cause pandemics will help us predict what might be expected and how to plan to use our knowledge and resources to reduce the impact of a new pandemic."

The study, led by Yoshihiro Kawaoka of the University of Wisconsin–Madison, used a virus that was reassembled in 2005 out of fragments recovered from the tissues of 1918 victims and now is held in only two high-security biosafety level 4 laboratories: the Canadian lab in Winnipeg and the US Centers for Disease Control and Prevention in Atlanta.

The researchers compared clinical course, pathology, and genomic analyses for seven monkeys experimentally infected with high doses of the 1918 virus and three monkeys infected with a modern virus from the same H1N1 family as the 1918 strain.

Monkeys from both groups were euthanized on the third and sixth days after infection for analysis. The scientists had planned to let the experiment run for 21 days, but the 1918-infected monkeys were so gravely ill that they had to be euthanized at day 8.

Pathologic analysis revealed that the lungs of the 1918-infected group, but not the modern-virus group, were filled with blood and watery fluid and had widespread tissue destruction. Viral isolation from the tissues showed that the 1918 virus kept replicating throughout the monkeys' respiratory systems until they were put to death—unlike the modern virus, which the last monkey from the modern-virus group largely cleared from its system.

And analyses of gene expression in bronchial tissues from both sets of monkeys uncovered striking differences in the reactions of the monkeys' immune systems. The macaques that received the conventional virus spiked an immune response after three days, but that response faded by day 6 as healing began. The 1918-infected group, on the other hand, experienced an initially muted immune response that grew progressively stronger and never abated.

"There was an uncontrolled or aberrant inflammatory response," co-author Michael Katze of the University of Washington, Seattle, said in the media briefing. As in case reports from 1918, he said, "instead of protecting the individuals that were infected with the highly pathogenic virus, the immune response is actually contributing to the lethality of the virus."

That over-revved reaction, commonly called a "cytokine storm" after overproduction of one type of immune-system proteins, was recorded last fall in mice experimentally infected with the same recovered 1918 virus, by a team that included some of the authors of today's paper.

Kawaoka, who was not an author on the mouse study, told reporters it was important to repeat the work in nonhuman primates because organisms that are lethal to mice in the laboratory often show lesser effects on larger animals.

An uncontrolled immune system reaction has been hypothesized as the cause of death for 1918 victims, who were described in autopsy accounts as having lungs that resembled sodden sponges, and it has been identified in several deaths from H5N1 in Vietnam.

But it also has suggested a possible defense strategy if a pandemic begins — something dearly sought by public health planners, who acknowledge that vaccines cannot be produced quickly and antivirals will be in short supply.

On the basis of their findings, the authors of today's article recommend additional research into drugs that damp down the immune-system response triggered by the 1918 virus. "One can image that first-responders, the people on the front lines in the hospital, could perhaps be treated with a combination of drugs—let's say an antiviral drug like Tamiflu and drugs that already exist which may control that inflammatory response," Katze said in the briefing.

One possible pharmaceutical defense strategy hinges on statins, a class of drugs used against cardiovascular disease that target the same inflammatory response observed in the flu studies. Several studies have found that patients who are taking statins experience less sepsis and bacteremia.

And a forthcoming article in the journal Critical Care Medicine follows a group of 11,400 patients with atherosclerotic disease, half of whom were taking statins, and finds that statin use cut the risk of death from infections—mostly pneumonia—by two thirds.

"This is a clinical and epidemiologic signal of protection that we ought to pay attention to, that statins are beneficial in serious infectious disease syndromes that are associated with elevated levels of proinflammatory cytokines," David Fedson, a former professor of medicine and pharmaceutical researcher who recommended exploring statins as a defense against a pandemic in a 2006 article in Clinical Infectious Diseases, said in an interview.

Unlike pandemic vaccine, he said, statins can be produced in advance—and unlike the antivirals used against flu, they are widely produced around the world in generic format, and therefore both abundant and cheap.

But interventions that affect the immune system should be approached with caution until further research is conducted, said Michael Osterholm, director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of the CIDRAP Web site."The immune wiring of the human body is so complicated that what might appear at the outset to be an obvious way of dampening the immune system may have unseen complications," he said.

And distributing even inexpensive, widely available drugs may be impractical, he added, given the social and economic disruption that a pandemic would cause: "Given our lack of surge capacity, and the fact that the vast majority of pharmaceutical products we use in this country today are produced offshore, I have no sense those drugs would really be available."

Kobasa D, Jones S, Shinya K, et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. (Letter) Nature 2007 Jan 18;445 [Full text]

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