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How can we protect patients with weakened immune systems from influenza?

The flu is bad enough for healthy people, but the disease can place a special burden on those with weakened immune systems, such as patients on chemotherapy. A five-year, $10.7 million federal grant to The Children's Hospital of Philadelphia will support research to determine how adults and children with impaired immune systems may be uniquely vulnerable to influenza, and will seek better ways to protect them.

Because patients with compromised immune systems may be contagious longer than people with healthier immune systems, they may be a reservoir for the disease. In addition to the yearly toll of ordinary influenza (as many as 36,000 annual fatalities in the U.S.), added concerns over potential threats -- an avian flu pandemic or the use of flu as a weapon of biological warfare -- put anti-flu measures into the category of biodefense.

Under a biodefense program mandated by Congress, the National Institute of Allergy and Infectious Diseases, in conjunction with the Department of Defense, has awarded the grant to researchers at The Children's Hospital of Philadelphia and the University of Pennsylvania, led by pediatric immunologist Kathleen Sullivan, M.D., Ph.D., chief of Allergy and Immunology at Children's Hospital.

"Our research focuses on the basic question of who benefits most from influenza vaccine," said Dr. Sullivan. "This question becomes paramount if influenza reaches epidemic proportions and supplies of vaccine are limited. We want to offer protection to these special populations of immunocompromised patients, but not to vaccinate them needlessly."

Patients on chemotherapy, on immunosuppressive drugs, or with diseases that weaken the immune system may be especially vulnerable to influenza, whether the ordinary annual variety or deadlier types. The researchers will study how such patients' vaccine responses change over time: "Some patients may not benefit from flu vaccine at one point in time, but they may benefit just two o r three weeks later," said Dr. Sullivan.

The research teams will measure T cell and B cell counts in the targeted patients. Both types of cells play important roles in the immune system. T cells that recognize and fight influenza may help predict whether a patient will produce protective antibodies after vaccination. Producing those antibodies is the job of B cells. "We hope to be able to use a simple blood test to help determine which immunocompromised patients will benefit from an influenza vaccine," added Dr. Sullivan.

The full grant encompasses six projects, each of which focuses on particular immunocompromised subpopulations. Ultimately, the researchers expect to have customized treatment recommendations for each group.

Half of the projects cover children at The Children's Hospital of Philadelphia. One project will study immune responses in children receiving different intensities of chemotherapy for solid tumors and two types of leukemia. Another project is dedicated to children with neuroblastoma, a solid tumor of the peripheral nervous system, who are treated with a novel type of stem cell transplant. Both chemotherapy and stem cell transplants involve suppressing the patients' immune defenses. A third group of patients has chromosome 22q.11.2 deletion syndrome, a congenital multisystem disorder that impairs the immune system. Children's Hospital is a world leader in studying and treating this syndrome.

Three projects involving adults are led by researchers in the University of Pennsylvania Health System. Two projects involve cancer patients: those receiving stem cell transplants for multiple myeloma (a cancer originating in bone marrow) and patients with ovarian cancer receiving an experimental treatment--an anti-cancer vaccine made from dendritic cells. Carl June, M.D., director of translational research at Penn's Abramson Cancer Center, leads both projects.

A third group of adult patients suffers from autoimmune d iseases, those in which an abnormal immune system turns on itself: systemic lupus erythematosus and Sjogren's syndrome.

Core research facilities will assist all the projects in systematically measuring T cell and B cell counts and developing specialized assays. The researchers will begin enrolling patients this fall under the five-year program.

"A major reason to study influenza is the quick-changing nature of the influenza virus," said Dr. Sullivan. The virus mutates its outer coating from year to year, a process called viral drift, which is why new flu vaccines are developed each year. The potential threat of avian flu is that mutations in the avian virus could allow it to easily pass from person to person. An epidemic with a completely new type of virus such as this represents viral shift, and is usually far deadlier because there is no pre-existing immunity in the population.

Furthermore, although it has never been known to have been developed as a bioterror weapon, the influenza virus may be relatively easy to manipulate for such purposes in a laboratory ?which is why the federal government is funding medical research to improve defenses against flu.

Dr. Sullivan looks to broader and longer-term benefits of her funded program. "Even if the worst-case scenarios of flu pandemic or weaponized flu attack do not occur in the next few years, we will have greater understanding of how to protect vulnerable patients."


Source:Children's Hospital of Philadelphia

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