Pathogenesis Of Severe Sepsis Research Articles

Патогенез тяжелого сепсиса и септического шока: анализ современных концепций

В статье в хронологическом порядке представлен анализ современных концепций патогенеза тяжелого сепсиса и септического шока.

The tyrosine kinase inhibitor imatinib prevents lung injury and death after intravenous LPS in mice.

Severe sepsis and septic shock are frequent causes of the acute respiratory distress syndrome, and important sources of human mortality. Lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls, plays a major role in the pathogenesis of severe sepsis and septic shock. LPS exposure induces the production of harmful reactive oxygen species, and the resultant oxidant injury has been implicated in the pathogenesis of both severe sepsis and ARDS. We previously showed that the tyrosine kinase inhibitor imatinib increases lung endothelial antioxidant enzymes and protects against pulmonary endothelial antioxidant injury. In the present study, we tested the hypothesis that imatinib would protect against lung injury and systemic inflammation caused by intravenous LPS in an intact mouse model of endotoxemia mimicking early sepsis. We found that intravenous LPS induced a significant increase in the activity of lung xanthine oxidoreductase (XOR), an enzyme which is a major source of reactive oxygen species and implicated in the pathogenesis of acute lung injury. Imatinib had no effect of LPS-induced XOR activity. However, pretreatment of mice with imatinib increased lung catalase activity and decreased intravenous LPS-induced lung oxidant injury as measured by γ-H2AX, a marker of oxidant-induced DNA damage, lung apoptosis, and pulmonary edema. Imatinib also attenuated systemic cytokine expression after intravenous LPS exposure. Finally, imatinib completely prevented mortality in an in vivo, intravenous LPS mouse model of endotoxemia and lung injury. These results support the testing of imatinib as a novel pharmacologic agent in the treatment of Gram-negative sepsis and sepsis-induced ARDS.

Endotoxin activity assay and polymyxin B hemoperfusion use in a cohort of critically ill patients

Endotoxin plays a crucial role in the pathogenesis of severe sepsis and septic shock (SS&SSh) [1]. The aim of this study is to analyze the impact of extracorporeal endotoxin removal with polymyxin B hemoperfusion (PMX-DHP) (Toraymyxin®).

Reply

Reply We thank Koga and colleagues for referring to our article (1) and reporting the successful use of endotoxin adsorption therapy for pediatric endotoxin shock, in their letter to the editor. We would like to make a few comments regarding this case report. Sepsis remains a major cause of morbidity and mortality among children despite the availability of various treatments using antibiotics, fluids, or vasopressive/inotropic approaches. Children with severe sepsis have hospital mortality rates of 10.3% in the United States (2) and 17% in the United Kingdom (3). Several factors, including age and immune status, influence the defense mechanisms against infection in children. Susceptibility to infection in some children is linked to immaturity of the immune system or the immunocompromising effects of chemotherapy. In these children, bacteria and virulence such as endotoxin in the blood stimulate the systemic inflammatory response. Even under intensive care, these processes can rapidly progress to multiple organ dysfunction syndrome and death. Endotoxin, an outer membrane component of gram-negative bacteria, plays an important role in the pathogenesis of severe sepsis and septic shock. Endotoxemia is common in children admitted to pediatric intensive care units and may be associated with increased severity of illness (4). The international guidelines for the management of severe sepsis and septic shock recommend fluid resuscitation, antibiotics, source control, inotropes/vasopressors, and corticosteroids, if needed, for the treatment for pediatric septic shock (5). When these treatments are ineffective and the plasma endotoxin concentration or endotoxin activity assay is increased, endotoxin adsorption therapy by polymyxin B–immobilized fiber column direct hemoperfusion (PMX-DHP) can be used as an optional treatment in Japan. In their letter to the editor, Koga and colleagues reported the effective use of PMX-DHP therapy for endotoxin shock in an immunocompromised child. Polymyxin B–immobilized fiber column direct hemoperfusion therapy has been widely used in adult patients with septic shock in Japan. We have shown in the meta-analysis that PMX therapy for adult patients with septic shock had beneficial effects on the hemodynamics, pulmonary oxygenation, and mortality (1). These beneficial effects may be attributable to the direct adsorption of endotoxin, monocytes, activated neutrophils, and anandamide, as well as indirect decrease in inflammatory cytokines and other mediators. Children with septic shock have also received PMX-DHP therapy, but the pediatric use of the therapy has only been reported in English once, in a letter to the editor in Digestive Diseases and Sciences (6). The Japan Society for Premature and Newborn Medicine issued a guideline for PMX-DHP therapy for infants/neonates in Japanese in 2010. Polymyxin B–immobilized fiber column direct hemoperfusion therapy is indicated for pediatric patients with septic shock when the patients manifest endotoxemia associated with the criteria for pediatric sepsis (7). The criterion for excluding PMX-DHP therapy for pediatric patients with septic shock is intracranial bleeding or a tendency to bleed in general. The following are important points for PMX-DHP performance in children: (1) an appropriately sized catheter should be inserted for vascular access; (2) an appropriately sized PMX column should be used; (3) the blood flow rate should be gradually increased to 2 to 5mL/kg per minute to prevent circulatory collapse; (4) nafamostat mesilate should be infused at a rate of 0.5 to 1.0 mg/kg per hour for anticoagulant and thereafter maintained at the rate necessary to sustain activated clotting time for 150 to 200 s. When the priming volume is greater than 10% of the patient’s body weight, a mixture of a red blood cell suspension and physiological saline is needed to prevent anemia. The PMX-05R column or PMX-01R column is usually used for children with endotoxin shock, because circulating blood volumes are low. The former, the PMX-05R column, has a low priming volume (40 mL) and is used for children with body weights of 10 kg or over. The PMX-01R column, which has a lower priming volume (8 mL), has been used for smaller children (body weights <10 kg) since its introduction in Japan in April 2012. When administering PMX-DHP for children, physicians should be mindful of their lower circulating blood volumes. Electrocardiogram and blood pressure must be monitored during this therapy. Severe arrhythmia such as ventricular tachycardia or ventricular fibrillation may occur as a consequence of low circulating volumes several minutes after the initiation of extracorporeal circulation. Hence, the safety and efficacy of PMX-DHP therapy for high-risk children with septic shock have not yet to be confirmed. Nevertheless, we believe that PMX-DHP is a useful therapy for severe pediatric endotoxin shock. Chieko Mitaka Department of Critical Care Medicine Tokyo Medical and Dental University Graduate School Tokyo, Japan Makoto Tomita Clinical Research Center Tokyo Medical and Dental University Hospital of Medicine Tokyo, Japan

