The Cutaneous Wound Innate Immunological Microenvironment.

The skin represents the first line of defense and innate immune protection against pathogens. Skin normally provides a physical barrier to prevent infection by pathogens; however, wounds, microinjuries, and minor barrier impediments can present open avenues for invasion through the skin. Accordingly, wound repair and protection from invading pathogens are essential processes in successful skin barrier regeneration. To repair and protect wounds, skin promotes the development of a specific and complex immunological microenvironment within and surrounding the disrupted tissue. This immune microenvironment includes both innate and adaptive processes, including immune cell recruitment to the wound and secretion of extracellular factors that can act directly to promote wound closure and wound antimicrobial defense. Recent work has shown that this immune microenvironment also varies according to the specific context of the wound: the microbiome, neuroimmune signaling, environmental effects, and age play roles in altering the innate immune response to wounding. This review will focus on the role of these factors in shaping the cutaneous microenvironment and how this ultimately impacts the immune response to wounding.

The gut microbiome distinguishes mortality in trauma patients upon admission to the emergency department.

BACKGROUND: Traumatic injury can lead to a compromised intestinal epithelial barrier, decreased gut perfusion, and inflammation. While recent studies indicate that the gut microbiome (GM) is altered early following traumatic injury, the impact of GM changes on clinical outcomes remains unknown. Our objective of this follow-up study was to determine if the GM is associated with clinical outcomes in critically injured patients. METHODS: We conducted a prospective, observational study in adult patients (N = 67) sustaining severe injury admitted to a level I trauma center. Fecal specimens were collected on admission to the emergency department, and microbial DNA from all samples was analyzed using the Quantitative Insights Into Microbial Ecology pipeline and compared against the Greengenes database. α-Diversity and ß-diversity were estimated using the observed species metrics and analyzed with t tests and permutational analysis of variance for overall significance, with post hoc pairwise analyses. RESULTS: Our patient population consisted of 63% males with a mean age of 44 years. Seventy-eight percent of the patients suffered blunt trauma with 22% undergoing penetrating injuries. The mean body mass index was 26.9 kg/m. Significant differences in admission ß-diversity were noted by hospital length of stay, intensive care unit hospital length of stay, number of days on the ventilator, infections, and acute respiratory distress syndrome (p < 0.05). ß-Diversity on admission differed in patients who died compared with patients who lived (mean time to death, 8 days). There were also significantly less operational taxonomic units in samples from patients who died versus those who survived. A number of species were enriched in the GM of injured patients who died, which included some traditionally probiotic species such as Akkermansia muciniphilia, Oxalobacter formigenes, and Eubacterium biforme (p < 0.05). CONCLUSION: Gut microbiome diversity on admission in severely injured patients is predictive of a variety of clinically important outcomes. While our study does not address causality, the GM of trauma patients may provide valuable diagnostic and therapeutic targets for the care of injured patients. LEVEL OF EVIDENCE: Prognostic and epidemiological, level III.

Facing the facts on prophylactic antibiotics for facial fractures: 1 day or less.

BACKGROUND: To evaluate the role of initial prophylactic antibiotics on facial fractures, outcomes were compared between a short course (≤24 hours) of antibiotics to those who received an extended course (>24 hours). METHODS: Adults admitted (2010-2015) to a Level I trauma center intensive care unit with at least one facial bone fracture and major injuries isolated to the head and neck were included. Our primary analysis compared infectious complications of the head or neck (H/N infection) between patients given short or extended courses of antibiotic prophylaxis. Multivariate logistic regression and analysis of propensity score matched pairs were performed. RESULTS: A total of 403 patients were included, 85.6% had blunt injuries and 72.7% had their facial fracture managed nonoperatively. The H/N infection rate was 11.2%. Two hundred eighty patients received a short course of antibiotics and 123 patients received an extended course. Median Injury Severity Score was 14 in both groups (p = 0.78). Patients receiving an extended course of antibiotics had higher rates of H/N infection (20.3% vs. 7.1%, p < 0.001). Factors associated with development of H/N infection included younger age, penetrating injury, open fracture, upper face or mandible fracture, fractures in multiple facial thirds, vascular injury, hypertension, and extended antibiotic course. Multivariate logistic regression identified younger age (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.96-1.00; p = 0.02), multiple facial third fractures (OR, 4.9; 95% CI, 2.4-10.2; p < 0.001), and penetrating mechanism (OR, 3.1; 95% CI, 1.5-6.4; p = 0.003) as independent predictors of H/N infection, but not antibiotic duration. Propensity score-matched analysis found no differences in H/N infection between short and extended antibiotic courses (11.4% vs. 12.5%; p = 1.0). Subgroup analyses demonstrated no differences in H/N infection between short or extended antibiotic courses by injury pattern, mechanism, or treatment (operative or nonoperative). CONCLUSION: These results lead us to believe that we should limit antibiotics to 24 hours or less upon admission for facial fractures. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Neutralizing Alpha-Toxin Accelerates Healing of Staphylococcus aureus-Infected Wounds in Nondiabetic and Diabetic Mice.

