Hibbert et al, Front Pediatr. 2018
Neonates, especially those born preterm, are at increased risk of sepsis and adverse long-term effects associated with infection-related inflammation. Distinct neonatal immune responses and dysregulated inflammation are central to this unique susceptibility. The traditional separation of sepsis into an initial hyper-inflammatory response followed by hypo-inflammation is continually under review with new developments in this area of research. There is evidence to support the association of mortality in the early acute phase of sepsis with an overwhelming hyper-inflammatory immune response. Emerging evidence from adults suggests that hypo- and hyper-inflammation can occur during any phase of sepsis and that sepsis-immunosuppression is associated with increased mortality, morbidity, and risk to subsequent infection. In adults, sepsis-induced immunosuppression (SII) is characterised by alterations of innate and adaptive immune responses, including, but not limited to, a prominent bias toward anti-inflammatory cytokine secretion, diminished antigen presentation to T cells, and reduced activation and proliferation of T cells. It is unclear if sepsis-immunosuppression also plays a role in the adverse outcomes associated with neonatal sepsis. This review will focus on exploring if key characteristics associated with SII in adults are observed in neonates with sepsis.
Sepsis mortality in neonates may be associated with alterations in immune function that are in agreement with SII findings in adults. Whether immune cell dysfunction or impairment underpins immunosuppression in neonatal sepsis requires further investigation and stronger evidence. Large, collaborative longitudinal studies, from birth through to childhood, are essential to evaluate immune changes in neonates with sepsis, including the role for SII. Yet, first a definitive consensus on the definition of neonatal sepsis and severity needs to be established. Until then, sepsis severity could be measured by mortality. Advances in further understanding the immunological mechanisms behind immunosuppression may lead to effective targeted treatment therapies for reversing or modulating SII and improve outcomes. Immunosuppression reversal with PD-1/PD-L1 antibody blockade is currently being trialled in adult cancer patients who share similar immune defects as those with SII (151). Furthermore, pentoxifylline, an immune modulatory drug, is currently being trialled to improve long-term outcomes, primarily neurodevelopment impairment, associated with neonatal sepsis (ANZCTR ACTRN12616000405415). Assessing the impact of such interventions on SII-associated markers may provide a mechanistic insight into the success or failure of these interventions in preventing short and long-term negative sepsis outcomes.