Genetic Variation in the TNF Gene Is Associated with Susceptibility to Severe Sepsis, but Not with Mortality

BackgroundTumor necrosis factor (TNF) and TNF receptor superfamily (TNFR)-mediated immune response play an essential role in the pathogenesis of severe sepsis. Studies examining associations of TNF and lymphotoxin-α (LTA) single nucleotide polymorphisms (SNPs) with severe sepsis have produced conflicting results. The objective of this study was to investigate whether genetic variation in TNF, LTA, TNFRSF1A and TNFRSF1B was associated with susceptibility to or death from severe sepsis in Chinese Han population.Methodology/Principal FindingsTen SNPs in TNF, LTA, TNFRSF1A and TNFRSF1B were genotyped in samples of patients with severe sepsis (n = 432), sepsis (n = 384) and healthy controls (n = 624). Our results showed that rs1800629, a SNP in the promoter region of TNF, was significantly associated with risk for severe sepsis. The minor allele frequency of rs1800629 was significantly higher in severe sepsis patients than that in both healthy controls (Padj = 0.00046, odds ratio (OR)adj = 1.92) and sepsis patients (Padj = 0.002, ORadj = 1.56). Further, we investigated the correlation between rs1800629 genotypes and TNF-α concentrations in peripheral blood mononuclear cells (PBMCs) of healthy volunteers exposed to lipopolysaccharides (LPS) ex vivo, and the association between rs1800629 and TNF-α serum levels in severe sepsis patients. After exposure to LPS, the TNF-α concentration in culture supernatants of PBMCs was significantly higher in the subjects with AA+AG genotypes than that with GG genotype (P = 0.007). Moreover, in patients with severe sepsis, individuals with AA+AG genotypes had significantly higher TNF-α serum concentrations than those with GG genotype (Padj = 0.02). However, there were no significant associations between SNPs in the four candidate genes and 30 day mortality for patients with severe sepsis.Conclusions/SignificanceOur findings suggested that the functional TNF gene SNP rs1800629 was strongly associated with susceptibility to severe sepsis, but not with lethality in Chinese Han population.

