When a serious infection sets in, systemic inflammation can be triggered and result in the potentially fatal condition of sepsis. Although treatment with large amounts of intravenous fluids and antibiotics can resolve this, fatalities still occur, particularly in intensive care patients. A greater understanding of the underlying pathology, at the level of the immune response, may present new avenues for treatment. Data on this is particularly lacking in paediatric sepsis. In a recent study in Critical Care, Mark Hall and Jennifer Muszynski from the Nationwide Children’s Hospital, USA, and colleagues investigate the early adaptive immune response in children with septic shock, revealing the role of adaptive immune suppression in determining clinical outcomes. Here Hall and Muszynski discuss their key findings and the implications for treatment.
How common is sepsis in adults and children, and how effective are current treatments in both of these groups?
The prevalence of severe sepsis and septic shock are increasing in children, estimated at around 0.9 cases/1000 children (Pediatr Crit Care Med. 2013, Sep,14, 7:686-93). Numbers are similar in adults (0.5 – 1 case/1000 adults) (New England Journal of Medicine. 2003, Apr 17, 348, 16:1546-54). The sepsis-related case fatality rate in children in the US is 8 -10 percent, though this rises to 10 -20 percent in children with co-morbidities (Pediatr Crit Care Med. 2013, Sep,14, 7:686-93 and Am J Respir Crit Care Med. 2003, Mar 1,167, 5:695-701). While outcomes have improved in adults in recent years, mortality rates of 20 – 40 percent are still reported (New England Journal of Medicine. 2003, Apr 17, 348, 16:1546-54).
Sepsis, therefore, represents a major ongoing burden to the healthcare system and is responsible for significant morbidity and mortality across the age spectrum. In adults and children, sepsis treatment is largely supportive, with an emphasis on fluid resuscitation, aggressive antibiotic use, and organ support. Therapies specifically targeting sepsis pathophysiology related to the immune response have largely been unsuccessful, but the vast majority of these studies have targeted the initial pro-inflammatory response. We believe that the function of immune suppression that follows the onset of sepsis may be a more attractive target of therapy.
Innate immune suppression has previously been shown in children with sepsis. What led you to specifically investigate the adaptive immune response in children with sepsis?
Indeed, we have demonstrated that impairment of the innate immune response is associated with adverse outcomes in children with life-threatening infection (Intensive Care Med. 2011, Mar, 37, 3:525-32 and Crit Care Med. 2013, Jan, 41, 1:224-36). We and others have also shown that the adaptive, or lymphocyte, arm of the immune system can also be impaired in the setting of sepsis with similar associations with mortality (JAMA. 2011, Dec 21, 306, 23:2594-605 and J Immunol. 2005, Mar 15,174, 6:3765-72). Some investigators have suggested that lymphocyte suppression may occur very early in the setting of sepsis based on mRNA profiles (Pediatr Crit Care Med. 2010, 11, 3:349-55), but changes in lymphocyte function were thought to play a role in the more subacute phase of the disease. The temporal relationships between innate and adaptive immune suppression were poorly understood and the role of lymphocyte function in children with sepsis was unknown.
What were your main findings and how do these compare to what was previously known about sepsis in adults?
Our work shows, for the first time, that critically ill children with sepsis demonstrate reduced CD4+ T cell function within 48 hours of sepsis onset. Further, the degree of reduction in T cell function was predictive of infectious complications as evidenced by failure to resolve infection or the development of new infection. Interestingly, we were unable to demonstrate an increased prevalence of immunosuppressive regulatory T cells, a cell type that is thought to promote immune suppression in the subacute phase of sepsis in adults (Crit Care Med. 2003, Jul, 31, 7:2068-71).
What are the clinical implications of adaptive immune suppression in children with sepsis? How may this inform early detection and treatment in children?
We have shown that restoration of innate immune function in critically ill children and adults is possible through the use of immunostimulatory therapy such as the drug GM-CSF (Intensive Care Med. 2011, Mar, 37, 3:525-32 and Am J Respir Crit Care Med. 2009, Oct 1,180, 7:640-8). Others have suggested, however, that stimulation of the adaptive arm of the immune system may be an appropriate goal of therapy (Nat Med. 2009, May,15, 5:496-7). As yet however, stimulation of neither arm of the immune system is part of standard sepsis treatment. This is in part due to a lack of a standardised approach to immune function monitoring in sepsis. Our data suggest that measurement of T cell responsiveness may be an important element of an immune monitoring regimen, so that T cell-targeted therapies can be developed and tested in a patient-specific manner.
Do you think suppression of the adaptive immune system in children is specific to sepsis, or is it likely to occur in other conditions during critical illness?
Innate immune suppression has been shown to occur in many forms of critical illness including sepsis, trauma, and cardiopulmonary bypass. While adaptive immune function has not been previously evaluated using our approach in other forms of paediatric critical illness, we suspect that lymphocyte function may well be abnormal in other settings. We view this to be an important area for future study.
What’s next for your research?
We are actively engaged in investigations focused on understanding mechanisms and risk factors for critical illness-induced immune suppression. In addition, we are performing a first-of-its kind clinical trial of immune stimulation with GM-CSF in critically injured paediatric trauma patients who demonstrate severe innate immune suppression. We look forward to more work evaluating the interplay between innate and adaptive immune function in our critically ill septic children, potentially including stimulation studies targeting both innate and adaptive immune suppression in an immunophenotype-specific way, paving the way for a precision medicine-focused approach to sepsis therapy.