Luke P. H. Leenen

A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1

Suppression of immune responses is necessary to limit damage to host tissue during inflammation, but it can be detrimental in specific immune responses, such as sepsis and antitumor immunity. Recently, immature myeloid cells have been implicated in the suppression of immune responses in mouse models of cancer, infectious disease, bone marrow transplantation, and autoimmune disease. Here, we report the identification of a subset of mature human neutrophils (CD11cbright/CD62Ldim/CD11bbright/CD16bright) as what we believe to be a unique circulating population of myeloid cells, capable of suppressing human T cell proliferation. These cells were observed in humans in vivo during acute systemic inflammation induced by endotoxin challenge or by severe injury. Local release of hydrogen peroxide from the neutrophils into the immunological synapse between the neutrophils and T cells mediated the suppression of T cell proliferation and required neutrophil expression of the integrin Mac-1 (αMβ2). Our data demonstrate that suppression of T cell function can be accomplished by a subset of human neutrophils that can be systemically induced in response to acute inflammation. Identification of the pivotal role of neutrophil Mac-1 and ROS in this process provides a potential target for modulating immune responses in humans.

Functional heterogeneity and differential priming of circulating neutrophils in human experimental endotoxemia

Neutrophils play an important role in host defense. However, deregulation of neutrophils contributes to tissue damage in severe systemic inflammation. In contrast to complications mediated by an overactive neutrophil compartment, severe systemic inflammation is a risk factor for development of immune suppression and as a result, infectious complications. The role of neutrophils in this clinical paradox is poorly understood, and in this study, we tested whether this paradox could be explained by distinct neutrophil subsets and their functionality. We studied the circulating neutrophil compartment immediately after induction of systemic inflammation by administering 2 ng/kg Escherichia coli LPS i.v. to healthy volunteers. Neutrophils were phenotyped by expression of membrane receptors visualized by flow cytometry, capacity to interact with fluorescently labeled microbes, and activation of the NADPH‐oxidase by oxidation of Amplex Red and dihydrorhodamine. After induction of systemic inflammation, expression of membrane receptors on neutrophils, such as CXCR1 and ‐2 (IL‐8Rs), C5aR, FcγRII, and TLR4, was decreased. Neutrophils were also refractory to fMLF‐induced up‐regulation of membrane receptors, and suppression of antimicrobial function was shown by decreased interaction with Staphylococcus epidermis. Simultaneously, activation of circulating neutrophils was demonstrated by a threefold increase in release of ROS. The paradoxical phenotype can be explained by the selective priming of the respiratory burst. In contrast, newly released, CD16dim banded neutrophils display decreased antimicrobial function. We conclude that systemic inflammation leads to a functionally heterogeneous neutrophil compartment, in which newly released refractory neutrophils can cause susceptibility to infections, and activated, differentiated neutrophils can mediate tissue damage.

Systemic inflammation and fracture healing

Apart from their pivotal role in the host defense against pathogens, leukocytes are also essential for bone repair, as fracture healing is initiated and directed by a physiological inflammatory response. Leukocytes infiltrate the fracture hematoma and produce several growth and differentiation factors that regulate essential downstream processes of fracture healing. Systemic inflammation alters the numbers and properties of circulating leukocytes, and we hypothesize that these changes are maintained in tissue leukocytes and will lead to impairment of fracture healing after major trauma. The underlying mechanisms will be discussed in this review.

Do designated trauma systems improve outcome

Purpose of reviewTrauma systems are introduced world wide with the goal to improve survival and outcome of the injured patient. This review is focused on the influence of trauma systems on the survival and outcome of injured patients. Recent findingsLarge population-based studies have been published over the last 2 years strengthening the hypothesis that trauma systems indeed improve survival rates in injured patients. Mortality was reduced by 15–25% when severely injured patients were treated at a trauma center. Although ‘inclusive’ trauma systems have been advocated since 1991 only recently did the first population-based study prove that ‘inclusive’ trauma systems do better than ‘exclusive’ trauma systems. Because further improvements in survival in mature trauma systems are likely to be small, more focus should be given to quality of life studies, rather than to survival in trauma system evaluation. SummaryTrauma systems indeed improve survival rates in injured patients. Inclusive trauma systems do better than exclusive trauma systems. More attention should be given to quality of outcome.

Regional trauma system reduces mortality and changes admission rates: a before and after study.