Positive effect of septimeb™ on mortality rate in severe sepsis: a novel non antibiotic strategy

BackgroundSeptimeb is a new herbal-derived remedy, recently approved for its potential immunomodulatory effects. Regarding the key role of immune system in the pathogenesis of severe sepsis and lack of any standard treatment for improving survival of these patients; we evaluated the effect of Septimeb -as an adjutant to standard treatment-on inflammatory biomarkers and mortality rates in patients with severe sepsis.MethodsIn this multicenter, randomized, single-blind trial, we assigned patients with severe sepsis and Acute Physiology and Chronic Health Evaluation (APACHE II) score of more than 20 to receive standard treatment of severe sepsis (control group) or standard treatment plus Septimeb. This group was treated with Septimeb for 14 days then followed up for another14 days. APACHE score, Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score (SAPS) were calculated daily. Blood samples were analyzed for interleukin 2 tumor necrosis factor-α, total antioxidant power, platelet growth factor and matrix metalloproteinase 2.ResultsA total of 29 patients underwent randomization (13 in control group and 16 in Septimeb group). There was significant difference between the Septimeb and control group in the 14 days mortality rate (18.8% vs. 53.85 respectively, P=0.048). Compared to control group, Septimeb was significantly effective in improving SAPS (P= 0.029), SOFA (P=0.003) and APACHE II (P=0.008) scores. Inflammatory biomarkers didn’t change significantly between the two groups (P>0.05).ConclusionSeptimeb reduces mortality rates among patients with severe sepsis and it could be added as a safe adjutant to standard treatment of sepsis.

PPAR gamma activation protects the brain against microvascular dysfunction in sepsis

Sepsis is a severe disorder characterized by systemic inflammatory responses in the presence of an infection and may progress to multiple organ dysfunction and death. Alterations in cerebral microcirculation fulfill a crucial role in the pathogenesis of severe sepsis, and include a decrease in capillary density and disturbances in leukocyte movement along capillaries. Nevertheless, the mechanisms involved in sepsis-associated cerebral microcirculatory alterations have so far not been defined. We investigated the effect of the peroxisome proliferator-activated receptor gamma (PPARγ) selective agonist rosiglitazone on leukocyte/endothelial cell interaction and functional capillary density in the brain in the cecal ligation and puncture (CLP) model of sepsis. Anti-inflammatory effects of rosiglitazone on the cerebral microcirculation were marked. Functional capillary density increased and leukocyte rolling and adhesion were decreased in animals submitted to CLP and treated with rosiglitazone. Our data provide evidence for involvement of PPARγ activation in leukocyte–endothelium interactions and alterations in capillary density. Improved cerebral perfusion in animals treated with rosiglitazone, suggests that PPARγ activation is protective against cerebral microvascular dysfunction in sepsis.

Why should we measure bacterial load when treating community-acquired pneumonia?

We focus on a number of studies in the past 2 years that herald a dramatic shift in how we treat patients with not just community-acquired pneumonia (CAP), but potentially all sepsis. Recent studies report that high bacterial load, and specifically pneumococcal load in CAP, appears to be significantly associated with worse outcomes. These findings change the sepsis paradigm. Bacterial load may identify potential candidates for adjunctive therapy, ICU admission and more aggressive management. Whereas we all acknowledge the importance of the virulence of the pathogen in the outcome of CAP, microbiological tests currently play little role in management of patients. Whereas molecular tests such as polymerase chain reaction have promised to deliver accurate results in a clinically useful period of time, apart from a few niche situations they have yet to enter routine practice. In particular the ability to calculate the bacterial load in blood, and specifically pneumococcal load in CAP, appears to have significant clinical utility. Not only does bacterial load predict clinical outcome, the data so far available challenge some of our fundamental assumptions about optimal antibiotic therapy and the pathogenesis of severe sepsis.

A Central Role for Free Heme in the Pathogenesis of Severe Sepsis

Low-grade polymicrobial infection induced by cecal ligation and puncture is lethal in heme oxygenase-1-deficient mice (Hmox1(-/-)), but not in wild-type (Hmox1(+/+)) mice. Here we demonstrate that the protective effect of this heme-catabolizing enzyme relies on its ability to prevent tissue damage caused by the circulating free heme released from hemoglobin during infection. Heme administration after low-grade infection in mice promoted tissue damage and severe sepsis. Free heme contributed to the pathogenesis of severe sepsis irrespective of pathogen load, revealing that it compromised host tolerance to infection. Development of lethal forms of severe sepsis after high-grade infection was associated with reduced serum concentrations of the heme sequestering protein hemopexin (HPX), whereas HPX administration after high-grade infection prevented tissue damage and lethality. Finally, the lethal outcome of septic shock in patients was also associated with reduced HPX serum concentrations. We propose that targeting free heme by HPX might be used therapeutically to treat severe sepsis.

