Study Title:

Flu Can Knock Out important Immune Function

Study Abstract

Among previously healthy children with severe influenza, the mechanisms leading to increased pathology are not understood. We hypothesized that children with severe influenza would have high levels of circulating cytokines. To examine this, we recruited patients with severe influenza and examined plasma cytokine levels as well as the ability of peripheral blood cells to respond to stimuli. Ten patients with severe influenza were enrolled during the 2005–2007 influenza seasons. We evaluated plasma cytokine levels, circulating NK cells, and responses to TLR ligands during the illness. We compared these patients with five patients with moderate influenza, six patients with respiratory syncytial virus (RSV), and 24 noninfected controls. Patients with influenza showed depressed responses to TLR ligands when compared with RSV patients and healthy controls (P<0.05). These normalized when retested during a convalescent phase. Plasma levels of IL-6, IL-12, and IFN- were elevated in influenza patients compared with controls (P<0.05). A compromised ability to produce TNF- was reproduced by in vitro infection, and the magnitude of the effect correlated with the multiplicity of infection and induction of IFN regulatory factor 4 expression. Aberrant, systemic, innate responses to TLR ligands during influenza infection may be a consequence of specific viral attributes such as a high inoculum or rapid replication and may underlie the known susceptibility of influenza-infected patients to secondary bacterial infections.

From May 5 press release:

As the swine flu continues its global spread, researchers from the Children's Hospital of Philadelphia have discovered important clues about why influenza is more severe in some people than it is in others.

In their research study published online in the Journal of Leukocyte Biology, the scientists show that the influenza virus can actually paralyze the immune systems of otherwise healthy individuals, leading to severe secondary bacterial infections, such as pneumonia. Furthermore, this immunological paralysis can be long-lived, which is important to know when developing treatment strategies to combat the virus.

According to Kathleen Sullivan, M.D., Ph.D., the senior researcher involved in the study and Chief of the Division of Allergy and Immunology at the Children's Hospital of Philadelphia, "We have a very limited understanding of why some people who get influenza simply have a bad cold and other people become very sick and even die. The results of this study give us a much better sense of the mechanisms underlying bacterial infections arising on top of the viral infection."

Sullivan and colleagues recruited pediatric patients with severe influenza and examined the level of cytokines, which serve as the first line initiators of immune response, in the blood plasma. Although they found elevated levels of cytokines, they also found a decreased response of toll-like receptors, which activate immune cell responses as a result of invading microbes. This suggests that the diminished response of these receptors may be responsible for the paralysis of the immune system, leading to secondary bacterial infections.

The influenza patients were compared with patients with moderate influenza, respiratory syncytial virus, and a control group of healthy individuals. The immune paralysis appeared to be specifically a result of influenza infection and was not seen in patients with respiratory syncytial virus. This process might explain why one quarter of children who die from influenza, die from a bacterial infection occurring on top of the virus.

"Despite major medical advances since the devastating flu outbreak of 1918 and 1919, influenza virus infection remains a very serious threat," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology, "and the current swine flu outbreak is a grim reminder of this fact. The work by Dr. Sullivan and colleagues brings us a step closer to understanding exactly what goes wrong in some people who get the flu, so, ultimately, physicians can develop more effective treatment strategies."

Study Information

Meredith L. Heltzer, Susan E. Coffin, Kelly Maurer, Asen Bagashev, Zhe Zhang, Jordan S. Orange, and Kathleen E. Sullivan.
Immune dysregulation in severe influenza.
Journal of Leukocyte Biology,
2009 March

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