P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis

International audienceSepsis is characterized by a systemic inflammatory response followed by immunosuppres-sion of the host. Metabolic defects and mitochondrial failure are common in immunocom-promised patients with sepsis. The NLRP3 inflammasome is important for establishing an inflammatory response after activation by the purinergic P2X7 receptor. Here, we study a cohort of individuals with intra-abdominal origin sepsis and show that patient monocytes have impaired NLRP3 activation by the P2X7 receptor. Furthermore, most sepsis-related deaths are among patients whose NLRP3 activation is profoundly altered. In monocytes from sepsis patients, the P2X7 receptor is associated with mitochondrial dysfunction. Furthermore, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1α. We show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. These data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection

Purinergic P2X7 receptor expression increases in leukocytes from intra-abdominal septic patients

Inflammation is a tightly coordinated response of the host immune system to bacterial and viral infections, triggered by the production of inflammatory cytokines. Sepsis is defined as a systemic inflammatory response followed by immunosuppression of the host and organ dysfunction. This imbalance of the immune response increases the risk of mortality of patients with sepsis, making it a major problem for critical care units worldwide. The P2X7 receptor plays a crucial role in activating the immune system by inducing the activation of peripheral blood mononuclear cells. In this study, we analyzed a cohort of abdominal origin septic patients and found that the expression of the P2X7 receptor in the plasma membrane is elevated in the different subsets of lymphocytes. We observed a direct relationship between the percentage of P2X7-expressing lymphocytes and the early inflammatory response in sepsis. Additionally, in patients whose lymphocytes presented a higher percentage of P2X7 surface expression, the total lymphocytes populations proportionally decreased. Furthermore, we found a correlation between elevated soluble P2X7 receptors in plasma and inflammasome-dependent cytokine IL-18. In summary, our work demonstrates that P2X7 expression is highly induced in lymphocytes during sepsis, and this correlates with IL-18, along with other inflammatory mediators such as IL-6, IL-8, and procalcitonin

Estudio sobre la sepsis grave de origen abdominal. Utilidad de la procalcitonina y otros marcadores pronósiticos.