MICROCIRCULATORY EVALUATION IN SEPSIS

Microcirculatory dysfunction plays a pivotal role in the pathogenesis of severe sepsis and septic shock; hence, microcirculation blood flow monitoring has gained increasing attention. However, microcirculatory imaging is still investigational in human sepsis and has not yet been incorporated into routine clinical practice for several reasons, including the difficult interpretation of microcirculation imaging data, difficulty to draw a parallel between sublingual microcirculation imaging and organ microcirculation dysfunction, as well as the absence of microvessel dysfunction parameters defining sequential microcirculatory changes from the early to late stages of the disease, which could aid in the context of therapeutic approaches and of prognostic parameters. The purpose of this review was to bridge the experimental abdominal organ microvascular derangement kinetics and clinical aspects of microcirculatory findings in the early phase of severe sepsis/septic shock.

Fluid therapy in septic shock

To examine the role of fluid therapy in the pathogenesis of severe sepsis and septic shock. The type, composition, titration, management strategies and complications of fluid administration will be examined in respect to outcomes. Fluids have a critical role in the pathogenesis and treatment of early resuscitation of severe sepsis and septic shock. Although this pathogenesis is evolving, early titrated fluid administration modulates inflammation, improves microvascular perfusion, impacts organ function and outcome. Fluid administration has limited impact on tissue perfusion during the later stages of sepsis and excess fluid is deleterious to outcome. The type of fluid solution does not seem to influence these observations.

Matrix- metalloproteinase -2, -8 and -9 in serum and skin blister fluid in patients with severe sepsis

IntroductionMatrix metalloproteinases (MMPs) have various roles in inflammatory states. They seem to be able to modulate endothelial barriers and regulate the activity of chemokines and cytokines. The timely development of the levels during severe sepsis and thereafter have not been investigated. In addition it was of interest to study alterations of MMP-levels in intact skin, as the skin is the largest barrier against external pathogens and MMPs have not been studied at organ level in human sepsis. The aim of this study was to investigate the timely development of serum and skin MMP-2, -8 and -9 levels in human severe sepsis and their association with disease severity and mortality.MethodsForty-four patients with severe sepsis and fifteen healthy controls were included in this prospective longitudinal study. The amounts of MMP-2, -8 and -9 were analyzed from serum at days 1, 4, 6, 8, and 10, and from skin suction blister fluid at days 1 and 5 from the beginning of severe sepsis. Additionally, samples from the survivors were obtained after three and six months.ResultsThe levels of MMP-2 and -8 were up-regulated in severe sepsis in comparison to healthy controls in skin blister fluid and serum. Compared to the controls MMP-9 levels were lower in sepsis from the fourth day on in serum and both the first and fifth day in skin blister fluid. Active forms of MMP-2 and -9 were present only in severe sepsis. The non-survivors had higher pro- and active MMP-2 levels than the survivors in skin blister fluid samples. Furthermore, MMP-2 levels were more pronounced in blister fluid and serum samples in patients with more severe organ failures. In the survivors at 3 and 6 month follow-up the MMP levels had returned to normal.ConclusionsMMP-2 and -8 are elevated in serum and blister fluid in severe sepsis, implying that they may play a significant role in the pathogenesis of severe sepsis and organ dysfunctions. Active forms of MMP-2 and 9 were only present in patients with severe sepsis, and higher MMP-2 levels in skin blister and serum were associated with more severe organ dysfunctions.

Caspase-3 is activated and rapidly released from human umbilical vein endothelial cells in response to lipopolysaccharide