Objective:To evaluate the effect of the introduction of a regionalized trauma system. Background:Trauma systems have proven to be efficacious in reducing mortality in trauma patients in the United States. To date, this was not proven for inclusive trauma systems outside the United States. The current study evaluates the effect of the introduction of an inclusive trauma system in the Netherlands in 1999. Methods:Retrospective pre- and post analyses of a trauma care system on hospital discharge data regarding trauma patients admitted to hospitals in the central region of The Netherlands. Patients treated during 1996 to 1998 (control group), before implementation of the inclusive trauma system were compared with patients treated during 2003 to 2005 (index group) after the trauma system was installed. Risk adjusted odds-ratios of death and admission to a trauma center were determined. Results:A total of 33,201 patients were included in the control group and compared with 34,840 patients in the index group. After implementation of the trauma system, in-hospital mortality for all injured patients decreased from 2.6% to 2.3% (OR: 0.89 with 95% CI: 0.80–0.98). After adjustment for differences in gender, age, injury severity, comorbidity, injured body region, mechanism and intent of injury between both groups, the odds-ratio was 0.84 with 95% CI (0.76–0.94). Multitrauma patients were the subgroup admitted more frequently to a trauma center (OR: 1.19 with 95% CI: 1.01–1.39). Conclusions:Implementation of an inclusive trauma system in The Netherlands results in a more efficient triage system of trauma patients among hospitals and is associated with a substantial and statistically significant risk reduction (16%) of death.

The definition of polytrauma revisited: An international consensus process and proposal of the new 'Berlin definition'

BACKGROUND The nomenclature for patients with multiple injuries with high mortality rates is highly variable, and there is a lack of a uniform definition of the term polytrauma. A consensus process was therefore initiated by a panel of international experts with the goal of assessing an improved, database-supported definition for the polytraumatized patient. METHODS The consensus process involved the following:1. Expert panel. Multiple meetings and consensus discussions (members: European Society for Trauma and Emergency Surgery [ESTES], American Association for the Surgery of Trauma [AAST], German Trauma Society [DGU], and British Trauma Society [BTS]).2. Literature review (original articles before June 8, 2014).3. A priori assumptions by the expert panel. The basis for a new definition should include the Injury Severity Score (ISS) based on the Abbreviated Injury Scale (AIS); “A patient classified as polytraumatized should have a mortality rate of approximately 30%, twice above the established mortality of ISS > 15.”4. Database-derived resources. Deductive calculation of parameters based on a nationwide trauma registry (TraumaRegister DGU) with the following inclusion criteria: multiple injuries and need for intensive care therapy. RESULTS A total of 28,211 patients in the trauma registry met the inclusion criteria. The mean (SD) age of the study cohort was 42.9 (20.2) years (72% males, 28% females). The mean (SD) ISS was 30.5 (12.2), with an overall mortality rate of 18.7% (n = 5,277) and an incidence of 3% of penetrating injuries (n = 886). Five independent physiologic variables were identified, and their individual cutoff values were calculated based on a set mortality rate of 30%: hypotension (systolic blood pressure ⩽ 90 mm Hg), level of consciousness (Glasgow Coma Scale [GCS] score ⩽ 8), acidosis (base excess ⩽ −6.0), coagulopathy (international normalized ratio ≥ 1.4/partial thromboplastin time ≥ 40 seconds), and age (≥70 years). CONCLUSION Based on several consensus meetings and a database analysis, the expert panel proposes the following parameters for a definition of “polytrauma”: significant injuries of three or more points in two or more different anatomic AIS regions in conjunction with one or more additional variables from the five physiologic parameters. Further validation of this proposal should occur, favorably by mutivariate analyses of these parameters in a separate data set.

Applicability of the trimodal distribution of trauma deaths in a Level I trauma centre in the Netherlands with a population of mainly blunt trauma

BACKGROUND Death due to trauma is assumed to follow a trimodal distribution. Since 1995 measures have been taken to regulate organisations involved in trauma care systems in the Netherlands. In estimating the effect of this system we have evaluated the time of death distribution in the University Medical Centre Utrecht (UMCU). STUDY DESIGN Prospectively collected databases of all trauma victims between January 1996 and December 2005 were retrospectively reviewed. All traumatic deaths were included. Cause of death was divided into exsanguination, thorax, CNS, organ failure, pneumonia, other and unknown. RESULTS Nine thousand eight hundred and five patients were admitted after trauma; of these patients 659 (6.7%) died. Blunt trauma occurred in 615/659 (93.3%) patients. The temporal distribution did not show a trimodal distribution. One predominant peak was observed, <or=1h after arrival at the emergency unit. Within the first day 310/659 (47%) deaths occurred, of which 76/310 (11.5%) <or=1h. CNS injuries were significantly the main cause of death; 334/659 (50.7%, p<0.05). Exsanguination was the main cause of death <or=1h; 31/76 (40.8%, p<0.05). Both CNS injuries and organ failure were the main causes of late death; >or=14 days, 28% and 29%, respectively. CONCLUSION No trimodal distribution was confirmed. Only one predominant peak, with a rapid decline, was observed within the first hour after trauma. Even analysed for different causes of death, the trimodal distribution could not be demonstrated. In particular death due to CNS injury showed a complete absence of any peaks.

