Objective To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis, propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research. Design Literature search using PubMed, MEDLINE, EMBASE, and Google Scholar. Results Sepsis remains one of the most debilitating and expensive illnesses, and its incidence is not declining. What is changing is our definition(s), its clinical course, and how we manage the septic patient. Once thought to be predominantly a syndrome of over exuberant inflammation, sepsis is now recognized as a syndrome of aberrant host protective immunity. Earlier recognition and compliance with treatment bundles has fortunately led to a decline in multiple organ failure and in-hospital mortality. Unfortunately, more and more sepsis patients, especially the aged, are suffering chronic critical illness (CCI), rarely fully recover and often experience an indolent death. Patients with CCI often exhibit ‘a persistent inflammatory-immunosuppressive and catabolic syndrome’ or PICS, and it is proposed here that PICS contributes to many of these adverse clinical outcomes. The underlying cause of PICS is currently unknown, but there is increasing evidence that altered myelopoiesis, reduced effector T-cell function and expansion of immature myeloid-derived suppressor cells are all contributory. Conclusion Although newer therapeutic interventions are targeting the inflammatory, the immunosuppressive, and the protein catabolic responses individually, successful treatment of the septic patient with CCI and PICS may require a more complementary approach.

BACKGROUND Cancer and sepsis have surprisingly similar immunologic responses and equally dismal long term consequences. In cancer, increased myeloid-derived suppressor cells (MDSCs) induce detrimental immunosuppression, but little is known about the role of MDSCs after sepsis. Based on our chronic sepsis animal models, we hypothesized that after sepsis in humans, MDSCs will be persistently increased, functionally immunosuppressive, and associated with adverse clinical outcomes. METHODS Blood was obtained from 74 patients within 12 hours of severe sepsis/septic shock (SS/SS), and at set intervals out to 28 days, as well as in 18 healthy controls. MDSCs were phenotyped for cell surface receptor expression and enriched by cell sorting. Functional and genome-wide expression analyses were performed. Multiple logistic regression analysis was conducted to determine if increased MDSC appearance was associated with in-hospital and long-term outcomes. RESULTS After SS/SS, CD33+CD11b+HLA-DR−/low MDSCs were dramatically increased out to 28 days (p<0.05). When co-cultured with MDSCs from SS/SS patients, antigen-driven T-cell proliferation and TH1/TH2 cytokine production were suppressed (p<0.05). Additionally, septic MDSCs had suppressed HLA gene expression and upregulated ARG1 expression (p<0.05). Finally, SS/SS patients with persistent increased percentages of blood MDSCs had increased nosocomial infections, prolonged ICU stays, and poor functional status at discharge (p<0.05). CONCLUSION After SS/SS in humans, circulating MDSCs are persistently increased, functionally immunosuppressive, and associated with adverse outcomes. This novel observation warrants further studies. As observed in cancer immunotherapy, MDSCs could be a novel component in multimodality immunotherapy targeting detrimental inflammation and immunosuppression after SS/SS to improve currently observed dismal long-term outcomes.

Determine what clinical role, if any, GM-CSF may have in the clinical treatment of sepsis in the adult patient.Advancements in the management of sepsis have led to significant decreases in early mortality; however, sepsis remains a significant source of long-term mortality and disability which places strain on healthcare resources with a substantial growing economic impact. Historically, early multiple organ failure (MOF) and death in patients with severe sepsis was thought to result from an exaggerated proinflammatory response called the systemic inflammatory response syndrome (SIRS).Numerous prospective randomized controlled trials (PRCTs) tested therapies aimed at decreasing the organ injury associated with an exaggerated inflammatory response. With few exceptions, the results from these PRCTs have been disappointing, and currently no specific therapeutic agent is approved to counteract the early SIRS response in patients with severe sepsis. It has long been recognized that there is a delayed immunosuppressive state that contributes to long-term morbidity. However, recent findings now support a concurrent proinflammatory and anti-inflammatory response present throughout sepsis. Multiple immunomodulating agents have been studied to combat the immunosuppressive phase of sepsis with the goal of decreasing secondary infection, reducing organ dysfunction, decreasing ICU stays, and improving survival. Granulocyte-macrophage colony stimulating factor (GM-CSF), a myelopoietic growth factor currently used in patients with neutropenia secondary to chemotherapy-induced myelosuppression, has been studied as a potential immune-activating agent.The applicability of GM-CSF as a standard therapy for generalized sepsis is still largely understudied; however, small-scale studies available have demonstrated some improved recovery from infection, decreased hospital length of stay, decreased days requiring mechanical ventilation, and decreased medical costs.

The elderly are particularly susceptible to trauma, and their outcomes are frequently dismal. Such patients often have complicated clinical courses and ultimately die from infection and sepsis. Recent research has revealed that although elderly subjects have increased baseline inflammation as compared to their younger counterparts, the elderly do not respond to severe infection/injury with an exaggerated inflammatory response. Initial retrospective analysis of clinical data from the Glue Grant trauma database demonstrated that despite a similar frequency, elderly trauma patients have worse outcomes to pneumonia than younger subjects. Subsequent analysis with a murine trauma model also demonstrated that elderly mice had increased mortality after post-trauma Pseudomonas pneumonia. Blood, bone marrow, and bronchoalveolar lavage sample analyses from juvenile and 20–24 month old mice showed that increased mortality to trauma combined with secondary infection in the aged are not due to an exaggerated inflammatory response. Rather, they are due to a failure of bone marrow progenitors, blood neutrophils, and bronchoalveolar lavage cells to initiate and complete an ‘emergency myelopoietic’ response, engendering myeloid cells that fail to clear secondary infection. In addition, the elderly appeared unable to effectively resolve their inflammatory response to severe injury.