Endothelial cell injury/dysfunction is considered to play a critical role in the pathogenesis of severe sepsis and septic shock. Although it is considered that endothelial cell apoptosis is involved in endothelial injury/dysfunction, physiological involvement remains ambiguous since the induction of apoptosis requires the inhibition of endogenous apoptosis inhibitors. Here we show that caspase-3 activation, a biological indicator of apoptosis, is observed in response to lipopolysaccharide (LPS) stimulation even under the influence of endogenous apoptosis inhibitors, and that activated caspase-3 is rapidly released from human umbilical vein endothelial cells (HUVEC). In the presence of cycloheximide (CHX), an increase in intracellular caspase-3/7 activity in response to LPS was not detected in HUVEC up to 24 h following stimulation even in the presence of LPS-binding protein (LBP), soluble CD14 and soluble MD-2, whereas the decrease in cell viability and increase in release of the cellular enzyme lactate dehydrogenase (LDH) were observed in a soluble CD14/LBP-dependent manner. On the other hand, even in the absence of CHX, a significant increase in caspase-3/7 activity and a cleaved caspase-3 fragment with a slight increase in LDH release was observed in culture supernatants in response to LPS. This increase in caspase-3/7 activity was observed even when LDH release was undetected. These results indicate that caspase-3 is activated by LPS under physiological conditions and suggest that HUVEC escape from cell death by rapidly releasing activated caspase-3 into extracellular space. Failure of this escape mechanism may result in endothelial injury/dysfunction.

Serial cytokine levels in patients with severe sepsis

The serial or dynamic changes of cytokine levels in severely septic patients, between shock and no shock, survivors and non-survivors are still unclear. Seventy-six patients with severe sepsis were enrolled to our study. Plasma levels of interferon-gamma, interleukin (IL)-6, IL-10, IL-12 and transforming growth factor-beta1 from day 1 to day 7 were determined. IL-6 level in non-survivors was higher than that in survivors on day 1. IL-10 level in non-survivors was higher than that in survivors on day 1, 2, and 3. IL-6 level in shock patients was higher than that in non-shock patients on day 1, 2, 6 and 7. IL-10 level in shock patients was higher than that in non-shock patients from day 1 to day 7. Plasma time-course curves of IL-6 and IL-10 were different between survivors and non-survivors. Plasma time-course curve of IL-6 was different between patients with shock and without shock. Regression analysis found that IL-6 was correlated with IL-10 and shock. IL-10 was correlated with IL-6 and mortality. IL-6 and IL-10 were the key cytokines in the pathogenesis of severe sepsis. IL-6 was comparatively more associated with septic shock and IL-10 was comparatively more associated with mortality.

Microcirculatory changes caused by magnesium sulphate infusion in severe sepsis and septic shock

Microcirculatory dysfunction is a key element in the pathogenesis of severe sepsis and septic shock and is related to endothelial dysfunction. Studies in vivo have shown that infusion of magnesium sulphate increased endothelium-dependent vasodilatation in healthy people and patients with cardiac disorders, but the effect on the septic patient's vessels, especially small ones, is unknown. We hypothesized that magnesium sulphate infusion can improve microcirculation in patients with severe sepsis and septic shock.

Inhibitory effects of staphylococcal enterotoxin type B on human platelet adhesion in vitro

Septic shock was formerly recognized as a consequence of Gram-negative bacteraemia, but at present the incidence of Gram-positive sepsis seems to be more relevant, contributing for more than 50% of cases. Staphylococcal aureus can induce toxic shock in humans through the production of potent toxins termed Staphylococcal enterotoxins, from which Staphylococcal enterotoxin type B (SEB) is one of most studied. Platelets are reported to participate in pathogenesis of severe sepsis, but the exact role of platelets in this event is poorly investigated, particularly that caused by Gram-positive bacteria. Therefore, we have used the model of platelet adhesion to fibrinogen-coated plates to investigate the actions of SEB on human platelets. Ninety-six-well microtiter plates were coated with human fibrinogen (50 µg/mL), and human washed platelet suspension (6 × 106 platelets) was added to each well. Adherent platelets were quantified through measurement of acid phosphatase activity. Staphylococcal enterotoxin B (0.0001–30 µg/mL, incubated for 5 to 60 min) time- and dose-dependently inhibited platelet adhesion. This response was modified neither by the protein synthesis inhibitor puromycin (0.01 and 0.1 mM) nor by the superoxide scavengers superoxide dismutase (SOD, 100 units/mL) and polyethylene glycol-SOD (30 U/mL). The peroxide hydrogen (H2O2) scavenger catalase polyethylene glycol (1000 U/mL) significantly attenuated the platelet adhesion inhibition by SEB. The cAMP and cGMP levels were not changed by SEB (0.0001–30 µg/mL, 60 min). Our findings suggest that H2O2 at least partly contributes to the inhibitory responses of human platelet adhesion by SEB.