Staphylococcus aureus wound infections delay healing and result in invasive complications such as osteomyelitis, especially in the setting of diabetic foot ulcers. In preclinical animal models of S. aureus skin infection, antibody neutralization of alpha-toxin (AT), an S. aureus-secreted pore-forming cytolytic toxin, reduces disease severity by inhibiting skin necrosis and restoring effective host immune responses. However, whether therapeutic neutralization of alpha-toxin is effective against S. aureus-infected wounds is unclear. Herein, the efficacy of prophylactic treatment with a human neutralizing anti-AT monoclonal antibody (MAb) was evaluated in an S. aureus skin wound infection model in nondiabetic and diabetic mice. In both nondiabetic and diabetic mice, anti-AT MAb treatment decreased wound size and bacterial burden and enhanced reepithelialization and wound resolution compared to control MAb treatment. Anti-AT MAb had distinctive effects on the host immune response, including decreased neutrophil and increased monocyte and macrophage infiltrates in nondiabetic mice and decreased neutrophil extracellular traps (NETs) in diabetic mice. Similar therapeutic efficacy was achieved with an active vaccine targeting AT. Taken together, neutralization of AT had a therapeutic effect against S. aureus-infected wounds in both nondiabetic and diabetic mice that was associated with differential effects on the host immune response.

An aggressive and fatal craniofacial group A Streptococcus infection resulting from a minimally displaced orbital floor fracture.

While sharp, penetrating trauma is often associated with group A Streptococcus (GAS) infections and subsequent necrotizing fasciitis (NF) and streptococcal toxic shock syndrome (STSS), there are scant reports in the oral and maxillofacial surgery literature regarding blunt, non-penetrating trauma in association with these conditions. With a clinical course that initially appears relatively benign following blunt trauma, NF can progress swiftly through the fascial planes and may quickly become life-threatening if the oral and maxillofacial surgeon fails to recognize some of the critical pathognomonic signs. The case of a 64-year-old female who suffered a ground-level mechanical fall with a minimally displaced lateral orbital wall fracture is reported here. This seemingly benign, non-penetrating injury subsequently developed into rapidly progressive, fatal NF and STSS. This case is used to highlight the necessity for early detection of NF and STSS prior to rapid clinical decline, as these scenarios, particularly bilateral peri-orbital NF with resulting mortality, have been reported infrequently following blunt, craniofacial trauma in the literature related to this specialty.

Protective effect of hypothermia in a blunt thoracic trauma and hemorrhagic shock model.

BACKGROUND: The aim of this study was to investigate the effect of volume-controlled hemorrhage and hypothermia on rats with blunt chest trauma, evaluating bacterial translocation (BT), lung tissue malondialdehyde (MDA), nitric oxide (NO) levels, and erythrocyte deformability (ED). METHODS: In our study, 10 animals each were included in 6 groups. Groups were as follows: a group with blunt chest trauma only (Group T), a group with hemorrhage only (Group H), a normothermic group with comorbidity of trauma and hemorrhage (Group NT), a mild hypothermic group with trauma and hemorrhage (Group MH), a moderate hypothermic group with trauma and hemorrhage (Group MoH), and a control group (Group C). Sodium pentobarbital (50 mg/kg, intraperitoneally) anesthesia was administered. Thoracic trauma was generated using kinetic energy at the middle of the chest (2.45 J). Stage 3 hemorrhagic shock was initiated. After 24 hours, the rats were killed and red blood cell deformability, BT development in the liver, spleen, and mesenteric lymph nodes, and NO and MDA levels in lung tissue, kept at -80°C, were measured. RESULTS: In Groups MH and MoH, there was no difference in ED values, though they were lower than those in Group NT (p<0.05). BT was more prevalent in Group NT than in the other groups. In Group NT, the growth of BT was greater than in other groups (p<0.05). The level of NO in Group H was higher than in the control group (p<0.05). In Group MoH, the level of MDA was lower than in Group MH (p<0.05). CONCLUSION: Hypothermia seems to demonstrate protective effects on ED and BT by reducing oxidative stress. The protective effects of therapeutic hypothermia on ED may be due to the effect of reducing NO and/or MDA. There was no difference in effect between mild and moderate hypothermia in terms of the formation of ED and BT.

