(From the October 2014 Research Now)
For the first time, a study published in Critical Care has found that children with septic shock demonstrate adaptive immune suppression with 48 hours of the onset of sepsis, a body-wide infection that leads to dangerously low blood pressure. These findings, led by scientists in The Research Institute at Nationwide Children’s Hospital, suggest that adaptive immune suppression, in addition to innate immune suppression, may be part of the immune system’s early response to septic shock and may be a target for new therapies.
Septic shock is a serious condition that commonly occurs in critically ill pediatric patients as a severe reaction to infection. Whether or not a patient can successfully recover from sepsis depends on whether the initial infection can be treated and new hospital-acquired infections can be prevented. But studies have shown that immune response is suppressed when patients are critically ill, which makes it difficult for patients to combat infections and recover from sepsis.
This suppression of both constituents of the immune system — innate immunity and adaptive immunity — is associated with adverse outcomes, including mortality. The innate immune system is comprised of cells and proteins that are always present in the body as the first step for fighting off infection, while the adaptive immune system consists of components that “adapt” to invaders and activate when the innate immune defenses fail.
“We know that the signs and symptoms of septic shock that we see at the bedside — for example, fever — are the result of an exaggerated immune response. However, mounting evidence suggests that many patients also demonstrate suppressed immune function in this setting,” says Jennifer Muszynski, MD, lead author of the study and principal investigator in the Center for Clinical and Translational Research at Nationwide Children’s.
Dr. Muszynski’s team and others at Nationwide Children’s and The Ohio State University have documented strong associations between poor outcomes and reduced innate immune functionin adults and children with sepsis. But until this study, there was little data on the adequacy of the adaptive immune response and patient outcomes in children with sepsis. “Understanding both the innate and adaptive immune response in septic children is important because it is a vital step toward developing targeted therapies to restore immune function in the ICU,” explains Dr. Muszynski.
To evaluate adaptive immune function, Dr. Muszynski and her team isolated CD4+ T cells from patient blood samples. CD4+ T cells play an important role in the adaptive immune system and help other immune cells by releasing T cell cytokines, which are small proteins important for cell signaling and the body’s response to conditions such as infection, sepsis and inflammation. Researchers then stimulated the CD4+ T cells in an external environment that mimics the human body and measured the cells’ cytokine production, along with other aspects of immune system function.
By identifying and measuring the amount of cytokines produced by the immune cells, as well as the amount of regulatory T cells involved in immune suppression, researchers found that children with septic shock demonstrated adaptive immune suppression within 48 hours of sepsis onset. They also discovered that early adaptive immune suppression was greatest for children who went on to develop infection-related adverse outcomes.
“These findings are important because they suggest that adaptive immune suppression, in addition to innate immune suppression, may be part of the early immunologic response to septic shock and may represent a promising therapeutic target,” says Dr. Muszynski, who is also a critical care physician at Nationwide Children’s and an assistant professor of pediatrics at The Ohio State University College of Medicine. “While we cannot make causal inferences from this type of study design, our data suggest that adaptive immune suppression in septic children might be due to a combination of lymphocyte (white blood cell) death leading to a deficiency in lymphocytes and lymphocyte cellular dysfunction, as has been previously reported in adults.”
Future studies will be aimed at elucidating the potential mechanisms of adaptive immune suppression in septic children and risk factors for immune suppression. Dr. Muszynski’s team plans to confirm this study’s findings in larger cohorts of children with sepsis, in order to more fully understand relationships between immune function measures and patient outcomes. Her team has also found recent data to suggest that red blood cell transfusion, particularly with red blood cells that have been stored for long periods of time, may suppress the immune system of critically ill patients. Studies are currently being conducted to determine how red blood cell storage time and transfusion impact immune suppression of patients in the ICU.
Muszynski JA, Nofziger R, Greathouse K, Nateri J, Hanson-Huber L, Steele L, Nicol K, Groner JI, Besner GE, Raffel C, Geyer S, El-Assal O, Hall MW. Innate immune function predicts the development of nosocomial infection in critically injured children.Shock. 2014 Oct, 42(4):313-21.
Muszynski JA, Nofziger R, Greathouse K, Steele L, Hanson-Huber L, Nateri J, Hall MW. Early adaptive immune suppression in children with septic shock: a prospective observational study.Critical Care. 2014 July 8, 18(4):R145.
Muszynski J, Nateri J, Nicol K, Greathouse K, Hanson L, Hall M. Immunosuppressive effects of red blood cells on monocytes are related to both storage time and storage solution.Transfusion. 2012 Apr, 52(4):794-802.