Purpose of Review Sepsis is the leading cause of pediatric death worldwide. In the United States alone, there are 72,000 children hospitalized for sepsis annually with a reported mortality rate of 25% and an economic cost estimated to be $4.8 billion. However, it is only recently that the definition and management of pediatric sepsis has been recognized as being distinct from adult sepsis. Recent Findings The definition of pediatric sepsis is currently in a state of evolution and there is a large disconnect between the clinical and research definitions of sepsis which impacts the application of research findings into clinical practice. Despite this, it is the speed of diagnosis and the timely implementation of current treatment guidelines that has been shown to improve outcomes. However, adherence to treatment guidelines is currently low and it is only through the implementation of protocols that improved care and outcomes have been demonstrated. Summary Current management of pediatric sepsis is largely based on adaptations from adult sepsis treatment; however, distinct physiology demands more prospective pediatric trials to tailor management to the pediatric population. Adherence to current and emerging practice guidelines will require that protocolized care pathways become commonplace.

Neutrophils play a crucial role in combating life-threatening bacterial infections in neonates. Previous studies investigating neonatal cell function have been limited because of restricted volume sampling. Here, using novel microfluidics approaches, we provide the first description of neutrophil chemotaxis and transcriptomics from whole blood of human term and preterm neonates, as well as young adults. Ex vivo percent cell migration, neutrophil velocity, and directionality to fMLP were measured from whole blood using time-lapse imaging of microfluidic chemotaxis. Genome-wide expression was also evaluated in CD66b+ cells using microfluidic capture devices. Neutrophils from preterm neonates migrated in fewer numbers compared to term neonates (preterm 12.3%, term 30.5%, p=0.008) and at a reduced velocity compared to young adults (preterm 10.1 μm/min, adult 12.7 μm/min, p=0.003). Despite fewer neutrophils migrating at slower velocities, neutrophil directionality from preterm neonates was comparable to adults and term neonates. 3,607 genes were differentially expressed among the three groups (p<0.001). Differences in gene expression between neutrophils from preterm and term neonates were consistent with reduced pathogen recognition and antimicrobial activity, but not neutrophil migration, by preterm neonates. In summary, preterm neonates have significant disturbances in neutrophil chemotaxis compared to term neonates and adults, and these differences in phenotype appear at the transcriptional level to target inflammatory pathways in general, rather than in neutrophil migration and chemotaxis.

Severe injury and shock remain major sources of morbidity and mortality worldwide. Immunologic dysregulation following trauma contributes to these poor outcomes. Few, if any, therapeutic interventions have benefited these patients, and this is due to our limited understanding of the host response to injury and shock. The Food and Drug Administration requires preclinical animal studies prior to any interventional trials in humans; thus, animal models of injury and shock will remain the mainstay for trauma research. However, adequate animal models that reflect the severe response to trauma in both the acute and subacute phases have been limited. Here we describe a novel murine model of polytrauma and shock that combines hemorrhagic shock, cecectomy, long bone fracture, and soft-tissue damage. This model produces an equivalent Injury Severity Score associated with adverse outcomes in humans, and may better recapitulate the human leukocyte, cytokine, transcriptomic, and overall inflammatory response following injury and hemorrhagic shock.

Background The neonatal innate immune system differs to microbial infection both quantitatively and qualitatively when compared to adults. Here, we provide the first genome-wide ex-vivo expression profile of umbilical cord blood (UCB) neutrophils from full-term infants prior to and in response to whole-blood LPS stimulation. Additionally, we provide cytokine expression prior to and following LPS stimulation. The genomic expression and cytokine profile are compared to LPS-stimulated whole blood from healthy adult subjects (HC). Methods Whole blood from UCB (n=6) and HC (n=6) was studied at baseline or was stimulated for 24 hours with 100 ngs/ml of lipopolysaccharide (LPS). CD66b+ neutrophils were subsequently isolated with microfluidic techniques and genome-wide expression analyses were performed. Ingenuity Pathway Analysis (IPA) software was utilized to predict downstream functional effects. Additionally, cytokine concentrations in whole blood prior to and after 24 hours of LPS incubation were determined. Results LPS stimulated whole blood from UCB demonstrated significant differences in both ex-vivo cytokine production and PMN gene expression. Mixed-effect modeling identified 1153 genes whose expression changed significantly in UCB and HC after exposure to LPS (p<0.001 with a minimum 1.5-fold change). IPA downstream predictions suggest that PMNs from UCB fail to effectively upregulate genes associated with activation, phagocytosis, and chemotaxis in response to LPS stimulation. Furthermore, whole blood from UCB showed increased IL-10 production to LPS, but failed to significantly increase several pro-inflammatory cytokines. Conclusions LPS-stimulated whole blood from UCB exhibited a markedly suppressed inflammatory cytokine production and PMN innate immune genome response. These differences in gene expression and cytokine production may be an adaptive response to a prior fetal environment, but may also explain their increased susceptibility to infections. Characterization of these deficits is the first step towards developing prophylactic and therapeutic interventions.