The role of thoracic trauma in inflammatory responses, apoptosis and bacterial translocation following multiple traumas.

BACKGROUND: Blunt chest trauma and its complications are commonly encountered in emergency medicine. Herein, we used a rat model to investigate the role of thoracic trauma in inflammation, apoptosis and bacterial translocation following multiple traumas. METHODS: Ninety Wistar rats were divided equally into nine groups. Rats underwent a standardized blunt thoracic and/or head trauma and were sacrificed 24 or 48 hours after the trauma. Specimens from various organs and blood samples were collected and quantitatively cultured for aerobic organisms. Interleukins, TNF-α, and MCP-1 levels were assessed in the sera and markers of apoptosis were detected in the lungs. RESULTS: Levels of interleukins, TNF-α and MCP-1 in all of the groups undergoing trauma were significantly higher than those of the control group (p=0.001). Levels of apoptotic cells in the groups undergoing head and thoracic trauma (HTT) were significantly higher than those of the control group (p=0.009). Light microscopic evaluation indicated that damage in the HTT groups was significantly higher than that in the control group. The incidence of bacterial translocation was also significantly higher in the HTT groups (p=0.003). CONCLUSION: Multiple inflammatory mediators are activated in multiple traumas (including blunt thoracic trauma), which allow bacterial translocation and apoptotic processes to occur. Our results indicate that thoracic trauma plays a major role in post-traumatic bacterial translocation, inflammation, and apoptosis following multiple traumas.

Increased apoptosis of peripheral blood neutrophils is associated with reduced incidence of infection in trauma patients with hemorrhagic shock.

OBJECTIVE: We aimed to describe the relationship between early peripheral leukocyte apoptosis and incidence of subsequent infection in trauma patients with hemorrhagic shock (T/HS). METHODS: T/HS patients requiring emergency surgery were prospectively enrolled. Nucleosome ELISA and TUNEL staining were performed on peripheral blood drawn pre-operatively, post-operatively and at 24 h. Subjects were followed for 30 days or until death or hospital discharge to record all episodes of infection. RESULTS: Forty-one subjects were enrolled. Six died within 24 h of surgery and were not included in the analysis. Nucleosome levels peaked post-operatively and dropped to baseline levels at 24 h (p = 0.03). TUNEL analysis revealed that polymorphonuclear neutrophils (PMNs) accounted for 72% of apoptotic leukocytes; the remaining apoptotic cells were mainly lymphocytes. Increased post-operative leukocyte apoptosis was associated with decreased systemic inflammatory response syndrome (SIRS) severity. Seventeen of the 35 survivors (48.6%) developed infections, while 18 (51.4%) did not. Pre-operative and post-operative nucleosome levels were 2.5 and 3 times higher, respectively, in T/HS patients who did not develop infection compared to those who did. Increased nucleosome levels were associated in particular with protection against sepsis (p=0.03) and multiple infections (p = 0.01). CONCLUSION: Peripheral blood PMN apoptosis in the early resuscitative period is associated with decreased incidence of subsequent infection in T/HS patients.

A genomic analysis of Clostridium difficile infections in blunt trauma patients.

BACKGROUND: Evidence demonstrates that susceptibility to Clostridium difficile infection is related to host risk factors as much as bacterial potency. Using blood leukocyte genome-wide expression patterns of severe blunt trauma patients obtained by the National Institute of General Medical Sciences-sponsored Glue Grant Inflammation and the Host Response to Injury, we examined leukocyte genomic profiles of patients with C. difficile infection to determine preinfection and postinfection gene expression changes. METHODS: The genomic responses of 21 severe trauma patients were analyzed (5 C. difficile, 16 controls matched for age and severity of injury). After elimination of probe sets whose expression was below baseline or were unchanged, remaining probe sets underwent hierarchical clustering and principal component analysis. Molecular pathways were generated through Ingenuity Pathways Analysis. RESULTS: Supervised analysis demonstrated 118 genes whose expression in patients with C. difficile infection varied before and after their infection. Supervised analysis comparing patients with C. difficile infection with matched non-C. difficile patients before infection suggested that the expression of 501 genes were different in the two groups with up to 87% class prediction (p < 0.05). Many of these genes are related to cell-mediated immune responses, signaling, and interaction. CONCLUSION: Genomic analysis of severe blunt trauma patients reveals a distinct leukocyte expression profile of C. difficile both before and after infection. We conclude that an association may exist between a severe trauma patient's leukocyte genomic expression profile and subsequent susceptibility to C. difficile infection. Further prospective expression analysis of this C. difficile population may reveal potential therapeutic interventions and allow early identification of C. difficile-susceptible patients. LEVEL OF EVIDENCE: Prognostic/diagnostic study, level III.

