Study shows how H5N1 ravages the body.
Avian influenza kills so many of its human victims because it replicates profusely and over-stimulates the immune system: those findings, from the most extensive analysis of those infected, suggest that drugs to calm the immune system might help when standard antiviral treatment is unavailable or given too late.
Since 2003, more than 240 people have been diagnosed with H5N1 infections, and more than 140 of them have died. But there has been little information about how the virus ravages the body because many individuals are treated in rural or ill-equipped hospitals and too few samples have been collected. Autopsy tissue has also been hard to come by because of cultural taboos.
Vietnamese researchers collected and analyzed samples from 18 individuals infected in 2004 and 2005, 13 of whom later died. The researchers, led by Menno de Jong of the Oxford University Clinical Research Unit in Ho Chi Minh City, took blood, nose and throat samples, typically about six days into an infection, and compared them with those from individuals infected with H3N2 or H1N1 human flu strains.
The team found that H5N1 multiplies to levels up to hundreds of times higher than those of the human strains. The virus appears to prefer the lower respiratory tract, rather than the nose and throat favored by regular flu viruses. The team also detected viral RNA in the blood of patients who died, suggesting that it reached particularly high levels in these people, they report in Nature Medicine1.
"It's really going to be a landmark paper in describing what happens when humans are infected with avian influenza," says Peter Openshaw, an Imperial College London expert in immune response to respiratory infections.
The immune systems of those infected with H5N1 show hallmarks of intense activation. The researchers found high levels of several cytokines and chemokines in blood, particularly in patients who died, and a marked drop in infection-fighting white blood cells, or lymphocytes.
This uncontrolled outpouring of molecules, dubbed a 'cytokine storm,' can be triggered by toxins and bacterial infection, and is thought to eventually lead to the failure of lungs or other organs.
Researchers have previously suspected that avian flu can trigger a cytokine storm, which is also thought to have been important in severe acute respiratory syndrome and in the 1918 flu pandemic. But for H5N1, this is "the first time there is real data to support that concept," Openshaw says.
It is possible that the virus triggers this reaction because it replicates so fast, or because it makes proteins that aggressively stimulate the human immune system.
The study may explain why Tamiflu (oseltamivir), a drug that blocks viral replication, has so far saved few lives. The inflammatory response might have spun out of control by the time those infected began treatment, underscoring the need for early diagnosis and treatment.
It also suggests that drugs that quell the immune response might cut the death rate. Some doctors have already tried using steroids, which broadly suppress the immune system, but those drugs have not shown a clear benefit. Medicines that instead act on specific molecules — such as the anti-tumor necrosis factor therapy used for rheumatoid arthritis — might be more effective.
De Jong says researchers need to collect more samples to test, for example, whether genetic makeup makes some people particularly susceptible. "It's too bad we haven't learned more," De Jong says. "If samples had been collected from all those patients, we would be a lot further in understanding this disease."
de Jong M. D., et al. Nature Medicine, advance online publication DOI: 10.1038/nm1477(2006).
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Pearson, H. Controlling immune response may cut bird flu death rate. Nat Med 12, 1105 (2006). https://doi.org/10.1038/nm1493
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