Long-term quality of life after surgical intensive care admission.

OBJECTIVES To quantify the long-term (>6 years) health-related quality of life (HRQOL) of a large cohort of patients admitted to a surgical intensive care unit (ICU). In addition, we aimed to explore the influence of different surgical classifications on long-term health status and to make comparisons with general population norms. DESIGN Prospective observational cohort study. SETTING A Dutch teaching hospital. PATIENTS All surviving surgical ICU patients admitted to the Dutch teaching hospital between 1995 and 2000. MAIN OUTCOME MEASURES Patient-reported data on HRQOL were collected with the EuroQol-6D (EQ-6D) after a mean follow-up of 8 years (range, 6-11 years). Patient characteristics, surgical classification, length of ICU stay, and survival were prospectively registered. The EQ utility scores (measured with the EQ-5D US index tariff), EQ visual analog scale scores, and prevalences of domain-specific health problems were calculated. The effect of surgical classification on EQ utility scores and EQ visual analog scale scores was assessed by multivariable generalized linear regression analysis. Logistic regression was used to explore the influence of surgical classification on domain-specific health problems. Long-term HRQOL of surgical ICU patients was compared with an age- and sex-matched general Dutch population using t test analysis. RESULTS Eight hundred thirty-four patients survived the ICU and were available for follow-up. In 575 patients (69%), the HRQOL was measured. For all surgical classifications combined, after 6 to 11 years, nearly half of all patients still had problems with mobility (52%), usual activity (52%), pain/discomfort (57%), and cognition (43%). Compared with the age- and sex-matched general population, HRQOL was worse, with a difference of 0.11 on the EQ utility score (range, 0-1). Oncological surgery patients had the best (EQ utility score, 0.83) and vascular patients had the worst (EQ utility score, 0.72) HRQOL. Trauma (odds ratio between 2.47-3.47) and vascular surgery (odds ratio between 2.27-5.37) patients showed significantly increased prevalences of problems in mobility, self-care, usual activities, and cognition. CONCLUSIONS More than 6 years after a surgical ICU admission, HRQOL of this patient population is largely reduced. Many patients still have a variety of health problems, including decreased cognitive functioning. Treatment advances should be made to reduce the current health deficit of surgical ICU survivors compared with the general population.

Operative or conservative treatment in patients with Rockwood type III acromioclavicular dislocation: a systematic review and update of current literature

PurposeDespite previous studies the management of Rockwood type III acromioclavicular (AC) dislocations remains controversial and the debate continues about whether patients with Rockwood type III AC injuries should be treated conservatively or operatively. In this study, we will review the current literature and present an overview of the outcome of conservative versus operative treatment of Rockwood type III dislocations.MethodsThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was used to conduct this review. A systematic search was performed in the Pubmed, Cochrane library, Embase, Scopus and Cumulative Index to Nursing and Allied Health Literature databases. Titles and abstracts were screened using predefined criteria and articles were critically appraised on relevance and validity.ResultsAfter critical appraisal eight articles were included in the study. The objective and subjective shoulder function outcome was better in the operative group, especially in young adults, though the rate of complications and radiographic abnormalities were higher. The rehabilitation time was shorter in the conservative group, however the cosmetic outcome was worse.ConclusionsThis review showed no conclusive evidence for the treatment of Rockwood type III AC dislocations. Overall, physically active young adults seem to have a slight advantage in outcome when treated operatively.

The role of neutrophils in immune dysfunction during severe inflammation

Critically ill post-surgical, post-trauma and/or septic patients are characterised by severe inflammation. This immune response consists of both a pro- and an anti-inflammatory component. The pro-inflammatory component contributes to (multiple) organ failure whereas occurrence of immune paralysis predisposes to infections. Strikingly, infectious complications arise in these patients despite the presence of a clear neutrophilia. We propose that dysfunction of neutrophils potentially increases the susceptibility to infections or can result in the inability to clear existing infections. Under homeostatic conditions these effector cells of the innate immune system circulate in a quiescent state and serve as the first line of defence against invading pathogens. In severe inflammation, however, neutrophils are rapidly activated, which affects their functional capacities, such as chemotaxis, phagocytosis, intra-cellular killing, NETosis, and their capacity to modulate adaptive immunity. This review provides an overview of the current understanding of neutrophil dysfunction in severe inflammation. We will discuss the possible mechanisms of downregulation of anti-microbial function, suppression of adaptive immunity by neutrophils and the contribution of neutrophil subsets to immune paralysis.