Blunt trauma as a cause of rib chondro-osteitis: a case study.

Rib chondro-osteitis is rare and usually caused by tuberculosis. A 63-year-old man presented with fever, painful swelling, and a burning sensation in the parasternal right submammary region. He had a history of cardiac interventions: percutaneous transcatheter angioplasty with stenting 1 year prior and coronary artery bypass graft surgery 16 years before; therefore, he was on dual antiplatelet therapy. He sustained blunt chest trauma 5 months before admission. A chest wall abscess was suspected and fine needle aspiration of the lesion revealed the presence of purulent fluid. Culture results were positive for Staphylococcus aureus and intravenous antibiotic therapy was started. Computed tomography showed a lesion involving the sternal, chondral, and proximal costal portions of the fourth, fifth, and sixth anterior costal arches. The patient was diagnosed with costal chondo-osteitis following blunt trauma. Following aggressive surgical debridement, the wound was managed with topical negative pressure therapy (constant -125 mm Hg setting with daily dressing changes). After 15 days, culture results were negative, the wound bed contained healthy granulation tissue, and the defect was surgically closed using a myocutaneous flap. No recurrence or complications have been observed during the 2-year follow-up. This is the first reported case of pyogenic, posttraumatic, costal chondro-osteitis secondary to a blunt trauma of the chest wall.

Endophthalmitis caused by Stenotrophomonas maltophilia.

BACKGROUND AND OBJECTIVE: The authors investigate clinical settings, antibiotic susceptibility and resistance patterns, and visual outcomes associated with endophthalmitis caused by Stenotrophomonas maltophilia. PATIENTS AND METHODS: Records of six patients with S. maltophilia endophthalmitis between January 1, 1998, and December 31, 2007, were reviewed. RESULTS: Clinical settings included post-trauma (2 eyes), post-cataract extraction (2 eyes), post-keratoplasty with keratitis (1 eye), and post-vitreous lavage (1 eye). Presenting visual acuity ranged from counting fingers to no light perception. Final visual acuity ranged from 10/20 to no light perception. Initial treatment included pars plana vitrectomy in 4 eyes and tap in 2 eyes. Most isolates were susceptible to fluoroquinolones (ciprofloxacin, levofloxacin, or moxifloxacin) and sulfamethoxazole-trimethoprim; however, they were resistant to ceftazidime and aminoglycosides. CONCLUSION: S. maltophilia is an uncommon causative agent of endophthalmitis and is resistant to commonly used antibiotics, such as ceftazidime and aminoglycosides. Based on in vitro antibiotic susceptibility testing, sulfamethoxazole-trimethoprim and new-generation fluoroquinolones may be preferable in the treatment of endophthalmitis caused by S. maltophilia.

Intact autocrine activation and cytokine production by PMNs from injured adults with elevated Candida antigen titres.

Injured patients with Candida antigen titres have increased mortality due to sepsis. Polymorphonuclear leucocytes (PMNs) from injured patients with elevated Candida antigen titres demonstrate impaired function against Candida albicans growth when compared with PMNs from injury matched controls. To determine if PMN dysfunction is global, PMNs from patients with positive Candida antigen titres were evaluated for their ability to activate the anticandidal function of normal PMNs (autocrine activation) and to produce tumour necrosis factor (TNF) and interleukin 8 (IL8), known activators of PMN anticandidal function, this study demonstrates that the PMN dysfunction is not global, as PMN cytokine production and autocrine activation remain intact.

Candida antigen titre dilution and death after injury.

BACKGROUND: Candida infections affect outcome after injury. Candida antigen titres were used to detect these infections early. This study was undertaken to correlate Candida antigen titre dilution with conventional injury scoring and outcome after severe injury. METHODS: Candida antigen titres were determined by agglutination when clinically apparent source(s) of Candida were noted, when Candida was grown in culture of body fluids, or when unexplained clinical deterioration occurred. The findings were compared with the Injury Severity Score (ISS). RESULTS: Seventy-five seriously injured adults (median ISS 25 (range 18-50)) developed raised Candida antigen titres. Multivariate analysis showed that age and Candida antigen titre correlated significantly with mortality, but not with each other. Culture evidence of Candida, or lack thereof, did not correlate with Candida antigen titre or mortality. Sixteen of 75 patients died, 14 from bacterial sepsis and none from Candida infection. CONCLUSION: In seriously injured adults, the mortality rate is related to raised Candida antigen titres. The association between Candida antigen titre and mortality, although real, remains unexplained.