Robert D. Winfield

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell-directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b(+) cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality.

Sepsis Induces Early Alterations in Innate Immunity That Impact Mortality to Secondary Infection

Sepsis, the systemic inflammatory response to microbial infection, induces changes in both innate and adaptive immunity that presumably lead to increased susceptibility to secondary infections, multiorgan failure, and death. Using a model of murine polymicrobial sepsis whose severity approximates human sepsis, we examined outcomes and defined requirements for survival after secondary Pseudomonas aeruginosa pneumonia or disseminated Listeria monocytogenes infection. We demonstrate that early after sepsis neutrophil numbers and function are decreased, whereas monocyte recruitment through the CCR2/MCP-1 pathway and function are enhanced. Consequently, lethality to Pseudomonas pneumonia is increased early but not late after induction of sepsis. In contrast, lethality to listeriosis, whose eradication is dependent upon monocyte/macrophage phagocytosis, is actually decreased both early and late after sepsis. Adaptive immunity plays little role in these secondary infectious responses. This study demonstrates that sepsis promotes selective early, impaired innate immune responses, primarily in neutrophils, that lead to a pathogen-specific, increased susceptibility to secondary infections.

Neutrophil Mobilization from the Bone Marrow during Polymicrobial Sepsis Is Dependent on CXCL12 Signaling

Neutrophils are essential for successful host eradication of bacterial pathogens and for survival to polymicrobial sepsis. During inflammation, the bone marrow provides a large reserve of neutrophils that are released into the peripheral circulation where they traverse to sites of infection. Although neutrophils are essential for survival, few studies have investigated the mechanisms responsible for neutrophil mobilization from the bone marrow during polymicrobial sepsis. Using a cecal ligation and puncture model of polymicrobial sepsis, we demonstrated that neutrophil mobilization from the bone marrow is not dependent on TLR4, MyD88, TRIF, IFNARα/β, or CXCR2 pathway signaling during sepsis. In contrast, we observed that bone marrow CXCL12 mRNA abundance and specific CXCL12 levels are sharply reduced, whereas splenic CXCR4 mRNA and cell surface expression are increased during sepsis. Blocking CXCL12 activity significantly reduced blood neutrophilia by inhibiting bone marrow release of granulocytes during sepsis. However, CXCL12 inhibition had no impact on the expansion of bone marrow neutrophil precursors and hematopoietic progenitors. Bone marrow neutrophil retention by CXCL12 blockade prevented blood neutrophilia, inhibited peritoneal neutrophil accumulation, allowed significant peritoneal bacterial invasion, and increased polymicrobial sepsis mortality. We concluded that changes in the pattern of CXCL12 signaling during sepsis are essential for neutrophil bone marrow mobilization and host survival but have little impact on bone marrow granulopoiesis.

Differences in outcome between obese and nonobese patients following severe blunt trauma are not consistent with an early inflammatory genomic response.

Objectives:Obesity has been demonstrated to alter a number of acute and chronic medical conditions. The effect of obesity on severely injured patients, however, remains incompletely defined. We sought to unravel potential physiologic and genomic alterations induced by obesity in severely injured blunt trauma patients. Design:A retrospective review of clinical and genomic information contained in the Inflammation and the Host Response to Injury multicenter trauma-related database examining the relationship between body mass index and the early genomic response from peripheral blood leukocytes to patient outcome following severe blunt trauma was performed. Setting:Multicenter collaboration between university-based academic trauma centers. Patients:Severely injured blunt trauma patients enrolled in the database. Interventions:None. Measurements and Main Results:Univariate analysis of 455 severely injured trauma patients using the National Institutes of Health/World Health Organization body mass index classification system revealed significant increases in morbidity, including longer intensive care unit stays and a greater number of ventilator days, cardiac arrests, episodes of acute renal failure, and patients developing multiple organ failure. Regression modeling identified body mass index class as being independently associated with adverse outcomes and increased morbidity but an inverse relationship with mortality in patients who suffered severe blunt traumatic injury. Initial leukocyte genomic expression patterns between 163 patients in the four different body mass index groupings did not differ; however, analysis of gene differences between body mass index classes occurring over time demonstrated significant changes in 513 probe sets with significant pathway differences being related to cellular metabolism. Conclusions:Increasing body mass index is associated with increased morbidity following severe blunt trauma. The initial blood leukocyte inflammatory response to blunt trauma does not appear to differ significantly between patients despite increasing body mass index. Resolution of the inflammatory response may differ between patients on the basis of body mass index; however, additional work is needed to clarify the potential causality of this finding.