Association of IL-6 promoter polymorphism -174C/G with outcome in severe sepsis

IL-6 is a multifunctional cytokine that plays an essential role in the pathogenesis of severe sepsis. The G/C polymorphism at position -174 of the IL-6 gene is associated with an adverse outcome in a number of inflammatory diseases, although its association with outcome in adult patients with severe sepsis remains unclear. We tested the hypothesis that IL-6 promoter polymorphism -174 C/G is associated with increased mortality among ICU patients with severe sepsis.

Association of Interleukin 6 Promoter Polymorphism (-174G/C) with IL-6 Level and Outcome in Severe Sepsis

Association of Interleukin 6 Promoter Polymorphism (-174G/C) with IL-6 Level and Outcome in Severe SepsisInterleukin (IL-6) is a key cytokine in the pathogenesis of severe sepsis. The importance of a regulatory polymorphism within the IL-6 promoter remains unclear in these patients. The aim of the study was to determine if IL-6 (-174 G/C) promoter polymorphism has an effect on IL-6 plasma level and outcome of severe sepsis. The study was conducted in general ICU of Stradiñš Clinical University Hospital. A total of 103 critically ill patients with confirmed severe sepsis were prospectively included. Association analysis of the IL-6 (-174C) allele with serum level and clinical outcome was performed. We found no differences in genotype distribution between survivors and nonsurvivors. The serum IL-6 level was significantly higher in nonsurvivors compared with survivors. We found an association of genotype with the IL-6 level in nonsurvivors, but not in survivors. Our findings show a functional significance of IL-6 promoter polymorphisms in nonsurviving severe sepsis patients.

The interleukin‐6 (IL6)–174 G/C promoter genotype is associated with the presence of septic shock and the ex vivo secretion of IL6

Septic shock is associated with a high mortality and an excessive activation of immune cascades. Interleukin (IL)-6 has been found to be a key cytokine in the pathogenesis of severe sepsis, but the importance of a regulatory polymorphism within the IL6 promoter has been controversial in these patients. The aim of the study was therefore to systematically investigate the IL6-174 G/C promoter genotype with regard to the presence of shock in patients with sepsis, the IL6 serum levels, and the ex vivo secretion of IL6, respectively. Overall, 112 consecutive subjects with severe sepsis and septic shock according to consensus criteria were enrolled. The ex vivo secretion of IL6 after stimulation with lipopolysaccharide (LPS) in a whole blood assay and the IL6 serum concentrations were determined after admission of the patients. Among the 112 subjects with severe sepsis, 85 patients fulfilled the criteria of septic shock. In these patients, the frequency of the mutated C-allele of the IL6 promoter polymorphism was significantly (P = 0.04) higher compared to that in individuals without shock. IL6 serum concentrations were highest in patients with the GG genotype (mean 2209 pg mL(-1)), followed by CG genotype (mean 1113 pg mL(-1)), and lowest in individuals with the CC genotype (mean 256 pg mL(-1)). Interestingly, a significantly (P = 0.005) higher ex vivo secretion of IL6 is detected in heterozygote individuals (535 pg mL(-1)) and patients with the IL6 CC genotype (555 pg mL(-1)) compared to patients with the -174 GG genotype (276 pg mL(-1)). In conclusion, the IL6-174 G/C promoter genotype is associated with shock in patients with sepsis. Functionally, the mutated C-allele is correlated with low IL6 serum concentrations, but a high ex vivo secretion after LPS stimulation. These results further indicate a complex regulation of the expression of IL6 during infection and have implications for the design of immune intervention trials.

Genomic variations within DEFB1 are associated with the susceptibility to and the fatal outcome of severe sepsis in Chinese Han population

Sepsis is a systemic inflammatory response syndrome to infection. Human beta-defensin 1 (DEFB1) is a multifunctional mediator in infection and inflammation, which has been largely explored in ex vivo studies. The present case-control study was designed to investigate whether DEFB1 genomic variations are associated with the susceptibility to and the outcome of severe sepsis in 211 patients with severe sepsis and 157 ethnic-matched healthy controls. After correcting for multiple testing, the -44G/C was the only polymorphism found to show significant associations with both the susceptibility to and the fatal outcome of severe sepsis (P=0.0049, odd ratio (OR) 1.971 and P=0.002, OR 2.406, respectively). Haplotype -20A/-44C/-52G showed a protective role against severe sepsis (P=0.0066, OR 0.6751), whereas haplotype -20G/-44G/-52G served as a risk factor for the fatal outcome of severe sepsis (P=0.0052, OR 2.427). These findings provide further evidence that beta-defensin 1 may play a role in the pathogenesis of severe sepsis.