Early Immune Responses Suppressed in Children With Sepsis, Septic Shock

(From the May 2018 issue of Research Now)

Severity of suppression, gauged by blood tests, is a potential guide to therapy trials and treatment

Critically ill children suffering from severe sepsis or septic shock show suppressed innate and adaptive immune responses within 48 hours of sepsis onset, a study by researchers at Nationwide Children’s Hospital found.

And, the severity of suppression is associated with a greater number of days of single and multiple organ dysfunction and death.

“The data and a growing body of work suggests that while the body is inflamed by sepsis, the immune system is suppressed, impairing the immune system’s ability to respond to new insult,” says Jennifer Muszynski, MD, a critical care physician and principal investigator at the Center for Clinical and Translational Research. Dr. Muszynski is also lead author of the study, published in the American Journal of Respiratory and Critical Care Medicine.

Beyond the findings, the study also suggests that early measures of innate and adaptive immune responses may be useful in stratifying patients’ risk and provide targets for future pediatric sepsis therapy trials.

Sepsis occurs when an infection in one part of the body leads to systemic responses, such as fever and higher heart and breathing rates. Severe sepsis occurs when one or more organs start failing and turns to septic shock when organ dysfunction continues and blood pressure drops dramatically.

“Severe sepsis and septic shock are a major public health problem; the mortality rate in children is 10 to 25 percent around the world,” says Mark Hall, MD, FCCM, division chief of Critical Care Medicine, a principal investigator in the Center for Clinical and Translational Research and senior study author.

Most therapies for sepsis and septic shock, such as antibiotics, intravenous fluids, ventilators and renal therapies, are supportive, says Dr. Hall, who is also an associate professor of Pediatrics at The Ohio State University College of Medicine.  “A working immune system does more, clearing out pathogens and helping remodel injured tissue.”

Other studies have shown that late immune suppression in critically ill adults and children is associated with poor outcomes, but the Nationwide Children’s researchers wanted to explore early immune suppression in children and its relationship to organ function.

To make their findings, the researchers tested blood samples taken from 102 septic children within 48 hours of sepsis onset and compared them to blood samples from 35 healthy children.

Septic children’s blood had a reduced ability to secrete pro-inflammatory cytokine tumor necrosis factor (TNF)-α in response to exposure to lipopolysaccharide, indicating innate immune suppression. Those who went on to develop new or progressive multiple organ dysfunction had lower TNFα responses than those who did not suffer this secondary outcome. Non-survivors tended to have lower TNFα responses than survivors.

Septic children’s blood produced less interferon (IFN)-γ when exposed to phytohemmagglutinin, indicating suppression of the adaptive, or lymphocyte, arm of the immune system as well. Early adaptive immune suppression was significantly associated with new or progressive multiple organ dysfunction and mortality.

Critical care physicians typically use blood cell counts to gauge immune function, but in a comparison with cell counts, the ex vivo stimulated responses better predicted which children went on to develop prolonged multiple organ dysfunction.

“One reason to do this study is to understand how to design subsequent studies on drugs that may improve outcomes,” says Muszynski, who is an assistant professor of Pediatrics at The Ohio State University College of Medicine.

Dr. Hall is currently leading research on a drug that may turn on immune cells during trauma-induced immune suppression, he says. If they were to expand that research into sepsis-induced immune suppression, “this study may help identify who would benefit from specific intervention targeting restoration of the host immune response.”

Citation:  Muszynski JA, Nofziger R, Moore-Clingenpeel M, Greathouse K, Anglim L, Steele L, Hensley J, Hanson-Huber L, Nateri J, Ramilo O, Hall MW. Early immune function and duration of organ dysfunction in critically ill septic children. American Journal of Respiratory and Critical Care Medicine. 2018 Feb 22. doi: 10.1164/rccm.201710-2006OC. [Epub ahead of print]