The massive inflammation caused by the H5N1 strain of the avian influenza virus explains why the virus is so deadly, but it also provides clues to better treatments, experts say.
In a letter published online ahead of print publication on 10 September in Nature Medicine (www.nature.com/nm, doi: 10.1038/nm1477) the authors document how the immune systems of 18 Vietnamese people who contracted the infection in 2004/5 became stoked up to an extraordinary degree by the virus.
The Vietnamese doctors’ comparison of these 18 people—13 of whom died—with eight patients with normal H3N2 or H1H1 human flu showed the extent of immune dysfunction.
Among the striking observations was a massive release of inflammatory cytokines, causing immune cells to proliferate and provoking inflammation. Some of these cytokines were present at amounts hundreds or thousands of times higher than in patients with ordinary flu.
These observations explain how the infection typically kills patients through pneumonia and multi-organ failure, the researchers say.
So far the World Health Organization has recorded 141 deaths from H5N1 flu, mostly in South East Asia.
As a result of the latest findings, “the focus of clinical management must be in preventing this intense cytokine response,” said the lead investigator, Meno de Jong, of the Oxford University Clinical Research Unit at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam.
His team’s report says that of all the patients the ones who died from H5N1 had the highest levels of cytokines and the highest levels of virus circulating in their bodies.
This underlined the need to treat victims with antivirals very quickly, he said. Once the cytokine burst had started it was usually too late to alter the course of the disease.
In theory, Dr de Jong said, using drugs to dampen down patients’ immune systems might help. But so far such methods had not proved particularly effective in practice.
Another important discovery was that, in addition to stoking up some components of the immune system, H5N1 infection fatally weakened another arm of the immune response: the body’s ability to fight viral infection with T cells. The number of these cells, crucial for combating viruses, plummeted in people who died from the infection.
Wendy Barclay, a virologist at Reading University who studies the effects of flu viruses on the immune system, emphasised the importance of the research.
“This is the first good clinical evidence we have of what really happens when people have H5N1 infection,” she said. “It shows us that in some people H5N1 causes this cascade of cytokines and macrophage activity that gets out of control. It suggests that stopping the virus replicating early on in the infection with antivirals is the key to treatment.”
She noted that treating patients with anti-inflammatory drugs, as some doctors have suggested, “might do more harm than good.”
“Immunomodulatory drugs are blunt instruments. The last thing you want to do is weaken parts of the immune system needed to fight the virus,” she said.