Lab study supports idea of 'cytokine storm' in H5N1 flu

Nov 16, 2005 (CIDRAP News) – A recent laboratory study has produced more evidence that infection of human lung cells with the H5N1 avian influenza virus leads to intense inflammation similar to what was seen in victims of the 1918 Spanish flu pandemic.

Researchers from Hong Kong report that lung cells growing in a laboratory responded much more intensely to the H5N1 virus than to an ordinary flu virus, even though the viruses reproduced at about the same rate, according to the report published online by Respiratory Research.

The H5N1 viruses were "more potent inducers" of cytokines and chemokines—chemical messengers that trigger inflammation—than H1N1 viruses were, says the report by a team led by J.S.M. Peiris of the University of Hong Kong. A flood of inflammation-triggering chemicals released by the immune systems has been referred to as a "cytokine storm."

Autopsies of H5N1 avian flu victims in Vietnam and elsewhere have revealed lungs choked with debris from the excessive inflammation triggered by the virus. Similar severe lung damage was frequently reported in victims of the 1918 pandemic, which disproportionately killed people with the strongest immune systems—young, healthy adults.

The Hong Kong researchers sought to test their hypothesis that the H5N1 virus's ability to trigger a flood of cytokines may contribute to the unusually severe disease it causes in humans. They used H5N1 viruses isolated from a patient who died of the infection in Hong Kong in 1997 and from two Vietnamese patients who were infected in 2004, plus an ordinary H1N1 virus isolated in Hong Kong in 1998.

Laboratory cultures of human alveolar cells and bronchial epithelial cells were exposed to these viruses. Using real-time polymerase chain reaction (RT-PCR), the researchers assessed the levels of various cytokines and chemokines at several time intervals after infection.

They found that all the H5N1 viruses caused cells to secrete significantly higher levels of IP-10 (interferon-gamma-inducible protein 10), interferon beta, a type of T cell known as RANTES, and interleukin-6 than the H1N1 virus did. In addition, the 2004 versions of H5N1 caused cells to release more IP-10 at 6 hours than the 1997 version did.

"We have found that infection with H5N1 viruses led to the production of 10 times higher levels of cytokines from human cells than normal human flu viruses," said Peiris, as quoted Nov 12 in The Standard, a Chinese business newspaper.

The different cytokine responses are not explained by different viral growth rates, because all three virus subtypes replicated with similar efficiency, the article says. "The cellular mechanisms underlying this differential cytokine hyper-induction by H5N1 viruses are presently poorly understood," it states.

The report says previous research has shown that patients with H5N1 disease have higher levels of IP-10 and other chemokines in their blood than do people infected with ordinary flu, a finding that parallels the present laboratory findings.

In addition, the article says that studies of recombinant flu viruses carrying genes from the 1918 pandemic virus showed that the recombinant viruses were highly lethal and induced high levels of macrophage-derived chemokines in mice. However, it is not yet clear whether the increased chemokine levels were due to "hyper-induction" of the chemokines or just rapid growth of the virus.

Chan MCW, Cheung CY, Chui WH, et al. Proinflamatory cytokine responses induced by influenza A(H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 2005 (published online Nov 11) [Abstract]

See also:

Oct 11 CIDRAP News story "Experts cite differences between H5N1 and ordinary flu"

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