Traditional resuscitative practices fail to resolve metabolic acidosis in morbidly obese patients after severe blunt trauma.

BACKGROUND Obesity is a risk factor for postinjury complications; in particular, obese patients develop multiple organ failure (MOF) at a greater rate than do normal weight counterparts. Evaluation of differences in resuscitative practices altered by body mass index (BMI) might provide an explanation for the increased risk of MOF seen in these high-risk patients. METHODS We used prospectively collected multicenter data to retrospectively compare patients grouped by BMI with regard to resuscitation volumes and traditional end points during the first 48 hours after injury. Marshall MOF score was used as the primary outcome measure. RESULTS One thousand sixty-six patients were analyzed, with 877 meeting inclusion and exclusion criteria. All patients received similar volumes of resuscitation per kilogram lean and ideal body weight. Morbidly obese patients attained greater central venous pressures but otherwise differed little in attainment of standard cardiovascular end points. Despite this, morbidly obese patients resolved base deficit more slowly and remained in metabolic acidosis for 48 hours postinjury. Morbidly obese patients with persistent metabolic acidosis developed MOF at a significantly greater rate than did normal weight patients with or without persistent metabolic acidosis. CONCLUSIONS Morbidly obese trauma patients show prolonged metabolic acidosis despite receiving similar volumes and attaining similar end points of resuscitation when compared with patients in other BMI groups. Inadequate resuscitation based on inaccurate end points and metabolic disturbances associated with increased BMI are likely responsible; identification of the etiology, sources, and consequences of this acidosis may provide further insight into the susceptibility of the morbidly obese patient to develop postinjury organ failure.

Dose adjusting enoxaparin is necessary to achieve adequate venous thromboembolism prophylaxis in trauma patients.

BACKGROUND Standard venous thromboembolism (VTE) prophylaxis with enoxaparin results in inadequate protection in certain patients, with subtherapeutic plasma anti-Xa levels associated with elevated VTE rates. We hypothesized that many trauma patients would be subtherapeutic on the standard prophylactic dose of enoxaparin. Our goal was to adjust the enoxaparin dose to achieve target anti-Xa levels to take advantage of the drug based on its pharmacologic properties. METHODS Patients admitted to the trauma service were included if they received at least three doses of prophylactic enoxaparin and underwent at least two screening venous duplex. Peak plasma anti-Xa levels of 0.2 IU/mL or less were considered low, and the dose was increased by 10 mg twice daily until adequate anti-Xa levels were obtained. A strict screening venous duplex protocol was followed. Patients were excluded if they were diagnosed with a deep venous thrombosis before beginning enoxaparin or did not have correctly timed anti-Xa levels. RESULTS Sixty-one trauma patients met inclusion criteria. There were three patients diagnosed with VTE (4.9%). Patients had a mean age of 45.9 years and were predominantly male (70.5%). Of the 61 patients, 18 (29.5%) had therapeutic anti-Xa levels on standard enoxaparin 30 mg twice daily. Compared with patients who had therapeutic anti-Xa levels on enoxaparin 30 mg twice daily, the 43 patients (70.5%) who were subtherapeutic were more likely to be male, have greater body weight, and larger body surface area. There were no significant bleeding events in the group that received an enoxaparin dose adjustment. CONCLUSION Most patients had subtherapeutic anti-Xa levels while on enoxaparin 30 mg twice daily, suggesting inadequate VTE prophylaxis. The need for routine use of a higher dose of prophylactic enoxaparin in trauma patients and the effects of routinely dose adjusting enoxaparin on VTE rates should be the study of future prospective, randomized trials. LEVEL OF EVIDENCE Therapeutic study, level IV.

