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Long before last spring’s H1N1 epidemic, Adrienne Randolph, MD, MSc, of Children’s Hospital Boston’s Division of Critical Care Medicine, was concerned about hospitalizations and deaths among children with influenza. "Some children were quickly overwhelmed, and many died despite centers doing everything to save them," she says. "It was getting more and more worrisome."
Why were otherwise healthy school-aged children–without known risk factors like asthma–developing deep pneumonias, requiring ventilators and heart–lung bypass and succumbing to serious co–infections with bacteria like Staphylococcus aureus? Randolph and her colleagues in pediatric intensive care units (ICUs) across the country (part of the Pediatric Acute Lung Injury and Sepsis Investigators Network) are trying to understand what’s going on in these critically ill flu patients. "Some people may have defects in their immune system that allow influenza to go rampant," Randolph says.
So far, the network has enrolled 145 patients (70 with H1N1, the rest with ordinary seasonal flu) from more than 21 sites in the United States and Canada. Using patients’ blood and lung–fluid samples, the investigators are exploring possible genetic differences, susceptibility factors such as vitamin D levels and co–infecting bacteria and viruses. Immune responses are being carefully quantified, including measurement of immune cells and cytokines (immune–stimulating proteins) in the blood and lungs.
The genetic studies, aided by Louis Kunkel, PhD, director of the Program in Genomics, are focusing on the genes that control people’s first–line (innate) immune response to viral invasion. With a team from the Division of Immunology, led by Raif Geha, MD, Randolph’s group is also looking closely at what’s happening to T–lymphocytes. They’ve observed that these essential immune cells are virtually absent in some of the ICU patients’ blood: Have they died off, or have they just moved to the lung to fight the infection? Separately, with Wayne Marasco, MD, PhD, at the Dana–Farber Cancer Institute, they are testing people’s ability to make antibodies to the stable "stalk" of the flu virus (rather than just the head, which constantly mutates), hoping for clues to better vaccines that provide more durable immunity.
In the meantime, Randolph hopes that a better understanding of the disease process in critically ill flu patients will help in targeting treatments. For example, some patients may have an extremely weak immune response, while others may have an excessive response that needs to be suppressed.
Results from laboratory analyses of the first 126 critically ill children will be available soon. "If the flu season gets extreme this year, some data are better than none," says Randolph.
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