When 8-year-old Tiffany* was rushed into the emergency room at Nationwide Children’s Hospital, she was suffering from multiple fractures and internal bleeding after being in a horrific car accident. Physicians were able to stabilize her, and within a few hours, she was on a ventilator in the intensive care unit. Here, she began a second fight for her life – battling hospital-acquired infections, which nationally, affect as many as 40 percent of critically injured kids in the ICU.
“Sometimes, injuries are so severe that the innate immune system becomes deeply impaired and unable to respond to normally to infection,” says Mark Hall, MD, a critical care medicine physician and scientist at the Center for Clinical and Translational Research at Nationwide Children’s (NCH). “These secondary infections represent serious complications, can result in extended hospital stays and, in very rare instances, death.”
Usually, Tiffany would simply be observed for signs of infection while she was in the ICU. But as part of a clinical trial led by Hall, she is one of the first kids in the country to receive a drug called GM-CSF that researchers hope will boost her immune system enough so that it can fight off potential infections.
GM-CSF has been used for more than 20 years to help restore the immune systems of pediatric cancer patients after they have undergone chemotherapy or received a bone marrow transplant. GM-CSF helps improve the function of existing immune system cells and prompts the bone marrow to make new cells, which can help normalize the immune response. Researchers think just a fraction of the dose of GM-CSF usually used in cancer patients may also help reset an immune system disrupted by extreme trauma.
“In the aftermath of a critical injury we sometimes see a strong inflammatory immune response followed by an overactive anti-inflammatory response which in effect, paralyzes the immune system,” says Hall. “By using a simple blood test, within hours we know which kids with trauma are in this immunoparalyzed state, and who may benefit from GM-CSF.”
Tiffany’s blood was put through a panel of tests in Hall’s Immune Surveillance Laboratory, designed specifically to look at several parameters in immune response. “We basically take a chemical stick and poke the blood cells to see if they react the way they should, and that gives us a window into the strength of a child’s immune system, ” says Hall.
The “stick” is designed to induce the production of TNFα, a key immune response chemical. Hall conducted several earlier observational studies that helped establish a TNFα production threshold that is associated with infection risk; if the TNFα response is below this threshold, the child’s risk for developing a secondary infection or dying increases.
Tiffany was enrolled in the GIFT (GM-CSF for Immunomodulation Following Trauma) study, and every day, for the first three days Tiffany was in the ICU, Hall’s team tested her immune function. They found she was producing very low quantities of TNFα, so she was given GM-CSF. Tiffany’s immune system bounced back. She made a full – and infection-free- recovery in the ICU.
Funded by a 5-year grant from the National Institute of General Medical Sciences and supported by the Ohio State Center for Clinical and Translational Science (CCTS), the GIFT study is in the first of two phases, where researchers are determining the lowest tolerable, yet effective dose. Within one year, researchers will begin the efficacy phase, where critically injured children will be randomized to receive either GM-CSF or placebo.
Hall says that the team is also stratifying the study group based on pubertal status, hypothesizing that sex hormones may alter the dose-response, and by children who have severe traumatic brain injury (TBI), noting that neurohormonal influences affect immune function after severe TBI.
Hall is also optimistic that his approach to same-day immune function monitoring will become a standard part of lab tests performed on kids with life-threatening injuries so that they can receive targeted, patient-specific immune system support.
“We’re hoping that within the next five to 10 years, our findings will help establish a new standard of care for children whose immune systems have been impaired by life-threatening injuries,” says Hall. “Plus, what we’ve learned about the trauma related immune response could be applied to other critical conditions like sepsis or influenza where kids are particularly vulnerable.”
Hall has been studying immune system dysfunction for more than 15 years. Currently the director of the Immune Surveillance Laboratory at NCH, Hall is a longtime collaborator with Mark Wewers, MD at the Dorothy M. Davis Heart and Lung Research Institute at The Ohio State University Wexner Medical Center. The current GM-CSF study is also being conducted in partnership with the surgical trauma team at Ohio State.
*Details have been changed to protect patient’s privacy
Source: Ohio State University Center for Clinical and Translational Science