Novel Role for Tumor-Induced Expansion of Myeloid-Derived Cells in Cancer Cachexia

Cancer progression is associated with inflammation, increased metabolic demand, infection, cachexia, and eventually death. Myeloid-derived suppressor cells (MDSCs) commonly expand during cancer and are associated with adaptive immune suppression and inflammatory metabolite production. We propose that cancer-induced cachexia is driven at least in part by the expansion of MDSCs. MDSC expansion in 4T1 mammary carcinoma-bearing hosts is associated with induction of a hepatic acute-phase protein response and altered host energy and fat metabolism, and eventually reduced survival to polymicrobial sepsis and endotoxemia. Similar results are also seen in mice bearing a Lewis lung carcinoma and a C26 colon adenocarcinoma. However, a similar cachexia response is not seen with equivalent growth of the 66C4 subclone of 4T1, in which MDSC expansion does not occur. Importantly, reducing MDSC numbers in 4T1-bearing animals can ameliorate some of these late responses and reduce susceptibility to inflammation-induced organ injury and death. In addition, administering MDSCs from both tumor- and nontumor-bearing mice can produce an acute-phase response. Thus, we propose a previously undescribed mechanism for the development of cancer cachexia, whereby progressive MDSC expansion contributes to changes in host protein and energy metabolism and reduced resistance to infection.

Obese patients show a depressed cytokine profile following severe blunt injury.

ABSTRACT We hypothesized that severely injured obese patients would display increased concentrations of proinflammatory cytokines when compared with patients of normal body mass index (BMI) and that this would be associated with multiple organ failure (MOF). This was a retrospective review of prospectively collected data in the “Inflammation and the Host Response to Injury” trauma-related database. Data were collected prospectively from US level I trauma centers. The subjects were severely injured adult blunt trauma patients. Cytokine concentrations obtained within 12 h of injury and on days 1 and 4 were compared between subjects on the basis of BMI (normal, 18.5–24.9 kg/m2, and obese, ≥30 kg/m2). Demographic measures, injury severity, cytokine concentrations, and outcome measures were compared between groups. Seventy-four adult blunt trauma victims were evaluated. Relative to patients of normal BMI (n = 34), obese patients (n = 40) demonstrated an overall depressed cytokine response to severe injury, with significantly lower concentrations of several cytokines. Obese patients showed greater incidences of nosocomial infection (60 vs. 45%, not statistically significant) and MOF (63% vs. 44%, not statistically significant) and a later onset of maximum MOF score (5 vs. 3 days, P < 0.04) when compared with those of normal BMI. Despite prior reports suggesting a proinflammatory cytokine profile in obese individuals, obese patients sustaining severe injury show a depressed early cytokine response when compared with patients of normal BMI. This may confer increased susceptibility to nosocomial infection and later MOF. Further study of immune dysfunction in the postinjury obese patient should assess the possibility of early immune suppression.

Myeloid-derived suppressor cells in cancer cachexia syndrome: A new explanation for an old problem

Cachexia accompanies many chronic inflammatory diseases, including cancer. Lean tissue wasting is only one component of the cancer cachexia response, which also includes anemia, anorexia, a hepatic acute phase protein response, and increased susceptibility to secondary infections. The etiologies of cancer cachexia are multifactorial and include an overproduction of inflammatory mediators, including cytokines produced by inappropriate activation of innate immunity. However, anticytokine therapies have generally not been seriously considered for cancer cachexia, in large part because of the overlapping activities of several inflammatory cytokines and the inability to prospectively identify the contributions of individual mediators. In contrast, recent evidence has focused on an immature myeloid cell population that expands dramatically in the tumors and secondary lymphoid organs of animals with some actively growing tumors. These immature GR-1(+)CD11b(+) cells are metabolically active and secrete large quantities of inflammatory cytokines and chemokines with the potential to produce cachexia. Their expansion is temporally associated with the development of cachexia. Future studies are required to determine whether therapeutic efforts intended to block the expansion of these cells can prevent the lean tissue wasting that accompanies active tumor growth.

Ashes, embers, and coals: significant sources of burn-related morbidity in children.

Burn injuries remain the leading source of pediatric morbidity and mortality, with burns to the feet presenting unique management challenges. Characterization of the etiology of these burns may identify strategies for injury prevention. A retrospective review of pediatric patients with isolated foot burns was performed. Between September 1992 and February 2006, 155 patients were admitted with isolated foot burns. The majority (69%) of these injuries resulted from walking on hot ashes, with the remainder being from scald, flame, or contact burns. The median percent TBSA burned was similar in ash and nonash burns, but median LOS was 1 day less in ash burns. Children with ash burns were significantly older and less likely to have full thickness burns than children with nonash burns. Patients with ash burns were also less likely to require excision and grafting than those who were burned by other mechanisms. Both short and long-term complications were infrequent. Although ash burns tend to be more superficial than burns of other etiologies and are associated with a shorter length of stay, they often require surgical intervention. Because of their relative frequency and severity, ash burns to the feet warrant attention as an area for preventive focus.