INTRODUCCIÓN: La sepsis es una de las principales causas de morbimortalidad en las unidades de cuidados intensivos (UCIs). La sepsis grave de origen abdominal es uno de los cuadros más frecuentes en las UCIs Posquirúrgicas. Su mortalidad es elevada y oscila entre 40% y el 70% según las series. Sin embargo, es un cuadro que suele tener poco protagonismo en la literatura científica. Los biomarcadores son elementos fundamentales para el diagnóstico, seguimiento y pronóstico de la sepsis. Uno de los biomarcadores más estudiados en las últimas décadas ha sido la procalcitonina. Muchos autores consideran que su cinética se relaciona con la evolución, el pronóstico o con un tratamiento correcto de diversas patologías. Las escalas de gravedad, como el Acute Physiology And Chronic Health Evaluation II (APACHE II) y la escala Sequential Organ Failure Assessment (SOFA) tienen utilidad pronóstica en pacientes críticos. El APACHE II no es específico para pacientes sépticos, pero identifica pacientes con gravedad aumentada. La escala SOFA es un sistema específico de valoración de la gravedad del paciente séptico. Se diseñó para evaluar la afectación orgánica secundaria a la sepsis, aunque posteriormente, también se ha empleado con fines pronósticos. El objetivo principal de esta Tesis Doctoral es identificar los factores que influyen en la evolución (Éxitus o supervivencia) de los pacientes con sepsis grave de origen abdominal. Analizamos la utilidad de la procalcitonina como marcador de supervivencia y evaluamos si las escalas de gravedad, APACHE II y SOFA, permiten predecir la mortalidad de estos pacientes. MATERIAL Y MÉTODO: Se incluyeron en el estudio todos los pacientes con diagnóstico de sepsis grave de origen abdominal ingresados en una Unidad de Cuidados Críticos Posquirúrgicos entre los años 2007 y 2008. Se recogieron datos demográficos, los valores de la procalcitonina en los días primero, tercero y séptimo de ingreso y se calcularon las puntuaciones de las escalas APACHE II y SOFA al ingreso y de la escala SOFA en los días tercero y séptimo. RESULTADOS: Estudiamos 69 pacientes. La mortalidad de nuestra serie fue del 23,19% (IC95%: 13,19;33,19%). La edad media de estos pacientes fue 64,94 años (IC95%: 61;69 años). La mayoría de los pacientes (57,97%) presentó sepsis de origen comunitario (p<0,05). La patología previa más frecuente fue la hipertensión arterial (49,27%; IC95%: 37,27;61,27%), seguida de la diabetes mellitus (24,63%; IC95%: 14,43;34,83%) El foco de infección más frecuente fue el intestino grueso (40,57%; IC95%: 28,57;52,57%). La puntuación APACHE II media al ingreso fue de 16,43 puntos (IC95%: 14,95;17,91puntos) y fue superior entre los Éxitus (p<0,00001). La puntuación SOFA media al ingreso fue de 6,46 puntos (IC95%: 5,71;7,2puntos). En el estudio de regresión logística binario, los dos factores que más influyeron en la mortalidad de estos pacientes fueron la edad y el ascenso de las puntuaciones de la escala SOFA entre los días primero y séptimo. La procalcitonina presentó una dinámica diferente entre Éxitus, cuyos valores se mantuvieron elevados y Supervivientes, en los que los valores disminuyeron con el tiempo (p<0,05). El valor de procalcitonina que mejor identificó pronóstico fue el del día séptimo (AUC-ROC 0,768), niveles mayores o iguales a 3,5ng/mL detectaron mortalidad con una sensibilidad del 55% y una especificidad del 73%. CONCLUSIONES: En nuestra serie de pacientes con sepsis grave posquirúrgica de origen abdominal, el valor de procalcitonina en el séptimo día de observación se relaciona con el pronóstico. El ascenso en la puntuación de la escala SOFA entre los días primero y séptimo, junto con la edad, fueron los elementos que mejor identificaron el pronóstico de los pacientes con sepsis grave de origen abdominal. BACKGROUND: Sepsis represents a major cause of morbidity and mortality in Intensive Care Units (ICU). Severe sepsis of intraabdominal origin is a frequent pathology in Surgical ICU. It presents a high mortality rate, 40% in some series, but even 70% has been reported. Nevertheless, it has little prominence in scientific literature. Biomarkers are main elements in the battery of diagnostic, monitoring and prognostic tests. Procalcitonin has been one of the most studied markers in lasts decades. Many authors consider its dynamics well related with evolution, outcome or a correct treatment of different pathologies. Severity scales, such as Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment score (SOFA) are some of the prognostic tools used in critical patients. APACHE II is not specific for septic patients, but has utility identifying patients with augmented severity. SOFA score is a specific system for severity assessment in septic patients. It identifies and allows the monitoring of organ failure secondary to sepsis. Initially it was design for the evaluation of organ dysfunction during the ICU stay of these patients, though its prognostic value has also been proved. The purpose of this Doctoral Thesis is to study which elements characterize patients with severe sepsis of intraabdominal origin, and try to identify which factors can influence the outcome of these patients. We assess the utility of procalcitonin and severity scores, APACHE II and SOFA, as outcome predictors in patients with severe sepsis of intraabdominal origin. PATIENTS AND METHOD: We included all patients admitted in a Surgical Intensive Care Unit with the diagnosis of severe sepsis of intraabdominal origin, between 2007 and 2008. We recorded demographic data, procalcitonin levels at days one, three and seven, and APACHE II and SOFA scores on admission, as well as SOFA score on days three and seven. RESULTS: 69 patients were included in the study. Mortality rate of our series was 23.19% (95%ic, 13.19-33.19%). Mean age of these patients was 64.94 (95%ic, 61;69y). More than 55% of patients had community acquired sepsis (p<0.05). Most frequent previous pathologies were hypertension (49.27%; 95%ci, 37.27;61.27%), followed by mellitus diabetes (24.63%; 95%ci, 14.43;34.83%). The most frequent focus of infection was colonic (40.57%; 95%ci, 28.57;52.57%). Mean APACHE II score on admission was 16.43 points (95%ci, 14.95;17.91points) and was higher in those patients who finally died (p<0.00001). Mean SOFA score on admission was 6.46 points (95%ci, 5.71;7.2points). In the binary regression logistic study, those factors identified as more related with outcome were age and the increase in SOFA score between days one and seven. Procalcitonin presented a different dynamic among Nonsurvivors (levels maintained or increased) and Survivors (whose levels decreased)(p<0.05). Procalcitonin levels on day seven identified better the outcome of these patients (AUC-ROC 0.768). Levels equal or higher than 3.5ng/mL identified mortality with 55% sensibility and 73% specificity. CONCLUSIONS: In our series of patients with severe sepsis of intraabdominal origin, procalcitonin does not identify outcome of patients on admission, but on day seven of observation. Increase on SOFA score between days one and seven and age were the factors that identified outcome in a more accurate way on patients with severe sepsis of intraabdominal origin

Critically ill patients with community-onset intraabdominal infections: influence of healthcare exposure on resistance rates and mortality

The concept of healthcare-associated infections (as opposed to hospital-acquired infections) in intraabdominal infections (IAIs) is scarcely supported by data in the literature. The aim of the present study was to analyse community-onset IAIs (non-postoperative/non-nosocomial) in patients admitted to intensive care units (ICUs), to investigate differences in resistance patterns linked to healthcare exposure and mortality-associated factors. A one-year prospective observational study (17 Spanish ICUs) was performed distributing cases as healthcare-associated infections (HCAI), community-acquired infections (CAI) and immunocompromised patients (ICP). Bacteria producing extended-spectrum β-lactamases (ESBL) and/or carbapenemase (CPE), high-level aminoglycoside- and/or methicillin- and/or vancomycin- resistance were considered antimicrobial resistant (AMR). Mortality-associated factors were identified by regression multivariate analysis. Of 345 patients included (18.8% HCAI, 6.1% ICP, 75.1% CAI), 51.6% presented generalized peritonitis; 32.5% were >75 years (55.4% among HCAI). Overall, 11.0% cases presented AMR (7.0% ESBL- and/or CPE), being significantly higher in HCAI (35.4%) vs. CAI (5.8%) (p75 years (OR = 6.67, 95%CI = 2.56-17.36,p75 years, severity and Candida isolation but not with AMR